TYK2 degraders

Abstract

The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof T-L-B (I), useful for the modulation of TYK2 protein via degradation, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and / or prophylactic treatment of autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinflammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease. Aicardi-Goiuteieres syndrome (AGS). Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity' and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

Description

[0001] Case P39856

[0002] DEGRADERS

[0003] Background Art

[0004] The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is responsible for transmitting signals from cytokines and growth factors. Tyrosine kinase 2 (TYK2) is a part of this pathway and was the first identified member of the JAK family. TYK2 controls the phosphorylation of STAT proteins, leading to the activation of STAT-dependent transcription. It mediates the downstream signaling of cytokine receptors for p40-containing cytokines such as IL- 12 and IL-23, as well as type I interferons like IFNα and IFNβ. TYK2 is linked to inflammatory and autoimmune diseases like Inflammatory Bowel Disease (IBD), psoriasis, cancer, and diabetes1.

[0005] IBD refers to a collection of disorders, including Crohn's disease and ulcerative colitis, that result in persistent inflammation of the gastrointestinal tract. These diseases typically experience periodic episodes of diarrhea, abdominal pain, fatigue, and unintended weight loss. There is a continuous demand for effective treatments of diseases, particularly autoimmune and inflammatory disorders driven by pro-inflammatory molecules like IFN-a / 0, IL-12, and IL-23, without inhibiting JAK 1 / 2, which can lead to on-target side effects. Small molecule therapeutic agents that utilize E3 ligase-mediated protein degradation targeting pro-inflammatory proteins like tyrosine kinase 2 (TYK2), while sparing molecules crucial for wound healing and microbial defense, such as IL- 10 and IL-22, show potential as treatments for conditions like IBD (incl. Crohn’s disease and ulcerative colitis),. as TYK2 degraders have the potential to suppress the target and pathway longer than TYK2 inhibitors can do. This prolonged target coverage / efficacy allows TYK2 degraders to be effective in certain indications like for instance IBD, where small molecules are currently ineffective. Therefore, there is a need to develop compounds that degrade the TYK2 target for therapeutic use.

[0006] The present invention provides novel compounds of formula I, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as IBD. The novel compounds of formula I have improved pharmacological properties.

[0007] Field of the Invention

[0008] The present invention provides compounds useful for the modulation of TYK2 protein via degradation, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances.

[0009] of the Invention

[0010] SMU / 14.01.2025The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0011] T-L-B I

[0012] wherein the substituents and variables are as described below and in the claims, or a pharmaceutically acceptable salt thereof.

[0013] The present invention provides compounds useful for the modulation of TYK2 protein via degradation and these compounds can therefore be used in the therapeutic and / or prophylactic treatment of autoimmune diseases and disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinflammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory diseases and disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative diseases and disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine diseases and disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, neurodegenerative diseases and disorders caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or diseases and disorders associated with transplantation like transplant rejection and graft versus host disease.

[0014] Detailed Description of the Invention

[0015] The present invention provides a compound of formula I and its pharmaceutically acceptable salts thereof, the preparation of the above mentioned compounds, medicaments containing them and their manufacture as well as the use of the above mentioned compounds in the therapeutic and / or prophylactic treatment of diseases and disorders which are associated with modulation of TYK2 protein via degradation.

[0016] The following definitions of the general terms used in the present description apply irrespectively of whether the terms in question appear alone or in combination with other groups.

[0017] The term " Ci-6-alkyl", alone or in combination with other groups, stands for a hydrocarbon radical which may be linear or branched, with single or multiple branching points, wherein the alkyl group in general comprises 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-butyl), isopentyl, 2-ethyl-propyl (2-methyl-butyl), 1,2-dimethyl-propyl and the like. Particular “Ci-6-alkyl” are " Ci-5-alkyl". " Ci-3-alkyl" and " Ci-2-alkyl". A specific group is methyl (CH3).The term "halogen", alone or in combination with other groups, denotes chloro (Cl), iodo (I), fluoro (F) and bromo (Br). Particular “halogen” is F.

[0018] The term "heteroaryl", alone or in combination with other groups, refers to an aromatic carbocyclic group of having a single 4 to 8 membered ring, in particular 5 to 8, or multiple condensed rings comprising 6 to 14, in particular 6 to 10 ring atoms and containing 1, 2 or 3 heteroatoms individually selected from N, O and S, in particular IN or 2N, in which group at least one heterocyclic ring is aromatic. “Bicyclic heteroaryl” are heteroaryl with 2 rings. Examples of "heteroaryl" include benzofuryl, benzoimidazolyl. IH-benzoimidazolyl, benzooxazinyl. benzoxazolyl. benzothiazinyl. benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, IH-indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), IH-pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl, 6,7-dihydro-5H-[l]pyrindinyl, l,3-dihydrobenzimidazol-2-one, 3 / / - 1,3-benzo\azol-2-one and the like. Particular "heteroaryl" are pyridinyl, oxazolyl and pyrazinyl. Specific "heteroaryl" are 2,3-dihydro-IH-benzimidazolyl. IH-indazolyl. indolinyl, 2,3-dihydro-l,3-benzoxazolyl, 1H-pyrazolo[3,4-b]pyridyl, IH-pyrazolo|4.5-c|pyridyl or 1,2,3,4-tetrahydroquinoxalyl, pyrimidinyl, benzimidazol-5-yl, 6, 8-dihydro-5H-imidazo[ 1,2-a] pyrazinyl, pyrazolo[l,5-a]pyridinyl, indazolyl, indolyl, IH-indazolyl, benzoxazolyl, pyridinyl, l,3-dihydrobenzimidazol-2-one, 377-1,3-benzoxazol-2-one.

[0019] The term “C3-6-cycloalkyl” refers to a 3 to 8 membered carbon ring, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Particular are cycloalkyl groups having a 3, 4, 5 or 6 membered carbon ring. Specific are cyclopropyl, cyclobutyl.

[0020] The term “and” denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of and moi eties include phenyl and naphthyl. Specific “aryl” is phenyl.

[0021] The term “heterocyclyl”, alone or in combination with other groups, refers to a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 11 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two cycles having two ring atoms in common, i.e. the bridge separating the tw o rings is either a single bond or a chain of one or two ring atoms. Examples for monocyclic saturated heterocycloalkyl are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, oxetanyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, l,l-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples for bicyclic saturated heterocycloalkyl are 3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 6-azabicyclo[3.1.1]heptanyl. 2,6-diazaspiro[3.3]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,7-diazaspiro[3.4]octyl, 6-azaspiro[3.4]octyl, 2-oxabicyclo[2.1.1]hexanyl, 3,9-diazaspiro|5.5Jundecanyl, 8-aza-bicyclo|3.2.1]octyl, 2,7-diazaspiro|3.5Jnonyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1] octyl, 9-aza-bicyclo[3.3.1]nonyl. 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. Particular heterocyclyl are “5-membered heterocyclyl” having 5 ring atoms. Specific heterocyclyl are 2-oxabicyclo[2.1.1]hexane, 2.6-diazaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,7-diazaspiro[3.4]octyl, 3,9-diazaspiro[5.5]undecanyl, 6-azaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, tetrahydrofuranyl, oxetanyl, piperazinyl, pyrrolidinyl, morpholinyl and azetidinyl.

[0022] The term “Ci-6-alkoxy”, alone or in combination with other groups, refers to a group of the formula -O-Ci-6-alkyl. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy. Particular “C i-6-alkoxy” are " Ci-5-alkoxy", " Ci-3-alkoxy" and " Ci-2-alkoxy". A specific group is methoxy (OCH3).

[0023] The term “aromatic” denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, A. D. McNaught and A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).2The term “oxo” denotes a divalent oxygen atom =0.

[0024] The term “-CO”, alone or in combination with other groups, denotes the group -(C=O). The term "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but are not limited to, acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonic acid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid, trifluoroacetic acid and the like. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid. Specific acids are hydrochloric acid, trifluoroacetic acid and fumaric acid.

[0025] The terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

[0026] The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. Particularly it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, fromcombination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

[0027] The term “targeting ligand’’ denotes a compound which competes with, reduces or prevents the binding of a particular ligand to particular receptor or which reduces or prevents the inhibition of the function of a particular protein.

[0028] The term “degrader” denotes a a compound designed to selectively target and break down specific proteins within cells, often through a mechanism known as targeted protein degradation. A targeted protein degrader is a type of small molecule that induces the degradation of specific proteins by exploiting the ubiquitin-proteasome system, with cereblon often acting as a key component. Cereblon is a protein that functions as part of an E3 ubiquitin ligase complex. This complex tags proteins with ubiquitin, marking them for degradation by the proteasome. Cereblon degraders work by binding to cereblon and inducing the recruitment of target proteins to the E3 ubiquitin ligase complex. This results in the ubiquitination and subsequent proteasomal degradation of the target proteins.

[0029] The term “half maximal degradation concentration” (DCso) denotes the concentration of a particular compound required to degrade exactly 50% of the baseline cellular concentration of a protein in vitro.

[0030] In a degradation assay, the term “maximal effect” (Emax) denotes the amount of residual protein remaining in the cell following compound treatment. In an inhibition assay, the term “maximal effect” (Emax) denotes the amount of phosphorylated protein remaining in the cell following compound treatment.

[0031] The term “inflection point” (IP) denotes the concentration of compound in the doseresponse curve at which 50% of the maximal degradation or inhibition response is achieved, or the concentration of compound at which ' / KEmax) is achieved under the experimental conditions of the assay.

[0032] The term “half maximal inhibitory concentration” (IC50) denotes the concentration of a particular compound required for obtaining 50% inhibition of a biological process in vitro. IC50 values can be converted logarithmically to pICso values (-log IC50), in which higher values indicate exponentially greater potency. The IC50 value is not an absolute value but depends on experimental conditions (e.g. concentrations) employed. The IC50 value can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation3. The term “inhibition constant” (Ki) denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using competition binding assays and is equal to the concentration where the particular inhibitor would occupy 50% of the receptors if no competing ligand (e.g. a radioligand) waspresent. Ki values can be converted logarithmically to pKi values (-log Ki), in which higher values indicate exponentially greater potency.

[0033] “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

[0034] The terms “as defined herein” and “as described herein” when referring to a variable incorporates by reference the broad definition of the variable as well as particularly, more particularly and most particularly definitions, if any.

[0035] The terms “treating”, “contacting” and “reacting” when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or the desired product. It should be appreciated that the reaction which produces the indicated and / or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and / or the desired product.

[0036] The term “pharmaceutically acceptable excipient” denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.

[0037] Whenever a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon are encompassed by the structure as pure stereoisomers as well as mixtures thereof.

[0038] Certain compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempt to isolate individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates. Common prototropic tautomers include keto / enol (-C(=O)-CH- <->■ -C(-OH)=CH-), amide / imidic acid (-C(=O)-NH- -C(-OH)=N-) and amidine (-C(=NR)-NH- -C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings and the present invention encompasses all tautomeric forms of the compounds.Detection and especially quantification of components of a mixture can be accomplished with the use of response factors. The response of a detector in HPLC (e.g., UV detectors or refractive index detectors) can be and typically is different for each compound eluting from the HPLC column. Response factors, as known, account for this difference in the response signal of the detector to different compounds eluting from the column.

[0039] In general, the nomenclature used in this Application is based on AUTONOM™ 2000, a Beilstein Institute computerized system for the generation of IUPAC systematic nomen-clature. Chemical structures shown herein were prepared using Biovia Draw 2024®, version 24.1. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[0040] The invention also provides pharmaceutical compositions, methods of using, and methods of preparing the aforementioned compounds.

[0041] All separate embodiments may be combined.

[0042] One embodiment (embodiment 1) of the invention provides a compound of formula I, T-L-B I,

[0043] wherein

[0044] T is a targeting ligand

[0045]

[0046] T, wherein

[0047] a is -C(CH3F F). -C(heterocyclyl. OCH?), -C((CH3)2, OCH3) or -C(CH3)2OH,

[0048] b is N or CH,

[0049] c is H, -CO-Ci-3-alkyl, -CO-C3-6-cycloalkyl, heterocyclyl or -Ci-3-alkyl, and

[0050] d is heteroaiyl,

[0051] e is absent, Ci-3-alkyl, -N(CH3)-. -N(CH3)-CO-(CH2)I-8-CO-, -N(CH3)-CO-(CH2)I-2. -N(CH3)-(CH2)i-2, -N(CH3)-CO-(CH2)i-2-heterocyclyl- or -N(CH3)-SO2-(CH2)I-2, -C3-6-cycloalkyl, heteroaiyl, optionally substituted by =0, heteroaiyl -heterocyclyl, or heteroaryl-heteroaryl.

[0052] L is a linker selected from the group consisting ofa

[0053]

[0054] ) wherein

[0055] LI is absent or selected from the group consisting of -CO-CH2-, -N-(CH2)I-5-CO-, -CO- (CH2)I-8-CO-, -heteroaryl-(CH2)o-i- and -(CH2)o-i-heteroaryl-,

[0056] l1 is CH or N,

[0057] 12 is CH or N,

[0058]

[0059] L2 is selected from the group consisting of a bond, -(CH2)i-2-, -CO-, and -(CH2)I-2-CO- (CH2)I-2-,

[0060] 13 is selected from the group consisting of CH and N,

[0061] 14 is absent or -CO-,

[0062] -i— L5-L4— L3-^\-i- -j— L5-L4—L3^°Al-j-e

[0063]

[0064] ) (0-1 eor O0-1 6, wherein

[0065] L3 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-, and -(CH2)I-2- CO-(CH2)I-2-,

[0066] L4 is absent, -Cs-e-cycloalkyl or heterocyclyl,

[0067] L5 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-, and -(CH2)I-2- CO-(CH2)I-2-,f), wherein 15 is -CH- or -N-, 16 is -O- or -CH2-, L6 is absent or heterocyclyl,

[0068] , wherein L7 is selected from the group consisting of - (CH2)i-2-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-, and

[0069] h), wherein L8 is selected from the group consisting of - (CH2)I-2-. -CO-, and -(CH2)I-2-CO-(CH2)I-2-. and B is a CRBN binder

[0070]

[0071] wherein e is a bicyclic heteroaryl, optionally substituted by Ci-3-alkyl, or aryl, optionally substituted by halogen or -O-Ci-3-alkyl.

[0072] 2. A further embodiment of the invention provides a compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein T is selected from the group consisting of

[0073] T1

[0074]

[0075] a), wherein

[0076] T1 is H, -CO-Ci-3-alkyl, -CO-Cs-e-cycloalkyl, heterocyclyl or -Ci-3-alkyl, andT2 is absent C1-3-alkyl, -CO-, -N(CH3)-, -N(CH3)-CO-(CH2)1-8-CO-, -N(CH3)-CO- (CH2)I-2, -N(CH3)-(CH2)I-2, -N(CH3)-CO-(CH2)i-2-heterocyclyl-, heteroaryl or - N(CH3)-SO2-(CH2)I-2.

[0077] F

[0078] F

[0079] , wherein

[0080] t1 is H or -CH3, and

[0081] T3 is absent, -N(CH3)-C-3-6-cycloalkyl or -C3-6-cycloalkyl,

[0082] T5

[0083] N

[0084]

[0085] , wherein

[0086] T4 is heteroaryl, and

[0087] T5 is absent. -CO- or heteroaryl,

[0088] , and

[0089]

[0090] , wherein

[0091] t2 is -C(CH3, F, F) or -C(CH3)2OH.A further embodiment of the invention provides a compound according to any one of embodiments 1-2 or a pharmaceutically acceptable salt thereof, wherein T is selected from the group consisting of

[0092] , wherein T1 is H, -CO-Ci-3-alkyl, a 4-5 membered O-heterocyclyl, or -Ci-3-alkyl, and T2 is absent, Ci-3-alkyl, -CO-, -N(CH3)-, -N(CH3)-CO-(CH2)1-8-CO-, -N(CH3)-CO- (CH2)1-2, -N(CH3)-(CH2)1-2, -N(CH3)-CO-(CH2)1-2-7-membered N-heterocyclyl-, 5- membered heteroaryl, or -N(CH3)-SO2-(CH2)I-2,

[0093]

[0094] b), wherein

[0095] tl is H or -CH3, and

[0096] T3 is absent or -cyclohexyl,

[0097]

[0098] , wherein

[0099] T4 is pyridinyl or pyrazolyl, and

[0100] T5 is absent, -CO- or a 5-membered heteroaryl,d)

[0101]

[0102] A further embodiment of the invention provides a compound according to any one of embodiments 1-3 or a pharmaceutically acceptable salt thereof, wherein T is selected from the group consisting of

[0103]

[0104] a), wherein

[0105]

[0106] T1 is H, -CO-CH3, -CO-CH2CH3,. ethyl or methyl, and

[0107] T2 is absent, Ci-3-alkyl, -CO-, -N(CH3)-, -N(CH3)-CO-(CH2)I-S-CO-, -N(CH3)-CO- (CH2)1-2. -N(CH3)-(CH2)1-2, -N(CH3)-SO2-(CH2)1-2. oxazolyl or -N(CH3)-CO-(CH2)1.2

[0108]

[0109] -N3> CN-i-

[0110]

[0111] t1 is H or -CH3, and

[0112] T3 is absent or -cyclohexyl,

[0113]

[0114] T4 is pyridinyl, and

[0115] T5 is absent. -CO-, oxazolyl or pyrazolyl.

[0116]

[0117] t2 is -C(CH3,F,F) or -C(CH3)2OH.

[0118] 5. A further embodiment of the invention provides a compound according to any one of embodiments 1-4 or a pharmaceutically acceptable salt thereof, wherein T is selected from the group consisting ofT1

[0119] a), wherein

[0120] T1 is H, -CO-CH3. -CO-CH2CH3,. ethyl or methyl, and T2 is absent, Ci-3-alkyl, -CO-, -N(CH3)-, -N(CH3)-CO-(CH2)1-8-CO-, -N(CH3)-CO- (CH2)1-2. -N(CH3)-(CH2)1-2, -N(CH3)-SO2-(CH2)1-2. oxazolyl. or -N(CH3)-CO-(CH2)I.2 -N> CN4-

[0121]

[0122] T4 is pyridinyl, and

[0123] T5 is absent, -CO-, oxazolyl or pyrazolyl.

[0124] A further embodiment of the invention provides a compound according to any one of embodiments 1-5 or a pharmaceutically acceptable salt thereof, wherein T is selected from the group consisting of

[0125]

[0126]

[0127] 7. A further embodiment of the invention provides a compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein T is selected from the group consisting of

[0128]

[0129] 8. A further embodiment of the invention provides a compound according to any one of embodiments 1-7 or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of

[0130]

[0131] wherein Cl is a bicyclic heteroaryl, optionally substituted by Ci-Cs-alkyl, and

[0132]

[0133] wherein C2 is a aryl, optionally substituted by halogen or -O-Ci-s-alkyl.

[0134] 9. A further embodiment of the invention provides a compound according to any one of embodiments 1-8 or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of

[0135]

[0136] wherein Cl is selected from the group consisting of

[0137] N-N

[0138] N

[0139] N

[0140]

[0141] , each optionally substituted by methyl, and

[0142]

[0143] wherein C2 is a phenyl, optionally substituted by F and -OCH3.

[0144] 10. A further embodiment of the invention provides a compound according to any one of embodiments 1-9 or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of

[0145]

[0146] 11. A further embodiment of the invention provides a compound according to any one of embodiments 1-10 or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of

[0147]

[0148] A further embodiment of the invention provides a compound according to any one of embodiments 1-11 or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of

[0149] , wherein LI is absent or selected from the group consisting of -CO-CH2-, -N-(CH2)1-5-CO-, -CO-(CH2)1-8-CO-. and -heteroaryl-(CH2)0-1-,

[0150] . B

[0151] c) -CO-(CH2)O-2-.

[0152]

[0153] a. L2 is selected from the group consisting of a bond, -(CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-,

[0154] b. 11 is selected from the group consisting of CH and N,

[0155] c. 12 is absent or -CO-,

[0156]

[0157] , wherein

[0158] a. L3 is absent or is selected from the group consisting of -(CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-,

[0159] b. L4 is absent, C3-6cycloalkyl or heterocyclyl,

[0160] c. L5 is absent or is selected from the group consisting of -(CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-,

[0161]

[0162] a. 13 is -CH- or -N-,

[0163] b. 14 is -O- or -CH2-,

[0164] c. L6 is absent or heterocyclyl,

[0165] g). wherein L7 is selected from the group consisting of - (CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-, and

[0166]

[0167] , wherein L8 is selected from the group consisting of - (CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-.

[0168] A further embodiment of the invention provides a compound according to any one of embodiments 1-12 or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of

[0169] , wherein LI is absent or selected from the group consisting of

[0170] -CO-CH2-, -N-(CH2)1-5-CO-, -CO-(CH2)1-8-CO-, and -heteroaryl-(CH2)0-1-, and

[0171] _ j—L5— L4— L3-Z^N-j- -4— L5-L4— L3^°Al-i-

[0172]

[0173] ( °‘1 6or O0-1 B. wherein

[0174] a) L3 is absent or is selected from the group consisting of -(CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-,

[0175] b) L4 is absent, C3-6cycloalkyl or heterocyclyl,

[0176] c) L5 is absent or is selected from the group consisting of -(CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-.

[0177] A further embodiment of the invention provides a compound according to any one of embodiments 1-13 or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of

[0178]

[0179]

[0180] A further embodiment of the invention provides a compound according to any one of embodiments 1-14 or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of

[0181]

[0182] A further embodiment of the invention provides a compound of formula I accordingy to any one of embodiments 1-15 or a pharmaceutically acceptable salt thereof

[0183] T-L-B

[0184]

[0185] wherein

[0186] T is a targeting ligand selected from the group consisting of

[0187]

[0188]

[0189] L is a linker selected from the group consisting of

[0190]

[0191] B is a CRBN binder selected from the group consisting of

[0192]

[0193] 17. A further embodiment of the invention provides a compound of formula I according to any of embodiments 1-16 wherein T is

[0194]

[0195] T, wherein

[0196] a is –C(CH3,F,F), -SO2CH3, -C(heterocyclyl, OCH3), -C((CH3)2, OCH3) or -C(CH3)2OH, b is N or CH,

[0197] c is H, -CO-Ci-3-alkyl, -CO-C3-6-cycloalkyl, optionally substituted by -OCH3, heterocyclyl or -Ci-3-alkyl, and

[0198] d is heteroaryl -O-heterocyclyl,

[0199] e is absent, Ci-3-alkyl, -N(CH3)-, -N(CH3)-CO-(CH2)1-8-CO-, -N(CH3)-CO-(CH2)I.2, -N(CH3)-(CH2)I-2, -N(CH3)-CO-(CH2)i-2-heterocyclyl- or -N(CH3)-SO2-(CH2)I-2, -C3-6-cycloalkyl, heteroaryl, optionally substituted by =0, heteroaryl-heterocyclyl, or heteroarylheteroaryl,

[0200] A further embodiment of the invention provides a compound of formula I according to any of embodiments 1-17, selected from the group consisting of

[0201] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-4-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-N-methyl-4-oxo-butanamide,

[0202] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-10-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-N-methyl-10-oxo-decanamide,

[0203] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-N-methyl-6-oxo-hexanamide,

[0204] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-4-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-N-methyl-4-oxo-butanamide,

[0205] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-6- [4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-N-methyl-6-oxo-hexanamide,N-[5-[6-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]piperidine-1-carbonyl]-2-pyridyl]-4-[[6-(1-methoxy-1-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0206] N-(5-(4-((l -(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-4-yl)oxy)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0207] N-(5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperazine-l-carbonyl)-4-hydroxypiperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0208] N-(5-(4-((4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0209] N-(5-(4-(6-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-2,6-diazaspiro[3.4]octan-2-yl)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0210] N-(5-(4-(3-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-3,5,6,7,8,8a-hexahydroimidazo[l,5-a]pyrazine-7-carbonyl)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(4-((1r,4r)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)phenyl)cyclohexyl)piperazine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(4-((l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-4-yl)oxy)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0211] N-(6-(4-((4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide.

[0212] N-(6-(4-(6-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-2,6-diazaspiro[3.4]octan-2-yl)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(6-(4-((1r,4r)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)phenyl)cyclohexyl)piperazine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0213] N-(6-(4-((l -(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol- 4-yl)piperidin-4-yl)oxy)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0214] N-(6-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0215] N-(6-(6-((l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol- 5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(6-(6-((l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, 6'-acetamido-N-(6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-6-oxohexyl)-4'-((6-((S)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,

[0216] 6'-acetamido-N-(6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-6-oxohexyl)-4'-((6-(3-methoxyoxetan-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,

[0217] 6'-acetamido-N-(6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-6-oxohexyl)-4'-((6-(2-hydroxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,

[0218] 6-[6-acetamido-4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-N-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-6-oxo-hexyl]pyridine-3-carboxamide,

[0219] N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)cyclohexyl)(methyl)amino)pyridin-2-yl)acetamide,

[0220] N-(4-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyridin-2-yl)acetamide,N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-methyl-10-oxo-decanamide,

[0221] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-N-methyl-acetamide,

[0222] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-N-methyl-acetamide,

[0223] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-l-((l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-N-methylpiperidine-4-carboxamide,

[0224] (lr,4r)-N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-4-((4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperazin-l -yl)methyl)-N-methylcyclohexane-l -carboxamide,

[0225] (lr,4r)-N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-4-(3-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)amino)phenyl)-N-methylcyclohexane-l -carboxamide,

[0226] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-((2, 6-dioxopiperi din-3 -yl)amino)-2 -fluorophenoxy )-N-methylacetamide,

[0227] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-3-(2,6-dioxopiperidin-3-yl)-N,l-dimethyl-lH-indazole-7-carboxamide,

[0228] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluoro-N-methylbenzamide.

[0229] N-(6'-amino-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-1 -yl)-N-methyl-6-oxohexanamide,

[0230] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[l-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl-methyl-amino]-2-pyridyl]-2-pyridyl] acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[6-t[l-tl-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-ylJ-4-piperidyl]methylJ-2.6-diazaspiro[3.3]heptan-2-yl]-N-methyl-acetamide,

[0231] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((8-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)-l-oxa-8-azaspiro[4.5]decan-3-yl)(methyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0232] N-(5-(l-((l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-lH-pyrazol-3-yl)-4-((6-(2-methoxypropan-2-yl)-4-methylpyri din-2 -yl)amino)pyridin-2-yl)acetami de,

[0233] N-(5-(l-((l-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-4-hydroxypiperidine-4-carbonyl)piperidin-4-yl)methyl)-lH-pyrazol-3-yl)-4-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)pyridin-2-yl)acetamide,

[0234] N-(5-(l-(4-((4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)phenyl)piperazin-l-yl)methyl)cyclohexyl)-lH-pyrazol-3-yl)-4-((6-(2-rnethoxypropan-2-yl)-4-methylpyridin-2-yl)amino)pyridin-2-yl)acetamide,

[0235] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0236] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetarnide,

[0237] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0238] N-[6-[6-acetamido-4-[[2-(l,l-dilluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazine-l -carbonyl]-4-hydroxy-l-piperidyl]-N-methyl-acetamide,

[0239] N-(6,-acetamido-4,-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-f2,3'-bipyridin]-5-yl)-2-(4-((4-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-y l)piperazin- 1 -yl)methyl)piperidin- 1 -y 1)-N -methylacetamide,

[0240] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(7- (l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-N-methylacetamide,N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidin- 1 -yl)-N-methy lacetamide.

[0241] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[l-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]-l-piperidyl]-N-methyl-acetamide,

[0242] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[l-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]-methyl-amino]-l-piperidyl]-N-methyl -acetamide,

[0243] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(((lr,4r)-4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperazine-l-carbonyl)cyclohexyl)(methyl)amino)-N-methy 1 acetami de,

[0244] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-((l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy)piperidin-l-yl)-N-methylacetamide,

[0245] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-(6-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-2,6-diazaspiro[3.4]octan-2 -yl)piperi din- 1 -yl)-N-methy lacetamide,

[0246] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.4]octan-6-yl)-N-methylacetamide,

[0247] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(3-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)-2-oxoethyl)azetidin- 1 -yl)-N-methylacetamide,

[0248] N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)azeti din-3-yl)acetyl)piperazin-l-yl)-N-methy lacetamide,

[0249] N-(6'-acetamido-4,-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4- (4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)-N-methylacetamide,N-(6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidin-1 -yl)-N-methylacetamide,

[0250] N-(4'-((2-(l,1 -difluoroethyl)pyrimidin-4-yl)amino)-5-((l -(4-(3-(2,6-dioxopiperidin-3-yl)-l -methyl-lH-indazol-7-yl)piperidin-l-yl)-N-methylmethyl)sulfonamido)-[2,3'-bipyridin]-6'-yl)acetamide,

[0251] N-(4'-((2-(l, 1 -difluoroethyl)pyrimidin-4-yl)amino)-5-((2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l -yl)methyl)piperi din-1 -yl)ethyl)(methyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0252] N-(4'-((2-(l, 1 -difluoroethyl)py rimidin-4-yl)amino)-6'-((tetrahy drofuran-3-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-N-methylacetamide,

[0253] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-6'-(oxetan-3-ylamino)-[2,3'-bipyridin]-5-yl)-2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidin- 1 -yl)-N-methylacetamide,

[0254] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-6'-(oxetan-2-ylamino)-[2,3'-bipyridin]-5-yl)-2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidin- 1 -yl)-N-methylacetamide,

[0255] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-6'-((tetrahydrofuran-2-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)-N-methylacetamide,

[0256] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-6'-(ethylamino)-[2,3'-bipyridin]-5-yl)-2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidin- 1 -yl)-N-methylacetamide,

[0257] N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-(4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)cyclohexyl)pyri din-2 -yl)acelami de,

[0258] N-(6-(4-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidin-l-yl)oxazol-2-yl)-4,-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide.

