Targeted protein degradation using bifunctional compounds that bind ubiquitin ligase and target protein kinase c

Abstract

A compound of formula (I) [Protein kinase C ligand moiety] - [linker] - [ligase ligand moiety] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, wherein [MCL-1 ligand moiety] is a compound of Formula (B) (Formula (B)) and its use in the treatment.

Description

[0001] TARGETED PROTEIN DEGRADATION USING BIFUNCTIONAL COMPOUNDS THAT BIND UBIQUITIN LIGASE AND TARGET PROTEIN KINASE C

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to bifunctional compounds which can bind to a ubiquitin ligase and also to a target protein, such that the target protein is placed in proximity to the ubiquitin ligase in order to induce its degradation.

[0004] BACKGROUND

[0005] The Ubiquitin-Proteasome System (UPS) is responsible for the maintenance of healthy and well-balanced proteome. In the process of ubiquitination, ubiquitin units are covalently attached to the protein, forming a polyubiquitin chain, which marks the protein for degradation via the proteasome. Ubiquitination is central to the regulation of nearly all cellular processes and is also tightly regulated itself. Ubiquitin ligases facilitate ubiquitination of different proteins in vivo and contribute to precise regulation of the system. Upon recognition, the ubiquitin ligases mediate the attachment of ubiquitin moieties to the target protein, which label it for degradation by the proteasome.

[0006] The idea of selective target protein degradation (TPD) by modulation of UPS was first described in 1999 (US2002173049 Al (PROTEINIX INC) 21 November 2002). One approach to TPD is by the use of bifunctional molecules that bind the ubiquitin ligase and the target protein simultaneously, allowing for efficient ubiquitin transfer to the latter. This concept was first described by Sakamoto KM et al. (Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8554-9) and more recently reviewed by Burslem GM and Crews CM (Cell. 2020 Apr 2;181(l):102-114).

[0007] Protein kinases C (PKCs) comprise a multigene family of related serine / threonine kinases present at the crossroads of many signal transduction pathways and are implicated in a wide range of cellular responses dependent on G-protein coupled receptors and growth factors. PKCs mediated phosphorylation regulates a variety of cellular signals including gene expression, growth regulation, differentiation, and proliferation of the cells. On the other hand, unregulated or excessive activation of PKC may lead to various pathologies like inflammation, cancer and cardiovascular diseases (W. Cho et al. JBC Papers in Press (2012).

[0008] PKC-0 (theta) plays a critical role in T-cell activation, proliferation, and differentiation. In various animal models of autoimmune diseases, the PKC0 deficient mice showed less T-cell infiltration, lower production of proinflammatory cytokine IFN-gamma, TNF, and IL-17 (Brezar V., et al., 2015(6): 1-100). Inhibition of PKC0 in Treg cells causes an increase of their suppressive activity towards Teff cells (Zanin-Zhorov A., et al., Science 2010 (328): 372-376). In cancer, PKC-0 inhibition enha nces the chemosensitivity of triple-negative breast cancer (Beryl J., et al., Breast Cancer Res 2020 (22): 72-82).

[0009] PKCE (epsilon) is overexpressed in various tumor types and is associated with different processes related to cancer development namely, cell transformation, cell survival, cell proliferation, EMT, cytoskeletal reorganization, extracellular matrix (ECM) rearrangement, disruption of cell-cell contacts, cell motility, stem cell properties and therapy resistance (Kirti Jain and Alakananda Basu. Cancers 2014, 6, 860-878).

[0010] PKC5 (delta) positively regulates proliferation via MEK / ERK pathway in K-Ras- dependent cell lines and PKC6 upregulation has been demonstrated in pancreatic cancer (with K-Ras mutation), hepatocellular carcinoma, and myelogenous leukaemia (Symonds J.M., et al., Cancer Res 2011 (71): 2087-2097; Mauro L.V., et al., Pancreas 2010 (39): e31-41). Inhibition of PKC6 reduces amyloid plaque formation in a cellular model of the Alzheimer disease (Du Y., et al., Journal of Experimental Medicine 2018 (215): 1665-1677), while liver-specific overexpression of PKC6 in mice is linked to the development of hepatic insulin resistance (Bezy O., et al., Journal of Clinical Investigation 2011 (121): 2504-2517).

[0011] The unregulated or excessive activation of various PKC isoforms may lead to various pathologies like inflammation, cancer and cardiovascular diseases. Pharmacological modulation of PKCs is considered a viable strategy for the treatment of various diseases, including cancer, inflammatory and autoimmune diseases such as psoriasis, arthritis, multiple sclerosis, inflammatory bowel disease, uveitis, dermatitis, diabetes, lupus erythematosus, asthma, colitis, osteoporosis, atherosclerosis, Duchenne Muscular Dystrophy (DMD), T-cell leukaemia, CNS diseases, Ischemic heart diseases, and other diseases or disorders mediated by T lymphocytes, as well as for the prevention of organ transplant rejection, prevention of graft-versus-host disease, and protection from ischemic or reperfusion injury.

[0012] SUMMARY OF INVENTION

[0013] In accordance with a first aspect of the invention, there is provided a compound of formula (I)

[0014] [Protein Kinase C ligand moiety] - linker - [ligase ligand moiety] or a salt, solvate, hydrate, isomer or prodrug thereof, wherein [ligase ligand moiety] is: wherein

[0015] M is 0, NMe or NH, or is absent; indicates attachment to R18of the linker;

[0016] R22is hydrogen, halogen or an amino group; and L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl; wherein [Protein Kinase C ligand moiety] is a co mpound of Formula (B) : wherein halogen or -NO2; or R8and R9together with the carbon atoms to which they are attached form a six-membered aryl ring;

[0017] R12is hydrogen or methyl,

[0018]

[0019] R20is -OCF3, -O-CHF2, -CF3, -CN, O-alkyl, -NH-alkyl, -NHR19, alkyl, phenyl, pyrrole, pyrazole, imidazole, triazole, tetrazole, -O-aryl, morpholine, piperazine or CN,

[0020] R23is hydrogen or methyl,

[0021] R24is hydrogen or methyl,

[0022] R25is hydrogen, methyl, -OH, -NH2, -O-alkyl, -NHalkyl, -COOH, -COOalkyl or halogen,

[0023] R26is hydrogen or R19,

[0024] R19is a bond connected to R14of the linker, and wherein Formula (B) contains a single R19; and wherein [linker] has following formula

[0025] R14-R1S-R16-R17-R18wherein

[0026] R14is -C(O)-, -CH2C(O)-, linear -Ci-io alkyl, or is absent;

[0027] R1Sis linear -Ci-w alkyl, -C2.6alkenyl, -C2e alkynyl, -(C2H4O)X, -(C2H4O)x-(linear Ci-w alkyl), - CH2O-, - CH2O(linear Ci-w alkyl), -(C3H6-O)X, -(C3H6-O)x(linear Ci-io alkyl), -CH2(C2H4-O)y, - CH2(C2H4- O)y(linear Cuo alkyl), or heterocycloalkyl,

[0028] R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, -CH2-, - CH2NMe-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,

[0029] R17is -CH2-, -CH2O-, -(C2H4O)X, (C3H6-O)X, CH2(C2H4-O)y, heterocycloalkyl, or is absent x is 1-10 y is 2-10

[0030] R18is linear -Ci-w alkyl, heterocycloalkyl, or is absent.

[0031] In some embodiments, R22is hydrogen, fluorine or an amino group. In some embodiments, R22is hydrogen or an amino group. In some embodiments, R22is hydrogen.

[0032] In some embodiments, L' is hydrogen or methyl. In some embodiments, L' is hydrogen. In some embodiments, M is O or NH, or is absent

[0033] In some embodiments, [ligase ligand moiety] is:

[0034] In some embodiments, [ligase ligand moiety] is:

[0035] In some embodiments, [ligase ligand moiety] is:

[0036] In some embodiments, [ligase ligand moiety] is In some embodiments, [ligase ligand moiety] is

[0037] In some embodiments, [ligase ligand moiety] is:

[0038] In some embodiments, [ligase ligand moiety] is:

[0039]

[0040] In some embodiments, [ligase ligand moiety] is:

[0041] In some embodiments, [ligase ligand moiety] is

[0042] In some embodiments, [linker] is selected from:

[0043] indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

[0044] In some embodiments, [Protein Kinase C ligand moiety] is

[0045] In some embodiments, [Protein Kinase C ligand moiety] is

[0046] In some embodiments, [Protein Kinase C ligand moiety] is

[0047] In some embodiments, [Protein Kinase C ligand moiety] is selected from

[0048]

[0049] In some embodiments, [Protein Kinase C ligand moiety] is selected from:

[0050] In some embodiments, [Protein Kinase C ligand moiety] is In some embodiments, the compound is selected from:

[0051]

[0052]

[0053]

[0054]

[0055] In some embodiments, the compound is selected from compounds 200-230.

[0056] In some embodiments, the compound is selected from:

[0057]

[0058] In some embodiments, the compound is selected from:

[0059]

[0060]

[0061] In some embodiments, each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl is unsubstituted.

[0062] In accordance with a second aspect of the invention, there is provided a compound of formula (I)

[0063] [Protein Kinase C ligand moiety] - [linker] - [ligase ligand moiety] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, wherein [ligase ligand moiety] is:

[0064] (a) Formula (IV)

[0065] wherein: each of Xi and X2is independently O or S; each of Qi and Cb is independently N or CR5, wherein at least one of Qi and Cb is N; each of Ei, E2, E3and E4 is independently N or CR'; n is 0, 1 or 2;

[0066] L2is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R'", -C(O)OR"', -C(O)NH2, -C(O)NHR'", -C(O)NR'"2, -OR'", -NR'"2, or -S(O)2R'"; each R5is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'", -NR"2, -NR'"C(O)R'", -NR'"C(O)OR'", -NO2, -CN, -C(O)R'", -C(O)OR'", -C(O)NH2, -C(O)NHR'", -C(O)NR'"2, -OR'", -OC(O)R'", -OC(O)OR'",

[0067] -OC(O)NH2, -OC(O)NHR'", -OC(O)NR'"2, -SR'", -S(O)2R'", -S(O)2OR'", -S(O)2NH2,

[0068] -S(O)2NHR'", -S(O)2NR'"2; -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'", -NR'"2, -NR'"C(O)R'", -NR'"C(O)OR'", -NO2,

[0069] -CN, -C(O)R'", -C(O)OR'", -C(O)NH2, -C(O)NHR'", -C(O)NR'"2, -OR'", -OC(0)R"',

[0070] -OC(O)OR"', -OC(O)NH2, -OC(O)NHR'", -OC(O)NR'"2, -SR'", -S(O)2R'", -S(O)2OR'",

[0071] S(O)2NH2, -S(O)2NHR'", -S(O)2NR'"2, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; and each R'" is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; wherein R21is a bond connected to R18of the linker, and wherein Formula (IV) contains a single R21; or

[0072] (b) Formula (Va) or (Vb):

[0073] or a pharmaceutically acceptable salt or tautomer thereof, wherein each of Xi and X2is independently O or S;

[0074] Zi is 0, S or NR6;

[0075] T is is C=O or SO2;

[0076] R1is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; each of Ys, Ye, Y7, and Y8is independently N or CR7, wherein at least one of Ys, Y6and Y7in Formula (Va) is CR7, and at least one of Ys, Ysand Ysin Formula (Vb) is CR7; n is 0, 1 or 2;

[0077] L3is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R"", -

[0078] CH2C(O)OR'"', -C(O)OR"", -C(0)NH2, -C(O)NHR"", -C(O)NR""2, -OR"", -NR""2, or

[0079] -S(O)2R""; each R7is independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR"",

[0080] -NR""2, -CH2NR""2|-NR""C(O)R"", -NR""C(O)CH2NR""2, -NR""C(O)CH2-heterocycloalkyl,

[0081] -NR""C(O)CH(OH)R'"', -CH2NR""C(O)OR"", -NR""C(O)OR"", -NR'"'SO2R"", -NO2, -CN,

[0082] -C(O)R"", -C(O)OR"", -C(O)NH2, -C(O)NHR"", -C(O)NR""2, -OR"", -OC(O)R"", -OC(O)OR"", -OC(O)NH2, - OC(O)NHR"", -OC(O)NR""2, -NHC(S)NHR"", SR"", or -S(O)2R"",-S(O)2OR"", -S(O)2NH2, -S(O)2NHR"", - S(O)2NR""2, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; each R"" is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0083] R6is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR"", -NR""2, -NR""C(O)R"", -N [C(O)R""]2, -NR""C(O)OR"", -NO2, -CN, -C(O)R"", - C(O)OR”", -C(O)NH2, -C(O)NHR"", -C(O)NR""2, -OR"", -OC(O)R'"', -OC(O)OR"", -OC(O)NH2, -OC(O)NHR"", -OC(O)NR""2, -SR"", or -S(O)2R"",-S(O)2OR"",

[0084] -S(O)2NH2, -S(O)2NHR"", -S(O)2NR""2, -R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; wherein R21is a bond connected to R18of the linker, and wherein formula (Va) and formula (Vb) each contain a single R21; wherein when Zi is O, then Yg is CR7and wherein when the compound is of Formula (Va), then

[0085] (i) when each of Ys, Yg and Y7is CR7, then at least one of R7is not H;

[0086] (ii) when Zi is NR6, then Yg and Y7are CR7;

[0087] (iii) when Zi is S, then Ysis not C-OMe and Yg is not C-OMe;

[0088] (iv) when Zi is S and Y5is C-NHCOMe, then Y7is not C-CH2NR'"'C(O)OR"";

[0089] (v) when Zi is S and Ysis N, then Yg is not C-H, C-aryl or C-C(O)OR""; and

[0090] (vi) when Zi is S and Yg is N, then Y7is C-NH2, C-NHR"", C-NR""2, C-NR""C(0) OR"", C- CH2NR""C(O)OR"", C-haloalkyl, C-‘Butyl, C-OR"", C-COOR"" or C-SR""; wherein when Y7is C-NH2, C- NHR"" or C-NR""2, then Y5is C-H; and when the compound is of Formula (Vb), then:

[0091] (vii) when each of Yg, Yg and Yg is CR7, then at least one of R7is not H;

[0092] (viii) when Zi is S, then Ysis not C-COOH or C-NHC(O)Me, and Y8is not C-Br;

[0093] (ix) when Zi is S and Yg is C-Br, then Y8is C-OR""

[0094] (x) when Zi is S, Ys is N and Yg is C-H or C-NH2, then Y8is not C-H

[0095] (xi) when Zi is S and Y5is N, then Yg is not C- halogen, C-alkyl, C-cycloalkyl, C-aryl, C-heteroaryl, C- CH2NH2, C-COOalkyl, or C-N HC(O)alkyl; (xii) when Zi is NR6, then Ys, Yg and Y8are CR7. or

[0096] (c) Formula (Ila) or (lib): each of Xi and X2 is independently O or S;

[0097] Z is O, S or NR2;

[0098] T is C=O or SO2;

[0099] Y3is N or CR;

[0100] Y4is N or CR; indicates a single or double bond, wherein when each is a double bond, each of Wi, W2, W3and W4is independently N or CRa, wherein at least one of Wi, W2, W3and W4is N, and when each is a single bond, Wi, W2, W3and W4are each CRa2and Y4is CR; n is 0, 1 or 2;

[0101] L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)Rh, -C(O)ORh, - C(O)NH2, -C(O)NHRh, -C(O)NRh2, -ORh, -NRh2, or -S(O)2Rh; each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHRh, -NRh2, -NRhC(O)Rh, -NRhC(O)CH2Rh, - NRhC(O)CH(OH)Rh, -NRhC(O)ORh, -NRhSO2Rh, -NO2, -CN, -C(O)Rh, -C(O)ORh, -C(O)NH2, -C(O)NHRh, - C(O)NRh2, -ORh, -OC(O)Rh, -OC(O)ORh, -OC(O)NH2, -OC(O)NHRh, -OC(O)NRh2, -SRh, or -S(O)2Rh,-S(O)2ORh, - S(O)2NH2, -S(O)2NHRh, or -S(O)2NRh2; each Rais independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHRh, -NRh2, -NRhC(O)Rh, -NRhC(O)CH(OH)Rh, - NRhC(O)ORh, -NRhSO2Rh, -NO2, -CN, -C(O)Rh, -C(O)ORh, -C(O)NH2, -C(O)NHRh, -C(O)NRh2, -ORh, -OC(0)Rh, - OC(O)ORh, -OC(O)NH2, -OC(O)NHRh, -OC(O)NRh2, -SRh, -S(O)2Rh, -S(O)2ORh, -S(O)2NH2, -S(O)2NHRh, - S(O)2NRh2, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; each Rhis independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0102] R2is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHRh, -NRh2, -NRhC(O)Rh, -N[C(O)Rh]2, -NRhC(O)ORh, -NO2, -CN, -C(O)Rh, -C(O)ORh, - C(O)NH2, -C(O)NHRh, -C(O)NRh2, -ORh, -OC(O)Rh, -OC(O)ORh, -OC(O)NH2, -OC(O)NHRh, -OC(O)NRh2, -SRh, - S(O)2Rh,-S(O)2ORh, -S(O)2NH2, -S(O)2NHRh, or -S(O)2NRh2; and

[0103] R1is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0104] R21is a bond connected to R18of the linker, and wherein formula (Ila) and formula (lib) each contain a single R21; wherein when each is a double bond, Z is NR2, R2is hydrogen, and each Rais hydrogen, then W4is CRa; wherein [Protein Kinase C ligand moiety] is a compound of Formula (B): wherein

[0105] R8is halogen or N02; or R8and R9together with the carbon atoms to which they are attached form a six-membered aryl ring;

[0106] R12is hydrogen or methyl,

[0107]

[0108] R20is -OCF3, -O-CHF2, -CF3, -CN, O-alkyl, -NH-alkyl, -NHR19, alkyl, phenyl, pyrrole, pyrazole, imidazole, triazole, tetrazole, -O-aryl, morpholine, piperazine or CN,

[0109] R23is hydrogen or methyl,

[0110] R24is hydrogen or methyl,

[0111] R25is hydrogen, methyl, -OH, -NH2, -O-alkyl, -NH alkyl, -COOH, -COOalkyl or halogen,

[0112] R26is hydrogen or R19,

[0113] R19is a bond connected to R14of the linker, and wherein Formula (B) contains a single R19; and wherein [linker] has following formula

[0114] R14.R15.R16.R17.R18 wherein

[0115] R14is -C(0)-, -CHzCfO)-, linear -Cno alkyl, or is absent;

[0116] R15is linear -Ci-io alkyl, -Cz s alkenyl, -C2 -e alkynyl, -(CzFUOjx, -(CzFUOjx-Oinear Ci-ioalkyl), -CH2O- , - CH2O(linear Ci-io alkyl), -(C3H6-O)X, -(C3H6-O)x(linear C1-10 alkyl), -CH2(C2H4-O)Y, - CH2(C2H4-O)Y(linear Ci-10 alkyl), or heterocycloalkyl,

[0117] R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, -CH2-, - CH2NMe-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,

[0118] R17is -CH2-, -CH2O-, -(C2H4O)X, (C3H6-O)X, CH2(C2H4-O)y, heterocycloalkyl, or is absent x is 1-10 y is 2-10

[0119] R18is linear -C1-10 alkyl, heterocycloalkyl, or is absent.

[0120] In some embodiments, each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl groups is unsubstituted.

[0121] In some embodiments, each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR"", -NR""2, -NR""C(O)R"", - NR""C(O)CH(OH)R"", -NR""C(O)OR"", -NR""SO2R"", -N02, -CN,-C(O)R"", -C(O)OR"", -C(O)NHz, - C(O)NHR"", -C(O)NR""Z, -OR"", -OC(O)R"", -OC(O)OR"", -OC(O)NH2, -OC(O)NHR"", -OC(O)NR""2, -SR"", or -S(O)2R"", -S(O)2OR"", -S(O)2NH2, -S(O)2NHR"", or -S(O)2NR""2, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2- NH-C(O)-R21.

[0122] In some embodiments, R1is hydrogen.

[0123] In some embodiments, R6is hydrogen.

[0124] In some embodiments, when Zi is S in Formula (Vb), then Y$ is not C- NHC(O)R"" or -C(O)OR"".

[0125] In some embodiments, Zi is NR6.

[0126] In some embodiments, [ligase ligand moiety] is of Formula (Va) and Ys, Ysand Y7are each CR7. In some such embodiments, Ys is -C-NHC(O)R"", Y6is CH, and Y7is CH or CCL In some embodiments, L3is hydrogen; Zi is S; R1is hydrogen; T is C=O; and Y7is CH.

[0127] In some embodiments, the compound is of Formula (Vb) and Y5, Y6and Y8are each CR7. In some such embodiments:

[0128] L3is hydrogen;

[0129] Zi is S;

[0130] R1is H;

[0131] T is C=O;

[0132] Ysis CH, C-OR"", CCI, C-CN, or C-NHC(O)R"";

[0133] Yg is CH, CCI, C-alkyl, C-cycloalkyl, or C-haloalkyl; and

[0134] Ysis CH, C-OR"", C-NHC(O)R"", C-NHC(O)OR"", C-NHR"", C-NH2, or C-NHSO2R""; wherein, when Ys is CCI, then Ys is CH, C-alkyl, C-cycloalkyl, or C-haloalkyl.

[0135] In some embodiments, each R"" is independently alkyl, cycloalkyl, aryl or benzyl. In some embodiments, Ys is CH; Y6is CH or CCI; and Y8is C-OR"" or C-NH2. In some embodiments, Y8is C-OMe or C-NH2.

[0136] In some embodiments, Z is NR2. In other embodiments, Z is S. In some embodiments, each is a double bond.

[0137] In some embodiments, L is hydrogen.

[0138] In some embodiments, one of Wi, W2, W3and W4is N, and the remaining three of Wi, W2, W3and W4are each CRa; optionally wherein W4is CRa. In other embodiments, two of Wi, W2, W3and W4is N, and the remaining two of Wi, W2, W3and W4are each CRa. In other embodiments, one of Wi, W2, W3and W4is CRa, and the remaining three of Wi, W2, W3and W4are each N.

[0139] In some embodiments, each R is independently hydrogen, halogen or -NRhC(O)Rh.

[0140] In some embodiments, [ligase ligand moiety] is:

[0141] In some embodiments, Ei, E2, E3and E4are each CR'. In other embodiments, one of Ei, E2, E3and E4is N and the remaining three of Ei, E2, E3and E4are each CR'.

[0142] In some embodiments, Qi is CR5.ln other embodiments, Ch is CR5.

[0143] In accordance with a third aspect of the invention, there is provided a compound of formula (I)

[0144] [Protein Kinase C ligand moiety] - [linker] - [ligase ligand moiety] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, wherein [ligase ligand moiety] is:

[0145] (a) Formula (II):

[0146] wherein: each of Xi and X2is independently O or S;

[0147] T is C=0 or SO2;

[0148] R1is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2;

[0149] U is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R",-

[0150] C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2, -OH, -OR", -NH2, -NHR", -NR"2, -S(O)2H or -S(O)2R"; wherein -; indicates attachment to T,

[0151] Z3is O, S or NR3;

[0152] U is O, S, NRbor CRb2; each of Yi, Y2and Y3is independently N or CRd; each Rdis independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, -C(O)H, C(O)R", - C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", -OC(O)OH,- OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S{O)2OH, -S(O)2OR", - S(O)2NH2, -S(O)2NHR", -S(O)2NR"2, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; each Rbis independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, -C(O)H, C(O)R", - C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", -OC(O)OH,- OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(0)2OH, -S(C)2OR", - S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2; each R3is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(0)CH(OH)R", - NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, -C(O)H, C(O)R", - C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(0)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", -OC(0)OH,- OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, -S(O)20R", - S(O)2NH2, -S(O)2NHR", -S(O)2NR"2, -R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; each R" is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0153] R21is a bond connected to R18of the linker, wherein Formula (II) contains a single R21; wherein: each of Xi and X2is independently O or S; T is C=0 or SO2;

[0154] R1is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2;

[0155] Li is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R",-C(O)OH, -C(O)OR", -CH2C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2, -OH, -OR”, -NH2, -NHR", -NR"2, -S( O)2H or - S(O)2R";

[0156] Rxis selected from wherein indicates attachment to T,

[0157] Z4is O, S or NR4;

[0158] V is CRf2, NR4or S; each of Gi, G2, G3 and G4is independently N or CRC, each of Yi and Y2is independently N or CRf, each Rfis independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", - NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, -C(O)H, C(O)R", - C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", -OC(O)OH,- OC(0)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, -S(O)2OR", - S(O)2NH2, -S(O)2NHR", -S(O)2NR"2, - R21.-O-R21, -NH-R21, -C(O)-NH-R21, or-CH2-NH-C(O)-R21; orwhen Yi and Y2are CRfthen each Rf, together with the carbon atom to which it is attached, forms a 5- or 6- membered ring; each Rcis independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl substituted with at least one -OR", heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, - CH2NH2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", - NHSO2R", -NR"SO2R", -NO2, -CN, -C(O)H, C(O)R", -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", - OC(O)H, -OC(O)R", -OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, - S(O)2R", -S(O)2OH, -S(O)2OR", -S(O)2NH2, -S(O)2NHR", -S(O)2NR"2, -O-R21, -NH-R21, -C(O)-NH-R2X, or -CH2- NH-C(O)-R21; each R4is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", - C(O)NR"2, -OH, -OR”, -NH2, -NHR", -NR"2, -S(O)2H, -S(O)2R", - R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; and each R" is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;

[0159] R21is a bond connected to R18of the linker, wherein Formula (III) contains a single R21; wherein, when n = 2, each Rcis hydrogen, and each of Gi, G2, G3and G4is CRC, then C=Xi may be replaced by CH; and wherein:

[0160] (i) when Rxis then Li is hydrogen, -CH2C(O)OR”, or -OR”;

[0161] (ii) when Rxis then R4is not alkyl and at least one of R2and R is not H;

[0162] (iii) when Rxis are CRf, then at least one of Gi, G2and G3is N;

[0163] (iv) when Z4is NR4, and Yi and Y2are CRf, then Rxis not

[0164] then

[0165] R4is not alkyl;

[0166] (vi) when Rxis wherein [Protein Kinase C ligand moiety] is a compound of Formula (B):

[0167] wherein halogen or NO2; or R8and R9together with the carbon atoms to which they are attached form a six-membered aryl ring;

[0168] R20is -OCF3, -O-CHF2, -CF3, -CN, O-alkyl, -NH-alkyl, -NHR19, alkyl, phenyl, pyrrole, pyrazole. imidazole, triazole, tetrazole, -O-aryl, morpholine, piperazine or CN, R23is hydrogen or methyl,

[0169] R24is hydrogen or methyl,

[0170] R25is hydrogen, methyl, -OH, -NH2, -O-alkyl, -NHalkyl, -COOH, -COOalkyl or halogen,

[0171] R26is hydrogen or R19,

[0172] R19is a bond connected to R14of the linker, and wherein Formula (B) contains a single R19; and wherein [linker] has following formula

[0173] R14-R15-R16-R17-R18wherein

[0174] R14is -C(O)-, -CH2C(O)-, linear -Ci-io alkyl, or is absent;

[0175] R15is linear -Ci-io alkyl, -Cj-salkenyl, -C2-ealkynyl, -(C2H4O)X, -(C2H4O)x-(linear CHO alkyl), -CH2O- , - CH2O(linear Ci-w alkyl), -(C3H6-O)X, -(C3H6-O)x(linear CHO alkyl), -CH2(C2H4-O)V, - CH2(C2H4-O)y(linear Ci-io alkyl), or heterocycloalkyl,

[0176] R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, -CH2-, - CH2NMe-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,

[0177] R17is -CH2-, -CH2O-, -(C2H4O)X, (C3HS-O)X, CH2(C2H4-O)y, heterocycloalkyl, or is absent x is 1-10 y is 2-10

[0178] R18is linear -CHO alkyl, heterocycloalkyl, or is absent.

[0179] In some embodiments, each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl is unsubstituted.

[0180] In some embodiments, in Formula (III): each of Xi and X2is 0;

[0181] T is C=O;

[0182] R1is hydrogen,

[0183] Li is hydrogen,

[0184] Rxis

[0185] Z4is NR4; each of Gi, G2and G4is CRC,

[0186] Yi is N, and

[0187] Y2is CRf, wherein Rfis not hydrogen.

[0188] In some embodiments, [ligase ligand moiety] is Formula (III):

[0189] In some embodiments, one of Rcis -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21.

[0190] In some embodiments, Gi is C-O-R21, C-NH-R21, C-C(O)-NH-R21, or C-CH2-NH-C(O)-R21.

[0191] In some embodiments, G2is C-O-R21, C-NH-R21, C-C(O)-NH-R21, or C-CH2-NH-C(O)-R21.

[0192] In some embodiments, R4is R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21.

[0193] In some embodiments, one of Rfis - R21, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21.

[0194] In some embodiments, Y2is C- R21,CO-R21, C-NH-R21, C-C(O)-NH-R21, or C-CH2-NH-C(O)-R21.

[0195] In some embodiments, [ligase ligand moiety] is selected from

[0196]

[0197] In some embodiments, [ligase ligand moiety] is of Formula (II):

[0198] In some embodiments, Ryis selected from

[0199]

[0200] In some embodiments, Z3is S or NR3; U is O or S; and each of Yj, Y2and Y3is independently N or CRd.

[0201] In some embodiments, Rbis hydrogen or alkyl.

[0202] In some embodiments, R3is hydrogen, alkyl, cycloalkyl, -R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21.

[0203] In some embodiments, each Rdis independently hydrogen, alkyl, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2- NH-C(O)-R21.

[0204] In some embodiments of any of the above aspects:

[0205] Rlsis linear -Ci-9 alkyl, -C2H4O-(linear Ci-4alkyl), piperidinyl, or piperazinyl, piperazinyl,

[0206] R17is -CH2O-, -(C2H4O)X, -CH2-, piperidinyl, piperazinyl, or is absent x is 1-6

[0207] R18is linear -Ci-8alkyl, piperidinyl, piperazinyl, or is absent.

[0208] In some embodiments of any of the above aspects:

[0209] R14is absent; R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and (CaHe-Ojx, CH2(C2H4-O)y, heterocycloalkyl, or is absent.

[0210] In some embodiments of any of the above aspects:

[0211] R15is linear -Ci-8 alkyl, -C2H4O-(linear C1.4 alkyl), or piperazinyl, r piperazinyl, piperazinyl, or is absent x is 1-6

[0212] R18is linear -Ci-s alkyl, piperazinyl, or is absent.

[0213] In some embodiments of any of the above aspects,

[0214] R15is linear -Ci-s alkyl or -C2H4O-(linear Ci-4alkyl),

[0215] R18is linear -Ci-8alkyl, or is absent.

[0216] In some embodiments of any of the above aspects, x is 2

[0217] R18is linear -Ci-e alkyl, or is absent.

[0218] In some embodiments of any of the above aspects, R18is linear-Ci-3alkyl, or is absent.

[0219] In some embodiments of any of the above aspects, R15is linear -C3alkyl, linear -C5alkyl, linear -C7alkyl or -C2H4O-(linear C4 alkyl). In some embodiments of any of the above aspects, R16is In other embodiments, R16is -

[0220] NH-C(O)-.

[0221] In some embodiments of any of the above aspects, [linker] is selected from:

[0222] wherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

[0223] In some embodiments of any of the above aspects, R8is

[0224] embodiments, R16is In other such embodiments, R16is -NH-C(O)-.

[0225] In some embodiments of any of the above aspects, R8is linear -Ci-8alkyl; R16is -NH-C(O)-; and R1Sis linear -Ci.8alkyl.

[0226] In some embodiments of any of the above aspects, [linker] is selected from

[0227] wherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

[0228] In some embodiments of any of the above aspects, [linker] is selected from

[0229] wherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

[0230] In some embodiments of any of the above aspects, [Protein Kinase C ligand moiety] is

[0231] In some embodiments of any of the above aspects, [Protein Kinase C ligand moiety] is

[0232] In some embodiments of any of the above aspects, [Protein Kinase C ligand moiety] is

[0233] In some embodiments of any of the above aspects, [Protein Kinase C ligand moiety] is selected from

[0234] In some embodiments of any of the above aspects, [Protein Kinase C ligand moiety] is selected from: In some embodiments of any of the above aspects T is C=O. In other embodiments, T is SO2.

[0235] In some embodiments of any of the above aspects Xi and X2are O. In other embodiments,

[0236] Xi is 0 and X2is S. In other embodiments, Xi is S and X2is 0. In other embodiments, Xi and X2are S.

[0237] In some embodiments of any of the above aspects n is 0. In other embodiments, n is 1 or 2. In some embodiments, n is 1. In other embodiments, n is 2.

[0238] In accordance with a fourth aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to any of the above aspects of the present invention.

[0239] The invention also provides a compound or composition according to any of the above aspects of the present invention, for use in medicine.

[0240] The invention also provides a compound or composition according to any of the above aspects of the present invention, for use in the treatment of a disease selected from cancer, psoriasis, arthritis, multiple sclerosis, inflammatory bowel disease, uveitis, dermatitis, diabetes, lupus erythematosus, asthma, colitis, osteoporosis, atherosclerosis, Duchenne Muscular Dystrophy (DMD), T-cell leukaemia, CNS diseases, Ischemic heart diseases, and other diseases or disorders mediated by T lymphocytes. In some embodiments, the disease is selected from cancer, psoriasis, arthritis, multiple sclerosis, inflammatory bowel disease, uveitis, dermatitis, diabetes, lupus erythematosus, asthma, colitis, osteoporosis, atherosclerosis, Duchenne Muscular Dystrophy (DMD), T-cell leukaemia, CNS diseases, and Ischemic heart diseases.

[0241] In some embodiments, the disease is cancer.

[0242] The invention also provides a compound or composition according to any of the above aspects of the present invention, for use in preventing organ transplant rejection, preventing graft-versus-host disease, and protection from ischemic or reperfusion injury. The present invention also provides a method of treating a disease selected from cancer, psoriasis, arthritis, multiple sclerosis, inflammatory bowel disease, uveitis, dermatitis, diabetes, lupus erythematosus, asthma, colitis, osteoporosis, atherosclerosis, Duchenne Muscular Dystrophy (DMD), T-cell leukaemia, CNS diseases, Ischemic heart diseases, and other diseases or disorders mediated by T lymphocytes in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or composition according to any of the above aspects of th e present invention.

[0243] The present invention also provides a method of preventing organ transplant rejection or graft-versus- host disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or composition according to any of the above aspects of the present invention.

[0244] The present invention also provides a method for protecting against ischemic or reperfusion injury in a subject in need thereof, the method comprising administering to the subject an effective amount of a or composition according to any of the above aspects of the present invention.

[0245] In some embodiments, the methods further comprise administering at least one additional active agent to the subject.

[0246] The present invention also provides a combined preparation of a compound according to any of the above aspects of the present invention and at least one additional active agent, for simultaneous, separate or sequential use in therapy. In some embodiments, the therapy is the treatment of a disease selected from cancer, psoriasis, arthritis, multiple sclerosis, inflammatory bowel disease, uveitis, dermatitis, diabetes, lupus erythematosus, asthma, colitis, osteoporosis, atherosclerosis, Duchenne Muscular Dystrophy (DMD), T-cell leukaemia, CNS diseases, Ischemic heart diseases, and other diseases or disorders mediated by T lymphocytes. In some embodiments, wherein the disease is cancer. In some embodiments, the therapy is the prevention of organ transplant rejection, the prevention of graft- versus-host disease, or protection from ischemic or reperfusion injury. As used herein the term "alkyl" is intended to include both unsubstituted alkyl groups, and alkyl groups which are substituted by one or more additional groups. In some embodiments, the alkyl group is an unsubstituted alkyl group. In some embodiments, the alkyl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkyl group is a Ci-Ci2alkyl, a C1-C10 alkyl, a Ci-C8alkyl, a Ci-C6alkyl, or a C1-C4 alkyl group. In some embodiments the alkyl group is a linear alkyl group. In some embodiments the alkyl group is an unsubstituted linear alkyl group. In some embodiments the alkyl group is a linear al kyl group which is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, - C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments the alkyl group is a branched alkyl group. In some embodiments the alkyl group is an unsubstituted branched alkyl group. In some embodiments the alkyl group is a branched alkyl group which is substituted by one or more groups selected from -OH, - ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0247] As used herein the term "alkenyl" is intended to include both unsubstituted alkenyl groups, and alkenyl groups which are substituted by one or more additional groups. In some embodiments, the alkenyl group is an unsubstituted alkenyl group. In some embodiments, the alkenyl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkenyl group is a C2-Ci2alkenyl, a C2-Cio alkenyl, a C2-C8alkenyl, a C2-C6alkenyl, or a C2-C4 alkenyl group. In some embodiments the alkenyl group is a linear alkenyl group. In some embodiments the alkenyl group is an unsubstituted linear alkenyl group. In some embodiments the alkenyl group is a linear alkenyl group which is substituted by one or more groups selected from -OH, - ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments the alkenyl group is a branched alkenyl group. In some embodiments the alkenyl group is an unsubstituted branched alkenyl group. In some embodiments the alkenyl group is a branched alkenyl group which is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. As used herein the term "alkynyl" is intended to include both unsubstituted alkynyl groups, and alkynyl groups which are substituted by one or more additional groups. In some embodiments, the alky nyl group is an unsubstituted alkynyl group. In some embodiments, the alkynyl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkynyl group is a C2-Ci2alkynyl, a C2-C10alkynyl, a C2-C8alkynyl, a C2-C6alkynyl, or a C2-C4alkynyl group. In some embodiments the alkynyl group is a linear alkynyl group. In some embodiments the alkynyl group is an unsubstituted linear alkynyl group. In some embodiments the alkynyl group is a linear alkynyl group which is substituted by one or more groups selected from -OH, -O RW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments the alkynyl group is a branched alkynyl group. In some embodiments the alkynyl group is an unsubstituted branched alkynyl group. In some embodiments the alkynyl group is a branched alkynyl group which is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0248] As used herein the term "aryl" is intended to include both unsubstituted aryl groups, and aryl groups which are substituted by one or more additional groups. In some embodiments, the aryl group is an unsubstituted aryl group. In some embodiments, the aryl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the aryl group is a Ce-Cio aryl, a Cs-C8aryl, or a Ce aryl.

[0249] As used herein the term "heteroaryl" is intended to include both unsubstituted heteroaryl groups, and heteroaryl groups which are substituted by one or more additional groups. In some embodiments, the heteroaryl group is an unsubstituted heteroaryl group. In some embodiments, the heteroaryl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the heteroaryl group is a C6-Cio heteroaryl, a C6-C9heteroaryl, a Ce-Cs heteroaryl, or a Ce heteroaryl. As used herein the term "benzyl" is intended to include both unsubstituted benzyl groups, and benzyl groups which are substituted by one or more additional groups. In some embodiments, the benzyl group is an unsubstituted benzyl group. In some embodiments, the benzyl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0250] In some embodiments of any of the above aspects of the invention, all alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl groups in the compounds are unsubstituted.

[0251] BRIEF DESCRIPTION OF THE FIGURES

[0252] Figure 1 is a schematic presentation of the disclosed mechanism of action. Bifunctional compounds comprise E3 ligase binding moiety (LBM) on the one end and PKC binding moiety on the other end (PBM).

[0253] Figure 2 is an assay showing the dose-dependent effect of various compounds of the invention (as exemplified by 248) on the level of PKC proteins in the Jurkat cell line (antibody mix co-stimulated Jurkat cells; Western Blot assay).

[0254] DETAILED DESCRIPTION OF THE INVENTION

[0255] As discussed above, the present invention provides provided a compound of formula (I)

[0256] (Protein Kinase C ligand moiety] - linker - [ligase ligand moiety] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, wherein [ligase ligand moiety] is:

[0257]

[0258] wherein [Protein Kinase C ligand moiety] is a compound of Formula (B): and wherein [linker] has following formula

[0259] R15-R16-R17-R18wherein

[0260] R15is linear -Ci-io alkyl, -C2-s alkenyl, -C2-6 alkynyl, -(C2H4O)X, -(C2H4O)x-(linear Ci-io alkyl), - CH2O-, - CH2O(linear Cuo alkyl), -(C3H6-O)X, -(C3H6-O)x(linear Ci-io alkyl), -CH2(C2H4-O)y, - CH2(C2H4- O)y(linear Ci 10 alkyl), or heterocycloalkyl,

[0261] R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,

[0262] R17is -CH2O-, -(C2H4O)X, (C3H6-O)X, CH2(C2H4-O)V, heterocycloalkyl, or is absent x is 1-10 y is 2-10

[0263] R18is linear -C1-10 alkyl, heterocycloalkyl, or is absent. LIGASE LIGAND MOIETIES

[0264] Ligase ligand moieties with thalidomide-type structure

[0265] In one aspect, the ligase ligand moiety is: wherein

[0266] M is O, NMe or NH, or is absent; indicates attachment to R18of the linker;

[0267] R22is hydrogen, halogen or an amino group; and

[0268] L' is hydrogen, alkyl, benzyl, acetyl or pivaloyl.

[0269] Examples of the above ligase ligand moieties are shown in Table 1 below: Table 1: Compounds 108-110 and 112-115 are commercially available in the forms shown below. The synthesis of compound 111 is disclosed in the Examples section, below. In some embodiments of the above ligase ligands, the moiety may be replaced with one of the following moieties: wherein

[0270] A is , hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH2OC(O)tBu, - CH2C(O)OR27, -C(O)R27, -C(O)OR27, -C(O)NH2, -C(O)NHR27, -C(O)NR272, -OR27, -NR272, -S(O)2R27or P(O)(OR27)(OR27), wherein each R27is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl,

[0271] B is hydrogen, deuterium or alkyl,

[0272] C is hydrogen, deuterium or alkyl.

[0273] Ligase ligand moieties of Formula (II) and Formula (III)

[0274] The synthesis of the ligase ligand moieties of Formula (II) and Formula (III) (as defined above) can be summarized as follows: Example ligase ligand moieties of Formula (II) and Formula (III) are shown in Table 2 belo-w. These compounds could be modified to allow attachment to the [linker] (for example, by bromination of the aromatic ring followed by attachment - by palladium coupling - of either the [linker] itself, or of a functional group to which the [linker] could be attached).

[0275] Table 2:

[0276]

[0277]

[0278] In some embodiments of Formula (II) and Formula (III), the moieties may be replaced with one of the following moieties: wherein

[0279] A is hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH2OC(O)‘Bu, - CH2C(O)OR27, -C(O)R27, -C(O)OR27, -C(O)NH2, -C(O)NHR27, -C(O)NR272, -OR27, -NR272, -S(O)2R27or P(O)(OR27)(OR27), wherein each R27is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl,

[0280] B is hydrogen, deuterium or alkyl,

[0281] C is hydrogen, deuterium or alkyl. Ligase ligand moieties of Formula (IV)

[0282] The synthesis of the ligase ligand moieties of Formula (IV) (as defined above) can be summarized as follows:

[0283] Example ligase ligand moieties of Formula (IV) are shown in Table 3 below. These compounds could be modified to allow attachment to the [linker] (e.g. by nucleophilic aromatic substitution; or by exchange of fluorine for bromine followed by attachment - by palladium coupling - of either the [linker] itself, or of a functional group to which the [linker] could be attached).

