IRF4 degraders and their use for treating cancer and autoimmune disease

Abstract

The invention relates to compounds useful for degradation of interferon regulatory factor 4 (IRF4), pharmaceutical compositions comprising such compounds and methods for treating diseases related to IRF4 activity, such as cancer, using such compounds.

Description

3453.W01WO IRF4 DEGRADERS AND THEIR USE FOR TREATING CANCER AND AUTOIMMUNE DISEASE

[0001] Compounds useful for degrading interferon regulatory factor 4 (IRF4) are provided, as are pharmaceutical compositions comprising such compounds and methods for treating diseases related to IRF4 activity, such as cancer, using such compounds. BACKGROUND

[0002] Transcription factors are promising therapeutic targets in cancers and other disease states but are often mislabeled as ‘undruggable’ due to their dynamic structures, lack of small molecule binding pockets, non-globular tertiary structures, and lack of feasible paths for bioactive small molecules. Interferon regulatory factor 4 (IRF4) is a transcription factor in the interferon regulatory factor family encoded by the IRF4 gene. Distinct from other IRF family members, IRF4 is expressed upon activation of T-cell receptor signaling in T-cells, B-cell receptor, IL-4, CD40 signaling in B cells, and Toll-like receptor signaling by lipopolysaccharide in macrophages. It is noted that IRF4 has been referred to by different names in earlier studies including LSIRF, MUM1, ICSAT, Pip1, NF-EM5, and SHEP8.

[0003] IRF4 overexpression is known in melanoma, leukemia, myeloma, and lymphoma and is associated with a unique gene expression pattern in each. More specifically, IRF4 overexpression is shown in diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), classical Hodgkin lymphoma (cHL), plasma cell myeloma, and primary effusion lymphoma (PEL). High levels of IRF4 also are noted in Epstein-Barr virus (EBV)-transformed cells, B- cell lymphomas with Type 3 latency, and Human T-cell Leukemia Virus-1 (HTLV1)-infected cell lines, acute lymphocytic leukemia (ALL), and adult T-cell leukemia / lymphoma (ATL). Additionally, translocation and genetic mutation of IRF4 have been shown in MM, peripheral T-cell lymphomas, and chronic lymphocytic leukemia (CLL).

[0004] Dysregulated IRF4 is observed in the pathogenesis of immune-inflammatory or autoimmune diseases such as ulcerative colitis, Crohn’s disease, type 1 diabetes, multiple sclerosis, and lupus. Therefore, targeting IRF4 may also have therapeutic potential in the treatment of immune disorders.

[0005] IRF4 is a well-validated clinical target with immunomodulatory drug (IMiD) based treatment regimens. Attempts at targeting IRF4 have relied on the clinically used IMiDs, such 13453.W01WO as lenalidomide and pomalidomide, which target Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) – upstream transcription factors of IRF4. Unfortunately, IMiDs are highly susceptible to resistance mechanisms in the clinic and fail to provide deep and sustained downregulation of IRF4 due to their indirect mechanism of action. IRF4 expression is driven by numerous transcriptional activators including STAT6, NF-kB, and c-Myc, which often counteract the effects of IMiD based treatments.

[0006] The effectiveness of direct IRF4 inhibition has been demonstrated using a selective antisense oligonucleotide (ASO), ION251, to treat MM. (Cell Stem Cell 28, 623-636, April 1, 2021). Pre-clinical models showed a reduction in myeloma regeneration and sensitized myeloma cells to standard of care treatments, specifically, lenalidomide. This is mechanistically achieved via disruption of cell cycle progression and downregulation of stem cell and cell adhesion transcript expression. However, antisense oligonucleotides often are limited by pharmacological effects including off-target toxicities, poor cellular delivery, biochemical attack, and poor target binding.

[0007] Given the validation of IRF4 as a clinical target with IMiD-based and ASO therapy, orally available small molecules that can directly target IRF4 are expected to have significant benefit for patients with MM. Small molecule therapies are generally more stable with predictable pharmacokinetics and pharmacodynamics and oral bioavailability. The predictability of chemical synthesis also provides manufacturing and development benefits for small molecule drugs.

[0008] In this regard, the present inventors reported in Blood 142 (2023) 3635–3636 (https: / / doi.org / 10.1182 / blood-2023-186864) the discovery of a first-in-class small molecule inhibitor of the IRF4-PU.1 interaction, with a TR-FRET IC50 of 2 ^M. The structure of said inhibitor, was later disclosed as 1-(4-methoxyphenyl)-N-[2-(methylamino)-2-oxo-1- phenylethyl]cyclopropanecarboxamide at the American Society of Hematology (ASH) Annual Meeting and Exposition on 10 December 2023.

[0009] Even so, degradation of IRF4 is severely under-explored, and therefore presents the possibility for discovering new therapeutic strategies for cancers and autoimmune diseases. There is an urgent need, in particular, for novel MM therapeutics as over 100,000 MM patients die annually, and those newly diagnosed have a 5-year survival rate of only 53.9%. 23453.W01WO SUMMARY

[0010] Further investigations have led to the discovery of new compounds that are IRF4 degraders.

[0011] In a first aspect, there is provided a compound of formula (I): I), or a pharmaceutically accewherein: the mole fraction of the S-enantiomer at the stereocentre * is greater than zero, except when R2 is CH2C(O)NHCH3 in which case the mole fraction of the R-enantiomer in said compound of formula (I) is greater than zero; R1is H, methyl, hydroxy, methoxy, fluoro or chloro; and when R1 is H, one CH of the phenyl ring to which it is attached may be replaced by N to form a pyridine ring; or R1,together with the phenyl ring to which it is attached, forms a naphthalene group as shown below ;R is C(O)NH2, C(O)NHCH3, CH2C(O)NHCH3, C(O)OH, C(O)OCH3, or tetrazolyl; each R3is independently methyl, hydroxy, methoxy, ethoxy, fluoro, chloro, bromo, phenyl, pyrazolyl optionally substituted with one methyl substituent, triazolyl optionally substituted with one methyl substituent, pyridinyl optionally substituted with one methyl or amino substituent, or OCH2CO2H; m is 1 or 2; n is 1 or 2; 33453.W01WO X is an oxygen atom or a pyrazole ring; L is a moiety that links the oxygen atom to B in a manner that enables the compound of formula (I) to bind simultaneously to an interferon regulatory factor 4 (IRF4) protein and an E3 ubiquitin ligase; and B is a moiety capable of binding to an E3 ubiquitin ligase.

[0012] In a second aspect, there is provided a pharmaceutical composition, comprising a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] In a third aspect, there is provided a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0014] In a fourth aspect, there is provided a method of treating cancer or an autoimmune disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof.

[0015] This fourth aspect includes: a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer or an autoimmune disease; and the use of a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer or an autoimmune disease. DETAILED DESCRIPTION

[0016] In a first aspect, there is provided a compound of formula (I): I), or a pharmaceutically acce, wherein: 43453.W01WO the mole fraction of the S-enantiomer at the stereocentre * is greater than zero, except when R2 is CH2C(O)NHCH3 in which case the mole fraction of the R-enantiomer in said compound of formula (I) is greater than zero; R1is H, methyl, hydroxy, methoxy, fluoro or chloro; and when R1 is H, one CH of the phenyl ring to which it is attached may be replaced by N to form a pyridine ring; or R1, together with the phenyl ring to which it is attached, forms a naphthalene group as shown below ;, , )NHCH3, C(O)OH, C(O)OCH3, or tetrazolyl; each R3is independently methyl, hydroxy, methoxy, ethoxy, fluoro, chloro, bromo, phenyl, pyrazolyl optionally substituted with one methyl substituent, triazolyl optionally substituted with one methyl substituent, pyridinyl optionally substituted with one methyl or amino substituent, or OCH2CO2H; m is 1 or 2; n is 1 or 2; X is an oxygen atom or a pyrazole ring; L is a moiety that links the oxygen atom to B in a manner that enables the compound of formula (I) to bind simultaneously to an interferon regulatory factor 4 (IRF4) protein and an E3 ubiquitin ligase; and B is a moiety capable of binding to an E3 ubiquitin ligase.

[0017] The skilled artisan will appreciate that the described compounds, or pharmaceutically acceptable salts thereof, are comprised of a core that contain a chiral center, represented by * in formula (I) below: 53453.W01WO

[0018] All individual enntre, as well as mixtures of the enantiomers including racemates, except for pure R-enantiomers when R2is C(O)NH2, C(O)NHCH3, C(O)OH, C(O)OCH3or tetrazolyl and pure S-enantiomers when R2is CH2C(O)NHCH3, are contemplated. Enantiomerically enriched samples of compounds of formula (I) may be prepared beginning with chiral reagents or by stereoselective or stereospecific synthetic techniques. Alternatively, enantiomerically enriched samples of compounds of formula (I) may be prepared from enantiomeric mixtures by standard chiral chromatographic or crystallization techniques at any convenient point in the synthesis of compounds of the invention.