[0259] N-(6-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidin-l-yl)oxazol-2-yl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyri din-2-yl)amino)-[2.3'-bipyridin]-6,-yl)acetamide.N-(4'-((2-(l, 1 -difluoroethyl)pyrimidin-4-yl)amino)-5-(4-(4-(3-(2,6-dioxopiperidin-3-yl)- 1 - methyl-lH-indazol-7-yl)piperidin-l-yl)oxazol-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0260] N-(4"-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-3-(4-(3-(2,6-dioxopiperidin-3-yl)-l- methyl-lH-indazol-7-yl)piperidin-l-yl)-2-oxo-2H-[l,3':6',3"-terpyridin]-6"-yl)acetamide, N-(4"-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-3-((4-(3-(2,6-dioxopiperidin-3-yl)-l- methyl-lH-indazol-7-yl)piperi din-1 -yl)methyl)-2-oxo-2H-[l,3':6',3"-terpyridin]-6"- yl)acetamide, and

[0261] N-(5-(l-(7-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidine-4- carbonyl)-5,6,7,8-tetrahydroimidazo[l,5-a]pyrazin-3-yl)-lH-pyrazol-3-yl)-4-((6-(2- methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)pyri din-2 -yl)acetamide,

[0262] or a pharmaceutically acceptable salt thereof.

[0263] 19. A further embodiment of the invention provides a compound of formula I according to any of embodiments 1-18. selected from the group consisting of

[0264] N-(5-(4-((l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol- 5-yl)piperidin-4-yl)oxy)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4- methylpyri din-2 -yl)amino)-[2,3'-bipyridin]-6,-yl)acetamide. N-(5-(4-((4-(l-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperazin-l- yl)methyl)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyri din-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide N-[6-[6-acetamido-4-[[2-(l,l- difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[l-(2.6-dioxo-3-piperidyl)-3- methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-N-methyl-acetamide, and N-(6'-acetamido-4'- ((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-((l-(4-((2,6- dioxopiperi din-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy)piperi din-1 -yl)-N- methylacetamide

[0265] or a pharmaceutically acceptable salt thereof.

[0266] 20. A further embodiment of the invention provides a compound of formula I according to any of embodiments 1-19 for use as therapeutically active substance.

[0267] 21. A further embodiment of the invention provides a compound of formula I according to embodiments 1-19 for the use as therapeutically active substance for the therapeutic and / or prophylactic treatment of autoimmune disorders like type 1 diabetes, ankylosing spondylitis,cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome- associated autoinflammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory’ bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury’, glutamate neurotoxicity’ and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

[0268] 22. A further embodiment of the invention provides a pharmaceutical composition comprising a compound of formula I according to any of embodiments 1-19 and a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable auxiliary’ substance.

[0269] 23. A further embodiment of the invention provides a use of a compound of formula I according to any of embodiments 1-19 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of IBD.

[0270] 24. A further embodiment of the invention provides a use of a compound of formula I according to any of embodiments 1-19 for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome- associated autoinflammatory’ syndromes (PRAAS), ISG15 deficiency, and inflammatory’ bowel disease; inflammatory’ disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory’ bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovaiy syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

[0271] All separate aspects of the invention described herein may be combined.One aspect (aspect 1) of the invention provides a compound of formula I,

[0272] T-L-B

[0273]

[0274] wherein

[0275] T is a targeting ligand selected from the group consisting of

[0276] and

[0277]

[0278] T, wherein

[0279] a is –C(C1-3-alkyl,F,F), –C(heterocyclyl,OCH3), –C(heterocyclyl,F), –heterocyclyl, -C(C3-6-cycloalkyl, H), -C(C3-6-cycloalkyl, OCH3), -C(C3-6-cycloalkyl substituted by 1-2 halogen, H), -SO2CH3, –C((CH3)2,OCH3) or –C(CH3)2OH,

[0280] a’ is Ci-3-alkyL -O-Ci-3-alkyl, -O-C3-6-cycloalkyl or C3-6-cycloalkyl,

[0281] a” is Ci-s-alkyl, -O-Ci-3-alkyl or halogen,

[0282] b is N or CH,

[0283] c is H, -CO-Ci-3-alkyl, -CO-Cs-e-cycloalkyl, CO-N(H, CH3), -CO-NH2, SO2-Ci-3-alkyl, heterocyclyl or -Ci-3-alkyl, and

[0284] d is selected from the group consisting of C3-6-cycloalkyl, aryl, aryl substituted by 1-2 halogen, heteroaryl and heteroaryl substituted by 1-2 halogen,e is absent Ci-3-alkyl, -N(CH3)-, -N(CH3)-CO-(CH2)I-8-CO-, -N(CH3)-CO-(CH2)I-2, -N(CH3)-(CH2)I-2, -N(CH3)-CO-(CH2)i-2-heterocyclyl- or -N(CH3)-SO2-(CH2)i-2, -C3-6-cycloalkyl, heteroaryl, optionally substituted by =0. heteroarvl-heterocyclvl. or heteroaryl-heteroaryl, L is a linker selected from the group consisting of

[0285]

[0286] wherein

[0287] LI is absent or selected from the group consisting of -CO-(CH2)i-3-. -(CH2)I-3-CO-, -N- (CH2)I-9-CO-, -CO-(CH2)I-8-CO-, -(CH2)I-8-, -(CH2)I-8-CO-, -(CH2)o-i-heterocyclyl, - heterocyclyl-(CH2)o-2-0-(CH2)i-2-, -heteroaryl-(CH2)o-i- and -(CH2)o-i-heteroaryl-, 11 is CH or N,

[0288] 12 is CH or N,

[0289]

[0290] c) -CO-(CH2)O-2-.

[0291]

[0292] L2 is selected from the group consisting of a bond, -(CH2)I-2-, -CO-, -O-, -C3-6- cycloalkyl and -(CH2)O-2-CO-(CH2)I-2-,

[0293] 13 is selected from the group consisting of CH and N,

[0294] 14 is absent, -CH2N(H, CH3)-, -(CH2)I-2- or -CO-,' ( / h-A ' ' \)-A '

[0295] — j— L5— L4— L3-^ N-j- -^L5-L4— L3-Z N-j-e x

[0296]

[0297] )THu / 1B ° orT H0B, w Uherei •n

[0298] L3 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-. -O-, and - (CH2)I.2-CO-(CH2)I.2-,

[0299] L4 is absent, -C3-6-cycloalkyl or heterocyclyl,

[0300] L5 is absent or is selected from the group consisting of -(CH2)I-2-, CH2N(H, CH3)-, heterocyclyl-CO-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-,

[0301] or

[0302]

[0303] . wherein 15 is -CH- or -N-,

[0304] 16 is -O-, -CF2-, or -CH2-,

[0305] L6 is absent, -(CH2)I-2-, -O-, -C3-6-cycloalkyl or -(CH2)o-2-heterocyclyl, optionally substituted by halogen,

[0306]

[0307] , wherein L7 is selected from the group consisting of -(CH2)I- 2-, -O-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-, and

[0308]

[0309] , wherein L8 is selected from the group consisting of - (CH2)I.2-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-, and

[0310]

[0311] wherein L9 is absent or selected from the group consisting of - (CH2)I-2-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-, and

[0312] B is a CRBN binder selected from the group consisting of

[0313]

[0314] wherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by Ci-3-alkyl, halogen or =0 and -(CH2)o-iaryl, optionally substituted by halogen or -O-Ci-3-alkyl. Aspect 2 is a compound according to aspect 1 or a pharmaceutically acceptable salt thereof wherein

[0315] T is a targeting ligand selected from the group consisting of

[0316]

[0317] wherein

[0318] a is –C(C1-3-alkyl,F,F), –C(heterocyclyl,OCH3), –C(heterocyclyl,F), –heterocyclyl, -C(C3-6-cycloalkyl, OCH3), -C(C3-6-cycloalkyl substituted by 1-2 halogen, H), -SO2CH3, or –C((CH3)2,OCH3),

[0319] a’ is Ci-3-alkyl, -O-Ci-3-alkyl, -O-C3-6-cycloalkyl or C3-6-cycloalkyl,

[0320] a’ ’ is halogen,

[0321] b is N or CH,c is -CO-C1-3-alkyl,

[0322] d is selected from the group consisting of aryl substituted by 1-2 halogen, heteroaryl and heteroaryl substituted by 1-2 halogen, and

[0323] e is absent,

[0324] L is a linker selected from the group consisting of

[0325]

[0326] L1 is absent or selected from the group consisting of -N-(CH2)1-9-CO-, -(CH2)1-8 -(CH2)0-1-heterocyclyl and-heterocyclyl-(CH2)0-2-O-(CH2)1-2-,

[0327] l1 is CH or N,

[0328] l2 is CH or N,

[0329]

[0330]

[0331] L2 is selected from the group consisting of-(CH2)i-2-, -CO-, -O- and -C3-6-cycloalkyl, 13 is N,

[0332] l4 is absent or -(CH2)1-2-.

[0333]

[0334] 15 is -CH- or -N-,

[0335] 16 is -CH2-,

[0336] L6 is absent, or -(CH2)o-2-heterocyclyl, optionally substituted by halogen,

[0337]

[0338] wherein L7 is selected from the group consisting of -(CH2)1-2-, -O- and -CO-,

[0339]

[0340] f), wherein L9 is absent, and

[0341] B is a CRBN binder selected from the group consisting of

[0342]

[0343] wherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by C1-3-alkyl, halogen or =O and -(CH2)0-1aryl, optionally substituted by halogen or -O-C1-3-alkyl. Aspect 3 is a compound according to any one of aspects 1-2 or a pharmaceutically acceptable salt thereof wherein

[0344] T is a targeting ligand selected from the group consisting of

[0345]

[0346] wherein

[0347] a is -C(C1-3-alkyl,F,F), -C(heterocyclyl,OCH3), -C(heterocyclyl,F), -heterocyclyl, -C(C3-6-cycloalkyl, OCH3), -C(C3-6-cycloalkyl substituted by 1-2 halogen, H), -SO2CH3, or -C((CH3)2, OCH3).

[0348] a’ is Ci-3-alkyl, -O-Ci-s-alkyl, -O-C3-6-cycloalkyl or C3-6-cycloalkyl,

[0349] a’ ’ is halogen,

[0350] b is N or CH,c is -CO-C1-3-alkyl,

[0351] d is selected from the group consisting of aryl substituted by 1-2 halogen, heteroaryl and heteroaryl substituted by 1-2 halogen, and

[0352] e is absent.

[0353] Aspect 4 is a compound according to any one of aspects 1-3 or a pharmaceutically acceptable salt thereof wherein T is a targeting ligand

[0354] is a targeting ligand selected from the group consisting of

[0355]

[0356] wherein

[0357] a is -C(C1-3-alkyl,F,F), or -C(heterocyclyl,OCH3),

[0358] a’ is Ci-3-alkyl or -O-Ci-s-alkyl,

[0359] a' ’ is halogen,

[0360] b is N or CH,

[0361] c is -CO-C1-3-alkyl,

[0362] d is heteroaryl, and

[0363] e is absent.

[0364] Aspect 5 is a compound according to any one of aspects 1-4 or a pharmaceutically acceptable salt thereof wherein T is a targeting ligand

[0365] T is a targeting ligand selected from the group consisting of

[0366]

[0367] and T,wherein

[0368] a is -C(CH3, F, F), or -C(tetrahydrofuranyl, OCH3),

[0369] a is CH3or -O- CH3,

[0370] a" is F.

[0371] b is N or CH,

[0372] c is -CO-CH3,

[0373] d is pyridinyl, and

[0374] e is absent.

[0375] Aspect 6 is a compound according to any one of aspects 1-5 or a pharmaceutically acceptable salt thereof wherein T is selected from the group consisting of

[0376]

[0377] 

[0378]

[0379] 

[0380]

[0381] L

[0382] means the site of the target ligand T attached to L.

[0383] Aspect 7 is a compound according to any one of aspects 1-6 or a pharmaceutically acceptable salt thereof wherein T is selected from the group consisting of

[0384]

[0385] L wherein means the site of the target ligand T attached to L.

[0386] Aspect 8 is a compound according to any one of aspects 1-7 or a pharmaceutically acceptable salt thereof wherein T is selected from the group consisting of

[0387]

[0388] wherein

[0389] L

[0390] means the site of the target ligand T attached to L.

[0391] Aspect 9 is a compound according to any one of aspects 1 -8 or a pharmaceutically acceptable

[0392]

[0393] means the site attached to L.

[0394] Aspect 10 is a compound according to any one of aspects 1 -9 or a pharmaceutically acceptable salt thereof wherein B is a CRBN binder selected from the group consisting of

[0395]

[0396] wherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by C1-3-alkyl or halogen and -(CH2)0-1aryl, optionally substituted by halogen. Aspect 11 is a compound according to any one of aspects 1-10 or a pharmaceutically acceptable salt thereof wherein B is selected from the group consisting of

[0397]

[0398] wherein e is selected from the group consisting of a 1H-indazolyl by CH3-alkyl and F and phenyl substituted by 2 F.

[0399] Aspect 12 is a compound according to any one of aspects 1-11 or a pharmaceutically acceptable salt thereof wherein B is selected from the group consisting of

[0400]

[0401]

[0402] attached to L.

[0403] Aspect 13 is a compound according to any one of aspects 1-12 or a pharmaceutically acceptable salt thereof wherein B is selected from the group consisting of

[0404]

[0405] means the site of the CRBN binder B attached to L.Aspect 14 is a compound according to any one of aspects 1-13 or a pharmaceutically acceptable

[0406] L

[0407] salt thereof wherein B is and wherein means the site attached

[0408]

[0409] Aspect 15 is a compound according to any one of aspects 1-14 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting of

[0410]

[0411] L2 is -(CH2)1-2-,

[0412] 13 is N.

[0413] 14 is absent.

[0414] Aspect 16 is a compound according to any one of aspects 1-15 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting of

[0415]

[0416] L2 is -CH2-,

[0417] 13 is N,

[0418] 14 is absent.

[0419] Aspect 17 is a compound according to any one of aspects 1-16 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting of

[0420]

[0421]

[0422]

[0423]

[0424] T

[0425] attached to the CRBN binder B and means the site attached to the target ligand T.

[0426] Aspect 18 is a compound according to any one of aspects 1-17 or a pharmaceutically acceptable

[0427]

[0428] salt thereof wherein L is selected from the group consisting of

[0429]

[0430] B T means the site attached to the CRBN binder B and means the site attached to the target ligand T.

[0431] Aspect 19 is a compound according to any one of aspects 1-18 or a pharmaceutically acceptable

[0432]

[0433] and

[0434]

[0435] B T

[0436] wherein means the site attached to the CRBN binder B and means the site attached to the target ligand T.

[0437] Aspect 20 is a compound according to any one of aspects 1-19 or a pharmaceutically acceptable

[0438]

[0439] salt thereof wherein L is wherein means the site

[0440]

[0441] T

[0442] attached to the CRBN binder B and means the site attached to the target ligand T. Aspect 21 is a compound according to any one of aspects 1-20 or a pharmaceutically acceptable salt thereof wherein T is a targeting ligand selected from the group consisting of

[0443]

[0444] wherein

[0445] a is -C(C1-3-alkyl,F,F), or -C(heterocyclyl,OCH3),

[0446] a' is C1-3-alkyl or -O-C1-3-alkyl,

[0447] a” is halogen,

[0448] b is N or CH,

[0449] c is -CO-C1-3-alkyl,

[0450] d is heteroaryl, and

[0451] e is absent,

[0452]

[0453] wherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by Ci-3-alkyl or halogen and -(CH2)0-1aryl, optionally substituted by halogen, and L is selected from the group consisting of

[0454]

[0455] L2 is -(CH2)1-2-,

[0456] 13 is N, and

[0457] 14 is absent.

[0458] Aspect 22 is a compound according to any one of aspects 1-21 or a pharmaceutically acceptable salt thereof wherein Tis a targeting ligand selected from the group consisting of

[0459]

[0460] wherein

[0461] a is -C(CH3,F,F), or -C(tetrahydrofuranyl,OCH3),

[0462] a' is CH3or -O- CH3,

[0463] a” is F.

[0464] b is N or CH.

[0465] c is -CO-CH3,

[0466] d is pyridinyl, and

[0467] e is absent,

[0468] B is selected from the group consisting of

[0469]

[0470] wherein e is selected from the group consisting of a 1H-indozalyl by CH3-alkyl and F and phenyl substituted by 2 F, and

[0471] L is selected from the group consisting of

[0472]

[0473] L2 is -CH2-, 13 is N and 14 is absent.

[0474] Aspect 23 is a compound according to any one of aspects 1-22 or a pharmaceutically acceptable salt thereof wherein

[0475]

[0476]

[0477] 

[0478]

[0479]

[0480] L

[0481] wherein means the site of the target ligand T attached to L,

[0482] B is selected from the group consisting of

[0483] O

[0484]

[0485] o

[0486]

[0487] wherein means the site of the CRBN binder B attached to L, and L is selected from the group consisting of

[0488]

[0489]

[0490]

[0491]

[0492] Aspect 24 is a compound according to any one of aspects 1-23 or a pharmaceutically acceptable salt thereof wherein

[0493] T is selected from the group consistingL

[0494]

[0495] means the site of the target ligand T attached to L,

[0496]

[0497] and wherein

[0498]

[0499] B T

[0500] means the site attached to the CRBN binder B and means the site attached to

[0501]

[0502] CRBN binder B attached to L.

[0503] Aspect 25 is a compound of formula I according to any of aspects 1-23. or a pharmaceutically acceptable salt thereof, selected from the group consisting of

[0504] N-(5-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)oxy)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0505] N-(5-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0506] N-(5-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carbonyl)-4-hydroxypiperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0507] N-(5-(4-((1r,4r)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)phenyl)cyclohexyl)piperazine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0508] N-(5-(4-(6-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-2,6-diazaspiro[3.4]octan-2-yl)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0509] N-(5-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)oxy)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0510] 6'-acetamido-N-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-2-oxoethyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,

[0511] 6'-acetamido-N-(6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-6-oxohexyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,

[0512] 6'-acetamido-N-(10-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-10-oxodecyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,

[0513] 6'-acetamido-N-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-2-oxoethyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,

[0514] N-[5-[6-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]piperidine-1-carbonyl]-2-pyridyl]-4-[[6-(1-methoxy-1-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0515] N-(6-(6-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0516] N-(6-(6-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0517] N-(6-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0518] N-(6-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)oxy)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0519] N-(6-(4-((1r,4r)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)phenyl)cyclohexyl)piperazine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0520] N-(6-(4-(6-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-2,6-diazaspiro[3.4]octan-2-yl)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(6-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0521] 6'-acetamido-N-(6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-6-oxohexyl)-4'-((6-(2-hydroxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,

[0522] N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0523] N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[4-[[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7-yl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0524] N-[4-[[6-(1,1-difluoroethyl)-2-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[6-(1,1-difluoroethyl)-2-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0525] N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-4-[(4-methyl-6-methylsulfonyl-2-pyridyl)amino]-2-pyridyl]acetamide,

[0526] N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]azetidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0527] N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-1-piperidyl]methyl]-3-hydroxy-azetidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0528] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidin-1-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0529] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)pyrrolidin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0530] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2S)-2-((6-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)morpholine-4-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-hydroxypiperidine-l-carbonyl)-|2,3'-bipyridin] -6'-yl)acetamide.

[0531] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((4-(3-(2,6-dioxopiperidin-3-yl)- I -methyl- 1 H-indazol-6-y I Jpiperidin- 1 -yl)methyl)-3-hydroxy pyrrolidine- 1 -carbonyl)-| 2.3'-bipyridin] -6'-y l)acetamide,

[0532] A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((6-(3-(2,6-dioxopiperidin-3-yl)- l-methyl-1H-indazol-6-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0533] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)phenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0534] A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((l-(3-(2.6-dioxopiperidin-3-yl)- 1-methyl-1H-indazol-6-yl)pynolidin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0535] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)phenyl)piperidin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide, A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin] -6'-yl)acetamide,

[0536] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-1H-indazol-6-yl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0537] V-(4'-((6-(l J-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((6-(3-(2,6-dioxopiperidin-3-yl)- 2-oxo-2,3-dihydrobenzo[< / ]oxazol-6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0538] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((6-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-l / 7-indazol-7-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyrrolidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0539] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperidin-4-yl)methoxy)piperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0540] JV-(4'-((6-(1, 1 -difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-(( 1 -(3-(2,6-dioxopiperidin-3-yl)- l-methyl-l / 7-indazol-6-yl)piperidin-4-yl)methoxy)piperidine-l-carbonyl)-[2,3,-bipyridin]-6,-yl)acetamide.A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((4-(3-(2,6-dioxopiperidin-3-yl)- l-methyl-l / / -indazol-7-yl)piperazin-l-yl)methyl)pyrrolidine-l-carbonyl)-|2,3'-bipyridinJ-6'-yl)acetamide.

[0541] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((4-(3-(2,6-dioxopiperidin-3-yl)- l-methyl-l / / -indazol-7-yl)piperazin-l-yl)methyl)azetidine-l-carbonyl)-|2.3'-bipyridin|-6'-yl)acetamide,

[0542] A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-(2-(4-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-1H-indazol-7-yl)piperazin-l-yl)ethyl)azetidine-l-carbonyl)-f2,3'-bipyridin]-6'-yl)acetamide.

[0543] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((6-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0544] A^-(4,-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperazin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0545] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0546] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((l-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0547] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(6-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-l / 7-indazol-7-yl)piperazin-l-yl)methyl)-3-azabicyclo[3.1.1]heptane-3-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0548] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-3,3-difluoropiperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0549] A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.

[0550] 2V-(4'-((6-(l,l-difluoropropyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0551] (> S')-A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide.(7?)-A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin- 3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-|2,3'-bipyridin]-6'-yl)acetamide.

[0552] 2V-[4-[[4-(cyclopropoxy)-6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridy 1] acetamide,

[0553] 7V-[4-[[2-(l, 1 -difluoroethyl )-4-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2, 6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl]acetamide, jV-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl | methyl |piperidine- 1 -carbonyl |-2-pyridyl |-4-||6-| (3 / )-3-methoxytetrahydrofiiran-3-yl |-4-methyl -2-pyridyl] amino] -2 -pyridyl] acetamide,

[0554] 7V-[5-[5-[2-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-26-difluoro-phenyl]piperazin-l-yl]methyl]morpholine-4-carbonyl]-2-pyridyl]-4-[[6-[(37?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide.

[0555] jV-[5-[5-[4-[[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]-l-piperidyl]methyl]piperidine-l-carbonyl]-2-pyridyl]-4-[[6-[(3?)-3-methoxytetrahydrofuran-3-yl]- 4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0556] -[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-4-fluoro-piperidine-l-carbonyl]-2-pyridyl]-4-[[6-[(3 )-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide.

[0557] jV-[5-[5-[4-[[4-[3-(2,6-dioxo-3-piperidyl)pyrazolo[l,5-a]pyridin-7-yl]piperazin-l-yl]methyl]-4-fluoro-piperidine-l-carbonyl]-2-pyridyl]-4-[[6-[(3?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0558] 2V-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2.6-difluorophenyl)cyclohexyl)methyl)piperazine- 1-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin] -6'-y l)acetamide,

[0559] jV-(5-(2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[r7]oxazol-7-yl)-6-azaspiro|3.4|octane-6-carbonyl)-4'-((6- )-3-methoxytetrahydrofiiran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6,-yl)acetamide,

[0560] jV-(5-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-6-yl)piperazin-l-yl)methyl)pyrrolidine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin- 2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0561] A^-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)cyclohexyl)methyl)piperazine-l-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran- 3-yl)-4-methylpyndin-2-yl)amino)-[2,3,-bipyridin]-6,-yl)acetamide.A^-(5-((27?)-2-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)morpholine-4-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,

[0562] 2V-(5-((2< S)-2-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)morpholine-4-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0563] A^-(5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)pyrazolo[L5-a]pyridin-6-yl)piperazin-l-yl)methyl)piperi dine- l-carbonyl)-4'-((6-((J?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide.

[0564] Ar-(5-(4-((6-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-7-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0565] A-(5-(4-((l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-l / 7-indazol-7-yl)pyrrolidin-3-yl)methyl)piperazine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,

[0566] jV-(5-(4-((l-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0567] JV-(5-((3R)-3-((4-(3-(2.6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-7-yl)piperazin-l-yl)methyl)pyrrolidine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide.

[0568] jV-(5-((31S')-3-((4-(3-(2,6-dioxopiperidin-3-yl)-l -methyl- 1H-indazol-7-yl)piperazin- 1-yl)methyl)pyrrolidine-l-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0569] JV-(5-(4-((l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-6-yl)pyrrolidin-3-yl)methyl)piperazine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0570] A^5-(4-((6-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l -methyl- l f-indazol-6-yl)-2, 6-diazaspiro[3.3]heptan-2-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-(( )-3-methoxytetrahydrofuran-3-yl)-4-methylpyndm-2-yl)arnino)-|2,3'-bipyridin]-6'-yl)acetamide. 2V-(5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)benzo[<7|isoxazol-7-yl)piperidin-l-yl)methyl)piperidine- 1-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin] -6'-y l)acetamide,

[0571] A-(5-(3-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)pyrrolidine-l-carbonyl)-4'-((6-((A)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin- 2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,A^-(5-(3-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-3-hydroxypyrrolidine-1 -carbonyl)-4'-((6-(( / )-3-methoxytetrahydroluran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide.

[0572] 2V-(5-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-7-yl)piperazin-l-yl)methyl)pyrrolidine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin- 2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0573] 7V-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidin-l-yl)methyl)piperidine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2 -yl)amino)-[2.3'-bipyridin] -6'-y l)acetamide,

[0574] Ar-(5-(4-((4-(4-(((7?)-2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0575] 7V-(5-(4-((4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperi dine- l-carbonyl)-4'-((6-((J?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide+l,

[0576] jV-(5-((2r,4s')-2-(4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[< |oxazol-7-yl)-3,3-difluoropiperidin-l-yl)-6-azaspiro[3.4]octane-6-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran- 3-yl)-4-methylpyri din-2 -yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0577] JV-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2.6-difluorophenyl)piperidin-l-yl)methyl)-4- H uoropipendine- 1 -carbonyl )-4'-((6-(( / ?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0578] jV-(5-(4-((4-(4-(((7?)-2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3,-bipyridin]-6,-yl)acetamide,

[0579] JV-(5-(4-((4-(4-(((5)-2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4- H uoropiperi dine- 1 -carbonyl )-4'-((6-((7 )-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl),

[0580] jV-(5-((2y4r)-2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)-6-azaspiro[3.4]octane-6-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyndm-2-yl)amino)-|2 '-bipyridin]-6'-yl)acetamide.

[0581] V-(5-((27-,- / x)-2-(4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)-6-azaspiro[3.4]octane-6-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran- 3-yl)-4-methylpyri din-2 -yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0582] 6'-acetamido-A^-(6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-177-benzo|«'|imidazol-4-yl)piperidin-l-yl)-6-oxohexyl)-4'-((6-((X)-3-methoxytelrahydrofuran-3-yl)- 4-methylpyridin-2-yl)amino)-[2.3'-bipyridine]-5-carboxamide,jV-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridylJ-4-t[6-(3-methoxyoxetan-3-yl)-4-methyl-2-py ridyl] amino] -2-pyridyl] acetamide.

[0583] 2V-(4'-((4-cyclopropyl-6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0584] A^-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-((7?)-3-fluorotetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide.

[0585] Ar-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-((<S,)-3-fluorotetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0586] A-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-(l-fluorocyclobutyl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin] -6'-y l)acetamide,

[0587] jV-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-4'-((6-(l -methoxy cyclopropyl)-4-methylpyridin-2-yl)amino)-P^'-bipyridinJ- '-y^acetamide,

[0588] 2V-(4'-((6-(2,2-difluorocyclopropyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l -carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0589] jV-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6,-yl)acetamide,

[0590] jV-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-4- H uoropiperi dine- 1 -carbonyl )-4'-((6-((7 )-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0591] jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]pyrrolidine-l-carbonyl]-2-pyridyl]-2-pyridy 1] acetamide.

[0592] 2V-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-4-fluoro-piperidine-l-carbonyl]-2-pyridyl] -2-pyridyl] acetamide,

[0593] jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino] -2,6-difluoro-pheny 11 pi perazi n- 1 -yl] methyl] -4-hy droxy -piperidine- 1 -carbonyl] -2-pyridyl] -2-pyridyl] acetamide,A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)-2-oxopiperazin-l-yl)methyl)piperidine-l-carbonyl)-|2,3'-bipyridin]-6'-yl)acetamide.

[0594] 2V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0595] A^-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[2-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]morpholine-4-carbonyl]-2-pyridyl]-2-pyridy 1] acetamide,

[0596] Ar-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((l-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)piperidin-4-yl)oxy)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide, 7V-[4-[[2-(l, 1 -difluoroethyl )pyrimidin-4-yl]amino]-5-[5-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]phenoxy]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl]acetamide.