[0284] Table 3: Ligase ligand moieties of Formula (Va) and Formula (Vb), and Formula (Ila) and Formula (lib)

[0285] The synthesis of the ligase ligand moieties of Formulae (Va), (Vb), (Ila) and (lib) (as defined above) can be summarized in the following general procedure (carried out under Synthetic Conditions D, E, F or G, as set out below:

[0286] 3-aminopiperidine-2, 6-dione

[0287] Reaction Scheme 2: General procedure

[0288] Synthetic Conditions D

[0289] An appropriate acid (RXCOOH in the above reaction scheme) (1.1 eq), DMAP (0.04 eq), and EDC (1.2 eq) were added to a solution of 3-aminopiperidine-2, 6-dione (l eq) and A / -hydroxybenzotriazole (1.2 eq) in DMF (0.5 M). The reaction mixture was stirred overnight at room temperature (20-25°C). Water (2 x DMF volume) was added and the obtained solution was extracted with dichloromethane (3 x DMF volume). The combined organic layers were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC or by column chromatography.

[0290] Synthetic Conditions E

[0291] An appropriate acid R’COOH in the above reaction scheme) (1 eq) and EDC (1.2 eq) were added to a solution of 3-aminopiperidine-2, 6-dione (hydrochloride salt, 1.1 eq), triethylamine (1.2 eq) and N- hydroxybenzotriazole (1.2 eq) in DMA (0.5 M). The reaction mixture was stirred overnight at rt. Water (2 x DMA volume) was added and obtained mixture was extracted with dichloromethane (3 x DMA volume). The combined organic layers were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was isolated by preparative HPLC or by column chromatography.

[0292] Synthetic Conditions F

[0293] To a solution of appropriate acid (RXCOOH in the above reaction scheme) (1 eq) and HATU (1.5 eq) in dry DMF were added 3-aminopiperidine-2, 6-dione (hydrochloride salt, 1.2 eq) and DIPEA (3 eq). The reaction mixture was stirred overnight at rt. The crude product was purified by preparative HPLC or / and by preparative TLC. Synthetic Conditions G

[0294] To a solution of appropriate acid (RXCOOH in the above reaction scheme) (1 eq) 3-aminopiperidine- 2, 6-dione (hydrochloride salt, 1.2 eq) and DMAP (0.1 eq.) in an inert atmosphere in dry DM F were added DIPEA (2.2 eq.) and HATU (1.5 eq) in dry DMF. The reaction mixture was stirred overnight at rt. The crude product was purified by preparative HPLC or / and by preparative TLC.

[0295] Example method 1: formation of chlorinated Rxgroup of RXCOOH (or its ester RXCOORV)

[0296] NCS (1.1 eq) was added to a solution of an appropriate starting material (1 eq) in DMF (0.5 Ml) and the reaction mixture was stirred for 2 h at room temperature (20-25°C). The reaction mixture was poured into water (2 x DMF volume) and occurred precipitate was filtered. The solids were washed with water and dried in vacuum to give the acid, ROOH.

[0297] Example method 2: synthesis of RXCOOH from corresponding ester RXCOORV)

[0298] LiOH (1.1 eq) was added to a solution of an appropriate ester (1 eq) in THF:water mixture (3:1 or 5:1, 85 mM) and the resulting mixture was stirred overnight at room temperature (20-25°C). The mixture was concentrated under reduced pressure, diluted with water, and acidified with concentrated HCI to pH=2- 3. The precipitate was filtered, washed with water, and dried in vacuum to give the target carboxylic acid.

[0299] Example method 3: formation of acetylated Rxgroup of RxCOORy

[0300] A mixture of an appropriate amine (1 eq.), Ac2O (3 eq.), and DMAP (0.2 eq.) in dioxane (0.2 M) was heated to 80°C for 2 h. Upon completion, the mixture was cooled down to room temperature (20-25°C) and concentrated under reduced pressure. The residue was diluted with water (1 x dioxane volume) and extracted with EtOAc (3 x dioxane volume). The organic layers were washed with water, brine, dried over Na2SO4, and evaporated to dryness to afford an acylated product typically used without further purification.

[0301] Example ligase ligand moieties of Formula (Va) and Formula (Vb) are shown in Table 4 below. These compounds could be modified to allow attachment to the [linker] (e.g. by C-H bond activation or by bromination of the aromatic ring followed by attachment - by palladium coupling - of either the [linker] itself, or of a functional group to which the [linker] could be attached). Table 4: Example ligase ligand moieties of Formula (Ila) and Formula (lib) are shown in Table 5 below. These compounds could be modified to allow attachment to the [linker] (e.g. by C-H bond activation or by bromination of the aromatic ring followed by attachment - by palladium coupling - of either the [linker] itself, or of a functional group to which the [linker] could be attached).

[0302] Table 5: In some embodiments of Formulas (Va), (Vb), (Ila) and (lib) the wherein

[0303] A is , hydrogen, alkyl, alkenyl, benzyl, aryl, heteroaryl, haloalkyl, haloalkenyl, -CH2OC(O)’:Bu, - CH2C(O)OR27, -C(O)R27, -C(O)OR27, -C(O)NH2, -C(O)NHR27, -C(O)NR272, -OR27, -NR272, -S(O)2R27or P(O)(OR27)(OR27), wherein each R27is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl,

[0304] B is hydrogen, deuterium or alkyl,

[0305] C is hydrogen, deuterium or alkyl.

[0306] LINKERS

[0307] In the compounds of the present invention, the [linker] has following formula:

[0308] R14-R15-R16-R17-R18wherein

[0309] R14is -C(O)-, -CHzCfO)-, linear -Ci-w alkyl, or is absent;

[0310] R15is linear -Ci- 10 alkyl, -C2-6 alkenyl, -C2-e alkynyl, -(C2H4O)X, -(C2H4O)x-(linear Ci-i0alkyl), - CH2O-, - CH2O(linear C1-10 alkyl), -(C3H6-O)X, -(C3H6-O)x(linear Ci-Walkyl), -CH2(C2H4-O)y, - CH2(C2H4- O)y(linear Cuo alkyl), or heterocycloalkyl, R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, -CH2CkhNMe-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,

[0311] R17is -CH2-, -CH2O-, -(C2H4O)X, (CaHe-OJx, CH2(C2H4-O)V, heterocycloalkyl, or is absent x is 1-10 y is 2-10

[0312] R18is linear -Ci-io alkyl, heterocycloalkyl, or is absent.

[0313] In some embodiments:

[0314] R15is linear -Ci-9 alkyl, -C2H4O-(linear C14 alkyl), piperidinyl, or piperazinyl, piperazinyl,

[0315] R17is -CH2O-, -(C2H4O)X, -CH2-, piperidinyl, piperazinyl, or is absent x is 1-6

[0316] R18is linear -Ci-s alkyl, piperidinyl, piperazinyl, or is absent.

[0317] In some embodiments:

[0318] R14is absent;

[0319] R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and

[0320] R17is -CH2O-, -(C2H4O)X, (CsHg-Ojx, CH2(C2H4-O)y, heterocycloalkyl, or is absent.

[0321] In some embodiments:

[0322] R15is linear -C1-8 alkyl, -C2H4O-(linear Ci^alkyl), or piperazinyl

[0323] R17is -CH2O-, -(C2H4O)X, piperazinyl, or is absent x is 1-6

[0324] R18is linear -Ci-8 alkyl, piperazinyl or is absent.

[0325] In some embodiments, R15is linear -Ci-8alkyl or -C2H4O-(linear Ci 4a I ky I ),

[0326] R17is -CH2O-, -(C2H4O)X, or is absent x is 1-6

[0327] R18is linear -Ci.galkyl, or is absent.

[0328] Examples of linkers which can be used in the compounds of the present invention include:

[0329] wherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety]. PROTEIN KINASE C LIGAND MOIETIES

[0330] In the compound of the present invention, [Protein Kinase C ligand moiety] is a compound of Formula

[0331] (B): wherein halogen or -NO2; or R8and R9together with the carbon atoms to which they are attached form a six-membered aryl ring;

[0332]

[0333] R20is -OCF3, -O-CHF2, -CF3, -CN, O-alkyl, -NH-alkyl, -NHR19, alkyl, phenyl, pyrrole, pyrazole, imidazole, triazole, tetrazole, -O-aryl, morpholine, piperazine or CN,

[0334] R23is hydrogen or methyl,

[0335] R24is hydrogen or methyl,

[0336] R2Sis hydrogen, methyl, -OH, -NH2, -O-alkyl, -NHalkyl, -COOH, -COOalkyl or halogen,

[0337] R26is hydrogen or R19,

[0338] R19is a bond connected to R14of the linker, and wherein Formula (B) contains a single R19.

[0339] Examples of Protein Kinase C ligand moieties which may be used in the compounds of the present EXAMPLES

[0340] The bifunctional compounds [Protein Kinase C ligand moiety]-[linker]-[ligase ligand moiety] of the present application may be synthesized by various general methods, as summarized below:

[0341] General Method A: Synthesis of Intermediate A

[0342] Step 1. To a suspension of NaH (60% dispersion in mineral oil, 11.5 g, 479 mmol) in THF (300 mL) at 0 °C under an argon atmosphere was added ethyl acetoacetate (41.5 g, 319 mmol, 40.7 mL) dropwise over 20 min. The solvent was removed under reduced pressure and toluene (1000 mL) was added followed by 2,4-dichloroquinazoline (31.8 g, 160 mmol) and the reaction mixture was stirred at 110 °C for 1 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give ethyl 2-(2-chloroquinazolin-4-yl)acetate (22 g, 88 mmol, 55% yield). Step 2. NH4OH (139 g, 3.97 mol) was added to a suspension of ethyl 2-(2-chloroquinazolin-4- yl)acetate (49.8 g, 198 mmol) in MeOH (500 mL) and the mixture was stirred at room temperature for 1.5 h and then it was heated to 50 °C for 12 h. The reaction mixture was cooled to room temperature and the volume was reduced by half under reduced pressure forming a heterogeneous mixture. Afterwards the mixture was cooled to 0 °C. The precipitate was collected by filtration and the solids were washed with water to give 2-(2-chloroquinazolin-4-yl)acetamide (21.6 g, 49% yield).

[0343] Step 3. A mixture of 2-(2-chloroquinazolin-4-yl)acetamide (1.1 eq.), A / -alkylpiperazine (1.0 eq.) and DIPEA (1.2 eq.) in DMA was heated to 60 °C for 3 h. Upon completion of the reaction, the mixture was cooled down to room temperature and poured into water, followed by extraction with EtOAc. The organic layer was thoroughly washed with water, brine, dried over anhydrous Na2SO4 and evaporated in vacuo to afford the key intermediate (detailed below).

[0344] Step 4. To a solution of indole (28.8 g, 246 mmol) in dry EtjO (200 mL) at 0 °C was added dropwise oxalyl chloride (93.7 g, 738 mmol). Then the ice bath was removed. After the reaction was complete (monitored by TLC), it was quenched with MeOH (10 mL, 250 mmol). The crude reaction mixture was filtrated and washed with cold Et2O. Then the solid was dried to give methyl 2-(lH-indol-3-yl)-2- oxoacetate (44.2 g, 216 mmol, 88% yield) which was used directly in the next step without additional purification.

[0345] Step 5. To a solution of selected key intermediate (1 eq.) and methyl 2-(lH-indol-3-yl)-2-oxoacetate (1.5 eq.) in a mixture of THF and DMA (5 / 1, 10 mL of the mixture per 1 mmol)* at 0 °C was added dropwise a 1 M solution of t-BuOK (4 eq.) in THF. The mixture was allowed to warm up to room temperature and stirred overnight. Afterwards, the mixture was poured into water, which contains 5 eq. of AcOH. The mixture was extracted with EtOAc. The organic layer was washed with sodium bicarbonate, water, brine, dried over anhydrous NajSO4 and evaporated in vacuo to give the desired intermediate (Intermediate A) as detailed below.

[0346] Examples of Intermediate A which may be synthesized using General Method A include:

[0347] Example 1: 3-(2-(4-(3-Azidopropyl)piperazin-l-yl)quinazolin-4-yl)-4-(lH-indol-3-yl)-lH-pyrrole-2,5- dione

[0348]

[0349] Following General Method A Step 3 on 7.90 mmol scale delivered key intermediate 2-(2-(4-(3- azidopropyl)piperazin-l-yl)quinazolin-4-yl)acetamide (2.1 g, 5.92 mmol, 75% yield) which was used directly in Step 5 to deliver desired intermediate (1.1 g, 2.2 mmol, 37% yield) as a red solid. LC / MS (ESI) m / z: 507.8 [M+l]+; M NMR (500 MHz, DMSO-dg) 6 12.01 (s, 1H), 11.26 (s, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.71 - 7.68 (m, 1H), 7.65 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.09 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.01 (ddd, J = 8.1, 7.2, 1.0 Hz, 1H), 6.63 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 6.34 (d, J = 8.1 Hz, 1H), 3.69 (br s, 4H), 3.36 (t, J = 6.7 Hz, 2H), 2.29 (t, J = 7.0 Hz, 2H), 2.21 (br s, 4H), 1.68 (p, J = 6.8 Hz, 2H).

[0350] Example 2: 3-(2-(4-(5-Azidopentyl)piperazin-l-yl)quinazolin-4-yl)-4-(lH-indol-3-yl)-lH-pyrrole-2.5- dione

[0351] Following General Method A Step 3 on 13.70 mmol scale delivered key intermediate 2-(2-(4-(5- azidopentyl)piperazin-l-yl)quinazolin-4-yl)acetamide (3.6 g, 9.86 mmol, 72% yield) which was used in Step 5 starting with 9.3 mmol scale to deliver desired intermediate (1.0 g, 2.32 mmol, 37% yield) as a red solid. LC / MS (ESI) m / z: 535.8 [M+l]+;XH NMR (500 MHz, DMSO-dg) 6 12.01 (s, 1H), 11.26 (s, 1H), 8.12 (d, J = 3.0 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.53 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.04 - 6.96 (m, 1H), 6.69 - 6.58 (m, 1H), 6.35 (d, J = 8.1 Hz, 1H), 3.68 (br s, 4H), 3.33 (d, J = 6.9 Hz, 2H), 2.21 (br s, 5H), 1.61 - 1.50 (m, 2H), 1.43 (s, 2H), 1.33 (d, J = 6.9 Hz, 2H). Example 3: 3-(2-(4-(2-(4-Azidobutoxy)ethyl)piperazin-l-yl)quinazolin-4-yl)-4-(lH-indol-3-yl)-lH- pyrrole-2,5-dione

[0352] Following General Method A, Step 3 on 33.90 mmol scale delivered key intermediate 2-(2-(4-(2-(4- azidobutoxy)ethyl)-piperazin-l-yl)quinazolin-4-yl)acetamide (7.6 g, 18.31 mmol, 54% yield) which was used in Step 5 starting with 12.4 mmol scale and DMA (5 mL per 1 mmol) as a solvent to deliver desired intermediate (1.2 g, 2.11 mmol, 17% yield) as a red solid. LC / MS (ESI) m / z: 566.4 [M+l]+;XH NMR (500 MHz, DMSO-de) 6 12.01 (s, 1H), 11.26 (s, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.71 - 7.61 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.11 - 7.04 (m, 1H), 7.04 - 6.97 (m, 1H), 6.66 - 6.60 (m, 1H), 6.35 (d, J = 8.1 Hz, 1H), 3.67 (br s, 4H), 3.46 (t, J = 5.9 Hz, 2H), 3.39 (t, J = 5.9 Hz, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.43 (t, J = 5.8 Hz, 2H), 2.29 (br s, 4H), 1.61 - 1.49 (m, 4H).

[0353] General Method B: Synthesis of Intermediate B from Intermediate A where R =

[0354] (CH2)mO(CH2)nN3

[0355] The azide - Intemediate A - (1.0 eq) was dissolved in THF (0.05 M, 10 vol) and H2O (1 vol). Subsequently, the reaction mixture was purged by Ar for 10 min, and triphenylphosphine (2.0 eq) was added and the mixture was stirring at room temperature for 20 h. After the reaction was completed (monitored by LCMS), solvents were evaporated to dryness and the residue was purified by reverse-phase flash chromatography using gradient flow of HjO / ACN as an eluent with 0.1% formic acid as an additive to give the desired amine (Intermediate B).

[0356] Examples of Intermediate B which may be synthesized using General Method B include:

[0357] Example 4: 3-(2-(4-(3-Aminopropyl)piperazin-l-yl)quiriazolin-4-yl)-4-(lH-indol-3-yl)-lH -pyrrole-

[0358] 2,5-dione

[0359] Following General Method B on 0.059 mmol scale delivered the desired intermediate (17 mg, 0.036 mmol, 61% yield). LC / MS (ESI) m / z: 482.2 [M+l]+;1H NMR (500 MHz, DMSO-dg) 8 8.34 (s, 2H), 8.13 (s, 1H), 7.72 - 7.62 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.09 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.01 (ddd, J = 8.1, 6.8, 1.0 Hz, 1H), 6.62 (ddd, J = 8.1, 6.9, 0.9 Hz, 1H), 6.35 (d, J = 8.1 Hz, 1H), 3.71 (s, 4H), 2.81 (t, J = 7.2 Hz, 2H), 2.31 (t, J = 6.6 Hz, 2H), 2.23 (s, 4H), 1.67 (p, J = 6.8 Hz, 2H).

[0360] Example 5: 3-(2-(4-(2-(4-Aminobutoxy)ethyl)piperazin-l-yl)quinazolin-4-yl)-4-(lH-indol-3-yl)-lH- pyrrole-2,5-dione

[0361] Following General Method B on 0.530 mmol scale delivered the desired intermediate (270 mg, 0.500 mmol, 94% yield). LC / MS (ESI) m / z\ 540.1 [M+l]+;XH NMR (500 MHz, DMSO-d6): 6 8.32 (s, 2H), 8.13 (s, 1H), 7.72 - 7.61 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.08 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.04 - 6.96 (m, 1H), 6.66 - 6.59 (m, 1H), 6.35 (d, J = 8.1 Hz, 1H), 3.69 (s, 4H), 3.48 (s, 2H), 3.38 (s, 2H), 2.77 (t, J = 7.1 Hz, 2H), 2.43 (t, J = 5.8 Hz, 2H), 2.30 (s, 4H), 1.62 - 1.50 (m, 4H).

[0362] General Method C: Synthesis of [Protein kinase C ligand moiety]-[linker]-[ligase ligand moiety] from Intermediate A where R = (CH?)

[0363] The azide - Intermediate A - (1.0 eq) was dissolved in THF (0.04 M) and alkyne (1.3 eq) was added. Reaction mixture was purged with argon and Cui (1.0 eq) was added. The reaction mixture was stirred under argon and monitored by LCMS. After completion of the reaction, the mixture was diluted with THF and filtered via 0.2 pm PTFE syringe filter. The filtrate was loaded directly on prepTLC (1000 pm, 10% MeOH in DCM) for purification to isolate the desired product as a red solid. Examples of [Protein kinase C ligand moiety]-[linker]-[ligase ligand moiety] which may be synthesized using General Method C include:

[0364] Example 6: 2-(2,6-Dioxopiperidin-3-yl)-4-[({l-(3-(4-{4-[4-(lH-indol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-

[0365] Pyrrol-3-yl1quinazolin-2-yl}piperazin-l-yl)propyll-lH-l,2,3-triazol-4-yl}methyl)aminol-2,3-dihvdro- lH-isoindole-l,3-dione (200)

[0366] Following General Method C on 0.039 mmol scale delivered claimed compound 200 (20.7 mg, 0.025 mmol, 64% yield). LC / MS (ESI) m / z: 819.0 [M+l]+;XH NMR (500 MHz, DMSO-cfe) 6 12.00 (s, 1H), 11.26 (s, 1H), 11.08 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.71 - 7.67 (m, 1H), 7.65 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.56 (dd, J = 8.4, 7.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.09 (ddd, J = 8.1, 5.6, 1.1 Hz, 2H), 7.04 (d, J = 7.0 Hz, 1H), 7.01 - 6.94 (m, 1H), 6.65 - 6.57 (m, 1H), 6.33 (d, J = 8.1 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.60 (d, J = 6.1 Hz, 2H), 4.35 (t, J = 6.9 Hz, 2H), 3.66 (s, 4H), 2.86 (ddd, J = 17.3, 14.0, 5.4 Hz, 1H), 2.60 - 2.53 (m, 2H), 2.14 (t, J = 6.7 Hz, 6H), 2.04 - 1.96 (m, 1H), 1.93 (dd, 7 = 13.7, 6.8 Hz, 2H).

[0367] Example 7: 2-(2,6-Dioxopiperidin-3-yl)-4-[(2-{l-f3-(4-{4-r4-(lH-indol-3-yl)-2,S-dioxo-2,5-dihvdro- lH-pyrrol-3-yl1quinazolin-2-yl}piperazin-l-yl)propyl1-lH-l,2,3-triazol-4-yl}ethyl)aminol-2,3- dihydro-lH-isoindole-1, 3-dione (201)

[0368]

[0369] Following General Method C on 0.039 mmol scale delivered claimed compound 201 (25.2 mg, 0.030 mmol, 77% yield). LC / MS (ESI) m / z: 833.6 [ M+l]+;JH NMR (500 MHz, DMSO-c / 6) 6 12.00 (d, J = 2.5 Hz, 1H), 11.26 (s, 1H), 11.09 (s, 1H), 8.12 (d, J = 3.0 Hz, 1H), 7.94 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.65 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.57 (dd, J = 8.4, 7.2 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.14 - 7.05 (m, 2H), 7.02 (d, J = 7.0 Hz, 1H), 7.01 - 6.95 (m, 1H), 6.70 (t, J = 6.0 Hz, 1H), 6.64 - 6.58 (m, 1H), 6.34 (d, J = 8.2 Hz, 1H), 5.04 (dd, J = 12.7, 5.4 Hz, 1H), 4.34 (t, J = 6.9 Hz, 2H), 3.68 (br s, 4H), 3.60 (dd, J = 13.2, 6.8 Hz, 3H), 2.95 (t, J = 7.0 Hz, 2H), 2.87 (ddd, J = 16.7, 13.8, 6.3 Hz, 1H), 2.60 - 2.54 (m, 1H), 2.18 (t, J = 6.7 Hz, 6H), 2.06 - 1.97 (m, 1H), 1.97 - 1.87 (m, 2H).

[0370] Example 8: 2-(2,6-Dioxopiperidin-3-yl)-4-({2-[2-(2-{l-r3-(4-{444-(lH-indol-3-yl)-2,5-dioxo-2,5- dihvdro-lH-pyrrol-3-yl1quinazolin-2-yl}piperazin-l-yl)propyll-lH-l,2,3-triazol-4- yl}ethoxy)ethoxy]ethyl}amino)-2,3-dihydro-lHisoindole-l,3-dione (202)

[0371] Following General Method C on 0.039 mmol scale delivered claimed compound 202 (19.6 mg, 0.021 mmol, 54% yield). LC / MS (ESI) m / z: 920.8 [M+l]+;XH NMR (500 MHz, DMSO-c / 6) 6 12.00 (d, J = 2.7 Hz, 1H), 11.26 (s, 1H), 11.08 (s, 1H), 8.12 (d,J = 3.1 Hz, 1H), 7.83 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.65 (ddd, = 8.4, 6.9, 1.4 Hz, 1H), 7.56 (dd, J = 8.4, 7.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.09 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H), 7.01 - 6.9S (m, 1H), 6.61 (dt, J = 11.6, 3.2 Hz, 2H), 6.33 (d, J = 8.1 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.31 (t, J = 7.0 Hz, 2H), 3.68 (br s, 3H), 3.65 - 3.59 (m, 5H), 3.59 - 3.50 (m, 4H), 3.45 (q, J = 5.5 Hz, 2H), 2.92 - 2.80 (m, 3H), 2.61 - 2.52 (m, 3H), 2.17 (t, J = 6.7 Hz, 5H), 2.05 - 1.96 (m, 1H), 1.92 (p, J = 6.9 Hz, 2H).

[0372] Example 9: 2-(2,6-Dioxopiperidin-3-yl)-4-r({l-r5-(4-{4-(4-(lH-indol-3-yl)-2,5-dioxo-2.5-dih'vdro-lH- pyrrol-3-yll quinazolin-2-yl}piperazin-l-yl)pentyll-lH-l,2,3-triazol-4-yl}methyl)aminol-2,3-dihydro-lH- isoindole-l,3-dione (203)

[0373] Following General Method C on 0.037 mmol scale delivered claimed compound 203 (18.0 mg, 0.021 mmol, 57% yield). LC / MS (ESI) m / z: 847.3 [M+l]+;JH NMR (500 MHz, DMSO-d6) 6 12.01 (s, 1H), 11.27 (s, 1H), 11.08 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.75 - 7.62 (m, 2H), 7.56 (dd, J = 8.5, 7.1 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.10 - 7.03 (m, 2H), 7.00 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.65 - 6.56 (m, 1H), 6.38 - 6.29 (m, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.59 (d, J = 6.1 Hz, 2H), 4.32 (t, J = 6.9 Hz, 2H), 3.75 - 3.55 (m, 3H), 2.94 - 2.79 (m, 1H), 2.63 - 2.54 (m, 2H), 2.27 - 2.05 (m, 4H), 2.09 - 1.95 (m, 1H), 1.89 - 1.75 (m, 2H), 1.71 - 1.51 (m, 1H), 1.50 - 1.34 (m, 2H), 1.31 - 1.14 (m, 5H).

[0374] Example 10: 2-(2.6-Dioxopiperidin-3-yl)-4-((2-{l-r5-(4-{4-r4-(lH-indol-3-yl)-2,5-dioxo-2,5-dihvdro- lH-pyrrol-3-yllquinazolin-2-yl}piperazin-l-yl)pentyl]-lH-l,2,3-triazol-4-yl}ethyl)aminol-2,3- dihydro-lH-isoindole-l,3-dione (204)

[0375]

[0376] Following General Method C on 0.037 mmol scale delivered claimed compound 204 (20.2 mg, 0.0.023 mmol, 63% yield). LC / MS (ESI) m / z: 861.7 [M+l]+;XH NMR (500 MHz, DMSO-d6) 8 12.00 (s, 1 H), 11.26 (s, 1H), 11.10 (s, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.94 (s, 1H), 7.71 - 7.67 (m, 1H), 7.65 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.56 (dd, J = 8.4, 7.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.13 - 7.06 (m, 2H), 7.05 -6.98 (m, 2H), 6.69 (t, J = 6.0 Hz, 1H), 6.66 - 6.59 (m, 1H), 6.35 (d, J = 8.2 Hz, 1H), 5.04 (dd, J = 12.8, 5.5 Hz, 1H), 4.30 (t, J = 7.0 Hz, 2H), 3.66 (br s, 4H), 3.59 (dd, J = 13.2, 6.8 Hz, 2H), 2.93 (dd, J = 12.9, 5.9 Hz, 2H), 2.91 - 2.81 (m, 1H), 2.62 - 2.54 (m, 1H), 2.24 - 2.11 (m, 5H), 2.06 - 1.96 (m, 1H), 1.83 - 1.73 (m, 2H), 1.41 (dt, J = 14.7, 7.4 Hz, 2H), 1.25 - 1.17 (m, 4H).

[0377] Example 11: 4-r(2-{l-(5-(4-{4-[4-(lH-lndol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yllquinazolin-2- yl}piperazin-l-yl)pentyll-lH-l,2,3-triazol-4-yl}ethyl)aminol-2-(l-methyl-2,6-dioxopiperidin-3-yl)-

[0378] 2, 3-dihydro-lH-isoindole-l, 3-dione (205)

[0379] Following General Method C on 0.058 mmol scale delivered claimed compound 205 (37.0 mg, 0.043 mmol, 74% yield). LC / MS (ESI) m / z: 875.1 [M+l]+;rH NMR (500 MHz, DMSO-d6): 6 8.11 (s, 1H), 7.94 (s, 1H), 7.69 - 7.62 (m, 2H), 7.57 (dd, J = 8.4, 7.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.13 - 7.05 (m, 2H), 7.05 - 6.97 (m, 2H), 6.70 (t, J = 6.0 Hz, 1H), 6.65 - 6.59 (m, 1H), 6.36 (d, J = 8.1 Hz, 1H), 5.11 (dd, J = 13.0, 5.4 Hz, 1H), 4.30 (t, J = 7.0 Hz, 2H), 3.66 (br s, 2H), 3.59 (dd, J = 13.2, 6.8 Hz, 2H), 3.01 (s, 3H), 2.98 - 2.90 (m, 3H), 2.75 (ddd, J = 17.1, 4.2, 2.6 Hz, 1H), 2.59 - 2.51 (m, 1H), 2.23 - 2.13 (m, 5H), 2.06 - 1.92 (m, 2H), 1.83 - 1.74 (m, 2H), 1.41 (dt, J = 14.7, 7.5 Hz, 2H), 1.32 - 1.17 (m, 6H). Example 12: 5-((2-(l-(5-(4-(4-(4-(lH-lndol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)pentyl)-lH-l,2,3-triazol-4-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (206)

[0380] Following General Method C on 0.018 mmol scale delivered claimed compound 206 (10 mg, 0.012 mmol, 64% yield). LC / MS (ESI) m / z: 861.2 [M+l]+; M NMR (500 MHz, DMSO-cfc): 6 8.14 (s, 1H), 7.95 (s, 1H), 7.76 - 7.62 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 5.7 Hz, 1H), 7.15 - 7.06 (m, 1H), 7.06 - 6.94 (m, 2H), 6.89 (dd, J = 8.4, 2.1 Hz, 1H), 6.64 (dd, J = 11.6, 4.5 Hz, 1H), 6.37 (d, J = 8.1 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.32 (t, J = 7.0 Hz, 2H), 3.69 (br s, 3H), 3.49 (dd, J = 12.9, 7.1 Hz, 2H), 3.00 - 2.83 (m, 3H), 2.63 - 2.54 (m, 2H), 2.30 - 2.17 (m, 5H), 2.03 - 1.98 (m, 2H), 1.86 - 1.77 (m, 2H), 1.46 - 1.41 (m, 2H), 1.25 - 1.19 (m, 6H).

[0381] Example 13: 4-((3-(l-(5-(4-(4-(4-(lH-lndol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)pentyl)-lH-l,2,3-triazol-4-yl)propyl)amino)-2-(2,6-dioxopiperidin-3- vDisoindoline-l, 3-dione (210) s, 3H), 3.36 (dd, J = 13.7, 6.7 Hz, 4H), 2.87 (ddd, J = 16.7, 13.7, 5.4 Hz, 1H), 2.69 (t, J = 7.5 Hz, 2H), 2.62 - 2.51 (m, 2H), 2.23 - 2.14 (m, 5H), 2.07 - 1.94 (m, 2H), 1.93 - 1.86 (m, 2H), 1.84 - 1.77 (m, 2H), 1.42 (dt, J = 14.7, 7.5 Hz, 2H), 1.36 - 1.14 (m, 4H).

[0382] Example 14: 4-((2-((l-(5-(4-(4-(4-(lH-lndol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)pentyl)-lH-l,2,3-triazol-4-yl)methoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3- vDisoindoline-l, 3-dione (211)

[0383] Following General Method C on 0.037 mmol scale delivered claimed compound 211 (19.0 mg, 0.021 mmol, 57% yield). LC / MS (ESI) m / z: 890.5 [M+l]+;XH NMR (500 MHz, DMSO-c / 6): 8 8.10 (s, 1H), 8.06 (s, 1H), 7.69 - 7.62 (m, 2H), 7.55 (dd, J = 8.4, 7.2 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.08 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 7.01 - 6.96 (m, 1H), 6.63 - 6.56 (m, 2H), 6.36 (d, J = 8.1 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.57 (s, 2H), 4.33 (t, J = 7.0 Hz, 2H), 3.73 - 3.59 (m, 5H), 3.47 (dd, J = 11.3, 5.5 Hz, 2H), 2.88 (ddd, J = 16.7, 13.7, 5.3 Hz, 1H), 2.57 (ddd, J = 21.2, 6.6, 3.2 Hz, 2H), 2.22 - 2.13 (m, 5H), 2.06 - 1.94 (m, 2H), 1.84 - 1.77 (m, 2H), 1.40 (dd, J = 14.7, 7.3 Hz, 2H), 1.28 - 1.18 (m, 6H).

[0384] Example 15: 2-(2,6-Dioxopiperidin-3-yl)-4-({2-(2-(2-{l-[5-(4-{4-r4-(lH-indol-3-yl)-2,5-dioxo-2,5- dihvdro-lH-pyrrol-3-yllquinazolin-2-yl}piperazin-l-yl)pentyll-lH-l,2,3-triazol-4- yl}ethoxy)ethoxylethyl}amino)-2,3-dihvdro-lH-isoindole-l,3-dione (212)

[0385]

[0386] Following General Method C on 0.037 mmol scale delivered claimed compound 212 (13.1 mg, 0.014 mmol, 37% yield). LC / MS (ESI) m / z: 948.8, 949.6 [M+l]+;TH NMR (500 MHz, DMSO-cfc) 6 12.00 (d, J = 2.4 Hz, 1H), 11.26 (s, 1H), 11.08 (s, 1H), 8.12 (d, J = 3.0 Hz, 1H), 7.82 (s, 1H), 7.68 (dd, J = 8.3, 0.7 Hz, 1H), 7.65 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.56 (dd, J = 8.4, 7.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.08 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H), 7.02 - 6.98 (m, 1H), 6.66 - 6.57 (m, 2H), 6.35 (d, J = 8.1 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.27 (t, J = 7.1 Hz, 2H), 3.66 (br s, 3H), 3.65 - 3.58 (m, 5H), 3.58 - 3.51 (m, 4H), 3.45 (q, J = 5.5 Hz, 2H), 2.93 - 2.79 (m, 3H), 2.60 - 2.52 (m, 2H), 2.27 - 2.07 (m, 6H), 2.07 - 1.95 (m, 1H), 1.84 - 1.72 (m, 2H), 1.40 (dt, J = 14.8, 7.6 Hz, 2H), 1.28 - 1.14 (m, 2H).

[0387] Example 16: 4-(l-(4-(2-(4-(4-(4-(lH-lndol-3-yl)-2,5-dioxo-2,5-dihydro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)ethoxy)butyl)-lH-l,2,3-triazol-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione (213)

[0388] Following General Method C on 0.035 mmol scale delivered claimed compound 213 (10.0 mg, 0.011 mmol, 32% yield). LC / MS (ESI) m / z: 847.9 [M+l]+;2H NMR (500 MHz, DMSO-d6): 6 11.99 (s, 1H), 11.25 (s, 1H), 11.14 (s, 1H), 8.98 (s, 1H), 8.60 (dd, J = 7.9, 1.0 Hz, 1H), 8.11 (s, 1H), 7.96 (t, J = 7.6 Hz, 1H), 7.90 (dd, J = 7.3, 1.0 Hz, 1H), 7.71 - 7.59 (m, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.11 - 7.04 (m, 1H), 7.04 - 6.95 (m, 1H), 6.62 (dd, J = 11.6, 4.5 Hz, 1H), 6.35 (d, J = 8.1 Hz, 1H), 5.19 (dd, J = 12.8, 5.4 Hz, 1H), 4.53 (t, J = 7.0 Hz, 2H), 3.65 (s, 4H), 3.46 (t, J = 5.9 Hz, 2H), 3.41 (t, J = 6.3 Hz, 2H), 2.96 - 2.83 (m, 1H), 2.60 - 2.51 (m, 2H), 2.42 (t, J = 5.8 Hz, 2H), 2.27 (s, 4H), 2.03 - 1.96 (m, 1H), 1.96

[0389] - 1.89 (m, 2H), 1.55 - 1.48 (m, 2H).

[0390] Example 17: 5-(l-(4-(2-(4-(4-(4-(lH-lndol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)ethoxy)butyl)-lH-l,2,3-triazol-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dlone (209)

[0391] Following General Method C on 0.044 mmol scale delivered claimed compound 209 (15.0 mg, 0.017 mmol, 39% yield). LC / MS (ESI) m / z: 849.2 [M+l]+; *H NMR (500 MHz, DMSO-d6): 6 11.99 (s, 1H), 11.26 (s, 1H), 11.13 (s, 1H), 8.95 (s, 1H), 8.40 - 8.29 (m, 2H), 8.11 (d, J = 2.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.73 - 7.58 (m, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.11 - 7.04 (m, 1H), 6.99 (dd, J = 11.2, 4.0 Hz, 1H), 6.62 (dd, J = 11.2, 4.1 Hz, 1H), 6.35 (d, J = 8.1 Hz, 1H), 5.17 (dd, J = 12.8, 5.4 Hz, 1H), 4.50 - 4.42 (m, 2H), 4.35 (dt, J = 10.2, 5.4 Hz, 1H), 3.66 (br s, 4H), 3.51 - 3.38 (m, 5H), 2.90 (ddd, J = 16.5, 13.6, 5.1 Hz, 1H), 2.66 - 2.52 (m, 2H), 2.28 (br s, 4H), 2.12 - 1.87 (m, 3H), 1.58 - 1.49 (m, 2H).

[0392] Example 18: 4-(((l-(4-(2-(4-(4-(4-(lH-lndol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)ethoxy)butyl)-lH-l,2,3-triazol-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione (207) Following General Method C on 0.035 mmol scale delivered claimed compound 207 (24.1 mg, 0.0.027 mmol, 78% yield). LC / MS (ESI) m / z: 877.2 [M+l]+;XH NMR (500 MHz, DMSO-d6) 8 12.00 (d, J = 2.7 Hz, 1H), 11.26 (s, 1H), 11.08 (s, 1H), 8.12 (d, J = 3.1 Hz, 1H), 8.01 (s, 1H), 7.70 - 7.62 (m, 2H), 7.58 - 7.50 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.10 - 6.97 (m, 4H), 6.65 - 6.60 (m, 1H), 6.35 (d, J = 8.1 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.34 (t, J = 7.0 Hz, 2H), 3.66 (s, 4H), 3.42 (t, J = 5.9 Hz, 2H), 3.35 (t, J = 6.3 Hz, 2H), 2.87 (ddd, J = 16.8, 13.8, 5.4 Hz, 1H), 2.61 - 2.52 (m, 2H), 2.40 (t, J = 5.7 Hz, 2H), 2.27 (s, 4H), 2.05 - 1.98 (m, 1H), 1.86 - 1.78 (m, 2H), 1.47 - 1.38 (m, 2H).

[0393] Example 19: 2-(2,6-Dioxopiperidin-3-yl)-4-{[2-(l-{4-(2-(4-{4-[4-(lH-indol-3-yl)-2,5-dioxo-2,5- dihvdro-lH-pyrrol-3-yllquinazolin-2-yl}piperazin-l-yl)ethoxylbutyl}-lH-l,2,3-triazol-4- yl)ethyl1amino}-2,3-dihydro-lH-isoindole-l, 3-dione (208)

[0394] Following General Method C on 0.035 mmol scale delivered claimed compound 208 (18.7 mg, 0.021 mmol, 60% yield). LC / MS (ESI) m / z: 891.2 [M+l]+;XH NMR (500 MHz, DMSO-dg) 6 12.00 (d, J = 2.6 Hz, 1H), 11.26 (s, 1H), 11.08 (s, 1H), 8.12 (d, J = 3.1 Hz, 1H), 7.94 - 7.92 (m, 1H), 7.70 - 7.62 (m, 2H), 7.58 - 7.49 (m, 2H), 7.37 (d, J = 8.1 Hz, 1H), 7.11 - 7.04 (m, 2H), 7.04 - 6.97 (m, 2H), 6.69 (t, J = 6.0 Hz, 1H), 6.65 - 6.59 (m, 1H), 6.35 (d, J = 8.2 Hz, 1H), 5.04 (dd, J = 12.8, 5.5 Hz, 1H), 4.32 (t, J = 7.0 Hz, 2H), 3.66 (s, 4H), 3.59 (dd, J = 13.2, 6.8 Hz, 2H), 3.44 (t, J = 5.8 Hz, 2H), 3.36 (t, J = 6.1 Hz, 2H), 2.93 (t, J = 7.0 Hz, 2H), 2.90 - 2.83 (m, 1H), 2.54 (s, 2H), 2.45 - 2.38 (m, 2H), 2.28 (s, 4H), 2.04 - 1.97 (m, 1H), 1.85 - 1.77 (m, 2H), 1.42 (dq, J = 11.9, 6.0 Hz, 2H).

[0395] Example 20: 2-(2,6-Dioxopiperidin-3-yl)-4-{f3-(l-{4-[2-(4-{4-r4-(lH-indol-3-yl)-2,5-dioxo-2,5- dihvdro-lH-pyrrol-3-yllquinazolin-2-yl}piperazin-l-yl)ethoxylbutvn-lH-l,2,3-triazol-4- yl)propyllamino}-2,3-dihvdro-lH-isoindole-l, 3-dione (214)

[0396]

[0397] Following General Method C on 0.035 mmol scale delivered claimed compound 214 (19.4 mg, 0.021 mmol, 61% yield). LC / MS (ESI) m / z: 905.3 [M+l]+;XH NMR (500 MHz, DMSO-cfe) 6 12.01 (s, 1H), 11.27 (s, 1H), 11.08 (s, 1H), 8.13 (d, J = 3.0 Hz, 1H), 7.90 (s, 1H), 7.66 (ddd, J = 9.6, 8.4, 4.8 Hz, 2H), 7.58 - 7.51 (m, 2H), 7.37 (d, J = 8.1 Hz, 1H), 7.08 (dd, J = 15.4, 8.4 Hz, 2H), 7.01 (dd, J = 8.2 Hz, 2H), 6.63 (t, J = 7.1 Hz, 2H), 6.36 (d, J = 8.3 Hz, 1H), 5.05 (dd, J = 12.7, 5.5 Hz, 1H), 4.32 (t, J = 7.0 Hz, 2H), 3.67 (s, 4H), 3.45 (t, J = 5.8 Hz, 2H), 3.36 (dt, J = 9.3, 6.4 Hz, 4H), 2.93 - 2.83 (m, 1H), 2.70 (t, J = 7.4 Hz, 2H), 2.59 (ddd, J = 11.1, 8.2, 5.4 Hz, 1H), 2.44 - 2.40 (m, 3H), 2.28 (s, 4H), 2.05 - 1.99 (m, 1H), 1.94 - 1.87 (m, 2H), 1.83 (dd, J = 14.8, 7.3 Hz, 2H), 1.48 - 1.42 (m, 2H).

[0398] Example 21: 2-(2,6-Dioxopiperidin-3-yl)-4-[(2-{2-r2-(l-{4-f2-(4-{444-(lH-indol-3-yl)-2,S-dioxo-2,5- dihvdro-lH-pyrrol-3-yllquinazolin-2-yl}piperazin-l-yl)ethoxylbutyl}-lH-l,2,3-triazol-4- yl)ethoxylethoxy}ethyl)-amino1-2,3-dihvdro-lH-isoindole-l, 3-dione (215)

[0399] Following General Method C on 0.035 mmol scale delivered claimed compound 215 (13.7 mg, 0.014 mmol, 40% yield). LC / MS (ESI) m / z: 979.2 [M+l]+;XH NMR (500 MHz, DMSO-d6) 6 11.98 (s, 1H), 11.26 (s, 1H), 8.12 (s, 1H), 7.83 (s, 1H), 7.71 - 7.62 (m, 2H), 7.60 - 7.51 (m, 2H), 7.37 (d, J = 8.1 Hz, 1H), 7.16 - 6.98 (m, 4H), 6.61 (dt, J = 14.3, 8.1 Hz, 2H), 6.37 (d, J = 8.2 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.34 - 4.28 (m, 2H), 3.63 (ddd, J = 17.0, 12.2, 7.2 Hz, 8H), 3.55 (td, J = 5.0, 2.6 Hz, 4H), 3.48 - 3.42 (m, 4H), 3.38 - 3.34 (m, 2H), 2.93 - 2.80 (m, 3H), 2.59 (s, 1H), 2.57 - 2.54 (m, 2H), 2.41 (t, J = 5.9 Hz, 2H), 2.27 (s, 4H), 2.05 - 1.98 (m, 1H), 1.81 (dd, J = 14.7, 7.3 Hz, 2H), 1.48 - 1.39 (m, 2H).