[0019] S-enantiomers at the stereocentre * in said described compounds are a preferred embodiment of the invention, except when R2 is CH2C(O)NHCH3 in which case R- enantiomers are preferred. When present, the mole fraction of the S-enantiomer (or R- enantiomer when R2is CH2C(O)NHCH3) at the stereocentre * in said compound of formula (I) is greater than 0.5, preferably greater than 0.8, more preferably greater than 0.95, still more preferably greater than 0.99, and most preferably 1.00.

[0020] In some embodiments of the first aspect, R1is H.

[0021] In some embodiments of the first aspect, R2is C(O)NHCH3

[0022] In some embodiments of the first aspect, each R3is independently methyl, methoxy, phenyl, pyrazolyl, triazolyl optionally substituted with one methyl substituent, pyridinyl, or OCH2CO2H. Preferably, each R3 is methoxy, and more preferably p-methoxy.

[0023] In some embodiments of the first aspect, m is 1.

[0024] In some embodiments of the first aspect, n is 1.

[0025] In some embodiments of the first aspect, X is an oxygen atom. 63453.W01WO

[0026] In some embodiments of the first aspect, X is a pyrazole ring linked to L via one of its N atoms and to the phenyl or naphthyl moiety via one of its C atoms, preferably via the C atom at the 3-position on the ring.

[0027] In some embodiments of the first aspect, L is selected from: ;wherein p is 1, 2, 3, 4 or 5; wherein q is 1, 2, 3, 4 or 5; and wherein r is 3, 4 or 5.

[0028] In some embodiments of the first aspect, L is selected from: ,3453.W01WO ein

[0029] In some embodiments of the first aspect, B is selected from the group of: or .p , g ucture: 83453.W01WO ; wherein the connection point joins to X. pect,1 2 3the combination of R, R, R, m, n, and X provide the structure: , ,3453.W01WO , or133453.W01WO r a

[0033] In a second aspect, there is provided a pharmaceutical composition, comprising a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier

[0034] In a third aspect, there is provided a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0035] In a fourth aspect, there is provided a method of treating cancer or an autoimmune disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof.

[0036] This fourth aspect includes: a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer or an autoimmune disease; and the use of a compound of formula (I) as defined in the first aspect, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer or an autoimmune disease

[0037] Unless otherwise defined herein, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs and as commonly used in the art to which this application belongs. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control. To facilitate ready understanding, certain terms used herein are first defined below.

[0038] The term “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Likewise, the term "and / or" as used in a phrase such as “A, B, 163453.W01WO and / or C” is used interchangeably with “A and / or B and / or C” and is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0039] The word “comprise”, or variations such as “comprises”, or “comprising” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. It is further understood that wherever embodiments are described herein with the language “comprising” or grammatical equivalents thereof, otherwise analogous embodiments described in terms of “consisting of” and / or “consisting essentially of” are also provided. In other words, if a composition comprising A, B and C is recited, a composition consisting essentially of A, B and C is also contemplated as is a composition consisting of A, B and C.

[0040] All publications and other reference materials referenced herein are hereby incorporated by reference in their entirety. Although a number of documents are cited herein, this citation does not constitute an admission that any one of these documents forms part of the common general knowledge in the art.

[0041] The term “cancer” is used herein to describe a disease characterized by the uncontrolled, abnormal growth of cells.

[0042] The term “hematological cancer” (or “blood cancer”) is used herein to describe any type of cancer that affects blood cells. This definition encapsulates the five subtypes of hematological cancer: leukemia, lymphoma, myeloma, myelodysplastic syndrome (MDS), and myeloproliferative disorder (MPD).

[0043] “Leukemia” refers to a type of hematological cancer that affects blood cells in bone marrow – usually white blood cells. Examples of leukemia include: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), childhood leukemia and blastic plasmacytoid dendritic cell neoplasm (BPDCN) (although the last of these has features different than traditional leukemias).

[0044] "Lymphoma” refers to a type of hematological cancer that affects the immune system – specifically white blood cells called lymphocytes. Examples of lymphoma include: diffuse large B-cell lymphoma, follicular lymphoma, primary mediastinal B cell lymphoma, 173453.W01WO mantle cell lymphoma, post-transplant lymphoproliferative disorder, marginal zone lymphoma, Waldenström's macroglobulinemia, and Burkitt lymphoma.

[0045] “Myeloma” (or “multiple myeloma”) refers to a type of hematological cancer that affects plasma cells. Examples of myeloma include: light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma, and immunoglobulin E (IgE) myeloma.

[0046] “Myelodysplastic syndrome (MDS)” refers to a type of hematological cancer characterized by the bone marrow producing faulty blood cells and insufficient healthy blood cells. Examples of MDS include: MDS with single lineage dysplasia (MDS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with multilineage dysplasia (MDS-MLD), and MDS with excess blasts (MDS-EB).

[0047] “Myeloproliferative disorder (MPD)” refers to a type of hematological cancer whereby the bone marrow produces too many of a particular type of blood cell. Examples of MPD include: polycythaemia vera (PV), essential thrombocythaemia (ET), and myelofibrosis (MF).

[0048] The term “autoimmune disease” refers to any condition that results from a subject’s immune system attacking their own tissue. Examples of autoimmune disease include: rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and type I diabetes.

[0049] The terms “treating” or “treatment” describe the management and care of a subject for the purpose of combating a disease, condition, or disorder. Treating includes preventing the onset of symptoms or complications, alleviating or eliminating symptoms or complications, or eliminating the underlying disease, condition, or disorder. For example, treating cancer in a subject includes reducing, repressing, delaying or preventing the growth of cancerous cells as well as killing cancerous cells within the subject.

[0050] The terms “administering” and “administration” refer to any method of providing the active substance to a subject. Where the method involves administration of two or more active substances, it results in them exerting their desired pharmacodynamic effects at the same time, or for an overlapping period of time, within the patient's body. Thus, administration of the two or more active substances is not limited to simultaneous 183453.W01WO administration, nor administration via the same route. It encompasses separate, sequential and simultaneous administration via the same or different routes and in the same or different medicaments, provided that it results in them exerting their desired pharmacodynamic effects at the same time, or for an overlapping period of time, within the patient’s body.

[0051] Methods of administration are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intraaural administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable administration such as intravenous administration, intra- arterial administration, intramuscular administration, intradermal administration, intrathecal administration, and subcutaneous administration. Administration can be continuous or intermittent. While the above means of administration may provide systemic exposure to the active substance(s), local administration / exposure is also contemplated, e.g., to the bone marrow of cells.

[0052] “Pharmaceutically acceptable salt” means a salt such as those described in standard texts on salt formation, see for example: S.M. Berge, et al., “Pharmaceutical Salts” (1977) Journal of Pharmaceutical Sciences, 66, 1-19. Suitable salts include those formed with organic or inorganic acids or bases.

[0053] “Pharmaceutical composition” refers to a formulation of the described compounds (or a pharmaceutical salt thereof) in association with one or more pharmaceutically acceptable excipients. Pharmaceutical compositions suitable for the delivery of described compounds and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in “Remington’s Pharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).

[0054] A compound is considered to be an “IRF4 degrader” if it exhibits degradation at less than or equal to 50 µM in the described gel electrophoresis and immunoblotting assay. Accordingly, IRF4 degraders are compounds which bind to the interferon accessory domain (IAD) of the IRF4 protein, and stabilize a ternary complex with a specific E3 ligase. Suitable moieties capable of binding to a specific E3 ubiquitin ligase include, but are not limited to CRBN ligands, VHL ligands, IAP ligands, MDM2 ligands, DCAF ligands, RNF ligands, AhR ligands, FEM1B ligands, KEAP1 ligands. 193453.W01WO

[0055] The term "subject” refers to mammals, preferably humans.

[0056] The cancer or the autoimmune disease may be one which is characterized by overexpression and / or dysregulation of interferon regulatory factor 4 (IRF4).

[0057] The cancer may be a hematological cancer, such as lymphoma, myeloma, or leukemia. Preferably, the hematological cancer is multiple myeloma.

[0058] The autoimmune disease may be a rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, or type I diabetes.

[0059] The compound of the formula (I) is generally effective over a wide dosage range. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0060] It is well known in the art that agents for the treatment of cancer may be combined with other agents for the treatment of cancer. The compound of formula (I), or a pharmaceutically acceptable salt thereof, may be co-administered, simultaneously or sequentially, with other effective treatment(s) for cancer.