[0597] Ar-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,

[0598] 2V-[4-f[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-f4-[fl-[4-f(2.6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methoxy]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,

[0599] jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]oxymethyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridy 1] acetamide,

[0600] -[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperazine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,

[0601] jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4,7-diazaspiro[2.5]octan-4-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0602] jV-[4-[[2-(l,l-dilluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,

[0603] A-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[2-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,6-diazaspiro[3.3]heptan-6-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl]acetamide.A^-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]- 2.6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonylJ-2-pyridylJ-2-pyridyl] acetamide,

[0604] 2V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide, A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyndin]-6'-yl)acetamide, 2V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(9-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-l / 7-indazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide, A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-(l-(4-((2,6-dioxopiperidin-3-yl)amino)- 26-difluorophenyl)piperidin-4-yl)pyrrolidine-l-carbonyl)-|23'-bipyridin]-6'-yl)acetamide. 2V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-(l-(4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)cyclopropyl)piperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0605] A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)piperazin-l-yl)methyl)azetidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.

[0606] 2V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)piperazin-l-yl)methyl)-3-azabicyclo[3.1.1]heptane-3-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0607] A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)piperazin-l-yl)methyl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0608] jV-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-(2-(4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)ethyl)azetidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0609] A^-(4'-((2-(l,l-difluoroethyl)-5-fluoropyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2.3'-bipyridin]-6'-yl)acetamide,

[0610] jV-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluoropheny l)piperazin- 1 -yl)methy l)piperidine- 1 -carbony l)-3 -fl uoro-[2, 3 -bipyridin] -6'-yl)acetamide,

[0611] (7?)-7V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.(5)-V-(4'-((2-(l,l -difl uoroethyl)pyrimi din-4-yl)amino)-5-(4-((4-(4-((2,6-di ox opiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin- 1 -yl)methyl)piperidine- 1 -carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.

[0612] 2V-(4'-((2-(l,l -difl uoroethyl)pyrimidin-4-yl)amino)-5-((25,4r)-2-(4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)-6-azaspiro[3.4]octane-6-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0613] A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((2r,45')-2-(4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)-6-azaspiro[3.4]octane-6-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0614] jV-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine- 1 -carbonyl] -2 -pyridyl] -4-[[6-methyl-2-(2-oxabicyclo[2.1.1 ]hexan- 1 -yl)pyrimidin-4-yl] amino] -2 -pyridyl] acetami de,

[0615] 4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2.6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-iV-methyl-pyridine-2-carboxamide,

[0616] N-(4'-((6-(1,1-difluoroethyl)-4-methoxypyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0617] 2V-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-hydroxy-4-piperidyl]methyl]piperidine-l-carbonyl]-2-py ridyl] -2 -pyridyl] acetamide,

[0618] 7V-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[4-[[4-[l-(2,6-dioxo-3-piperidyl)indolin-5-yl]piperazin-l-yl]methyl]-4-fluoro-piperidine-l-carbonyl]-2-pyridyl]-2-py ridyl] acetamide,

[0619] V-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[ rac}-(2 R})-2-[[6-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-2-azaspiro[3.3]heptan-2-yl]methyl]morpholine-4-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0620] jV-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-l-piperidyl]methyl]-3-hydroxy-pyrrolidine-l-carbonyl]-2-pyridyl] -2 -pyridyl] acetamide,

[0621] V-[5-[5-[2-[3-(2.6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-6-azaspiro[3.4]octane-6-carbonyl]-2-pyridyl]-4-[[4-methyl-6-[ rac}-(3 R})-3-methoxytetrahydrofuran-3-yl]-2-py ridyl] amino] -2-pyridyl] acetamide,

[0622] jV-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)oxy]-3-fluoro-2-pyridyl]piperazin-l-yl]methyl]-4-fluoro-pipendine-l-carbonyl]-2-pyridyl] -2-pyridyl] acetamide,jV-[5-[5-[4-[[4-[3-(2,6-dioxo-3-piperidyl)pyrazolo[l,5-a]pyridin-7-yl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-4-t|4-methyl-6-| / rac}-(3 / R})-3-methoxy tetrahy drofuran-3 -y 1] -2-pyridyl] amino] -2-pyridyl] acetamide.

[0623] JV-[5-[5-[4-[[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-4-methoxy-benzoyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-4-[[6-[(3)rR})-3-methoxytetrahydrofuran-3-yl]-4-methyl -2-pyridyl] amino] -2-pyridyl] acetamide,

[0624] Af-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[6-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3-pyridyl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,

[0625] jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[5-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2-pyridyl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,

[0626] jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]phenyl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-py ridyl] acetamide,

[0627] JV-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-fluoro-phenyl]-2-py ridyl] acetamide,

[0628] jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,

[0629] jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,

[0630] 7V-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-di fluoro-phenyl] piperazine- 1 -carbonyl] -2-pyridyl] -2 -pyridyl] acetamide,

[0631] jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[7-[4-[(2,6-dioxo-3-piperidyl)amino]- 2-fluoro-phenyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2-pyridyl]-2-pyridyl]acetamide, 6-[6-acetamido-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-jV-[6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-6-oxo-hexyl] pyridine-3 -carboxamide,

[0632] 6-[6-acetamido-4-[[6-(l,1 -difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-jV-[6-[4-[l -(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-6-oxo-hexyl]pyridine- 3-carboxamide,

[0633] JV-[5-[5-[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperidine-l-carbonyl]-2-pyridyl]-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2 -pyridyl] acetamide,6-[6-acetamido-4-[[6-(1-methoxy-1-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-N-[10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-10-oxo-decyl]pyridine-3-carboxamide.

[0634] JV-[5-[5-[9-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]-3,9-diazaspiro[5.5]undecane-3-carbonyl]-2-pyridyl]-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl] amino] -2-pyridyl] acetamide,

[0635] ]N}-[4-[[2-(l,l-difluoroethyl)-5-fluoro-pyrimidin-4-yl]amino]-5-[5-[~{rac}-(3~{a}~{S},6~{a}~{S})-2-[3-(2,6-dioxo-3-piperidyl)-5-fluoro-l-methyl-indazol-6-yl]-1.3.3~{a},4,6,6~{a}-hexahydropyrrolo[3,4-c]pyrrole-5-carbonyl]-2-pyridyl]-2-py ridyl] acetamide,

[0636] {N}-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[5-[(3~{R})-3-hydroxy-3-[[4-[l-methyl-3-[(3~{R})-3-methyl-2,6-dioxo-3-piperidyl]indazol-6-yl]-l-piperidyl]methyl]pyrrolidine-l-carbonyl] -2-pyridyl] -2-pyridyl] acetamide,

[0637] {N]-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[5-[(3~{S})-3-hydroxy-3-[[4-[l-methyl-3-[(3~{R})-3-methyl-2,6-dioxo-3-piperidyl]indazol-6-yl]-l-piperidyl]methyl]pyrrolidine-l-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0638] {N}-[4-[[2-(l,l-difluoroethyl)-5-fluoro-pyrimidin-4-yl]amino]-5-[5-[9-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,

[0639] {N}-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[6-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-3-pyridyl]-2-pyridyl] acetamide,

[0640] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]cyclohexyl]-2-pyridyl]acetamide,

[0641] 6-[6-acetamido-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-N-[6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-6-oxo-hexyl] pyridine-2-carboxami de,

[0642] 6-[6-acetamido-4-[[6-(l -methoxy- l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-N-[2-|4-tl-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-2-oxo-ethyl] pyridine-2-carboxamide.and

[0643] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-l-yl]methyl]piperidine-l-carbony 1] cy clohexen- 1 -y 1] -2-pyridyl] acetamide.

[0644] Aspect 24 is a compound of formula I according to any of aspects 1-23, or a pharmaceutically acceptable salt thereof, selected from the group consisting ofN-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]azetidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0645] N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-1-piperidyl]methyl]-3-hydroxy-azetidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0646] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0647] N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0648] N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]pyrrolidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0649] N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]-4-fluoro-piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0650] N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0651] N-(4'-((2-(1,1-difluoroethyl)-5-fluoropyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide, and

[0652] N-(4'-((6-(1,1-difluoroethyl)-4-methoxypyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.

[0653] Aspect 25 is a compound of formula I according to any of aspects 1-24, or a pharmaceutically acceptable salt thereof, that is selected from the group consisting of

[0654] N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-1-piperidyl]methyl]-3-hydroxy-azetidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,

[0655] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-1-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.

[0656] N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0657] N-(5-(4-((4-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0658] N-(5-(4-((4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0659] N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-4-[[6-(3-methoxyoxetan-3-yl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0660] N-(4'-((6-(2,2-difluorocyclopropyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0661] N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperazine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide and

[0662] N-(4'-((2-(l,l-difluoroethyl)-5-fluoropyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.

[0663] Aspect 27 is a compound of formula I according to any of aspects 1-25. or a pharmaceutically acceptable salt thereof, that is N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide.

[0664] Aspect 28 is a process for the preparation of a compound according to any one of aspects 1-27 or a pharmaceutically acceptable salt thereof comprising reacting a compound of formula (A) with a compound of formula (C) to a compound of formula (I')

[0665]

[0666] wherein X₁ is H or C₁₋₃alkyl.

[0667] Aspect 29 is a compound of formula I according to aspects 1-27, or a pharmaceutically acceptable salt thereof, when manufactured according to a process of aspect 28.

[0668] Aspect 30 is a pharmaceutical composition comprising a compound in accordance with any one of aspects 1-29 and a pharmaceutically acceptable excipient.

[0669] Aspect 31 is a compound or pharmaceutically acceptable salt according to any one of aspects 1-29 for use as therapeutically active substance.

[0670] Aspect 32 is the use of a compound according to any one of aspects 1-29 as therapeutically active substance for the therapeutic and / or prophylactic treatment of autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinfl ammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory’ bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary’ syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease,Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis. Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

[0671] Aspect 33 is the use of a compound according to any one of aspects 1-29 as therapeutically active substance for the therapeutic and / or prophylactic treatment of inflammatory bowel disease.

[0672] Aspect 34 is a compound of formula I according to aspects 1-29 for the use as therapeutically active substance for the therapeutic and / or prophylactic treatment of autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus ery thematosus, systemic lupus erythematosus, lupus nephntis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinfl ammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory’ bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary’ syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury’, glutamate neurotoxicity7and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

[0673] Aspect 35 is a compound of formula I according to aspects 1-29 for the use as therapeutically active substance for the therapeutic and / or prophylactic treatment of inflammatory7bowel disease.

[0674] Aspect 36 is a method of preventing or treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is an autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinfl ammatory7syndromes (PRAAS), ISG15 deficiency, and inflammatory’ bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, andneurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease and wherein the method comprises administering a therapeutically effective amount of a compound according to any one of aspects 1-29 or a pharmaceutically acceptable salt thereof, to the subject.

[0675] Furthermore, the invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and / or tautomers as well as their solvates of the compounds of formula I.

[0676] The compounds of formula I may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology- disclosed herein. Their absolute stereochemistry- may be determined by x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well know n in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

[0677] In the embodiments, where optically pure enantiomers are provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound. Chirally pure or chirally’ enriched compounds may' be prepared by chirally selective synthesis or by' separation of enantiomers. The separation of enantiomers may- be carried out on the final product or alternatively on a suitable intermediate.

[0678] The compounds of formula I may be prepared in accordance with the following schemes. The starting material may be prepared in accordance with known methods. Any previously defined residues and variables will continue to have the previously defined meaning unless otherwise indicated.

[0679]

[0680] Synthesis of 4-chloro-2-(l,l-difluoroethyl)pyrimidine

[0681] t-BuOK, BnOH 1. Pd(PPh3)2Cl2, DMF DAST DMF / THF 2. HCl, Acetone / H2O DCM Step-1 Step-2 / 3 Step-4

[0682] OBn 2

[0683] TFA POCI3Step-5 Step-6

[0684]

[0685] Step-1:

[0686] A 500 mL three-neck round-bottom flask containing a well-stirred solution of potassium tert-butoxide (1 M, 67.12 mL) and benzyl alcohol (14.52 g, 134.25 mmol, 13.89 mL) in THF (50 mL) was heated under reflux temperature for 30 minutes. The reaction mixture was cooled to 0 °C and added dropwise to 2,4-dichloropyrimidine (1, 10 g, 67.12 mmol) in DMF (50 mL), while maintaining the temperature below -78 °C. After stirring for one hour, the reaction mixture was warmed up to room temperature and stirred for 16 h. The reaction mixture was then diluted with water (150 mL) under cooling and then extracted with DCM (250 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude was purified by column chromatography (EtOAc in pet ether, 0% to 10%) to afford 4-benzyloxy-2-chloro-pyrimidine (2, 13 g, 57.15 mmol, 85% yield) as an off-white solid. LC-MS (ES+): m / z 221.1 [M + H]+.

[0687] Step-2 and Step-3:

[0688] To a stirred solution of 4-benzyloxy-2-chloro-pyrimidine (2, 10 g, 43.96 mmol) in DMF (100 mL) were added tributyl (1 -ethoxy vinyl)stannane (3, 15.88 g, 43.96 mmol, 14.85 mL) and bis(triphenylphosphine)palladium (II) di chloride (1.54 g, 2.20 mmol) and the reaction mixture was heated at 100 °C for 3 h and then stirred at room temperature for 16 h. The reaction mixture was quenched with aqueous KF solution (50 mL) and extracted with EtOAc (2 x 250 mL). The separated organic layers were washed with water (150 mL), brine (150 mL), dried over NaiSOr and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica gel) using a gradient of EtOAc in petroleum ether (0-30%) to afford (4-(benzyloxy)-2-(l -ethoxy vinyl)pyrimi dine (3a, 7 g) as a pale yellow semi-solid. The compound 3a was dissolved in acetone (30 mL), water (30 mL) and acidified with 4 M HCI in 1,4-dioxane (109.90 mL), stirred at room temperature for 1 h, and extracted with EtOAc (2 x 250mL). The separated organic layers were washed with water (150 mL), brine (150 mL), dried over Na2SO4, and concentrated under reduced pressure to afford l-(4-benzyloxypyrimi din-2 - yl)ethanone (4, 6 g, 17.09 mmol, 39% yield) as a pale yellow semi-solid, which was used without further purification. LC-MS (ES+): m'z 229.0 [M + H]+.

[0689] Step-4:

[0690] To a 250 mL single-neck round-bottom flask containing a well-stirred solution of l-(4- benzyloxypyrimidin-2-yl)ethanone (4, 6 g, 17.09 mmol) in DCM (50 mL) was added N-ethyl-N-(trifluoro-sulfanyl)ethanamine (4.13 g, 25.63 mmol, 3.39 mL) and the reaction was stirred at 25 °C for 3 h. The mixture was quenched with aq. NaHCCL (100 mL) and extracted with DCM (100 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over NazSOr and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc in pet ether) to give 4-benzyloxy-2-(l,l- difluoroethyl)pyrimidine (5, 2.5 g, 9.40 mmol, 55% yield) as a yellow oil. LC-MS (ES+): m / z 251.2 [M + H]+.

[0691] Step-5:

[0692] In a 50 mL single-neck round-bottom flask, a solution of 4-benzyloxy-2-(l,l-difluoroethyl) pyrimidine (5, 2.5 g, 9.40 mmol) in TFA (10.72 g, 94.04 mmol, 7.20 mL) was stirred at 100 °C for 16 h. The reaction mixture was monitored by LCMS. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure and the resulting crude was triturated with MTBE (10 mL) and dried under reduced pressure to give 2- (1,1 -difl uoroethyl)pyrimidin-4-ol (6, 1.6 g, 9.29 mmol, 99% yield) as a brown solid, which was used without further purification. UP LC-MS (ES‘): m z 159.0 [M - H]

[0693] Step-6:

[0694] In a 100 mL single-neck round-bottom flask, a solution of 2-(1,1-difluoroethyl)pyrimidin-4-ol (6, 1.6 g, 9.29 mmol) in phosphorus oxychloride (28.50 g, 185.86 mmol, 17.32 mL) was stirred at 100 °C for 3 h. Then the mixture was evaporated to dryness. The resulting residue was diluted with DCM (50 mL), added slowly into water, and then extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude was purified by column chromatography using a gradient of 0% to 30% EtOAc in pet ether to give 4-chloro-2-(l,l-difluoroethyl)pyrimidine (7, 1.3 g, 6.12 mmol, 66% yield) as a yellow liquid. LC-MS (ES+): m / z 179.1 [M + H]+.

[0695] The following building block was prepared using the method described above, with the corresponding chloride in Step-1.

[0696] Chloride in Step-1 Building block Analytical Data

[0697]

[0698]

[0699] Synthesis of 2-(2-oxabicyclo[2.1.1]hexan-l-yl)-4-chloro-6-methylpyrimidine

[0700]

[0701] Step-1:

[0702] To a solution of 2-oxabicyclo[2.1.1]hexane-l-carboxylic acid (1, 2.2 g, 17.17 mmol) in DCM (30 mL) was added DMF (0.13 rnL, 1.72 mmol) and oxalyl chloride (1.76 mL, 20.6 mmol) under a N2 atmosphere. The resulting reaction mixture was stirred at 20°C for 1 h. Then the reaction mixture was concentrated in vacuo to afford the crude residue. The crude residue was dissolved in DCM (20 mL) and cooled to 0°C. then NH₃ / MeOH (26.4 mL, 184.8 mmol) was slowly added into the mixture, and the resulting reaction was stirred at 0°C for 2 h. The reaction mixture was filtered, and the filter cake was washed with MeOH (2 mL). The filtrate was concentrated in vacuo to afford a residue, which was triturated with MeCN (2 mL) to afford 2- oxabicyclo[2.1.1]hexane-l-carboxamide (2, 2.18 g, 17.15 mmol, 99.86% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.30 - 7.13 (m, 2H), 3.16 (s, 2H), 2.88 (t, J = 2.8 Hz, 1H), 2.04 - 1.99 (m, 2H), 1.50 - 1.47 (m, 2H) ppm.

[0703] Step-2:

[0704] To a solution of 2-oxabicyclo[2.1.1]hexane-l-carboxamide (2, 2.18 g, 17.15 mmol) in DCM (20 mL) was added trimethyloxonium tetrafluoroborate (7608.4 mg, 51.44 mmol), and the resulting reaction mixture was stirred at 20°C for 12 h. The reaction mixture was poured into a saturated sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to afford methyl 2-oxabicyclo[2.1.1]hexane-1-carbimidate (3, 2.4 g, 17.0 mmol, 99.15% yield) as a yellow oil, which was used without further purification.1H NMR (400 MHz, DMSO-d6) δ 3.75 - 3.74 (m, 2H), 3.69 - 3.61 (m, 3H), 2.94 - 2.88 (m, 1H), 2.05 - 2.00 (m, 2H), 1.53 - 1.46 (m, 2H) ppm. Step-3:

[0705] A solution of methyl 2-oxabicyclo[2.1.1]hexane-1-carbimidate (3, 2.4 g, 17.0 mmol) in NH₃ / MeOH (20.0 mL, 140.0 mmol) was stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to afford 2-oxabicyclo[2.1.1]hexane-1-carboximidamide (4, 2140.0 mg, 16.96 mmol, 99.78% yield) as an off-white gum, which was used without further purification. Step-4:

[0706] To a solution of 2-oxabicyclo[2.1.1]hexane-l-carboximidamide (4, 2.14 g, 16.96 mmol) in methanol (20 mL) was added sodium methoxide (1832.77 mg, 33.93 mmol) and methyl acetoacetate (5, 1969.7 mg, 16.96 mmol). The resulting reaction mixture was stirred at 20 °C for 12 h. Then H2O (10 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were concentrated in vacuo to afford the crude residue, which was purified by reversed phase column chromatography (CombiFlash; Column: Phenomenex Synergi C18 150 mm x 25 mm x 10 pm; Mobile Phase: A: water modified with 0.1% FA, B: MeCN; Gradient: B%: 12%-30% over 20 min) to afford 2-(2-oxabicyclo[2. l.l]hexan-l-yl)-6-methylpyrimidin-4(3H)-one (6, 1120.0 mg, 5.83 mmol, 34.35% yield) as a white solid. LC-MS (ES+): m / z 193.1 [M + H]+.1H NMR (400 MHz, METHANOL-d4) δ 6.18 (s, 1H), 3.95 (s, 2H), 3.04 (t, J = 3.2 Hz, 1H), 2.36 - 2.31 (m, 2H), 2.29 (s, 3H), 1.83 - 1.76 (m, 2H) ppm.

[0707] Step-5:

[0708] To a solution of 2-(2-oxabicyclo[2.1.1]hexan-l-yl)-6-methylpyrimidin-4(3H)-one (6, 1000 mg, 5.2 mmol) in DCM (15 mL) was added dimethylformamide (0.04 mL, 0.52 mmol) and phosphorus oxychloride (1.94 mL. 20.81 mmol). The resulting reaction mixture was stirred at 20 °C for 1 h. Then the reaction mixture was poured into a saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed by brine (20 mL x 3). dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo to afford 2-(2-oxabicyclo[2.1.1]hexan-l-yl)-4-chloro-6-methylpyrimidine (7, 1030.0 mg, 4.89 mmol, 93.04% yield) as an orange solid, which was used without further purification. LC-MS (ES+): m / z 210.9 [M + H]+.Synthesis of 2-(6-bromo-4-methyl-2-pyridyl)propan-2-ol and 2-bromo-6-(l-methoxy-l-methyl-ethyl)-4-methyl-pyridine

[0709]

[0710] O -i 2 3 Step-1:

[0711] To a 100 mL single-neck round-bottom flask containing a well stirred solution of 1 -(6-bromo-4-methyl-2-pyridyl)ethanone (1, 1.5 g, 6.94 mmol) in THF (20 mL) was added methylmagnesium bromide, 3 M in ether (6.94 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. After completion of the reaction, the reaction mixture was quenched wi th saturated NH4CI solution and the aqueous layer was extracted with EtOAc (3 x 60 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel) using a gradient of 20% EtOAc in pet ether to afford 2-(6-bromo-4-methyl-2-pyridyl)propan-2-ol (2, 900 mg, 3.46 mmol, 33.83% yield) as a light brown liquid. LC-MS (ES+): m / z 230.1 [M + H]+.

[0712] Step-2:

[0713] To a 100 mL single-neck round-bottom flask containing a well stirred solution of 2-(6-bromo-4-methyl-2-pyridyl)propan-2-ol (2, 900 mg, 2.35 mmol) in THF (10 mL) was added sodium hydride (60% dispersion in mineral oil) (140.79 mg, 3.52 mmol) at 0 °C. The mixture was stirred at room temperature for 15 minutes, then cooled to 0 °C, before iodomethane (499.65 mg, 3.52 mmol, 219.14 pL) in THF (2 mL) was added. The reaction mixture was then stirred at room temperature for 3 h. Upon completion of the reaction, the reaction mixture w as quenched with cold water and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SOr, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary' Phase: 230-400 mesh silica gel) using a gradient of 10% EtOAc in pet ether to afford of 2-bromo-6-(l-methoxy-l-methyl-ethyl)-4-methyl-pyridine (3, 500 mg, 1.62 mmol, 69.11% yield) as a light brown liquid. LC-MS (ES+): m / z 244.1 [M + H]+.

[0714] Synthesis of 2-bromo-6-(l,l-difluoroethyl)-4-methyl-pyridine

[0715]

[0716] To a 250 mL single-neck round-bottom flask containing a well stirred solution of 1 -(6-bromo-4-methyl-2-pyridyl)ethanone (1, 2 g, 9.24 mmol) in 1,2-DCE (70 mL) was added N-ethyl-N-(trifluoro-sulfanyl)ethanamine (7.44 g, 46.18 mmol, 6.10 mL) at 0 °C. The resulting reaction mixture was stirred at 55 °C for 24 h. The reaction mixture was cooled and neutralised with a 10% aqueous NaOH solution. Aqueous layer was extracted with EtOAc (3 X 200 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to get crude compound. This reaction crude was punfied by flash silica gel (Stationary Phase: 230-400 mesh) column chromatography (5% EtOAc in pet ether) to afford 2-bromo-6-(l,l-difluoroethyl)-4-methyl-pyridine (2, 1 g, 3.76 mmol, 40.67% yield) as a light brown color syrupy liquid. LC-MS (ES+): m / z 238.1 [M+ H]+.

[0717] Synthesis of 2-chloro-6-(l,l-difluoroethyl)-4-methyl-pyridine

[0718]

[0719] To a 500 mL single-neck round-bottom flask containing a well stirred solution of l-(6-chloro-4-methyl-2-pyridyl)ethanone (1, 10 g, 58.96 mmol) in 1,2-DCE (100 mL) was added A-ethyl-TV-(trifluoro-sulfanyl)ethanamine (47.52 g, 294.80 mmol, 38.95 mL) at 0 °C. The resulting reaction mixture was stirred at 55 °C for 16 h. After completion of the reaction indicated by TLC, the reaction mixture was cooled and neutralized with 10% aqueous NaOH solution. Aqueous layer was extracted with Ethyl acetate (3 *100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (Stationary Phase: 230-400 mesh silica gel, 50 g snap cartridge; Eluent: 0-5% ethyl acetate in petroleum ether, flow rate = 20 rnL / min) to afford 2-chloro-6-(l,l-difluoroethyl)-4-methyl-pyridine (2, 4 g, 20.06 mmol, 34.02% yield) as a light-yellow liquid. LC-MS (ES+): m / z 192.2 [M + H]+

[0720] Synthesis of 2-bromo-6-(l,l-difluoropropyl)-4-methyl-pyridine

[0721]

[0722] Step-1:

[0723] To a 25 mL two neck round-bottom flask containing well stirred solution of 2,6-dibromo-4-methyl -pyridine (1, 1 g, 3.99 mmol) in DCM (10 mL) was added n-butyl lithium (2.5 M, 1.59 mL) at -78 °C. The resulting reaction mixture was stirred at the same temperature for 30 minutes.Then A-methoxy-A-methyl-propanamide (2, 466.87 mg, 3.99 mmol) in DCM (1 mL) was added at -78 °C and the reaction mixture was stirred at this temperature for 3 h before slowly warmed up to room temperature and quenched with saturated ammonium chloride solution. Aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, fdtered and the fdtrate was concentrated under reduced pressure. The crude material was purified by flash silica gel (Stationary’ Phase: 230-400 mesh) column chromatography (15 to 20% DCM in Pet ether) to afford of l-(6-bromo-4-methyl -2-pyridyl)propan-l-one (3, 0.3 g, 1.24 mmol, 31.02% yield) as a white solid. LC-MS (ES+): m / z 228.0 [M + H]+

[0724] Step-2:

[0725] To a 50 mL two neck round-bottom flask containing well stirred solution of 1 -(6-bromo-4-methyl-2-pyridyl)propan-l-one (3, 300 mg, 1.24 mmol) in 1,2-DCE (5.05 mL) was added N-ethyl-A-(trifluoro-sulfanyl)ethanamine (1.22 g, 7.57 mmol, 1 mL) at room temperature. The resulting reaction mixture was stirred at 45 °C for 24 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was added to a cold NaHCO3solution. The reaction mixture was passed through a Celite pad. The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash silica gel (Stationary' Phase: 230-400 mesh) column chromatography (15 to 20% DCM in pet ether) to afford 2-bromo-6-( 1,1 -difluoropropyl)-4-methyl-pyri dine (4. 120 mg, 355.08 pmol, 28.72% yield) as a colorless syrupy liquid. LC-MS (ES+): m / z 249.9 [M + H]+

[0726] Synthesis of 2-chloro-4-methyl-6-(methylsulfonyl)pyridine

[0727]

[0728] 1 2 3

[0729] Step-1:

[0730] To a solution of 2,6-dichloro-4-methylpyridine (1, 5.0 g, 30.86 mmol) in DMF (50 mL) was added sodium methanethiolate (2.16 g, 30.86 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. Then the reaction mixture was concentrated to afford the crude residue, which was purified on normal phase column chromatography (Stationary Phase: Silica Gel; Eluent: Gradient from 10 / 1 to 5 / 1 Petroleum / EtOAc) to afford 2-chloro-4-methyl-6-(methylthio)pyridine (2, 4.0 g, 23.03 mmol, 74.63% yield) as a colorless liquid. LC-MS (ES+): m / z 173.9 [M+ H]+.

[0731]

[0732] NMR (400 MHz, CHLOROFORM-d): 8 6.90 (s, 1H), 6.83 (s, 1H), 2.54 (s, 3H), 2.27 (s, 3H) ppm.Step-2:

[0733] To a solution of 2-chloro-4-methyl-6-(methylthio)pyridine (2, 1.9 g, 10.94 mmol) in DCM (30 mL) was added 3-chlorobenzenecarboperoxoic acid (5.55 g, 27.35 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 2 h, then quenched by the addition of saturated NajSO? aqueous solution (50 mL) at 0 °C under a N2 atmosphere. The resulting reaction mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to afford the crude residue, which was purified by Prep-HPLC (Column: Phenomenex luna C18 (150 x 40 mm) x 15 um; Mobile Phase: [A: H2O modified with 0.225% Formic Acid; B: MeCN]; Gradient: B%: 20.00% -50.00% over 15.00 min; flow rate: 60.00 mL / min) and lyophilized to afford 2-chloro-4-methyl-6-(methylsulfonyl)pyridine (3. 1200.0 mg, 5.83 mmol, 53.33% yield) as an off-white solid. LC-MS (ES+): m / z 205.9 [M+ H]+. 'H NMR (400 MHz, CHLOROFORM-d): 8 7.83 (s, 1H), 7.39 (s, 1H), 3.23 (s, 3H), 2.48 (s, 3H) ppm.