[0400] General Method D: Synthesis of [Protein kinase C ligand moietyl-[linkerl-[ligase ligand

[0401] X = CH2or C=O

[0402] Y = NH or O

[0403] Amine (1 eq.), carboxylic acid (1.2 eq.) and HATU (1.5 eq.) were dissolved in DMF (0.02 M) followed by addition of DIPEA (5 eq.). The reaction mixture was stirred at room temperature and monitored by LCMS. After completion of the reaction, the solvent was evaporated to dryness and the residue was loaded on prepTLC (1000 pm, 15% MeOH in DCM) and / or prepHPLC (H2O / ACN as an eluent with 0.1% formic acid as an additive) for purification to isolate the desired product as a red solid.

[0404] Examples of [Protein kinase C ligand moiety]-[linker]-[ligase ligand moiety] which may be synthesized using General Method D include: Example 22: N-(4-(2-(4-(4-(4-(lH-lndol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)ethoxy)butyl)-2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)acetamide formate (223)

[0405] Following General Method D on 0.037 mmol scale delivered claimed compound 223 (6.0 mg, 0.007 mmol, 19% yield). LC / MS (ESI) m / z: 839.5 [M+l]+; NMR (500 MHz, DMSO-d6): 8 12.01 (s, 1H), 11.26 (s, 1H), 10.99 (s, 1H), 8.15 (s, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.94 (t, J = 5.8 Hz, 1H), 7.73 - 7.60 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.08 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.04 - 6.93 (m, 2H), 6.68 - 6.59 (m, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.2 Hz, 1H), 6.04 (t, J = 6.0 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.24 (dd, J = 45.9, 17.0 Hz, 2H), 3.73 (d, J = 6.0 Hz, 2H), 3.67 (br s, 4H), 3.43 (t, J = 5.9 Hz, 2H), 3.12 - 3.05 (m, 2H), 2.97 - 2.86 (m, 1H), 2.66 - 2.51 (m, 2H), 2.40 (t, J = 5.9 Hz, 2H), 2.34 - 2.23 (m, 4H), 2.02 (dd, J = 9.0, 3.7 Hz, 1H), 1.41 (d, J = 13.0 Hz, 4H), 1.23 (s, 2H).

[0406] Example 23: N-(4-(2-(4-(4-(4-(lH-indol-3-yl)-2.5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)ethoxy)butyl)-2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)acetamide formate (226)

[0407] Following General Method D on 0.057 mmol scale of amine (1.2 eq.), carboxylic acid (1.0 eq.), and CDI (1.2 eq.) as a coupling agent delivered claimed compound 226 (7.0 mg, 0.008 mmol, 18% yield). LC / MS (ESI) m / z: 840.2 [M+ 1]+;JH NMR (500 MHz, DMSO) 6 12.00 (d, J = 2.4 Hz, 1H), 11.26 (s, 1H), 10.99 (s, 1H), 8.15 (s, 1H), 8.12 (d, J = 3.0 Hz, 1H), 8.07 (t, J = 5.8 Hz, 1H), 7.70 - 7.67 (m, 1H), 7.65 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 16.6, 7.7 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.08 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.01 (ddd, J = 8.1, 6.8, 0.9 Hz, 1H), 6.63 (ddd, J = 8.1, 6.8, 0.9 Hz, 1H), 6.35 (d, J = 8.2 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (dd, J = 14.8, 2.3 Hz, 2H), 4.40 (dd, J = 55.0, 17.5 Hz, 2H), 3.79 - 3.57 (m, 4H), 3.44 (t, J = 5.9 Hz, 2H), 3.39 - 3.32 (m, 2H), 3.16 - 3.10 (m, 2H), 2.92 (ddd, J = 17.5, 13.7, 5.4 Hz, 1H), 2.62 - 2.57 (m, 1H), 2.45 - 2.38 (m, 4H), 2.34 - 2.17 (m, 4H), 2.05 - 1.93 (m, 1H), 1.51 - 1.39 (m, 4H).

[0408] General Method E: Synthesis of Intermediates C and D

[0409] Intermediate C Step 1. To a solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.0 eq.) in DMI (0.67 M), Boc-protected aliphatic amine (1.0 eq.) and DIPEA (2.0 eq.) were added at 0 °C under argon. The reaction mixture was stirred at 0 °C for 1 h until completion. Then, the reaction mixture was poured into saturated aqueous NH4CI solution and the precipitation occurred, which was collected by filtration. The solids were washed twice with H2O and dried to give the desired 4-W-substituted 2- (methylthio)-pyrimidine-5-carbonitrile.

[0410] Step 2. To a solution of 4- / V-substituted 2-(methylthio)-pyrimidine-5-carbonitrile (1.0 eq.) in DCM (0.24 M) was added m-CPBA (50-55%, 1.0 eq.) and the mixture was stirred at at 0 °C for 3 h until completion. Then, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCCh solution. The organic phase was additionally washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was loaded on Celite® 545 for flash chromatography purification (silica, n-hexane / EtOAc gradient 50-100%) to give the desired 4-A / -substituted 2- (methylsulfinyl)pyrimidine-5-carbonitrile.

[0411] Step 3. To a solution of 4-A / -substituted 2-(methylsulfinyl)pyrimidine-5-carbonitrile (1.0 eq.) in DMF (0.32 M) was added benzylamine derivative or aniline derivative (2.0 eq.) and the reaction mixture was stirred at room temperature for 20 h until completion. Then, the reaction mixture was concentrated in vacuo. The residue was loaded on Celite® 545 for flash chromatography purification (silica, n-hexane / EtOAc gradient 10-60%) to give the desired 4-A / -substituted-2- / V-substituted pyrimidine-5-carbonitrile.

[0412] Step 4. Deprotection was performed as and when required using standard deprotection methods. For example, for A / -Boc deprotection a classical protocol using TFA / DCM or HCI / dioxane / MeOH was applied to deliver the desired deprotected 4- / V-substituted-2- / V-substituted pyrimidine-5- carbonitrile.

[0413] Step 5. Deprotected 4-A / -substituted-2- / V-substituted pyrimidine-5-carbonitrile (1.0 eq.) was dissolved in DCM (0.04 M); for some HCI salts a portion of DIPEA (equivalent equal to the salt composition) was added to improve solubility. Then, haloalkanal (2.0 eq.) was added under argon followed by NaBH(OAc)a (1.0-4.0 eq.) and the reaction mixture was stirred at room temperature for 18 h until completion. The reaction was quenched with a saturated aqueous NaHCCh solution, extracted with DCM, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in DMSO for reverse-phase flash chromatography using gradient flow of H2O / ACN as an eluent with 0.1% formic acid to give the desired A / -haloa Ikyl 4-W-substituted-2-A / -substituted pyrimidine-5- carbonitrile.

[0414] Step 6. To a solution of N-haloalkyl 4-A / -substituted-2- / V-substituted pyrimidine-5-carbonitrile (1.0 eq.) in DMF (0.11 M) was added sodium azide (3.0 eq.) and the reaction mixture was heated at 60 °C until completion. Then, the reaction mixture was cooled and H2O was added and the precipitation occurred, which was collected by filtration. The solids were washed with H2O, followed by diethyl ether, and dried to give the desired / V-azidoalkyl 4- / V-substituted-2- / V-substituted pyrimidine-5-carbonitrile.

[0415] Examples of Intermediates C and D which may be synthesized using General Method E include:

[0416] Example _ 24: _ 4-({f(lr,4r)-4-r(6-Bromohexyl)amino1cvclohexyl1methyl}amino)-2-(n2-

[0417] (trifluoromethoxy)-phenyllmethyl}amino)pyrimidine-5-carbonitrile

[0418] Following General Method E Step 5 on 0.617 mmol scale delivered the desired intermediate (137 mg, 0.218 mmol, 35% yield). LC / MS (ESI) m / z: 582.89, 584.87 [M+l]+;XH NMR (500 MHz, MeOD-c / 3) 58.11 (s, 1H), 7.41 - 7.29 (m, 4H), 4.65 (s, 2H), 3.47 (t, J = 6.6 Hz, 2H), 3.21 - 3.16 (m, 2H), 2.96 (t, J = 7.9 Hz, 2H), 2.02 (d, J = 11.6 Hz, 2H), 1.92 (d, J = 8.7 Hz, 2H), 1.91 - 1.84 (m, 3H), 1.74 - 1.61 (m, 4H), 1.58 - 1.49 (m, 2H), 1.44 (q, J = 7.7 Hz, 3H), 1.29 (s, 1H), 1.19 (d, J = 12.2 Hz, 2H), 0.87 (d, J = 13.6 Hz, 2H).

[0419] Example _ 25: _ 4-({f(lr,4r)-4-[(6-Azidohexyl)amino1cvclohexyllmethyl}amino)-2-({[2-

[0420] (trifluoromethoxy)phenyll-methyl}amino)pyrimidine-5-carbonitrile Following General Method E Step 6 on 0.213 mmol scale delivered desired intermediate (89.6 mg, 0.164 mmol, 77% yield). LC / MS (ESI) m / z: 546.1 [M+l]+;XH NMR (500 MHz, MeOD-d3) 6 8.11 (s, 1H), 7.45 - 7.17 (m, 4H), 4.65 (s, 2H), 3.19 (d, J = 6.8 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H), 2.84 (d, J = 12.9 Hz, 1H), 2.02 (d, J = 12.0 Hz, 2H), 1.79 - 1.57 (m, 6H), 1.45 (t, J = 3.7 Hz, 5H), 1.31 (d, J = 22.2 Hz, 2H), 1.18 (q, J = 12.3 Hz, 2H), 0.89 (dd, J = 16.5, 9.0 Hz, 2H).

[0421] General Method F: Synthesis of Intermediates E, F and G

[0422] Intermediate G Step 1. To a solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.0 eq.) in DMI (0.67 M), Boc-protected aliphatic amine (1.0 eq.) and DIPEA (2.0 eq.) were added at 0 °C under argon. The reaction mixture was stirred at 0 °C for 1 h until completion. Then, the reaction mixture was poured into saturated aqueous NH4CI solution and the precipitation occurred, which was collected by filtration. The solids were washed twice with H2O and dried to give the desired 4- / V-substituted 2- (methylthio)-pyrimidine-5-carbonitrile.

[0423] Step 2. To a solution of 4- / V-substituted 2-(methylthio)-pyrimidine-5-carbonitrile (1.0 eq.) in DCM (0.24 M) was added m-CPBA (50-55%, 1.0 eq.) and the mixture was stirred at at 0 °C for 3 h until completion. Then, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCCh solution. The organic phase was additionally washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was loaded on Celite® 545 for flash chromatography purification (silica, n-hexane / EtOAc gradient 50-100%) to give the desired 4-A / -substituted 2- (methylsulfinyl)pyrimidine-5-carbonitrile.

[0424] Step 3. To a solution of 4-A / -substituted 2-(methylsulfinyl)pyrimidine-5-carbonitrile (1.0 eq.) in DMF (0.32 M) was added benzylamine derivative or aniline derivative (2.0 eq.) and the reaction mixture was stirred at room temperature for 20 h until completion. Then, the reaction mixture was concentrated in vacuo. The residue was loaded on Celite® 545 for flash chromatography purification (silica, n-hexane / EtOAc gradient 10-60%) to give the desired 4-A / -substituted-2- / V-substituted pyrimidine-5-carbonitrile.

[0425] Step 4. Deprotection was performed as and when required using standard deprotection methods. For example, for A / -Boc deprotection a classical protocol using TFA / DCM or HCI / dioxane / MeOH was applied to deliver the desired deprotected 4- / V-substituted-2-A / -substituted pyrimidine-5- carbonitrile.

[0426] Step 5. Deprotected 4- / V-substituted-2- / V-substituted pyrimidine-5-carbonitrile (1.0 eq.) was dissolved in DCM (0.06 M); for some HCI salts a portion of DIPEA (equivalent equal to the salt composition) was added to improve solubility. Then, A / -Boc-aminoalkanal (1.1 eq.) was added under argon and the mixture was stirred for 30 min. The reaction mixture was cooled to 0 °C and NaBH(OAc)3 (3.0 eq.) was added and the reaction mixture was stirred at room temperature until completion. The reaction was quenched with H2O, extracted with DCM, washed with saturated aqueous NaHCCh and brine, dried over MgSCh, filtered and concentrated in vacuo. The res idue was purified by flash chromatography (silica, EtOAc / MeOH gradient 0-1%) to give the desire d / V-Boc- aminoalkyl 4- / V-substituted-2- / V-substituted pyrimidine-5-carbonitrile.

[0427] Step 6. To / V-Boc-aminoalkyl 4- / V-substituted-2- / V-substituted pyrimidine-5-carbonitrile (1.0 eq.) was added a solution of 4M HCI in dioxane (10 eq.) and the reaction mixture stirred at room tem perature for lh until completion. Then, the reaction mixture evaporated to dryness in vacuo to give th e desired A / -aminoalkyl 4-A / -substituted-2-A / -substituted pyrimidine-5-carbonitrile.

[0428] Examples of Intermediates E, F and G which may be synthesized using General Method F include:

[0429] Example 26: tert-Butyl N-(7-{f(lr,4r)-4-({[5-cyano-2-({[2-

[0430] (trifluoromethoxy)phenyllmethyl}amino)pyrimidin-4- yllamino}methyl)cvdohexyllamino}heptyl)carbamate

[0431] Following General Method F Step 5 on 0.748 mmol scale delivered desired intermediate (235 mg, 0.371 mmol, 50% yield). LC / MS (ESI) m / z: 634.1 [M+l]+;XH NMR (500 MHz, DMSO-cfe): 6 8.25 - 8.13 (m, 4H), 7.52 (t, J = 5.9 Hz, 1H), 7.38 (ddd, J = 15.1, 7.5, 3.5 Hz, 4H), 6.76 (s, 1H), 4.54 (dd, J = 24.8, 5.9 Hz, 2H), 3.04 (t, J = 6.2 Hz, 2H), 2.90 (dd, J = 13.2, 6.7 Hz, 4H), 2.77 (s, 1H), 1.91 (t, J = 5.3 Hz, 2H), 1.53 (t, J = 15.3 Hz, 4H), 1.37 (s, 12H), 1.27 (dd, J = 21.4, 9.6 Hz, 10H), 1.08 (dd, J = 22.3, 12.3 Hz, 2H), 0.70 (q, J = 12.4 Hz, 2H).

[0432] Example _ 27: _ 4-({[(lr,4r)-4-r(7-Aminoheptyl)amino]cvclohexyl]methyl}amino)-2-({[2-

[0433] (trifluoromethoxy)phenyl]-methyl}amino)pyrimidine-5-carbonitrile hydrochloride

[0434]

[0435] Following General Method F Step 6 on 0.027 mmol scale delivered the desired intermediate (15 mg, 0.027 mmol, 100% yield). LC / MS (ESI) m / z: 534.1 [M+l]+;XH NMR (500 MHz, DMSO) 6 8.94 ( br s, 2H), 8.80 - 8.70 (m, 1H), 8.43 (s, 1H), 8.37 - 8.28 (m, 1H), 7.98 (br s, 3H), 7.48 - 7.34 (m, 4H), 4.59 (d, J = 5.8 Hz, 2H), 3.08 (t, J = 6.2 Hz, 2H), 2.86 - 2.78 (m, 2H), 2.75 (dd, J = 13.8, 6.5 Hz, 3H), 1.96 (d, J = 10.2 Hz, 2H), 1.70 - 1.60 (m, 2H), 1.60 - 1.48 (m, 4H), 1.37 - 1.26 (m, 9H), 1.26 - 1.15 (m, 2H), 0.69 (dd, J = 24.3, 12.2 Hz, 2H).

[0436] Example 28: tert-Butyl N-(8-{[(lr,4r)-4-({[5-cyano-2-i

[0437] (trifluoromethoxy)phenyl1methyl}amino)pyrimidin-4- yllamino}methyl)cvclohexyl1amino}octyl)carbamate

[0438] Following General Method F Step 5 on 0.374 mmol scale delivered the desired intermediate (89 mg, 0.137 mmol, 37% yield). LC / MS (ESI) m / z: 648.3 [M+l]+; NMR (500 MHz, DMSO) 58.33 (s, 1H), 8.17 (s, 1H), 8.15 (t, J = 6.3 Hz, 1H), 7.49 (t, J = 6.0 Hz, 1H), 7.38 - 7.31 (m, 3H), 6.75 - 6.71 (m, 2H), 4.52 (d, J = 5.5 Hz, 2H), 4.34 - 4.25 (m, 1H), 3.39 - 3.33 (m, 2H), 3.02 (t, J = 6.4 Hz, 2H), 2.88 (q, J = 6.7 Hz, 3H), 1.79 (d, J = 12.3 Hz, 1H), 1.60 - 1.40 (m, 4H), 1.37 (s, 9H), 1.30 - 1.14 (m, 12H), 0.93 - 0.81 (m, 2H), 0.66 (q, J = 12.7 Hz, 2H).

[0439] Example 29: 4-({r(lr,4r)-4-[(8-Aminooctyl)amino]cvclohexyl]methyl}amino)-2-({[2-

[0440] (trifluoromethoxy)phenyll-methyl}amino)pyrimidine-5-carbonitrile; bis(trifluoroacetic acid)

[0441]

[0442] Following General Method F Step 6 on 0.137 mmol scale delivered the desired intermediate (91 mg, 0.117 mmol, 85% yield). LC / MS (ESI) m / z: 548.7 [M+l]+;XH NMR (500 MHz, DMSO-d6) 6 8.28 (s, 1H), 8.21 (d, J = 5.3 Hz, 1H), 8.20 (s, 1H), 7.63 (s, 5H), 7.56 (t, J = 5.8 Hz, 1H), 7.41 - 7.24 (m, 3H), 4.59 - 4.50 (m, 2H), 4.38 (t, J = 6.6 Hz, 2H), 4.09 (td, J = 6.6, 0.8 Hz, 1H), 3.37 (t, J = 6.5 Hz, 2H), 3.04 (t, J = 6.3 Hz, 2H), 2.86 (s, 1H), 2.82 - 2.69 (m, 6H), 1.93 - 1.85 (m, 2H), 1.68 (dt, J = 7.9, 6.3 Hz, 2H), 1.57 - 1.45 (m, 6H), 1.17 - 1.02 (m, 2H), 0.70 (q, J = 12.7 Hz, 2H).

[0443] Example 4-{((piperidin-4-vl)methvllamino}-2-({f2-

[0444] (trifluoromethoxy)phenyllmethyl}amino)pyrimidine-5-carbonitrile tri hydrochloride

[0445] Following General Method F Step 4 on 0.030 mmol scale delivered the desired intermediate (15.2 mg, 0.029 mmol, 99% yield). LC / MS (ESI) m / z: 407.2 [M+l]+;XH NMR (500 MHz, MeOD-d3) 6 8.44 (s, 1H), 7.53 - 7.34 (m, 4H), 4.79 (s, 2H), 3.42 - 3.35 (m, 3H), 2.78 (t, J = 12.8 Hz, 2H), 1.91 - 1.74 (m, 3H), 1.42 - 1.32 (m, 3H).

[0446] Example 31: 4-{[(4-aminoadamantan-l-vl)methyl]amino}-2-({[2-

[0447] (trifluoromethoxy)phenyllmethyl}amino)pyrimidine-5-carbonitrile Following General Method F Step 4 on 0.241 mmol scale delivered claimed compound (128.0 mg, 0.257 mmol, 100 % yield). LC / MS (ESI) m / z: 473.2 [M+l]+ XH NMR (500 MHz, CD3OD, 300 K) 68.44 (s, 1H), 8.12 (s, 1H), 7.43 - 7.23 (m, 4H), 4.66 (s, 2H), 3.20 - 3.16 (m, 1H), 3.11 (s, 2H), 2.12 - 1.80 (m, 5H), 1.54 - 1.46 (m, 3H), 1.42 (d, J = 18.0 Hz, 3H), 1.37 - 1.29 (m, 2H).

[0448] General Method G: Synthesis of [Protein kinase C ligand moietyl-[linker]-[ligase ligand moiety] from Intermediate D or heterocyclic derivative

[0449] Intermediate D

[0450] Cui

[0451] THF

[0452] Azide (1.0 eq.) was dissolved in THF (0.01 M) and alkyne (1.5 eq.) was added. Reaction mixture was purged with argon and Cui (1.0 eq.) was added. The reaction mixture was stirred under argon and monitored by LCMS. After completion of the reaction, the mixture was diluted with THF and filtered via 0.2 pm PTFE syringe filter. The filtrate was loaded directly on prepTLC (1000 pm, 5-10% MeOH in DCM) for purification to isolate the desired product. Examples of [Protein kinase C ligand moiety]-[linker]-[ligase ligand moiety] which may be synthesized using General Method G include:

[0453] Example 32: 4-((((lr,4r)-4-((6-(4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoi ndolin-4- yl)amino)methyl)-lH-l,2,3-triazol-l-yl)hexyl)amino)cvclohexyl)methyl)amino)-2-((2- (trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (216)

[0454] Following General Method G on 0.018 mmol scale delivered the claimed compound 216 (2 mg, 0.002 mmol, 9.6% yield). LC / MS (ESI) m / z: 858.2 [M+l]+;:H NMR (500 MHz, MeOD, 300K) 6 8.09 (s, 1H), 7.91 (s, 1H), 7.54 (dd, J = 8.5, 7.2 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.33 (dd, J = 7.6, 2.3 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.09 (dd, J = 7.8, 3.9 Hz, 2H), 5.37 - 5.32 (m, 1H), 5.06 (dd, J = 12.5, 5.4 Hz, 1H), 4.66 - 4.62 (m, 4H), 4.39 (t, J = 6.9 Hz, 2H), 3.50 (s, 2H), 2.90 - 2.67 (m, 5H), 2.22 - 2.07 (m, 4H), 2.07 - 1.99 (m, 3H), 1.94 - 1.90 (m, 2H), 1.69 - 1.56 (m, 5H), 1.56 - 1.47 (m, 4H).

[0455] Example 33: 4-({r(lr,4r)-4-({6-[4-(2-{f2-(2.6-dioxopiperidin-3-vn-l,3-dioxo-2,3-dihydro-lH-isoindol-

[0456] 4-yllamino}ethyl)-lH-l,2,3-triazol-l-yllhexyl}amino)cvcloHexyllmethyl}amino)-2-({(2-

[0457] (trifluoromethoxy)phenyllmethyl}amino)pyrimidine-5-carbonitrile (217)

[0458] Following General Method G on 0.027 mmol scale delivered the claimed compound 217 (1 mg, 0.001 mmol, 4.8% yield). LC / MS (ESI) m / z: 870.7 [M+l]+;XH NMR (500 MHz, MeOD, 300K) 6 8.11 (s, 1H), 7.78 (s, 1H), 7.53 (dd, J = 8.5, 7.2 Hz, 1H), 7.42 - 7.24 (m, 5H), 7.05 (dd, J = 7.9, 2.6 Hz, 2H), 5.04 (dd, J = 12.7, 5.5 Hz, 1H), 4.65 (s, 2H), 4.37 (t, J = 6.8 Hz, 2H), 3.66 (t, J = 6.6 Hz, 2H), 3.04 (t, J = 6.5 Hz, 2H), 2.98 - 2.80 (m, 4H), 2.78 - 2.67 (m, 2H), 2.13 - 2.07 (m, 1H), 2.06 - 1.97 (m, 2H), 1.92 - 1.83 (m, 2H), 1.76 - 1.66 (m, 2H), 1.63 - 1.56 (m, 2H), 1.49 - 1.34 (m, 4H), 1.36 - 1.24 (m, 8H).

[0459] General Method Hl: Synthesis of [Protein kinase C ligand moietyl-flinkerl-nigase ligand moiety] from Intermediate G

[0460] L = NH or CH-NH2X = CH2or C=O

[0461] Y = NH or O

[0462] R = benzyl derivative or heterocyclic derivative

[0463] Intermediate G

[0464] Step 1. Carboxylic acid (1.1 eq.) was dissolved in DMF (0.015 M). Subsequently, HATU (1.5 eq.) and DIPEA (10.0 eq.) were added and the mixture was stirred at room temperature for 15 min. Then, amine - Intermediate G - (1.0 eq.) was added and the mixture was stirred at room temperature for 24 h. After completion of the reaction (monitored by LC / MS) DMF and excess DIPEA were evaporated and the material was re-dissolved in DMSO. Product was purified by prepHPLC using gradient flow of HjO : ACN (with 0.1 % FA) as an eluent to give the desired product as a yellow solid. Step 2. Deprotection was performed as and when required using standard proced ure with

[0465] HCI / dioxane or TFA / DCM.

[0466] General Method H2 V = NH or O

[0467] R = benzyl derivative or heterocyclic derivative

[0468] To a solution of carboxylic acid (1.0 eq.) in DMSO (0.02 M) was added EDC (1.5 eq.), Oxyma Pure (1.5 eq.) and N-Methylmorpholine (1.5 eq.). The mixture was stirred at room temperature for 15 min, then amine - Intermediate G - (1.0 eq.) was added and the reaction mixture was stirred at room temperature for 24 h. After completion of the reaction (monitored by LC / MS), the mixture was filtered and the product was purified by prepHPLC using gradient flow of H2O : ACN (with 0.1 % FA) as an eluent to give the desired product as a yellow solid.

[0469] Examples of [Protein kinase C ligand moiety]-[linker]-[ligase ligand moiety] which may be synthesized using General Methods Hl and H2 include:

[0470] Example 34: N-(7-(((lr,4r)-4-(((5-cvano-2-((2-(trifluoromethoxy)benzyl)amino)pyrimidin-4- yl)amino)methyl)cvclohexyl)amino)heptvn-2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yllaminolacetamide (218)

[0471] Following General Method Hl Step 1 on 0.046 mmol scale delivered claimed compound 218 (1.6 mg, 0.002 mmol, 3.8% yield). LC / MS (ESI) m / z: 847.3 [M+l]+;XH NMR (500 MHz, MeOD, 300K) 6 8.55 (s, 1H), 8.11 (s, 1H), 7.58 (dd, J = 8.5, 7.2 Hz, 1H), 7.42 - 7.26 (m, 4H), 7.14 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 5.08 (dd, J = 12.6, 5.5 Hz, 1H), 4.65 (s, 2H), 3.99 (s, 2H), 3.22 (t, J = 7.0 Hz, 2H), 2.95 - 2.88 (m, 2H), 2.88 - 2.82 (m, 1H), 2.79 - 2.76 (m, 1H), 2.75 - 2.70 (m, 1H), 2.14 - 2.08 (m, 1H), 2.01 (d, J = 13.6 Hz, 2H), 1.70 (d, J = 12.6 Hz, 2H), 1.64 - 1.56 (m, 2H), 1.50 (dt, J = 14.2, 7.1 Hz, 2H), 1. 36 - 1.27 (m, 10H), 1.22 - 1.12 (m, 2H), 0.92 - 0.83 (m, 2H).

[0472] Example 35: N-(7-(((lr,4r)-4-(((5-cvano-2-((2-(trifluoromethoxy)benzyl)amino)pyrimidin-4- yl)amino)methyl)cvclohexyl)amino)heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)acetamide (224)

[0473] Following General Method Hl Step 1 on 0.046 mmol scale delivered claimed compound 224 (4 mg, 0.005 mmol, 10.9% yield). LC / MS (ESI) m / z: 833.3 [M+l]+;XH NMR (500 MHz, MeOD, 300K) 6 8.11 (s, 1H), 7.41 - 7.29 (m, 5H), 7.17 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.17 (dd, J = 13.3, 5.2 Hz, 1H), 4.65 (s, 2H), 4.39 (dd, J = 17.0, 7.8 Hz, 2H), 3.88 (dd, J = 17.5, 2.7 Hz, 2H), 3.25 - 3.14 (m, 4H), 2.97 - 2.84 (m, 4H), 2.80 (ddd, J = 17.6, 4.5, 2.4 Hz, 1H), 2.49 (qd, J = 13.3, 4.7 Hz, 1H), 2.20 (tdd, J = 10.0, 6.3, 3.6 Hz, 1H), 2.06 - 2.00 (m, 2H), 1.77 - 1.67 (m, 2H), 1.62 - 1.54 (m, 2H), 1.45 (dd, J = 14.5, 7.1 Hz, 2H), 1.34 - 1.25 (m, 6H), 1.26 - 1.14 (m, 4H), 0.92 - 0.84 (m, 2H).

[0474] Example 36: N-(7-(((lr,4r)-4-(((5-cvano-2-((2-(trifluoromethoxy)benzyl)amino)pyrimidin-4- yl)amino)methyl)cvclohexyl)amino)heptyl)-5-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)amino)pentanamide (227) Following General Method Hl Step 1 on 0.046 mmol scale delivered claimed compound 227 (6 mg, 0.007 mmol, 14.2% yield). LC / MS (ESI) m / z: 875.3 [M+l]+;XH NMR (500 MHz, MeOD, 300K) 6 8.53 (s, 1H), 8.11 (s, 1H), 7.43 - 7.37 (m, 1H), 7.37 - 7.26 (m, 4H), 7.07 (d, J = 7.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.65 (s, 2H), 4.28 (dd, J = 17.1, 11.0 Hz, 2H), 3.27 - 3.22 (m, 2H), 3.21 - 3.17 (m, 1H), 3.15 (t, J = 7.1 Hz, 2H), 2.98 - 2.83 (m, 4H), 2.82 - 2.76 (m, 1H), 2.47 (qd, J = 13.4, 4.7 Hz, 1H), 2.24 (t, J = 7.1 Hz, 2H), 2.22 - 2.15 (m, 1H), 2.07 - 1.96 (m, 2H), 1.77 - 1.64 (m, 6H), 1.63 - 1.55 (m, 2H), 1.52 - 1.39 (m, 2H), 1.38 - 1.31 (m, 8H), 1.25 - 1.11 (m, 2H), 0.93 - 0.82 (m, 2H).

[0475] Example 37: 2-{f2-(2,6-dioxopiperidin-3-yl)-l,3-clioxo-2,3-dihvdro-lH-isoindol-4-yllamino}-N-(8- n(lr,4r)-4-((r5-cvano-2- (trifluoromethoxy)phenyllmethyl}amino)pyrimidin-4- yl1amino}methyl)cvclohexyl]amino)octyl)acetamide (219)

[0476] Following General Method H2 on 0.041 mmol scale delivered claimed compound 219 (4 mg, 0.004 mmol, 10% yield). LC / MS (ESI) m / z: 860.8 [M+l]+; *H NMR (500 MHz, DMSO-d6, 300 K): 6 11.10 (s, 1H), 8.28 (s, 1H), 8.22 - 8.12 (m, 2H), 8.06 (t, J = 5.7 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 5.8 Hz, 1H), 7.42 - 7.29 (m, 4H), 7.07 (d, J = 7.1 Hz, 1H), 6.94 (t, J = 5.6 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 5.07 (dd, J = 12.7, 5.5 Hz, 1H), 4.54 (dd, J = 22.9, 5.9 Hz, 2H), 3.91 (d, J = 5.6 Hz, 2H), 3.09 (dd, J = 12.8, 6.6 Hz, 2H), 3.02 (t, J = 6.3 Hz, 2H), 2.89 (ddd, J = 16.6, 13.5, 5.2 Hz, 1H), 2.70 - 2.63 (m, 2H), 2.63 - 2.53 (m, 2H), 2.08 - 1.97 (m, 2H), 1.85 - 1.73 (m, 2H), 1.52 - 1.38 (m, 6H), 1.27 - 1.23 (m, 10H), 0.99 - 0.87 (m, 2H), 0.74- 0.59 (m, 2H).

[0477] Example _ 38: 2- (2,6-dioxoplperidin-3-yl)-l-oxo-2,3-dihydro-lH-isoindol-4-vnamino}-N-(8-

[0478] H(lr,4r)-4-(n5-cvano-2-({[2-(trifluoromethoxy)phenyllmethyl}amino)pyrimidin-4- yllamino}methyl)cvclohexynamino}octyl)acetamide (225)

[0479] Following General Method H2 on 0.039 mmol scale delivered claimed compound 225 (3 mg, 0.004 mmol, 9.6% yield). LC / MS (ESI) m / z: 846.7 [M+l]+;XH NMR (500 MHz, CD3OD, 300 K): 8 8.49 (s, 1H), 8.06 (s, 1H), 7.37 - 7.21 (m, 5H), 7.11 (d, J= 7.0 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 5.12 (dd, J = 13.3, 5.2 Hz, 1H), 4.60 (s, 2H), 4.33 (dd, J = 16.7, 6.6 Hz, 2H), 3.82 (d, J = 3.2 Hz, 2H), 3.19 - 3.04 (m, 4H), 2.94 - 2.67 (m, 4H), 2.44 (qd, J = 13.3, 4.6 Hz, 1H), 2.18 - 2.03 (m, 1H), 2.00 - 1.94 (m, 2H), 1.72 - 1.61 (m, 2H), 1.59 - 1.51 (m, 2H), 1.43 - 1.37 (m, 2H), 1.34 - 1.19 (m, 10H), 1.19 - 1.06 (m, 2H), 0.87 - 0.80 (m, 2H).

[0480] Example 39: l-{f2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-lH-isoindol-4-yl]amino}-N-(8-

[0481] {[(lr,4r)-4-({f5-cvano-2- (trifluoromethoxy)phenyl]methyl}amino)pyrimidin-4- yl]amino)methyl)cvclohexyl]amino}octyl)-3,6,9,12,15,18-hexaoxahenicosan-21-amide (220) , , , , 7.51 (dd, J = 8.6, 7.1 Hz, 1H), 7.37 - 7.24 (m, 4H), 7.05 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 5.00 (dd, J = 12.4, 5.5 Hz, 1H), 4.60 (s, 2H), 3.80 (td, J = 5.7, 1.6 Hz, 1H), 3.69 - 3.64 (m, 6H), 3.62 - 3.60 (m, 4H), 3.60 - 3.51 (m, 25H), 3.51 - 3.44 (m, 5H), 3.12 (dd, J = 13.0, 6.0 Hz, 5H), 2.93 - 2.87 (m, 2H), 2.81 (ddd, J = 18.0, 14.2, 5.4 Hz, 2H), 2.73 - 2.61 (m, 2H), 2.37 (td, J = 6.1, 3.4 Hz, 3H), 2.07 (ddd, J = 15.5, 8.2, 4.4 Hz, 1H), 1.97 (d, J = 10.6 Hz, 2H), 1.66 (d, J = 10.4 Hz, 2H), 1.58 (s, 2H), 1.45 (dd, J= 12.6, 6.2 Hz, 4H), 1.14 (d, J = 12.6 Hz, 2H), 0.88 - 0.76 (m, 2H). General Method I

[0482] Step 1. Azide (1.1 eq.) and alkyne (1.0 eq.) were dissolved in THF (0.15 M). Then Copper(ll) Sulfate Pentahydrate, (+)-Sodium L-ascorbate and water (0.3 M) were added. Reaction was stirred at RT and monitored by LCMS. After 18 h reaction mixture was diluted with THF, and filtered through a syringe filter. The filtrate was concentrated in vacuo and purified on reverse phase chromatography (column C18, H2O / ACN) to give the desired triazole alcohol drvivaties

[0483] Step 2. Alcohol from the previous step (1.0 eq.) was dissolved in DCM (0.03 M) and cooled to 0°C. Subsequently, Dess-Martin Periodinane (1.1 eq.) was added and the reaction mixture was stirred for a further 24 h. The reaction was quenched with water, washed with NaHCOs and dried. The product was give desired aldehyde derivatives which was used for the next step without additional purification Step 3. Amine (1.0 eq.) and aldehyde (1.1 eq.) were dissolved in DCE (0.08 M) and the mixture was stirring for 30 min. Subsequently, the mixture was cooled to 0 °C and NaBH(OAc)3 (4.0 eq.) was added and the mixture was stirring for 20 h. The reaction mixture was quenched with water, was hed with NaHCOa and dried, evaporated. The product was purified by prepHPLC using gradient flow of H2O:ACN to give desired product.

[0484] Example 40: 4-({[4-({544-(2-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-lH-isoindol-4- yllamino}ethyl)-lH-l,2,3-triazol-l-yl1pentyl}amino)cvclohexynmethyl}amino)-2-({[2- (trifluoromethoxy)phenyllmethyl}amino)pyrimidine-5-carbonitrile (228)

[0485] Following General Method I on 0.013 mmol scale delivered claimed compound 228 (5.6 mg, 0.007 mmol, 55.4% yield). LC / MS (ESI) m / z: 857.5 [M+l]+;TH NMR (500 MHz, DMSO-d6, 300 K): 6 8.33 (s, 1H), 7.92 (s, 1H), 7.60 (dd, J = 8.4, 7.2 Hz, 1H), 7.42 - 7.30 (m, 5H, 7.13 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 5.06 (dd, J = 12.8, 5.5 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.54 (d, J = 6.1 Hz, 2H), 3.61 (dd, J = 13.1, 6.8 Hz, 3H), 3.04 (t, J = 6.3 Hz, 2H), 2.99 - 2.85 (m, 4H), 2.64 - 2.61 (m, 2H), 2.61 - 2.58 (m, 1H), 2.09 - 1.97 (m, 2H), 1.84 - 1.76 (m, 4H), 1.52 - 1.42 (m, 5H), 1.29 - 1.23 (m, J = 11.3 Hz, 9H).

[0486] Example 41: 4-({[4-({4-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yllamino}ethyl)-lH-l,2,3-triazol-l-yllbutyl}amino)adamantan-l-yllmethyl}amino)-2-({(2- (trifluoromethoxy)phenyl]methyl}amino)pyrimidine-5-carbonitrile) (229) Following General Method I Step 3 on a 0.063 mmol scale delivered the claimed compound 229 (9 mg, 0.010 mmol, 15.8 % yield). LC / MS (ESI) m / z: 895.3 [M+l]+;XH NMR (500 MHz, DMSO-d6, 300 K): 6 8.20 (s, 1H), 8.15 (t, J = 6.3 Hz, 1H), 7.96 (s, 1H), 7.60 (dd, J = 7.5, 1.5 Hz, 1H), 7.40 - 7.26 (m, 5H), 7.13 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 7.1 Hz, 1H), 6.73 (t, J = 6.1 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.34 (t, J = 7.1 Hz, 2H), 3.61 (q, J = 6.7 Hz, 2H), 2.95 (t, J = 6.8 Hz, 4H), 2.89 (ddd, J = 17.7, 13.7, 5.4 Hz, 1H), 2.64 - 2.57 (m, 1H), 2.57 - 2.54 (m, 1H), 2.48 - 2.43 (m, 1H ), 2.07 - 2.00 (m, 1H), 1.91 - 1.80 (m, 4H), 1.72 - 1.67 (m, 2H), 1.67 - 1.62 (m, 1H), 1.57 - 1.45 (m, 1H), 1.45 - 1.36 (m, 2H), 1.28 - 1.21 (m, 4H), 1.21 - 1.15 (m, 4H), 1.12 (d, J = 12.3 Hz, 2H

[0487] Example 42: 4-({14-({5-[4-(2- (2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yllamino}ethyl)-lH-l,2,3-triazol-l-yllpentyl}amino)adamantan-l-yllmethvnamino)-2-({(2- (trifluoromethoxy)phenyl1methyl}amino)pyrimidine-5-carbonitrile (230)

[0488] Following General Method I Step 3 on a 0.063 mmol scale delivered the claimed compound 230 (5 mg, 0.005 mmol, 8.6 % yield). LC / MS (ESI) m / z: 909.18 [M+l]+;XH NMR (500 MHz, DMSO, 300 K): 6 8.19 (s, 1H), 8.15 (t, J = 6.4 Hz, 1H), 7.94 (s, 1H), 7.58 (dd, J = 8.6, 7.0 Hz, 1H), 7.39 - 7.26 (m, 5H), 7.11 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.71 (t, J = 6.0 Hz, 1H), 5.04 (dd, J = 12.8, 5.5 Hz, 1H), 4.53 (d, J = 6.3 Hz, 2H), 4.31 (t, J = 7.0 Hz, 2H), 3.59 ( q, J = 6.8 Hz, 2H), 2.99 - 2.90 (m, 4H), 2.89 - 2.83 (m, 1H), 2.75 - 2.64 (m, 1H), 2.62 - 2.55 (m, 2H), 2.07 - 1.98 (m, 2H), 1.89 - 1.75 (m, 6H), 1.71 - 1.63 (m, 1H), 1.60 - 1.43 (m, 3H), 1.30 - 1.10 (m, 11H)

[0489] General Method J

[0490] Step 1. Amine (1.2 eq.) and HATU (1.5 eq.) were dissolved in DMF (0.018 M) and the mixture was stirred at room temperature for 15 min. Subsequently, DIPEA (5.0 eq.) and carboxylic acid (1.0 eq.) were added and the mixture was stirred at room temperature for 20 h. After the reaction was completed (monitored by LCMS) the material was purified by prepHPLC using gradient flow of ACN : H2O as an eluent to give desirable alcohol derivatives.

[0491] Step 2. Alcohol from the previous step (1.0 eq.) was dissolved in DCM (0.005 M) and cooled to 0°C. Subsequently, Dess-Martin Periodinane (1.25 eq.) was added and the reaction mixture was stirred for 1 h. The reaction was quenched with water, washed with NaHCOs then brine, dried and filtered by silica gel plug to give desirable aldehyde derivatives and was used for the next step without additional purification.

[0492] Step 3. Amine (1.0 eq.), aldehyde (1.0 eq.) and NaBH(OAc)a (2.0 eq.) were dissolved in DCM (0.006 M) and the mixture was stirring at RT for 20 h. After the reaction was stopped (monitored by LCMS), the solvent was evaporated, the material was dissolved in DMSO and was purified by prepHPLC using gradient flow of H2O : ACN as an eluent. Then, the product was repurified by prepTLC using DCM : MeOH in the ratio 90 : 10 as an eluent to give desirable product. Example 43: 8-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yllamino}-N-(2-

[0493] {l(lr,4r)-4- cvano-2-({[2-(trifluoromethoxy)phenyl1methyl)amino)pyrimidin-4- yllamino}methyl)cvclohexyl]amino}ethyl)octanamide (221)

[0494] Following General Method J on 0.047 mmol scale delivered the claimed compound 221 (4 mg, 0.004 mmol, 9.2% yield). LC / MS (ESI) m / z: 861.2 [M+l]+;XH NMR (500 MHz, methanol-cM, 300 K): 8 8.55 (s, 1H), 8.09 (s, 1H), 7.54 (dd, J = 8.5, 7.2 Hz, 1H), 7.33 (dt, J = 25.2, 7.5 Hz, 4H), 7.03 (dd, J = 7.8, 2.4 Hz, 2H), 5.05 (dd, J = 12.5, 5.5 Hz, 1H), 4.64 (s, 2H), 3.17 - 3.10 (m, 2H), 2.85 (ddd, J = 17.9, 14.2, 5.2 Hz, 1H), 2.81 - 2.65 (m, 4H), 2.25 - 2.17 (m, 2H), 2.14 - 2.06 (m, 1H), 1.85 (d, J = 10.9 Hz, 2H), 1.70 - 1.53 (m, 6H), 1.49 - 1.23 (m, 10H), 1.02 - 0.86 (m, 2H), 0.82 - 0.70 (m, 2H).