[0061] The compounds of formula (I) may be prepared by a variety of procedures known in the art, some of which are illustrated in the Examples below. EXAMPLES

[0062] The following Examples further illustrate the invention and represent typical syntheses of the compounds of the invention. The reagents and starting materials are readily available, or may be readily synthesized by one of ordinary skill in the art. It should be understood that these Examples are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art.

[0063] The R or S configuration of the described compounds may be determined by standard techniques such as X-ray analysis and correlation with chiral-HPLC retention time. The naming of the compounds prepared in the following Examples is generally performed using the IUPAC naming feature in PerkinElmer CHEMDRAW®version 22.0.0.22. 203453.W01WO

[0064] Unless otherwise specified, percentages in the below Procedures and Examples refer to percent yield. Procedure 1: [00.122 mmol) and carboxylic acid [2] (0.134 mmol, 1.1eq) and dissolved in anhydrous DMF (2 mL). HATU (92 mg, 0.244 mmol, 2 equiv.), and DIPEA (52.8 µL, 0.366 mmol, 3 equiv.) were then added and the mixture was stirred at rt for 16 h. The solvent was then removed under flow of nitrogen. The resulting residue was then purified by silica gel column chromatography gradient (DCM / MeOH) 0-10%. Average yield = 60% (0.073 mmol).

[0066] The compounds in Table 1, below, were prepared in accordance with Procedure 1, by using the appropriately substituted carboxylic acid [2]. Table 1 Cpd. Structure Name -3453.W01WO 3 1-(4-chlorophenyl)-N-(2-(methylamino)-2- oxo-1-phenylethyl)cyclopropane-1- - - -223453.W01WO 11 1-(4-hydroxyphenyl)-N-(2-(methylamino)- 2-oxo-1-phenylethyl)cyclopropane-1-Procedure 2:, 0.305 mmol) and 1-(3 / 4-bromophenyl)cyclopropane-carboxylic acid [3] (80.9 mg , 0.335 mmol, 1.1 equiv.) and dissolved in anhydrous DMF (2 mL). HATU (231.8 mg, 0.610 mmol), and DIPEA (132 µL, 0.915 mmol) were then added and the mixture was stirred at room temperature for 16 h. The solvent was then removed under flow of nitrogen and the resulting residue was dissolved in dichloromethane. The mixture was purified by silica gel column chromatography gradient (DCM / MeOH) 0-10%. Average yield = 60% (0.183 mmol).

[0068] (b) A dry flask was charged with 1-(4 / 3-bromophenyl)-N-(2-(methylamino)-2-oxo- 1-phenylethyl)cyclopropane-1-carboxamide [4] (10 mg, 0.026 mmol), Pd(dppf)Cl2 (0.9 mg, 0.001 mmol), aryl boronic acids (0.026 mmol, 1 equiv.), and potassium carbonate (10.8 mg, 0.078 mmol. The flask was then purged with nitrogen gas and a solution (3 mL) of dioxane:water (4:1) mixture was added. The reaction was refluxed for 16 h under nitrogen gas. After cooling the reaction to room temperature, the solvent was removed under vacuum, and then purified by silica gel column chromatography gradient (DCM / MeOH) 0-10%. Average yield = 40% (0.01 mmol).

[0069] The compounds in Table 2, below, were prepared in accordance with Procedure 2, by using the appropriately substituted carboxylic acid [3], the appropriately substituted amide [4], and the appropriately substituted boronic acid of step (b). 233453.W01WO Table 2 Cpd. Structure Name No. - 3-243453.W01WO 17 1-(3-(1H-pyrazol-3-yl)phenyl)-N-(2- (methylamino)-2-oxo-1- 3-Procedure 3: 253453.W01WOylic acid derivative [6] (0.770 mmol, 1.1 equiv.) and then dissolved in anhydrous DMF (2 mL). To the same flask, HATU (532 mg, 1.4 mmol), and DIPEA (303 µL, 2.1 mmol) were then added and the mixture was stirred at room temperature for 16 h. The solvent was then removed under flow of nitrogen, and the resulting residue was dissolved in dichloromethane. The mixture was then purified by silica gel column chromatography gradient (DCM / MeOH) 0-10%. Average yield = 70% (0.539 mmol).

[0071] (b) A flask was charged with methyl-ester derivative [7] (0.539 mmol, 1 equiv.) and LiOH (38.8 mg, 1.62 mmol) and then dissolved in a solution of THF / H2O (1:1) and stirred at room temperature for 24 h. The solution was then acidified with conc. HCl, diluted with water, and then extracted 3 x with EtOAc. The combined organic phases were then dried with sodium sulfate and concentrated under reduced pressure, and used in the next reaction without further purification.

[0072] (c) A flask was charged with carboxylic acid [8] (0.050 mmol, 1 equiv.), amine- derivative (0.050 mmol, 1 equiv.), EDCI (15.5 mg, 0.10 mmol), and HOBt (13.5 mg, 0.10 mmol) and then dissolved in anhydrous DCM (2 mL). DIPEA (21.6 µL, 0.15 mmol) was then added and the reaction was stirred at room temperature overnight. The solvent was then removed under reduced pressure and the resulting residue was purified by silica gel column chromatography gradient (DCM / MeOH) 0-10%. Average yield = 80% (0.040 mmol). 263453.W01WO

[0073] The Compounds in Table 3, below, were prepared in accordance with Procedure 3, by using the appropriately substituted ester [5], the appropriately substituted carboxylic acid [6], and the appropriately substituted amine of step (c). Table 3 Cpd. Structure Name N - -273453.W01WO 27 N-(1-(2-chlorophenyl)-2-(methylamino)-2- oxoethyl)-1-(4-methoxyphenyl)cyclopropane- - - - -283453.W01WO Procedure 4 – preparation of 1-(4-methoxyphenyl)-N-(phenyl(1H-tetrazol-5- yl)methyl)cyclopropane-1-carboxamide (compound 34)mmol), 1-(4-methoxyphenyl) cyclopropane-1-carboxylic acid

[0010] (72.6 mg, 0.380 mmol), and HATU (288.8 mg, 0.760 mmol) and dissolved in dry DMF (2 mL). To the same flask, DIPEA (165 µL, 1.14 mmol) was then added and the reaction was stirred for 16 h. The solvent was then removed under reduced pressure and purified by silica gel column chromatography (DCM / MeOH) 0-10%. Yield = 90% (0.342 mmol)

[0075] (b) A dry flask was charged with N-(cyano(phenyl)methyl)-1-(4- methoxyphenyl)cyclopropane-1-carboxamide

[0011] (10 mg, 0.033 mmol), TEA•HCl (5.9 mg, 0.043 mmol), and sodium azide (2.8 mg, 0.043 mmol) and then dissolved in dry toluene (2 mL), and refluxed for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH) 0-15%. Yield = 34% (5.1 mg, 0.015 mmol). Procedure 53453.W01WO

[0076] (a) A flask was charged with 2-amino-N-methyl-2-phenylacetamide [1] (50 mg, 0.305 mmol) and 1-(4-hydroxyphenyl) cyclopropane-1-carboxylic acid

[0012] (60 mg, 0.336 mmol, 1.1 equiv.) and dissolved in anhydrous DMF (2 mL). HATU (232 mg, 0.610 mmol, 2 equiv.), and DIPEA (132 µL, 0.915 mmol, 3 equiv.) were then added and the mixture was stirred at room temperature for 16 h. The solvent was then removed under flow of nitrogen. The resulting residue was then purified by silica gel column chromatography gradient (DCM / MeOH) 0-10%. Average yield = 60% (0.183 mmol).

[0077] (b) A dry flask was charged with 1-(4-hydroxyphenyl)-N-(2-(methylamino)-2-oxo- 1-phenylethyl)cyclopropane-1-carboxamide

[0013] (10 mg, 0.031 mmol), potassium carbonate (12.9 mg, 0.093 mmol), and Bromo-derivatives (0.093 mmol) and then dissolved in dry acetone (2 mL), and refluxed for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure, and then resulting residue was purified by silica gel column chromatography (DCM / MeOH) 0-15%. Average yield = 72% (0.022 mmol).