[0734] Synthesis of 2-chloro-4-(cyclopropoxy)-6-(l,l-difluoroethyl)pyridine

[0735]

[0736] Step-1:

[0737] To a 500 mL multi neck round-bottom flask containing well stirred solution of l-(4,6-dichloro-2-pyridyl)ethanone (1, 3.8 g, 19.90 mmol) in DCM (50 mL) was added, V-ethyl-A-(trif1uoro-sulfanyl)ethanamine (32.07 g, 198.97 mmol, 26.29 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled, quenched with sodium bicarbonate solution and extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. This crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 3% EtOAc in pet ether) to afford 2, 4-dichloro-6-(l,l -difluoroethyl)pyridine (2, 1.7 g, 7.86 mmol. 39.48% yield) as a light-yellow liquid. GC-MS: m / z 211 [M]

[0738] Step-2:

[0739] To a 25 mL single-neck round-bottom flask containing a well stirred solution of cyclopropanol (300 mg, 5.17 mmol) in DMF (7 mL) was added 60 % sodium hydride (309.89 mg, 7.75 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 15 minutes. Then 2,4-dichloro-6-(l,l-difluoroethyl)pyridine (2, 495.72 mg, 2.22 mmol) in DMF (1 mL) was added at0 °C. The resulting reaction mixture was stirred at room temperature for 5 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with aqueous NH4CI solution and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SOr, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary' Phase: 230-400 mesh silica gel, Eluent: 4-6 % EtOAc in pet ether) to afford 2-chloro-4-(cyclopropoxy)-6-(l,l-difluoroethyl)pyridine (3, 450 mg, 1.64 mmol, 31.69% yield) as a colorless syrupy liquid. LC-MS (ES+): m / z 234.1 [M + H]+.

[0740] Synthesis 2-bromo-6-[(3 / ?)-3-methoxytetrahydrofiiian-3-yl|-4-methyl-pyiidine and 2-bromo-6-[(35)-3-methoxytetrahydrofuran-3-yl]-4-methyl-pyridine

[0741]

[0742] Step-1:

[0743] In a 500 mL three-neck round-bottom flask, a well-stirred solution of 2,6-dibromo-4-methyl-pyridine (1, 10 g, 39.85 mmol) in DCM (100 mL) was cooled to -78°C before w-BuLi in hexane (2.5 M, 15.94 mL) was added dropwise. The reaction was stirred at this temperature for about 15 min, then tetrahydrofuran-3-one (2, 3.43 g. 39.85 mmol) was added in one portion. The reaction was then stirred for 40 min at -78 °C. Upon completion of the reaction, the reaction mixture was poured into a mixture of saturated aqueous NH4CI (110 mL) and DCM (80 mL) and stirred for about 30 min. The separated organics were dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (Stationary Phase: silica gel; Eluent: 0-50% EtOAc in hexane) to afford 3-(6-bromo-4-methyl-2-pyridyl)tetrahydrofuran-3-ol (3, 11 g, 30.68 mmol, 76.99% yield) as a brown solid. LC-MS (ES+): m / z 260.0 [M + H]+.

[0744] Step-2:

[0745] To a 500 mL two-neck round-bottom flask containing a well-stirred solution of 3-(6-bromo-4-methyl-2-pyridyl)tetrahydrofuran-3-ol (3, 11 g, 30.68 mmol) in THF (100 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil) (3.07 g, 76.71 mmol) and then lodomethane (6.53 g, 46.03 mmol, 2.87 mL). The resulting mixture was stirred at 25 °C for16 h under N2 atmosphere. The reaction was quenched with saturated aq. NH4CI (100 mL). and the resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over Na₂SO₄. filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography (Eluent: 0-20% ethyl acetate in petroleum ether) to yield 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-pyridine (4, 8 g, 28.73 mmol, 93.62% yield) as a colorless liquid. LC-MS (ES+): m / z 272.0 [M + H]+.

[0746] Step-3:

[0747] The enantiomeric mixture of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-pyridine (4, 8 g, 27.52 mmol) was separated by SFC [Column Name: YMC Cellulose-SC, Flowrate: 3 mL / min, Co-Solvent: 10%, Co-Solvent Name: 0.5% Isopropylamine in IP A, Injected Volume: 2 pL, Temperature: 35 °C, Outlet Pressure: 100 bar].

[0748] The early-eluting isomer 2-bromo-6-[(37?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-pyridine (5, 3 g, 10.25 mmol, 37.25% yield) was obtained as a white solid. UPLC-MS (ES+): m / z 272.1 [M + H]+. SFC RT = 3.17 min. [α]25.0= + 2.40, c = 1, CH₃OH (Literature value [α]25.0= + 5.6, c = 0.2, CH₃OH).

[0749] The late-eluting isomer 2-bromo-6-[(3V)-3-methoxytetrahydrofuran-3-yl]-4-methyl-pyridine (6, 3.5 g, 12.26 mmol, 44.56% yield) was obtained as a white solid. LCMS (ES+): m / z 272.1 [M + H]+. SFC RT = 4.09 min. [α]25.0= - 2.60, c = 1, CH₃OH (Literature value [α]25.0= - 3.5, c = 0.2, CH₃OH).

[0750] Note: Stereocenters are assigned by matching the SOR values in literature (W020221095804). According to literature, first fraction was R and second fraction was S.

[0751] Synthesis of 2-bromo-6-[(3 / ?)-3-fhiorotetiahydrofuran-3-yl|-4-methyl-pyridine and 2-bromo-6-[(35)-3-fluorotetrahydrofuran-3-yl]-4-methyl-pyridine

[0752]

[0753] To a 0 °C solution of 3-(6-bromo-4-methyl-2-pyridyl)tetrahydrofuran-3-ol (900 mg, 3.22 mmol) in DCM (14.97 mL) was added V-ethyl-A-(trifluoro-sulfanyl)ethanamine (1.04 g, 6.44 mmol, 850.44 pL) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with DCM (100 mL). The organic layer was washed with NaHCO? solution, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude residue was purified by flash column chromatography (Stationary Phase: 230-400mesh silica gel; Eluent: 5% ethyl acetate in petroleum ether) to afford 2-bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-methylpyridine (900 mg, 3.22 mmol) as an off-white solid.

[0754] The enantiomeric mixture was separated by chiral SFC [Column: Chiralpak IG, Flow rate: 3 rnL / min, Co-Solvent: 10%, Co-Solvent Name: 0.5% Isopropylamine in Methanol] to afford 2-bromo-6-[(37?)-3-fluorotetrahydrofuran-3-yl]-4-methyl-pyridine (2a, early-eluting peak arbitrarily assigned as 7?-isomer, 360 mg, 1.32 mmol, 41% yield) and 2-bromo-6-[(3S)-3-fluorotetrahydrofuran-3-yl]-4-methyl-pyridine (2b, late-eluting peak arbitrarily assigned as 5-isomer 170 mg, 607.51 pmol, 19% yield). LC-MS (ES+): m / z 261.3 [M +2 + H]+Synthesis of 2-bromo-6-[(3»y)-3-methoxytetrahydrofuran-3-yl] pyridine and 2-bromo-6- [(3 / ?)-3-methoxytetrahydrofiiran-3-yl|pyridine

[0755]

[0756] Step-1:

[0757] To a 500 mL three-neck round-bottom flask containing a well-stirred solution of 2,6-dibromopyridine (1, 5 g, 21.11 mmol) in DCM (50 mL) was added 2.5 M / r-BuLi in hexane (21.11 mmol, 8.44 mL) dropwise at -78 °C. The reaction was stirred at this temperature for about 15 min, then tetrahydrofuran-3 -one (2, 1.82 g, 21.11 mmol) was added and the reaction was stirred -78 °C for 4 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with saturated NFLCl solution (110 mL) and extracted with DCM (80 mL). The organic layer was separated, washed with saturated NaCl solution (40 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to yield the crude product. This crude was purified by column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 0-50% ethyl acetate in petroleum ether) to afford the 3-(6-bromo-2-pyridyl)tetrahydrofuran-3-ol (3, 2.2 g, 8.58 mmol, 41% yield) as a brown solid. LCMS (ES+): m / z 245.9 [M + H]+as bromo isotopic mass.

[0758] Step-2:

[0759] To a 250 mL two-neck round-bottom flask containing a well-stirred solution of 3-(6-bromo-2-pyridyl)tetrahydrofuran-3-ol (3, 2.2 g, 8.58 mmol) in THF (30 mL) at 0 °C were added 60 % sodium hydride (857.71 mg, 21.44 mmol) and iodomethane (12.87 mmol, 801.01 pL). The resulting mixture w as stirred at room temperature for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with saturated aq. NH4CI (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried overNa2SO4, filtered, and the filtrate concentrated under reduced pressure. The crude material was purified by column chromatography (Stationary Phase: 60-120 mesh silica gel: Eluent: 20% ethyl acetate in petroleum ether) to afford 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridine (4, 1.5 g, 5.56 mmol, 65% yield) as a colorless liquid. LCMS (ES+): m z 259.1 [M + H]+as bromo isotopic mass.

[0760] Step-3:

[0761] The enantiomeric mixture of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridine (4, 1.5 g, 5.56 mmol) was separated by SFC [Column Name: Chiralpak IG (250 x 30) mm, flowrate: 3 mL / min, Co-Solvent: 10%, Co-Solvent Name: 0.1% Formic acid in MeOH, injected Volume: 15 pL, Temperature: 35 °C, Outlet Pressure: 100 bar] to afford 2-bromo-6-[(3S)-3-methoxytetrahydrofuran-3-yl]pyridine (5a, early-eluting peak. 500 mg, 1.76 mmol. 32% yield) as a white solid and 2-bromo-6-[(37?)-3-methoxytetrahydrofuran-3-yl]pyridine (5b, late-eluting peak, 600 mg, 2.26 mmol, 41% yield) as a white solid.

[0762] Early-eluting peak: LCMS (ES+): m / z 258.0 [M + H]+. SFC Rt = 4.08 min. [α]25.0= - 3.60, c = 0.5, CH3OH

[0763] Late-eluting peak: LCMS (ES+): m / z 258.0 [M + HJ+. SFC Rt = 4.74 mm. [α]25.0= + 2.40, c = 0.5, CH₃OH.

[0764] Note: Stereocenters are assigned by matching the SFC retention time with those values in the literature (US105081135). According to literature values, first fraction was S and second fraction was R.

[0765] Synthesis of 2-bromo-6-(3-methoxyoxetan-3-yl)-4-methyl-pyridine

[0766]

[0767] Step-1:

[0768] To a 250 mL three-neck round-bottom flask containing a well-stirred solution of 2,6-dibromo-4-methyl-pyridine (1, 2 g, 7.97 mmol) in DCM (30 mL) cooled to -78°C was added nBuLi (2.5 M, 3.67 mL) dropwise (internal temperature maintained below -74 °C). The reaction was stirred at this temperature for 15 min before oxetan-3-one (2, 689.27 mg, 9.56 mmol, 613.23 LIL) was added in one portion. The reaction was stirred for 30 min at -78 °C. Upon completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4CI (150 mL) and DCM (500 mL) and stirred for 5 min. The combined organic layers were washed with water, brine, dried over anhydrous Na₂SO₄. filtered and the filtrate was concentrated underreduced pressure. The crude was purified by flash column chromatography (Stationary' Phase: 230-400 mesh silica gel; Eluent: 20% EtOAc in pet ether) to afford 3-(6-bromo-4-methyl-2-pyridyl)oxetan-3-ol (3, 1.82 g, 7.29 mmol, 91.50% yield) as a white solid. LC-MS (ES‘): m / z 243.9 [M - H]-.

[0769] Step-2:

[0770] To a 250 mL two-neck round-bottom flask containing a well-stirred solution of 3-(6-bromo-4-methyl-2-pyridyl)oxetan-3-ol (3. 1.8 g, 7.15 mmol) in THF (30 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil) (715.33 mg, 17.88 mmol) and then iodomethane (1.52 g, 10.73 mmol, 667.97 pL). The resulting mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction was then quenched with saturated aq. NH4CI (100 mL) at 0°C, and the resulting mixture was extracted with ethyl acetate (2 x 250 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography (Eluent: 0-20% ethyl acetate in petroleum ether) to yield 2-bromo-6-(3-methoxyoxetan-3-yl)-4-methyl-pyridine (4, 1.82 g, 6.76 mmol, 94.46% yield) as an off white solid. LC-MS (ESI): m / z 258.1 [M + H]+.

[0771] Synthesis of 2-chloro-4-cyclopropyl-6-(l,l-difluoroethyl)pyridine

[0772]

[0773] Step-1:

[0774] To a 100 mL single-neck round-bottom flask containing a well-stirred solution of4-bromo-6-chloro-pyridine-2-carboxylic acid (1, 2 g, 8.46 mmol) and A-methoxymethanamine hydrochloride (2, 907.57 mg, 9.30 mmol) in DMF (5 mL) were added HATU (4.82 g, 12.69 mmol) and DIPEA (25.38 mmol, 4.42 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 6 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with water, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filteredand the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 20 to 25% Ethyl acetate in Petroleum ether) to afford 4-bromo-6-chloro-A-methoxy-A-methyl-pyridine-2-carboxamide (3, 1.5 g, 4.94 mmol, 58% yield) as a yellow liquid. LC-MS (ES+): m / z 281.2 [M +2+ H]+.

[0775] Step-2:

[0776] To a 100 mL two-neck round-bottom flask containing a well-stirred solution of4-bromo-6-chloro-A-methoxy-A^-methyl-pyridine-2-carboxamide (3, 1.5 g, 4.94 mmol) in THF (15 mL) was added a 2 M solution of bromo(methyl)magnesium in THF (4.97 mL, 9.94 mmol) at 0 °C and the resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with saturated NH4CI solution and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SOr. filtered and the filtrate was concentrated under reduced pressure to afford l-(4-bromo-6-chloro-2-pyridyl)ethanone (4, 1.1 g, 4.67 mmol, 93% yield) as a palebrown liquid.

[0777] XH NMR (400 MHz, CDCh) 5: 8.21 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 2.71 (s, 3H).

[0778] Step-3:

[0779] To a 40 mL screw-cap vial containing a well-stirred solution of 1 -(4-bromo-6-chloro-2-pyridyl)ethanone (4, 950 mg, 4.03 mmol) and cyclopropylboronic acid (5, 363.59 mg, 4.23 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added potassium carbonate (1.67 g. 12.09 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 2 min. Then, bis(1-diphenylphosphanylcyclopenta-2,4-dien-1-yl)iron;dichloromethane;dichloropalladium (164.61 mg, 201.57 pmol) was added and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction as indicated by UPLC-MS. the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 10-15% Ethyl acetate in Petroleum ether) to afford l-(6-chloro-4-cyclopropyl-2-pyridyl)ethanone (6, 700 mg, 3.42 mmol, 84% yield) as a pale-yellow liquid. LC-MS (ES+): m / z 196.2 [M + H]+

[0780] Step-4:

[0781] To a 100 mL two-neck round-bottom flask containing a well-stirred solution of l-(6-chloro-4-cyclopropyl-2-pyridyl)ethanone (6, 700 mg, 3.42 mmol) in DCM (10.00 mL) was added A-ethyl-A-(trifluoro-sulfanyl)ethanamine (2.76 g, 17.11 mmol, 2.26 mL) dropwise at 0 °C. The resulting reaction mixture was stirred at 50 °C for 24 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was cooled, neutralized with saturated NaHCO3solution and theaqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 5 to 10% Ethyl acetate in Petroleum ether) to afford 2-chloro-4-cyclopropyl-6-(l,l-difluoroethyl)pyridine (7, 600 mg, 2.40 mmol) as a colorless liquid. LC-MS (ES+): m / z 218.1 [M + H]+.

[0782] Synthesis of 2-chloro-6-(l,l-difluoroethyl)-4-methoxy-pyridine

[0783]

[0784] Step-1:

[0785] To a 250 mL two-neck round-bottom flask containing a well stirred solution of l-(4,6-dichloro-2-pyridyl)ethanone (1. 13 g, 67.58 mmol) in DCM (150 mL) was added A-ethyl -A-(trifluoro-sulfanyl)ethanamine (54.46 g, 337.88 mmol, 44.64 mL) dropwise at 0 °C. The resulting reaction mixture was stirred at 25 °C for 24 h. The reaction mixture was then cooled and neutralized with saturated NaHCO3solution and the aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. This crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 5% EtOAc in pet ether) to afford 2, 4-dichloro-6-(l,l-difluoroethyl)pyridine (2, 9.7 g, 43.74 mmol, 64.73% yield) as a colorless oil. 'H NMR (400 MHz, CDCh) 57.61 (d. J = 1.6 Hz, 1H), 7.47 (d, J = 1.6 Hz. 1H), 2.06-1.97 (t, J / = 18.8, J2= 18.4 Hz, 3H).

[0786] Step-2:

[0787] To a 100 mL two-neck round-bottom flask containing well stirred solution of 2,4-dichloro-6-(1,1 -difluoroethyl)pyri dine (9.26 g, 41.74 mmol) in DMF (30 mL) was added sodium methoxide (2.37 g, 43.83 mmol) portionwise at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with brine (50 mL) solution and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford the crude compound. The crude was then purified with flash silica gel (230-400 mesh) column chromatography (Eluent: 5-10% EtOAc in pet ether) to afford 2-chloro-6-(l,l-difluoroethyl)-4-methoxy-pyridine (3, 5.65 g.26.67 mmol, 63.90% yield) as a colorless oil. 'H NMR (400 MHz, CDCh) 5 7.12 (d, J = 2 Hz. 1H), 6.90 (s, 1H), 3.92 (s, 3H), 2.05-1.95 (1. J= 18.8 Hz, 3H).

[0788] Synthesis of 2-bromo-6-(l-fluorocyclobutyl)-4-methyl-pyridine

[0789] DAST DCM

[0790] Step-2

[0791]

[0792] Step-1:

[0793] To a 250 mL three-neck round-bottom flask containing a well-stirred solution of 2,6-dibromo-4-methyl-pyridine (1, 3 g, 11.96 mmol) in DCM (50 mL) was added 2.5 M n-BuLi (11.96 mmol, 4.78 mL) in hexane dropwise at -78 °C. The reaction was stirred at the same temperature for about 15 min, before cyclobutanone (2, 11.96 mmol, 893.39 pL) was added and the reaction mixture was stirred at -78 °C for 40 min. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with saturated aqueous NH4CI (50 mL) solution and extracted with DCM (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 30-35% Ethyl acetate in Petroleum ether) to afford l-(6-bromo-4-methyl-2-pyridyl)cyclobutanol (3, 2.5 g, 8.05 mmol, 67% yield) as a brown solid. UPLC-MS (ES+): m / z 242.0 [M + H]+.

[0794] Step-2:

[0795] To a 100 mL single-neck round-bottom flask containing a well stirred solution of 1 -(6-bromo-4-methyl-2-pyridyl)cyclobutanol (3, 2.5 g, 8.05 mmol) in DCM (30 mL) was added A-ethyl-A-(trifluoro-sulfanyl)ethanamine (8.05 mmol, 1.06 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with sodium bicarbonate solution (100 mL) and extracted with DCM (200 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4and filtered. The filtrate was concentrated under reduced pressure to afford the crude compound which was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 15-20% Ethyl acetate in Petroleum ether) to afford 2-bromo-6-(l-fluorocyclobutyl)-4-methyl-pyridine (4, 1.3 g, 4.69 mmol, 58% yield) as a yellow liquid. UPLC-MS (ES+): m / z 246.1 [M +2+ H]+

[0796] Synthesis of 2-chloro-6-(l-methoxycydopropyl)-4-methyl-pyridine

[0797]

[0798] Step-1:

[0799] To a 100 mL multi-neck round-bottom flask containing a well-stirred solution of l-(6-chloro-4-methyl-2-pyridyl)ethanone (1, 2 g, 11.67 mmol) in ACN (20.01 mL) were added Nal (7.00 g, 46.70 mmol, 1.91 mL), triethylamine (5.91 g, 58.37 mmol, 8.14 mL) and TBDMS-C1 (7.04 g, 46.70 mmol) at 0 °C. The resulting reaction mixture was heated at 80 °C for 5 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was treated with ice-cooled water (25 mL) and extracted with DCM (2 x 25 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh Silica gel; Eluent: 5-7 % of ethyl acetate in petroleum ether) to afford tert-butyl-[1-(6-chloro-4-methyl-2-pyridyl)vinyloxy]-dimethylsilane (2, 2 g, 6.70 mmol, 57% yield) as a colorless liquid. LC-MS (ES+): m / z 284.1[M + H]+. Step-2:

[0800] To a 250 mL multi-neck round-bottom flask containing a well-stirred solution of 1 M di ethylzinc (20.09 mL, 20.9 mmol) in DCM (20 mL) was added chloroiodo methane (7.09 g, 40.18 mmol, 2.93 mL) in DCM (5 mL) at 0 °C and the reaction mixture was stirred at this temperature for 1 h. Then, tert-butyl-[1-(6-chloro-4-methyl-2-pyridyl)vinyloxy]-dimethyl-silane (2, 2.0 g, 6.70 mmol) in DCM (2 mL) was added and the reaction mixture was stirred at 0 °C for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was treated with ice-cold ammonium chloride solution (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford tert-butyl-[1-(6-chloro-4-methyl-2-pyridyl)cyclopropoxy]-dimethyl-silane (3, 2 g, 1.48 mmol, 22% yield) as a colorless liquid. LC-MS (ES+): m / z 298.2 [M + H]+.

[0801] Step-3:To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl-[1-(6-chloro-4-methyl-2-pyridyl)cyclopropoxy]-dimethyl-silane (3, 1.5 g. 5.04 mmol) in DCM (10.00 mL) was added 4 M HC1 in 1,4-dioxane (6.29 mL, 25.16 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the crude residue was triturated with methyl tert-butyl ether to afford l-(6-chloro-4-methyl-2-pyridyl)cyclopropanol (4, 250 mg, 1.34 mmol, 27% yield) as an off-white solid. LC-MS (ES+): m / z 184.1 [M + H]+

[0802] Step-4:

[0803] To a 100 mL three-neck round-bottom flask containing a well-stirred solution of l-(6-chloro-4-methyl-2-pyridyl)cyclopropanol (4. 250 mg, 1.34 mmol) in anhydrous THF (10 mL) was added sodium hydride (133.98 mg, 3.35 mmol) at 0 °C and the reaction mixture was stirred at this temperature for 10 min. Then, iodomethane (2.01 mmol, 125.12 pL) was added dropwise at 0 °C and the reaction mixture w as stirred at room temperature for 4 h. After completion of the reaction as indicated by LC-MS, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-chloro-6-(l -methoxy cyclopropyl)-4-methyl-pyridine (5, 100 mg, 487.55 pmol, 36% yield) as a yellow- solid. LC-MS (ES+): m / z 198.2 [M + H]+

[0804] Synthesis of 2-chloro-6-(2,2-difluorocyclopropyl)-4-methyl-pyridine

[0805]

[0806] Step-1:

[0807] To a 100 mL single-neck round-bottom flask containing a w-ell-stirred solution of 2,6-dichloro-4-methyl-pyridine (1, 2.5 g, 15.43 mmol) and 2,4, 6-trivinylcyclotriboroxane pyridine complex (2, 1.6 g, 6.65 mmol) in 1,2-dimethoxy ethane (30 mL) was added 2 M aqueous K.2CO3 solution (10 mL, 20 mmol) at room temperature. Nitrogen gas was purged into the reaction for 2 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (356.62 mg, 308.61 pmol) was added and the reaction mixture was stirred at 80 °C for 3 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with ethyl acetate (100 mL). The organic layer waswashed with 5% aqueous citric acid solution (6 x 50 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 20 to 25% DCM in Petroleum ether) to afford 2-chloro-4-methyl-6-vinyl-pyridine (3, 1.1 g, 6.66 mmol, 43.16% yield) as a colorless liquid. LC-MS (ES+): m / z 154.1 [M + H]+

[0808] Step-2:

[0809] To a 100 mL sealed tube containing a well-stirred solution of 2-chloro-4-methyl-6-vinyl-pyridine (3, 1 g, 6.05 mmol) in acetonitrile (10 mL) were added sodium iodide (3.00 g, 20.01 mmol) and trimethyl(trifluoromethyl)silane (4, 516.54 mg, 3.63 mmol, 577.14 pL) at room temperature. The resulting reaction mixture was stirred at 110 °C for 5 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with brine (2 x 40 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 20 to 25% DCM in Petroleum ether) to afford 2-chloro-6-(2,2-difluorocyclopropyl)-4-methyl-pyridine (5, 0.7 g, 2.99 mmol, 49.40% yield) as a colorless liquid. LC-MS (ES+): m / z 204.1 [M + H]+.

[0810] Synthesis of 6-[6-acetamido-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-3-carboxylic acid (A-l)

[0811] (BOC)2O DMAP, Et3N DCM

[0812] Step-1 Pd(PPh3)4, Pd(dppf)CI2

[0813]

[0814] Trimethyl(tributylstannyl)silane 1,4-dioxane

[0815] Step-2

[0816] Cs2CO3, Xantphos, Pd2(dba)3

[0817]

[0818] 1,4-dioxane Step-3

[0819]

[0820] Step-1:

[0821] To 250 mL single-neck round-bottom flask containing a stirred solution of 5-bromo-2-chloro-pyridin-4-amine (1, 5 g, 24.10 mmol) in dichloromethane (100 mL) was added DMAP (235.56 mg. 1.93 mmol), and the reaction mixture was purged with N2 for 5 mins. Triethylamine (7.32 g, 72.30 mmol, 10.08 mL) and di- / ert-butyl dicarbonate (6.31 g, 28.92 mmol, 6.64 mL) were added to the reaction mixture slowly and the reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography (60-120 mesh silica gel) using a gradient of 0-100% ethyl acetate in petroleum ether to afford tert-butyl 7V-(5-bromo-2-chloro-4-pyridyl)carbamate (2, 4.5 g, 14.31 mmol, 59.37% yield) as an off-white solid. LC-MS (ES+): m / z 307.0 [M + H]+

[0822] Step-2:

[0823] To a 40 mL screw-cap vial containing a well-stirred solution of tert-butyl / V-(5-bromo-2-chloro-4-pyridyl)carbamate (2, 2 g, 6.36 mmol) in 1,4-dioxane (10 mL) was added methyl 6-bromopyridine-3-carboxylate (3, 1.51 g, 6.99 mmol) and the reaction mixture was purged with N2 for 5 mins. To the resulting mixture was added tetrakis(triphenylphosphine)palladium(0) (734.73 mg, 635.82 pmol), trimethyl(trimethylstannyl)stannane (3.12 g. 9.54 mmol) and bis(l-diphenylphosphanylcyclopenta-2,4-dien-l-yl)iron;dichloromethane;dichloropalladium (519.23 mg, 635.82 pmol). The resulting reaction mixture was stirred at 110 °C for 16 h. Then the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted withethyl acetate (2 x 50 mL). The combined organic phases were washed with brine solution (25 mL) and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (60-120 mesh silica gel) using a gradient of 0-100% ethyl acetate in petroleum ether to afford methyl 6-[4-(to7-butoxycarbonylamino)-6-chloro-3-pyridyl]pyridine-3-carboxylate (4. 250 mg, 331.78 pmol, 5.22% yield) as an off-white solid. LC-MS (ES+): m / z 364.1 [M + H]+

[0824] Step-3:

[0825] To a 20 mL screw-cap vial containing a well-stirred solution of methyl 6-[4-(tert-butoxycarbonylamino)-6-chloro-3-pyridyl]pyridine-3-carboxylate (4, 500 mg, 663.56 pmol) in 1.4-dioxane (10 mL) was added acetamide (5, 78.39 mg, 1.33 mmol), and the reaction mixture was purged with N2 for 5 min. To the resulting mixture were added Cesium carbonate (648.60 mg, 1.99 mmol) and Xantphos (76.79 mg, 132.71 pmol) and the reaction mixture was stirred at 110 °C for 16 h. Then the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by reverse phase column chromatography [Cl 8 RediSep® Rf Gold (120 g HP C18); Mobile phase A: 0.1% formic acid in MQ-water and B: acetonitrile; Flow rate: 10 mL / min] to afford methyl 6-[6-acetamido-4-(tert-butoxycarbonylamino)-3-pyridyl]pyridine-3-carboxylate (6, 300 mg, 612.11 pmol, 92.25% yield) as alight-yellow solid. LC-MS (ES‘): m / z 385.1 [M-H].