[0495] General Method X

[0496] Intermediate l-a (Y = C=O)

[0497] Intermediate l-b (Y = CH2)

[0498] Step la. Amine (1.0 eq.), l-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (1.0 eq.) and HATU (1.5 eq.) were dissolved in DMF (0.2 M). Then DIPEA (5.0 eq.) was added and the mixture was stirred at room temperature for 5 h. After completion of the reaction, the solvent was evaporated. The residue material was dissolved in DMSO and purified by reverse-phase flash chromatography (Column C18, H?O:MeCN + 0.1% FA). The desired product was used in Step 2 without additional purification. Step lb. To the solution of amine (1.0 eq.) in 1,2-dichloroethane (0.1 M) and MeOH (0.5 M) was added tert-butyl 4-formylpiperidine-l-carboxylate (1.1 eq.) and acetic acid (1.0 eq.). The mixture was stirred at room temperature for 0.5 h. Then NaBH(OAc)3 (6.0 eq.) was added and the reaction mixture was stirred at room temperature for 18 h until completion. The reaction was quenched with water, extracted with DCM, washed with saturated aqueous NaHCOa and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product, which was used directly in Step 2 without additional purification.

[0499] Step 2. To the solution of N-Boc compound (1.0 eq.) in 1,4-dioxane (0.2 M) was added 4 M HCI in dioxane (20.0 eq.). The reaction mixture was stirred at room temperature for 18 h, after which time full conversion was observed. The solvent was evaporated under reduced pressure to give the desired deprotected product typically used without further purification.

[0500] Method X4:

[0501] Step 1 .

[0502] Intermediate l-c

[0503] Intermediate l-d

[0504] Step 1. To the stirred solution of 5,6-difluorothalidomide (1.0 eq.) in DMSO (0.1 M) were added 1-

[0505] Boc-4-piperidin-4-yl-piperazine (for Intermediate l-c, 1.2 eq.) or tert-butyl 4-(piperazin-l- yl)piperidine-l-carboxylate (for Intermediate l-d, 1.2 eq.) followed by DIPEA (5.0 eq.) at room temperature under argon atmosphere and the reaction mixture was allowed to stir at 90°C for 16 h. Then reaction mixture was cooled to room temperature, diluted with EtOAc and washed by water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude material, which was triturated with diethyl ether to afford Boc- protected Intermediates l-c and l-d.

[0506] Step 2. Boc-deprotection was carried out analogically to General Method X Step 2.

[0507] General Method K

[0508] Step 1. Amino-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-lH-isoindole-l, 3-dione (1.0 eq.), 10-Bromodecanoic acid (1.0 eq.) and Pyridine (2.0 eq.) were solubilized in THF (0.2 M) and cooled to 0°C. Then solution of 1-Propanephosphonic anhydride 50% in THF, T3P (1.5 eq.) was added and the resulting mixture was stirred at 60°C for 24 h until completion. Then THF was evaporated, residue material was dissolved in EtOAc. The solution was washed with water, NaHCOs and brine. Organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the desired 10-bromo-N-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindolyl]decanamide.

[0509] Step 2. To a stirred solution of 3-(lH-indol-3-yl)-4-[2-(piperazin-l-yl)quinazolin-4-yl]-2,5-dihydro-lH- pyrrole-2, 5-dione (1.0 eq.) in dry DMF (0.2 M) was added DIPEA (3.0 eq.) followed by 10-bromo-N- [2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindolyl]decanamide (1.0 eq.) and the mixture was reacted at 70°C for 24 h. The mixture was concentrated under reduced pressure and was purified by reverse-phase flash chromatography (column C18, HzO:MeCN + 0.1% FA). In some cases obtained compound was needed additional purification by preparative TLC (1000 pm, 5-10% MeOH in DCM) to isolate the desired product as detailed below.

[0510] Example 44: N42-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-lH-isoindol-4-yl]-10-(4-{4-[4-(lH- indol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yllquinazolin-2-yl}piperazin-l-vDdecanamide (240)

[0511] Following General Method K on 0.140 mmol scale delivered the claimed compound 240 (40.9 mg, 0.038 mmol, 12.2% yield). LC / MS (ESI) m / z: 850.7 [M+H]+;XH NMR (500 MHz, DMSO, 300K) 6 12.00 (d, J = 3.1 Hz, 1H), 11.26 (s, 1H), 11.14 (s, 1H), 9.68 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 3.0 Hz, 1H), 7.82 (dd, J = 8.4, 7.4 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 7.00 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 6.62 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 5.14 (dd, J = 12.9, 5.4 Hz, 1H), 3.67 (br s, 4H), 2.94 - 2.83 (m, 1H), 2.60 - 2.55 (m, 1H), 2.55 - 2.52 (m, 1H), 2.47 - 2.42 (m, 2H), 2.20 (br s, 4H), 2.10 - 1.95 (m, 2H), 1.61 (q, J = 7.2 Hz, 2H), 1.39 (s, 2H), 1.28 - 1.21 (m, 12H).

[0512] Example 45: N-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-lH-isoindol-5-yll-10-(4-{4-(4-(lH- indol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yllquinazolin-2-yl}piperazin-l-yl)decanamide (247)

[0513] Following General Method K (without additional purification by preparative TLC) on 0.087 mmol scale delivered the claimed compound 247 (27.0 mg, 0.032 mmol, 36.6% yield). LC / MS (ESI) m / z: 850.4 [M+H]+;JH NMR (500 MHz, DMSO, 300K) 6 12.00 (d, J = 3.1 Hz, 1H), 11.26 (s, 1H), 11.10 (s, 1H), 10.52 (s, 1H), 8.25 (d, J = 1.8 Hz, 1H), 8.12 (d, J = 3.1 Hz, 1H), 7.90 (dd, J = 8.2, 1.9 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.52 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.08 (ddd, J = 8.2, 6.6, 1.2 Hz, 1H), 7.00 (ddd, J = 8.4, 6.9, 1.0 Hz, 1H), 6.63 (ddd, J = 8.4, 6.8, 0.9 Hz, 1H), 6.35 (d, J = 8.2 Hz, 1H), 5.11 (dd, J = 12.8, 5.5 Hz, 1H), 3.68 (br s, 4H), 2.93 - 2.83 (m, 1H), 2.63 - 2.52 (m, 2H), 2.39 (m, 2H), 2.20 (m, 4H), 2.08 - 1.99 (m, 1H), 1.62 (p, J = 7.0 Hz, 2H), 1.39 (t, J = 7.2 Hz, 2H), 1.34 - 1.22 (m, 12H).

[0514] Synthesis of Intermediate H and its derivative:

[0515] Step 1. To a solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.0 eq.) in DMI (0.67 M), tert-butyl N-[5-(aminomethyl)adamantan-2-yl]carbamate (1.0 eq.) and DIPEA (2.0 eq.) were added at 0°C under argon. The reaction mixture was stirred at 0°C for 1 h until completion. Then, the reaction mixture was poured into saturated aqueous NH4CI solution and the precipitation occurred, which was collected by filtration. The solids were washed twice with H2O and dried to give the desired tert-butyl N-[5-({[5-cyano-2-(methylsulfanyl)pyrimidin-4-yl]amino}methyl)adamantan-2-yl]carbamate).

[0516] Step 2. To a solution of tert-butyl N-[5-({[5-cyano-2-(methylsulfanyl)pyrimidin-4-yl]amino}- methyl)adamantan-2-yl]carbamate (1.0 eq.) in DCM (0.24 M) was added m-CPBA (50-55%, 1.0 eq.) and the mixture was stirred at 0°C for 3 h until completion. Then, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3solution. The organic phase was additionally washed with H2O and brine, dried over Na2$O4, filtrated and concentrated under reduced pressure. The residue was loaded on Celite® 545 and purified by flash chromatography (silica, n-hexane / EtOAc gradient 50-100%) to give the desired tert-butyl N-(5-{[(5-cyano-2-methanesulfinylpyrimidin-4- yl)amino)-methyl}adamantan-2-yl)carbamate. Step 3. To a solution of tert-butyl N-(5-{[(5-cyano-2-methanesulfinylpyrimidin-4-yl)amino]methyl}- adamantan-2-yl)carbamate (1.0 eq.) in DMF (0.32 M) was added 2-(trifluoromethoxy)benzylamine (2.0 eq.) and the reaction mixture was stirred at room temperature for 20 h until completion. Then, the reaction mixture was concentrated under reduced pressure. The residue was loaded on Celite® 545 and purified by flash chromatography (silica, n-hexane / EtOAc gradient 10-60%) to give the desired tert-butyl N-[5-({[5-cyano-2-({[2-(trifluoromethoxy)phenyl]methyl}amino)pyrimidin-4- yl]amino}methyl)adamantan-2-yl]carbamate.

[0517] Step 4. To a solution of tert-butyl N-[5-({[5-cyano-2-({[2-(trifluoromethoxy)phenyl]methyl}- amino)pyrimidin-4-yl]amino}methyl)adamantan-2-yl]carbamate (1.0 eq.) in MeOH (0.1 M) was added 4 M HCl solution in 1,4-dioxane (20 vol.) and the reaction mixture was stirred at room temperature for 20 h, after which time reaction mixture was concentrated under reduced pressure to give the desired 4-{[(4-aminoadamantan-l-yl)methyl]amino}-2-({[2- (trifluoromethoxy)phenyl]methyl}-amino)pyrimidine-5-carbonitrile.

[0518] Step 5. To the solution of 4-{[(4-aminoadamantan-l-yl)methyl]amino}-2-({[2- (trifluoromethoxy)phenyl]-methyl}amino)pyrimidine-5-carbonitrile (1.0 eq.) in DMF (0.1 M) was added DIPEA (6.0 eq.) and tert-butyl 2-bromoacetate (1.2 eq.). Reaction mixture was stirred at 80°C for 20 h, after which time reaction mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (C18, water+0.1% FA, MeCN+0.1% FA) to obtain desired tertbutyl 2-{[5-({[5-cyano-2-({[2-(trifluoromethoxy)phenyl]methyl}amino)pyrimidin-4- yl]amino}methyl)adamantan-2-yl]amino}acetate.

[0519] Step 6. Tert-butyl 2-{[5-({[5-cyano-2-({[2-(trifluoromethoxy)phenyl]methyl}amino)pyrimidin-4- yl]amino}methyl)adamantan-2-yl]amino}acetate (1.0 eq.) was dissolved in 4 M HCl in dioxane (20 vol.) and the reaction mixture was stirred at room temperature for 20 h. Then, the reaction mixture was concentrated under reduced pressure to give the desired 2-{[5-({[5-cyano-2-({[2- (trifluoromethoxy)phenyl]methyl}amino)pyrimidin-4-yl]amino}methyl)adamantan-2-yl]amino}acetic acid. General Method X2

[0520] Step 1. Tert-butyl amino ester (1.0 eq.) and 2-(2,6-dioxopiperidin-3-yl)fluoro-2,3-dihydro-lH- isoindole-1, 3-dione (1.0 eq.) were dissolved in dry DMSO (0.2 M). To the reaction mixture was added DIPEA (4.0 eq.) and was stirred at 90°C for 18 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (using gradient flow of H2O:MeCN + 0.1% FA) to give the desired product. Step 2. To a solution of protected carboxylic acid (1.0 eq.) in DCM (0.2 M) TFA (10.0 eq.) was added and the mixture was stirred at room temperature for 24 h. After this time full conversion was observed. The mixture was evaporated to dryness to give desired carboxylic acid which was used in the Step 3 without additional purification.

[0521] Step 3. To a solution of carboxylic acid (1.0 eq.), Intermediate H-a (1.05 eq.) and HATU (2.0 eq.) in dry DMF (0.2 M), DIPEA (3.0 eq.) and the mixture was stirred at room temperature for 4 h. The crude material was diluted with DCM and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Product was purified by preparative HPLC (using gradient flow of H2O:MeCN + 0.1% FA) to obtain the desired compound as detailed below.

[0522] Example 46: N-[5-({[5-cvano-2-(n2-(trifluoromethoxy)phenvnmethyl}amino)pyrimidin-4- yllamino}methyl)adamantan-2-yll-3-[2-(2-W2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-lH- isoindol-4-yl]amino}ethoxy)ethoxy1propanamide (252)

[0523] Following General Method X2 on 0.067 mmol scale delivered the claimed compound 252 (16.0 mg, 0.018 mmol, 26.4% yield). LC / MS (ESI) m / z: 888.35 [M+H]+;XH NMR (500 MHz, DMSO) 6 11.08 (s, 1H), 8.18 (s, 1H), 8.15 (t, J = 6.3 Hz, 1H), 7.57 (dd, J = 8.6, 7.1 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.36 - 7.26 (m, 5H), 7.13 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 5.8 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.52 (d, J = 6.2 Hz, 2H), 3.64 - 3.57 (m, 5H), 3.55 (dd, J = 6.1, 3.5 Hz, 2H), 3.50 (dd, J = 5.6, 3.2 Hz, 2H), 3.45 (q, J = 5.6 Hz, 2H), 2.95 (d, J = 6.4 Hz, 2H), 2.92 - 2.83 (m, 1H), 2.62 - 2.52 (m, 2H), 2.38 (d, J = 6.4 Hz, 2H), 2.06 - 1.98 (m, 1H), 1.80 (d, J = 12.1 Hz, 2H), 1.68 - 1.61 (m, 2H), 1.54 - 1.50 (m, 1H), 1.25 - 1.14 (m, 8H). Example 47: N-(5-({[5-cvano-2-({[2-{trifluoromethoxy)phenyllmethyl}amino)pyrirnidin-4- yllamino}methyl)adamantan-2-yll-l-{f2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihvdro-lH- isoindol-5-yl]amino}-3,6,9,12-tetraoxapentadecan-15-amide (237)

[0524] Following General Method X2 on 0.048 mmol scale delivered the claimed compound 237 (7.3 mg, 0.007 mmol, 15.7% yield). LC / MS (ESI) m / z: 976.30 [M+H]+; NMR (500 MHz, DMSO, 300K) 6 11.04 (s, 1H), 8.14 (t, J = 6.3 Hz, 1H), 7.56 (dd, J = 7.9, 3.1 Hz, 2H), 7.37 - 7.26 (m, 5H), 7.14 (t, J = 5.6 Hz, 1H), 7.00 (d, J = 2.1 Hz, 1H), 6.89 (dd, J = 8.4, 2.1 Hz, 1H), 5.02 (dd, J = 12.8, 5.4 Hz, 1H), 4.53 (d, J = 6.2 Hz, 2H), 3.61 - 3.57 (m, 4H), 3.56 - 3.50 (m, 4H), 3.48 (dt, J = 7.8, 1.2 Hz, 8H), 3.40 - 3.34 (m, 3H), 2.95 (d, J = 6.4 Hz, 2H), 2.93 - 2.82 (m, 1H), 2.60 - 2.57 (m, 1H), 2.56 - 2.53 (m, 1H), 2.38 (d, J = 6.4 Hz, 1H), 1.99 (ddd, J = 10.4, 5.6, 3.2 Hz, 1H), 1.81 (d, J = 12.0 Hz, 2H), 1.69 - 1.61 (m, 3H), 1.55 - 1.45 (m, 1H), 1.38 (t, J = 1.7 Hz, 1H), 1.24 - 1.17 (m, 8H).

[0525] Method X3: Synthesis of compound from Intermediate J and ligand with alternative exit vector

[0526] Step 1. To a solution of carboxylic acid (1.0 eq.), amine (1.0 eq.) and HATU (2.0 eq.) in dry DMF (0.2 M), DIPEA (3.0 eq.) was added and the mixture was stirred at room temperature for 4 h. The crude material was diluted with DCM and washed with brine. The organic layer was dried over NazSOn, filtered and concentrated under reduced pressure. Then residue material was purified by reverse- phase flash chromatography (using gradient flow of H?O:MeCN + 0.1% FA) to obtain the desired product as yellow solid (33.9% yield).

[0527] Step 2. For / V-Boc deprotection was using standard method with TFA (10.0 eq.) in DCM (0.2 M). The reaction mixture was stirred at room temperature for 24 h. After this time full conversion was observed, the solvent was evaporated and the product was purified by preparative HPLC (using gradient flow of HzO:MeCN+0.1% FA) to give final compound (detailed below).

[0528] Example 48: N-(2-(((4-((((ls,3R,4s,5S)-4-aminoadarnantan-l-yl)methyl)anriino)-5-cvanopyrimidin-2- yl)amino)methyl)phenyl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanamide (251)

[0529] Following General Method X3 on 0.022 mmol scale delivered the claimed compound 251 (16.0 mg, 0.019 mmol, 87.1% yield). LC / MS (ESI) m / z: 819.50 [M+H]+;XH NMR (500 MHz, DMSO) 6 8.20 (s, 1H), 8.16 (s, 1H), 7.60 - 7.53 (m, 2H), 7.46 (s, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.19 (td, J = 7.6, 1.6 Hz, 1H), 7.10 (td, J = 8.3, 7.9, 1.7 Hz, 2H), 7.03 (d, J = 7.1 Hz, 1H), 6.70 (s, 1H), 6.51 (t, J = 5.9 Hz, 1H), 5.00 (dd, J = 12.6, 5.5 Hz, 1H), 4.48 (d, J = 6.3 Hz, 2H), 3.77 (t, J = 6.3 Hz, 2H), 3.65 (t, J = 5.5 Hz, 2H), 3.60 (p, J = 2.0 Hz, 4H), 3.45 (q, J = 5.7 Hz, 2H), 3.13 (d, J = 6.3 Hz, 2H), 2.86 (d, J = 3.5 Hz, 1H), 2.60 (t, J = 6.4 Hz, 3H), 2.57 - 2.53 (m, 1H), 2.10- 2.01 (m, 1H), 1.97 (d, J = 12.7 Hz, 2H), 1.77 (s, 1H), 1.68 (s, 2H), 1.47 - 1.36 (m, 7H), 1.28 (d, J = 7.7 Hz, 5H). Method X

[0530] Step 1. To a stirred solution of Intermediate H-a (1.0 eq.) in dry DMF (0.2 M) was added DIPEA (3.0 eq.) followed by 2-Bromoethanol (1.0 eq.) and the mixture was stirred at 60°C for 24 h. After this time reaction mixture was concentrated under reduced pressure, then residue material was dissolved in DMSO and purified on reverse-phase flash chromatography (using gradient flow of HzO.MeCN + 0.1% FA) to give the desired product which was used directly in the Step 2.

[0531] Step 2. To a solution of 4-[({4-[(2-hydroxyethyl)amino]adamantan-l-yl}methyl)amino]-2-({[2- (trifluoromethoxy)phenyl]methyl}amino)pyrimidine-5-carbonitrile (1.0 eq.) in chloroform (0.1 M) was added thionyl chloride (6.0 eq.). The reaction mixture was stirred at room temperature for 7 h, after which time full conversion was observed. Reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (using gradient flow of 5-20% MeOH in DCM) to give the desired product.

[0532] Step 3. To the solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-[4-(piperidine-4-carbonyl)piperazin- l-yl]-2,3-dihydro-lH-isoindole-l, 3-dione (1.1 eq.) and 4-[({4-[(2-chloroethyl)amino]adamantan-l- yl}methyl)amino]-2-({[2-(trifluoromethoxy)phenyl]methyl}amino)pyrimidine-5-carbonitrile (1.0 eq.) in DMF (0.2 M) was added DIPEA (2.5 eq.) and potassium iodide (0.1 eq.) and the reaction mixture was stirred at 80°Cfor 20 h. Reaction mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (using gradient flow of HzO:MeCN + 0.1% FA). The product was needed additional purification on preparative HPLC (gradient flow of FhCkMeCN + 0.1% FA as an eluent) to isolate the final product as yellow solid (detailed below). Example 49: 4-{[(4-{r2-(4-{4-r2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxo-2,3-dihydro-lH- isoindol-5-yllpiperazine-l-carbonyl}piperidin-l-yl)ethyllamino}adamantan-l-yl)methyl]amino}-2- ({[2-(trlfluoromethoxy)phenyllmethyl}amino)pyrimidine-5-carbonitrile (262)

[0533] Following Method X on 0.019 mmol scale delivered the claimed compound 262 (5 mg, 0.005 mmol, 27.5% yield). LC / MS (ESI) m / z: 970.25 [M+H]+; 1H NMR (500 MHz, DMSO) 6 11.10 (s, 1H), 8.18 (s, 1H), 8.13 (t, J = 6.2 Hz, 1H), 7.76 (d, J = 11.3 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.36 - 7.26 (m, 5H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 4.54 (d, J = 6.4 Hz, 2H), 3.68 (s, 2H), 3.63 (s, 2H), 3.24 - 3.18 (m, 4H), 2.95 (d, J = 6.4 Hz, 2H), 2.91 - 2.84 (m, 4H), 2.63 - 2.55 (m, 1H), 2.52 (s, 2H), 2.44 - 2.40 (m, 2H), 2.09 - 1.97 (m, 3H), 1.83 (d, J = 12.5 Hz, 2H), 1.71 (s, 2H), 1.61 (q, J = 15.4, 11.0 Hz, 6H), 1.51 - 1.45 (m, 1H), 1.28 - 1.11 (m, 9H)

[0534] General Method Yl:

[0535] Step 1. To the mixture of Intermediate I (1.0 eq.) and tert-butyl 4-(2-chloroethyl)piperazine- carboxylate (1.2 eq.) in anhydrous DMF (0.05 M) KI (1.0 eq.) and DIPEA (6.0 eq.) were added. Reaction mixture was stirred at 100 °C for 2 h, after which time full conversion was observed. Reaction mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (C18, water+0.1% FA, MeCN+0.1% FA) to obtain pure tert-butyl 4-{2-[4-({4-[2-(2,6- dioxopiperidin-3-yl)-6-fluoro-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidin- l-yl]ethyl}piperazine-l-carboxylate).

[0536] Step 2. Tert-butyl 4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxo-2,3-dihydro-lH-isoindol- 5-yl]piperazin-l-yl}methyl)piperidin-l-yl]ethyl}piperazine-l-carboxylate (1.0 eq.) was dissolved in 4 M HCI solution in 1,4-dioxane (40 vol.) and the reaction mixture was stirred at room temperature for 20 h. Then, reaction mixture was concentrated under reduced pressure to obtain the desired deprotected compound.

[0537] Step 3. To the solution of amine (1.0 eq.) and 3-(2-chloroquinazolin-4-yl)-4-(lH-indol-3-yl)-2,5- dihydro-lH-pyrrole-2, 5-dione (2.0 eq.) in anhydrous DMF (0.1 M) was added DIPEA (8.0 eq.). Reaction mixture was stirred at 80°C for 18 h, after which time reaction mixture was concentrated under reduced pressure. Crude was purified by preparative HPLC (C18, water+0.1% FA, MeCN+0.1% FA) to obtain the desired product.

[0538] Example 50: 5-(4-((l-(2-(4-(4-(4-(lH-indol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)ethyl)piperidin-4-yl)methyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-yl)-6- fluoroisoindoline-1, 3-dione (2431

[0539] Following General Method Y1 Step 3 on 0.035 mmol scale delivered claimed compound 243 (21.5 mg, 0.024 mmol, 67.5% yield). LC / MS (ESI) m / z: 908.51 [M+H]+; NMR (500 MHz, DMSO) 6 12.01 (d, J = 3.0 Hz, 1H), 11.26 (s, 1H), 11.09 (s, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.72 (d, J = 11.5 Hz, 1H), 7.69 (dd, J = 8.3, 1.5 Hz, 1H), 7.65 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.09 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.05 - 6.97 (m, 1H), 6.63 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 6.35 (d, J = 8.1 Hz, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.77 - 3.60 (m, 6H), 3.26 - 3.17 (m, 8H), 2.94 - 2.84 (m, 2H), 2.62 - 2.57 (m, 1H), 2.56 - 2.53 (m, 1H), 2.47 - 2.41 (m, 2H), 2.41 - 2.35 (m, 2H), 2.32 - 2.23 (m, 3H), 2.18 (d, J= 7.2 Hz, 2H), 2.07- 1.95 (m, 3H), 1.69 (d, J = 12.0 Hz, 2H), 1.58

[0540] - 1.47 (m, 1H), 1.18 - 1.05 (m, 2H).

[0541] Example 51: 5-(4-((l-(2-(4-(4-(4-(lH-indol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)ethyl)piperidin-4-yl)methyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (236)

[0542] Following General Method Y1 Step 3 on 0.061 mmol scale delivered claimed compound 236 (9.5 mg, 0.011 mmol, 17.6% yield). LC / MS (ESI) m / z: 890.30 [M+H]+, 888.25 [M-H]’XH NMR (500 MHz, DMSO) 8 12.01 (d, J = 2.8 Hz, 1H), 11.27 (s, 1H), 11.06 (s, 1H), 8.12 (d, J = 2.5 Hz, 1H), 7.72 - 7.61 (m, 3H), 7.52 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.8, 2.3 Hz, 1H), 7.09 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.05 - 6.97 (m, 1H), 6.63 (ddd, J = 8.3, 6.7, 1.0 Hz, 1H), 6.35 (d, J = 8.2 Hz, 1H), 5.06 (dd, J = 12.7, 5.4 Hz, 1H), 3.67 (br s, 4H), 3.43 (t, J = 4.9 Hz, 6H), 2.92 - 2.83 (m, 2H), 2.62 - 2.55 (m, 1H), 2.55 - 2.52 (m, 1H), 2.46 (t, J = 5.1 Hz, 4H), 2.43 - 2.33 (m, 4H), 2.26 (br s, 3H), 2.16 (d, J = 7.2 Hz, 2H), 2.05 - 1.99 (m, 1H), 1.94 (t, J = 11.3 Hz, 2H), 1.68 (d, J = 12.6 Hz, 2H), 1.58 - 1.41 (m, 1H), 1.16 - 1.05 (m, 2H). General Method Y2:

[0543] Step 1. To the solution of Intermediate l-b (1.0 eq.) in DMF (0.1 M) was added DIPEA (6.0 eq.) and tert-butyl 2-bromoacetate (1.2 eq.). Reaction mixture was stirred at 80°C for 20 h, after which time reaction mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (C18, water+0.1% FA, MeCN+0.1% FA) to obtain the desired tert-butyl ester.

[0544] Step 2. Tert-butyl ester (1.0 eq.) was dissolved in 1,4-dioxane (20 vol.) and 4 M HCI was added. Reaction mixture was stirred at room temperature for 20 h. Then, the reaction mixture was concentrated under reduced pressure to give the desired carboxylic acid.

[0545] Step 3. To the mixture of Intermediate l-acetic acid derivative (1.0 eq.), amine (1.0 eq.) and HATU (1.5 eq.) in anhydrous DMF (0.1 M) was added DIPEA (5.0 eq.). Reaction mixture was stirred at room temperature for 20 h, after which time full conversion was observed. Reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (C18, water+0.1% FA, MeCN+0.1% FA) to obtain the desired compound. Example 52: N-((lR,2s,3S,5s)-5-(((5-cvano-2-((2-(trifluoromethoxy)benzyl)amino)pyriinnidin-4- yl)amino)methyl)adamantan-2-yl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1.3- dioxoisoindolin-5-yl)piperazin-l-yl)methyl)piperidin-l-yl)acetamide (250)

[0546] Following General Method Y2 Step 3 on 0.039 mmol scale delivered claimed compound 250 (7.3 mg, 0.008 mmol, 19.4% yield) LC / MS (ESI) m / z: 970.67 [M+H]+;XH NMR (500 MHz, DMSO) 6 11.09 (s, 1H), 8.18 (s, 1H), 8.16 (t, J = 6.1 Hz, 1H), 7.72 (d, J = 11.4 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.39 - 7.27 (m, 5H), 5.10 (dd, J = 12.9, 5.4 Hz, 1H), 4.53 (d, J = 6.2 Hz, 2H), 3.64 (d, J = 8.1 Hz, 1H), 3.26 - 3.21 (m, 5H), 2.97 (d, J = 6.4 Hz, 2H), 2.92 - 2.89 (m, 2H), 2.89 - 2.84 (m, 1H), 2.80 (d, J = 10.7 Hz, 2H), 2.62 - 2.56 (m, 1H), 2.56 - 2.53 (m, 1H), 2.20 (d, J = 7.2 Hz, 2H), 2.10 (t, J = 11.2 Hz, 2H), 2.03 (ddd, J = 11.0, 5.9, 3.4 Hz, 2H), 1.76 - 1.70 (m, 3H), 1.67 (br s, 2H), 1.62 (d, J = 12.9 Hz, 2H), 1.59 - 1.48 (m, 3H), 1.31 (d, J = 12.5 Hz, 2H), 1.24 (d, J = 3.6 Hz, 6H), 1.20 (br s, 2H), 1.13 (q, J = 11.6, 11.1 Hz, 2H).

[0547] Example 53: 5-(4-((l-(2-(4-(4-(4-(lH-indol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)-2-oxoethyl)piperidin-4-yl)methyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3-yl)-6- fluoroisoindoline-1.3-dione (248)

[0548]

[0549] Following General Method Y2 Step 3 on 0.025 mmol scale delivered claimed compound 248 (6.0 mg, 0.007 mmol, 25.5% yield). LC / MS (ESI) m / z: 922.56 [M+H]+;2H NMR (500 MHz, DMSO) 6 12.04 (d, J = 3.1 Hz, 1H), 11.28 (s, 1H), 11.09 (s, 1H), 8.15 (d, 7 = 3.1 Hz, 1H), 7.76 - 7.67 (m, 3H), 7.57 (d, J = 8.5 Hz, 1H), 7.44 (d, 7 = 7.4 Hz, 1H), 7.38 (d, 7 = 8.1 Hz, 1H), 7.13 (ddd, 7 = 8.1, 6.8, 1.2 Hz, 1H), 6.99 (ddd, 7 = 8.2, 7.0, 1.1 Hz, 1H), 6.63 (ddd, 7 = 8.2, 7.1, 1.1 Hz, 1H), 6.30 (d, 7 = 8.1 Hz, 1H), 5.10 (dd, J = 12.9, 5.5 Hz, 1H), 3.82 - 3.59 (m, 10H), 3.26 - 3.21 (m, 8H), 2.88 (ddd, J = 17.0, 13.7, 5.5 Hz, 2H), 2.62 - 2.56 (m, 1H), 2.56 - 2.51 (m, 4H), 2.20 (d, 7 = 6.9 Hz, 2H), 2.06 - 2.00 (m, 1H), 1.73 (d, 7 = 12.5 Hz, 2H), 1.56 (s, 1H), 1.31 - 1.06 (m, 2H).

[0550] Example 54: 5-(4-((l-(2-(4-(4-(4-(lH-indol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)-2-oxoethyl)piperidin-4-yl)methyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3- vDisoindoline-l, 3-dione (242) Following General Method Y2 Step 3 on 0.123 mmol scale delivered claimed compound 242 (26.0 mg, 0.029 mmol, 23.3% yield). LC / MS (ESI) m / z: 904.63 [M+H]+;XH NMR (500 MHz, DMSO) 6 12.05 (d, J = 3.1 Hz, 1H), 11.29 (s, 1H), 11.06 (s, 1H), 8.16 (d, J = 3.1 Hz, 1H), 7.74 (dt, J = 8.2, 1.0 Hz, 1H), 7.72 - 7.66 (m, 2H), 7.57 (dt, J = 8.6, 0.9 Hz, 1H), 7.38 (dt, J = 8.0, 0.9 Hz, 1H), 7.35 (s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.13 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.00 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 6.63 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 6.30 (dd, J = 8.2, 1.0 Hz, 1H), 5.07 (dd, J = 12.7, 5.5 Hz, 1H), 4.25 (br s, 1H), 3.77 (br s, 2H), 3.70 (br s, 2H), 3.57 - 3.33 (m, 16H), 3.09 - 2.73 (m, 2H), 2.62 - 2.56 (m, 1H), 2.55 - 2.52 (m, 3H), 2.32 - 2.11 (m, 2H), 2.06 - 1.96 (m, 1H), 1.95 - 1.66 (m, 3H).

[0551] Example 55: 4-(4-((l-(2-(4-(4-(4-(lH-indol-3-yl)-2,5-dioxo-2,5-dihvdro-lH-pyrrol-3-yl)quinazolin-2- yl)piperazin-l-yl)-2-oxoethyl)piperidin-4-yl)methyl)piperazin-l-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione (241)

[0552] Following General Method Y2 Step 3 on 0.105 mmol scale delivered claimed compound 241 (30.0 mg, 0.033 mmol, 31.2% yield). LC / MS (ESI) m / z: 904.69 [M+H]+;XH NMR (500 MHz, DMSO) 6 12.07 (d, J = 3.0 Hz, 1H), 11.31 (s, 1H), 11.09 (s, 1H), 8.17 (d, J = 3.1 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.75 - 7.69 (m, 2H), 7.59 (dt, J = 8.5, 0.9 Hz, 1H), 7.40 (dt, J = 8.2, 1.0 Hz, 1H), 7.38 (d, J = 7.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.15 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.02 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 6.65 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 6.32 (dd, J = 8.0, 1.0 Hz, 1H), 5.11 (dd, J = 12.7, 5.5 Hz, 1H), 4.55 - 3.94 (m, 2H), 3.76 (br s, 2H), 3.69 (br s, 2H), 3.63 - 3.40 (m, 10H), 3.30 - 3.21 (m, 4H), 2.94 - 2.83 (m, 3H), 2.64 - 2.59 (m, 1H), 2.58 - 2.54 (m, 1H), 2.35 - 2.14 (m, 2H), 2.08 - 1.98 (m, 1H), 1.96 - 1.66 (m, 3H), 1.53 - 1.22 (m, 2H). Synthesis scheme of Example 56:

[0553] Example 56: N-«lR.2s,3S,5s)-5-(((5-cvano-2-((2-(trifluoromethoxy)benzyl)amino)pyrimidin-4- yl)amino)methyl)adamantan-2-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)butanamide (249) . , , , , 5 11.08 (s, 1H), 8.18 (s, 1H), 8.15 (t, J = 6.2 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.58 (dd, J = 8.6, 7.1 Hz, 1H), 7.39 - 7.26 (m, 5H), 7.11 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 6.9 Hz, 1H), 6.62 (t, J = 6.1 Hz, 1H), 5.05 (dd, J = 12.7, 5.5 Hz, 1H), 4.53 (d, J = 6.2 Hz, 2H), 3.63 (d, J = 7.4 Hz, 1H), 2.96 (d, J = 6.4 Hz, 2H), 2.94 - 2.83 (m, 1H), 2.61 - 2.56 (m, 1H), 2.56 - 2.52 (m, 1H), 2.23 (t, J = 7.2 Hz, 2H), 2.06 - 1.97 (m, 1H), 1.86 - 1.74 (m, 4H), 1.70 - 1.61 (m, 3H), 1.25 - 1.12 (m, 10H).

[0554] Synthesis scheme of Examples 57-60:

[0555] Example 57: 4-((((ls,3R,4s,5S)-4-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-n5- vDpiperazin-l-yl)-2-oxoethyl)amino)adamantan-l-yl)methyl)amino)-2-((2- (trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (235)

[0556] Following General Method Y2 Step 3 on 0.019 mmol scale delivered claimed compound 235 (4.8 mg, 0.005 mmol, 27.9% yield). LC / MS (ESI) m / z: 873.20 [M+H]+, 871.15 [M-H]',JH NMR (500 MHz, DMSO) 5 11.09 (s, 1H), 8.18 (s, 1H), 8.13 (t, J = 6.3 Hz, 1H), 7.76 (d, J = 11.3 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.41 - 7.23 (m, 5H), 5.11 (dd, J = 12.9, 5.4 Hz, 1H), 4.53 (d, 7 = 6.3 Hz, 2H), 3.64 (s, 2H), 3.61 (s, 2H), 3.38 (s, 2H), 3.26 - 3.21 (m, 4H), 2.95 (d, J = 6.4 Hz, 2H), 2.88 (ddd, J = 17.0, 13.8, 5.5 Hz, 1H), 2.60 (ddd, J = 16.9, 4.4, 2.4 Hz, 1H), 2.57 - 2.52 (m, 1H), 2.39 - 2.35 (m, 1H), 2.04 (dtd, J = 13.1, 5.4, 2.4 Hz, 1H), 1.94- 1.84 (m, 2H), 1.71 - 1.61 (m, 3H), 1.58 - 1.42 (m, 1H), 1.34 - 1.03 (m, 8H).

[0557] Example _ 58: _ 4-((((ls,3R,4s,5S)-4-((2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3- dioxoisoindolin-5-yl)piperazin-l-yl)methyl)piperidin-l-yl)-2-oxoethyl)amino)adamantan-l- yl)methyl)amino)-2-((2-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (234)

[0558] Following General Method Y2 Step 3 on 0.028 mmol scale delivered claimed compound 234 (5.0 mg, 0.005 mmol, 18.2% yield). LC / MS (ESI) m / z: 970.25 [M+H]+, 968.25 [M-H]' ,XH NMR (500 MHz, DMSO) 5 11.09 (s, 1H), 8.18 (s, 1H), 8.14 (t, J = 6.1 Hz, 1H), 7.72 (d, J = 11.4 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.39 - 7.24 (m, 5H), 5.10 (dd, J = 12.9, 5.4 Hz, 1H), 4.53 (d, J = 6.3 Hz, 2H), 4.36 (d, J = 12.8 Hz, 1H), 3.80 (d, J = 13.3 Hz, 1H), 3.40 - 3.34 (m, 4H), 3.27 - 3.19 (m, 8H), 2.95 (d, J = 7.5 Hz, 2H), 2.88 (ddd, J = 17.0, 13.9, 5.4 Hz, 1H), 2.62 - 2.57 (m, 1H), 2.56 - 2.52 (m, 1H), 2.19 (d, J = 7.0 Hz, 2H), 2.04 (dtd, J = 11.4, 6.4, 5.9, 3.2 Hz, 1H), 1.93 - 1.85 (m, 2H), 1.78 - 1.62 (m, 6H), 1.57 - 1.42 (m, 1H), 1.33 - 1.09 (m, 9H), 1.09 - 0.99 (m, 1H), 0.99 - 0.88 (m, 1H).

[0559] Example 59: 4-((((ls,3R,4s,5S)-4-((2-(4-(l-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-

[0560] 5-yl)piperidin-4-yl)piperazin-l-yl)-2-oxoethyl)amino)adamantan-l-yl)methyl)amino)-2-((2- (trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (233) Following General Method Y2 Step 3 on 0.028 mmol scale delivered claimed compound 233 (11.0 mg, 0.011 mmol, 38.9% yield). LC / MS (ESI) m / z: 956.25 [M+H]+, 954.20 [M-H]',XH NMR (500 MHz, DMSO) 5 11.09 (s, 1H), 8.18 (s, 1H), 8.17 - 8.11 (m, 1H), 7.71 (d, J = 11.3 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.39 - 7.25 (m, 5H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 4.53 (d, J = 6.2 Hz, 2H), 3.65 (d, J = 12.1 Hz, 2H), 3.52 - 3.43 (br s, 4H), 3.42 - 3.37 (br s, 4H), 2.98 - 2.84 (m, 5H), 2.63 - 2.56 (m, 1H), 2.54 - 2.52 (m, 2H), 2.48 - 2.43 (m, 2H), 2.07 - 2.02 (m, 1H), 2.02 - 1.95 (m, 1H), 1.92 - 1.81 (m, 4H), 1.80 - 1.70 (m, 2H), 1.67 (br s, 1H), 1.63 - 1.50 (m, 2H), 1.28 - 1.09 (m, 9H).

[0561] Example 60: 4-((((ls,3R,4s,5S)-4-((2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-

[0562] 5-yl)piperazin-l-yl)piperidin-l-yl)-2-oxoethyl)amino)adamantan-l-yl)methyl)amino)-2-((2- (trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (232)

[0563] Following General Method Y2 Step 3 on 0.028 mmol scale delivered claimed compound 232 (14.0 mg, 0.015 mmol, 51.7% yield). LC / MS (ESI) m / z: 956.25 [M+H]+, 954.20 [M-H]' ,XH NMR (500 MHz, DMSO) 6 11.09 (s, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.72 (d, J = 11.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.37 - 7.26 (m, 5H), 5.10 (dd, J = 12.9, 5.4 Hz, 1H), 4.53 (d, J = 6.2 Hz, 2H), 4.39 (d, J = 12.7 Hz, 1H), 3.85 (d, J = 13.2 Hz, 1H), 3.25 - 3.22 (m, 4H), 3.01 - 2.92 (m, 3H), 2.88 (ddd, J = 17.1, 13.9, 5.4 Hz, 1H), 2.66 (t, J = 5.1 Hz, 4H), 2.64 - 2.58 (m, 2H), 2.60 - 2.53 (m, 1H), 2.56 - 2.51 (m, 1H), 2.48 - 2.39 (m, 2H), 2.07 - 1.95 (m, 2H), 1.89 (d, J = 12.6 Hz, 2H), 1.81 (d, J = 12.5 Hz, 2H), 1.72 (br s, 2H), 1.66 (br s, 1H), 1.33 - 1.08 (m, 11H). Example 61: 4-((((ls,3R,4s,5S)-4-((2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-

[0564] 5-yl)piperazine-l-carbonyl)piperidin-l-yl)-2-oxoethyl)amino)adamantan-l-yl)methyl)amino)-2- ((2-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (231)

[0565] Following General Method Y-HATU on 0.032 mmol scale delivered the claimed compound 231 (4.9 mg, 0.005 mmol, 15.6% yield). LC / MS (ESI) m / z: 984.25 [M+H]+;XH NMR (500 MHz, DMSO, 300 K) 6 11.10 (s, 1H), 8.15 (s, 1H), 8.13 (t, 1H), 7.77 (d, J = 11.2 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.36 - 7.26 (m, 5H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 4.53 (d, J = 6.3 Hz, 2H), 4.37 (d, J = 12.8 Hz, 1H), 3.84 (d, J = 13.3 Hz, 1H), 3.73 (s, 2H), 3.63 (s, 2H), 3.23 - 3.20 (m, 3H), 3.06 (t, J = 12.6 Hz, 2H), 2.95 (d, J = 6.9 Hz, 2H), 2.93 - 2.83 (m, 2H), 2.77 - 2.66 (m, 1H), 2.63 - 2.56 (m, 1H), 2.54 (s, 1H), 2.06 - 2.00 (m, 1H), 1.89 (d, = 12.2 Hz, 2H), 1.71 - 1.68 (m, 5H), 1.53 (d, J = 12.2 Hz, 2H), 1.46 (s, 1H), 1.40 - 1.37 (m, 2H), 1.26 - 1.06 (m, 9H).

[0566] General Method Y3:

[0567] Step la. Fluoro-thalidomide (1.0 eq.) and alkanolamine (1.2-1.5 eq.) were dissolved in NMP or DMSO (0.1 M), then DIPEA (5.0 eq.) was added and reaction mixture was stirred at 90°Cfor 20 h, after which time reaction mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (C18, water+0.1% FA, MeCN+0.1% FA) to obtain the desired alcohol.

[0568] Step lb. Glycine-thalidomide derivative (1.0 eq.), alkanolamine (1.1 eq.) and HATU (1.5 eq.) were dissolved in DMF (0.1 M), then DIPEA was added (2.5-5.0 eq.) and reaction mixture was stirred at room temperature for 20 h, after which time reaction mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (C18, water+0.1% FA, MeCN+0.1% FA) to obtain the desired alcohol.

[0569] Step 2. To a stirred solution of alcohol (1.0 eq.) in anhydrous DCM (0.1 M) was added DIPEA (5.0-10.0 eq.) and the solution was cooled to 0°C. In a separate vessel SO3-pyridine complex (3.0-6.0 eq.) was added to anhydrous DMSO (20.0 eq.) cooled to 0°C and stirred for 10 min. Then the DMSO solution was added to the DCM solution at 0°C and the reaction mixture was allowed to reach room temperature over the course of 4 h, after which time reaction mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (C18, water+O.1% FA, MeCN+0.1% FA) to obtain the desired aldehyde.