[0078] The compounds in Table 4, below, were prepared in accordance with Procedure 5, by using the appropriately substituted alkyl bromine of step (b). Table 4 Cpd. Structure Name n -Procedure 6 - preparation of N-(2-amino-2-oxo-1-phenylethyl)-1-(4- methoxyphenyl)cyclopropane-1-carboxamide (compound 37) 303453.W01WO

[0079] ol), 1-(4-methoxyphenyl) cyclopropane-1-carboxylic acid

[0015] (7.26 mg, 0.038 mmol), and HATU (28.9 mg, 0.076 mmol) and then dissolved in dry DMF (2 mL). DIPEA (16.5 µL, 0.11 mmol) was then added and the reaction was stirred for 16 h. The solvent was then removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH) 0-10%. Yield = 90% (0.034 mmol). Procedure 7 – Preparation of (S)-1-(4-methoxyphenyl)-N-(2-(methylamino)-2-oxo-1- phenylethyl)cyclopropane-1-carboxamide (compound 38) [0080as was c a ge w - - e - u o yca o y a o - -p enylacetic acid

[0016] (100 mg, 0.40 mmol) and dissolved in anhydrous DMF (2 mL). NMI (66 mg, 0.80 mmol) and TCFH (224 mg, 0.80 mmol) were then added and the mixture was stirred at room temperature for 2 h. The solvent was then removed under reduced pressure, and the resulting 313453.W01WO residue was dissolved in DCM. The mixture was then purified by silica gel column chromatography gradient (DCM / MeOH) 0-10%.

[0081] (b) A flask was charged with tert-butyl (S)-(2-(methylamino)-2-oxo-1- phenylethyl)carbamate

[0017] (20 mg, 0.075 mmol) and dissolved in a solution of 6M HCl / Dioxane (2mL) and stirred att room temperature for 24 h. The solvent was then removed under reduced pressure. The product was used in the next reaction without further purification.

[0082] (c) A flask was charged with (S)-2-amino-N-methyl-2-phenylacetamide

[0018] (10 mg, 0.037 mmol), 1-(4-methoxyphenyl) cyclopropane-1-carboxylic acid

[0015] (7.3 mg, 0.037 mmol), NMI (6.6 mg, 0.074 mmol), and TCFH (20.7 mg, 0.074 mmol) and then was stirred at room temperature for 2 h. The solvent was then removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography gradient (DCM / MeOH) 0-10%. Yield = 61% (7.8 mg, 0.032 mmol).

[0083] The reference cxample in Table 5 below was prepared in accordance with Procedure 7, by using the (R) enantiomer of

[0016] . Table 5 Ref. Structure NameProcedure 7.5 – Preparation of 1-(4-methoxyphenyl)-N-(3-(methylamino)-3-oxo-1- phenylpropyl)cyclopropane-1-carboxamide (compound 39) 323453.W01WO To a solution of compound 1 (2.00 g, 7.50 mmol) in MeCN (20 mL) was added NMI (1.00 g, 15.0 mmol), 1-methylimidazole(1.30 g, 15.7 mmol) and TCFH (2.30 g, 8.25 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (10 mL), extracted with EA (20 mL x 3), washed with brine, dried over Na2SO4, combined the organic layer and concentrated under reduced pressure to give a residue. The residue was purified by chromatographic column on silica gel, eluted with 50% to 100% EA in PE to give compound 2 (200 mg, 9.5% yield) as a white solid. LCMS: [M+H]+=279.1.1H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.64 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.31 – 7.25 (m, 4H), 7.22 – 7.16 (m, 1H), 4.96 – 4.83 (m, 1H), 2.50 – 2.47 (m, 3H), 2.47 – 2.42 (m, 2H), 1.35 (s, 9H).13C NMR (101 MHz, DMSO-d6) δ 169.74, 154.68, 143.57, 128.09, 126.66, 126.23, 77.77, 51.42, 42.59, 28.23, 25.42. To a solution of compound 2 (200 mg, 0.720 mmol) in DCM (2 mL) was added 4M-HCl in dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford compound 3 (150 mg, crude) as a white solid. LCMS: [M+H]+=179.1To a solution of compound 3 (100 mg, 0.560 mmol) in DMF (5 mL) was added compound 4 (1.07 g, 0.560 mmol), DIEA (220 mg, 1.68 mmol) and HATU (320 mg, 0.84 mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the filtrate was purified by prep-HPLC to afford IRF4-int-R (32 mg, 16% yield) 333453.W01WO as a white solid. LCMS: [M+H]+=353.2.1H NMR (400 MHz, DMSO-d6) δ 7.69 – 7.61 (m, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.33 – 7.24 (m, 4H), 7.22 – 7.12 (m, 3H), 6.97 – 6.90 (m, 2H), 5.15 – 5.07 (m, 1H), 3.76 (s, 3H), 2.51 – 2.48 (m, 1H), 2.48 – 2.44 (m, 1H), 2.44 – 2.41 (m, 3H), 1.38 – 1.18 (m, 2H), 0.97 – 0.86 (m, 2H).13C NMR (101 MHz, DMSO-d6) δ 172.48, 170.62, 158.87, 143.11, 132.04, 131.85, 128.58, 127.10, 126.43, 114.56, 55.55, 50.80, 41.32, 29.89, 25.78, 15.28. Procedure 8[ ] (a) o a so ut on o compoun [ ] ( mg, . mmo ) n ( m ) was added TFA (1 mL), the mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to give compound 3-2 (250 mg, crude) as a yellow solid, which was used for next step without a further purification.

[0085] (b) To a solution of

[0020] (350 mg, 1.03 mmol) in CH3CN (10 mL) was added the corresponding tert-butyl-bromoester (301 mg, 1.54 mmol), DIEA (398 mg, 3.09 mmol) and KI (25 mg, 0.21 mmol). The mixture was heated to 70℃ and stirred for 16 h. Diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column eluting with 5% MeOH in DCM to give

[0021] (approximately 85% yield).

[0086] (c) To a solution of

[0021] (100 mg, 0.22 mmol) in DCM (5 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated 343453.W01WO under reduced pressure. The residue was purified by silica gel column eluting with 10% MeOH in DCM to give

[0022] (approximately 85% yield).

[0087] The compounds in Table 6 below were prepared in accordance with procedure 8, by using the appropriately substituted tert-butyl-bromoester of step (b). Table 6 Structure Name 2 4 2 26 di i idi 3 l 13Procedure 9

[0088] (a) To a stirred solution of compound

[0023] (1.272 mmol, 1eq) in DMF (5mL) was added the corresponding tert-butyl amino carboxylate or tert-butyl hydroxy carboxylate (1.272 mmol, 1eq), diisopropyl ethylamine (2.545 mmol, 2eq), and the reaction mixture was stirred for 16 h at 90 °C. After completion of the reaction, the reaction mixture was cooled down to room temperature, diluted with 50 mL of cold water, and extracted with ethyl acetate (3 x 50 353453.W01WO mL). The combined organic layers were then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (0-10% MeOH / DCM) to afford compound

[0024] .

[0089] (b) TFA (2 mL) was added to a solution of compound

[0024] (0.22 mmol, 1eq) in DCM (5 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to produce a yellow oil, that was sufficiently pure to be used in the next step of the synthesis without further purification (Average yield over steps (a) and (b) was approximately 60%).

[0090] The compounds in Table 7 below were prepared in accordance with procedure 9, by using the appropriate regioisomer of

[0023] , and the corresponding tert-butyl amino carboxylate or tert-butyl hydroxy carboxylate of step (a). Table 7 Structure Name -363453.W01WO 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-Procedure 10

[0091] (a) A flask was charged with (2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0026] (10 mg, 0.037 mmol), the corresponding carboxylic acid (0.037 mmol, 1 eq), NMI (6.6 mg, 0.074 mmol), and TCFH (20.7 mg, 0.074 mmol), and the mixture was stirred at rt for 2 h. The solvent was then removed under reduced pressure and the residue was purified by silica gel column chromatography gradient (DCM / MeOH) 0-10%) to afford

[0027] in approximately 80% yield (0.030 mmol). 373453.W01WO

[0092] (b) TFA (2 mL) was added to a solution of

[0027] (0.02 mmol, 1eq) in DCM (5 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to produce a yellow oil, that was sufficiently pure to be used in the next step of the synthesis without further purification (Average yield 95%).

[0093] The compounds in Table 8 below were prepared in accordance with procedure 10, by using the appropriately substituted carboxylic acid of step (a). Table 8 Structure Name - n- )- -3453.W01WO Procedure 11

[0094] (a) To a solution of compound

[0029] (500 mg, 2.6 mmol) and compound

[0030] (479 mg, 2.6 mmol) in dichloromethane (5 mL) was added EDCI (749 mg, 3.9 mmol) and DMAP (31.7 mg, 0.26 mmol). The mixture was stirred at room temperature for 4 h. The solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel column eluting with 0%-6% ethyl acetate in petroleum ether to give compound

[0031] (550 mg, 59% yield) as a colorless oil.