[0826] Step-4:

[0827] To an 8 mL screw-cap vial containing a well-stirred solution of methyl 6-[6-acetamido-4-(tert-butoxycarbonylamino)-3-pyridyl]pyridine-3-carboxylate (6, 300 mg, 612.11 pmol) in DCM (5 mL) was added TFA (348.96 mg, 3.06 mmol, 234.20 pL) and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated in vacuo to afford methyl 6-(6-acetamido- 4-amino-3-pyridyl)pyridine-3-carboxylate (7, 130 mg, 443.60 pmol, 72.47% yield) as a lightyellow solid, which was used without further purification. LC-MS (ES+): m / z 287.2 [M + H]+Step-5:

[0828] To a 20 mL screw cap vial containing a well-stirred solution of methyl 6-(6-acetamido-4-amino-3-pyridyl)pyridine-3-carboxylate (7. 60 mg. 163.47 pmol) and 2-bromo-6-(l -methoxy- 1-methyl-ethyl)-4-methyl-pyridine (8, 65.07 mg, 245.21 pmol) in 1,4-dioxane (4 mL) was added Cs2CO3(159.79 mg, 490.42 pmol) at room temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes, then Pd2(dba)3(14.97 mg, 16.35 pmol) and Xantphos (9.46 mg, 16.35 pmol) were added and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by reverse-phase Prep-HPLC [X-bridge C8(250x19) mm 5 microns, Mobile Phase A 10 mM aq NH4HCO3and Mobile Phase B MeCN] to afford methyl 6-[6-acetamido-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3- pyridyl]pyridine-3-carboxylate (9, 6 mg, 13.29 pmol, 8.13% yield) as an off-white solid.!H NMR (400 MHz, DMSO-6) 8 12.25 (s, 1H), 10.42 (s, 1H), 9.32 (dd, J= 2.3, 0.7 Hz, 1H), 9.24 (s, 1H), 8.79 (s, 1H), 8.39 (dd, J= 8.6, 2.3 Hz, 1H), 8.24 (d, J= 8.3 Hz, 1H), 6.97 (s, 1H), 6.91 (s, 1H), 3.94 (s, 3H), 3.13 (s, 3H), 2.33 (s, 3H), 2.11 (s, 3H), 1.51 (s, 6H) LC-MS (ES+): m / z 450.1 [M + H]+.

[0829] Step-6:

[0830] To a 100 mL single-neck round-bottom flask containing a well-stirred solution of methyl 6-[6- acetamido-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-3- carboxylate (9, 200 mg, 444.94 pmol) in THF (5 mL) and methanol (5 mL) was added a solution of lithium hydroxide monohydrate (186.68 mg, 4.45 mmol) in water (5 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The solvent was removed from the reaction mixture, and the resulting residue was acidified with an aqueous 1.5 N HC1 solution. The resulting off-white precipitate was filtered, and the filter cake was dried under reduced pressure to afford 6-[6-acetamido-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2- pyridyl]amino]-3-pyridyl]pyridine-3-carboxylic acid (A-l, 150 mg, 315.72 pmol, 70.96% yield) as an off-white solid, which was used without further purification. LC-MS (ES+): m / z 436.2 [M + H]+

[0831] The following targeting ligand was prepared using the method described above, with the corresponding building blocks in Step-5.

[0832] Bromide ester 8 in Step-5 Targeting ligand MS

[0833] CK. OH LC-MS (ES+): m / z 436.4 Br X NiL yo.x- [M + H]+.

[0834] O 30

[0835] 0

[0836] H 1

[0837] f l

[0838] A-2

[0839]

[0840] Table 2: Preparation of A-2Synthesis of methyl 6-(6-acetamido-4-amino-3-pyridyl)pyridine-3-carboxylate

[0841] (BOC)20 DMAP, Et3N DCM

[0842] Step-1 Pd(dppf)CI2’DCM 1 2 H KOAc, 1,4-dioxane

[0843]

[0844] Step-2

[0845] Pd(dppf)CI2-DCM Cs2CO3, Xantphos K3PO4, 1,4-dioxane Pd2(dba)3

[0846] 1,4-dioxane

[0847]

[0848] Step-3 Step-4

[0849] TFA, DCM

[0850] Step-5

[0851]

[0852] Step-1:

[0853] To a 500 mL single-neck round-bottom flask containing a stirred solution of 5-bromo-2-chloro-pyridin-4-amine (1, 20 g. 96.41 mmol) in di chloromethane (500 mL) was added triethylamine (29.27 g, 289.22 mmol, 40.31 mL) and the resulting mixture was purged with N2 for 5 minutes. Di-tert-butyl dicarbonate (25.25 g, 115.69 mmol, 26.55 mL) and DMAP (942.24 mg, 7.71 mmol) were then slowly added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography (silica gel, 60-120 mesh) using a gradient of 0-100% ethyl acetate in petroleum ether to afford tert-butyl / V-(5-bromo-2-chloro-4-pyridyl)carbamate (2, 20 g, 57.31 mmol, 59.45% yield) as an off-white solid. LC-MS (ES+): m / z 306.9 [M + H]+.

[0854] Step-2:

[0855] To a 1 L round-bottom flask containing a well-stirred suspension of tert-butyl A-(5-bromo-2-chloro-4-pyridyl)carbamate (2, 22 g, 71.53 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (3, 27.25 g, 107.29 mmol) in 1,4-dioxane (500 mL) was added potassium acetate (14.04 g. 143.06 mmol) and the mixture was purged with N2 for 5 minutes. Then Pd(dppf)C12'CH2C12(2.92 g, 3.58 mmol) was added and the reaction mixture was stirred at 90 °C for 12 h. After completion of the reaction, the reactionmixture was filtered through a pad of Celite, which was subsequently washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl N-[2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-pyridyl]carbamate (4, 25 g, 28.90 mmol, 40.41% yield) as a brown gummy solid. LC-MS (ES+): m / z 255.1 [M - Boc + H]+.

[0856] Step-3:

[0857] To a 1 L four-neck round-bottom flask containing a well-stirred solution of methyl 6-bromopyridine-3-carboxylate (5, 20 g, 92.58 mmol) in 1,4-di oxane (500 mL) was added tert-butyl jV-[2-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4-pyridyl]carbamate (4, 39.40 g, 111.09 mmol) and the mixture was purged with N2 for 5 minutes. Then K3PO4 (58.96 g, 277.74 mmol) and Pd(dppf)C12 CH2CI2 (7.56 g, 9.26 mmol) were added and the reaction mixture was stirred at 90 °C for 1 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, which was subsequently washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (silica gel, 60-120 mesh) using a gradient of 0-100% ethyl acetate in petroleum ether to afford methyl 6-[4-(tert-butoxycarbonylamino)-6-chloro-3-pyridyl]pyridine-3-carboxylate (6, 15 g, 38.68 mmol, 41.78% yield) as an off-white solid. LC-MS (ES+): m / z 364.1 [M + H]+.

[0858] Step-4:

[0859] To a well-stirred solution of methyl 6-[4-(tert-butoxycarbonylamino)-6-chloro-3-pyridyl]pyridine-3-carboxylate (6, 4 g, 10.31 mmol) and acetamide (7, 731.03 mg, 12.38 mmol) in 1,4-dioxane (40 mL) was added Cesium carbonate (3.36 g, 10.31 mmol) and the mixture was degassed with N2 for 5 minutes. Then Pd2(dba)3(9.44 g, 10.31 mmol) and Xantphos (5.97 g, 10.31 mmol) were added and the reaction mixture was stirred at 110 °C for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was triturated with 30% EtOAc in pet ether followed by MTBE to afford methyl 6-[6-acetamido-4-(tert-butoxycarbonylamino)-3-pyridyl]pyridine-3-carboxylate (8, 2.2 g, 4.53 mmol, 43.89% yield) as a light brown solid. LC-MS(ES+): m / z 387.2 [M + H]+.

[0860] Step-5:

[0861] To a solution of methyl 6-[6-acetamido-4-(tert-butoxycarbonylamino)-3-pyridyl]pyridine-3-carboxylate (8, 2.14 g, 4.40 mmol) in DCM (40 mL) cooled to 0 °C was added TF A (5.02 g, 44.00 mmol, 3.37 mL) and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the crude residue was triturated with MTBE to afford methyl 6-(6-acetamido-4-amino-3-pyridyl)pyridine-3-carboxylate trifluoroacetate (9, 1.4 g, 3.18 mmol, 72.34% yield) as an off-white solid. LC-MS(ES+): m / z 287.1 [M + H]+.

[0862] Synthesis of 6-[6-acetamido-4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-3-carboxylic acid (A-3)

[0863]

[0864] Step-1:

[0865] To an 8 mL screw-capped vial containing a well-stirred solution of methyl 6-(6-acetamido-4-amino-3-pyridyl)pyridine-3-carboxylate (1, 500 mg, 1.52 mmol) and 2-chloro-6-(1,1-difluoroethyl)-4-methyl-pyridine (2, 306.23 mg, 1.52 mmol) in 1.4-di oxane (20 mL) was added Cs2CO3(1.24 g. 3.81 mmol) and the resulting mixture was degassed with nitrogen gas for 5 min. Pd2(dba)3(139.62 mg, 152.47 pmol) and Xantphos (88.22 mg, 152.47 pmol) were then added and the reaction mixture was stirred at 110 °C for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was triturated with 30% EtOAc in pet ether followed by MTBE to afford methyl 6-[6-acetamido-4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-3-carboxylate (3, 300 mg, 658.54 pmol, 43.19% yield) as alight brown solid. LC-MS (ES+): m / z 442.7 [M + H]+

[0866] Step-2:

[0867] To a 50 mL single-neck round-bottom flask containing a well stirred solution of methyl 6-[6-acetamido-4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-3-carboxylate (3, 206.40 mg, 453.07 pmol) in THF (6 mL) and methanol (4 mL) was added lithium hydroxidemonohydrate, 98% (19.01 mg, 453.07 pmol) in water (2 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The solvent was removed under vacuum, and the residue was acidified with an aqueous 1.5 N HC1 solution under cooling. The observed off-z\

[0868] white precipitate was filtered and dried under reduced pressure to afford 6-[6-acetamido-4-[[6- (1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-3-carboxylic acid (A-3, 140 mg. 301.35 pmol, 66.51% yield) as an off-white solid. LC-MS (ES+): m / z 428.4 [M + H]+. The following targeting ligands were prepared using the method described above, with the corresponding building blocks in Step-1.

[0869] Bromide / Chloride Targeting ligand MS

[0870] in Step-1

[0871] Br 0 LC-MS (ES+): m / z 422.1 NA A / A [M + H]+. ji i

[0872] HCT | O N'A^ff

[0873] H X

[0874] jl.1

[0875] H< T |

[0876] A-4

[0877] 0 LC-MS (ES+): m / z 414.1 NAA)H [M + H]+.

[0878] 0

[0879] K jl \

[0880] H A AN UCF

[0881] rF

[0882] A-5

[0883] 0 UPLC-MS (ES+): m / z 442.2 [M + H]+.

[0884] O

[0885] Jf A A

[0886] H I AN A

[0887] A-6

[0888]

[0889] 0 LC-MS (ES+): m / z 414.1

[0890] [M + H]+.

[0891] 0

[0892] K Ji J

[0893] o

[0894] H JL

[0895] A-7

[0896] Br 0 LC-MS (ES+): m / z 442.1 r^N [M + H]+.

[0897] L _ if

[0898] 0

[0899] F F jf Ji \

[0900] H JL

[0901] J]1

[0902] F F

[0903] A-8

[0904]

[0905] Table 3: Preparation of A-4 to A-8

[0906] Synthesis of 6-[6-acetamido-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-3-carboxylic acid (A-9)

[0907]

[0908] Step-1:To an 8 mL screw-capped vial containing a well-stirred solution of methyl 6-(6-acetamido-4- amino-3-pyridyl)pyridine-3-carboxylate trifluoroacetate (1, 300 mg, 717.20 pmol) and 2-bromo- 6-[(3?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-pyridine (2, 197.75 mg, 717.20 pmol) in 1,4- dioxane (6 mL) was added Cesium carbonate (584.19 mg, 1.79 mmol) and the resulting mixture degassed with N2 for 5 min. Then Pd2(dba)3(65.67 mg, 71.72 pmol) and Xantphos (41.50 mg, 71.72 pmol) were added, and the reaction mixture was stirred at 110 °C for 2 h. Upon completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude residue was triturated with 30% EtOAc in pet ether followed by MTBE to afford methyl 6-[6-acetamido-4-[[6-[(3?)-3- methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-3-carboxylate (3, 170 mg, 288.01 pmol, 40.16% yield) as a light-brown solid. LC-MS (ES+): m / z 478.1 [M + H]+Step-2:

[0909] To a 50 mL single-neck round-bottom flask containing a well stirred solution of methyl 6-[6- acetamido-4-[[6-[(37?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-3- pyridyl]pyridine-3-carboxylate (3. 123.61 mg, 209.42 pmol) in THF (3 mL) and Methanol (2 mL) was added lithium hydroxide monohydrate, 98% (17.58 mg, 418.84 pmol) in water (1 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. Then the solvent was removed from the reaction mixture under high vacuum. The residue was acidified with an aqueous 1.5 N HC1 solution under cooling and an off-white color solid formed. This solid was filtered and dried under reduced pressure to afford 6-[6-acetamido-4-[[6-[(37?)-3- methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-3-carboxylic acid (A-9, 65 mg, 110.51 pmol, 52.77% yield) as an off-white solid. LC-MS (ES+): m / z 464.1 [M + H]+.

[0910] The following targeting ligands were prepared using the method described above, with the corresponding bromide / chloride in Step-1.

[0911] Bromide / chloride 2 Targeting ligand MS

[0912] in Step-1

[0913] Br O LC-MS (ES+): m / z 464.1 [M + H]+.

[0914] O

[0915] A 1 J.

[0916] H X

[0917] AST\

[0918] \x°

[0919]

[0920] o A- 10

[0921] °'? LC-MS (ES+): m / z 450.0 [M Yr + H]+.

[0922] JAXY^

[0923] N-T

[0924] CD —5 T H

[0925] HNx^xs. Mx / '

[0926] T T Y 0

[0927] HO^ JYN

[0928] 0

[0929] A-ll

[0930] 0 LC-MS (ES+): m / z 470.3 [M NA OH + H]+.

[0931] A J

[0932] Cl X A Y

[0933] ' / ^N'XX-x^NH

[0934] H A A XX

[0935] ° Y

[0936] A-12

[0937] Cl 0 UPLC-MS (ES+): m / z N' T 444.3 [M + H]+. j] J NX[ 'OH

[0938] 0

[0939] A °" JT Ji \

[0940] HN' AX

[0941] FA Y A V

[0942] A-25

[0943] 0 UPLC-MS (ES ): m / z 454.4 YYi NX| 'OH[M + H]+.

[0944] A / N

[0945] 0 N'^Ar ^

[0946] Cl

[0947] •^ AN' A^Y^NH

[0948] HN" AA

[0949] X J.

[0950] FT'XV

[0951] A-13

[0952]

[0953] UPLC-MS (ES+): m / z 452.1

[0954] Q [M + H]+.

[0955] FO Y HHNx^X / N\X

[0956] Y Y Y

[0957] 0

[0958] HO^ J^N

[0959] 0

[0960] A- 14

[0961] UPLC-MS (ES+): m / z 452.0 °Q

[0962] [M + H]+.

[0963] FNCI Y HHNXVN\ /

[0964] Y Y Y

[0965] / ^ Yx-No

[0966] HO^ JL^ N

[0967] o

[0968] A- 15

[0969] Z\ / FUPLC-MS (ES+): m / z 436.5

[0970] CO CD [M + H]+.

[0971] N^Y

[0972] XJY

[0973] Br H Y

[0974] VNvX /

[0975] Y Y |NH

[0976] 0N-SYX^^,

[0977] N^JLX°H

[0978] 0

[0979] A-16

[0980] 1 LC-MS (ES+): m / z 434.1 [M XN^CI + H]+.

[0981] XJ N -XY

[0982] Y H Y Y Y

[0983] ^NXYX-No

[0984] HO-xXX

[0985] 0

[0986] A-17

[0987]

[0988] 0 LC-MS (ES+): m / z 440.3 [M A / OH + H]+.

[0989] o

[0990] 4°’ 1 1 / 1

[0991] □□ o H X

[0992] A / A

[0993] A-18

[0994] 0 UPLC-MS (ES+): m / z 450.2 A / OH [M + H]1.

[0995] o

[0996] X 1 J.

[0997] H X L Q

[0998] X / °

[0999] A-19

[1000]

[1001] Table 4: Preparation of A-10 to A-19

[1002] Synthesis of 6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]pyridine-3-carboxylic acid (A-20)

[1003]

[1004] Step-1:To an 8 mL screw-cap vial containing a well-stirred solution of methyl 6-(6-acetamido-4-amino- 3-pyridyl)pyridine-3-carboxylate (1, 1.4 g, 4.45 mmol) and 4-chloro-2-(l,l- difluoroethyl)pyrimidine (2, 1.17 g, 5.34 mmol) in 1,4-dioxane (20 mL) was added Cs2CO3(3.62 g, 11.13 mm Io Vl) L z and the resulting mixture was degassed with N2 for 5 minutes, then Pdildba)? (407.50 mg, 445.01 pmol) and Xantphos (257.49 mg, 445.01 pmol) were added and the resulting 0

[1005] reaction mixture stirred at 110 °C for 1 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was triturated with 30% EtOAc in pet ether followed by MTBE to afford methyl 6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3- pyridyl]pyridine-3-carboxylate (3, 500 mg, 948.90 pmol, 21.32% yield) as a light brown solid. LCMS(ES+): m / z 429.2 [M + H]+.

[1006] Step-2:

[1007] To a 50 mL single-neck round-bottom flask containing a well stirred solution of methyl 6-[6- acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]pyridine-3-carboxylate (3, 500 mg, 948.90 pmol) in THF (5 mL) and methanol (3 mL) was added lithium hydroxide monohydrate, 98% (79.64 mg, 1.90 mmol) in water (1 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ice-cold water (30 mL) and acidified with an aqueous 1.5 N HC1 solution. The resulting precipitate was filtered and the filter cake was dried under reduced pressure to afford 6-[6-acetamido-4-[[2-(l,l- difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]pyridine-3-carboxylic acid (A-20, 340 mg, 631.81 pmol, 66.58% yield) as an off-white solid. LC-MS (ES+): m / z 415.1 [M + H]+.

[1008] The following targeting ligands were prepared using the method described above, with the corresponding chloride 2 in Step-1.

[1009] Chloride 2 in Step-1 Targeting ligand MS

[1010] HO UPLC-MS (ES+): m / z 447.3

[1011] [M + H]+.

[1012] % 3“

[1013] / =VNH

[1014] N\ Z'N\L_ /

[1015] HN

[1016] A-21

[1017]

[1018]

[1019] Synthesis of 6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-5-fluoro-pyridine-3-carboxylic acid (A-23)

[1020] Pd(dppf)CI2CH2CI2K3PO4, 1,4-dioxane Step-1

[1021] Pd2(dba)3, XantPhos K3PO4, 1,4-dioxane Step-3

[1022] LiOH THF, MeOH, H2O Step-4

[1023]

[1024] Step-1:

[1025] To a 100 mL multi -neck round-bottom flask containing a well-stirred solution of methyl 6- bromo-5-fluoro-pyridine-3-carboxylate (2. 2 g, 8.55 mmol) in 1,4-dioxane (10 mL) was added 2- chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-amine (1, 2.61 g, 10.26 mmol). The resulting mixture was purged with nitrogen gas for 2 min. Then, Pd(dppf)Cl₂·CH₂Cl₂(697.92 mg, 854.62 pmol) and K3PO4 (5.44 g, 25.64 mmol) were added, and the reaction mixture was stirred at 90 °C for 1 h. After completion of the reaction as indicated by LC-MS. the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude product was purified by flash chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: 40-50% Ethyl acetate in Petroleum ether) to afford methyl 6-(4-amino-6-chloro-3-pyridyl)-5-fluoro-pyridine-3-carboxylate (3, 1.1 g, 3.13 mmol, 37% yield) as an off-white solid. LC-MS (ES+): m / z 280.1 [M - H]+

[1026] Step-2:

[1027] To a 20 mL screw-cap vial containing a well-stirred solution of methyl 6-(4-amino-6-chloro-3-pyridyl)-5-fluoro-pyridine-3-carboxylate (3. 300 mg. 853.87 pmol) in 1,4-di oxane (5 mL) was added acetamide (100.87 mg, 1.71 mmol). The reaction mixture was purged with nitrogen gas for 2 min. Then, Pd2(dba)3(78.19 mg, 85.39 pmol), XantPhos (98.81 mg, 170.77 pmol) and Cs2CO3(556.42 mg, 1.71 mmol) were added to the reaction mixture and stirred at 90 °C for 2 h. After completion of the reaction as indicated by LC-MS, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude product was purified by flash chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: 40-50% Ethyl acetate in Petroleum ether) to afford methyl 6-(6-acetamido-4-amino-3-pyridyl)-5-fluoro-pyridine-3-carboxylate (4, 110 mg, 251.43 pmol, 29% yield) as an off-white solid. LC-MS (ES+): m / z 305.1 [M + H]+

[1028] Step-3:

[1029] To a 20 mL screw-cap vial containing a well-stirred solution of methyl 6-(6-acetamido-4-amino-3-pyridyl)-5-fluoro-pyridine-3-carboxylate (4. 80 mg, 182.86 pmol) in 1,4-dioxane (5 mL) was added 4-chloro-2-(1,1-difluoroethyl)pyrimidine (5, 42.83 mg, 237.72 pmol) and the mixture was purged with nitrogen gas for 2 min. Then Pd2(dba)3(16.74 mg, 18.29 pmol), XantPhos (21.16 mg, 36.57 pmol) and K3PO4 (77.63 mg, 365.72 pmol) were added, and the reaction mixture was stirred at 90 °C for 4 h. After completion of the reaction as indicated by LC-MS, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude compound was purified by flash chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: 40-50% Ethyl acetate in Petroleum ether) to afford methyl 6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-5-fluoro-pyridine-3-carboxylate (6, 50 mg, 77.76 pmol, 43% yield) as an off-white solid. LC-MS (ES+): m / z 447.1 [M + H]+

[1030] Step-4:To a 50 mL single-neck round-bottom flask containing a well-stirred solution of methyl 6- [6-acetamido-4-[ [2-( 1, 1 -difluoroethyl)py rimidin-4-yl] amino] -3-py ridy 1] -5 -fluoro-py ridine-3 -carboxylate (6, 40 mg, 62.21 pmol) in THF (2 mL), methanol (1 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (1.79 mg, 74.65 pmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. The solvent was removed from the reaction mixture, and the residue was diluted with water. The mixture was then acidified with aqueous 1.5 N HC1 solution and extracted with DCM (10 mL x 2). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-5-fluoro-pyridine-3-carboxylic acid (A-23, 25 mg, 40.97 pmol, 66% yield) as an off-white solid. LC-MS (ES+): m / z 433.1 [M + H]+. Synthesis of 6-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-6-(methylcarbamoyl)-3-pyridyl]pyridine-3-carboxylic acid (A-24)

[1031]

[1032] Step 1:

[1033] To a 100 mL single-neck round-bottom flask containing a well-stirred solution of methyl 4-aminopyridine-2-carboxylate (1, 2 g, 13.14 mmol) in 1,2-di chloroethane (20 mL) was added N-bromo succinimide (2.34 g. 13.14 mmol) at room temperature. The resulting reaction mixture w as stirred at room temperature for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with water and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (Stationary Phase: 230-400 mesh silica gel; 15-20% ethyl acetate in dichloromethane) to afford methyl 4-amino-5-bromo-pyridine-2-carboxylate (2, 3 g, 12.85 mmol, 97% yield) as an off-white solid. LC-MS (ES+): m / z 231.0 [M + H]+.

[1034] Step 2:

[1035] To a 250 mL sealed-tube containing a well-stirred solution of methyl 4-amino-5-bromo-pyridine-2-carboxylate (2, 3 g, 12.85 mmol) in 33% methyl amine in methanol (3, 1.063 mol, 100 mL) was heated to 60 °C and stirred for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 25 to 30% ethyl acetate in dichloromethane) to afford 4-amino-5-bromo-A-methyl-pyridine-2-carboxamide (4, 1.5 g, 6.45 mmol. 50% yield) as an off-white solid. LC-MS (ES+): m / z 229.9 [M + H]+.

[1036] Step 3:

[1037] To a 100 mL multi-neck round-bottom flask containing a well-stirred solution of 4-amino-5-bromo-A-methyl-pyridine-2-carboxamide (4, 1.5 g, 6.45 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-L3.2-dioxaborolane (5, 1.97 g, 7.75 mmol) in 1,4-dioxane (30 mL) was added potassium acetate (1.90 g, 19.36 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes. Then bis(triphenylphosphine)palladium (II) chloride (453.06 mg, 645.48 pmol) was added and the reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure to afford [4-amino-6-(methylcarbamoyl)-3-pyridyl]boronic acid (6, 1.5 g, 5.15 mmol, 79% yield) as a dark brown oily liquid. LC-MS (ES+): m / z 196.1 [M + H]+.

[1038] Step 4:

[1039] To a 100 mL multi-neck round-bottom flask containing a well-stirred mixture of [4-amino-6-(methylcarbamoyl)-3-pyridyl]boronic acid (6, 1.5 g, 5.15 mmol) and methyl 6-bromopyridine-3-carboxylate (7, 927.91 mg, 4.30 mmol) in 1,4-dioxane (30 mL) was added potassium carbonate (1.19 g. 8.59 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes. Then bis(triphenylphosphine)palladium (II) chloride (301.48 mg, 429.52 pmol) was added and stirred at 100 °C for 2 h. After completion of the reaction as indicated by UPLC-MS,the reaction mixture was passed through a pad of C elite, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase column chromatography [Column: RediSep R / Gold C18-120 g; Mobile phase A: 10 mM Ammonium Bicarbonate in water and Mobile phase B: Acetonitrile] to afford methyl 6-[4-amino-6-(methylcarbamoyl)-3-pyridyl]pyridine-3-carboxylate (8, 150 mg, 461.08 pmol, 11% yield) as an off-white solid. LC-MS (ES+): m / z 287.1 [M + H]+

[1040] Step 5:

[1041] To a 40 mL screw-cap reaction vial containing a well-stirred mixture of methyl 6-[4-amino-6-(methylcarbamoyl)-3-pyridyl]pyridine-3-carboxylate (8, 170.45 mg, 523.95 pmol) and 4-chloro-2-(l,l -difl uoroethyl)pyrimi dine (9, 141.76 mg, 785.93 pmol) in 1,4-dioxane (5 mL) were added. V. / V-diisopropylethylamine (338.58 mg, 2.62 mmol, 456.30 pL) and cesium carbonate (341.43 mg, 1.05 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 min. Then 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (60.63 mg, 104.79 pmol) and tris(dibenzylideneacetone)dipalladium(0) (47.98 mg, 52.40 pmol) were added and the reaction mixture was stirred at 110 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase column chromatography [Column: RediSep R Gold® Cl 8-60 g; Mobile phase A: 10 mM Ammonium bicarbonate in water and Mobile phase B: Acetonitrile] to afford methyl 6-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-6-(methylcarbamoyl)-3-pyridyl]pyridine-3-carboxylate (10, 70 mg, 119.28 pmol, 22% yield) as a pale yellow solid. LC-MS (ES+): m / z 429.0 [M + H]+.

[1042] Step 6:

[1043] To a 50 mL single-neck round-bottom flask containing a well stirred solution of methyl 6-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-6-(methylcarbamoyl)-3-pyridyl]pyridine-3-carboxylate (10, 68.49 mg, 116.72 pmol) in THF (3 mL) and methanol (3 mL) was added lithium hydroxide monohydrate (24.49 mg, 583.58 pmol) in water (3 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase column chromatography [Column: RediSep R / Gold® Cl 8-60 g; Mobile phase A: 0.1% Formic acid in water and Mobile phase B: Acetonitrile] to afford 6-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-6-(methylcarbamoyl)-3-pyridyl]pyridine-3-carboxylic acid (A-24, 25 mg, 50.68 pmol, 43% yield) as an off-white solid. UPLC-MS (ES+): m / z 415.1 [M + H]+.

[1044]

[1045] Example 2: Synthesis of CRBN Binders and IntermediatesReferences for the Synthesis of Building Blocks

[1046] Building Block Reference

[1047] OBn Compound was prepared using the method described on page 308-311 of BnO"\ j /

[1048] WO20222717276.

[1049] Br'^ F^T^N >°

[1050] 5-bromo-l-(2.6-dibenzyloxy-3-pyridyl)-3-methyl- benzimidazol-2-one

[1051] OBn Compound was prepared using theNmethod described on page 181-183 ofBn0' \==F WO20222717276

[1052] 4-bromo-l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl- benzimidazol-2-one

[1053]

[1054] Table 6: Preparation of building blocks

[1055] 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6- dione (B-l)

[1056]

[1057] Compound 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2, 6-dione was prepared using the method described on page 119-122 of WO20232836107.3-(3-methyl-2-oxo-5-(piperazin-l-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (B-2)

[1058]

[1059] Compound 3-(3-methyl-2-oxo-5-(piperazin-l-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione was prepared using the method described on page 190-191 of WO20230191668.

[1060] 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (B-3)

[1061] O

[1062] O

[1063]

[1064] H

[1065] Compound 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione was prepared using the method described on page 167-170 of WO20230191668.