[0570] Step 3. Amine (1.0 eq.) and aldehyde (1.0 eq.) were dissolved in DCE, DMF or THF (0.05 M), then NaBH(OAc)3 (4.0-10.0 eq.) and acetic acid (0.1 eq.) were added and the reaction mixture was stirred for 20 h, after which time the mixture was concentrated under reduced pressure and purified by preparative-HPLC (C18, water+0.1% FA, MeCN+0.1% FA gradient flow) to obtain the desired compound.

[0571] Example 62: 4-((((ls,3R,4s,5S)-4-((14-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)-

[0572] 3,6,9,12-tetraoxatetradecyl)amino)adamantan-l-yl)methyl)amino)-2-((2-

[0573] (trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (255)

[0574] Following General Method Y3 Step 3 on 0.070 mmol scale delivered claimed compound 255 (2.7 mg, 0.003 mmol, 4.0% yield) LC / MS (ESI) m / z: 948.35 [M+H]+, 946.35 [M-H]’ / H NMR (500 MHz, DMSO) 6 11.05 (s, 1H), 8.18 (s, 1H), 8.12 (t, J = 6.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.36 - 7.25 (m, 4H), 7.14 (t, J = 5.6 Hz, 1H), 7.00 (d, J = 2.1 Hz, 1H), 6.89 (dd, J = 8.4, 2.1 Hz, 1H), 5.02 (dd, J = 12.7, 5.4 Hz, 1H), 4.53 (d, 7 = 6.3 Hz, 2H), 3.59 (t, 7 = 5.5 Hz, 2H), 3.56 - 3.53 (m, 4H), 3.52 - 3.49 (m, 8H), 3.49 - 3.43 (m, 6H), 2.94 (d, 7 = 6.4 Hz, 2H), 2.92 - 2.82 (m, 1H), 2.63 - 2.58 (m, 2H), 2.57 - 2.53 (m, 2H), 2.40 - 2.37 (m, 1H), 1.98 (ddd, J = 12.9, 5.7, 2.9 Hz, 1H), 1.83 (d, 7 = 12.1 Hz, 2H), 1.63 (s, 2H), 1.55 - 1.42 (m, 1H), 1.22 (d, J = 12.1 Hz, 2H), 1.15 (d, 7 = 13.9 Hz, 4H), 1.09 (d, 7 = 12.2 Hz, 2H). Example 63: 4-((((ls,3R,4s,5S)-4-((2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoi ndolin-4- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)amino)adamantan-l-yl)methyl)amino)-2-((2- (trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (253)

[0575] Following General Method Y3 Step 3 on 0.027 mmol scale delivered claimed compound 253 (15.7 mg, 0.017 mmol, 62.8% yield) LC / MS (ESI) m / z: 904.25 [M+H]+, 902.30 [M-HJ / H NMR (500 MHz, DMSO) 6 11.07 (s, 1H), 8.18 (d, 1H), 8.13 (t, J = 6.2 Hz, 1H), 7.57 (dd, J = 8.6, 7.0 Hz, 1H), 7.35 - 7.25 (m, 5H), 7.14 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 5.8 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.53 (d, J = 6.3 Hz, 2H), 3.62 (t, J = 5.5 Hz, 2H), 3.58 - 3.53 (m, 4H), 3.53 - 3.49 (m, 4H), 3.46 (q, J = 6.1 Hz, 6H), 2.94 (d, J = 6.4 Hz, 2H), 2.88 (ddd, J = 16.7, 13.6, 5.3 Hz, 1H), 2.64 - 2.59 (m, 2H), 2.58 - 2.52 (m, 1H), 2.43 - 2.39 (m, 1H), 2.07 - 1.98 (br s, 1H), 1.83 (d, J = 12.0 Hz, 2H), 1.66 - 1.60 (m, 2H), 1.49 (dd, J = 33.4, 12.3 Hz, 1H), 1.27 - 1.03 (m, 8H).

[0576] Example 64: N-(14-(((lR,2s,3S,5s)-5-(((5-cvano-2-((2-(trifluoromethoxy)benzyl)amino)pyrimidin-4- yl)amino)methyl)adamantan-2-yl)amino)-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-5-yl)amino)acetamide (254) Following General Method Y3 Step 3 on 0.011 mmol scale delivered claimed compound 254 (6.1 mg, 0.006 mmol, 52.8% yield). LC / MS (ESI) m / z: 1005.30 [M+H]+, 1003.30 [M-H];JH NMR (500 MHz, DMSO) 6 11.05 (s, 1H), 8.18 (s, 1H), 8.13 (t, J = 6.3 Hz, 1H), 8.09 (t, J = 5.7 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.38 - 7.28 (m, 4H), 7.30 - 7.26 (m, 1H), 6.94 (d, J = 2.1 Hz, 1H), 6.86 (dd, J = 8.4, 2.2 Hz, 1H), 5.03 (dd, J = 12.8, 5.3 Hz, 1H), 4.53 (d, J = 6.4 Hz, 2H), 3.84 (d, J = 6.0 Hz, 2H), 3.55 - 3.44 (m, 12H), 3.47 - 3.39 (m, 4H), 3.28 - 3.21 (m, 4H), 2.94 (d, J = 6.4 Hz, 2H), 2.87 (ddd, J = 16.4, 13.6, 5.2 Hz, 1H), 2.61 (t, J = 5.7 Hz, 2H), 2.59 - 2.53 (m, 2H), 2.39 - 2.37 (m, 1H), 2.03 - 1.96 (m, 1H), 1.84 (d, J = 12.3 Hz, 2H), 1.65 - 1.61 (m, 2H), 1.49 (dd, J = 33.3, 11.8 Hz, 1H), 1.22 (d, J = 14.3 Hz, 2H), 1.15 (d, J = 14.1 Hz, 4H), 1.09 (d, J = 12.1 Hz, 2H).

[0577] Example 65: N-(14-(((lR,2s,3S,5s)-5-(((5-cvano-2-((2-(trifluoromethoxy)benzyl)amino)pyrimidin-4- yl)amino)methyl)adamantan-2-yl)amino)-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-4-yl)amino)acetamide (260)

[0578] Following General Method Y3 Step 3 on 0.041 mmol scale delivered claimed compound 260 (11.6 mg, 0.011 mmol, 28.0% yield) LC / MS (ESI) m / z: 1005.35 [M+H]+, 1003.35 [M-H]’,XH NMR (500 MHz, DMSO) 6 11.10 (s, 1H), 8.18 (s, 1H), 8.17 - 8.09 (m, 2H), 7.59 (dd, J = 8.5, 7.1 Hz, 1H), 7.35 - 7.25 (m, 5H), 7.07 (d, J = 7.0 Hz, 1H), 6.94 (t, J = 5.7 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 5.07 (dd, J = 12.8, 5.5 Hz, 1H), 4.53 (d, J = 6.3 Hz, 2H), 3.93 (d, J = 5.7 Hz, 2H), 3.53 - 3.47 (m, 12H), 3.47 - 3.44 (m, 2H), 3.44 - 3.40 (m, 2H), 3.26 (q, J = 5.8 Hz, 4H), 2.94 (d, J = 6.4 Hz, 2H), 2.89 (tdd, J = 15.8, 4.6, 2.9 Hz, 1H), 2.67 - 2.59 (m, 2H), 2.59 - 2.54 (m, 1H), 2.54 - 2.51 (m, 1H), 2.41 - 2.37 (br s, 1H), 2.07 - 1.99 (m, 1H), 1.88 - 1.77 (m, 2H), 1.66 - 1.59 (br s, 2H), 1.30 - 1.18 (m, 2H), 1.19 - 1.12 (m, 4H), 1.12 - 1.04 (m, 2H). Example 66: 4-((((ls,3R,4s,5S)-4-((14-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-

[0579] 3,6,9.12-tetraoxatetradecyl)amino)adamantan-l-yl)methyl)amino)-2-((2-

[0580] (trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (259)

[0581] Following Method Red-Am on 0.042 mmol scale delivered the claimed compound 259 (4.5 mg, 0.005 mmol, 10.9% yield). LC / MS (ESI) m / z: 949.4 [M+H]+;XH NMR (500 MHz, DMSO) 6 11.08 (s, 1H), 8.18 (s, 1H), 8.12 (t, J = 6.3 Hz, 1H), 7.57 (dd, J = 8.5, 7.1 Hz, 1H), 7.35 - 7.31 (m, 3H), 7.30 - 7.26 (m, 2H), 7.14 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 12.7, 5.4 Hz, 1H), 4.53 (d, J = 6.3 Hz, 2H), 3.62 (t, J = 5.4 Hz, 2H), 3.58 - 3.42 (m, 18H), 3.40 - 3.34 (m, 2H), 2.94 (d, J = 6.3 Hz, 1H), 2.92 - 2.83 (m, 1H), 2.58 (dd, J = 11.4, 5.9 Hz, 3H), 2.54 (d, J = 1.0 Hz, 1H), 2.05 - 1.99 (m, 1H), 1.83 (d, J = 12.9 Hz, 2H), 1.61 (s, 2H), 1.47 (d, J = 32.6 Hz, 1H), 1.28 - 1.04 (m, 7H).

[0582] Example 67: 4-((((lr,4r)-4-((14-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-

[0583] 3.6,9.12-tetraoxatetradecyl)amino)cvclohexyl)methyl)amino)-2-((2-

[0584] (trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (258)

[0585] Following Method Red-Am on 0.033 mmol scale delivered the claimed compound 258 (11.5 mg, 0.012 mmol, 37.9% yield). LC / MS (ESI) m / z: 896.35 [M+H]+;XH NMR (500 MHz, DMSO) 6 10.69 (s, 1H), 8.20 (d, J = 6.4 Hz, 1H), 8.16 (t, J = 6.2 Hz, 1H), 7.60 (dd, J = 8.5, 7.1 Hz, 1H), 7.51 (t, J = 6.0 Hz, 1H), 7.40 - 7.31 (m, 4H), 7.16 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 6.62 (t, J = 5.8 Hz, 1H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.54 (d, J = 6.2 Hz, 2H), 3.64 (t, J = 5.4 Hz, 2H), 3.60 - 3.57 (m, 2H), 3.57 - 3.44 (m, 14H), 3.04 (t, J = 6.6 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.71 (t, J = 5.7 Hz, 2H), 2.62 (dd, J = 4.5, 2.4 Hz, 1H), 2.60 - 2.55 (m, 2H), 2.25 (s, 1H), 2.08 - 2.01 (m, 1H), 1.75 (d, J = 12.3 Hz, 2H), 1.47 (d, J = 12.8 Hz, 2H), 1.29 (s, 1H), 0.80 (q, J = 12.2 Hz, 2H), 0.66 (q, J = 12.6 Hz, 2H).

[0586] Example 68: 4-((((ls,3R,4s,5S)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)amino)adamantan-l-yl)methyl)amino)-2-((2- (trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (257)

[0587] Following Method Red-Am on 0.037 mmol scale delivered the claimed compound 257 (4.5 mg, 0.005 mmol, 14.1% yield). LC / MS (ESI) m / z: 861.55 [M+H]+;JH NMR (500 MHz, DMSO) 6 11.09 (s, 1H), 8.20 (s, 1H), 8.14 (t, J = 6.3 Hz, 1H), 7.59 (dd, J = 8.6, 7.0 Hz, 1H), 7.40 - 7.32 (m, 3H), 7.32 - 7.27 (m, 2H), 7.16 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.63 (t, J = 5.9 Hz, 1H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 3.65 (t, J = 5.5 Hz, 2H), 3.60 (dd, J = 6.1, 3.5 Hz, 2H), 3.57 - 3.52 (m, 2H), 3.52 - 3.45 (m, 6H), 2.95 (d, J = 6.4 Hz, 2H), 2.95 - 2.84 (m, 1H), 2.61 (t, J = 5.7 Hz, 2H), 2.58 - 2.55 (m, 1H), 2.03 (ddd, J = 11.5, 6.2, 3.7 Hz, 1H), 1.84 (d, J = 12.5 Hz, 3H), 1.62 (br s, 3H), 1.26 - 1.05 (m, 8H).

[0588] Example 69: 4-((((ls,3R,4s,5S)-4-((17-((2-(2,6-dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4-yl)amino)-

[0589] 3,6,9,12, 15-pentaoxaheptadecyl)amino)adamantan-l-yl)methyl)amino)-2-((2-

[0590] (trifluoromethoxy)benzyl)amino|pyrimidine-5-carbonitrile (256) Following Method Red-Am on 0.037 mmol scale delivered the claimed compound 256 (7.0 mg, 0.007 mmol, 18.9% yield). LC / MS (ESI) m / z: 992.5 [M+H]+;JH NMR (500 MHz, DMSO, 300K) 6 11.08 (s, 1H), 8.19 - 8.16 (m, 1H), 8.12 (t, J = 6.3 Hz, 1H), 7.62 - 7.54 (m, 1H), 7.37 - 7.30 (m, 3H), 7.27 (d, J = 7.0 Hz, 2H), 7.14 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.1 Hz, 1H), 6.60 (t, J = 5.8 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.53 (d, J = 6.4 Hz, 2H), 3.62 (t, J = 5.4 Hz, 2H), 3.55 (q, J = 4.1, 3.4 Hz, 2H), 3.54 - 3.42 (m, 18H), 2.94 (d, J = 6.4 Hz, 2H), 2.92 - 2.83 (m, 1H), 2.63 - 2.54 (m, 3H), 2.56 - 2.50 (m, 3H), 2.06 - 1.98 (m, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.62 (s, 2H), 1.52 - 1.42 (m, 1H), 1.26 - 1.05 (m, 8H).

[0591] General Method Y3-a: Reductive amination with Ligand 1

[0592] Step 1. Following General Method Y3, Step la.

[0593] Step 2. Following General Method Y3, Step 2.

[0594] Step 3. Following General Method Y3, Step 3. Example 70: 2-(2,6-dioxopiperidin-3-yl)-4-fl2-(4-{4-(4-(lH-indol-3-yl)-2,5-dioxo-2,5-dihvdro-lH- pyrrol-3-yllquinazolin-2-yl}piperazin-l-yl)-4,7,10-trioxa-l-azadodecan-l-yl)-2,3-dihvdro-lH- isoindole-1, 3-dione (246)

[0595] Following Method Y3-a on 0.134 mmol scale delivered the claimed compound 246 (54.0 mg, 0.062 mmol, 46.1% yield). LC / MS (ESI) m / z: 856.3 [M+H]+;2H NMR (500 MHz, DMSO) 6 12.00 (d, J = 3.1 Hz, 1H), 11.26 (s, 1H), 11.08 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 3.0 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.61 - 7.48 (m, 2H), 7.40 - 7.34 (m, 1H), 7.18 - 7.04 (m, 2H), 7.05 - 6.98 (m, 2H), 6.66 - 6.56 (m, 2H), 6.35 (d, J = 8.1 Hz, 1H), 5.05 (ddd, J = 12.7, 5.5, 2.5 Hz, 1H), 3.66 (br s, 3H), 3.65 - 3.59 (m, 2H), 3.58 - 3.38 (m, 14H), 2.93 - 2.82 (m, 1H), 2.61 - 2.56 (m, 1H), 2.57 - 2.53 (m, 1H), 2.40 (t, J = 5.9 Hz, 2H), 2.28 (m, 3H), 2.07 - 1.97 (m, 1H).

[0596] Example 71: 2-(2,6-dioxopiperidin-3-yl)-5-ri2-(4-{4-(4-(lH-indol-3-yl)-2,5-dioxo-2.5-dihvdro-lH-

[0597] Pyrrol-3-yllquinazolin-2-yl}piperazin-l-yl)-4,7,10-trioxa-l-azadodecan-l-yll-2,3-dihydro-lH- isoindole-l,3-dione (245) 2H ), 7.37 (d, J = 8.2 Hz, 1H), 7.13 (dd, J = 7.0, 4.1 Hz, 1H), 7.08 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H ), 7.03 - 6.98 (m, 2H), 6.89 (td, J = 8.1, 2.2 Hz, 1H), 6.63 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 6.35 (d, J = 8.1 Hz, 1H), 5.02 (ddd, J = 12.8, 5.6, 2.8 Hz, 1H), 3.67 (br s, 3H), 3.59 (td, J = 5.5, 2.9 Hz, 2H), 3.55 (dt, J = 3.7, 2.1 Hz, 4H), 3.52 - 3.44 (m, 6H), 3.44 - 3.37 (m, 1H), 3.38 - 3.33 (m, 3H), 2.92 - 2.82 (m, 1H), 2.61 - 2.56 (m, 1H), 2.56 - 2.52 (m, 1H), 2.41 (t, J = 5.9 Hz, 2H), 2.27 (t, J = 8.1 Hz, 3H), 2.03 - 1.94 (m, 1H).

[0598] Example 72: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-[12-(4-{4-r4-(lH-indol-3-yl)-2,5-dioxo-2,5- dihvdro-lH-pyrrol-3-yllquinazolin-2-yl}piperazin-l-yl)-4,7,10-trioxa-l-azadodecan-l-yll-2,3- dihydro-lH-isoindole-l,3-dione <239)

[0599] Following Method Y3-a on 0.037 mmol scale delivered the claimed compound 239 (6.0 mg, 0.007 mmol, 18.8% yield). LC / MS (ESI) m / z: 874.7 [M+H]+;JH NMR (500 MHz, DMSO) 6 12.00 (d, J = 3.1 Hz, 1H), 11.25 (s, 1H), 11.06 (s, 1H), 8.12 (d, J = 3.0 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.55 (d, J = 10.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.08 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.00 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 6.79 (q, J = 5.3 Hz, 1H), 6.63 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 6.35 (d, J = 8.2 Hz, 1H), 5.04 (dd, J = 12.7, 5.4 Hz, 1H), 3.66 (br s, 4H), 3.60 (t, J = 5.6 Hz, 2H), 3.56 - 3.50 (m, 4H), 3.50 - 3.44 (m, 8H), 2.92 - 2.81 (m, 1H), 2.58 (d, J = 2.6 Hz, 1H), 2.54 (d, J = 3.1 Hz, 1H), 2.40 (t, J = 5.9 Hz, 2H), 2.27 (s, 4H), 2.03 - 1.95 (m, 1H).

[0600] Example 73: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-{(8-(4-{4-r4-(lH-indol-3-yl)-2,5-dioxo-2,5- dihvdro-lH-pyrrol-3-yllquinazolin-2-yl}piperazin-l-yl)octyllamino}-2,3-dihydro-lH-isoindole-l,3- dione (244)

[0601] Following Method Y3-a on 0.067 mmol scale delivered the claimed compound 244 (35.0 mg, 0.042 mmol, 63.2% yield). LC / MS (ESI) m / z: 825.8 [M+H]+;XH NMR (500 MHz, DMSO, 300K) 5 12.00 (d, J = 3.0 Hz, 1H), 11.26 (s, 1H), 11.06 (s, 1H), 8.12 (d, J = 3.0 Hz, 1H), 7.71 - 7.61 (m, 2H), 7.58 - 7.49 (m, 2H), 7.41 - 7.34 (m, 1H), 7.12 - 7.05 (m, 2H), 7.00 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 6.89 (td, J = 5.7, 2.8 Hz, 1H), 6.63 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 6.35 (d, J = 8.2 Hz, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 3.68 (br s, 4H), 3.28 - 3.22 (m, 2H), 2.92 - 2.81 (m, 1H), 2.59 (m, 1H), 2.54 (d, J = 5.1 Hz, 1H), 2.20 (t, J = 7.0 Hz, 6H), 2.04 - 1.95 (m, 1H), 1.58 (p, J = 7.0 Hz, 2H), 1.40 (t, J = 7.1 Hz, 2H), 1.36 - 1.24 (m, 8H).

[0602] Synthesis scheme of Example 74:

[0603] Example _ 74: _ 4-((((ls,3R,4s,5S)-4-((2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3- dioxoisoindolin-5-yl)piperazin-l-yl)methyl)piperidin-l-yl)ethyl)amino)adamantan-l- yl)methyl)amino)-2-((2-(trifluoromethoxy)benzyl)amino)pyrimidine-5-carbonitrile (238)

[0604]

[0605] Following General Method Y3 Step 3 on 0.044 mmol scale delivered the claimed compound 238 (4.5 mg, 0.005 mmol, 10.6% yield). LC / MS (ESI) m / z: 956.30 [M+H]+, 954.25 [M-H]‘, 1H NMR (500 MHz, DMSO) 6 11.09 (s, 1H), 8.18 (s, 1H), 8.14 (t, J = 6.3 Hz, 1H), 7.72 (d, J = 11.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.38 - 7.26 (m, 5H), 5.10 (dd, J = 12.9, 5.4 Hz, 1H), 4.54 (d, J = 6.3 Hz, 2H), 3.26 - 3.22 (m, 10H), 2.95 (d, J = 6.4 Hz, 2H), 2.90 - 2.81 (m, 3H), 2.68 - 2.62 (m, 2H), 2.59 (ddd, J = 17.1, 4.4, 2.4 Hz, 1H), 2.56 - 2.53 (m, 1H), 2.46 - 2.42 (m, 2H), 2.18 (d, J = 7.2 Hz, 2H), 2.07 - 2.00 (m, 1H), 2.00 - 1.93 (m, 2H), 1.82 (d, J = 12.6 Hz, 2H), 1.71 (br s, 2H), 1.69 - 1.64 (m, 2H), 1.27 - 1.14 (m, 10H), 1.14 - 1.06 (m, 2H).

[0606] Method XYZ

[0607] Step 1. Following General Method X2, Step 1.

[0608] Step 2. and Step 4. Following General Method X2, Step 2.

[0609] Step 3. Following General Method Y3, Step 3.

[0610] Step 5. Following General Method X2, Step 3. Example _ 75: _ 4-((((ls,3R,4s,5S)-4-((2-(4-(((2-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3- dioxoisoindolin-5-yl)(methyl)amino)ethyl)(methyl)amino)methyl)piperidin-l-yl)-2- oxoethyl)amino)adamantan-l-yl)methyl)amino)-2-((2-

[0611] (trifluoromethoxy)benzyl)amino)pyrimldine-5-carbonitrile (261)

[0612] Following Method XYZ on 0.074 mmol scale delivered the claimed compound 261 (3.5 mg, 0.004 mmol, 4.9% yield). LC / MS (ESI) m / z: 972.25 [M+H]+, 970.30 [M-H]', 1H NMR (500 MHz, DMSO) 5 11.08 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 6.3 Hz, 1H), 7.63 (d, J = 12.6 Hz, 1H), 7.37 - 7.30 (m, 3H), 7.28 (dd, J = 7.3, 4.0 Hz, 3H), 5.07 (dt, J = 12.6, 5.0 Hz, 1H), 4.53 (d, J = 6.4 Hz, 2H), 4.28 (d, J = 12.8 Hz, 1H), 3.71 (d, J = 13.3 Hz, 1H), 3.50 (t, J = 6.6 Hz, 2H), 3.05 (d, J = 1.4 Hz, 3H), 2.97 - 2.92 (m, 2H), 2.87 (dd, J = 16.8, 12.5 Hz, 3H), 2.59 (s, 1H), 2.54 (s, 1H), 2.35 (s, 1H), 2.13 (s, 3H), 2.11 (s, 1H), 2.06 - 1.95 (m, 2H), 1.88 (d, J = 12.1 Hz, 2H), 1.65 (s, 3H), 1.57 (d, J = 11.9 Hz, 4H), 1.48 (m, 1H), 1.24 (s, 3H), 1.21 - 1.19 (m, 1H), 1.18 - 1.08 (m, 7H), 0.93 - 0.77 (m, 2H).

[0613] SYNTHESIS OF LIGASE LIGAND MOIETIES - COMPOUND 111

[0614] Example 76: 4-amino-2-(2,6-dioxopiperidin-3-yl)-6-(2-hvdroxyethyl)isoindoline-l,3-dione

[0615] (Compound 111)

[0616]

[0617] BISPIN (8.855 g, 34.869 mmol), LiOMe (1.766 g, 46.492 mmol), triphenylphosphine polymer-bound (2.3 g, 3.022 mmol) and Cui (0.433 g, 2.325 mmol) were weighed in a round-bottomed flask equipped with a stir bar, under argon atmosphere. The flask was closed with a septum, evacuated, and backfilled with nitrogen. A solution of ((2-bromoethoxy)methyl)benzene (5.0 g, 23.246 mmol) in DMF (116ml) was added with a syringe and the resulting mixture was vigorously stirred at room temperature for 20 h. The reaction mixture was then diluted with dichloromethane and filtered through a Celite pad. The resulting solution was concentrated, poured into sat. aq NH4CI, and extracted with Et2O (2x150ml). The organic layers were washed successively with H2O (3x100 ml) and brine (100 ml). The organic layer was dried over anhydrous NazSOn, and concentrated to get the crude product which was dissolved in THF (100 ml). A saturated solution of KHF2 (15 ml, 91.547 mmol) was added to it and the reaction mixture was stirred for 2 h in RT. The reaction mixture was dried, and resulting salt was extracted with hot acetone (2x100 ml). The organic part was concentrated and precipitation was achieved by dropwise addition of diethyl ether at 0°C. The resulting product was collected by filtration and dried to get potassium (2-benzyloxyethyl)trifluoroborate (5 g, 13.6 mmol, 59%) as white solid.

[0618] Step B

[0619] To a well stirred solution of 3-Nitrophthalic acid (15 g, 71 mmol) in concentrated H2SO4 (60 ml) was added l,3-Dibromo-5,5-dimethylhydantoin (11 g, 38.38 mmol) at 0°C and the reaction mixture was allowed to stir at ambient temperature for 16 h. Reaction mixture was then poured into ice cold water to get the a white precipitate. The precipitate was filtered, the residue was washed with cold water several times then dried under vacuum to get 5-bromo-3-nitrophthalic acid (15 g, 51.7 mmol; 72%) as white solid.

[0620] Step C

[0621] To a solution of 5-bromo-3-nitrophthalic acid (10 g, 34.5 mmol) in DMF (5 ml) was added sodium bicarbonate (23.2 g, 276 mmol) followed by methyl iodide (12.9 ml, 206.9 mmol) and the reaction mixture was allowed to stir at 100°C for 16 h under nitrogen. After complete consumption of the starting material the reaction mixture was diluted with ethyl acetate, washed successively with water and brine, the organic layer was dried over sodium sulphate and evaporated under reduced pressure to get the crude compound, which was then purified by column chromatography (SiO2, 30% ethyl acetate in hexane) to get dimethyl 5-bromo-3-nitrophthalate (6 g, 21 mmol, 60%) as off white solid.

[0622] Step D

[0623] A suspension of dimethyl 5-bromo-3-nitrophthalate (2.0 g, 6.289 mmol), potassium (2- benzyloxyethyljtrifluoroborate (3.805 g, 15.723 mmol) and CS2CO3 (6.148 g, 18.868 mmol) in a toluene:water mixture (4:1, 30 ml) was deoxygenated using argon for 10 min. To the reaction mixture was added Pd(amphos)2Cl2 (0.891 g, 1.258 mmol) and it was allowed to stir at 100°C for 16 h. After complete consumption of the starting material the volatiles were evaporated under reduced pressure to get the crude compound, which was diluted with ethyl acetate, washed successively with water and brine, the organic layer was dried over sodium sulphate and evaporated under reduced pressure to get the crude compound, which was then purified by column chromatography (SiCh, 20% ethyl acetate in hexane) to get dimethyl 5-(2-(benzyloxy)ethyl)-3-nitrophthalate (1.6 g, 4.28 mmol, 68%) as gummy solid.

[0624] Step E

[0625] To a solution of dimethyl 5-(2-(benzyloxy)ethyl)-3-nitrophthalate (1.6 g, 4.285 mmol) in methanol

[0626] (30 ml) was added NaOH (1.714 g, 42.853 mmol) and the reaction mixture was then refluxed for 4 h. The reaction mixture was cooled to room temperature; volatiles were evaporated under reduced pressure. The residue was dissolved in water (100 ml) and acidified by 2M HCI solution. The aqueous part was extracted by ethyl acetate. Next, the combined organic layer was washed by water and brine, dried over anhydrous NazSCU and concentrated under reduced pressure to get 5-(2- (benzyloxy)ethyl)-3-nitrophthalic acid (1.4 g, 4.05 mmol, 94.6%) as off white solid.

[0627] Step F

[0628] To a solution of 5-(2-(benzyloxy)ethyl)-3-nitrophthalic acid (1.4 g, 4.06 mmol) in acetic acid (40 ml) and was added 3-aminopiperidine-2, 6-dione hydrochloride (670 mg, 4.06 mmol) followed by sodium acetate (1 g, 12.17 mmol) and the reaction mixture was allowed to stir at 120°C for 4 h under nitrogen. After complete consumption of the starting material the reaction mixture was evaporated under reduced pressure get the crude material which was then purified by column chromatography (SiOz, 10% ethyl acetate in dichloromethane) to get 6-(2-(benzyloxy)ethyl)-2-(2,6- dioxopiperidin-3-yl)-4-nitroisoindoline-l, 3-dione (1 g, 2.28 mmol, 56%) as light brown solid.

[0629] LCMS (ESI+): m / z 438.3 [M+H]+

[0630] Step G

[0631] 6-(2-(benzyloxy)ethyl)-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline- 1,3-dione (500 mg, 1.14 mmol) was dissolved in acetic acid (10 ml). To it was added 10% Pd / C (50 mg), the reaction vessel was then filled with hydrogen (using balloon) and the reaction mixture was allowed to stir at room temperature for 16 h. After complete consumption of the starting material the reaction mixture was filtered through Celite pad and evaporated under reduced pressure to get the crude compound which was purified by column chromatography (SiOz, 5% methanol in dichloromethane) to get 4-amino-2-(2,6- dioxopiperidin-3-yl)-6-(2-hydroxyethyl)isoindoline-l, 3-dione (200 mg, 0.63 mmol, 55%) as yellow solid.

[0632] LCMS (ESI+): m / z 318.2 [M+H]+

[0633] XH NMR (400 MHz, DMSO) 5 11.07 (s, 1H), 6.90 (s, 1H), 6.84 (s, 1H), 6.42 (s, 2H), 5.02 (dd, J = 12.9, 5.4 Hz, 1H), 4.69 (t, J = 5.2 Hz, 1H), 3.61 (q, J = 6.2 Hz, 2H), 2.94 - 2.80 (m, 1H), 2.72 (t, J = 6.6 Hz, 2H), 2.62 - 2.52 (m, 2H), 2.06 - 1.94 (m, 1H).

[0634] SYNTHESIS OF LIGASE LIGAND MOIETIES - COMPOUNDS OF FORMULA (II) AND FORMULA (III)

[0635] Reaction Scheme 1

[0636] (Rzis Rxor Rv)

[0637] Synthetic Conditions A

[0638] An appropriate acid (RZCOOH in the above Reaction Scheme 1) (1. eq), DMAP (0.04 eq), and EDC (1.2 eq) were added to a solution of 3-aminopiperidine-2, 6-dione (1 eq) and A / -hydroxybenzotriazole (1.2 eq) in DMF (0.5 M). The reaction mixture was stirred overnight at room temperature (20-25°C). After removal of the solvent under reduced pressure, the crude product was purified by preparative HPLC, flash column chromatography or preparative TLC.

[0639] Synthetic Conditions B

[0640] DIPEA (2-3 eq) was added to a solution of an appropriate acid (RZCOOH in the above Reaction Scheme 1), DMAP (0-0.1 eq), HATU (1.0-1.5 eq) and 3-aminopiperidine-2, 6-dione hydrochloride (1.2-3.0 eq) in DMF (0.1-0.5 M). The reaction mixture was stirred overnight at room temperature (20-25°C). After removal of the solvent under reduced pressure, the crude product was purified by preparative HPLC, flash column chromatography or preparative TLC.

[0641] Synthetic Conditions C CDI (1.2-2 eq) was added to a solution of an appropriate acid (RZCOOH in the above Reaction Scheme 1) in DMF (0.1-0.5 M) and stirred for lh at 50 °C. After cooling to room temperature, 3- aminopiperidine-2, 6-dione hydrochloride (1.2-1.5 equiv) was added and the reaction mixture was stirred overnight at room temperature (20-25°C). After removal of the solvent under reduced pressure, the crude product was purified by preparative HPLC, flash column chromatography or preparative TLC.

[0642] Table 6:

[0643] Example 77: Synthesis of N-(2,6-dioxopiperidin-3-yl)-lH-l,3-benzodiazole-7-carboxamide (2)

[0644] To a solution of 3-aminopiperidine-2, 6-dione (0.96 g, 7.5 mmol) and A / -hydroxybenzotriazole (1.22 g, 9.0 mmol) in DMF (15 mL) were added lH-benzo[d]imidazole-7-carboxylic acid (8.25 g, 1.3 mmol), DMAP (37 mg, 0.30 mmol), and EDC (1.40 g, 9.0 mmol). The reaction mixture was stirred overnight at room temperature. Water (30 mL) was added and the obtained solution was extracted with dichloromethane (3x20 mL). The combined organic layers were washed with water, dried over NajSCU, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain target compound (0.41 g, 20% yield).

[0645] JH NMR: (400MHz, DMSO-d6) 6 10.49 (s, 1H), 9.67 - 9.52 (m, 1H), 9.45 - 9.28 (m, 1H), 8.12 (d, J= 7.4 Hz, 1H) 8.01 (d, J= 8.1 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 4.90 - 4.78 (m, 1H), 3.85 (brs, 1H), 2.92 - 2.77 (m, 1H), 2.65 - 2.54 (m, 1H), 2.36 - 2.16 (m, 1H), 2.15 - 2.02 (m, 1H)

[0646] LCMS (m / z [M+H]+): 273.1

[0647] Example 78: Synthesis of / V-(2,6-dioxopiperidin-3-yl)-5-hexanamido-l-methyl-lH- benzofcflimidazole-7-carboxamide (6)

[0648] Step A: 5-amino-l-methyl-lH-benzo[d]imidazole-7-carboxylic acid dihydrochloride (20 mg, 0.076 mmol) and hexanoyl chloride (l.leq.) were dissolved in 4 mL of dry DCM and cooled in water / ice bath. TEA (4 eq.) was slowly injected into the reaction mixture. The ice bath was removed and the reaction was allowed to warm up to ambient temperature. The reaction was completed in two hours, monitored by LCMS. The solution was diluted with DCM (lOmL) and washed with 7mL 3% HCI water soln. The aqueous phase was then evaporated to yield off-white crystals and S-hexanamido-1- methyl-lH-benzo[d]imidazole-7-carboxylic acid was used directly in the next step.

[0649] Step B: This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (29% yield), and 5-hexanamido-l-methyl-lH-benzo[d]imidazole-7- carboxylic acid (20 mg) as a starting material.

[0650] JH NMR (500 MHz, DMSO) 6 10.87 (s, 1H), 10.00 (s, 1H), 8.97 (t, J = 14.9 Hz, 1H), 8.21 (s, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 4.79 (ddd, J = 12.6, 8.4, 5.4 Hz, 1H), 3.82 (s, 3H), 2.82 (ddd, J = 17.4, 13.1, 5.6 Hz, 1H), 2.57 (dt, J = 16.6, 3.2 Hz, 1H), 2.31 (t, J = 7.4 Hz, 2H), 2.20 - 2.09 (m, 1H), 2.09 - 2.01 (m, 1H), 1.67 - 1.56 (m, 2H), 1.37 - 1.25 (m, 4H), 0.87 (dt, J = 7.1, 5.0 Hz, 3H). LCMS (m / z [M+H]+): 400.2

[0651] Example 79: Synthesis of A / -(2,6-dioxopiperidin-3-yl)-2-methyl-lH-benzofcflimidazole-4- carboxamide (15)

[0652] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (20% yield), and 2-methyl-lH-benzo[d]imidazole-4-carboxylic acid (20 mg) as a starting material.

[0653] XH NMR (500 MHz, DMSO) 6 12.73 (s, 1H), 10.90 (s, 1H), 10.29 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.63 (s, 1H), 7.32 - 7.23 (m, 1H), 4.87 (ddd, J = 12.6, 7.1, 5.4 Hz, 1H), 2.89 - 2.76 (m, 1H), 2.58 (s, 3H), 2.55 (d, J = 3.7 Hz, 1H), 2.28 - 2.19 (m, 1H), 2.18 - 2.07 (m, 1H).

[0654] LCMS (m / z (M+H]+): 286.5

[0655] Example 80: Synthesis of 2-methyl-A / -(2-oxoazepan-3-yl)-lH-l,3-benzodiazole-4-carboxamide (19)

[0656] A vial was charged with 2-methyl-lH-l,3-benzodiazole-4-carboxylic acid (60.0 mg, 0.341 mmol, 1.000 eq), 3-aminoazepan-2-one hydrochloride (67.3 mg, 0.409 mmol, 1.200 eq), DMAP (4.2 mg, 0.034 mmol, 0.100 eq) and purged with Argon for 15 min. DMF (10 mL) added via syringe followed by DIPEA (0.119 mL, 0.681 mmol, 2.000 eq) and HATL) (155.4 mg, 0.409 mmol, 1.200 eq) and the reaction mixture was stirred overnight. Solvent was evaporated under reduced pressure and the crude compound was purified by preparative TLC to provide 81 mg (82% yield) of the product. 1H), 2.58 (s, 3H), 2.03 - 1.90 (m, 2H), 1.82 - 1.70 (m, 2H), 1.53 (dd, J = 24.4, 11.9 Hz, 1H), 1.34 - 1.21 (m, 1H).

[0657] LCMS (m / z [M+H]+): 286.9

[0658] Example 81: Synthesis of A / -(2,7-dioxoazepan-3-yl)-2-methyl-lH-benzo(d|imidazole-4- carboxamide (20)

[0659] To a solution of 2-methyl-N-(2-oxoazepan-3-yl)-lH-l,3-benzodiazole-4-carboxamide (20.0 mg, 0.070 mmol, 1.000 eq) in MeCN (4.0 mL) / DMS0 (0.085 mL) / water (0.010 mL) was added Dess-Martin periodinane (74.1 mg, 0.175 mmol, 2.500 eq). The suspension was heated at 80 °C for 1 h. Solvent was evaporated under reduced pressure and the crude product was purified by preparative TLC and HPLC to provide 16 mg (76%) of the product.

[0660] XH NMR (500 MHz, DMSO) 6 12.73 (s, 1H), 10.67 (s, 1H), 10.38 (d, J = 6.5 Hz, 1H), 7.81 (dd, J = 7.6, 1.0 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 5.19 - 5.06 (m, 1H), 3.08 - 2.95 (m, 1H), 2.65 - 2.61 (m, 1H), 2.60 (s, 3H), 2.35 - 2.22 (m, 1H), 2.08 - 1.94 (m, 1H), 1.89 - 1.69 (m, 2H).

[0661] LCMS (m / z (M+H]+): 301.1

[0662] Example 82: Synthesis of 6-amino- / V-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)-lH-l,3- benzodiazole-7-carboxamide (26) Step A: To a stirred solution of methyl 2-amino-6-fluoro-3-nitrobenzoate (2 g, 9.339 mmol) in DMSO (20 mL) was added K2CO3 (2.58 g, 18.67 mmol) followed by addition of (4-methoxyphenyl) methanamine (1.59 mL, 12.14 mmol). Then the reaction mixture was stirred at RT for 16 h. After completion of the reaction, quenched with ice water and precipitate was filtered and dried to give methyl 2-amino-6-((4-methoxybenzyl)amino)-3-nitrobenzoate 2.0 g (64% yield).

[0663] Step B: To a stirred solution of methyl 2-amino-6-((4-methoxybenzyl)amino)-3-nitrobenzoate (550 mg, 1.66 mmol) in THF (16 ml) was added Zn (1.5 g, 21.6 mmol) followed by addition of NH4CI (1.15 g, 21.6 mmol) in water (3 ml) at 0 °C and stirred at RT for lh. After completion of the reaction, reaction mixture was filtered through celite, washed with ethyl acetate. Organic layer was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure to give methyl 2,3- diamino-6- ((4-methoxybenzyl)amino)benzoate (250 mg, crude) as brownish solid.

[0664] Step C: Methyl 2,3-diamino-6-((4-methoxybenzyl)amino)benzoate (2 g, 6.645 mmol) in TFA (20 mL) was stirred at rt for 16 h . After completion of the reaction, TFA was removed and quenched with aqueous NaHCOs and extracted with ethyl acetate. Organic layer washed with brine and dried over NazSO4 and concentrated and purified by flash column chromatography to give methyl 6-amino-2- (trifluoromethyl)-l / - / -benzo[cf|imidazole-7-carboxylate 200 mg (13% yield).

[0665] Step D: To a stirred solution of methyl 6-amino-2-(trifluoromethyl)-lM-benzo[d]imidazole-7- carboxylate (600 mg, 2.317 mmol) in dioxane (5 mL) was added aq NaOH (IN) (15 mL) followed by addition of BOC2O (3.2 mL , 13.9 mmol) at 0 °C and stirred at RT for 72h. After completion of the reaction quenched with ice water and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by flash column chromatography to give methyl 6- ((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-lH-benzo[d]imidazole-7-carboxylate 600 mg (72% yield).

[0666] Step E: Solution of methyl 6-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-lH-benzo[d]imidazole- 7-carboxylate in 50% aq NaOH (13 mL) was stirred at 80 °C for 4 h. After completion of reaction, reaction mixture was acidified with 2M HCI and the precipitate was filtered to give 6-((tert- butoxycarbonyl)amino)-2-(trifluoromethyl)-lH-benzo[d]imidazole-7-carboxylic acid 300 mg (52% yield). Step F: tert-butyl A / -{7-[(2,6-dioxopiperidin-3-yl)carbamoyl]-2-(trifluoromethyl)-lH-l,3-benzodiazol- 6-yl}carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (36% yield) using 5-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)- lH-benzo[d]imidazole-4-carboxylic acid (30.0 mg) as a starting material.

[0667] Step G: Tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-(trifluoromethyl)-lH-benzo[d]irnidazol- 5-yl)carbamate (10.0 mg, 0.022 mmol, 1.000 eq) was dissolved in THF (0.220 mL) and 4M HCI in dioxane (0.038 mL, 1.098 mmol, 50.000 eq) was added. The mixture was stirring in RT for 4 h. Solvent was evaporated under reduced pressure to give 6-amino- / V-(2,6-dioxopiperidin-3-yl)-2- (trifluoromethyl)-lH-l,3-benzodiazole-7-carboxamide hydrochloride 8.0 mg (88.0% yield).

[0668] 1H NMR (500 MHz, DMSO) S 14.15 (s, 1H), 10.91 (s, 1H), 10.19 (s, 1H), 7.54 (d, J = 9.0 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 4.86 - 4.77 (m, 1H), 2.88 - 2.75 (m, 1H), 2.63 - 2.54 (m, 1H), 2.33 - 2.22 (m, 1H), 2.10 (qd, J =12.9, 4.4 Hz, 1H).

[0669] LCMS (m / z (M+H]+): 356.3

[0670] Example 83: Synthesis of 5-amino- / V-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)-lH- benzo[dlimidazole-7-carboxamide (27)

[0671] Step A: TFA (2 mL) and 4(N) HCI (5 mL) were added to 2,3-diamino-5-nitrobenzoic acid (500 mg , 2.54 mmol). Then the resulting reaction mixture was allowed to reflux for 12 h. After completion of reaction, the reaction mixture was cooled to 0 °C and then carefully neutralized with 10M NaOH solution. Aqueous part was extracted by DCM (100 mL x 3). Organic layer was washed with brine and dried over NazSO4 and concentrated to get the crude. Finally the crude was triturated with pentane and ether to get crude compound of 5-nitro-2-(trifluoromethyl)-lW-benzo[d]imidazole-7-carboxylic acid (500 mg) as dark brown solid. Compound was used in next step without further purification Step B: To a stirred solution of 5-nitro-2-(trifluoromethyl)-lH-benzo[d]imidazole-7-carboxylic acid (500.0 mg, 1.82 mmol) in MeOH (10 mL) was added 10% Pd / C (193 mg). The reaction mixture was allowed to stir at rt for 4 h under hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure to get methyl 5-amino- 2-(trifluoromethyl)-lH-benzo[d]imidazole-7-carboxylic acid (500 mg) as crude which was used in next step without further purification.