[0095] (b) To a solution of compound

[0031] (140 mg, 0.84 mmol) in DMF (5 mL) was added DIPEA (541 mg, 4.2 mmol) and compound

[0032] (300 mg, 0.84 mmol). The reaction mixture was stirred at room temperature for 4 h. The solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were adjusted to 393453.W01WO pH=3 by 2M HCl. The mixture was diluted with water and extracted with dichloromethane / methanol (10 / 1). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by C18 column (acetonitrile with 0.1% of FA in water 40% to 70%) to give compound

[0033] (200 mg, 69.8% yield) as a white solid.

[0096] (c) To a solution of compound

[0033] (200 mg, 0.59 mmol) and methylamine hydrochloride (79 mg, 1.17 mmol) in dichloromethane (50 mL) was added EEDQ (289 mg, 1.17 mmol). The mixture was stirred at room temperature for 4 h. The solution was diluted with water (100 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel column eluting with 40%-70% ethyl acetate in petroleum ether to give compound

[0034] (20 mg, 9.57% yield) as a white solid.

[0097] (d) To a solution of compound

[0034] (15 mg, 0.042 mmol) in DMF (3 mL) was added K2CO3 (18 mg, 0.13 mmol), the corresponding tert-Butyl N-(2-bromoethyl)carbamate

[0035] (19 mg, 0.084 mmol) and KI (3.5 mg, 0.021 mmol). The mixture was stirred at room temperature for 24 h. The solution was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4and concentrated. The residue was purified by prep-HPLC to afford compound

[0036] (average yield of 10%) as a white solid.

[0098] (e) To a solution compound

[0036] (100 mg, 0.20 mmol) in DCM (5 mL) was added 4M HCl in dioxane (2 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to give compound

[0037] (100 mg, crude) as a white solid, which was used for next step without a further purification.

[0099] (f) To a solution of

[0037] (40 mg, 0.1 mmol) and Carboxy Acid

[0038] (0.1 mmol, 1 eq) in DMF (20 mL) was added DIPEA (64.9 mg, 0.5 mmol) and HATU (42 mg, 0.11 mmol) The mixture was stirred at 25℃ for 16 h. The solution was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4and concentrated. The residue was purified by Prep- HPLC (acetonitrile with 0.1% of NH3.H2O in water 5% to 95%) to afford the compound

[0039] (average yield ~20%) as yellow solid.

[0100] The Examples in Table 9 below were prepared in accordance with procedure 11, by using the appropriately substituted linker / ligase (see procedure 8-10) of step (f). 403453.W01WO Table 9 Ex. Structure Name No 2- 3- - - e413453.W01WO 4 4-(((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4- - - e -423453.W01WO 8 N1-((S)-1-((2S,4R)-4-hydroxy-2- (((S)-1-(4-(4-methylthiazol-5-3453.W01WO

[0101] (a) To a solution of compound

[0029] (500 mg, 2.6 mmol) and compound

[0030] (479 mg, 2.6 mmol) in dichloromethane (5 mL) was added EDCI (749 mg, 3.9 mmol) and DMAP (31.7 mg, 0.26 mmol). The mixture was stirred at room temperature for 4 h. The solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel column eluting with 0%-6% ethyl acetate in petroleum ether to give compound

[0031] (550 mg, 59% yield) as a colorless oil.

[0102] (b) To a solution of compound

[0031] (140 mg, 0.84 mmol) in DMF (5 mL) was added DIPEA (541 mg, 4.2 mmol) and compound

[0032] (300 mg, 0.84 mmol). The reaction mixture was stirred at room temperature for 4 h. The solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were adjusted to pH=3 by 2M HCl. The mixture was diluted with water and extracted with dichloromethane / methanol (10 / 1). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by C18 column (acetonitrile with 0.1% of FA in water 40% to 70%) to give compound

[0033] (200 mg, 69.8% yield) as a white solid.

[0103] (c) To a solution of compound

[0033] (200 mg, 0.59 mmol) and methylamine hydrochloride (79 mg, 1.17 mmol) in dichloromethane (50 mL) was added EEDQ (289 mg, 1.17 mmol). The mixture was stirred at room temperature for 4 h. The solution was diluted with water (100 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over Na2SO4and concentrated. The residue was purified by silica gel column eluting with 40%-70% ethyl acetate in petroleum ether to give compound

[0034] (20 mg, 9.57% yield) as a white solid.

[0104] (d) To a solution of compound

[0034] (15 mg, 0.042 mmol) in DMF (3 mL) was added K2CO3(18 mg, 0.13 mmol), the corresponding tert-butyl bromoacetate

[0040] (19 mg, 0.084 mmol) and KI (3.5 mg, 0.021 mmol). The mixture was stirred at room temperature for 24 h. The solution was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4and concentrated. The residue was purified by prep-HPLC to afford compound

[0041] (average yield of 10%) as a white solid.

[0105] (e) To a solution compound

[0041] (100 mg, 0.20 mmol) in DCM (5 mL) was added 4M HCl in dioxane (2 mL). The mixture was stirred at room temperature for 2 h. The solution 443453.W01WO was concentrated under reduced pressure to give compound

[0042] (100 mg, crude) as a white solid, which was used for next step without a further purification.

[0106] (f) To a solution of

[0042] (40 mg, 0.1 mmol) and Carboxy Acid

[0043] (0.1 mmol, 1 eq) in DMF (20 mL) was added DIPEA (64.9 mg, 0.5 mmol) and HATU (42 mg, 0.11 mmol) The mixture was stirred at 25℃ for 16 h. The solution was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4and concentrated. The residue was purified by Prep- HPLC (acetonitrile with 0.1% of NH3.H2O in water 5% to 95%) to afford the compound

[0044] (average yield ~20%) as yellow solid.

[0107] The Examples in Table 10 below were prepared in accordance with procedure 12, by using the appropriately substituted linker / ligase (see procedure 11) of step (f). Table 10 Ex. Structure Name e o e453453.W01WO 11 (2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(3-((S)- 1-(1-(4-methoxyphenyl)cyclopropane-1- - eProcedure 13 O H O N H N(a) K2CO3N HN O

[0108] (a) To a solution of compound

[0045] (50 mg, 0.14 mmol) in Acetone (3 mL) was added K2CO3 (20 mg, 0.14 mmol), tert-Butyl N-(2-bromoethyl)carbamate

[0035] (63 mg, 0.28 mmol). The mixture was stirred at reflux for 16h. The solvent was dried under nitrogen and dissolved in ethyl-acetate. The mixture was purified by silica gel column chromatography gradient (EtOAc / Hexane) 20-100% to afford compound

[0046] . Yield = 60% as a white solid (42mg, 0.084mmol).

[0109] (b) to a solution of compound

[0046] (40mg, 0.080 mmol) in DCM (3mL), 500uL of TFA was added and the mixture was stirred at RT for 16h. The solvent was evaporated under reduced pressure and compound

[0047] was carried on without purification as a TFA-salt yellow-oil. Average yield = 100% (41mg, 0.080 mmol). 463453.W01WO

[0110] (c) A solution of compound

[0047] (5mg, 0.010 mmol) and carboxy-acid

[0038] (0.011 mmol, 1.1 eq) was dissolved in DMF 1mL. To the flask HATU (7.6 mg, 0.02 mmol) and DIPEA (4.3 uL, 0.03 mmol) was added and the mixture was stirred at RT for 16h under nitrogen. The solvent was dried under nitrogen and dissolved in dichloromethane. The mixture was purified by silica gel column chromatography gradient (DCM / MeOH) 0-10% to afford compound

[0048] . Average yield = 30% (0.003 mmol).