[1066] Synthesis of 3-[2-oxo-7-(4-piperidyl)-l,3-benzoxazol-3-yl]piperidine-2, 6-dione (B-4)

[1067] Pd-XPhos-G2 K3CO3, 1,4-dioxane / H2O Step-3

[1068]

[1069] H2, Pd(OH)2 / C 1,4-dioxane Step-4

[1070]

[1071] Step-1:

[1072] To a 500 mL multi-neck round-bottom flask containing a solution of 2-amino-6-bromo-phenol (1, 10 g, 53.19 mmol) in THF (150 mL) was added 1,1'-carbonyldiimidazole (25.87 g, 159.56 mmol) at room temperature. The resulting reaction mixture was heated to 70 °C for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was treated with a 1.5 N aqueous hydrogen chloride solution (200 mL) and stirred at 0 °C for 1 h, at which point a precipitate formed. The solid precipitate was filtered, washed with water (2 x 200 mL), and dried in vacuo to afford 7-bromo-3H-1,3-benzoxazol-2-one (2, 8 g, 36.99 mmol, 70% yield) as a brown solid, which was used without further purification. LC-MS (ES‘): m,z 212 [M - H] Step-2:

[1073] To a 500 mL multi-neck round-bottom flask containing a solution of 7-bromo-3H-1,3-benzoxazol-2-one (2, 8 g, 37.38 mmol) and 3-bromopiperidine-2,6-dione (3, 28.71 g, 149.52 mmol) in acetonitrile (100 mL), was added cesium carbonate (36.54 g, 112.14 mmol). The resulting reaction mixture was heated to 70 °C and stirred for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was brought to room temperature and treated with water (200 mL), and then stirred for 30 min at room temperature, at which time a precipitate formed. The precipitated solid was filtered, washed with water (2 x 50 mL), and dried in vacuo to afford 3-(7-bromo-2-oxo-l,3-benzoxazol-3-yl)piperidine-2, 6-dione (4, 7 g, 20.37 mmol, 54% yield) as a grey solid, which was used without further purification. LC-MS (ES‘): m / z 323.0 [M - H] ’.

[1074] Step-3:

[1075] To a 500 mL multi-neck round-bottom flask containing a solution of 3-(7-bromo-2-oxo-l,3-benzoxazol-3-yl)piperidine-2, 6-dione (4, 6 g, 17.16 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)-3,6-dihydro-2 / f-pyridine-l-carboxylate (5, 5.30 g, 17.16 mmol) in 1,4-dioxane (100 mL) was added potassium carbonate (7.11 g, 51.47 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was purged by bubbling nitrogen gas through the reaction mixture for 5 min, then Pd XPhos G2 (2.02 g, 2.57 mmol) was added to the reactionmixture. The resulting reaction mixture was heated to 70 °C and stirred for 16 h. The reaction mixture was diluted with ethyl acetate (300 mL) and tetrahydrofuran (300 mL) and stirred at room temperature for 10 min. The reaction mixture was filtered through a pad of Celite, and the Celite bed was washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (Stationary' Phase: 60-120 mesh silica gel; Eluent: 60-70% ethyl acetate in petroleum ether) to afford tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]-3,6-dihydro-2 / / -pyridine-l-carboxylate (6, 2.8 g, 6.23 mmol, 36% yield) as an off-white solid. LC-MS (ES+): m / z 328.0 [M -COOtBu + H]+.

[1076] Step-4:

[1077] To a 100 mL single-neck round-bottom flask containing a solution of tert-butyl 4-[3-(2.6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]-3,6-dihydro-27 / -pyridine-l-carboxylate (6, 3 g, 6.12 mmol) in 1,4-dioxane (60 mL) was added 20% palladium hydroxide on carbon (2.58 g, 18.37 mmol) at room temperature. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was filtered through a pad of Celite, and the Celite bed was washed with a 1: 1 mixture of ethyl acetate and tetrahydrofuran (500 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]piperidine-l-carboxylate (7, 2.5 g, 5.76 mmol, 93.98% yield) as an off-white solid, which was used without further purification. LC-MS (ES1): m / z 374.1 [M - isobutene + H].

[1078] Step-5:

[1079] A 100 mL single-neck round-bottom flask containing a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]piperidine-l-carboxylate (7, 3 g, 6.54 mmol) in dichloromethane (30 mL) was cooled to 0 °C. Then a 4.0 M hydrogen chloride solution in 1,4-dioxane (16.4 mL, 65.38 mmol) was added to the reaction mixture dropwise. The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was concentrated under reduced pressure to afford a crude product, which was treated with methyl tert-butyl ether (50 mL). resulting in the formation of a precipitate. The precipitate was filtered, washed with methyl tert-butyl ether (2 x 50 mL) and dried in vacuo to afford 3-[2-oxo-7-(4-piperidyl)-l,3-benzoxazol-3-yl]piperidine-2, 6-dione hydrochloride (B-4, 2.5 g, 6.48 mmol, 99% yield) as an off-white solid, which was used without further purification. LC-MS (ES+): m / z 330.2 [M + H]+.Synthesis of 3-[7-(3,3-difhioro-4-piperidyl)-2-oxo-l,3-benzoxazol-3-yl]piperidine-2, 6-dione (B-5)

[1080]

[1081] Step-1:

[1082] To a 40 mL screw-cap vial containing a well-stirred solution of 3-(7-bromo-2-oxo-l,3-benzoxazol-3-yl)piperidine-2, 6-dione (1. 300 mg, 916.38 pmol) and 4.4.5.5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (349.06 mg, 1.37 mmol) in 1,4-di oxane (10 mL) was added potassium acetate (449.67 mg, 4.58 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 min. Then. Pd(dppf)C12 DCM (37.42 mg. 45.82 pmol) was added and the reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with water (150 mL) and the aqueous layer was extracted with EtOAc (2 x 150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford 3-[2-oxo-7-(4.4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-benzoxazol-3-yl]piperidine-2.6-dione (2, 250 mg, 503.05 pmol, 55% yield) as a pale yellow solid. LC-MS (ES‘): nvz 289.1 [M - H] '.

[1083] Step-2:

[1084] To a 20 mL screw-cap vial containing a well-stirred solution of 3-[2-oxo-7-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)-l,3-benzoxazol-3-yl]piperidine-2, 6-dione (2, 160 mg, 343.92 pmol) and tert-butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)-2,6-dihydropyridine-1-carboxylate (3, 140.35 mg, 343.92 pmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was added sodiumcarbonate (36.45 mg, 343.92 pmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 min. Then Pd(dppf)Ch. DCM (28.09 mg, 34.39 pmol) was added and the reaction mixture was stirred at 90 °C for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with water (150 mL) and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase column chromatography [Column: RediSep Rf Gold C18-120 g; Mobile phase A: 10 mM NH4HCO3 in water and Mobile phase B: MeCN] to afford tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]-3,3-difluoro-2,6-dihydropyridine-l-carboxylate (4, 80 mg, 132.63 pmol, 38.56% yield) as a pale-yellow solid. LC-MS (ES‘): m / z 462.1 [M - H] ’.

[1085] Step-3:

[1086] To a 100 mL single-neck round-bottom flask containing a well-stirred suspension of ferf-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]-3,3-difluoro-2,6-dihydropyridine-l-carboxylate (4, 80 mg. 132.63 pmol) in anhydrous 1,4-dioxane (10 mL) was added 20% palladium hydroxide on carbon (139.70 mg, 198.94 pmol). The resulting reaction mixture was stirred under hydrogen atmosphere (bladder pressure) at room temperature for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, which was subsequently washed with THF (50 mL). The filtrate was concentrated under reduced pressure and the crude residue was triturated with MTBE (5 mL) and dried to afford tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]-3,3-difluoro-piperidine-1 -carboxylate (5, 60 mg, 123.78 pmol, 93% yield) as a pale-yellow solid. LC-MS (ES‘ ): m / z 463.9 [M - H] ’.

[1087] Step-4:

[1088] To a 50 mL single-neck round-bottom flask containing a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]-3,3-difluoro-piperidine-l-carboxylate (5, 60 mg, 123.78 pmol) in DCM (3 mL) was added 4 M HC1 in 1,4-dioxane (618.89 pmol, 154.72 pL) at 0 °C and the resulting reaction mixture was stirred room temperature for 2 h. After completion of the reaction as indicated by UPLC-MS. the reaction mixture was concentrated under reduced pressure. The crude residue which was triturated with MTBE (5 mL) and dried to afford 3-[7-(3, 3-difluoro-4-piperidyl)-2-oxo-l,3-benzoxazol-3-yl]piperidine-2, 6-dione hydrochloride (B-5, 50 mg, 116.96 pmol, 94% yield) as a pale-yellow solid. LC-MS (ES+): m / z 366.1 [M + H]+.Synthesis of 3-[7-(6-azaspiro[3.4]octan-2-yl)-2-oxo-l,3-benzoxazol-3-yl]piperidine-2, 6-dione (B-6)

[1089]

[1090] Step-1:

[1091] To a 20 mL screw-cap vial containing a well-stirred solution of 3-[2-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-3-yl]piperidine-2,6-dione (1, 250 mg, 358.43 pmol) and tert-butyl 2-(trifluoromethylsulfonyloxy)-6-azaspiro[3.4]oct-2-ene-6-carboxylate (2, 133.42 mg, 358.43 pmol) in 1,4-dioxane (10 mL) and water (1.5 mL) was added sodium carbonate (37.99 mg, 358.43 pmol) at room temperature. Nitrogen gas was purged through a reaction mixture for 2 min. Then, Pd(dppf)C12-DCM (29.27 mg, 35.84 pmol) was added, and the reaction mixture was stirred at 90 °C for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with water (150 mL) and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 50 to 60% Ethyl acetate in Petroleum ether) to afford tert-butyl 2-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1, 3-benzoxazol-7-yl]-6-azaspiro[3.4]oct-2-ene-6-carboxylate (3, 250 mg, 292.02 pmol, 81% yield) as a pale-yellow solid. LC-MS (ES’): m / z 452.4 [M - H]‘.

[1092] Step-2:

[1093] To a 100 mL single-neck round-bottom flask containing a well-stirred suspension of tert-butyl 2-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]-6-azaspiro[3.4]oct-2-ene-6-carboxylate 3(3, 250 mg, 292.02 pmol) in anhydrous 1,4-dioxane (10 mL) and DMF (1.5 mL) was added 20% Palladium hydroxide on carbon (307.58 mg, 438.02 pmol). The resulting reaction mixture was stirred under hydrogen atmosphere (bladder pressure) at room temperature for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, which was subsequently washed with THF (100 mL) and 1,4-dioxane (50 mL). The filtrate was concentrated under reduced pressure to afford / m-butyl 2-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]-6-azaspiro[3.4]octane-6-carboxylate (4, 150 mg, 276.62 pmol, 95% yield) as a pale-yellow solid. LC-MS (ES ): m / z 356.0 [M- COOl-Bu + H]+.

[1094] Step-3:

[1095] To a 50 mL single-neck round-bottom flask containing a solution of tert-butyl 2-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1.3-benzoxazol-7-yl]-6-azaspiro[3.4]octane-6-carboxylate (4, 50 mg, 92.21 pmol) in DCM (3 mL) was added 4 M HC1 in 1,4-dioxane (461.03 pmol, 115.26 pL) at 0 °C and the resulting reaction mixture was stirred room temperature for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the crude residue was triturated with MTBE (5 mL) and dried to afford 3-[7-(6-azaspirot3.4Joctan-2-yl)-2-oxo-l,3-benzoxazol-3-yl]piperidine-2,6-dione hydrochloride (B-6, 35 mg, 75.78 pmol, 82% yield) as a pale-yellow solid. LC-MS (ES+): m / z 356.0 [M + H]+.

[1096] Synthesis of 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-2-oxo-l,3-benzoxazol-3-yl]piperidine-2,6-dione (B-7)

[1097]

[1098] Step-1:

[1099] To a well-stirred solution of 6-bromo-3 / / - 1,3-benzoxazol-2-one (1, 1 g, 4.67 mmol) and tertbutyl 2, 6-diazaspiro[3.3]heptane-2 -carboxylate (2, 926.39 mg, 4.67 mmol) in toluene (10 mL) was added sodium fe / 7-butoxide (1.12 g, 11.68 mmol, 1.10 mL) and the mixture was degassed with nitrogen gas for 5 min. Then, Pd2(dba)3(213.94 mg, 233.63 pmol) and RuPhos(174.43 mg, 373.80 pmol) were added to the reaction mixture and stirred at 110 °C for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: 40-50% ethyl acetate in petroleum ether) to afford tert-butyl 6-(2-oxo-3H-1,3-benzoxazol-6-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (3, 500 mg. 1.48 mmol, 32% yield) as an off-white solid. LC-MS (ES+): m,z 332.1 [M + H]+

[1100] Step-2:

[1101] To a 100 mL multi-neck round-bottom flask containing a well-stirred solution of tert-buty l 6-(2- oxo-3H-l,3-benzoxazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (3, 510.20 mg. 1.51 mmol) in anhydrous acetonitrile (2 mL) was added Cs2CO3(2.46 g, 7.54 mmol) at room temperature. The resulting mixture was stirred at 0 °C for 10 min. Then, 3-bromopiperidine-2,6- dione (4, 869.18 mg, 4.53 mmol) was added at room temperature and stirred at 60 °C for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (60 mL). The organic layer was washed with brine solution (30 mL), dried over anhydrous Na2SO4and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: 40-50% ethyl acetate in petroleum ether) to afford tert-butyl 6-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-2,6- diazaspiro[3.3]heptane-2-carboxylate (5, 200 mg, 428.42 pmol. 28% yield) as an off-white solid. LC-MS (ES+): m / z 442.1[M + H]+

[1102] Step-3:

[1103] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 6-[3- (2,6-dioxo-3-piperidyl)-2-oxo-1.3-benzoxazol-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (5, 250 mg, 559.37 pmol) in DCM (5 mL) was added TFA (1.86 mmol, 142.68 pL) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure. The crude material was triturated with methyl tert-butyl ether (30 mL) to afford 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-2-oxo-l,3-benzoxazol-3-yl]piperidine-2.6-dione trifluoroacetate (B-7, 100 mg, 177.49 pmol, 95% yield) as a brown solid. LC-MS (ES+): m / z 343.3 [M + H]+.

[1104] References for the Synthesis of Building Blocks

[1105] Building Block Reference

[1106]

[1107] Compound was prepared using the method described on page 270-272 of XX?

[1108] WO20211275869.

[1109] OBn

[1110] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-l- methyl-IH-indazole

[1111]

[1112] Table 7: Preparation of building block

[1113] Synthesis of 7-broino-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole

[1114] l2. K3PO4

[1115] DMF

[1116] Step-1

[1117]

[1118] Step-1:

[1119] To a 500 mL multi-neck round-bottom flask containing a well-stirred solution of 7 -bromo- 1H- indazole (1, 10 g, 50.75 mmol) in DMF (110 mL) was added potassium phosphate tribasic (16.16 g. 76.13 mmol) and iodine (19.32 g, 76.13 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction as determined by UPLC- MS, the reaction mixture was quenched by the addition of an aqueous sodium sulphite solution, at which point a precipitate formed. The precipitate was filtered and dried under reduced pressure to afford 7-bromo-3-iodo-1H-indazole (2, 15 g, 45.99 mmol, 90% yield) as an off-white solid, which was used without further purification. LC-MS (ES+): m / z 322.9 [M + H]+.

[1120] Step-2:

[1121] To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 7-bromo-3-iodo-1H-indazole (2, 7.5 g, 22.45 mmol) in DMF (75 mL) was added potassium hydroxide (4.41 g. 78.56 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 10 min. Then dimethyl sulfate (44.89 mmol, 4.26 mL) was added, and the resulting reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was diluted with ice-cold water (150 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude residue was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 30% ethyl acetate in petroleum ether) to afford 7-bromo-3-iodo-l -methylindazole (3, 3.5 g, 9.48 mmol, 42% yield) as a white solid and 7-bromo-3-iodo-2 -methylindazole (2 g, 5.61 mmol, 25% yield) as an off-white solid. LC-MS (ES+): m / z 336.9 [M + H]+Step-3:

[1122] To a 500 mL single-neck round-bottom flask containing a well-stirred solution of 7-bromo-3-iodo-1-methyl-indazole (3, 5 g, 13.95 mmol) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (4, 5.24 g. 12.55 mmol) in 1.4-dioxane (42 mL) and water (8 mL) was added sodium carbonate (4.44 g, 41.85 mmol, 1.75 mL) at room temperature. The resulting reaction mixture was purged by bubbling nitrogen gas through the reaction mixture for 2 min. Then Pd(dppf)Cl2·DCM (569.54 mg, 697.42 pmol) was added, and the resulting reaction mixture was heated to 90 °C and stirred for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the Celite bed was washed with ethyl acetate (100 mL). The filtrate was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford the crude residue, which was purified by flash column chromatography (Stationary' Phase: 60-120 mesh silica gel; Eluent: 4-8% ethyl acetate in petroleum ether) to afford 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (5, 3.4 g, 6.51 mmol, 46% yield) as an off-white solid. LC-MS (ES+): m / z 500.0 [M + H]+.

[1123] Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-indazole and 3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazole

[1124] l2, NaOH Mel, KOH

[1125] 1,4-dioxane / H2O DMF Step-1 Step-2

[1126]

[1127] 1B2pin2, KOAc Pd(dppf)CI2-DCM 1,4-dioxane Step-4 Pd(dppf)CI2-DCM Na2CO3, 1,4-dioxane / H20

[1128]

[1129] Step-3

[1130] Step-1:

[1131] To a 500 mL single-neck round-bottom flask containing a well stirred solution of 6-bromo-5-fluoro-1H-indazole (1, 7 g, 32.55 mmol) in 1,4-dioxane (70 mL) and water (7 mL) was added sodium hydroxide pellets, 98% (3.91 g, 97.66 mmol) and iodine (9.92 g, 39.07 mmol) under nitrogen atmosphere at room temperature, the resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (500 mL). The organic layer was washed with 10 % sodium bicarbonate solution (250 mL), sodium thiosulfate solution (250 mL) and brine (100 mL). The organic layer was then dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford 6-bromo-5-fluoro-3-iodo-lH-indazole (2, 10 g, 27.54 mmol, 84.60% yield) as a brown solid. LC-MS (ES ): m / z 340.8 [M - H]’.

[1132] Step-2:

[1133] To 500 mL single-neck round-bottom flask containing a w ell stirred solution of 6-bromo-5-fluoro-3-iodo-lH-indazole (2, 10 g, 29.33 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added potassium hydroxide, flake, 85% (4.94 g, 88.00 mmol) followed by iodomethane (5.00 g, 35.20 mmol, 2.19 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After complete consumption of the starting material, the reaction mixture was diluted w ith ice cold water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (60-120 mesh silica gel) using a gradient of 0-10% ethyl acetate in petroleum ether to afford 6-bromo-5-fluoro-3-iodo-l-methyl-indazole (3, 4.5 g, 12.60 mmol, 42.97% yield) as an off-white solid. LC-MS (ES+): m / z 357.0 [M + H]+.

[1134] Step-3:

[1135] To a 250 mL sealed tube containing a well-stirred solution of 6-bromo-5-fluoro-3-iodo-l-methyl -indazole (3, 4.5 g, 12.68 mmol) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (4, 5.82 g, 13.95 mmol) in a mixture of 1,4-dioxane (50 mL) and water (5 mL) was added sodium carbonate (4.03 g, 38.03 mmol) at roomtemperature under a nitrogen atmosphere. The resulting mixture was purged with nitrogen gas for 10 min before bis(l-diphenylphosphanylcyclopenta-2,4-dien-l-yl)iron;dichloromethane;dichloropalladium (1.04 g, 1.27 mmol) was added. The resulting mixture was heated at 80 °C for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature, poured into water (200 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Stationary Phase: silica gel, 100-200 mesh) using a gradient of 0-100% ethyl acetate in petroleum ether to afford 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-indazole (5, 5.3 g, 8.81 mmol, 69.48% yield) as a off white solid. LC-MS (ES+): m / z 520.1 [M + H]+.

[1136] Step-4:

[1137] To a 250 mL single-neck round-bottom flask containing a well stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-indazole (5, 1.8 g, 2.99 mmol) in dry 1,4-dioxane (30 mL) was added 4.4.5.5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.28 g, 8.97 mmol) and potassium acetate (880.76 mg, 8.97 mmol) under a nitrogen atmosphere. The reaction mixture was degassed by bubbling nitrogen gas into the reaction mixture for 10 minutes. Subsequently, Pd(dppf)Cl2·CH2Cl2(244.29 mg, 299.15 pmol) was added, and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was then filtered through a pad of Celite and the Celite pad was washed with dichloromethane (200 mL). The filtrate was concentrated under reduced pressure and the crude was purified by flash column chromatography (100 g, silica gel 230-400 mesh) using a gradient of 0-100% ethyl acetate in pet ether to afford 3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-6-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazole (6, 1.7 g, 1.96 mmol, 66.0% yield) as a brown gummy liquid. LC-MS (ES+): m / z 566.3 [M + H]+.

[1138] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (B-8)

[1139]

[1140] Compound 3-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)piperidine-2, 6-dione was prepared using the method described on page 197 of WO202112758610.3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (B-9)

[1141]

[1142] Compound 3-(l-methyl-6-(piperazin-l-yl)-1H-indazol-3-yl)piperidine-2, 6-dione was prepared using the method described on page 301-303 of WO202513760511.

[1143] Synthesis of 3-(l-methyl-7-piperazin-l-yl-indazol-3-yl)piperidine-2, 6-dione (B-10)

[1144]

[1145] Step-1:

[1146] To a 40 mL screw-capped vial containing well-stirred solution of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (500 mg, 829.36 pmol) and terf-butyl piperazine- 1 -carboxyl ate (154.47 mg, 829.36 pmol) in 1,4-dioxane (5 mL) was added sodium terf-butoxide (199.26 mg, 2.07 mmol) at room temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Then RuPhos Pd G3 (69.36 mg. 82.94 pmol) was added and the reaction mixture was stirred at 90 °C for 5 h. The resulting reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 25 to 30% EtOAc in pet ether) to afford tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl] piperazine- 1 -carboxyl ate (550 mg, 293.38 pmol, 35.37% yield) as a yellow viscous oil. LC-MS (ES+): m / z 606.2 [M + H]+

[1147] Step-2:

[1148] To a 100 mL single-neck round-bottom flask containing a well-stirred suspension of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-7-yl]piperazine-1-carboxylate (550 mg, 293.38pmol) in ethanol (5 mL) and 1,4-dioxane (20 mL) was added 20 wt.% Palladium hydroxide on carbon. 50% water (412.02 mg, 586.75 pmol) at room temperature and the resulting suspension was stirred at room temperature under hydrogen atmosphere for 5 h with 1 atm of hydrogen pressure. After completion of the reaction as indicated UPLC, the reaction mixture was filtered through a pad of Celite, which was subsequently washed with a mixture of ethanol and 1,4-dioxane (1:9). The combined filtrate was concentrated under reduced pressure to afford tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperazine-l-carboxylate (140 mg, 289.17 pmol, 98.57% yield) as a light-brown solid. LC-MS (ESI): m / z 428.3 [M + H]+

[1149] Step-3:

[1150] To a 50 mL single neck round bottom flask containing well stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperazine-l-carboxylate (140 mg. 289.17 pmol) in DCM (3 mL) was added 4.0 M HC1 in 1,4-dioxane (4 M, 72.29 pL) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. After completion of reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with MTBE (5 mL x 3) and dried over under reduced pressure to afford 3-(l-methyl-7-piperazin-l-yl-indazol-3-yl)piperidine-2,6-dione hydrochloride (110 mg, 278.14 pmol, 96.19% yield) as a light-brown solid. UPLC-MS (ES+): m / z 328.2 [M + H]+

[1151] Synthesis of 3- [6-(3,9-diazaspiro [5.5]undecan-3-yl)-l-methyl-indazol-3-yl] piperidine-2,6-dione (B-ll)

[1152]

[1153] Step-1:To a 500 mL three-neck round-bottom flask containing a well-stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1, 3 g, 6.00 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2, 1.98 g, 7.79 mmol) in 1,4-dioxane (40 mL) was added Cesium carbonate (3.91 g, 11.99 mmol). Then the mixture was degassed by bubbling nitrogen gas into the reaction mixture for 10 minutes. Subsequently, XPhos (571.62 mg, 1.20 mmol) and Pd2(dba)3 (549.01 mg, 599.54 pmol) were added and the contents were stirred at 90 °C for 16 h. After completion of the reaction as indicated by LC-MS, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The resulting crude material was purified by flash silica-gel column (230-400 mesh silica-gel) using a gradient of 0-100% ethyl acetate / pet ether as eluent to afford / e / 7-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (3, 3.5 g, 4.92 mmol, 81.99% yield) as a yellow solid LC-MS (ES+): m / z 674.4 [M + H]+.

[1154] Step-2:

[1155] To a 500 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-ylJ-3,9-diazaspiro[5.5Jundecane-3-carboxylate (3.5 g, 4.92 mmol) in methanol (60 mL) was added acetic acid (295.19 mg, 4.92 mmol, 5 mL) and 20% Pd(OH)2 on Carbon (wetted with ca. 55% water) (1.38 g, 1.97 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere (~1 kg / cm2) for 16 h. After completion of the reaction as indicated by LC-MS, the reaction mixture was filtered through a pad of celite and the celite bed was washed with mixture of dichloromethane (250 mL) and methanol (250 mL). The filtrate was concentrated under reduced pressure and the crude was purified by flash column chromatography (silica gel, 230-400 mesh) using a gradient of 0-100%ethyl acetate in pet ether as eluent to afford tert- butyl 9-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.8 g, 3.58 mmol, 72.85% yield) as an off white solid. LCMS (ES+): m / z 496.4 [M + H]+.

[1156] Step-3:

[1157] To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-l -methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.8 g, 3.58 mmol) in anhydrous dichloromethane (10 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (17.90 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. After completion of the starting material as indicated by LC-MS, excess solvent was removed from the reaction mixture under reduced pressure. The crude product was washed with pet ether (2 x 50 mL) to afford 3-[6-(3,9-diazaspiro[5.5]undecan-3-yl)-l-methyl-indazol-3-yl]piperidine-2, 6-dione (1.3 g, 3.14 mmol, 87.79% yield) as an off-white solid. LC-MS (ES+): m / z 396.3 [M + H]+.

[1158] Synthesis of 3- [6-(2,6-diazaspiro [3.3] heptan-2-yl)- l-methyl-indazol-3-yl] piperidine-2,6-dione (B-12)

[1159]

[1160] Step-1:

[1161] To a 40 mL screw-cap vial containing a well-stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (1, 1 g, 1.95 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2, 387.58 mg, 1.95 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (1.27 g. 3.91 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes. Then XPhos (93.19 mg, 195.49 pmol) and Pd2(dba)3(179.01 mg, 195.49 pmol) were added and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 50% to 55% Ethyl acetate in Petroleum ether) to afford tert-butyl 6-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (3, 1.1 g, 1.73 mmol, 88% yield) as an off-white solid. LC-MS (ES+): m / z 618.3 [M + H]+.

[1162] Step-2:

[1163] To a 50 mL single-neck round-bottom flask containing a well stirred solution of tert-butyl 6-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (3, 1.1 g, 1.74 mmol) in 1,4-dioxane (10 mL) was added 20% palladium hydroxide on carbon (214.95 mg, 1.74 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere (bladder pressure). After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude compound was triturated with petroleum ether to afford fe / 7-butyl 6-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (4, 600 mg, 1.27 mmol, 72% yield) as an off-white solid. LC-MS (ES+): m / z 440.3 [M + H]+.

[1164] Step-3:

[1165] To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 6-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (4, 250 mg. 528.38 pmol) in DCM (5 mL) was added TFA (2.64 mmol. 202.17 pL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. After completion the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the crude product was triturated with MTBE (10 mL) to afford 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-l-methyl-indazol-3-yl]piperidine-2, 6-dione trifluoroacetate (B-12, 250 mg, 463.15 pmol, 87% yield) as a light brown solid. LC-MS (ES+): m / z 340.0 [M + H]+.

[1166] Synthesis of 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-5-fluoro-l-methyl-indazol-3-yl]piperidine-2, 6-dione (B-13)

[1167]

[1168] Step-1:

[1169] To a 40 mL screw-cap vial containing a well stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-5 -fluoro- 1 -methyl-indazole (1, 1 g, 1.72 mmol) and ferf-buty 1 2,6-diazaspiro[3.3]heptane-2-carboxylate (2, 340.40 mg, 1.72 mmol) in anhydrous 1,4 dioxane (10 mL) was added Cs2CO3(1.12 g, 3.43 mmol) at ambient temperature. The mixture was purged with N2 for 5 min and PEPPSI™-IPr (116.66 mg, 171.69 pmol) was added at ambient temperature and the reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through a pad of celite and the celite pad was washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure and the crude was purified by flash chromatography [Silica gel. 60-120 mesh: 100 g snap cartridge; flow rate = 30 mL / min] using a gradient of 0-100% ethyl acetate in petroleum ether as eluent to afford tert-buty l 6-[3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-indazol-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (3, 750 mg, 908.41 pmol, 52.91% yield) as a yellow solid. LC-MS (ES+): m / z 636.2 [M + H]+.