[0672] Step C: To an ice cooled solution of methyl 5-amino-2-(trifluoromethyl)-lH-benzo[d]imidazole-7- carboxylic acid (1.0 g, 4.1 mmol) in dioxane (5.0 mL) and H2O (5.0 mL) was added TEA (0.85 mL, 6.1 mmol). The reaction mixture was allowed to stir at ice cool condition for 2-3 min. B0C2O (1.0 mL, 4.49 mmol) was added and the reaction mixture was stirred at RT for 6h. After completion of reaction, solvent was evaporated and the crude product was purified by preparative HPLC to give 5-((tert- butoxycarbonyl)amino)-2-(trifluoromethyl)-lH-benzo[d]imidazole-7-carboxylic acid (50 mg) as white solid (2.8% yield over 3 steps).

[0673] Step D: Tert-butyl (7-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-(trifluoromethyl)-lH-benzo[d]imidazol- 5-yl)carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (37% yield) using 5-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)- lH-benzo[d]imidazole-7-carboxylic acid (30.0 mg) as a starting material.

[0674] Step E: Tert-butyl (7-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-(trifluoromethyl)-lH-benzo[d]imidazol- 5-yl)carbamate (10.0 mg, 0.022 mmol, 1.000 eq) was dissolved in THF (0.220 mL) and 4 M HCl in dioxane_(0.038 mL, 1.098 mmol, 50.000 eq) was added. The mixture was stirring in RT for 4 h. Solvent was evaporated under reduced pressure to give 5-amino-A / -(2,6-dioxopiperidin-3-yl)-2- (trifluoromethyl)-lH-benzo[d]imidazole-7-carboxamide hydrochloride.

[0675] XH NMR (500 MHz, DMSO) 6 13.67 (s, 1H), 10.91 (s, 1H), 9.71 (s, 1H), 7.48 - 7.34 (m, 1H), 6.86 (d, J = 2.1 Hz, 1H), 5.53 (s, 1H), 4.84 (ddd, J = 12.4, 7.0, 5.2 Hz, 2H), 2.80 (ddd, J = 17.3, 13.5, 5.5 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.32 - 2.21 (m, 1H), 2.15 - 2.03 (m, 1H).

[0676] LCMS (m / z [M+H]+): 355.9

[0677] Example 84: Synthesis of 7-amino- / V-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)-lH- benzo[cflimidazole-4-carboxamide (28)

[0678]

[0679] Step A: To ethyl 3-acetamido-4-chlorobenzoate (20.0 g, 82.97 mmol) was dropwise added 40.0 mL of 100% HNO3 at -15 °C and the resultant reaction mixture was stirred and warmed up slowly to 10°C during 2 h and then stirred at RT for 12 h, poured into crashed ice, the solids were filtered, dried under reduced pressure and the mixture of nitro compounds (16 g) was used directly in the next step. To a stirred solution of nitro compounds in 160 mL of ethanol was added 7.5 mL of cone. H2SO4. The reaction mixture was refluxed for 16 h, concentrated under reduced pressure and ice-cold water was added. The product was extracted into DCM, the combined organic layers were washed with brine, dried over NajSCU and concentrated. The crude product was purified by flash column chromatography to give ethyl 3-amino-4-chloro-2-nitrobenzoate (6.3 g, 30%).

[0680] Step B: To a stirred solution of ethyl 3-amino-4-chloro-2-nitrobenzoate (6.3 g, 25.753 mmol) in ethanol (60.0 mL) and water (30.0 mL) was added Fe powder (10.78 g) followed by NH4CI (1.791 g). The reaction mixture was refluxed for 12 h, concentrated under reduced pressure, diluted with DCM, filtered through celite bed and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give ethyl 2,3-diamino-4-chlorobenzoate (5 g, 90.45%).

[0681] Step C: To ethyl 2,3-diamino-4-chlorobenzoate (2.0 g , 9.317 mmol , 1.0 eq) was added 15 ml of TFA and the reaction mixture was refluxed for 12 h and concentrated under reduced pressure. To the residue was added NaHCO3solution and the product was extracted with ethyl acetate, washed with brine, dried over NazSCU and concentrated. The crude product was purified by flash column chromatography to give ethyl 7-chloro-2-(trifluoromethyl)-lH-benzo[d]imidazole-4-carboxylate (2.4 g, 88% yield).

[0682] Step D: A solution of ethyl 7-chloro-2-(trifluoromethyl)-lH-benzo[d]imidazole-4-carboxylate (1.0 g, 3.417 mmol) in dioxane (12 mL) was degassed under argon atmosphere for 10-15 min. Cs2CO3(2.22 g, 6.834 mmol), NH2B0C (1.60 g, 13.669 mmol), X-phos (326 mg, 0.683 mmol) and X-phosPdG3 (0.289 g, 0.342 mmol) were added and reaction mixture was stirred at 85°C for 16 h. Reaction mixture was filtered through celite bed, concentrated and purified by flash column chromatography to give ethyl 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-lH-benzo[d]imidazole-4-carboxylate (800mg, 62% yield).

[0683] Step E: A stirred solution of ethyl 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-lH- benzo[d]imidazole-4-carboxylate (500.0 mg, 1.339 mmol) in MeOH (3.0 mL) and THF (3.0mL) was added slowly 50% aqueous NaOH solution (6.0 mL) at ice cool condition. Then the resultant reaction mixture was allowed to stir at rt for 16 h. Reaction mixture was concentrated under reduced pressure and then it was diluted with water and washed with ethyl acetate. After that the aqueous part was gently neutralized with saturated aqueous citric acid solution in ice cool condition and then it was extracted with ethyl acetate. Then the combined organic layer was washed with brine and then dried over NazSCU, filtered and concentrated to get the crude which was triturated with pentane and ether to get 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)-lH-benzo[d]imidazole-4-carboxylic acid (250mg, 54.06% yield) as white solid.

[0684] Step F: Tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-(trifluoromethyl)-lW-benzo[d]imidazol- 7-yl)carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (80% yield), and 7-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)- lH-benzo[d]imidazole-4-carboxylic acid (30 mg) as a starting material.

[0685] 1H NMR (500 MHz, DMSO) 6 14.02 (s, 1H), 10.93 (s, 1H), 9.57 (s, 1H), 8.93 (s, 1H), 7.98 (s, 2H), 4.86 (dt, J = 12.3, 5.9 Hz, 1H), 2.88 - 2.79 (m, 1H), 2.57 (s, 1H), 2.29 (d, J = 12.4 Hz, 1H), 2.11 (td, J = 13.1, 4.5 Hz, 1H), 1.53 (s, 9H).

[0686] LCMS (m / z [M+H]+): 456.5

[0687] Step G: To the mixture of tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-(trifluoromethyl)-lH- benzo[d]imidazol-7-yl)carbamate (8 mg, 0.018 mmol) in DCM (0.5 mL) was added TFA (0.1 mL) and the reaction mixture was stirred at RT for 18h. The mixture was concentrated under reduced pressure and was purified by HPLC to give 7-amino-N-(2,6-dioxopiperidin-3-yl)-2-(trifluoromethyl)-lH-l,3- benzodiazole-4-carboxamide trifluoroacetate (44% yield).

[0688] XH NMR (500 MHz, DMSO) 6 10.51 (s, 1H), 7.75 (d, J = 8.3 Hz, 1H), 6.58 (s, 1H), 5.97 (d, J = 72.1 Hz, 2H), 4.76 (d, J = 10.7 Hz, 1H), 2.81 - 2.73 (m, 1H), 2.60 (dd, J = 17.5, 3.9 Hz, 1H), 2.12 (d, J = 26.4 Hz, 2H). LCMS (m / z [M+H]+): 356.0

[0689] Example 85: Synthesis of 6-(aminomethyl)-M-(2,6-dioxopiperidin-3-yl)-2-methyl-lH- benzofcflimidazole-4-carboxamide (31)

[0690] Step A: To a degassed solution of ethyl 6-bromo-2-methyl-lH-benzo[d]imidazole-4-carboxylate (SOOmg, 1.76 mmol) in DMF (12 mL) were added ZN(CN)2(518 mg, 4.41 mmol) and Pd(PPha)4 (408 mg, 0.35 mmol) and the reaction mixture was at 120 °C for 16h, quenched with ice water, extracted with ethyl acetate, dried over Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give ethyl 6-cyano-2-methyl-lH-benzo[d]imidazole-4-carboxylate (27% yield).

[0691] Step B: To a solution of ethyl 6-cyano-2-methyl-lH-benzo[d]imidazole-4-carboxylate (400 mg, 1.747 mmol) in ethanol (13 ml) were added Raney-nickel and Boc2O (2.1 ml, 8.734 mmol) and the reaction mixture was stirred under hydrogen (15 psi) for 16h, filtered through celite bed, filtrates were concentrated under reduced pressure and purified by flash column chromatography to give l-(tert- butyl) 4-ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-lH-benzo[d]imidazole-l,4- dicarboxylate (47% yield).

[0692] Step C: To a solution of l-( tert-butyl) 4-ethyl 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-lH- benzo[d]imidazole-l,4-dicarboxylate (430 mg, 0.993 mmol) in THF:MeOH 1:1 (10 mL) was added 50% aqueous NaOH (4 mL) and the reaction mixture was stirred at RT for 16h, neutralized with IM HCI, and filtered. The solids were dried to give 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-lH- benzo[d]imidazole-4-carboxylic acid (62% yield).

[0693] Step D: Tert-butyl ((4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-methyl-lH-benzo[d]imidazol-6- yl)methyl)carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (45 % yield), and 6-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-lH- benzo[d]imidazole-4-carboxylic acid (30 mg) as a starting material.

[0694] XH NMR (500 MHz, DMSO) 6 12.64 (s, 1H), 10.89 (s, 1H), 10.24 (d, J = 7.3 Hz, 1H), 8.16 (s, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.45 (t, J = 6.4 Hz, 1H), 4.88 (dt, J = 12.6, 6.4 Hz, 1H), 4.24 (d, J = 6.2 Hz, 2H), 2.82 (ddd, J = 17.3, 13.3, 5.5 Hz, 1H), 2.61 - 2.52 (m, 4H), 2.27 - 2.20 (m, 1H), 2.11 (qd, J = 12.9, 4.3 Hz, 1H), 1.40 (s, 9H).

[0695] LCMS (m / z [M+H]+): 416.0

[0696] Step E: Tert-butyl ((4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-methyl-lH-benzo[d]imidazol-6- yl)methyl)carbamate was suspended in DCM (0.5 mL). To the mixture was added TFA (0.1 mL) and stirred for 2 h at RT. The crude was concentrated in vacuo, dissolved in water and freeze-dried to give 6-(aminomethyl)- / V-(2,6-dioxopiperidin-3-yl)-2-methyl-lH-benzo[d]imidazole-4-carboxamide.

[0697] XH NMR (500 MHz, DMSO) 6 10.93 (s, 1H), 10.12 (s, 1H), 8.14 (s, 3H), 7.97 (d, J = 1.6 Hz, 1H), 7.79 (s, 1H), 4.88 (dt, J= 13.0, 7.1 Hz, 1H), 4.20 (q, J= 5.8 Hz, 2H), 2.84 (ddd, J= 17.3, 13.0, 6.0 Hz, 1H), 2.67 - 2.53 (m, 4H), 2.25 - 2.09 (m, 2H).

[0698] LCMS (m / z [M+H]+): 315.8

[0699] Example 86: Synthesis of 7-(aminomethyl)- / V-(2,6-dioxopiperidin-3-yl)-2-methyl-lH- benzoMimidazole-4-carboxamide (32)

[0700] Step A: To a stirred solution of ethyl 2,3-diamino-4-chlorobenzoate (1.5 g, 6.99 mmol) in toluene (20.0 mL) was added respectively triethyl orthoacetate (5.1 mL, 27.95 mmol) and PTSA (0.337 g, 1.957 mmol) and the reaction mixture was refluxed for 16 h, concentrated under reduced pressure and the crude product was purified by flash column chromatography to give ethyl 7-chloro-2-methyl- lH-benzo[d]imidazole-4-carboxylate 1.2 g (71% yield). Step B: A solution of ethyl 7-chloro-2-methyl-lH-benzo[d]imidazole-4-carboxylate (400 mg, 1.676 mmol) in DMF (10 mL) was degassed under argon atmosphere for 10-15 minutes. Zn(CN)? (492 mg, 4.19 mmol), X-phos (159.792 mg, 0.335 mmol) and X-phosPdG3 (0141.86 mg, 0.168 mmol) were added and the reaction mixture was heated to 110°C for 16 h. The mixture was filtered through celite bed, diluted with water, the product was extracted with ethyl acetate, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give ethyl 7-cyano-2-methyl-lH-benzo[d]imidazole-4-carboxylate 251 mg (65% yield).

[0701] Step C: The a stirred solution of ethyl 7-cyano-2-methyl-lH-benzo[d]imidazole-4-carboxylate (3) (375 mg, 1.636 mmol) in ethanol (10 mL) was added BocjO (0.564 mL, 2.454 mmol) and Raney-nickel (200 mg) and reaction mixture was stirred at RT under hydrogen atmosphere for 16 h, filtered through celite bed and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give ethyl 7-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-lH- benzo(d]imidazole-4-carboxylate 230 mg (42% yield).

[0702] Step D: To a solution of ethyl 7-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-lH- benzo[d]imidazole-4-carboxylate (200.0 mg, 0.6 mmol) in MeOH (1 mL) and THF (1 mL) was added 50% NaOH solution (2 mL) at 0 °C. The reaction mixture was stirred at RT for 16 h, concentrated under reduced pressure, diluted with water and washed with DCM. The aqueous phase was gently acidified by citric acid solution and the product was extracted with ethyl acetate, washed with brine, dried over NajSCU and concentrated under reduced pressure. The crude product was triturated with diethyl ether to give 7-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-lH-benzo[d]imidazole-4- carboxylic acid 60 mg (32%).

[0703] Step E: Tert-butyl ((4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-methyl-lH-benzo[cflimidazol-7- yl)methyl)carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (47 % yield), and 7-(((tert-butoxycarbonyl)amino)methyl)-2-methyl-lH- benzo[d]imidazole-4-carboxylic acid (20 mg) as a starting material.

[0704] XH NMR (500 MHz, DMSO) 6 12.66 (s, 1H), 10.89 (s, 1H), 10.24 (d, J = 7.3 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 6.1 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 4.86 (ddd, J = 12.5, 7.2, 5.2 Hz, 1H), 4.42 (d, J = 6.1 Hz, 2H), 2.81 (ddd, J = 17.3, 13.5, 5.5 Hz, 1H), 2.61 - 2.51 (m, 4H), 2.26 - 2.20 (m, 1H), 2.16 - 2.07 (m, 1H), 1.40 (s, 9H).

[0705] LCMS (m / z [M+H]+): 416.0

[0706] Step F: Tert-butyl ((4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-methyl-lH-benzo[d]imidazol-7- yl)methyl)carbamate was suspended in DCM (0.5 mL). To the mixture was added TFA (0.1 mL) and stirred for 2 h at RT. The crude was concentrated in vacuo, dissolved in water and freeze-dried to give 7-(aminomethyl)- / V-(2,6-dioxopiperidin-3-yl)-2-methyl-lH-benzo[d]imidazole-4-carboxamide.

[0707] TH NMR (500 MHz, DMSO) 510.91 (s, 1H), 10.12 (s, 1H), 9.20 (s, 1H), 8.30 (s, 3H), 7.85 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 4.82 (d, J = 10.7 Hz, 1H), 4.39 (d, J = 5.7 Hz, 2H), 2.88 - 2.77 (m, 1H), 2.64 (s, 3H), 2.62 - 2.50 (m, 1H), 2.17 (s, 2H).

[0708] LCMS (m / z [M+H]+): 316.1

[0709] Example 87: Synthesis of 5-(2,4-dimethoxyphenyl)- / V-(2,6-dioxopiperidin-3-yl)-2-methyl-3H- imidazo[4,5-blpyridine-7-carboxamide (33)

[0710] Step A: To a suspension of 5-(2,4-dimethoxyphenyl)-2-methyl-lM-imidazo[4,5-b)pyridine-7- carboxylic acid (10.0 mg, 31.917 pmol, 1.000 eq) and HOSu (4.4 mg, 38.300 pmol, 1.200 eq) in DCM (1.0 mL) was added a solution of DCC (7.9 mg, 38.300 pmol, 1.200 eq) in DCM (0.500 mL). The reaction mixture was stirred at RT for 18h. The reaction mixture was concentrated under reduced pressure and purified by preparative TLC to give 2,5-dioxopyrrolidin-l-yl 5-(2,4-dimethoxyphenyl)-2-methyl- lH-imidazo[4,5-b]pyridine-7-carboxylate (71% yield).

[0711] Step B: To a solution of 3-aminopiperidine-2, 6-dione hydrochloride (8.4 mg, 51.171 pmol, 3.000 eq) and DIPEA (9 pL, 51.171 pmol, 3.000 eq) in DMF (2.0 mL) was added 2,5-dioxopyrrolidin-l-yl 5-(2,4- dimethoxyphenyl)-2-methyl-lH-imidazo[4,5-b]pyridine-7-carboxylate (7.0 mg, 17.057 pmol, 1.000 eq) in one portion. The reaction mixture was stirred at RT for 18h. The solvent was evaporated under reduced pressure and the residue was purified by preparative TLC to provide 4.1 mg (56%) of product.

[0712] XH NMR (500 MHz, DMSO) 5 13.04 (s, 1H), 10.54 (s, 1H), 8.72 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 8.6, 2.4 Hz, 1H), 4.81 (q, J = 8.2 Hz, 1H), 3.87 (s, 3H), 3.87 (s, 3H), 2.81 (dt, J = 18.0, 9.5 Hz, 1H), 2.67 - 2.57 (m, 1H), 2.53 (s, 3H), 2.15 (dq, J = 9.1, 5.2, 4.1 Hz, 2H).

[0713] LCMS (m / z [M+H]+): 423.9

[0714] Example 88: Synthesis of / V-(2,6-dioxopiperidin-3-yl)-2-methyl-lH-thieno[2,3-cflimidazole-6- carboxamide (59)

[0715] Step A: A mixture of methyl 4,5-diaminothiophene-3-carboxylate (400 mg, 2.04 mmol) in dioxane (3 mL), triethyl orthoacetate (3 mL) and PTSA (102 mg, 0.40 mmol) was heated to reflux for 16 h, the reaction mixture was concentrated under reduced pressure and the crude material was purified by flash column chromatography to give methyl 2-methyl-lH-thieno[2,3-d]imidazole-6-carboxylate 200 mg (50% yield).

[0716] Step B: To a stirred solution of methyl 2-methyl-lH-thieno[2,3-d]imidazole-6-carboxylate (0.13 g, 1.02 mmol) in methanol (0.5 mL) and THF (2 mL) was added NaOH (27 mg, 0.68 mmol) in water (0.5 mL) and the resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous part was acidified with 6N HCI to pH~5 and the resulting precipitate was filtered, washed with water and purified by HPLC to give 2-methyl-lH-thieno[2,3- d]imidazole-6-carboxylic acid 70 mg (37%).

[0717] Step C: W-(2,6-dioxopiperidin-3-yl)-2-methyl-lH-thieno[2,3-d]imidazole-6-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (17% yield), and 2-methyl-3W-thieno[2,3-d]imidazole-6-carboxylic acid (20 mg) as a starting material.XH NMR (500 MHz, DMSO): 6 12.53 (s, 1H), 10.87 (s, 1H), 8.70 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 4.78 - 4.67 (m, 1H), 2.81 (ddd, J = 17.4, 13.3, 5.5 Hz, 1H), 2.56 (ddd, J = 17.1, 4.1, 2.9 Hz, 1H), 2.43 (s, 3H), 2.16 (qd, J = 12.9, 4.5 Hz, 1H), 2.04 - 1.96 (m, 1H).

[0718] LCMS (m / z (M+H]+): 293.0

[0719] Example 89: Synthesis of / V-(2,6-dioxooiperidin-3-yl)-lH-thieno(2,3-cflimidazole-6-carboxamide

[0720] (60)

[0721] Step A: A Solution of methyl 4-acetamidothiophene-3-carboxylate (3 g, 12.3 mmol) in acetic anhydride (40 mL) was cooled at -15 °C. To it a precooled solution (at -15 °C) of concentrated nitric acid (6 mL) in 30 mL acetic anhydride was added drop wise very slowly with stirring. After 30 min the reaction mixture was poured into crushed ice and the resulting light yellow coloured solid was filtered. The solid was thoroughly washed with water and diethyl ether to give 2.4 g (81%) of methyl 4-acetamido-5-nitrothiophene-3-carboxylate.

[0722] Step B: To a stirred solution of methyl 4-acetamido-5-nitrothiophene-3-carboxylate (2g, 8.19 mmol) in 4N HCI-dioxane (20 mL), methanol (10 mL) was added and the resulting solution was heated at 100 °C for 16 h. After cooling, dioxane was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine and dried over NazSCU. After concentration under reduced pressure, the crude methyl 4-amino-5-nitrothiophene-3-carboxylate 850 mg (51%) was used in the next step without further purification.

[0723] Step C: To a stirred solution of methyl 4-amino-5-nitrothiophene-3-carboxylate (1 g, 4.95 mmol) in a mixture of dioxane-HCI (10 mL) and methanol (10 mL), SnCIz was added and the resulting solution was stirred at RT for 2h. The reaction mixture was then poured on to a precooled solution of ammonium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The crude methyl 4,5-diamino-thiophene- 3-carboxylate 700 mg (82%) was used in the next step without further purification.

[0724] Step D: To a stirred solution of methyl 4,5-diaminothiophene-3-carboxylate (650 mg, 3.78 mmol) in a mixture of trimethyl orthoformate (2.5 mL) and toluene (2.5 mL), a catalytic amount of PTSA (189 mg, 0.75 mmol) was added and the resulting solution was heated at 110 °C for 2h. After that the volatiles were removed under reduced pressure, the crude material was purified by flash column chromatography to give 350 mg (50%) of methyl lH-thieno[2,3-d]imidazole-6-carboxylate.

[0725] Step E: To a stirred solution of methyl lH-thieno[2,3-d]imidazole-6-carboxylate (400 mg, 2.2 mmol mmol) in methanol (3 mL) and THE (3 mL), NaOH (439 mg, 10.9 mmol) dissolved in water (1 mL) was added and the resulting solution was stirred for 16 h. The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous part was acidified with 6N HCI to pH~5 and the resulting brown coloured precipitate was filtered, washed with water and diethyl ether to obtain 1H- thieno[2,3-d]imidazole-6-carboxylic acid 230 mg (62%).

[0726] Step F: / V-(2,6-dioxopiperidin-3-yl)-lH-thieno[2,3-cf|imidazole-6-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (40% yield), and lH-thieno[2,3-d]imidazole-6-carboxylic acid (20 mg) as a starting material.

[0727] XH NMR (500 MHz, DMSO) 5 12.79 (s, 1H), 10.88 (s, 1H), 8.74 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 1.3 Hz, 1H), 7.90 (s, 1H), 4.74 (ddd, J = 13.3, 8.1, 5.3 Hz, 1H), 2.81 (ddd, J = 17.2, 13.3, 5.5 Hz, 1H), 2.57 (dt, J = 18.0, 4.1 Hz, 1H), 2.16 (qd, J = 12.9, 4.5 Hz, 1H), 2.01 (dtd, J = 13.1, 5.4, 2.8 Hz, 1H).

[0728] LCMS (m / z (M+H]+): 279.0

[0729] Example 90: Synthesis of A / -(2,6-dioxopiperidin-3-yl)-2,5,6-trimethyl-4H-thieno[3,2-blpyrrole-3- carboxamide (61) Step A: To a solution of ethyl 2,5,6-trimethyl-4H-thieno[3,2-b]-pyrrole-3-carboxylate (10.0 mg, 0.042 mmol, 1.000 eq) in a mixture of HsO (1.0 mL), THF (1.0 mL) and MeOH (1.0 mL) was added IM LiOH (2.0 mL, 2.000 mmol, 17.702 eq). The reaction was stirred for 24h at rt. After this time, to a mixture was added IM HCI (2.0 mL, 2.000 mmol, 17.702 eq) to neutralize pH. The crude was concentrated in vacuo and used to the next step without further purification.

[0730] Step B: N-(2,6-dioxopiperidin-3-yl)-2,5,6-trimethyl-4H-thieno[3,2-b]pyrrole-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions B, above (23% yield), and 2,5,6-trimethyl-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (8.8 mg) as a starting material.

[0731] 1H NMR (500 MHz, DMSO) 6 10.87 (s, 1H), 10.45 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 4.76 (ddd, J = 12.3, 8.2, 5.4 Hz, 1H), 2.80 (ddd, J = 17.3, 13.4, 5.6 Hz, 1H), 2.63 (s, 3H), 2.59 - 2.52 (m, 1H), 2.22 (s, 3H), 2.16 (qd, J = 13.0, 4.5 Hz, 1H), 2.05 (qd, J = 4.8, 2.3 Hz, 1H), 2.02 (s, 3H).

[0732] LCMS (m / z [M+H]+): 319.8

[0733] SYNTHESIS OF LIGASE LIGAND MOIETIES OF FORMULA (IV)

[0734] Example 91: Synthesis of 3-(5-amino-2-methylquinolin-3-yl)piperidine-2,6-dione (63)

[0735] Step 1: Synthesis of3-bromo-2-methyl-S-nitro-8,8a-dihydroquinoline 2-Methyl-5-nitro-8,8a-dihydroquinoline (19.8 g, 105.3 mmol) was dissolved in dichloromethane (250 mL) and cooled to 5°C in an ice bath. m-CPBA (32.9 g, 133.4 mmol, 70%) was added in portions thereto and the reaction mixture was stirred at room temperature (20-25°C) for 12 hrs. The mixture was washed with 2M NaOH solution (2x150 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to afford a yellow solid (22 g). The solid was dissolved in CHCI3(200 mL), the obtained solution was cooled to 5°C in the ice-bath, and phosphoryl bromide (62.6 g, 218.3 mmol) in CHCI3(300 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature (20-25°C) for 12 hrs, poured into ice-water, basified to pH=12 with solid potassium carbonate, and extracted with CHCI3(3 x 100 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated under vacuum. The crude product was purified by flash column chromatography (eluent Hexane-MTBE 0-100%) to afford 2.9 g of 3- bromo-2-methyl-5-nitro-8,8a-dihydroquinoline (10% yield) as a brown solid.

[0736] Step 2: Synthesis of3-[2,6-bis(benzyloxy)pyridin-3-yl]-2-methyl-S-nitro-8,8a-dihydroquinoline

[0737] 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (4.55 g, 10.9 mmol), tripotassium phosphate (4.8 g, 22.6 mmol), and Pd(dppf)CI2CH2CI2 (0.86 g, 1 mmol) were added sequentially to a solution of 3-bromo-2-methyl-5-nitro-8,8a-dihydroquinoline (2.9 g, 10.86 mmol) in 1,4- dioxane (50 mL) and water (5 mL). The obtained mixture was stirred at 100°C for 12 hrs under an argon atmosphere. The solvents were removed under vacuum, the residue was diluted with EtOAc (100 mL) and filtered through a pad of silica gel. The filtrate was evaporated under vacuum and recrystallized from EtOAc to afford 2.05 g 3-[2,6-bis(benzyloxy)pyridin-3-yl]-2-methyl-5-nitro-8,8a-dihydroquinoline (4.3 mmol, 39% yield) as a pale yellow solid.

[0738] Step 4: Synthesis of 3-(5-amino-2-methyiquinolin-3-yl)piperidine-2, 6-dione

[0739] Pd on activated charcoal (1.2 g) was added to a solution of 3-[2,6-bis(benzyloxy)pyridin-3-yl]-2-methyl-5- nitro-8,8a-dihydroquinoline (2.05 g, 4.29 mmol) in THF / methanol (5:1, 300 mL). The reaction mixture was stirred under H2atmosphere for 96 hrs. The catalyst was removed by filtration and the filtrate was evaporated under vacuum. The obtained crude product was purified by HPLC (eluent water-acetonitrile) to afford 0.05 g of the target compound 3-(5-amino-2-methylquinolin-3-yl)piperidine-2, 6-dione (4% yield) as a white solid.2H NMR: (500MHz, DMSO-d6) 6 10.92 (s, 1H), 8.25 (s, 1H), 7.33 (t, J= 7.9 Hz, 1H) 7.07 (d, J= 8.2 Hz, 1H), 6.61 (d, J= 7.5 Hz, 1H), 5.86 (brs, 2H), 4.25 - 4.17 (m, 1H), 2.89 - 2.79 (m, 1H), 2.69 - 2.61 (m, 1H), 2.59 (s, 3H), 2.46- 2.36 (m, 1H), 2.15 - 2.08 (m, 1H)

[0740] LCMS (m / z (M+H]+): 270.2

[0741] Example 92: Synthesis of 3-(2-methyl-S-nitroquinolin-3-yl)piperidine-2,6-dione (64)

[0742] Step A: To an ice cold solution of 5-nitro-2-methyl quinoline (2.3 g, 12.22 mmol) in DCM (25 mL) was added m-CPBA (2.3 g, 13.67 mmol). The reaction mixture was warmed to RT and stirred for 16 h. The mixture was filtered and filtrates were washed with 1 M KOH solution, dried over Na2SO4, and concentrated under reduced pressure to give 2-methyl-5-nitroquinoline 1-oxide (88% yield).

[0743] Step B: To an ice cold solution of 2-methyl-5-nitroquinoline 1-oxide (500.0 mg, 2.44 mmol) in DCM (5 mL) was added POBr3(1.4 g, 4.9 mmol) in DCM (5 mL). The reaction mixture warmed to RT and stirred for 48 h. Ice water was added, the solution was neutralized with 10% NH3solution, extracted with DCM, dried over Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give 2-methyl-3-bromo-5-nitroquinoline (14% yield).

[0744] Step C: To a solution of 2-methyl-3-bromo-5-nitroquinoline (600 mg, 2.24 mmol) in dioxane (8 mL) was added KOAc (441 mg, 4.49 mmol) followed by l-(tert-butyldimethylsilyloxy)-l-tert- butoxyethylene (2.07 g, 8.98 mmol) and the reaction mixture was degassed for 15 min under N2. Pd[P(o-Tol)3]2CI2(353.2 mg, 0.449 mmol) was added and the reaction mixture was stirred at 130 °C for 48 h, diluted with ethyl acetate, filtered through celite bed, concentrated under reduced pressure and purified by flash column chromatography to give tert-butyl 2-(2-methyl-5-nitroquinolin-3- yl)acetate (58% yield). Step D: To a solution of tert-butyl 2-(2-methyl-5-nitroquinolin-3-yl)acetate (200 mg, 0.662 mmol) in DMF (10 mL) were added K2CO3(150.6 mg, 0.662 mmol), benzyltriethylammonium chloride (91.4 mg, 0.662mmol) and acrylonitrile (0.043 mL, 0.662 mmol) and the reaction mixture was stirred at RT for 16h. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give tert-butyl 4-cyano-2-(2-methyl-5-nitroquinolin-3-yl)butanoate (40% yield).

[0745] Step E: To an ice cold solution of tert-butyl 4-cyano-2-(2-methyl-5-nitroquinolin-3-yl)butanoate (120.0 mg, 0.338 mmol) in DMSO (5 mL) were added H2O2(0.052 mL, 1.688 mmol) and K2CO3(6.533 mg, 0.047 mmol). The reaction mixture warmed to RT and stirred for 16h, diluted with water, extracted with ethyl acetate, dried over Na2SO4, concentrated under reduced pressure and purified by SFC to give tert-butyl 5-amino-2-(2-methyl-5-nitroquinolin-3-yl)-5-oxopentanoate (51% yield).

[0746] Step F: In a vial were placed tert-butyl 5-amino-2-(2-methyl-5-nitroquinolin-3-yl)-5-oxopentanoate (5.0 mg, 0.013 mmol, 1.000 eq), p-toluenesulfonic acid (25.5 mg, 0.134 mmol, 10.000 eq) and acetonitrile (0.5 mL) and the reaction mixture was stirred at 80°C for 2h. The mixture was concentrated under reduced pressure and purified by HPLC to give 3-(2-methyl-5-nitroquinolin-3- y I) pi peridi ne-2, 6-dione (77% yield).

[0747] XH NMR (500 MHz, DMSO) 6 10.98 (s, 1H), 8.60 (s, 1H), 8.40 - 8.30 (m, 2H), 7.89 (dd, J = 8.5, 7.7 Hz, 1H), 4.42 (dd, J = 12.5, 4.7 Hz, 1H), 2.82 (ddd, J = 17.8, 12.8, 5.3 Hz, 1H), 2.71 (s, 3H), 2.66 - 2.61 (m, 1H), 2.44 (dd, J = 12.8, 4.3 Hz, 1H), 2.14 (ddt, J = 10.0, 7.8, 3.9 Hz, 1H).

[0748] LCMS (m / z [M+H]+): 299.9

[0749] Example 93: Synthesis of 3-(5-fluoro-2-methylquinolin-3-yl)piperidine-2, 6-dione (65) Step A: To a solution of 2-amino-6-fluorobenzaldehyde (1.0 g, 7.19 mmol) in MeOH (20 ml) was added 4-oxopentanoic acid (0.739 ml_, 7.194 mmol) followed by 2M NaOH (5.0 mL). The reaction mixture was refluxed for 18 h, concentrated under reduced pressure, neutralized with acetic acid, the solids were filtered and washed with ether and pentane to give 2-(5-fluoro-2-methylquinolin-3- yl)acetic acid (38%).

[0750] Step B: To a solution of DCC (1.036 g, 5.023 mmol) in DCM (5.0 mL) were added DMAP (446 mg, 3.653 mmol) and 2-(5-fluoro-2-methylquinolin-3-yl)acetic acid (1.0 g, 4.566 mmol). Tert-butanol (0.406 mL, 13.7 mmol) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was diluted water, extracted with ethyl acetate, dried over NajSCU, concentrated under reduced pressure and purified by flash column chromatography to give tert-butyl 2-(5-fluoro-2- methylquinolin-3-yl)acetate (35% yield).

[0751] Step C: To a solution of tert-butyl 2-(5-fluoro-2-methylquinolin-3-yl)acetate (500 mg, 1.816 mmol) in DMF (10 mL) were added K2CO3 (251 mg, 1.816 mmol), benzyltriethylammonium chloride (413.6 mg, 1.816 mmol) and acrylonitrile (0.119 mL, 1.816 mmol) and the reaction mixture was stirred at RT for 16h. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give tert-butyl 4-cyano-2-(5-fluoro-2-methylquinolin-3-yl)butanoate (50% yield).

[0752] Step D: To an ice cold solution of tert-butyl 4-cyano-2-(5-fluoro-2-methylquinolin-3-yl)buta noate (500 mg, 1.524 mmol) in DMSO (5 mL) were added H2O2 (0.238 mL, 7.77 mmol) and K2CO3 (29.5 mg, 0.14 mmol). The reaction mixture warmed to RT and stirred for 16h, diluted with water, extracted with ethyl acetate, dried over Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give tert-butyl 5-amino-2-(5-fluoro-2-methylquinolin-3-yl)-5-oxopentanoate (45% yield).

[0753] Step E: In a vial were placed tert-butyl 5-amino-2-(5-fluoro-2-methylquinolin-3-yl)-5-oxopentanoate (5.0 mg, 0.014 mmol, 1.000 eq), p-toluenesulfonic acid (27.5 mg, 0.144 mmol, 10.000 eq) and acetonitrile (0.5 mL) and the reaction mixture was stirred at 80°C for 2h. The mixture was concentrated under reduced pressure and purified by HPLC to give 3-(5-fluoro-2-methylquinolin-3- yl) pi peridine-2, 6-dione (84% yield).XH NMR (500 MHz, DMSO) 6 10.94 (s, 1H), 8.24 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.70 (td, J = 8.2, 6.2 Hz, 1H), 7.37 (dd, J = 10.0, 7.6 Hz, 1H), 4.36 (dd, J = 12.7, 4.7 Hz, 1H), 2.82 (ddd, J = 17.8, 13.2, 5.4 Hz, 1H), 2.68 (s, 3H), 2.61 (dd, J = 17.4, 3.5 Hz, 1H), 2.57 - 2.51 (m, 1H), 2.12 (dtd, J = 12.8, 5.1, 2.6 Hz, 1H).

[0754] LCMS (m / z [M+H]+): 272.9

[0755] SYNTHESIS OF LIGASE LIGAND MOIETIES - COMPOUNDS OF FORMULA (Va) AND (Vb)

[0756] 3-aminopiperidine-2, 6-dione

[0757] Reaction Scheme 2: General procedure

[0758] Synthetic Conditions D

[0759] An appropriate acid (RXCOOH in the above reaction scheme) (1.1 eq), DMAP (0.04 eq), and EDC (1.2 eq) were added to a solution of 3-aminopiperidine-2, 6-dione (1 eq) and A / -hydroxybenzotriazole (1.2 eq) in DMF (0.5 M). The reaction mixture was stirred overnight at room temperature (20-25°C). Water (2 x DMF volume) was added and the obtained solution was extracted with dichloromethane (3 x DMF volume). The combined organic layers were washed with water, dried over NajSCU, and concentrated under reduced pressure. The crude product was purified by preparative HPLC or by column chromatography.

[0760] Synthetic Conditions E

[0761] An appropriate acid RXCOOH in the above reaction scheme) (1 eq) and EDC (1.2 eq) were added to a solution of 3-aminopiperidine-2, 6-dione (hydrochloride salt, 1.1 eq), triethylamine (1.2 eq) and N- hydroxybenzotriazole (1.2 eq) in DMA (0.5 M). The reaction mixture was stirred overnight at rt. Water (2 x DMA volume) was added and obtained mixture was extracted with dichloromethane (3 x DMA volume). The combined organic layers were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was isolated by preparative HPLC or by column chromatography.

[0762] Synthetic Conditions F

[0763] To a solution of appropriate acid (R’COOH in the above reaction scheme) (1 eq) and HATU (1.5 eq) in dry DMF were added 3-aminopiperidine-2, 6-dione (hydrochloride salt, 1.2 eq) and DIPEA (3 eq). The reaction mixture was stirred overnight at rt. The crude product was purified by preparative HPLC or / and by preparative TLC.

[0764] Synthetic Conditions G

[0765] To a solution of appropriate acid (RXCOOH in the above reaction scheme) (1 eq) 3-aminopiperidine- 2, 6-dione (hydrochloride salt, 1.2 eq) and DMAP (0.1 eq.) in an inert atmosphere in dry DMF were added DIPEA (2.2 eq.) and HATU (1.5 eq) in dry DMF. The reaction mixture was stirred overnight at rt. The crude product was purified by preparative HPLC or / and by preparative TLC.

[0766] Example method 1: formation of chlorinated Rxgroup of RXCOOH (or its ester RXCOOR')

[0767] N-chlorosuccinimide(l.l eq) was added to a solution of an appropriate starting material (1 eq) in DMF (0.5 M) and the reaction mixture was stirred for 2 h at room temperature (20-25°C). The reaction mixture was poured into water (2 x DMF volume) and occurred precipitate was filtered. The solids were washed with water and dried in vacuum to give the acid, RXCOOH.

[0768] Example method 2: synthesis of RXCOOH from corresponding ester RXCOOR')

[0769] UOH (1.1 eq) was added to a solution of an appropriate ester (1 eq) in THF:water mixture (3:1 or 5:1, 85 mM) and the resulting mixture was stirred overnight at room temperature (20-25°C). The mixture was concentrated under reduced pressure, diluted with water, and acidified with concentrated HCI to pH=2-3. The precipitate was filtered, washed with water, and dried in vacuum to give the target carboxylic acid.

[0770] Example method 3: formation of acetylated Rxgroup of RXCOOR'

[0771] A mixture of an appropriate amine (1 eq.), AC2O (3 eq.), and DMAP (0.2 eq.) in dioxane (0.2 M) was heated to 80°C for 2 h. Upon completion, the mixture was cooled down to room temperature (20- 25°C) and concentrated under reduced pressure. The residue was diluted with water (1 x dioxane volume) and extracted with EtOAc (3 x dioxane volume). The organic layers were washed with water, brine, dried over Na2SC>4, and evaporated to dryness to afford an acylated product typically used without further purification.

[0772] Table 7:

[0773] Example 94: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-(N-methylacetamido)thiophene-3- carboxamide (66)

[0774] Step A: 3-Aminopiperidine-2, 6-dione (3.3 g, 25.8 mmol) and triethylamine (2.45 g, 24.2 mmol) were added to a solution of l-methyl-lH,2H,4H-thieno[2,3-d][l,3]oxazine-2, 4-dione (3.7 g, 20.2 mmol) in ethanol (20 mL). The reaction mixture was refluxed for 16 h and filtered. The precipitate was washed with water to give N-(2,6-dioxopiperidin-3-yl)-2-(methylamino)thiophene-3-carboxamide (19% yield).

[0775] Step B: Acetic anhydride (0.265 g, 2.60 mmol) and DMAP (0.026 g, 0.213 mmol) were added to a solution of N-(2,6-dioxopiperidin-3-yl)-2-(methylamino)thiophene-3-carboxamide (0.579 g, 2.17 mmol) and triethylamine (0.263 g, 2.60 mmol) in dioxane (10 mL). The reaction mixture was stirred at 60°C for 16 h, washed with water and extracted with EtOAc (3 x 10 mL), dried over Na2SO4, concentrated under reduced pressure and purified by HPLC to give N-(2,6-dioxopiperidin-3-yl)-2-(N- methylacetamido)thiophene-3-carboxamide (11% yield).

[0776] XH NMR (500MHz, DMSO) 6 10.86 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 5.7 Hz, 1H), 7.34 (d, J = 5.7 Hz, 1H), 4.72 - 4.62 (m, 1H), 3.09 (s, 3H), 2.83 - 2.71 (m, 1H), 2.58 - 2.53 (m, 1H), 2.19 - 2.02 (m, 1H), 1.99 - 1.90 (m, 1H), 1.81 (s, 3H). LCMS (m / z [M+H]+): 310.2

[0777] Example 95: Synthesis of 5-chloro-2-cvclopropaneamido-N-(2,6-dioxopiperidin-3-yl)thiophene-3- carboxamide (68)

[0778] Step A: Methyl 5-chloro-2-cyclopropaneamidothiophene-3-carboxylate was synthesized using Example Method 1, above (80% yield) using methyl 2-cyclopropaneamidothiophene-3-carboxylate as a starting material.

[0779] Step B: 5-chloro-2-cyclopropaneamidothiophene-3-carboxylic acid was synthesized using Example Method 1, above (86% yield) using methyl 5-chloro-2-cyclopropaneamidothiophene-3-carboxylate as a starting material.

[0780] Step C: 5-chloro-2-cyclopropaneamido-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions E, above (30% yield), using 5-chloro-2-cyclopropaneamidothiophene-3-carboxylic acid as a starting material.