[0111] The Examples in Table 11 below were prepared in accordance with procedure 13, by using the appropriately substituted and linker / ligase (see procedure 10) of step (c). Table 11 Ex. Structure Name yl eProcedure 14To a solution of compound 1 (500 mg, 1.52 mmol) in acetonitrile (ACN) (5 ml) was added compound 2 (methylamine) (205 mg, 3.03 mmol) and N-methylimidazole (NMI) (440 mg, 5.30 mmol). The mixture was stirred at room temperature for 0.5 h. N,N,N',N'- tetramethylchloroformamidinium hexafluorophosphate (TCFH) (511 mg, 1.82 mmol) was 473453.W01WO added the mixture at 0℃. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was purified by chromatographic column to give compound 3 (400 mg, 76.9 % yield) as a white solid. LCMS: [M+H]+=345.0.1H NMR (400 MHz, DMSO-d6) δ 8.18 – 8.08 (m, 1H), 7.61 (s, 1H), 7.50 – 7.45 (m, 1H), 7.44 – 7.33 (m, 2H), 7.33 – 7.24 (m, 1H), 5.12 (d, J = 8.4 Hz, 1H), 2.57 (d, J = 4.6 Hz, 3H), 1.35 (s, 9H).13C NMR (101 MHz, DMSO-d6) δ 169.81, 154.83, 141.75, 130.42, 130.34, 129.91, 126.28, 121.50, 78.49, 57.18, 38.24, 28.12, 25.67, 0.10.To a solution of compound 3 (400 mg, 1.17 mmol) in dichloromethane (DCM) (5 mL) was added 4M-HCl in dioxane (5 mL). Then, the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give compound 4 (283 mg, crude) as a white solid. The crude was used for next step without further purification. LCMS: [M+H]+=242.9.To a solution of compound 4 (283 mg, 1.17 mmol) in DMF (4 mL) was added compound 5 (269 mg, 1.40 mmol), DIEA (760 mg, 5.85 mmol) and HATU (123 mg, 666.6 mmol) at 0℃. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water and 483453.W01WO extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was purified by chromatographic column to give compound 6 (306 mg, 63.0 % yield) as a white solid. LCMS: [M+H]+=419.2.1H NMR (400 MHz, DMSO-d6) δ 8.39 – 8.29 (m, 1H), 7.47 – 7.39 (m, 2H), 7.36 – 7.31 (m, 2H), 7.28 (t, J = 7.8 Hz, 1H), 7.21 – 7.16 (m, 1H), 7.02 – 6.94 (m, 2H), 6.79 (d, J = 7.1 Hz, 1H), 5.25 (d, J = 7.1 Hz, 1H), 3.78 (s, 3H), 2.51 – 2.49 (m, 3H), 1.33 – 1.20 (m, 2H), 1.03 – 0.88 (m, 2H).13C NMR (101 MHz, DMSO-d6) δ 172.07, 168.97, 158.74, 142.00, 131.69, 131.01, 130.73, 130.44, 129.27, 125.06, 121.58, 114.36, 55.55, 55.13, 29.29, 25.61, 15.17, 14.99.To a solution of compound 7-1 (5 g, 25.8 mmol) in DMF (70 ml) was added compound 7-2 (14 g, 77.3 mmol), KI (4.3 g, 25.8 mmol) and K2CO3(10.7 g, 77.3 mmol). The mixture was stirred at 80oC for overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over Na2SO4and concentrated. The residue was purified by chromatographic column to give compound 7 (1.2 g, 15.8 % yield) as a white solid. LCMS: [M+H]+=295.1.1H NMR (400 MHz, DMSO) δ 7.94 (s, 1H), 7.59 (s, 1H), 4.80 (t, J = 4.6 Hz, 1H), 4.24 – 4.18 (m, 2H), 3.93 – 3.88 (m, 2H), 3.83 – 3.74 (m, 2H), 2.17 – 2.02 (m, 2H), 1.25 (s, 12H). 493453.W01WO To a so u on o co pou mg, . mmo n oxane m was a e compound 7 (260 mg, 0.88 mmol), K3PO4(469 mg, 2.21 mmol) and Pd(dppf)Cl2(54 mg, 0.07 mmol). The mixture was stirred at 95oC for 2h. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over Na2SO4and concentrated. The residue was purified by chromatographic column to give compound 8 (120 mg, 32.3 % yield) as a white solid. LCMS: [M+H]+=505.1.1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.09 (s, 1H), 7.78 (s, 1H), 7.38 (s, 4H), 7.28 (s, 1H), 7.01 (s, 3H), 6.79 (s, 1H), 5.28 (s, 1H), 4.84 (s, 1H), 4.23 (s, 2H), 4.08 – 3.59 (m, 8H), 3.36 (s, 2H), 2.15 (s, 2H), 1.30 (s, 2H), 0.97 (d, J = 27.8 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 171.97, 169.54, 158.75, 139.87, 135.99, 132.64, 131.77, 131.18, 129.02, 127.12, 124.25, 123.55, 123.02, 121.44, 114.35, 101.35, 64.40, 56.08, 55.14, 46.98, 34.02, 29.35, 25.62, 15.11.To a mixture of compound 1 (27 mg, 0.05 mmol) in DCM (1 mL) and TFA (1 mL) were added H2O (1 drops) at room temperature for 1 h. The solution was concentrated under 503453.W01WO reduced pressure to give compound 2 (20 mg, crude) as a yellow solid, which was used for next step without further purification. LCMS: [M+H]+= 461.2.g , . g, . DCE (2 mL) was added DIEA (0.1 mL). The mixture was stirred at room temperature for 1 h. Then, STAB (15 mg, 0.12 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (5 mL) and extracted with DCM (5 mL x 3). The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to get IRF4-7-P1 (5.46 mg, 16.6 % yield) as a yellow solid. LCMS: [M+H]+= 787.4.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.28 (d, J = 4.6 Hz, 1H), 8.10 (s, 1H), 7.79 (s, 1H), 7.73 – 7.60 (m, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.42 – 7.32 (m, 4H), 7.32 – 7.22 (m, 2H), 7.06 – 6.94 (m, 3H), 6.79 (d, J = 7.3 Hz, 1H), 5.28 (d, J = 7.5 Hz, 1H), 5.07 (dd, J = 13.1, 5.3 Hz, 1H), 4.22 (s, 2H), 3.79 (s, 3H), 3.58 – 3.38 (m, 6H), 2.93 – 2.84 (m, 1H), 2.63 – 2.52 (m, 9H), 2.12 – 1.93 (m, 3H), 1.28 – 1.21 (m, 2H), 1.05 – 0.88 (m, 2H). Procedure 153453.W01WO To a mixture of compound 1 (20 mg, 0.04 mmol) and compound 2 (12 mg, 0.04 mmol) in DCE (2 mL) was added DIEA (0.1 mL). The mixture was stirred at room temperature for 1 h. Then, STAB (15 mg, 0.12 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (5 mL) and extracted with DCM (5 mL x 3). The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to get IRF4-8-P1 (5.16 mg, 16.0 % yield) as a white solid. LCMS: [M+H]+= 744.1.1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.34 – 8.21 (m, 1H), 8.13 (s, 1H), 7.80 (d, J = 2.4 Hz, 3H), 7.45 (d, J = 7.8 Hz, 1H), 7.42 – 7.35 (m, 3H), 7.29 (t, J = 7.7 Hz, 1H), 7.07 – 6.95 (m, 3H), 6.80 (d, J = 7.3 Hz, 1H), 5.28 (d, J = 7.5 Hz, 1H), 5.14 (dd, J = 12.9, 5.4 Hz, 1H), 4.25 (t, J = 6.8 Hz, 2H), 4.00 (s, 4H), 3.79 (s, 3H), 2.97 – 2.83 (m, 2H), 2.70 – 2.67 (m, 2H), 2.64 – 2.61 (m, 1H), 2.59 – 2.56 (m, 2H), 2.53 – 2.52 (m, 1H), 2.08 – 2.06 (m, 1H), 1.35 – 1.29 (m, 2H), 1.28 – 1.21 (m, 2H), 1.04 – 0.91 (m, 2H). Procedure 16To a solution of compound 1 (300 mg, 0.91 mmol) and compound 2 (178 mg, 0.91 mmol) in DMF (10 mL) was added DIEA (0.2 mL). The mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column to give compound 3 (200 mg, 49.5 % yield) as a yellow solid. LCMS: [M+H]+=443.2.1HNMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 5.09 – 4.98 (m, 1H), 4.35 – 4.17 (m, 2H), 3.30 – 3.29 (m, 2H), 2.98 – 2.85 (m, 2H), 2.68 – 2.63 (m, 4H), 2.61 – 2.54 (m, 2H), 2.40 – 2.26 (m, 2H), 2.04 – 1.91 (m, 2H), 1.42 (s, 9H). 523453.W01WO, mL). This reaction mixture was stirred at room temperature for 1 h. This reaction mixture was concentrated under reduced pressure to give compound 4 (100 mg, crude) as a yellow solid, which was used for next step without further purification. LCMS: [M+H]+=387.3. To a so ut on o compound 4 (60 mg, 0.16 mmo ) and compound 5 (64 mg, 0.16 mmo ) n DMF (5 mL) was added HATU (125 mg, 0.48 mmol) and DIEA (0.2 mL). The mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over Na2SO4and concentrated. The residue was purified by prep-HPLC to afford IRF4-11 (17.12 mg, 14.4 % yield) as a yellow solid. LCMS: [M+H]+=766.1.1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.33 – 8.21 (m, 1H), 8.00 (s, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.22 (t, J = 8.1 Hz, 1H), 7.10 – 7.02 (m, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.86 – 6.71 (m, 4H), 5.25 (d, J = 7.4 Hz, 1H), 5.09 – 4.98 (m, 1H), 4.37 – 4.17 (m, 2H), 4.06 – 3.94 (m, 2H), 3.77 (s, 3H), 3.55 – 3.46 (m, 2H), 3.32 – 3.24 (m, 4H), 3.10 – 2.97 (m, 2H), 2.95 – 2.86 (m, 1H), 2.68 – 2.52 (m, 6H), 2.49 – 2.47 (m, 2H), 2.42 – 2.32 (m, 1H), 2.04 – 1.90 (m, 1H), 1.34 – 1.23 (m, 2H), 1.04 – 0.86 (m, 2H).13C NMR (101 MHz, DMSO- d6) δ 173.41, 172.39, 171.78, 169.90, 168.80, 159.20, 158.84, 154.10, 144.50, 141.39, 132.19, 131.54, 130.05, 124.21, 121.99, 118.84, 115.19, 114.82, 113.73, 113.07, 108.89, 66.52, 56.40, 55.58, 52.95, 51.87, 47.88, 47.44, 38.43, 31.74, 29.77, 26.04, 23.06, 15.61, 15.41. 533453.W01WO Procedure 17 To, d 2 (3.2 g, 15.2 mmol) and K2CO3 (3.2 g, 22.82 mmol). The mixture was stirred at 25 ℃ for 16 h. This reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column to give compound 3 (3.2 g, 88.9% yield) as colorless oil; LCMS: [M+H]+=484.2. Toa solution of compound 3 (2.6 g, 5.38 mmol) in MeOH (20 mL) and THF (5 mL) was added LiOH (517 mg, 21.5 mmol), and stirred at room temperature for 1 h. The mixture was added FA (2 mL). The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column to give compound 4 (2.1 g, 83.2% yield) as a colorless oil; LCMS: [M+H]+=470.3.1H NMR (400 MHz, DMSO-d6) δ 7.39 – 7.32 (m, 2H), 7.19 (t, J = 7.9 Hz, 1H), 7.04 – 6.91 (m, 2H), 6.86 – 6.69 (m, 4H), 5.08 (d, J = 6.7 Hz, 1H), 4.36 (t, J = 5.6 Hz, 1H), 3.92 – 3.87 (m, 2H), 3.77 (s, 3H), 3.39 (s, 3H), 3.24 – 3.21 (m, 4H), 1.75 – 1.67 (m, 2H), 1.66 – 1.53 (m, 2H), 1.53 – 1.37 (m, 2H), 1.35 – 1.25 (m, 2H), 1.03 – 0.89 (m, 2H). 543453.W01WO Tg, 13.64 mmol) in DMF (20 mL) were added EDCI (1.9 g, 10.2 mmol), HOBt (1.38 g, 10.23 mmol) and DIEA (2.6 g, 20.5 mmol). The mixture was stirred at room temperature for 16 h. This reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column to give compound IRF4-12-Int5 (1.38 g, 83.9% yield) as colorless oil; LCMS: [M+H]+=483.2.1H NMR (400 MHz, DMSO- d6) δ 8.32 – 8.20 (m, 1H), 7.36 (d, 2H), 7.20 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.83 – 6.68 (m, 4H), 5.24 (d, J = 7.4 Hz, 1H), 4.80 (t, J = 4.7 Hz, 1H), 3.94 – 3.83 (m, 4H), 3.80 (s, 3H), 3.78 – 3.73 (m, 2H), 2.51 (d, J = 3.2 Hz, 3H), 1.79 – 1.69 (m, 2H), 1.68 – 1.59 (m, 2H), 1.57 – 1.44 (m, 2H), 1.34 – 1.25 (m, 2H), 1.04 – 0.89 (m, 2H).To a solution of IRF4-12-Int5-P1 (50 mg, 0.103 mmol) in DCM (0.5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure to give compound 6 (50 mg, crude) as a yellow solid, which was used for next step without a further purification; LCMS: [M+Na]+=461.2.3453.W01WO To a solution of compound 6 (40 mg, 0.091 mmol) and compound 7 (30 mg, 0.091 mmol) in DCE (5 mL) was added STAB (78 mg, 0.37 mmol). The mixture was stirred at room temperature for 0.5 h. The mixture was diluted with and extracted with. The combined organic layers were washed with brine, dried over Na2SO4and concentrated. The residue was purified by Prep-HPLC to give compound IRF4-12-P1 (3.22 mg, 4.71% yield) as white solid; LCMS: [M+H]+=751.7. Procedure 18p g, . p g, . DCE (1 mL) was added STAB (15 mg, 0.068 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with and extracted with. The combined organic layers were washed with brine, dried over Na2SO4and concentrated to give compound IRF4- 13-P1 (17 mg, crude) as white solid; LCMS: [M+H]+=765.7. Assays Protein Production Protocol:

[0112] For IAD domain production and purification, double-stranded fragments containing the IAD domain of IRF4 (residues 240-420) were cloned into bacterial expression vectors (addgene plasmid #29653). These vectors were transformed into BL21(DE3)pLysS (PROMEGA™ cat. L1195), grown to an optical density of 0.6 at 37 °C, and ITPG (100mM final concentration) was added and the cells were allowed to shake at 16 °C overnight. The cells were pelleted and lysed at 18,000 psi in a LM10 microfluidizer (lysis buffer 25 mM Tris pH 8.0, 500 mM NaCl, 1 mM TCEP, 20 mM Imidazole, 0.1% IGEPAL, 10% glycerol, 1 mM PMSF) and the supernatant was passed to nickel column chromatography with 2 mL of nickel beads. The supernatant was incubated with beads for 45 - 60 min at 0 °C, and the beads were washed with >20 column volumes (CVs) of lysis buffer and >5 CV of high salt buffer (lysis 563453.W01WO buffer + 1500 mM NaCl). The protein was eluted using 0.1 CV of elution buffer (lysis buffer + 400 mM Imidazole) and loaded onto an AKTA pure 25M FPLC (GEHealth product no. 29018226). The mixture was purified by FPLC in running buffer (20 mM TRIS, pH 8, 200 mM NaCl, 1 mM TCEP) and the purity of protein fractions were assessed by SDS / Page gel. Pure fractions were pooled, and the concentration was assessed using nanodrop absorbances at A260 / A280. Protein Labeling Protocol:

[0113] Recombinant IRF4 (240-420) was first labeled with terbium by incubating IRF4 (50 µM) with Corafluor-1 (TOCRIS™ cat.7920) (2500 µM) in labeling buffer (100 mM sodium carbonate, pH 8.5, 0.05% tween-20) then labeled for 40 min at rt. Following labeling, the reaction was buffered exchanged using Zebra-spin desalting columns (THERMOFISHER™ cat. 89882) into storage buffer (50 mM Tris, pH 8, 150 mM NaCl, 5 mM KCl, 20% glycerol). TR-FRET Assay General Protocol:

[0114] A master-mix solution of 10 nM Terbium-Labeled IRF4 (240-420) and 300 nM Probe (FITC-ahx-SPPLEV(pS)DG-NH2) was prepared using a 1X TR-FRET Buffer (10 mM NaCl, 100 mM HEPES™ pH = 8.0, 0.5 mg / mL BSA, 0.1% Tween-20). 19 µL of the master mix is multi-channeled into a corning 384-well white plates. Compounds were serial diluted in DMSO (in a 1:3 ratio) and added to the plate in 1 µL quantities to yield final drug concentrations of 0 – 100 µM. The plate was covered and incubated at rt for 30 min. TR-FRET values were measured using a CLARIOSTAR® plus plate reader at the 495 nm channel and the 520 nm channel. IC50values were calculated using PRISM software and fit using non-linear regression four parameter inhibitor vs. response. TR-FRET Assay Probe:

[0115] FITC-ahx-SPPLEV(pS)DGEAD-NH2(Purchased from peptide2.0) **N-Term = FITC dye C-Term = AMIDE (-CONH2) BRET Assay General Protocol: HEK293T (ATCC cat. CRL-3216) were stably transfected with plasmids expressing full- length IRF4-Nanoluc fusions which were cloned into a lentiviral GFP expression vector 573453.W01WO (addgene plasmid #21373). The cells stabling expressing IRF4-Nanoluc fusions were harvested and lysed using a 1X NP-40%, supplemented with 100X proteasome and phosphatase inhibitor (THERMOFISHER™, cat. 78440). The lysate was cleared and diluted using 1X BRET Buffer (10 mM NaCl, 100 mM HEPES pH = 8.0, 0.5 mg / mL BSA, 0.1% TWEEN® 20) to a concentration of 1x104cell lysate / mL. To the master mix, TAMRA-ahx- PEP1 was added to a final concentration of 1 µM (peptide2.0 custom peptide synthesis), and the NanoLuc substrate (PROMEGA™ cat no. N1661) was added to a 1X final concentration (e.g. 20uL substrate in 1mL of media). 49 µL of the master-mix is multi-channeled into a low- volume CORNING® 384-well white plate (cat. CLS4511). Compounds were serial diluted (in a 1:3 ratio) in DMSO and added to the plate in 1 µL quantities to yield final drug concentrations of 0 – 100 µM. The plate was covered and incubated for 30 min at rt. BRET values were measured using a PHERASTAR® Fsx plate reader at the 495 nm channel and the 610 nm channel. IC50 values were calculated using PRISM software and fit using non-linear regression four parameter inhibitor vs. response. BRET Assay Probe:

[0116] TAMRA-ahx-SPPLEV(pS)DGEAD-NH2 (Purchased from peptide2.0) **N-Term = TAMRA dye, C-Term = AMIDE (-CONH2) Gel electrophoresis and immunoblotting:

[0117] For Western blots, 1×106 MM1.S cells in 2mL were seeded into 12-well plates 24h before treatment. Cells were treated for the indicated times, washed with PBS and lyzed with lysis buffer (1% Triton X-100, 150mM NaCl, 1mM EDTA, 50mM Tris pH7.4, HALT protease inhibitor cocktail (Thermo Fisher). MM1.S cells were lyzed in 80 µl lysis buffer per well. Lysates were sonicated then cleared by centrifugation at 4 °C, at 15,800 x g for 10min and the supernatants stored at −20 °C. Protein concentration was determined by BCA assay (Pierce) and the absorbance at 562nm was measured by spectrophotometry (NanoDrop ND1000). Samples were separated by SDS– PAGE using 25μg of protein per well of BioRad 4–12% BIS-TRIS gels (BioRad) at 100V for 120 mins following the manufacturer’s instructions. Proteins were transferred to 0.2μm pore low-fluorescence nitrocellulose 583453.W01WO membrane (Bio-Rad) by wet transfer in 1× TOWBIN buffer with 10% methanol at 80V for 120 mins. Membranes were blocked in intercept (TBS) blocking buffer (LI-COR no. 927- 60001) for 1 h at 23 °C. Primary antibody binding was performed with the indicated antibodies diluted in Intercept (TBST) antibody diluent (Li-COR no. 927-65001) at 4 °C for at least 16 h. After washing the membrane three times with TBST (5 min each wash), secondary antibodies (goat anti-rabbit IgG-IRDye 800 and goat anti-mouse IgG-IRDye 680, Li-COR) were added as solutions in Intercept (TBST) antibody diluent supplemented with 0.01% SDS. Western blot images were obtained through detection of rabbit anti-IRF4 (1:1,000, Cell Signaling no. 15106), mouse anti-GAPDH (1:5,000, Cell Signaling no. 2118), antibodies with goat anti-rabbit IRDye 800CW secondary antibody (1:10,000, LI-COR no.926-32211) and goat anti-mouse IRFDye 680 (1:10,000, LI-COR no. 926-68071) using a Odyssey DLx (LI- COR). Measuring Degradation Levels: Degrader compounds 39-43 and 45 were dosed up to 50µM using the above methods. Degradation levels of each compound was measured by western blot after 24 hr treatment using Image Studio (version 6.0) by comparting the normalized band intensities (the 680 / 800 ratio, e.g. IRF4 / GAPDH) of the treated wells to that of the DMSO control. Cell Viability Assay:

[0118] Cells were seeded into 96-well white flat-bottom plates (5,000 cells per well) (Greiner Bio-One, 655083) and incubated overnight. Cells were treated with the indicated compounds in a 10-point threefold dilution series (100 µl final volume) and incubated for 72 h. Cell viability was assessed using a commercial CellTiter-Glo (CTG) luminescence- based assay (Promega). The 96-well plates were equilibrated to room temperature before the addition of CTG reagent (20 µl). Plates were placed on an orbital shaker for 30 min before recording luminescence using Claro plate reader. IC50 values were calculated in Prism using a [inhibitor] vs. response four-parameter non-linear regression fit normalizing the signal to that of the DMSO control. 593453.W01WO Table 11 Compound No.TR-FRET IC50 (^M) BRET IC50 (^M) 1 46 ± 07 N / A603453.W01WO 29 6 ± 3 N / A 30 11.0 ± 4 N / ATable 12 Example Structure Degradation No. at 50 ^M61

Claims

3453.W01WO What is claimed is:

1. A compound of formula (I): I), or a pharmaceutically acceptwherein: the mole fraction of the S-enantiomer at the stereocentre * is greater than zero, except when R2is CH2C(O)NHCH3in which case the mole fraction of the R-enantiomer in said compound of formula (I) is greater than zero; R1is H, methyl, hydroxy, methoxy, fluoro or chloro; and when R1 is H, one CH of the phenyl ring to which it is attached may be replaced by N to form a pyridine ring; or R1, together with the phenyl ring to which it is attached, forms a naphthalene group as shown below ;R is C(O)NH2, C(O)NHCH3, CH2C(O)NHCH3, C(O)OH, C(O)OCH3, or tetrazolyl; each R3is independently methyl, hydroxy, methoxy, ethoxy, fluoro, chloro, bromo, phenyl, pyrazolyl optionally substituted with one methyl substituent, triazolyl optionally substituted with one methyl substituent, pyridinyl optionally substituted with one methyl or amino substituent, or OCH2CO2H; m is 1 or 2; n is 1 or 2; X is an oxygen atom or a pyrazole ring; 633453.W01WO L is a moiety that links the oxygen atom to B in a manner that enables the compound of formula (I) to bind simultaneously to an interferon regulatory factor 4 (IRF4) protein and an E3 ubiquitin ligase; and B is a moiety capable of binding to an E3 ubiquitin ligase.

2. The compound of claim 1, wherein the mole fraction of the S-enantiomer (when R2 is C(O)NH2, C(O)NHCH3, C(O)OH, C(O)OCH3, or tetrazolyl) or R-enantiomer (when R2 is CH2C(O)NHCH3) at the stereocentre * in said compound of formula (I) is greater than 0.5, preferably greater than 0.8, more preferably greater than 0.95, still more preferably greater than 0.99, and most preferably 1.

00.

3. The compound of claim 1 or claim 2, wherein R1is H.

4. The compound of claims 1 to 3, wherein R2is C(O)NHCH3.

5. The compound of claims 1 to 4, wherein each R3is independently methyl, methoxy, phenyl, pyrazolyl, triazolyl optionally substituted with one methyl substituent, pyridinyl, or OCH2CO2H.

6. The compound of claim 5, wherein each R3is methoxy, preferably p-methoxy.

7. The compound of claims 1 to 6, wherein X is an oxygen atom.

8. The compound of claims 1 to 7, wherein m is 1.

9. The compound of claims 1 to 8, wherein n is 1.

10. The compound of claims 1 to 9, wherein L is selected from: ,3453.W01WO ;wherein p is 1, 2, 3, 4 or 5; wherein q is 1, 2, 3, 4 or 5; and wherein r is 3, 4 or 5.

11. The compound of claims 1 to 10, wherein L is selected from: , and12. The compound of claims 1 to 11, wherein B is selected from the group of: 653453.W01WO or .

13. The compound of claims 1 to 12, wherein L and B together form the structure: ,3453.W01WO , .

14. The compound of claims 1 to 13, wherein the combination of R1, R2, R3, m, n, and X provide the structure: 683453.W01WO O H N N ion15. The compound of claims 1 to 14, wherein the compound is: ,3453.W01WO or r a pharmaceutically16. A pharmaceutical composition, comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A compound of formula (I) as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in therapy.

18. A compound of formula (I) as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer or an autoimmune disease. 733453.W01WO 19. Use of a compound of formula (I) as defined in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer or an autoimmune disease.

20. A method for treating cancer or an autoimmune disease comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) as defined in any of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

21. A compound for use according to claim 18, use of a compound according to claim 19, or a method according to claim 20, wherein the cancer or the autoimmune disease is mediated by interferon regulatory factor 4 (IRF4).

22. A compound for use according to claim 18 or 21, use of a compound according to claim 19 or 21, or a method according to claim 20 or 21, wherein the cancer is a hematological cancer.

23. A compound for use according to claim 22, use of a compound according to claim 22, or a method according to claim 22, wherein the hematological cancer is lymphoma, myeloma, or leukemia.

24. A compound for use according to claim 22, use of a compound according to claim 22 or a method according to claim 22, wherein the hematological cancer is multiple myeloma.

25. A compound for use according to claim 18, use of a compound according to claim 19, or a method according to claim 20, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis), or type I diabetes. 74

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