[1170] Step-2:

[1171] To a stirred solution of tert-butyl 6-[3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-indazol-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (3, 750 mg, 908.41 pmol) in 1,4-dioxane (30 mL) was added 20% Pd(OH)2on Carbon (wetted with ca. 55% water) (637.86 mg, 908.41 pmol). The resulting reaction mixture was stirred at room temperature for 16 h under H2 atmosphere (bladder pressure). After completion of the reaction, the reaction mixture was filtered through a celite bed, which was subsequently washed with a mixture of THF and 1, 4-di oxane. The filtrate was concentrated under reduced pressure to afford tert-butyl 6-[3-(2,6-dioxo-3-piperidyl)-5-fluoro-l-methyl-indazol-6-yl]-2.6-diazaspiro[3.3]heptane-2-carboxylate (4, 400 mg, 837.60 pmol, 92.21% yield) as a brown gummy solid. LC-MS (ES+): m / z 458.1 [M + H]+

[1172] Step-3:

[1173] To a 10 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 6-[3-(2,6-dioxo-3-piperidyl)-5-fluoro-l-methyl-indazol-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (4, 400.00 mg, 837.60 pmol) in DCM (5 mL) was added TFA (1.49 g, 13.07 mmol, 1 mL) and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was then concentrated under reduced pressure to afford 3-[6-(2, 6-diazaspiro[3.3]heptan-2-yl)-5-fluoro-l-methyl-indazol-3-yl]piperidine-2, 6-dione trifluoroacetate (B-13, 350 mg, 690.49 pmol, 82.44% yield) as an off-white solid. LC-MS (ES+): m / z 358.1 [M + H]+.

[1174] Synthesis of 3-[7-(2,6-diazaspiro[3.3]heptan-2-yl)-1-methyl-indazol-3-yl]piperidine-2,6-dione (B-14)

[1175]

[1176] Step-1:

[1177] To a 40 mL screw-cap vial containing a well-stirred solution of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (1, 1 g, 1.72 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2, 683.00 mg, 3.44 mmol) in 1,4-dioxane (20 mL) was added Cs2CO3(1.68 g, 5.17mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes. Then. Pd-PEPPSI-IHept-Cl (167.56 mg, 172.25 pmol) was added and the reaction mixture was stirred at 110 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (Stationary' Phase: 60-120 mesh silica gel; Eluent: 30-35% ethyl acetate in petroleum ether) to afford tertbutyl 6-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (3, 1 g, 1.54 mmol, 89% yield) as an off-white solid. LC-MS (ES+): m / z 618.3 [M + H]+

[1178] Step-2:

[1179] To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 6-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (3, 1 g, 1.54 mmol) in 1,4-dioxane (30 mL) was added 20% palladium hydroxide on carbon (1.08 g, 7.68 mmol) at room temperature. The resulting reaction mixture was stirred under hydrogen atmosphere at room temperature for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 90-100% Ethyl acetate in Petroleum ether) to afford tert-butyl 6-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (4, 550 mg. 1.22 mmol, 79% yield) as an off-white solid. LC-MS (ES+): m / z 440.1 [M + H]+

[1180] Step-3:

[1181] To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 6-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (4. 250 mg, 553.46 pmol) in DCM (5 mL) was added TFA (6.53 mmol, 0.5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure, and the residue was co-distilled with toluene. The crude material was triturated with MTBE to afford 3-[7-(2,6-diazaspiro[3.3]heptan-2-yl)-l-methyl-indazol-3-yl]piperidine-2.6-dione trifluoroacetate (B-14, 200 mg, 361.17 pmol, 65% yield) as an off-white solid. LC-MS (ES+): m / z 340.3 [M + H]+Synthesis of 3- [6-(2-azaspiro [3.3]heptan-6-yl)-l-methyl-indazol-3-yl] piperidine-2, 6-dione (B-15)

[1182] I

[1183]

[1184] B-15 / Step-1:

[1185] To a 250 mL round-bottom flask containing a well-stirred suspension of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (1. 5 g. 9.99 mmol) in 1,4-dioxane (50 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (5.07 g, 19.98 mmol) and potassium acetate (2.45 g, 24.98 mmol) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 min before Pd(dppf)C12 CH2CI2 (408.01 mg, 499.61 pmol) was added to the mixture. The resulting mixture was heated at 80 °C for 16 h. The reaction mixture treated with ethyl acetate (250 mL) and filtered through a pad of celite (6 g) and the celite pad was washed with ethyl acetate (2 x 100 mL). The filtrate was concentrated under reduced pressure and the crude material was purified by flash column chromatography (silica gel, 100-200 mesh) using a gradient of 0-100% ethyl acetate in petroleum ether as eluent to afford 3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) indazole (2, 5 g, 7.86 mmol, 79% yield) as a brown gum. LCMS (ES+): m / z 548.2 [M + H]+.Step-2:

[1186] To a 500 mL multi -neck round botom flask containing a well-stirred solution of terr- butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1, 10 g, 47.34 mmol) in anhydrous tetrahydrofuran (150 mL) was added a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (94.67 mL, 94.67 mmol) at -78 °C. The resulting reaction mixture was stirred at -78 °C under nitrogen atmosphere for i h. Then, N-(5 -chloro-2-pyridy 1)- 1,1,1 -trill uoro-A-(trifluoromethylsulfonyl)methanesulfonamide (2, 27.88 g, 71.00 mmol) in anhydrous tetrahydrofuran (50 mL) was added to the reaction mixture at -78 °C and the resulting reaction mixture was gradually w armed to room temperature and stirred at room temperature for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with a brine solution (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the crude compound which was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 10-15% Ethyl acetate in Petroleum ether) to afford tert-butyl 6-(trifluoromethylsulfonyloxy)-2-azaspiro[3.3]hept-6-ene-2-carboxylate (3, 6 g, 17.46 mmol, 36% yield) as an off-white solid. LC-MS (ES+): m / z 244.1 [M-COOtBu + H]+.

[1187] Step-3:

[1188] To a 40 mL screw-cap vial containing a well-stirred solution of tert-butyl 6-(trifluoromethylsulfonyloxy)-2-azaspiro[3.3]hept-6-ene-2-carboxylate (3, 949.87 mg, 2.76 mmol) and 3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazole (4, 1 g, 1.63 mmol) in anhydrous 1,4-di oxane (18 mL) and water (2 mL) was added sodium carbonate (516.87 mg, 4.88 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 min. Then, Pd(dppf)Cl₂·CH₂Cl₂ (132.75 mg, 162.55 μmol) was added and the reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 45-50% Ethyl acetate in Petroleum ether) to afford tert-butyl 6-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-2-azaspiro[3.3]hept-6-ene-2-carboxylate (5, 1 g, 992.79 pmol. 61% yield) as an off-white solid. LC-MS (ES+): m / z 615.3 [M + H]+.

[1189] Step-4:

[1190] To a 50 mL single-neck round-bottom flask containing a w ell stirred solution of tert-butyl 6-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-2-azaspiro[3.3]hept-6-ene-2-carboxylate (5,1 g, 993.44 pmol) in anhydrous 1,4-dioxane (10 mL) was added 20% palladium hydroxide on carbon (697.59 mg, 993.44 pmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 30-35% acetonitrile in dichloromethane) to afford tert-butyl 6-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-2-azaspiro[3.3]heptane-2-carboxylate (6, 500 mg, 958.91 pmol, 96% yield) as an off-white solid. LC-MS (ES+): m / z 439.1 [M + H]+.

[1191] Step-5:

[1192] To a 25 mL single-neck round-bottom flask containing a well stirred solution of tert-butyl 6-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-2-azaspiro[3.3]heptane-2-carboxylate (6, 150 mg, 287.67 pmol) in anhydrous dichloromethane (5 mL) was added trifluoroacetic acid (1.31 mmol, 0.1 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. After complete consumption of the starting material as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure, and the crude product was co-distilled with toluene and triturated with methyl tert-butyl ether to afford 3-[6-(2-azaspiro[3.3]heptan-6-yl)-l-methyl-indazol-3-yl]piperidine-2, 6-dione trifluoroacetate (B-15, 150 mg, 194.29 pmol, 67% yield) as an off-white sold. LC-MS (ES+): m / z 339.0 [M + H]+.

[1193] Synthesis of 3-(7-piperazin-l-ylpyrazolo[l,5-a]pyridin-3-yl)piperidine-2, 6-dione (B-16)

[1194] OBn

[1195]

[1196] Step-1:To a 100 mL single-neck round-bottom flask containing a well-stirred solution of3-iodopyrazolo[l,5-a]pyridine (1, 5 g, 19.45 mmol) and 2,6-dibenzyloxy-3-(4.4.5.5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (2, 11.35 g, 19.45 mmol) in water (10 mL) and anhydrous 1,4 dioxane (40 mL) was added sodium carbonate (6.18 g, 58.34 mmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 5 minutes. Subsequently, Pd(dppf)C12-CH2C12(1.59 g, 1.94 mmol) was added and the reaction mixture was heated to 100 °C for 3 h. After completion of the reaction as indicated by LCMS, the reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (Stationary Phase: 60-120 mesh silica-gel; Eluent: 0-100% ethyl acetate / pet ether) to afford 3-(2,6-dibenzyloxy-3-pyridyl)pyrazolo[l,5-a]pyridine (3, 5.4 g, 11.48 mmol, 59.03% yield) as a brown solid. LC-MS (ESI): m / z 408.2 [M + H]+.

[1197] Step-2:

[1198] To a 100 mL three-neck round-bottom flask containing a well-stirred solution of3-(2,6-dibenzx loxy-3-pyridyl)pyrazolo[l,5-a]pyridine (3, 2 g, 4.25 mmol) in THF (20 mL) was added tetramethylpiperidine magnesium chloride (1 M, 8.50 mL) at -78 °C under inert atmosphere. The mixture was stirred at the same temperature for 30 min before 1,2-dibromotetrachloroethane (2.77 g. 8.50 mmol, 1.02 mL) in THF was added at -78°C and the reaction mixture was stirred to 25 °C for 16 h under an inert atmosphere. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 mL), quenched with an NH4CI solution (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)pyrazolo[l,5-a]pyridine (4, 1.68 g, 3.34 mmol, 78.50% yield) as a brown liquid. LCMS (ESI): m / z 488.0 [M + H]+.

[1199] Step-3:

[1200] To a 20 mL screw-cap vial containing a well-stirred solution of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)pyrazolo[l,5-a]pyridine (4, 600 mg, 1.232 mmol) in 1,4-dioxane (5 mL) was added tert-butyl piperazine- 1 -carboxylate (5, 229.8 mg, 1.232 mmol). The resulting reaction mixture was purged by bubbling nitrogen gas through the reaction mixture for 2 min. Then PEPPSI-ihept-Cl (83.8 mg. 123.3 pmol) and Cs2CO3(803.8 mg, 2.46 mmol) were added, and the reaction mixture was heated to 100 °C and stirred for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was cooled to room temperature and filtered through a pad ofCelite and the Celite bed was washed with ethyl acetate (100 mL). The filtrate was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: 30 % ethyl acetate in petroleum ether) to afford tert-butyl 4-[3-(2, 6-dibenzyloxy-3-pyridyl)pyrazolo[l,5-a]pyridin-7-yl]piperazine-l -carboxylate (6, 300 mg, 435.02 pmol, 36% yield) as a brown solid. LC-MS (ES+): m / z 592.3 [M + H]+.

[1201] Step-4:

[1202] To a well-stirred solution of terf-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)pyrazolo[l,5-a]pyridin-7 -yl]piperazine-l -carboxylate (6, 300 mg, 430.96 pmol) in ethanol (7.5 mL) and THF (7.5 mL) was added 20 % Pd(OH)2 on carbon (302.61 mg, 430.96 pmol). The resulting reaction mixture was stirred under a hydrogen atmosphere at bladder pressure at room temperature for 4 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with THF:l,4-dioxane (1:1, 100 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)pyrazolo[1,5-a]pyridin-7-yl]piperazine-1-carboxylate (7, 170 mg, 357.71 pmol, 83% yield) as a brown solid, which was used without further purification. LC-MS (ES+): m / z 414.1 [M + H]+

[1203] Step-5:

[1204] To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)pyrazolo[1,5-a]pyridin-7-yl]piperazine-1-carboxylate (7, 170.00 mg, 357.71 pmol) in DCM (2 mL) was added 4 M HC1 in 1,4-dioxane (894.26 pL, 3.576 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. Upon completion of reaction determined by UPLC-MS, the reaction mixture was concentrated under reduced pressure to afford 3-(7-piperazin-l-ylpyrazolo[1.5-a]pyridin-3-yl)piperidine-2, 6-dione hydrochloride (B-16, 150 mg, 248.70 pmol, 70% yield) as a brown solid, which was used without further purification. LC-MS (ES+): m / z 314.3 [M + H]+.Synthesis of 3-[7-(4-piperidyl)-l,2-benzoxazol-3-yl]piperidine-2, 6-dione (B-17)

[1205]

[1206] Step-7 Step-1:

[1207] To 250 mL single-neck round-bottom flask containing a well-stirred solution of l-(3-bromo-2-hydroxy-phenyl)ethanone (1, 7 g, 32.55 mmol) in toluene (100 mL) were added 60% sodium hydride (7.81 g, 195.31 mmol) and diethyl carbonate (2, 130.21 mmol, 15.78 mL) at 0 °C. The reaction mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with ice water (400 mL) and extracted with EtOAc (2 x 400 mL). The aqueous layer was acidified with 2 N HC1 (300 mL) until the pH was 3-4. The obtained solid was filtered and dried to afford 8-bromo-4-hydroxy-chromen-2-one (3, 6.5 g, 26.48 mmol, 81% yield) as an off -white solid. LC-MS (ES‘ ): m'Z 238.9 [M-H]’

[1208] Step-2:

[1209] To 250 mL single-neck round-bottom flask containing a well-stirred solution of 8-bromo-4-hydroxy-chromen-2-one (3, 6.5 g, 26.43 mmol) in ethanol (150 mL) were added sodium acetate (6.50 g, 79.28 mmol) and hydroxylamine hydrochloride (3.67 g. 52.85 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. After completion of the reaction as indicated by UPLC-MS. The reaction mixture was concentratedunder reduced pressure and the crude was acidified with 2 N HC1 (400 mL) until the pH was 3-4. The obtained solid was filtered and dried to afford 2-(7-bromo-l,2-benzoxazol-3-yl) acetic acid (4, 5 g, 19.08 mmol, 72% yield) as an off-white solid. LC-MS (ES+): m / z 256.0 [M + H]+.

[1210] Step-3:

[1211] To 100 mL single-neck round-bottom flask containing a well-stirred solution of 2-(7 -bromo- 1,2-benzoxazol-3-yl) acetic acid (4, 800 mg, 3.03 mmol) in ethanol (10 mL) was added H2SO4 (297.24 mg, 3.03 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 4 h under nitrogen atmosphere. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the residue was quenched with saturated sodium bicarbonate solution (100 mL), and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford ethyl 2-(7-bromo-l,2-benzoxazol-3-yl)acetate (5, 500 mg, 1.57 mmol, 52% yield) as a pale-yellow liquid. LC-MS (ES+): m / z 286.0 [M + H]+.

[1212] Step-4:

[1213] To a 500 mL single-necked round-bottomed flask containing a well-stirred of ethyl 2-(7-bromo-l,2-benzoxazol-3-yl)acetate (5, 4 g, 12.53 mmol) in THF (150 mL) were added prop-2-enamide (6, 12.53 mmol, 673.71 pL) and potassium tert-butoxide (1.41 g, 12.53 mmol) at 0 °C and the reaction mixture was stirred at the same temperature for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with cold water (300 mL) and extracted with ethyl acetate (2 x 350 mL). The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude material was triturated using the methyl tert-butyl ether (30 mL) to afford 3-(7-bromo-l,2-benzoxazol-3-yl)piperidine-2, 6-dione (7, 2 g, 6.44 mmol. 51% yield) as a pale-yellow solid. LC-MS (ES ):m / z 308.9 [M -H] ’.

[1214] Step-5:

[1215] To a 40 mL screw-cap vial containing a well-stirred solution of 3-(7-bromo-l,2-benzoxazol-3-yl)piperidine-2, 6-dione (7, 1 g, 3.20 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2 / 7-pyridine-l-carboxylate (8, 990.30 mg, 3.20 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added triethylamine (1.26 mmol, 174.95 pL) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes. Then, Pd(dppf)C12'DCM (51.25 mg, 62.76 pmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with water (150 mL) and the aqueous layer was extracted with EtOAc (3 x 250 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and filtrate was concentrated under reduced pressure. The crude material was purified by flash columnchromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 30 to 40% ethyl acetate in petroleum ether) to afford tert-butyl 4-[3-(2.6-dioxo-3-piperidyl)-L2-benzoxazol-7-yl]-3,6-dihydro-2H-pyridine-l -carboxyl ate (9, 650 mg, 1.34 mmol, 42% yield) as a pale-yellow solid. LC-MS (ES+): m / z 312.2 [M- COOt-Bu + H]+.

[1216] Step-6:

[1217] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-l,2-benzoxazol-7-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (9, 200 mg, 413.17 pmol) in ethyl acetate (10 rnL) was added 10% palladium on carbon (131.91 mg, 124.20 pmol) at room temperature. The resulting reaction mixture was stirred under hydrogen atmosphere (bladder pressure) at room temperature for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate (200 rnL). The filtrate was concentrated under reduced pressure and the crude material was triturated using methyl / c / 7-bulyl ether (7 mL) to afford tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-l,2-benzoxazol-7-yl]piperidine-l-carboxylate (10, 130 mg, 218.46 pmol, 52.87% yield) as a pale-yellow solid. LC-MS (ES+): m / z 314.1 [M- COOt-Bu + H]+.

[1218] Step-7:

[1219] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of / c / 7-butyl 4-[3-(2,6-dioxo-3-piperidyl)-l,2-benzoxazol-7-yl]piperidine-l-carboxylate (10, 130 mg, 220.09 pmol) in 1,4-dioxane (5 mL) was added 4 M HCl in 1,4-dioxane (2.19 mmoL 547.06 pL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the crude residue was triturated with MTBE (5 mL) and dried to afford 3-[7-(4-piperidyl)-l,2-benzoxazol-3-yl]piperidine-2.6-dione hydrochloride (B-17, 90 mg, 218.33 pmol, 99% yield) as a pale-yellow solid. LC-MS (ES+): m / z 314.3 [M + H]+.Synthesis of 2,6-dibenzyloxy-7V-(4-bromo-3,5-difluoro-phenyl)pyridin-3-amine and afford 2,6-dibenzyloxy-7V-[3,5-difhioro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl] pyridin-3-amine

[1220]

[1221] Step-1:

[1222] To five 40 mL vials containing a well stirred solution of 2-bromo-l,3-difluoro-5-iodo-benzene (1, 5 g. 15.68 mmol) and 2,6-dibenzyloxypyridin-3-amine (2. 5.31 g, 15.68 mmol) in anhydrous 1,4-dioxane (80 mL) was added sodium / e / 7-butoxide (3.77 g, 39.20 mmol) at ambient temperature. The mixture was purged with N2 for 5 min before Xantphos (1.81 g, 3.14 mmol) and Pd(dba)2 (901.58 mg, 1.57 mmol) were added to the reaction mixture at ambient temperature. The resulting reaction mixture was stirred at 90°C for 1 hour. After completion of reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure and the crude material was purified by flash chromatography (Stationary Phase: 60-120 mesh silica gel, 340 g snap cartridge; flow rate = 60 mL / min; Eluent: gradient from 0-20% ethyl acetate in petroleum ether) to afford 2.6-dibenzyloxy-A-(4-bromo-3,5-difluoro-phenyl)pyridin-3-amine (3, 7 g, 13.14 mmol, 83.83% yield) as a yellow gummy. LC-MS (ES+): m / z 497.1 [M + H]+.

[1223] Step-2:

[1224] To a 40 ml screw-cap vial containing a well-stirred solution of 2,6-dibenzyloxy-N-(4-bromo-3,5-difluoro-phenyl)pyridin-3-amine (3, 2.14 g, 4.02 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4, 1.02 g, 4.02 mmol) in 1,4-dioxane (20 mL) was added potassium acetate (1.18 g, 12.06 mmol) at room temperature. The reaction mixture was purged with N2 for 5 min before Pd(dppf)C12 DCM (328.41 mg, 402.15 pmol) and the reaction mixture was stirred at 90 °C for 12 h. After completion of the reaction indicated by LCMS, the reaction mixture was filtered through a pad of Celite and the Celite pad was washedwith ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure and the crude residue was quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine solution (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2,6-dibenzyloxy-N-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridin-3-amine (5, 1.5 g, 1.99 mmol, 49.43% yield) as a brown gummy solid. LC-MS (ES+): m / z 544.2 [M + H]+

[1225] 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione (B-18)

[1226]

[1227] Compound 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 265 of WO201823702612.

[1228] 3-((3,5-difhioro-4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione (B-19)

[1229]

[1230] H

[1231] Compound 3-((3,5-difluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dionewas prepared using the method described on page 254-255 of WO202226125013.

[1232] 3-((3^-difluoro-4-(piperazin- l-yl)phenyl)amino)piperidine-2, 6-dione (B-20)

[1233]

[1234] O

[1235] Compound 3-((3,5-difluoro-4-(piperazin-l-yl)phenyl)amino)piperidine-2, 6-dione was prepared using the method described on page 167-168 of W0202203202614.Synthesis of 3-[4-(3,3-difhioro-4-piperidyl)-3,5-difhioro-anilino]piperidine-2, 6-dione (B-21)

[1236]

[1237] Step-1:

[1238] To a 250 mL multi-neck round-bottom flask containing a well-stirred solution of tert-butyl 3,3-difluoro-4-oxo-piperidine-l -carboxylate (1, 5 g, 21.26 mmol) in dichloromethane (50 mL) was added EhN (63.77 mmol, 8.89 mL) and trifluoromethanesulphonic anhydride (25.51 mmol, 4.19 mL) at -75 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 h. Upon completion of the reaction as determined by TLC, the reaction mixture was diluted with saturated ammonium bicarbonate solution (300 mL) and extracted with dichloromethane (400 mL x 2). The combined organic layer was washed with water (350 mL), brine (300 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude compound, which was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: Gradient from 15 -20% ethyl acetate in petroleum ether) to afford tert-butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)-2,6-dihydropyridine-l -carboxylate (2, 2.6 g, 5.66 mmol, 26% yield) as a pale yellow liquid. 'H NMR (400 MHz, DMSO-d6): δ 6.32 (s. 1H), 4.26 (s. 2H). 3.99 (t, J=8. 2H), 1.51 (s, 9H).

[1239] Step-2:

[1240] To a 40 mL vial containing a well-stirred solution of / -butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)-2,6-dihydropyridine-l-carboxylate (2, 2.5 g, 5.45 mmol) and 2,6-dibenzyloxy-N-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridin-3-amine (3, 3.71 g, 5.45 mmol) in THF (15 mL) and water (2 mL) was added K3PO4 (2.31 g, 10.89mmol) at room temperature. The resulting reaction mixture was purged with nitrogen gas by bubbling nitrogen gas through the reaction mixture for 2 min. Then XPhos Pd G3 (460.92 mg, 544.53 pmol) was added, and the resulting reaction mixture was heated to 80 °C and stirred for 4 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the fdtrate was concentrated under reduced pressure to afford the crude compound, which was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 15-20% ethyl Acetate in petroleum ether) to afford tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2,6-difluoro-phenyl]-3,3-difluoro-2,6-dihydropyridine-l-carboxylate (4, 820 mg, 1.15 mmol, 21% yield) as a pale yellow solid. LC-MS (ES+): m / z 636.2 [M + H]+.

[1241] Step-3:

[1242] To a 50 mL single-neck round-bottom flask containing a well-stirred suspension of tert-butyl 4-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2,6-difluoro-phenyl]-3,3-difluoro-2,6-dihydropyridine-l-carboxylate (4, 820 mg, 1.15 mmol) in THF (7 mL) and ethanol (7 mL) was added 20% Palladium hydroxide on carbon (800 mg, 1.15 mmol). The resulting reaction mixture was stirred under a H2 atmosphere at bladder pressure at room temperature for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was filtered and washed with THF (180 mL) and ethanol (180 mL). The filtrate was concentrated under reduced pressure to afford the crude residue, which was purified by reverse phase column chromatography [Column: RediSep R / Gold® C18-120 g, Mobile phase A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile] to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,3-difluoro-piperidine-l -carboxylate (5, 300 mg, 605.57 pmol, 52% yield) as a pale yellow solid. LC-MS (ES‘): mz 458.1 [M - H]’.

[1243] Step-4:

[1244] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,3-difluoro-piperidine-l -carboxylate (5, 300 mg, 605.57 pmol) in anhydrous DCM (10 mL) was added trifluoroacetic acid (6.06 mmol, 463.40 pL) at 0 °C. The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was concentrated under reduced pressure to afford the crude residue which was triturated with MTBE (7 mL) and dried in vacuo to afford 3-[4-(3,3-difluoro-4-piperidyl)-3,5-difluoro-anilino]piperidine-2, 6-dione trifluoroacetate (B-21, 250 mg, 516.49 pmol, 85% yield) as a pale yellow solid, which was used without further purification. LC-MS (ES+): mz 360.1 [M + H]+.Syn thesis of 3- [4-(4,7-diazaspiro [2.5] octan-7-yl)-3,5-difluoro-anilino] piperidine-2, 6-dione (B-22)

[1245] O

[1246]

[1247] Step-1:

[1248] To a 20 mL screw-cap vial containing a well-stirred solution of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (1, 500 mg, 2.36 mmol) in anhydrous DMF (8 mL) was added l,2,3-trifluoro-5-nitro-benzene (2, 417.08 mg, 2.36 mmol) and DIPEA (7.07 mmol, 1.23 mL) at room temperature. The resulting suspension was heated to 70 °C and stirred for 16 h. Upon complete consumption of the starting material as determined by UPLC-MS, the reaction mixture was concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: Gradient from 20-30% ethyl acetate in petroleum ether) to afford tert-butyl 7-(2,6-difluoro-4-nitro-phenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (3, 480 mg, 986.22 pmol, 42% yield) as a pale-yellow solid. LC-MS (ES+): m / z 314.0 [M-isobutene + H]+.

[1249] Step-2:

[1250] To a 50 mL single-necked round-bottomed flask containing a well-stirred suspension of tertbutyl 7-(2,6-difluoro-4-nitro-phenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (3, 480 mg, 974.65 pmol) in 1,4-dioxane (10 mL) was added 10% palladium on carbon (518.61 mg, 487.33 pmol). The resulting reaction mixture was stirred under hydrogen atmosphere at bladder pressure at room temperature for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was filtered, washed with methanol (100 mL), and the filtrate was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: Gradient from 30-40%Ethyl acetate in Petroleum ether) to afford tert-butyl 7-(4-amino-2,6-difluoro-phenyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (4, 350 mg. 761.84 pmol, 78% yield) as a pale-yellow solid. LC-MS (ES+): m / z 340.1 [M + H]+.

[1251] Step-3:

[1252] To a 20 mL screw-cap vial containing a well-stirred solution of terf-butyl 7-(4-amino-2,6-difluoro-phenyl)-4.7-diazaspiro[2.5]octane-4-carboxylate (4, 250 mg. 677.71 pmol) and 3-bromopiperidine-2,6-dione (5, 390.38 mg, 2.03 mmol) in DMF (7 mL) was added sodium bicarbonate (113.86 mg, 1.36 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was heated to 80 °C and stirred for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: Gradient from 40-50% ethyl acetate in petroleum ether) to afford / c / 7-butyl 7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4,7-diazaspiro[2.5]octane-4-carboxylate (6, 150 mg, 306.34 pmol, 45% yield) as a pale yellow solid. LC-MS (ES+): m / z 451.1 [M + H]+.

[1253] Step-4:

[1254] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of / c / 7-butyl 7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4,7-diazaspiro[2.5]octane-4-carboxylate (6, 140 mg, 285.92 pmol) in anhydrous DCM (5 mL) was added TFA (2.86 mmol, 218.80 pL) at 0 °C. The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. Upon completion of the reaction as determined by UPLC-MS, the reaction was concentrated under reduced pressure, and the resulting crude material was triturated using methyl / c / 7-butyl ether (5 mL)to afford 3-[4-(4.7-diazaspiro[2.5]octan-7-yl)-3.5-difluoro-anilino]piperidine-2,6-dione trifluoroacetate (B-22, 140 mg, 279.65 pmol, 97% yield) as a pale-yellow solid, which was used without further purification. LC-MS (ES+): m / z 351.2 [M + H]+.

[1255] Synthesis of 3-[4-(2,6-diazaspiro[3.3]heptan-2-yl)-3,5-difluoro-anilino]piperidine-2, 6-dione (B-23)

[1256]

[1257]

[1258] Step-1:

[1259] To a 40 mL screw cap vial containing a well stirred solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1, 1.5 g, 7.57 mmol) and 1,2, 3-trifluoro-5-nitro-benzene (2, 1.34 g, 7.57 mmol) in DMF (15 mL) was added Cs2CO3(4.93 g, 15.13 mmol) at room temperature. The resulting reaction mixture was stirred at 90 °C for 5 h. After completion of the reaction as indicated by the UPLC-MS, the reaction mixture was passed through a Celite-bed and the filtrate was concentrated under reduced pressure to afford the crude compound which was purified by silica gel chromatography (Stationary Phase: silica gel; 230-400 mesh, Eluent: 30%-40% ethyl acetate in petroleum ether) to afford tert-butyl 6-(2,6-difluoro-4-nitro-phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (3, 2.5 g, 6.55 mmol, 86.54% yield) as a yellow solid. LC-MS (ES+): m / z 256.1 [M + H - Boc]+.