[0781] XH NMR (500MHz, DMSO) 6 12.11 (s, 1H), 10.88 (s, 1H), 8.69 - 8.60 (m, 1H), 7.50 (s, 1H), 4.79 - 4.69 (m, 1H), 2.84 - 2.72 (m, 1H), 2.61 - 2.53 (m, 1H), 2.21 - 2.08 (m, 1H), 2.04 - 1.92 (m, 2H), 0.98 - 0.84 (m, 4H).

[0782] LCMS (m / z [M+H]+): 356.2

[0783] Example 96: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-acetamido-4-methoxythiophene-3- carboxamide (70)

[0784] Step A: H2SO4 (1 mL) was added dropwise to a stirred suspension of methyl 2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)-4-oxo-4,5-dihydrothiophene-3-carboxylate (9.65 g, 24.4 mmol) in MeOH (200 mL). The reaction mixture was refluxed for 16 h, cooled to RT and filtered to give 2-({[(9H- fluoren-9-yl)methoxy]carbonyl}amino)-4-methoxythiophene-3-carboxylate (63% yield).

[0785] Step B: Morpholine (13.5 g, 155 mmol) was added to a solution of methyl 2-({[(9H-fl uoren-9- yl)methoxy]carbonyl}amino)-4-methoxythiophene-3-carboxylate (6.3 g, 15.4 mmol) in dichloromethane (100 mL) and the reaction mixture was stirred overnight at room temperature, concentrated under reduced pressure, diluted with MTBE, filtered, and rinsed with small amount of MTBE. The filtrate was evaporated in vacuo to give crude methyl 2-amino-4-methoxythiophene-3- carboxylate, which was used in the next step without further purification.

[0786] Step C: methyl 2-acetamido-4-methoxythiophene-3-carboxylate was obtained in 73% yield using Example Method 3, above, with methyl 2-amino-4-methoxythiophene-3-carboxylate as a starting material.

[0787] Step D: 2-acetamido-4-methoxythiophene-3-carboxylic acid was obtained in 20% yield using Example Method 2, above, with methyl 2-acetamido-4-methoxythiophene-3-carboxylate as a starting material.

[0788] Step E: N-(2,6-dioxopiperidin-3-yl)-2-acetamido-4-methoxythiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions E, above (47% yield), and 2-acetamido-4-methoxythiophene-3-carboxylic acid as a starting material.

[0789] XH NMR (500MHz, DMSO) 6 12.05 (s, 1H), 10.92 (s, 1H), 8.30 (d, J = 7.1 Hz, 1H), 6.14 (s, 1H), 4.76 - 4.66 (m, 1H), 3.83 (s, 3H), 2.82 - 2.70 (m, 1H), 2.58 - 2.52 (m, 1H), 2.19 (s, 3H), 2.16 - 2.06 (m, 2H) LCMS (m / z [M+H]+): 326.2

[0790] Example 97: Synthesis of 5-cvano-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3- carboxamide (71)

[0791] Step A: Ethyl 2-acetamidothiophene-3-carboxylate (11 g, 51.6 mmol) was dissolved in AcOH (110 mL) and solution of bromine (3.2 mL, 61.9 mmol) in AcOH (55 mL) was added dropwise over 15 min at RT. The reaction mixture was stirred at RT for 18h, concentrated under reduced pressure and diluted water. The precipitate was filtered, washed with water and dried to give ethyl 5-bromo-2- acetamidothiophene-3-carboxylate (93% yield).

[0792] Step B: Zn(CN)2 (8.45 g, 72 mmol) and Pd(dppf)CI2DCM (3.92 g, 4.8 mmol) were added to a solution of ethyl 5-bromo-2-acetamidothiophene-3-carboxylate (14 g, 48 mmol) in DMF (120 mL). Argon was bubbled through the reaction mixture for 10 min, then the reaction mixture was stirred at 150°C for 16 h, cooled to RT, filtered and washed with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give 5-cyano- 2-acetamidothiophene-3-carboxylate (83% yield).

[0793] Step C: Ethyl 5-cyano-2-acetamidothiophene-3-carboxylate (9.45 g, 39.7 mmol) was dissolved in EtOH:THF solution (120 mL:360 mL), the solution was cooled to +5°C and lithium hydroxide monohydrate (11.7 g, 278 mmol) in H2O (120 mL) was added dropwise over 20 min. The reaction mixture was stirred ar RT for 18h, concentrated under reduced pressure and acidified with 15% citric acid. The product was extracted with EtOAc, dried over Na2SO4 and evaporated under reduced pressure to give 5-cyano-2-acetamidothiophene-3-carboxylic acid (57% yield).

[0794] Step D: 5-cyano-A / -(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions D, above (35% yield), and 5-cyano-2-acetamidothiophene-3-carboxylic acid as a starting material. M NMR (400MHz, DMSO) 6 12.08 (s, 1H), 10.94 (s, 1H), 8.89 (d, J = 7.9 Hz, 1H), 8.27 (s, 1H ), 4.82 - 4.65 (m, 1H), 2.87 - 2.72 (m, 1H), 2.62 - 2.53 (m, 1H), 2.30 (s, 3H), 2.24 - 2.08 (m, 1H), 2.06 - 1.93 (m, 1H)

[0795] LCMS (m / z [M+H]+): 321.0

[0796] Example 98: Synthesis of S-acetamido-A / 4-(2,6-dioxopiperidin-3-yl)-5-acetamido- / V2- methylthiophene-2,4-dicarboxamide (74)

[0797] Step A: 4-tert-butyl 2-ethyl 5-aminothiophene-2,4-dicarboxylate (3.71 g, 13.7 mmol) was added to 20% solution of methylamine in methanol (20 mL) and the reaction mixture was stirred for 5 days at 70°C, concentrated under reduced pressure and triturated with isopropyl alcohohhexane (1:1). The precipitate was filtered to give tert-butyl 2-amino-5-(methylcarbamoyl)thiophene-3-carboxylate (93% yield).

[0798] Step B: Triethylamine (3.3 g, 32.6 mmol), DMAP (0.13 g, 1.06 mmol) and acetic acid (1.67 g, 27.8 mmol) were added to a solution of tert-butyl 2-amino-5-(methylcarbamoyl)thiophene-3-carboxylate (2.8 g, 10.9 mmol) in dry MeCN (30 mL). The reaction mixture was stirred overnight at 50°C, cooled to room temperature, diluted with water, extracted with DCM, dried over Na2SO4 and concentrated under reduced pressure to give tert-butyl 2-acetamido-5-(methylcarbamoyl)thiophene-3-carboxy(ate (95% yield).

[0799] Step C: 10% HCI in dioxane (20 mL) was added to a solution of tert-butyl 2-acetamido-5- (methylcarbamoyl)thiophene-3-carboxylate (3.1 g, 10.4 mmol) in DCM (20 mL) and the reaction mixture was stirred for 3 days at RT. The precipitate was filtered, washed with DCM and dried to give 2-acetamido-5-(methylcarbamoyl)thiophene-3-carboxylic acid (60% yield).

[0800] Step D: A / 4-(2,6-dioxopiperidin-3-yl)-5-acetamido-A / 2-methylthiophene-2,4-dicarboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions E, above (44% yield), and 2-acetamido-5-(methylcarbamoyl)thiophene-3-carboxylic acid as a starting material.XH NMR (400MHz, DMSO) 8 11.84 (s, 1H), 10.92 (s, 1H), 8.78 (d, J = 8.1 Hz, 1H), 8.35 - 8.25 (m, 1H), 7.96 (s, 1H), 4.81 - 4.68 (m, 1H), 2.85 - 2.74 (m, 1H), 2.73 (d, J = 4.4 Hz, 3H), 2.62 - 2.52 (m, 1H), 2.24 (s, 3H), 2.20 - 2.07 (m, 1H), 2.04 - 1.93 (m, 1H)

[0801] LCMS (m / z [M+H]+): 352.9

[0802] Example 99: Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-(methylamino)thiophene-3- carboxamide (76)

[0803] Step A: N-chlorosuccinimide (0.884 g, 6.62 mmol) was added to a solution of l-methyl-lH,2M,4H- thieno[2,3-d][l,3]oxazine-2, 4-dione (1 g, 5.46 mmol) in mixture of toluene (4 mL) and acetic acid (4 mL). The reaction mixture was stirred at 70°C for 2h, concentrated under reduced pressure, diluted with water and filtered. The solids were washed with water and dried 6-chloro-l-methyl-lH,2H,4H- thieno[2, 3-d] [l,3]oxazine-2, 4-dione (72% yield).

[0804] Step B: 3-Aminopiperidine-2, 6-dione hydrochloride (0.655 g, 3.98 mmol) and triethylamine (0.483 g, 4.77 mmol) were added to a solution of 6-chloro-l-methyl-lH,2H,4H-thieno[2,3-d][l,3]oxazine-2,4- dione (0.865 g, 3.97 mmol) in ethanol (20 mL) and the reaction mixture was refluxed for 18h, concentrated under reduced pressure and diluted with water. The precipitate was filtered, washed with water and isopropyl alcohol, and dried to give 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2- (methylamino)thiophene-3-carboxamide (44% yield).

[0805] XH NMR (400MHz, DMSO) 6 10.79 (s, 1H), 8.18 - 8.04 (m, 1H), 8.03 - 7.91(m, 1H), 7.26 (s, 1H), 4.68 - 4.52 (m, 1H), 2.85 (s, 3H), 2.79 - 2.67 (m, 1H), 2.60 - 2.53 (m, 1H), 2.16 - 2.01 (m, 1H), 1.99 - 1.85 (m, 1H).

[0806] LCMS (m / z [M+H]+): 302.2 Example 100: Synthesis of 4-chloro-5-cvclopropyl-N-(2,6-dioxopiperidin-3-yl)-2- acetamidothiophene-3-carboxamide (77)

[0807] Step A: SO2CI2 (0.207 g, 1.53 mmol) was added to a solution of methyl 5-cyclopropyl-2- acetamidothiophene-3-carboxylate (0.306 g, 1.28 mmol) in CHCh (15 mL). The reaction mixture was refluxed for 2 h, concentrated under reduced pressure and diluted with water. The product was extracted with EtOAc, dried over Na2SO4 and concentrated under reduced pressure to give methyl 4- chloro-5-cyclopropyl-2-acetamidothiophene-3-carboxylate (81% yield).

[0808] Step B: 4-chloro-5-cyclopropyl-2-acetamidothiophene-3-carboxylic acid was obtained in 78% yield using Example Method 2, above, with methyl 4-chloro-5-cyclopropyl-2-acetamidothiophene-3- carboxylate as a starting material.

[0809] Step C: HATU (0.370 g, 0.973 mmol) was added to the solution of 4-chloro-5-cyclopropyl-2- acetamidothiophene-3-carboxylic acid (0.211 g, 0.812 mmol), 3-aminopiperidine-2, 6-dione (0.134 g, 1.05 mmol) and A / -methyl morpholine (0.205 g, 2.03 mmol) in DMF (5 mL) at 0°C. The reaction mixture was stirred overnight at room temperature, diluted with water, extracted with AcOEt, dried over NaiSO4, concentrated under reduced pressure and purified by HPLC to give 4-chloro-5-cyclopropyl- N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide (41% yield).

[0810] XH NMR (400MHz, DMSO) 6 11.07 (s, 1H), 11.04 (s, 1H), 8.54 (d, J = 8.2 Hz, 1H), 4.90 - 4.78 (m, 1H), 2.89 - 2.72 (m, 1H), 2.65 - 2.52 (m, 2H), 2.16 (s, 3H), 2.12 - 1.98 (m, 2H), 1.08 - 0.98 (m, 2H), 0.71 - 0.58 (m, 2H).

[0811] LCMS (m / z [M+H]+): 369.8

[0812] Example 101: Synthesis of 5-cvclopropyl- / V-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3- carboxamide (83) Step A: To a stirred solution of 3,5-dibromo-2-methoxythiophene (500.0 mg, 1.845 mmol) in toluene (9 mL) was added cyclopropyl boronic acid (206 mg, 2.399 mmol) and K3PO4 (784 mg, 3.69 mmol) in water (3 ml), the reaction mixture was purged with argon for 15 min and then Pd(PPh3)4 (320 mg, 0.277 mmol) was added. The reaction was stirred at 90 °C for 20h, filtered through cel ite bed, concentrated under reduced pressure and purified by flash column chromatography to give 3-bromo- 5-cyclopropyl-2-methoxythiophene (34% yield).

[0813] Step B: To a stirred solution of 3-bromo-5-cyclopropyl-2-methoxythiophene (700 mg, 3 mmol) in THF (20 mL) was added n-BuLi (1.8 M in THF) (3.4 mL, 6.005 mmol) dropwise at -78°C. Reaction mixture was stirred for lh at -78°C and benzyl chloroformate (0.86 mL, 6 mmol) was added dropwise. The reaction was continued for lh, quenched with water, extracted with ethyl acetate and concentrated under reduced pressure. The product was purified by flash column chromatography to give benzyl 5- cyclopropyl-2-methoxythiophene-3-carboxylate (23% yield).

[0814] Step C: To a stirred solution of benzyl 5-cyclopropyl-2-methoxythiophene-3-carboxylate (350 mg, 1.215 mmol) in THF (6 mL) and methanol (6 mL) at 5-10 °C was added 50 % aq. NaOH (12 ml). The reaction mixture was stirred at RT for 16h and acidified with 6 M HCI. The solids were filtered, washed with pentane and dried to give 5-cyclopropyl-2-methoxythiophene-3-carboxylic acid (76% yield).

[0815] Step D: 5-cyclopropyl- / V-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (76% yield) using 5-cyclopropyl-2-methoxythiophene-3-carboxylic acid (20 mg) as a starting material.

[0816] 2H NMR (500 MHz, DMSO) 8 10.85 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 1.0 Hz, 1H), 4.67 (ddd, J = 12.1, 7.5, 5.8 Hz, 1H), 4.00 (s, 3H), 2.77 (ddd, J = 17.3, 13.1, 6.1 Hz, 1H), 2.60 - 2.51 (m, 1H), 2.15 - 1.95 (m, 3H), 0.95 - 0.88 (m, 2H), 0.65 - 0.59 (m, 2H).

[0817] LCMS (m / z (M+H]+): 309.0

[0818] Example 102: Synthesis of A / -(2,6-dioxopiperidin-3-yl)-2-methoxy-5-phenylthiophene-3- carboxamide (84)

[0819] Step A: To 3,5-dibromo-2-methoxythiophene (4.0 g, 14.71 mmol) in dry THF (30 mL) was added 2.5M n-BuLi hexane solution (6.47 mL, 16.2 mmol) at -78 °C under argon atmosphere and the solution was stirred for Ih. Tri-n-butyl borate (8.35 mL, 29.42 mmol) was added to the reaction mixture, the mixture was stirred for 1.5h and warmed to RT. 20% Na2CO3(33.6 mL), iodobenzene (1.65 mL, 14.71 mmol), and Pd(PPh3)4 (0.85 g, 0.73 mmol) were added and the reaction mixture was refluxed for 16h. The reaction mixture was extracted with ether, dried over MgSCU, concentrated under reduced pressure and purified by flash column chromatography to give 3-bromo-2-methoxy-5- phenylthiophene (50% yield).

[0820] Step B: 3-Bromo-2-methoxy-5-phenylthiophene (900 mg, 3.34 mmol) was dissolved in THF (15 mL) and cooled to -78 °C. 1.8M n-BuLi in hexane (3.7 mL, 6.68 mmol) was added dropwise at -78°C. Reaction mixture was stirred for Ih at -78°C and benzyl chloroformate (0.95 mL, 6.68 mmol) was added dropwise. The reaction was continued for lh, quenched with water, extracted with ethyl acetate and concentrated under reduced pressure. The product was purified by flash column chromatography to give benzyl 2-methoxy-5-phenylthiophene-3-carboxylate (23% yield).

[0821] Step C: Benzyl 2-methoxy-5-phenylthiophene-3-carboxylate (230 mg, 0.71 mmol) was dissolved in THF (5 mL). MeOH (5 mL) and 50% NaOH solution (10 mL) were added and the reaction mixture was stirred at RT for 16h and acidified with 6 M HCI. The solids were filtered, washed with pentane and dried to give 2-methoxy-5-phenylthiophene-3-carboxylic acid (130 mg, 78%) as off white solid.

[0822] Step D: A / -(2,6-dioxopiperidin-3-yl)-2-methoxy-5-phenylthiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (71% yield) using 2-methoxy-5-phenylthiophene-3-carboxylic acid (20 mg) as a starting material.

[0823] XH NMR (500 MHz, DMSO) 8 10.88 (s, IH), 7.87 (d, J = 7.6 Hz, IH), 7.63 - 7.57 (m, 2H), 7.51 (s, IH), 7.48 - 7.38 (m, 2H), 7.33 - 7.27 (m, IH), 4.73 (ddd, J = 12.7, 7.6, 5.6 Hz, IH), 4.12 (s, 3H), 2.79 (ddd, J = 17.3, 13.4, 5.8 Hz, IH), 2.57 - 2.52 (m, IH), 2.19 - 2.03 (m, 2H).

[0824] LCMS (m / z [M+H]+): 345.2 Example 103: Synthesis of 5 butyl)-N-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3- carboxamide (86)

[0825] Step A: To stirred solution of AICI3 (2.1 g, 15.544 mmol) in DCM (20 mL) at -78° C was added tert-butyl bromide (1.9 g, 13.472 mmol) in DCM (10 mL) dropwise at -78°C and stirred for 20 min. 3-bromo-2- methoxythiophene (2 g, 10.363 mmol) in DCM (10 mL) was added dropwise stirred for 2h. The reaction mixture was warmed to RT and stirred for another 16 h. The reaction mixture was quenched with water and extracted with DCM, concentrated under reduced pressure and purified by flash column chromatography to give 3-bromo-5-(tert-butyl)-2-methoxythiophene (31% yield).

[0826] Step B: To a stirred solution of 3-bromo-5-(tert-butyl)-2-methoxythiophene (900 mg, 3.614 mmol) in THF (22 mL) was added n-BuLi (1.8 M in THF) (4ml, 7.229 mmol) dropwise at -78°C. Reaction mixture was stirred for Ih at -78°C and benzyl chloroformate (1.03 ml, 7.229 mmol) was added dropwise. The reaction was continued for lh, quenched with water, extracted with ethyl acetate and concentrated under reduced pressure. The product was purified by flash column chromatography to give benzyl 5- (tert-butyl)-2-methoxythiophene-3-carboxylate (220 mg, 20% yield) as light yellow oil.

[0827] Step C: To a stirred solution of benzyl 5-(tert-butyl)-2-methoxythiophene-3-carboxylate (450 mg, 1.47 mmol) in THF (8 mL) and methanol (8mL) at 5 °C was added 50 % aq. NaOH (16 mL). The reaction mixture was stirred at RT for 16h and acidified with 6 M HCI. The solids were filtered, washed with pentane and dried to give 5-(tert-butyl)-2-methoxythiophene-3-carboxylic acid (69% yield).

[0828] Step D: 5-(tert-butyl)- / V-(2,6-dioxopiperidin-3-yl)-2-methoxythiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (75% yield) using 5-(tert-butyl)-2-methoxythiophene-3-carboxylic acid (20 mg) as a starting material.

[0829] 1H NMR (500 MHz, DMSO) 5 10.85 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 6.83 (s, 1H), 4.68 (ddd, J = 12.2, 7.5, 5.7 Hz, IH), 4.02 (s, 3H), 2.77 (ddd, J = 17.3, 13.3, 6.0 Hz, 1H), 2.57 - 2.52 (m, 1H), 2.17 - 1.99 (m, 2H), 1.31 (s, 9H).

[0830] LCMS (m / z (M+H]+): 325.2 Example 104: Synthesis of 2-amino-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (87)

[0831] Tert-butyl (3-((2,6-dioxopiperidin-3-yl)carbamoyl)thiophen-2-yl)carbamate (1.0 g, 2.8 mmol) was dissolved in dichloromethane (10 mL) and a 10% solution of HCI in dioxane (3 mL) was added dropwise. The reaction mixture was stirred for 48 h at room temperature. The mixture was concentrated under reduced pressure and purified by preparative HPLC to give 2-amino-N-(2,6- dioxopiperidin-3-yl)thiophene-3-carboxamide (4% yield).

[0832] XH NMR (500 MHz, DMSO) 6 10.78 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.22 (s, 2H), 7.07 (d, J = 5.8 Hz, 1H), 6.28 (d, J = 8.3 Hz, 1H), 4.69 - 4.61 (m, 1H), 2.82 - 2.68 (m, 1H), 2.57 - 2.52 (m, 1H), 2.15 - 2.04 (m, 1H), 1.96 - 1.84 (m, 1H).

[0833] LCMS (m / z (M+H]+): 254.0

[0834] Example 105: Synthesis of 2-amino-5-chloro-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (89)

[0835] Step A: W-chlorosuccinimide (2.2 g, 16.5 mmol) was added to a solution of 2-((tert- butoxycarbonyl)amino)thiophene-3-carboxylic acid (3.3 g, 13.6 mmol) in DMF (20 mL) and the reaction mixture was stirred at RT for 2 h. The mixture was diluted with water and filtered. The solids were washed with water and dried to give 2-{[(tert-butoxy)carbonyl]amino}-5-chlorothiophene-3- carboxylic acid (84% yield).

[0836] Step B: Tert-butyl N-{5-chloro-3-[(2,6-dioxopiperidin-3-yl)carbamoyl]thiophen-2-yl}carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions D, above (81% yield), and 2-{[(tert-butoxy)carbonyl]amino}-5-chlorothiophene-3-carboxylic acid as a starting material.

[0837] Step C: 10% HCI in dioxane (2 mL) was added dropwise to a solution of the tert-butyl A / -{5-chloro-3- [(2,6-dioxopiperidin-3-yl)carbamoyl]thiophen-2-yl}carbamate (2.0 g, 5.16 mmol) in dichloromethane (15 mL) and the mixture was stirred in ultrasonic bath for 8 h, concentrated under reduced pressure and purified by HPLC to give 2-amino-5-chloro-N-(2,6-dioxopiperidin-3-yl)thiophene-3-carboxamide (15% yield).

[0838] XH NMR (400MHz, DMSO) 5 10.81 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.41 (brs, 2H), 7.13 (s, 1H ), 4.66 - 4.56 (m, 1H), 2.83 - 2.68 (m, 1H), 2.59 - 2.52 (m, 1H), 2.13 - 1.99 (m, 1H), 1.97 - 1.82 (m, 1H)

[0839] LCMS (m / z [M+H]+): 288.1

[0840] Example 106: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-acetamido-5-(trifluoromethyl)thiophene-

[0841] 3-carboxamide (90)

[0842] Step A: Triethylamine (0.397 g, 3.92 mmol) and acetic anhydride (0.400 g, 3.92 mmol) were added to a solution of ethyl 2-amino-5-(trifluoromethyl)thiophene-3-carboxylate (0.852 g, 3.56 mmol) in MeCN (15 mL). The reaction mixture was stirred overnight at 50°C, cooled to rt, concentrated under reduced pressure, and extracted with DCM, dried over Na2SO4, and concentrated to give ethyl 2- acetamido-5-(trifluoromethyl)thiophene-3-carboxylate (91% yield).

[0843] Step B: 10% solution of LiOH (0.081 g, 3.4 mmol) was added to a solution of ethyl 2-acetamido-5- (trifluoromethyl)thiophene-3-carboxylate (0.911 g, 3.24 mmol) in THF (15 mL) and the resulting mixture was stirred for 5 days at RT. The solvents were evaporated under reduced pressure, the residue was diluted with water and washed with MTBE. The aqueous layer acidified by citric acid and the precipitate was filtered, washed with water, and dried to give 2-acetamido-5- (trifluoromethyl)thiophene-3-carboxylic acid (28% yield). Step C: / V-(2,6-dioxopiperidin-3-yl)-2-acetamido-5-(trifluoromethyl)thiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions D, above (26% yield), and 2-acetamido-5-(trifluoromethyl)thiophene-3-carboxylic acid as a starting material.

[0844] XH NMR (400MHz, DMSO) 6 11.98 (s, 1H), 10.93 (s, 1H), 9.00 - 8.81 (m, 1H), 8.13 (s, 1H), 4.87 - 4.62 (m, 1H), 2.98 - 2.65 (m, 2H), 2.28 (s, 3H), 2.20 - 2.08 (m, 1H), 2.07 - 1.88 (m, 1H).

[0845] LCMS (m / z (M+H]+): 364.2

[0846] Example 107: Synthesis of 5-cvclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3- carboxamide (91)

[0847] Step A: methyl 5-cyclopropyl-2-acetamidothiophene-3-carboxylate was synthesized in 69% yield using Example Method 3, above, using 2-amino-5-cyclopropylthiophene-3-carboxylate as a starting material.

[0848] Step B: 5-cyclopropyl-2-acetamidothiophene-3-carboxylic acid was synthesized in 57% yield using Example Method 2, above, and methyl 5-cyclopropyl-2-acetamidothiophene-3-carboxylate as a starting material.

[0849] Step C: 5-cyclopropyl-N-(2,6-dioxopiperidin-3-yl)-2-acetamidothiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions E, above (56% yield), and 5-cyclopropyl-2-acetamidothiophene-3-carboxylic acid as a starting material.

[0850] XH NMR (400MHz, DMSO) 6 11.73 (s, 1H), 10.89 (s, 1H), 8.52 (d, J = 8.5 Hz, 1H), 7.09 (s, 1H), 4.76 - 4.64 (m, 1H), 2.85 - 2.71 (m, 1H), 2.62 - 2.53 (m, 1H), 2.22 - 2.04 (m, 4H), 2.04 - 1.89 (m, 2H), 1.00 - 0.87 (m, 2H), 0.68 - 0.57 (m, 2H)

[0851] LCMS (m / z (M+H]+): 336.2 Example 108: Synthesis of 5-chloro-N-(2,6-dioxopiperidin-3-yl)-2-(2-phenylacetamido)thiophene-

[0852] 3-carboxamide (92)

[0853] Step A: Methyl 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylate was synthesized using Example Method 1, above (75% yield), using methyl 2-(2-phenylacetamido)thiophene-3-carboxylate as a starting material.

[0854] Step B: 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylic acid was synthesized using Example Method 2, above (82% yield), using methyl 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylate as a starting material.

[0855] Step C: 5-chloro-A / -(2,6-dioxopiperidin-3-yl)-2-(2-phenylacetamido)thiophene-3-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions D, above (15% yield), with 5-chloro-2-(2-phenylacetamido)thiophene-3-carboxylic acid as a starting material.

[0856] NMR (400MHz, DMSO) 6 11.94 (s, 1H), 10.91 (s, 1H), 8.72 - 8.54 (m, 1H), 7.66 - 7.45 (m, 2H), 7.43 - 7.21 (m, 4H), 4.82 - 4.64 (m, 1H), 3.90 (s, 2H), 2.89 - 2.71 (m, 1H), 2.61 - 2.53 (m, 1H), 2.17 - 2.02 (m, 1H), 2.01 - 1.88 (m, 1H)

[0857] LCMS (m / z [M+H]+): 406.2

[0858] Example 109: Synthesis of / V-(2,6-dioxopiperidin-3-yl)-5-methoxythiazole-4-carboxannide (100)

[0859] Step A: To a stirred solution of ethyl 5-bromothiazole-4-carboxylate (2.0 g, 8.475 mmol, leq) in methanol (24 mL) was added NaOMe (25% in MeOH) (3.8 ml, 16.95mmol, 2eq). The reaction mixture was refluxed for 2h, cooled to RT and quenched by saturated ammonium chloride solution (10 mL). The mixture was concentrated under reduced pressure and purified by flash column chromatography to give methyl 5-methoxythiazole-4-carboxylate (27% yield). Step B: To a stirring solution of methyl 5-methoxythiazole-4-carboxylate (100 mg, 0.578 mmol, leq) in a solution of THF, MeOH, H2O (4:2:1) (7 mL) was added LiOH, H2O (73 mg, 1.734 mmol, 3eq). The reaction mixture was stirred at RT for 16h, evaporated, redissolved in water and washed with ethyl acetate. The aqueous layer was acidified by 0.5 M HCI, extracted with 10% MeOH in DCM, dried over Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give 5-methoxythiazole-4-carboxylic acid (32% yield).

[0860] Step C: A / -(2,6-dioxopiperidin-3-yl)-5-methoxythiazole-4-carboxamide was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (9% yield) using 5-methoxythiazole-4-carboxylic acid (20 mg) as a starting material.

[0861] XH NMR (500 MHz, DMSO) 5 10.81 (s, 1H), 8.51 (s, 1H), 8.23 (d, J = 8.2 Hz, 1H), 4.67 (ddd, J = 12.5, 8.2, 5.3 Hz, 1H), 4.04 (s, 3H), 2.83 - 2.73 (m, 1H), 2.52 (dt, J = 3.9, 2.5 Hz, 1H), 2.19 - 2.09 (m, 1H), 1.97 (dtd, J = 12.7, 5.5, 2.6 Hz, 1H).

[0862] LCMS (m / z [M+H]+): 269.8

[0863] Example 110: Synthesis of 2-amino-JV-(2,6-dioxopiperidin-3-yl)-5-methoxythiazole-4-carboxamide (1011

[0864] Step A: To a stirring solution of methyl 2-amino-5-bromothiazole-4-carboxylate (1 g, 4.255 mmol, leq) in methanol (30 mL) was added NaOMe (25% in MeOH) (2.3 ml, 10.638 mmol, 2.5 eq). The reaction mixture was refluxed for 1.5 h, cooled to RT and quenched by saturated ammonium chloride solution (10 mL). The mixture was concentrated under reduced pressure and purified by flash column chromatography to give methyl 2-amino-5-methoxythiazole-4-carboxyfate (50% yield).

[0865] Step B: Methyl 2-amino-5-methoxythiazole-4-carboxylate (400 mg, 2.128 mmol, leq.) was dissolved in DCM then were added triethylamine (0.532 mmol, 2eq.) and BOC2O (0.532 mmol, 2 eq). The reaction mixture was stirred at RT for 18h, diluted with DCM and washed successively with water and brine, dried over Na2SO4, concentrated under reduced pressure and purified by flash column chromatography to give methyl 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4-carboxylate (49% yield).

[0866] Step C: To a stirring solution of methyl 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4- carboxylate (300 mg, 1.042 mmol, leq) in THF:MeOH:H2O 3:2:1 (12 mL) was added LiOH H2O (131 mg, 3.125 mmol, 3eq). The reaction mixture was stirred at RT for 16h, evaporated, redissolved in water and washed with ethyl acetate. The aqueous layer was acidified by 0.5 M HCI, extracted with 10% MeOH in DCM, dried over Na2SO4, concentrated under reduced pressure and triturated with ether and pentane to give 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4-carboxylic acid (49% yield).

[0867] Step D: Tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazol-2-yl)carbamate was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions F, above (50 % yield), and 2-((tert-butoxycarbonyl)amino)-5-methoxythiazole-4-carboxylic acid (20 mg) as a starting material.

[0868] Step E: To a solution of tert-butyl (4-((2,6-dioxopiperidin-3-yl)carbamoyl)-5-methoxythiazol-2- yljcarbamate (19.6 mg, 0.051 mmol, 1 eq.) in water (3 mL) and dioxane (3 mL) was added 36% HCI (1.5 mL). The reaction was stirred at RT for 3h and concentrated under reduced pressure to give 2- amino- / V-(2,6-dioxopiperidin-3-yl)-5-methoxythiazole-4-carboxamide hydrochloride (100% yield).

[0869] XH NMR (500 MHz, DMSO) 6 10.84 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.41 - 6.65 (m, 2H), 4.63 (ddd, J = 12.0, 7.8, 5.8 Hz, 1H), 3.89 (s, 3H), 2.75 (ddd, J = 17.3, 13.1, 6.2 Hz, 1H), 2.60 - 2.52 (m, 1H), 2.11 - 1.98 (m, 2H).

[0870] LCMS (m / z [M+H]+): 285.0

[0871] Example 111: Synthesis of 2-amino-A / -(2,6-dioxopiperidin-3-yl)thiazole-5-carboxamide (102) To the suspension of tert-butyl (5-((2,6-dioxopiperidin-3-yl)carbamoyl)thiazol-2-yl)carbamate (71, 30 mg, 0.085 mmol, 1 eq) in DCM (1.5 mL) was added TFA (0.2 mL) and mixture was stirred for 18h at RT, concentrated under reduced pressure and purified by HPLC to give 2-amino- / V-(2,6- dioxopiperidin-3-yl)thiazole-5-carboxamide (yield 37%).

[0872] XH NMR (500 MHz, DMSO) 8 10.81 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.49 (s, 2H), 4.64 (ddd, J = 12.5, 8.4, 5.4 Hz, 1H), 2.76 (ddd, J = 17.4, 13.3, 5.6 Hz, 1H), 2.53 - 2.51 (m, 2H), 2.05 (qd, J = 12.8, 4.3 Hz, 1H), 1.93 (dddd, J = 10.7, 8.1, 5.3, 2.9 Hz, 1H).

[0873] LCMS (m / z [M+H]+) : 255.2

[0874] Example 112: Synthesis of 7-bromo- / V-(2,6-dioxopiperidin-3-yl)thieno(3,4-61pyridine-5- carboxamide (103)

[0875] / V-bromosuccinimide (96.8 mg, 0.544 mmol, 1.1 eq) was added to a suspension of N-(2,6- dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide (143.0 mg, 0.494 mmol, 1.000 eq,) in DMF (4.9 mL) at ambient temperature. The reaction mixture was heated to 60°C and stirred for 3 h. The obtained crude compound was purified by HPLC to give 5-bromo- / V-(2,6-dioxopiperidin-3- yl)thieno[3,4-b]pyridine-7-carboxamide (15% yield).

[0876] JH NMR (500 MHz, DMSO) 6 10.97 (s, 1H), 9.53 (d, J = 7.4 Hz, 1H), 8.87 (dd, J = 4.0, 1.5 Hz, 1H), 8.11 (dd, J = 8.9, 1.5 Hz, 1H), 7.41 (dd, J = 8.9, 4.0 Hz, 1H), 4.91 (ddd, J = 12.8, 7.3, 5.6 Hz, 1H), 2.84 (ddd, J = 17.5, 13.4, 5.7 Hz, 1H), 2.57 (ddd, J = 17.4, 4.3, 2.3 Hz, 1H), 2.30 - 2.13 (m, 2H)

[0877] LCMS (m / z [M+H]+): 368.37 Example 113: Synthesis of 5-chloro- / V-(2,6-dioxopiperldin-3-yl)thieno[3,4-blpyridine-7- carboxamide (106)

[0878] / V-chlorosuccinimide (0.059 g, 0.442 mmol, 1.1 eq) was added to a suspension of A / -(2,6- dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide (0.116 g, 0.401 mmol) in DMF (5 ml) at RT. The reaction mixture was heated to 60°C and stirred for 3 h. The obtained crude compound was purified by HPLC to give 5-chloro-A / -(2,6-dioxopiperidin-3-yl)thieno[3,4-b]pyridine-7-carboxamide (43% yield).

[0879] XH NMR (400MHz, DMSO) 6 10.97 (s, 1H), 9.51 (d, J = 7.4 Hz, 1H), 8.91 - 8.83 (m, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.41 - 7.33 (m, 1H), 4.95 - 4.84 (m, 1H), 2.89 - 2.74 (m, 1H), 2.62 - 2.55 (m, 1H), 2.28 - 2.11 (m, 2H)

[0880] LCMS (m / z [M+H]+): 323.8

[0881] SYNTHESIS OF LIGASE LIGAND MOIETIES - COMPOUNDS OF FORMULA (Hal AND (lib)

[0882] Example 114: Synthesis of 4-chloro- / V-(2,6-dioxopiperidin-3-yl)-lH-pyrrolo[2,3-blpyridine-3- carboxamide (104)

[0883] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (15% yield) using 4-chloro-lH-pyrrolo[2,3-b]pyridine-3-carboxylic acid (20 mg) as a starting material.JH NMR (500 MHz, DMSO) 5 12.40 (s, 1H), 10.82 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.22 (d, J = 5.1 Hz, 1H), 7.96 (s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.79 - 4.72 (m, 1H), 2.79 (ddd, J = 17.9, 9.7, 7.0 Hz, 1H), 2.59

[0884] - 2.52 (m, 1H), 2.12 - 2.01 (m, 2H).

[0885] LCMS (m / z [M+H]+): 306.9

[0886] Example 115: Synthesis of 5-chloro- / V-(2,6-dioxopiperidin-3-yl)-lH-pyrrolof2,3-blpyridine-3- carboxamide (105)

[0887] This compound was synthesized using the general procedure shown in Reaction Scheme 1 and Synthetic Conditions C, above, (31% yield) using 5-chloro-lH-pyrrolo[2,3-£>]pyridine-3-carboxylic acid (20 mg) as a starting material.

[0888] XH NMR (500 MHz, DMSO) 6 12.40 (s, 1H), 10.85 (s, 1H), 8.44 (d, J = 2.5 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 2.9 Hz, 1H), 4.79 (ddd, J = 12.2, 8.3, 5.3 Hz, 1H), 2.81 (ddd, J = 17.3, 13.2, 5.5 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.11 (qd, J = 12.8, 4.4 Hz, 1H), 2.01 (dtd, J = 13.0, 5.4, 2.9 Hz, 1H).

[0889] LCMS (m / z [M+H]+): 307.2

[0890] BIOLOGICAL EXAMPLES

[0891] Example 116: PKC9 protein inhibition, ADP Gio dose-response assay

[0892] The effect of various compounds of the invention on PKC9 protein engagement was investigated using PKC9 Kinase Enzyme System from Promega (catalogue number: V4040) according to the manufacturer's protocol with the following modification: PKC9 was pre-incubated with tested compounds for 30 minutes before addition of ATP and substrate. Read-out was performed with CLARIOstar microplate reader in luminescence mode after 30 min. The data were analysed as follows:

[0893] 1) the average of luminescence for background signal (wells without kinase) was calculated and used as a negative control;

[0894] 2) the average of luminescence for positive control signal (wells with kinase and DMSO) was calculated;

[0895] 3) raw luminescence values were normalized against positive and negative controls;

[0896] 4) IC50 and average plC50 values per molecule were determined.

[0897] Table 8: PKCd protein inhibition

[0898] As illustrated in Table 8, the compounds of the present invention have the capability to engage and inhibit PKC0 protein. Example 117: In cell CRBN Target Engagement Assay, NanoBRET

[0899] The ability of various compounds of the invention to engage CRBN intracellularly was investigated using NanoLuc-CRBN HEK293 cells from Promega.

[0900] The NanoBRET In cell CRBN Target Engagement Assay is a cell-based Bioluminescence Resonance Energy Transfer assay (BRET assay) which uses NanoLuc CRBN HEK 293 cells (Promega, catalogue number: CS1810C397) and NanoBRET In-cell CRBN Tracer (Promega, catalogue number: CS1810C140). In the presence of a compound which targets CRBN, the proximity between NanoLuc and CRBN Tracer is lost and the fluorescence emission decreases.

[0901] This assay was performed in a live mode format consisting of 3 steps: (1) transfer of NanoLuc CRBN HEK 293 cells to a T182 flask and a subsequent culturing for 24 hours, (2) treatment of the cells with CRBN Tracer and compounds in 96-well assay plates followed by incubation for 2 hours at 37 °C, 5% CO2, and (3) NanoBRET assay with Nano-Gio substrate (Promega, catalogue number: N113C) which detects luminescence emission of NanoLuc (donor emission) and fluorescence emission of CRBN Tracer (acceptor emission).

[0902] The analysis of the results is the calculation of mBRET ratio with donor emission RLU (Relative Light Unit) at 450 nm (RLU450nm) and acceptor emission RFU (Relative Fluorescence Unit) at 610 nm (RFU610nm). The average of RLU450nm of Blank (Average RFU450nm B, n=2) and the average of RFU610nm of Blank (Average RFU610nm B, n=2) are used as a background: mBRET Xi = 1000 x (RFU610nm X, - Average RFU610nm B) / (RLU450nm X, - Average RFU450nm B)

[0903] Percentage inhibition of each well (%lnhibition X,) is calculated with the average of mBRET of Negative control (Average mBRET N) and the average of Positive control (Average mBRET P).

[0904] %l nhibition X, = 100 x (Average mBRET N - mBRET X,) / (Average mBRET N - Average mBRET P)

[0905] Negative control stands for tracer and DMSO to represent 0% inhibition. Positive control stands for pomalidomide dissolved in DMSO but without Tracer. Blank stands for Opti-MEM only. [% inhibition] values obtained after the treatment with compounds at luM concent ration is presented in Table 9. Wherever indicated, plC50 values were calculated following the measurement at 11 concentration points: 30 - 15 - 7.5 - 3.75 - 1.875 - 0.938 - 0.469 - 0.234 - 0.117 — 0.058 - 0.029 pM. All the experiments were performed at two biological repeats and the average values are displayed in the Table below.

[0906] Table 9: In cell CRBN Target Engagement Assay

[0907] As illustrated in Table 9, the compounds of the present invention have the capability to engage CRBN intracellularly. Example 118: PKC8 protein degradation in PMA stimulated Jurkat cells. Western blot

[0908] The effect of various compounds of the invention on PKC 0 protein degradation in the Jurka t cell line was investigated, using the degradation assay protocol below.

[0909] Jurkat cells were maintained in RPMI-1640 medium, supplemented with penicillin / streptomycin and 10% Fetal Bovine Serum (FBS). Prior to the treatment with the compounds, the cells were seeded on 6 well plates at the density of 5xl06cells / well. Immediately after the cells seeding, tested compounds dissolved in 100%DMSO were added directly to the wells (0.5% v / v of the vehicle) and incu bated an hour prior to Phorbol 12-myristate 13-acetate (PMA) application (lOOng / ml).

[0910] Following the treatment with the compounds, cells were collected from the plates, washed in cold PBS, and suspended in lysis buffer B (20mM TRIS-HCI pH 7.5, 2mM EDTA, 5mM EGTA lOmM betamercaptoethanol, lOpg / ml of each leupeptin, aprotinin and pepstatin A). The cell plasma membrane was disrupted by passing the solution thirty times through a 25-gauge (0.45 nm 0) needle.

[0911] Next, the suspension was centrifugated at 280xg for 5 min to remove the nuclei, and the supernatant was spun again at 16,000xg for 20 min. The pellet, containing the membrane fraction, was resuspended in 50pl of buffer B+ (buffer B with 1% Triton X-100) and incubated on ice for 30 min (or put into -20°C overnight and processed the next day after thawing the samples on ice). After vortexing the samples were centrifuged again at 16,000xg for 20 min, the supernatant containing the membrane proteins was used for the following analysis.

[0912] The amount of protein was determined via Redox-compatible BCA assay, and the equal quantity of each sample was loaded on the precast SDS-containing gel for the electrophoretic separation. Next, the proteins were transferred onto the nitrocellulose membrane and stained with Ponceau solution (0.1 % (w / v) Ponceau in 5% acetic acid). After total protein detection, the stain was washed out with TBST, and the membrane was immersed in a blocking solution (5% NFDM in TBST) for an hour prior to POI immunodetection with antibodies for PKC theta and COX IV. After incubation time the membranes were washed and the signal was developed with chemiluminescence.

[0913] Densitometric analysis was performed using ImageLab software. The level of the protein of interest in control cells (treated with DMSO) was assumed as 100%, and the signal was normalized to the COX IV loading control. The results for the 8h treatment with 500nM compounds are shown in Table 10, using the following labels:

[0914] > 30% for 30-59% of PKC0 protein reduction,

[0915] > 60% for 60-100% of PKC0 protein reduction.

[0916] Table 10: PKC& protein degradation in PMA stimulated Jurkat cells As illustrated in Table 10 and Figure 2, the compounds of the present invention have the capability to induce degradation of PKC0 protein.

[0917] Example 119: PKCepsilon protein degradation in PMA stimulated Jurkat cells. Western blot

[0918] The effect of various compounds of the invention on PKC epsilon protein degradation in the Jurkat cell line was investigated, using the protocol described for "PKC6 protein degradation in PMA stimulated Jurkat cells, Western blot" assay. Anti-PKC epsilon antibody was used to detect th e protein of interest.

[0919] The results for the 8h treatment with 500nM compounds are shown in Table 11.

[0920] As illustrated in Table 11, the compounds of the present invention have the capability to induce degradation of PKCe protein.

[0921] Table 11: PKCepsilon protein degradation in PMA stimulated Jurkat cells

[0922] As illustrated in Table 11, the compounds of the present invention have the capability to induce degradation of PKCepsilon protein Example 120: PKCdelta protein degradation in PMA-stimulated Jurkat cells. Western blot

[0923] The effect of various compounds of the invention on PKC delta protein degradation in the J urkat cell line was investigated, using the protocol described for "PKC0 protein degradation in PMA stimulated Jurkat cells, Western blot" assay. Anti-PKC delta antibody was used to detect the protein of interest.

[0924] The results for the 8h treatment with 500nM compounds are shown in Table 12.

[0925] Table 12: PKCdelta protein degradation in PMA stimulated Jurkat cells

[0926] As illustrated in Table 12 and Figure 2, the compounds of the present invention have the capability to induce degradation of PKCepsilon protein.

[0927] Example 121: PKC0 protein degradation in antibody mix co-stimulated Jurkat cells. Western blot

[0928] The effect of various compounds of the invention on PKC0 protein degradation in the Jurkat cell line was investigated, using the degradation assay protocol below.

[0929] Jurkat cells were maintained in RPMI-1640 medium, supplemented with penicillin / streptomycin and 10% Fetal Bovine Serum (FBS). Prior to the treatment with the compounds, the cells were seeded on 6 well plates at the density of 3xl06cells / well. Immediately after the cells seeding, tested compounds dissolved in 100% DMSO were added directly to the wells (0.5% v / v of the vehicle) and incubated for an hour prior to antibody mix (commercially available tetramer of anti-CD3 / anti-CD28) application (25pl / lxlOA6 cells). Following the treatment with the compounds, cells were collected from the plates, washed in ice- cold PBS, and suspended in lysis buffer B (20mM TRIS-HCI pH 7.5, 2mM EDTA, 5mM EGT / X lOmM beta-mercaptoethanol, 1% Triton X-100, lOpg / ml of each leupeptin, aprotinin and pepstatin A).

[0930] Next, the suspension was centrifugated at 500xg for 5 min (4°C) and the supernatant was d iscarded. Cells were resuspended in ice-cold PBS and transferred into a 1.5ml tube. Subsequent centrifugation (500xg for 5 min, 4°C) followed and the supernatant was removed. Next, the cell pellet was lysed using Buffer B+ (20pl / lxl0A6 cells) by incubation of the samples for 30 min on ice. Then, the samples were vortexed and centrifuged again - 16,000xg for 20min. The supernatant containing whole cell lysate proteins (WCL) was used for the following analysis.

[0931] The amount of protein was determined via Redox-compatible BCA assay, and the equal quantity of each sample was loaded on the precast SDS-containing gel for the electrophoretic separation. Next, the proteins were transferred onto the nitrocellulose membrane and stained with Ponceau solution (0.1 % (w / v) Ponceau in 5% acetic acid). After total protein detection, the stain was washed out with TBST, and the membrane was immersed in a blocking solution (5% NFDM in TBST) for an hour prior to POI immunodetection with antibodies for PKC theta and COX IV. After incubation time the membranes were washed and the signal was developed with chemiluminescence.

[0932] Densitometric analysis was performed using ImageLab software. The level of the protein of interest in control cells (treated with DMSO) was assumed as 100%, and the signal was normalized to the COX IV loading control.

[0933] The results for the 7h treatment with 500nM compounds are shown in Table 13, using the following labels:

[0934] > 30% for 30-59% of PKC9 protein reduction,

[0935] > 60% for 60-100% of PKC0 protein reduction.

[0936] Table 13: PKC& protein degradation in antibody mix co-stimulated Jurkat cells

[0937] As illustrated in Table 13 and Figure 2, the compounds of the present invention have the capability to induce degradation of PKC0 protein.

[0938] Example 122: PKC-epsilon protein degradation in antibody mix co-stimulated Jurkat cells.

[0939] Western blot

[0940] The effect of various compounds of the invention on PKC-epsilon protein degradation in the Jurkat cell line was investigated, using the protocol described for "PKC0 protein degradation in antibody mix co-stimulated Jurkat cells, Western blot" assay. Anti-PKC-epsilon antibody was used to detect the protein of interest.

[0941] The results for the 7h treatment with 500nM compounds are shown in Table 14.

[0942] Table 14: PKC-epsilon protein degradation in antibody mix co-stimulated Jurkat cells

[0943] As illustrated in Table 14, compounds of the present invention have capability to induce degradation of PKCE protein.

[0944] Example 123: PKC-alpha protein degradation in antibody mix co-stimulated Jurkat cells, Western blot

[0945] The effect of various compounds of the invention on PKC-alpha protein degradation in the Jurkat cell line was investigated, using the protocol described for "PKC0 protein degradation in antibody mix costimulated Jurkat cells, Western blot" assay. Anti-PKC-alpha antibody was used to detect the protein of interest.

[0946] The results for the 7h treatment with 500nM compounds are shown in Table 15. A representative membrane for compound 248 is shown in Figure 2.

[0947] Table 15: PKC-alpha protein degradation in antibody mix co-stimulated Jurkat cells As illustrated in Table 15, compounds of the present invention have capability to induce degradation of PKC-a protein.

[0948] Example 124: PKC-delta protein degradation in antibody mix co-stimulated Jurkat cells. Western blot

[0949] The effect of various compounds of the invention on PKC-delta protein degradation in the Jurkat cell line was investigated, using the protocol described for "PKC0 protein degradation in antibody mix costimulated Jurkat cells, Western blot" assay. Anti-PKC-delta antibody was used to detect the protein of interest.

[0950] The results for the 7h treatment with 500nM compounds are shown in Table 16.

[0951] Table 16: PKC-delta protein degradation in antibody mix co-stimulated Jurkat cells

[0952] As illustrated in Table 16 and Figure 2, compounds of the present invention have the capability to induce degradation of PKC-delta protein.

[0953] ABBREVIATIONS AND DEFINITIONS

[0954] A list of the abbreviations used in the present application is shown in Table 17 below:

[0955] Table 17: Abbreviations

[0956] As used herein, the term "room temperature" means a temperature of between 20°C and 25°C.

Claims

CLAIMS1. A compound of formula (I)[Protein Kinase C ligand moiety] - linker - [ligase ligand moiety] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, wherein [ligase ligand moiety] is:whereinM is O, NMe or NH, or is absent; indicates attachment to R18of the linker;R22is hydrogen, halogen or an amino group; andL' is hydrogen, alkyl, benzyl, acetyl or pivaloyl;wherein [Protein Kinase C ligand moiety] is a compound of Formula (B):whereinhalogen or -N02; or R8and R9together with the carbon atoms to which they are attached form a six-membered aryl ring;R20is -OCF3, -O-CHF2, -CF3, -CN, O-alkyl, -NH-alkyl, -NHR19, alkyl, phenyl, pyrrole, pyrazole, imidazole, triazole, tetrazole, -O-aryl, morpholine, piperazine or CN,R23is hydrogen or methyl,R24is hydrogen or methyl,R25is hydrogen, methyl, -OH, -NH2, -O-alkyl, -NHalkyl, -COOH, -COOalkyl or halogen,R26is hydrogen or R19,R19is a bond connected to R14of the linker, and wherein Formula (B) contains a single R19; and wherein [linker] has following formula-R14-R15-R16-R17-R18whereinR14is -C(O)-, -CH2C(O)-, linear -C1-10 alkyl, or is absent;R15is linear -Ci-w alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -(C2H4O)X, -(C2H4O)x-(linear C1-10 alkyl), - CH2O-, - CH20(linear Ci.io alkyl), -(C3H6-O)x, -(C3H6-O)x(linear Ci-w alkyl), -CH2(C2H4-O)y, - CH2(C2H4- O)y(linear CHO alkyl), or heterocycloalkyl,R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, -CH2-, - CH2NMe-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,R17is -CH2-, -CH2O-, -(C2H4O)X, (CaHe-Ojx, CH2(C2H4-O)y, heterocycloalkyl, or is absent x is 1-10 y is 2-10R18is linear -CHO alkyl, heterocycloalkyl, or is absent.

2. The compound of claim 1, wherein R22is hydrogen, fluorine or an amino group.

3. The compound of claim 2, wherein R22is hydrogen.

4. The compound of any one of claims 1-3, wherein L' is hydrogen or methyl.

5. The compound of claim 4, wherein L' is hydrogen.

6. The compound of any preceding claim, wherein M is 0 or NH, or is absent.

7. The compound of any one of claims 1-6, wherein [ligase ligand moiety] is:

8. The compound of claim 7, wherein [ligase ligand moiety] is:

9. The compound of claim 7, wherein [ligase ligand moiety] is:

10. The compound of claim 6, wherein [ligase ligand moiety] is11. The compound of claim 10, wherein [ligase ligand moiety] is12. The compound of any one of claims 1-6, wherein [ligase ligand moiety] is:

13. The compound of claim 12, wherein [ligase ligand moiety] is:

14. The compound of claim 12, wherein [ligase ligand moiety] is:

15. The compound of claim 12, wherein [ligase ligand moiety] is16. The compound of any one of claims 1-15, wherein:R15is linear -C1.9 alkyl, -C2H4O-(linear C1-4 alkyl), piperidinyl, or piperazinyl,piperazinyl,R17is -CH2O-, -(C2H4O)X, -CH2-, piperidinyl, piperazinyl, or is absent x is 1-6R18is linear -Ci-g alkyl, piperidinyl, piperazinyl, or is absent.

17. The compound of any one of claims 1-15, wherein:R14is absent;R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; andR17is -CH2O-, -(C2H4O)X, (CaHe-Ojx, CH2(C2H4-O)V, heterocycloalkyl, or is absent.

18. The compound of claim 17, wherein:R15is linear -Ci-8alkyl, -C2H4O-(linear C1-4 alkyl), or piperazinyl,piperazinyl,R17is -CH2O-, -(C2H4O)x, piperazinyl, or is absent x is 1-6R18is linear -Ci.8alkyl, piperazinyl, or is absent.The compound of claim 18, whereinR1Sis linear -C vs alkyl or -C2H4O-(linear Ci-4alkyl),R17is -CH2O-, -(C2H4O)X, or is absentR18is linear -Ci-g alkyl, or is absent.The compound of any one of claims 1-19, whereinx is 2R18is linear -Ci-s alkyl, or is absent.

21. The compound of any one of claims 18-20, wherein R18is linear-Ci-3 alkyl, or is absent.

22. The compound of any one of claims 18-21, wherein R15is linear -C3alkyl, linear -C3alkyl, linear -C7alkyl or -C2H4O-(linear C4alkyl).

23. The compound of any one of claims 1-22, wherein R16is24. The compound of any one of claims 1-22, wherein R16is -NH-C(O)-.

25. The compound of any one of claims 1-24, wherein [linker] is selected from:wherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

26. The compound of any one of claims 1-24, wherein [linker] is selected from:wherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

27. The compound of any one of claims 1-26, wherein28. The compound of claim 27, whereinR15is linear -Ci-8 alkylR17is -(C2H4-O)X, or is absent x is 1-6R18is linear -Ci.g alkyl.

29. The compound of claim 28, wherein R16is30. The compound of claim 28, wherein R16is -NH-C(O)-.

31. The compound of any one of claims 1-27, whereinR15is linear -Ci-salkylR16is -NH-C(O)-R18is linear -Ci-8 alkyl32. The compound of any one of claims 1-24 and 27-31, wherein [linker] is selected fromwherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

33. The compound of any one of claims 1-32, wherein [linker] is selected fromwherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

34. The compound of any one of claims 1-33, wherein [Protein Kinase C ligand moiety] is35. The compound of claim 34, wherein [Protein Kinase C ligand moiety] is36. The compound of claim 37, wherein [Protein Kinase C ligand moiety] is37. The compound of any one of claims 1-34, wherein [Protein Kinase C ligand moiety] is selected from38. The compound of claim 37, wherein [Protein Kinase C ligand moiety] is selected from:

39. The compound of any one of claims 1-33, wherein [Protein Kinase C ligand moiety] is40. The compound of claim 1, which is selected from:

41. The compound of claim 40, which is selected from:2995984380 vl 1082S®jW?6 v142. The compound of claim 40, which is selected from:

43. The compound of any one of claims 1-42, wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl is unsubstituted.

44. A compound of formula (I)[Protein Kinase C ligand moiety] - [linker] - [ligase ligand moiety] (I) or a salt, solvate, hydrate, isomer or prodrug thereof, wherein [ligase ligand moiety] is:(a) Formula (IV)wherein: each of Xi and X2is independently O or S; each of Qi and Ch is independently N or CRS, wherein at least one of Qi and Ch is N; each of Ei, E2, E3and E4is independently N or CR'; n is 0, 1 or 2;L2is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R"', -C(O)OR'", -C(O)NH2, -C(O)NHR"', -C(O)NR'"2, -OR'", -NR'"2, or -S(O)2R'";each R5is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR'", -NR" 2, -NR’”C(O)R’", -NR’"C(O)OR"', -NO2, -CN, -C(O)R"', -C(O)OR'", -C(O)NH2, -C(O)NHR'", -C(O)NR”’2, -OR"’, -OC(O)R"', -OC(0)OR"',each R' is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl. haloalkyl, haloalkenyl, -NH2, -NHR”’, -NR’”2, -NR"'C(O)R"', -NR"'C(O)OR"', -NO2,-CN, -C(O)R"', -C(O)OR"', -C(O)NH2, -C(O)NHR"', -C(O)NR'"2, -OR'", -OC(0)R"',-OC(O)OR"', -OC(O)NH2, -OC(O)NHR’", -OC(O)NR'”2, -SR’", -S(O)2R"', -S(O)2OR"',S(O)2NH2, -S(O)2NHR'", -S(O)2NR'”2, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; and each R'" is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl; wherein R21is a bond connected to R18of the linker, and wherein Formula (IV) contains a single R21; or(b) Formula (Va) or (Vb):or a pharmaceutically acceptable salt or tautomer thereof, wherein each of Xi and X2is independently O or S;Zi is 0, S or NR6;T is is C=O or SO2;R1is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; each of Ys, Y6, Y7, and Y8is independently N or CR7, wherein at least one of Ys, Ye and Y7in Formula (Va) is CR7, and at least one of Ys, Ysand YsinFormula (Vb) is CR7; n is 0, 1 or 2;L3is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)R"", -CH2C(O)OR"", -C(O)OR"", -C(O)NH2, -C(O)NHR"", -C(O)NR""2, -OR'"', -NR""2, or-S(O)2R""; each R7is independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR"",-NR""2, -CH2NR""2, -NR""C(O)R"", -NR""C(O)CH2NR""2, -NR""C(O)CH2-heterocycloalkyl,-NR""C(O)CH(OH)R"", -CH2NR""C(O)OR"", -NR""C(O)OR"", -NR""SO2R"", -NO2, -CN,-C(O)R"", -C(O)OR"", -C(O)NH2, -C(O)NHR"", -C(O)NR""2, -OR'"', -OC(O)R'"', -OC(O)OR"", -OC(O)NH2, - OC(O)NHR"", -OC(O)NR""2, -NHC(S)NHR"", SR'"', or -S(O)2R"",-S(O)2OR"", -S(O)2NH2, -S(O)2NHR"", - S(O)2NR""2, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; each R"" is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;R6is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR"", -NR""2, -NR""C(O)R"", -N[C(O)R""]2, -NR""C(O)OR"", -NO2, -CN, -C(O)R"", - C(O)OR"", -C(O)NH2, -C(O)NHR"", -C(O)NR""2, -OR"", -OC(O)R"",-OC(O)OR"", -OC(O)NH2, -OC(O)NHR"", -OC(O)NR""2, -SR"", or -S(O)2R"",-S(O)2OR"",-S(O)2NH2, -S(O)2NHR"", -S(O)2NR""2, -R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; wherein R21is a bond connected to R18of the linker, and wherein formula (Va) and formula (Vb) each contain a single R21; wherein when Zi is O, then Ysis CR7and wherein when the compound is of Formula (Va), then(i) when each of Ys, Y6and Y7is CR7, then at least one of R7is not H;(ii) when Zi is NR6, then Ysand Y7are CR7;(iii) when Zi is S, then Ysis not C-OMe and Ys is not C-OMe;(iv) when Zi is S and Y5is C-NHCOMe, then Y7is not C-CH2NR""C(O)OR"";(v) when Zi is S and Y5is N, then Y6is not C-H, C-aryl or C-C(O)OR""; and(vi) when Zi is S and Y6is N, then Y7is C-NH2, C-NHR"", C-NR""2, C-NR""C(O)OR"", C- CH2NR""C(O)OR"", C-haloalkyl, C-’Butyl, C-OR"", C-COOR"" or C-SR""; wherein when Y7is C-NH2, C- NHR"" or C-NR""2, then Ysis C-H; and when the compound is of Formula (Vb), then:(vii) when each of Y5, Ye and Y8is CR7, then at least one of R7is not H;(viii) when Zi is S, then Y5is not C-COOH or C-NHC(O)Me, and Y8is not C-Br;(ix) when Z2is S and Y6is C-Br, then Y8is C-OR""(x) when Zi is S, Ysis N and Y6is C-H or C-NH2, then Y8is not C-H(xi) when Zi is S and Ysis N, then Y6is not C- halogen, C-alkyl, C-cycloalkyl, C-aryl, C-heteroaryl, C- CH2NH2, C-COOalkyl, or C-NHC(O)alkyl; (xii) when Zi is NR6, then Y5, Ye and Y8are CR7. or(c) Formula (Ila) or (lib):each of Xi and X2is independently 0 or S;Z is O, S or NR2;T is C=O or SO2;Y3is N or CR;Y4is N or CR; indicates a single or double bond, wherein when eachis a double bond, each of Wi, W2, W3and W4is independently N or CR3, wherein at least one of Wi, W2, W3and W4is N, and when eachis a single bond, Wi, W2, W3and W4are each CRa2and Y4is CR; n is 0, 1 or 2;L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)Rh, -C(O)ORh, - C(O)NH2, -C(O)NHRh, -C(O)NRh2, -ORh, -NRh2, or -S(O)2Rh; each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHRh, -NRh2, -NRhC(O)Rh, -NRhC(O)CH2Rh, - NRhC(O)CH(OH)Rh, -NRhC(O)ORh, -NRhSO2Rh, -NO2, -CN, -C(O)Rh, -C(O)ORh, -C(O)NH2, -C(O)NHRh, -C(O)NRh2, -ORh, -OC(O)Rh, -OC(O)ORh, -OC(O)NH2, -OC(O)NHRh, -OC(O)NRh2, -SRh, or -S(0)2Rh,-S(O)20Rh, - S(O)2NH2, -S(O)2NHRh, or -S(O)2NRh2; each Rais independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHRh, -NRh2, -NRhC(O)Rh, -NRhC(O)CH(OH)Rh, - NRhC(O)ORh, -NRhSO2Rh, -NO2, -CN, -C(O)Rh, -C(O)ORh, -C(O)NH2, -C(O)NHRh, -C(O)NRh2, -ORh, -OC(O)Rh, - OC(O)ORh, -OC(0)NH2, -OC(O)NHRh, -OC(O)NRh2, -SRh, -S(O)2Rh, -S(O)2ORh, -S(O)2NH2, -S(O)2NHRh, - S(O)2NRh2, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; each Rhis independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;R2is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHRh, -NRh2, -NRhC(O)Rh, -N[C(O)Rh]2, -NRhC(O)ORh, -NO2, -CN, -C(O)Rh, -C(0)ORh, - C(O)NH2, -C(O)NHRh, -C(O)NRh2, -ORh, -OC(O)Rh, -OC(O)ORh, -OC(O)NH2, -OC(O)NHRh, -OC(O)NRh2, -SRh, - S(O)2Rh,-S(O)2ORh, -S(O)2NH2, -S(O)2NHRh, or -S(O)2NRh2; andR1is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;R21is a bond connected to R18of the linker, and wherein formula (Ila) and formula (lib) each contain a single R21; wherein when eachis a double bond, Z is NR2, R2is hydrogen, and each Rais hydrogen, then W4is CRa; wherein [Protein Kinase C ligand moiety] is a compound of Formula (B):whereinR8ishalogen or NO?; or R8and R9together with the carbon atoms to which they are attached form a six-membered aryl ring;R20is -OCF3, -O-CHF2, -CF3, -CN, O-alkyl, -NH-alkyl, -NHR19, alkyl, phenyl, pyrrole, pyrazole, imidazole, triazole, tetrazole, -O-aryl, morpholine, piperazine or CN,R23is hydrogen or methyl,R24is hydrogen or methyl,R25is hydrogen, methyl, -OH, -NH?, -O-alkyl, -NHalkyl, -COOH, -COOalkyl or halogen,R26is hydrogen or R19,R19is a bond connected to R14of the linker, and wherein Formula (B) contains a single R19; and wherein [linker] has following formulaR14.R15.R16.R17.R1*whereinR14is -C(0)-, -CH2C(O)-, linear -Ci-io alkyl, or is absent;R15is linear -Ci-io alkyl, -C2.6alkenyl, -C2.6alkynyl, -(C2H4O)X, -(C2H4O)x-(linear Ci-io alkyl), - CH2O-, - CH2O(linear Ci.Balkyl), -(C3H6-O)X, -(C3H6-O)x(linear Ci-w alkyl), -CH2(C2H4-O)y, - CH2(C2H4- O)y(linear Ci-ioalkyl), or heterocycloalkyl,R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, -CH2-, - CH2NMe-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,R17is -CH2-, -CH2O-, -(C2H4O)X, (CsHe-Ojx, CH2(C2H4-O)V, heterocycloalkyl, or is absent x is 1-10 y is 2-10R18is linear -Ci-io alkyl, heterocycloalkyl, or is absent.

45. The compound of claim 44, wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl groups is unsubstituted.

46. The compound of any one of claims 44-45, wherein each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, - NHR"", -NR""2, -NR""C(O)R"", -NR""C(O)CH(OH)R'"', -NR""C(O)OR"", -NR""SO2R"", -NO2, -CN,- C(O)R"", -C(O)OR"", -C(O)NH2, -C(O)NHR"", -C(O)NR""2, -OR"", -OC(O)R"", -OC(O)OR"", -OC(O)NH2, - OC(O)NHR"", -OC(O)NR""2, -SR"", or -S(O)2R"", -S(O)2OR"", -S(O)2NH2, -S(O)2NHR"", or -S(O)2NR""2, - O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21.

47. The compound of any one of claims 44-46, wherein R1is hydrogen.

48. The compound of any one of claims 44-47, wherein R6is hydrogen.

49. The compound of any one of claims 44-48, wherein when Zi is S in Formula (Vb), then Ysis notC- NHC(O)R"" or -C(O)OR"".

50. The compound of any one of claims 44-49, wherein Zi is NR6.

51. The compound of any one of claims 44-50, wherein [ligase ligand moiety] is of Formula (Va) andYs, Y6and Y7are each CR7.

52. The compound of claim 51, whereinYs is -C-NHC(O)R"",Ysis CH, andY7is CH or CCI.

53. The compound of claim 52, wherein:L3is hydrogen;Zt is S;R1is hydrogen;T is C=O; andY7is CH.

54. The compound of any one of claims 44-50, wherein the compound is of Formula (Vb) and Ys, Y6and Yg are each CR7.

55. The compound of claim 54, wherein:L3is hydrogen;Zi is S;R1is H;T is C=O;Ys is CH, C-OR”", CCI, C-CN, or C-NHC(O)R"";Y6is CH, CCI, C-alkyl, C-cycloalkyl, or C-haloalkyl; andYg is CH, C-OR'"', C-NHC(O)R"", C-NHC(0)OR"", C-NHR"", C-NH2, or C-NHSO2R""; wherein, when Y5is CCI, then Y6is CH, C-alkyl, C-cycloalkyl, or C-haloalkyl; optionally wherein each R"" is independently alkyl, cycloalkyl, aryl or benzyl.

56. The compound of claim 55, wherein:Ys is CH;Ye is CH or CCI; andYgis C-OR"" or C-NH2, optionally C-OMe or C-NH2.

57. The compound of any one of claims 44-56, wherein Z is NR2.

58. The compound of any one of claims 44-56, wherein Z is S.

59. The compound of any one of claims 44-58, wherein eachis a double bond.

60. The compound of any one of claims 44-59, wherein L is hydrogen.

61. The compound of claim 59, wherein one of Wi, W2, W3and W4is N, and the remaining three of Wi, W2, W3and W4are each CRa; optionally wherein W4is CRT62. The compound of claim 59, wherein two of Wi, W2, W3and W4is N, and the remaining two of Wi, W2, W3and W4are each CRa.

63. The compound of claim 59, wherein one of Wi, W2, W3and W4is CRa, and the remaining three of Wi, W2, W3and W4are each N.

64. The compound of any one of claims 44-63, wherein each R is independently hydrogen, halogen or -NRhC(O)Rh.

65. The compound of any one of claims 44-64, wherein [ligase ligand moiety] is:

66. The compound of any one of claims 44-65, wherein Ei, E2, E3and E4are each CR'.

67. The compound of any one of claims 44-66, wherein one of Ei, E2, E3and E4is N and the remaining three of Ei, E2, E3and E4are each CR'.

68. The compound of any one of claims 44-67, wherein Qi is CR569. The compound of any one of claims 44-68, wherein Cb is CR570. The compound of any one of claims 44-69, wherein:R15is linear -C1-9 alkyl, -C2H4O-(linear Ci-4alkyl), piperidinyl, or piperazinyl,piperazinyl,R17is -CH2O-, -(C2H4O)X, -CH2-, piperidinyl, piperazinyl, or is absent x is 1-6R18is linear -Ci-g alkyl, piperidinyl, piperazinyl, or is absent.

71. The compound of any one of claims 44-69, wherein:R14is absent;R15is linear -C1-10 alkyl, -C2-6 alkenyl, -C2-e alkynyl, -(C2H4O)X, -(C2H4O)x-(linear C1-10 alkyl), - CH2O-, - CH2O(linear Ci-w alkyl), -(C3H6-O)X, -(C3H6-O)x(linear Ci-Malkyl), -CH2(C2H4-O)y, - CH2(C2H4- O)y(linear Cno alkyl), or heterocycloalkyl;R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; andR17is -CH2O-, -(C2H4O)X, (C3HS-O)X, CH2(C2H4-O)V, heterocycloalkyl, or is absent.

72. The compound of any one of claims 44-71, wherein:R15is linear -C1-8 alkyl, -C2H4O-(linear Ci-4alkyl), or piperazinyl,R17is -CH2O-, -(C2H4O)X, piperazinyl, or is absent x is 1-6R18is linear -Ci.galkyl, piperazinyl, or is absent.The compound of claim 72, whereinR15is linear -Ci-8alkyl or -C2H4O-(linear Ci-4alkyl).R17is -CH2O-, -(C2H4O)X, or is absent R18is linear -Ci-s alkyl, or is absent.

74. The compound of any one of claims 44-73, whereinx is 2R18is linear -Ci-6alkyl, or is absent.

75. The compound of claim 74, wherein R18is linear-Ci-3alkyl, or is absent.

76. The compound of claim 74 or 75, wherein R15is linear -C3alkyl, linear -C5 alkyl, linear -C7 alkyl or - C2H4O-(linear C4alkyl).

77. The compound of any one of claims 44-76, wherein R16is78. The compound of any one of claims 44-76, wherein R16is -NH-C(O)-.

79. The compound of any one of claims 44-78, wherein [linker] is selected from:wherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

80. The compound of any one of claims 44-73, wherein81. The compound of claim 80, whereinR15is linear -Ci-8 alkylR17is -(C2H4-O)X, or is absent x is 1-6R18is linear -Ci.galkyl.

82. The compound of claim 81, wherein R16is83. The compound of claim 81, wherein R16is -NH-C(O)-.

84. The compound of any one of claims 44-73, whereinR18is linear -Ci-8alkyl85. The compound of any one of claims 44-73 and 80-84, wherein [linker] is selected fromwherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

86. The compound of any one of claims 44-85, wherein [linker] is selected fromwherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

87. The compound of any one of claims 44-86, wherein [Protein Kinase C ligand moiety] is88. The compound of claim 87, wherein [Protein Kinase C ligand moiety] is89. The compound of claim 88, wherein [Protein Kinase C ligand moiety] is90. The compound of any one of claims 44-86, wherein [Protein Kinase C ligand moiety] is selected from91. The compound of claim 90, wherein [Protein Kinase C ligand moiety] is selected from:

92. A compound of formula (I)[Protein Kinase C ligand moiety] - [linker] - [ligase ligand moiety]or a salt, solvate, hydrate, isomer or prodrug thereof, wherein [ligase ligand moiety] is:(a) Formula (II):wherein: each of Xi and X2is independently 0 or S;T is C=O or SO2;R1is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2;U is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, ha loalkyl, haloalkenyl, -C(O)H, -C(O)R",- C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2, -OH, -OR", -NH2, -NHR", -NR"2, -S(O)2H or -S(O)2R";Rvis selected fromwherein indicates attachment to T,Z3is O, S or NR3;U is O, S, NRbor CRb2; each of Yi, Y2and Y3is independently N or CRd; each Rdis independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", -OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, - S(O)2OR”, -S(O)2NH2, -S(O)2NHR", -S(O)2NR"2, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R2X; each Rbis independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alky nyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(0)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -0C(O)R", - OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, - S(O)2OR", -S(O)2NH2, -S(O)2NHR", or -S(O)2NR"2; each R3is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHSO2R", -NR"SO2R", -N02, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -0C(O)R", - OC(O)OH,-OC(D)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(0)2OH, - S(O)2OR", -S(O)2NH2, -S(O)2NHR", -S(O)2NR"2, -R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; each R" is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;R21is a bond connected to R18of the linker, wherein Formula (II) contains a single R21; wherein,hydrogen or(b) Formula (III):wherein: each of Xi and X2is independently O or S;T is C=O or S02;R1is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl; n is 0, 1 or 2;Li is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, -C(O)R",-C(O)OH, -C(O)OR", -CH2C(0)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2, -OH, -OR", -NH2, -NHR", -N R"2, -S(O)2H or - S(O)2R";Rxis selected fromindicates attachment to T,Z4is 0, S or NR4;V is CRf2, NR4or S; each of Gi, G2, G3and G4is independently N or CRC, each of Yi and Y2is independently N or CRf, each Rfis independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R", -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)OR", -NHS02R", -NR"SO2R", -NO2, -CN, - C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", -C(O)NR"2,-OH, -OR", -OC(O)H, -OC(O)R", - OC(O)OH,-OC(Q)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, - S(O)2OR", -S(O)2NH2, -S(O)2NHR", -S(O)2NR"2, - R21, -O-R21, -NH-R21, -C(0)-NH-R21, or -CH2-NH-C(O)-R21; orwhen Yi and Y2are CRfthen each Rf, together with the carbon atom to which it is attached, forms a 5- or6- membered ring; each Rcis independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl substituted with at least one -OR", heteroaryl, benzyl, haloalkyl, haloalkenyl, -NH2, -NHR", -NR"2, -CH2NH2, -NHC(O)R", -NR"C(O)R", NHC(O)CH(OH)R'', -NR"C(O)CH(OH)R", -NHC(O)OR", -NR"C(O)0R", -NHSO2R", -NR"SO2R", -NO2, -CN, -C(O)H, C(O)R", -C(O)OR", -C(O)NH2, -C(O)NHR", -C(0)NR"2,-OH, -OR",-OC(O)H, -OC(O)R", -OC(O)OH,-OC(O)OR", -OC(O)NH2, -OC(O)NHR", -OC(O)NR"2, -SH, -SR", -S(O)2H, -S(O)2R", -S(O)2OH, -S(O)2OR", -S(O)2NH2, -S(O)2NHR", -S(O)2NR"2, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; each R4is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, -C(O)H, C(O)R", -C(O)OH, -C(O)OR", -C(O)NH2, -C(O)NHR", - C(O)NR"2, -OH, -OR", -NH2, -NHR", -NR"2, -S(O)2H, -S(O)2R", - R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21; and each R" is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;R21is a bond connected to R18of the linker, wherein Formula (III) contains a single R21; wherein, when n = 2, each Rcis hydrogen, and each of Gi, G2, G3and G4is CRC, then C=Xi may be replaced by CH; and wherein:(i) when Rxisthen Li is hydrogen, -CH2C(O)OR", or -OR";(ii) when Rxisthen R4is not alkyl and at least one of R2and R is not H;(iii) when Rxisare CRf, then at least one of Gi, G2an d G3is N;(iv) when Z4is NR4, and Yi and Y2are CRf, then Rxis not(v) when Rxisthen R4is not alkyl;(vi) when Rxiswherein [Protein Kinase C ligand moiety] is a compound of Formula (B):whereinhalogen or NO2; or R8and R9together with the carbon atoms to which they are attached form a six-membered aryl ring;R20is -OCF3, -O-CHF2, -CF3, -CN, O-alkyl, -NH-alkyl, -NHR19, alkyl, phenyl, pyrrole, pyrazo le, imidazole, triazole, tetrazole, -O-aryl, morpholine, piperazine or CN,R23is hydrogen or methyl,R24is hydrogen or methyl,R25is hydrogen, methyl, -OH, -NH2, -O-alkyl, -NHalkyl, -COOH, -COOalkyl or halogen,R26is hydrogen or R19,R19is a bond connected to R14of the linker, and wherein Formula (B) contains a single R19; and wherein [linker] has following formulawhereinR14is -C(O)-, -CH2C(O)-, linear -Ci-w alkyl, or is absent;R15is linear -Ci-w alkyl, -C2-6 alkenyl, -C2-s alkynyl, -(C2H4O)X, -(C2H4O)x-(linear C1-10 alkyl), - CH2O-, - CH2O(linear Ci-w alkyl), -(C3H6-O)X, -(C3H6-O)x(linear Ci-io alkyl), -CH2(C2H4-O)y, - CH2(C2H4- O)y(linear Ci-walkyl), or heterocycloalkyl,R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, -CH2-, - CFhNMe-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,R17is -CH2-, -CH2O-, -(C2H4O)X, (C3H6-O)X, CH2(C2H4-O)V, heterocycloalkyl, or is absent x is 1-10 y is 2-10R18is linear -Ci-w alkyl, heterocycloalkyl, or is absent93. The compound of claim 92, wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl and benzyl is unsubstituted.

94. The compound of any one of claims 92-93, wherein in Formula (III): each of Xi and X2is 0;T is C=O;R1is hydrogen,LI is hydrogen,RxisZ4is NR4; each of Gi, G2and G4 is CRC,Yi is N, andY2is CRf, wherein Rfis not hydrogen.

95. The compound of any one of claims 92-94, wherein [ligase ligand moiety] is Formula (II I):

96. The compound of any one of claims 93-95, wherein one of Rcis -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21.

97. The compound of any one of claims 92-96, wherein Gi is C-O-R21, C-NH-R21, C-C(O)-NH-R21, or C- CH2-NH-C(O)-R21.

98. The compound of any one of claims 92-96, wherein G2is C-O-R21, C-NH-R21, C-C(O)-NH-R21, or C- CH2-NH-C(O)-R21.

99. The compound of any one of claims 92-95, wherein R4is R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21.

100. The compound of any one of claims 92-95, wherein one of Rfis - R21, -0-R21, -NH-R21, -C(O)-NH- R21, or -CH2-NH-C(O)-R21.

101. The compound of claim 100, wherein Y2is C- R21, CO-R21, C-NH-R21, C-C(O)-NH-R21, or C-CH2-NH-C(O)-R21.

102. The compound of any one of claims 92-101, wherein [ligase ligand moiety] is selected from103. The compound of any one of claims 92-93, wherein [ligase ligand moiety] is of Formula (II):

104. The compound of any one of claims 92-93 and 103, wherein Rvis selected from105. The compound of any one of claims 92-93 and 103-104, whereinZ3is S or NR3;U is O or S; each of Vi, Y2and Y3is independently N or CRd.

106. The compound of any one of claims 92-93 and 103-105, wherein Rbis hydrogen or alkyl.

107. The compound of any one of claims 92-93 and 103-106, wherein R3is hydrogen, alkyl, cycloalkyl, -R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21.

108. The compound of any one of claims 92-93 and 103-107, wherein each Rdis independently hydrogen, alkyl, -O-R21, -NH-R21, -C(O)-NH-R21, or -CH2-NH-C(O)-R21.

109. The compound of any one of claims 92-108, wherein:R15is linear -Ci-9 alkyl, -C2H4O-(linear C1-4 alkyl), piperidinyl, or piperazinyl,piperazinyl,R17is -CH2O-, -^FUOjx, -CH2-, piperidinyl, piperazinyl, or is absent x is 1-6R18is linear -Ci-8alkyl, piperidinyl, piperazinyl, or is absent.

110. The compound of any one of claims 92-108, wherein:R14is absent;R15is linear -Ci-w alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -(C2H4O)X, -(C2H4O)x-(linear Ci-w alkyl), - CH2O-, - CH2O(linear Cm alkyl), -(C3H6-O)X, -(C3H6-O)x(linear Ci-io alkyl), -CH2(C2H4-O)V, - CK2(C2H4- O)v(linear C1-10 alkyl), or heterocycloalkyl;R16is -NH-C(O)-, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O-, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; andR17is -CH2O-, -(C2H4O)X, (C3H6-O)X, CH2(C2H4-O)V, heterocycloalkyl, or is absent.

111. The compound of any one of claims 92-110, wherein:R15is linear -Ci-8alkyl, -C2H4O-(linear C1-4 alkyl), or piperazinyl,piperazinyl,R17is -CH2O-, -(C2H4O)X, piperazinyl, or is absent x is 1-6R18is linear -Ci-8alkyl, piperazinyl, or is absent.

112. The compound of claim 111, whereinR15is linear -Ci-8alkyl or -C2H4O-(linear C1-4 alkyl),R18is linear -Ci-s alkyl, or is absent.

113. The compound of any one of claims 92-112, whereinx is 2R18is linear -Ci.6alkyl, or is absent.

114. The compound of claim 113, wherein R18is linear-Ci-3alkyl, or is absent.

115. The compound of claim 113 or 114, wherein R15is linear -C3alkyl, linear -C5alkyl, linear -C7alkyl or -C2H4O-(linear C4alkyl).

116. The compound of any one of claims 92-115, wherein R16is117. The compound of any one of claims 92-116, wherein R16is -NH-C(O)-.

118. The compound of any one of claims 92-117, wherein [linker] is selected from:wherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

119. The compound of any one of claims 92-112, wherein120. The compound of claim 119, whereinR15is linear -Ci-s alkylR17is -(C2H4-O)X, or is absent x is 1-6R18is linear -Ci s alkyl.

121. The compound of claim 120, wherein R16is122. The compound of claim 120, wherein R1Sis -NH-C(O)-.

123. The compound of any one of claims 92-122, whereinR16is -NH-C(O)-R18is linear -Ci-8alkyl124. The compound of any one of claims 92-105 and 119-123, wherein [linker] is selected fromwherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

125. The compound of any one of claims 92-115, wherein [linker] is selected fromwherein indicates attachment to [Protein Kinase C ligand moiety] and indicates attachment to [ligase ligand moiety].

126. The compound of any one of claims 92-125, wherein [Protein Kinase C ligand moiety] is127. The compound of claim 126, wherein [Protein Kinase C ligand moiety] is128. The compound of claim 127, wherein [Protein Kinase C ligand moiety] is129. The compound of any one of claims 92-125, wherein [Protein Kinase C ligand moiety] is selected from130. The compound of claim 129, wherein [Protein Kinase C ligand moiety] is selected from :

131. The compound of any preceding claim, wherein T is C=O.

132. The compound of any one of claims 1-130, wherein T is SO2.

133. The compound of any preceding claim, wherein Xi and X2are O.

134. The compound of any one of claims 1-132, wherein Xi is O and X2is S.

135. The compound of any one of claims 1-132, wherein Xi is S and X2is 0.

136. The compound of any one of claims 1-132, wherein Xi and X2are S.

137. The compound of any preceding claim, wherein n is 0.

138. The compound of any one of claims 1-136, wherein n is 1 or 2.

139. The compound of claim 138, wherein n is 1.

140. The compound of claim 138, wherein n is 2.

141. A pharmaceutical composition comprising a compound of any one of claims 1-140.

142. The compound of any one of claims 1-140 or the pharmaceutical composition of claim 141, for use in medicine.

143. The compound of any one of claims 1-140 or the pharmaceutical composition of claim 141, for use in the treatment of a disease selected from cancer, psoriasis, arthritis, multiple sclerosis, inflammatory bowel disease, uveitis, dermatitis, diabetes, lupus erythematosus, asthma, colitis, osteoporosis, atherosclerosis, Duchenne Muscular Dystrophy (DMD), T-cell leukaemia, CNS diseases, Ischemic heart diseases, and other diseases or disorders mediated by T lymphocytes.

144. The compound or pharmaceutical composition for use of claim 143, wherein the disease is selected from cancer, psoriasis, arthritis, multiple sclerosis, inflammatory bowel disease, uveitis, dermatitis, diabetes, lupus erythematosus, asthma, colitis, osteoporosis, atherosclerosis, Duchenne Muscular Dystrophy (DMD), T-cell leukaemia, CNS diseases, and Ischemic heart diseases.

145. The compound or pharmaceutical composition for use of claim 144, wherein the disease is cancer.

146. The compound of any one of claims 1-140 or the pharmaceutical composition of claim 240, for use in preventing organ transplant rejection, preventing graft-versus-host disease, and protection from ischemic or reperfusion injury147. A method of treating a disease selected from cancer, psoriasis, arthritis, multiple sclerosis, inflammatory bowel disease, uveitis, dermatitis, diabetes, lupus erythematosus, asthma, colitis, osteoporosis, atherosclerosis, Duchenne Muscular Dystrophy (DMD), T-cell leukaemia, CNS diseases, Ischemic heart diseases, and other diseases or disorders mediated by T lymphocytes in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-140, or a pharmaceutical composition according to claim 141.

148. A method of preventing organ transplant rejection or graft-versus-host disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-140, or a pharmaceutical composition according to claim 141.

149. A method for protecting against ischemic or reperfusion injury in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-140, or a pharmaceutical composition according to claim 141.

150. The method of any one of claims 147-149, further comprising administering at least one additional active agent to the subject.

151. A combined preparation of a compound of any one of claims 1-140 and at least one additional active agent, for simultaneous, separate or sequential use in therapy.

152. The combined preparation of claim 151, wherein the therapy is the treatment of a disease selected from cancer, psoriasis, arthritis, multiple sclerosis, inflammatory bowel disease, uveitis, dermatitis, diabetes, lupus erythematosus, asthma, colitis, osteoporosis, atherosclerosis, Duchenne Muscular Dystrophy (DMD), T-cell leukaemia, CNS diseases, Ischemic heart diseases, and other diseases or disorders mediated by T lymphocytes153. The combined preparation of claim 152, wherein the disease is cancer,154. The combined preparation of claim 151, wherein the therapy is the prevention of organ transplant rejection, the prevention of graft-versus-host disease, or protection from ischemic or reperfusion injury

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