[1260] Step-2:

[1261] To a 250 mL single-neck round-bottom flask containing well stirred solution of tert-butyl 6-(2,6-difluoro-4-nitro-phenyl)-2.6-diazaspiro[3.3]heptane-2-carboxylate (3, 2.5 g, 6.55 mmol) in ethyl acetate (13 mL) and methanol (13 mL) was added 10% Palladium on Carbon (wetted with ca.

[1262] 55% Water) (2.09 g, 19.64 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature under hydrogen atmosphere for 6 h. Upon completion of the reaction, the reaction mixture was passed through a Celite bed. and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 20-30% EtOAc in pet ether) to afford tert-butyl 6-(4-amino-2,6-difluoro-phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (4, 2 g, 5.97 mmol, 91.11% yield). LC-MS (ES+): m / z 326.1 [M + H]+.

[1263] Step-3:

[1264] To a 50 mL sealed tube containing a well-stirred solution of tert-butyl 6-(4-amino-2,6-difluoro-phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (4, 2 g, 5.96 mmol) and 3-bromopiperidine-2, 6-dione (5, 3.43 g, 17.89 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added sodium bicarbonate (1.50 g, 17.89 mmol) at room temperature. The reactionmixture was stirred at 80 °C for 16 h. After complete consumption of the starting material, the reaction mixture was washed with water and extracted with ethyl acetate (3 * 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound which was purified by reverse phase column chromatography [Column: RediSep® column; Mobile phase A: 0.1% Formic acid in milli-Q-water and Mobile phase B: Acetonitrile] to afford tert-butyl 6-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (6, 600 mg, 1.29 mmol, 21.67% yield) as an off-white solid. LC-MS (ES+): m / z 437.3 [M + H]+.

[1265] Step-4:

[1266] To a 25 mL single-neck round-bottom flask containing a well stirred solution of tert-butyl 6-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (6, 212.77 mg, 458.24 pmol) in anhydrous dichloromethane (5 mL) was added trifluoroacetic acid, 99% (1.49 g, 13.07 mmol, 1 mL) at 0°C. The resulting reaction mixture was stirred at room temperature for 2 h. After complete consumption of the starting material, the reaction mixture was distilled under reduced pressure to afford 3-[4-(2,6-diazaspiro[3.3]heptan-2-yl)-3,5-difluoro-anilino]piperidine-2,6-dione trifluoroacetate (B-23, 200 mg, 48.85 pmol, 10.66% yield) as a dark blue gummy liquid. LC-MS (ES+): m / z 336.2 [M + H]+.

[1267] 3-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)piperi(line-2, 6-dione (B-24)

[1268]

[1269] Compound 3-((3-fluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2.6-dione was prepared using the method described on 209-211 of W0202203202615.

[1270] 3-(4-(piperidin-4-yl)phenoxy)piperidine-2, 6-dione (B-25)

[1271] O N O

[1272] H

[1273]

[1274] NHCompound 3-(4-(piperidin-4-yl)phenoxy)piperidine-2, 6-dione was prepared using the method described on page 555 of WO202125521216.

[1275] Synthesis of 3-(4-piperazin-l-ylphenoxy)piperidine-2, 6-dione (B-26)

[1276] Pd2(dba)3

[1277]

[1278] Step-1:

[1279] To a 250 mL two-neck round-bottom flask containing a well stirred solution of 4-bromophenol (1, 2 g, 11.56 mmol) in toluene (25 mL) were added tert-butyl piperazine- 1 -carboxylate (2, 2.58 g, 13.87 mmol), XPhos (551.09 mg, 1.16 mmol) and Pd2(dba)3 (529.29 mg, 578.01 pmol) at room temperature under nitrogen atmosphere. Then LiHMDS (I M, 34.68 mL) was added at 0 °C under N2 atmosphere. The resulting reaction mixture was stirred at 80 °C for 2 h. Upon completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was triturated with Pet ether / EtOAc (4:1, 50 mL) to afford tert-butyl 4-(4-hydroxyphenyl)piperazine-l -carboxylate (3, 3 g, 10.57 mmol, 91.42% yield) as a light-yellow solid. LC-MS (ES+): m / z 279.1 [M + H]+.

[1280] Step-2:

[1281] To a 25 mL two-neck round-bottom flask containing a well stirred solution of tert-butyl 4-(4-hydroxyphenyl)piperazine-l -carboxylate (3, 1 g, 3.52 mmol) was dissolved in DMF (10 mL) and cooled to 0-5°C. Then sodium hydride (60% dispersion in mineral oil) (352.23 mg, 8.81 mmol) was added portionwise and the mixture was stirred at 0-5°C for 30 min. Afterwards. 3-bromopiperidine-2.6-dione (4. 1.01 g, 5.28 mmol) was added and the reaction mixture was stirred at 0-5°C for 1 hour. Upon completion of the reaction, the reaction mixture was quenched by adding crushed ice and product was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude material w as purified by flash column chromatography(Stationary Phase: 60-120 mesh silica gel; Eluent: 50 to 60% EtOAc in pet ether) to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazine-l-carboxylate (5, 750 mg. 1.91 mmol, 54.30% yield) as a white solid. LC-MS (ES+): m / z 390.2 [M + H]+.

[1282] Step-3:

[1283] To a 100 mL single-neck round-bottom flask containing well-stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazine-l-carboxylate (5, 750 mg, 1.91 mmol) in DCM (10 mL) was added 4.0 M HC1 in 1,4-dioxane (4.78 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. The solvent was removed from the reaction mixture and the residue was co-distilled with toluene to afford 3-(4-piperazin-l-ylphenoxy)piperidine-2,6-dione hydrochloride (B-26, 600 mg, 1.70 mmol, 88.78% yield) as a brown gum. LC-MS (ES+): m / z 290.1 [M + H]+

[1284] Synthesis of 3-(3,5-difluoro-4-piperazin-l-yl-phenoxy)piperidine-2, 6-dione (B-27)

[1285] Boc Boc

[1286]

[1287] Step-1:

[1288] To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 1,2,3-trifluoro-5-nitro-benzene (1, 5 g, 28.24 mmol) and tert-butyl piperazine- 1 -carboxylate (2, 5.26 g, 28.24 mmol) in DMF (50 mL) was added Et₃N (11.8 mL, 84.71 mmol) and the resulting reaction mixture w as stirred at 100 °C for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate concentrated under reduced pressure to afford the cruderesidue. The crude residue was purified by flash silica gel column chromatography (Stationary' phase: 230-400 mesh silica gel; Eluent: 35 % ethyl acetate in petroleum ether) to afford tertbutyl 4-(2,6-difluoro-4-nitro-phenyl)piperazine-l -carboxylate (3, 7 g, 18.78 mmol, 66% yield) as a yellow solid. LC-MS (ES+): m / z 244.1 [M-COOtBu + H]+

[1289] Step-2:

[1290] To a 25 mL round-bottomed flask containing a well-stirred solution of tert-butyl 4-(2,6-difluoro-4-nitro-phenyl)piperazine-l -carboxylate (3, 7 g, 20.39 mmol) in THF (80 mL) was added 20% Pd(OH)₂ on carbon (5.73 g, 8.16 mmol), and the resulting reaction mixture was stirred under a H2 atmosphere with bladder pressure for 16 h. Upon completion of reaction as determined by UPLC-MS, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to afford the crude residue, which was triturated with methyl tert-buty l ether to afford tert-butyl 4-(4-amino-2,6-difluoro-phenyl)piperazine-l-carboxylate (4, 6.1 g, 19.38 mmol, 95% yield) as a brown solid, which was used without further purification.

[1291] Step-3:

[1292] To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(4-amino-2,6-difluoro-phenyl)piperazine-l -carboxylate (4, 1.01 g, 3.19 mmol) in anhydrous acetonitrile (10 mL) was added isoamyl nitrite (1.50 g, 12.77 mmol, 1.71 mL) at room temperature. Then CuBr (915.61 mg, 6.38 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was quenched by the addition of saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layer was washed with water (60 mL) and brine solution (40 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude compound, which was purified by flash chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: 40 % ethyl acetate in petroleum ether) to afford tert-butyl 4-(4-bromo-2,6-difluoro-phenyl)piperazine-l-carboxylate (5, 200 mg, 450.66 pmol, 14% yield) as a yellow solid. LC-MS (ES+): m / z 277.0 [M-COOtBu + H]+.

[1293] Step-4:

[1294] To a 20 mL vial containing a well-stirred solution of tert-butyl 4-(4-bromo-2,6-difluoro-phenyl)piperazine-l -carboxylate (5, 170 mg, 383.06 pmol) in 1,4-dioxane (2.01 mL) was added bis(pinacolato)diboron (2.43 g, 9.58 mmol) and potassium acetate (75.19 mg, 766.12 pmol) under nitrogen atmosphere. The resulting reaction mixture was degassed with nitrogen for 2 min. Then Pd(dppf)Cl₂·DCM (15.64 mg, 19.15 μmol) was added to the reaction mixture, and the resulting reaction mixture was heated to 90 °C for stirred for 16 h. Uponcompletion of the reaction as determined by UPLC-MS. the reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with DCM (50 mL) and ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure to afford / crt-butyl 4-[2,6-difluoro-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]piperazine-l -carboxylate (6, 200 mg, 138.91 pmol, 36% yield) as a brown solid, which was used without further purification. LC-MS (ES+): m / z 425.5 [M + H]+.

[1295] Step-5:

[1296] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[2, 6-difluoro-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl]piperazine-l -carboxylate (6, 600 mg, 424.24 pmol) in anhydrous ethyl acetate (6 mL) was added H2O2 solution (4.24 mmol, 130.00 pL) at 0 °C. The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was quenched by the addition of a saturated Na₂S₂O₃ solution (20 mL) and extracted with ethyl acetate (2 × 70 mL). The combined organic layer was washed with water (20 mL) and brine solution (20 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford the crude residue. The crude residue was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 35% ethyl acetate in petroleum ether) to afford / crt-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)piperazine-l -carboxylate (7, 155 mg, 400.56 pmol, 94% yield) as an off-white solid. LC-MS (ES‘): m / z 313.0 [M - H]'. Step-6:

[1297] To a 50 mL two-neck round-bottom flask containing a w ell-stirred solution of tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)piperazine-l -carboxylate (7, 200 mg, 521.75 pmol) in DMF (3 mL) was cooled to 0-5°C. Then NaH (60% dispersion in oil, 62.61 mg, 1.57 mmol) was added at 0-5 °C and the resulting reaction mixture was stirred for 15 min. Then, 3-bromopiperidine-2,6-dione 8 (200.36 mg, 1.04 mmol) was added, and the resulting reaction mixture was warmed to ambient temperature and stirred for 3 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was quenched by the addition of an ice cold aqueous 1.5 N HC1 solution and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford the crude residue, which was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 60% ethyl acetate in petroleum ether) to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazine-l -carboxylate (9, 125 mg, 195.98 pmol, 38% yield) as a white solid. LC-MS (ES+): m / z 370.1 [M-isobutene + H]+.

[1298] Step-7:To a 25 mL round-bottom flask containing a well-stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazine-l-carboxylate (9, 125 mg, 196.86 pmol) in DCM (5 mL) was added 4 M HC1 in 1,4-dioxane (2.01 mL, 8.04 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was concentrated under reduced pressure to afford the crude residue, which was triturated with methyl tert-butyl ether to afford 3-(3, 5-difluoro-4-piperazin-l-yl-phenoxy)piperidine-2, 6-dione hydrochloride (B-27, 95 mg, 192.38 pmol, 98% yield) as an off-white solid, which was used without further purification. Synthesis of 3-[3,5-difluoro-4-(4-piperidyl)phenoxy]piperidine-2,6-dione (B-28)

[1299]

[1300] Step-1:

[1301] To two 40 mL screw-cap reaction vials containing a well-stirred solution of 4-bromo-3,5-difluoro-phenol (1. 3 g, 14.35 mmol) in 1.4-dioxane (30 mL) was added tert-butyl 4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-27 / -pyridine-l-carboxylate (2, 4.44 g, 14.35 mmol), K3PO4 (7.62 g, 35.89 mmol) and water (3 mL) at room temperature. The reaction mixture was purged with nitrogen gas for 5 minutes. Then Pd(dppf)Cl₂·DCM (1.17 g, 1.44 mmol) was added, and the reaction mixture was stirred at 90 °C for 10 h. Progress of the reaction was monitored by UPLC.

[1302] After the starting material was consumed, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (Stationary Phase: 230-400 mesh silica gel: Eluent: 10-15% Ethyl acetate in Pet ether) to afford tert-butyl 4-(2.6-difluoro-4-hydroxy-phenyl)-3,6-dihydro-2Lt-pyndine-l -carboxylate (3, 3.85 g, 11.02 mmol, 76.78% yield) as a pale yellow solid. LC-MS (ES‘): m / z 310.0 [M - H]+.

[1303] Step-2:To a 100 mL round-bottom flask containing a well stirred solution of tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (3, 1 g, 2.89 mmol) in THF (10 mL) was added 20% Pd(OH)2 on carbon (wetted with ca. 55% water) (738.15 mg, 2.89 mmol) at room temperature and the reaction mixture was stirred at 25 °C for 16 hours under H2 atmosphere. The reaction progress was monitored by TLC and LCMS. The reaction mixture was then filtered through a pad of Celite, which was subsequently washed with a mixture of THF (200 mL) and 1,4-dioxane (100 mL). The filtrate was concentrated under reduced pressure, and the residue was triturated with DCM and MTBE. The obtained crude was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 20% EtOAc in pet ether) to afford tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)piperidine-l -carboxylate (4, 900 mg, 2.83 mmol. 97.99% yield) as a pale yellow solid. LCMS (ES ): m / z 312.3 [M - H]’.

[1304] Step-3:

[1305] To a 40 mL pressure-cap vial containing a well-stirred solution of tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)piperidine-l-carboxylate (4, 1.4 g, 4.29 mmol) and 3-bromopiperidine-2, 6-dione (5, 3.29 g, 17.16 mmol) in MeCN (10 mL) was added Cs2CO3(3.49 g, 10.72 mmol) and the reaction mixture was stirred at 70°C for 1 h. The reaction mixture was then filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 30% Ethyl acetate in pet ether) to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperidine-l-carboxylate (6, 900 mg, 1.80 mmol, 41.93% yield) as a yellow solid. LC-MS (ES+): m / z 325.0 [M-tBuCOO + H]+.

[1306] Step-4:

[1307] To a 50 mL round-bottom flask containing a well stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperidine-l-carboxylate (6, 1 g, 1.98 mmol) in DCM (10 mL) was added 4.0 M HCl in 1,4-dioxane (4 M, 4.20 mL) at 0°C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was then concentrated under reduced pressure and diluted with MTBE. The obtained precipitate was washed with MTBE 2-3 times and dried under reduced pressure to afford 3-[3,5-difluoro-4-(4-piperidyl)phenoxy]piperidine-2, 6-dione hydrochloride (B-28, 900 mg, 1.67 mmol. 84.40% yield) as a white solid. LC-MS (ES+): m / z 325.1 [M + H]+.

[1308] Synthesis of 3- [[6-(4-piperidyl)-3-pyridyl] oxy] piperidine-2, 6-dione (B-29)

[1309]

[1310] Pd(OH)2 / C, H2Na2CO31,4-dioxane Pd(dppf)CI2«DCM 1,4-dioxane, H2O Step-3 Step-2

[1311] 4 M HCI in 1,4-dioxane DCM Step-4

[1312]

[1313] B-29 Step-1:

[1314] To 500 mL single-neck round-bottom flask containing a well-stirred solution of 2,6-dibenzyloxypyridin-3-ol (1, 9 g, 27.34 mmol) in DMAc (100 mL) were added potassium carbonate (11.34 g, 82.02 mmol) and 2-bromo-5-fluoro-pyridine (2, 9.62 g, 54.68 mmol) at ambient temperature and was the reaction mixture was stirred to 90 °C for 16 h. The reaction mixture was then cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (230-400 mesh silica-gel) using a gradient of 0-100% ethyl acetate in petroleum ether as eluent to afford 2,6-dibenzyloxy-3-[(6-bromo-3-pyridyl)oxy]pyridine (3, 7 g, 9.14 mmol, 33.44% yield) as an off-white solid. LCMS (ES+): m / z 465.0 [M+ H]+.

[1315] Step-2:

[1316] To a 250 mL sealed tube containing a stirred solution of 2,6-dibenzyloxy-3-[(6-bromo-3-pyridyl)oxy] pyridine (3, 7 g, 9.14 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l -carboxylate (4, 2.83 g, 9.14 mmol) in 1,4-dioxane (70 mL) and water (20 mL) was added sodium carbonate (2.91 g, 27.43 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was purged with nitrogen gas for 10 min. Subsequently, Pd(dppf)Cl₂·DCM (746.57 mg, 914.20 pmol) was added, and the reaction mixture was heated at 90 °C for 16 h. The reaction mixture was then cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (230-400 mesh silica-gel) using a gradient of 0-100% ethyl acetate in petroleum ether as eluent to afford te / 7-butyl 4-[5-[(2,6-dibenzyloxy-3-pyridyl)oxy]-2-pyridyl]-3,6-dihydro-2H-pyridine-l-carboxylate (5, 5.5 g, 8.39 mmol, 91.73% yield) as a brown gum. LC-MS (ESI): m / z 566.2 [M + H]+.

[1317] Step-3:

[1318] To a 250 mL single-neck round-bottom flask containing a stirred solution of tert-butyl 4-[5-[(2,6-dibenzyloxy-3-pyridyl)oxy]-2-pyridyl]piperidine-l-carboxylate (5, 5.5 g, 8.36 mmol) in 1,4-di oxane (60 mL) was added Palladium hydroxide (5.87 g, 41.78 mmol) and the reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere (1 kg / cm2pressure). The reaction mixture was then filtered through a pad of Celite and the Celite pad was washed with ethyl acetate (500 mL). The filtrate was concentrated in vacuo to afford terf-butyl 4-[5-[(2,6-dioxo-3-piperidyl)oxy]-2-pyridyl]piperidine-l-carboxylate (6, 3 g, 7.49 mmol, 89.60% yield) as an off-white solid. LC-MS (ESI): m / z 390.2 [M + H]+.

[1319] Step-4:

[1320] To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[5-[(2,6-dioxo-3-piperidyl)oxy]-2-pyridyl]piperidine-l -carboxylate (6, 5.5 g, 13.73 mmol) in anhydrous DCM (60 mL) was added 4 M HC1 in 1.4-dioxane (17.16 mL) dropwise at 0 °C. The reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 3 h. Excess solvents were removed from the reaction mixture under reduced pressure and the crude mixture was co-distilled with toluene (10 mL) to afford 3-[[6-(4-piperidyl)-3-pyridyl]oxy]piperidine-2,6-dione hydrochloride (B-29, 3.28 g, 9.98 mmol, 72.67% yield) as an off-white solid. LCMS (ES+): m / z 290.2 [M + H]+.

[1321] Example 3; Synthesis of Protein Degraders

[1322] Synthesis of 7V-(5-(4-((l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-Lff-benzo[d]imidazol-5-yl)piperidin-4-yl)oxy)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)aniino)-[2,3'-bipyridin]-6'-yl)acetamide (Compound 1)

[1323] HATU, DI PEA DMF

[1324]

[1325]

[1326] To an 8 mL screw cap vial containing a well stirred solution of6-[6-acetamido-4-[[6-(l- methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-3-carboxylic acid (A-l, 40 mg, 91.85 pmol) and 3-[3-methyl-2-oxo-5-[4-(4-piperidyloxy)-l-piperidyl]benzimidazol-l- yl]piperidine-2, 6-dione (C-57, 40.56 mg, 91.85 pmol) in DMF (1 mL) were added DIPEA (35.61 mg, 275.56 pmol, 48.00 pL) and HATU (52.39 mg, 137.78 pmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. Upon completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse phase column chromatography [C18 RediSep® R / Gold (120 g HP C18); Mobile phase A: 0.1% formic acid in MQ-water and B: acetonitrile; Flow rate: 10 mL / min], The fractions containing the product were lyophilized to afford N-[5-[5-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-4-piperidyl]oxy]piperidine-l-carbonyl]-2-pyridyl]-4-[[6-(l-methoxy-l- methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide (Compound 1, 14 mg, 15.24 pmol, 16.59% yield) as an off-white solid. LC-MS (ES+): m / z 859.3 [M + H]+. ¹H NMR (400 MHz, DMSO-d₆) 5 12.11 (s, 1H), 11.07 (br s, 1H). 10.37 (s. 1H), 9.19 (s, 1H), 8.82 (d, J = 1.5 Hz. 1H), 8.73 (s. 1H). 8.13 (d, J = 8.1 Hz, 1H), 8.00 (dd, J = 8.4, 2.2 Hz. 1H), 7.00 - 6.89 (m, 2H), 6.86 - 6.80 (m, 2H), 6.64 (dd, J = 8.6, 2.1 Hz, 1H), 5.37 - 5.25 (m, 1H), 4.10 - 3.95 (m, 1H), 3.89 - 3.75 (m, 1H), 3.69 - 3.56 (m, 2H), 3.51 - 3.40 (m, 3H), 3.31 (s, 3H), 3.12 (s, 3H), 2.96 - 2.80 (m. 3H), 2.66 - 2.57 (m, 2H), 2.32 (s, 3H), 2.11 (s, 3H), 2.03 - 1.89 (m, 4H), 1.67 - 1.54 (m, 3H). 1.50 (s, 6H).

[1327] The following compounds were prepared using the method described above, with the corresponding targeting ligand and CRBN binder intermediate as reactants.

[1328] Targeting CRBN binder Compound

[1329] ligand Intermediate

[1330]

[1331] A-l C-56 0

[1332] HN¥ oX /

[1333] y C T >o

[1334] ° r p T \

[1335] HV A

[1336] n ¥ ¥ 7

[1337] ULNU

[1338] o

[1339] Compound 2

[1340] A-(5-(4-((4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lE7-benzo[d]imidazol-4-yl)piperazin-l- yl)methyl)pipendine-l-carbonyl)-4,-((6-(2-methoxypropan-2-yl)- 4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6,-yl)acetamide LC-MS (ES+): m / z 858.3 [M + H]+.

[1341] p o

[1342] ¹H NMR (400 MHz, DMSO-d₆) 5 12.10 (s, 1H), 11.10 (s, 1H), 10.38 (s, 1H), 9.19 (s, 1H), 8.81 (d, J = 1.6 Hz, 1H), 8.73 (s, 1H).

[1343] o

[1344] 8.13 (d, J = 8.1 Hz, 1H), 7.98 (dd, J = 8.4, 2.3 Hz, 1H), 7.03 - 6.80 (m, 5H), 5.43 - 5.31 (m, 1H), 4.61 - 4.43 (m, 1H), 3.79 - 3.65 (m, 1H), 3.63 (s, 3H), 3.12 (s, 3H), 3.06 – 2.77 (m, 8H), 2.75 – 2.69 (m, 1H), 2.66 – 2.58 (m, 2H), 2.57 – 2.53 (m, 1H), 2.32 (s, 3H), 2.30 - 2.24 (m, 3H), 2.11 (s, 3H). 2.05 - 1.96 (m, 1H), 1.94 - 1.82 (m, 2H), 1.80 - 1.68 (m, 1H), 1.50 (s, 6H),

[1345] 1.24 - 1.10 (m, 2H).

[1346] A-l C-6

[1347]

[1348] Compound 3

[1349] JV-(5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-l / f-benzo[d]imidazol-5-yl)piperazine-l-carbonyl)-4- hydroxypiperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4- methylpy ri din-2 -yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide LCMS (ES+): m / z 888.3 [M + H]+.

[1350] ¹H NMR (400 MHz, DMSO-d₆ 5 11.08 (s, 1H), 10.38 (s, 1H), 9.20 (s, 1H), 8.83 (d, J= 1.8 Hz, 1H), 8.73 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.00 (dd, J= 8.4, 2.2 Hz, 1H), 7.02 - 6.92 (m, 2H), 6.88 (d, J= 2.0 Hz, 1H), 6.84 (s, 1H), 6.70 - 6.63 (m, 1H). 5.87 (s, 1H), 5.35 - 5.26 (m, 1H). 4.29 - 4.18 (m, 1H). 4.15 - 4.02 (m.

[1351] 1H), 3.58 - 3.45 (m, 2H), 3.31 (s, 3H), 3.15 - 3.07 (m, 6H), 2.95 - 2.84 (m, 1H), 2.67 - 2.56 (m, 2H), 2.53 (br s, 2H), 2.49 - 2.43 (m, 4H), 2.32 (s, 3H), 2.10 (s, 3H), 2.05 - 1.95 (m, 3H), 1.89 - 1.79 (m. 1H), 1.77 - 1.68 (m, 1H), 1.50 (s, 6H). A-l C-82 O HN'A

[1352] TX XX >°HT ] T \ n H T

[1353] O

[1354] Compound 4

[1355] 2V-(5-(4-((lr,4r)-4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2, 3-dihydro- lE7-benzo[d]imidazol-5- yl)phenyl)cyclohexyl)piperazine-l-carbonyl)-4'-((6-(2- methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide

[1356] LC-MS (ES+): m / z 919.3 [M + H]+.

[1357] ¹H NMR (400 MHz, DMSO-d₆ 5 12.09 (s, 1H). 11.13 (s, 1H), 10.38 (s, 1H), 9.20 (s, 1H), 8.83 (d, J= 1.6 Hz, 1H), 8.73 (s, 1H), 8.14 (d, J= 8.1 Hz, 1H), 8.00 (dd, J= 8.4, 2.3 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.47 (d, J= 1.6 Hz, 1H), 7.36 - 7.27 (m, 3H), 7.18

[1358]

[1359] (d, J= 8.4 Hz, 1H), 6.96 (s, 1H), 6.84 (s, 1H). 5.41 (dd. J= 12.8,

[1360] 5.3 Hz, 1H), 3.75 - 3.63 (m, 2H), 3.51 - 3.43 (m, 2H), 3.41 (s, 3H), 3.13 (s, 3H), 2.99 - 2.86 (m, 1H), 2.81 - 2.71 (m, 1H), 2.66 - 2.53 (m, 7H), 2.36 - 2.33 (m, 1H), 2.32 (s, 3H), 2.11 (s, 3H), 2.07 - 2.00 (m, 1H), 1.97 - 1.84 (m, 4H), 1.60 - 1.53 (m,

[1361] 1H), 1.51 (s, 6H), 1.47 - 1.33 (m, 2H.

[1362] A-l C-80 0

[1363] / P o I 1H / NA AAA V w H J™

[1364] A A o—

[1365] Compound 5

[1366] jV-(5-(4-(6-(4-((2.6-dioxopiperidin-3-yl)amino)-2-fluoro-5- methoxyphenyl)-2,6-diazaspiro[3.4]octan-2-yl)piperidine-l- carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide

[1367] LC-MS (ES+): m / z 863.4 [M + H]+.

[1368] 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H). 10.84 (s, 1H), 10.36 (s, 1H), 9.18 (s, 1H), 8.84 - 8.78 (m, 1H), 8.72 (s, 1H), 8.12 (d, J= 8.0 Hz, 1H), 7.97 (dd, J= 8.4, 2.3 Hz, 1H), 6.96 (s, 1H), 6.83 (s, 1H), 6.54 (d, J= 15.1 Hz, 1H), 6.38 (d, J= 8.5 Hz, 1H), 4.89 (d, J= 5.8 Hz, 1H), 4.23 - 4.16 (m. 1H), 3.78 (s, 3H), 3.22 - 3.10 (m, 11H), 2.90 - 2.76 (m, 2H), 2.58 - 2.55 (m, 2H), 2.35 - 2.30 (m, 5H), 2.18 - 2.12 (m, 1H), 2.10 (s, 3H), 2.04 (t, J= 6.8 Hz, 2H), 1.95 - 1.82 (m, 1H), 1.79 - 1.69 (m, 1H), 1.69 - 1.59

[1369] (m. 1H), 1.50 (s, 6H), 1.30 - 1.14 (m, 3H.

[1370] A-l C-81x1

[1371] AA? o- AA / ? xAi— ( NA ANHI 1N)= / < HN F O=\ y Ax HNA 0 o

[1372]

[1373] Compound 6

[1374] N-(5-(2-( 1 -(4-((2.6-dioxopiperidin-3-yl)amino)-2-fluoro-5- methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-6- carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide

[1375] LC-MS (ES+): m / z 863.4 [M + H]+.

[1376] 1H NMR (400 MHz, DMSO-d6) δ 12.15 (d, J= 14.4 Hz, 1H), 10.85 (d, J= 5.3 Hz, 1H), 10.37 (s, 1H), 9.19 (d, J = 6.1 Hz, 1H), 8.94 (d, J = 1.4 Hz, 1H), 8.74 (s, 1H), 8.17 - 8.09 (m, 2H), 6.97 (s, 1H), 6.83 (s, 1H), 6.63 - 6.49 (m, 2H), 5.11 - 5.05 (m, 1H), 4.29 - 4.20 (m. 1H), 3.81 - 3.74 (m, 3H), 3.71 - 3.64 (m, 2H), 3.62 - 3.53 (m, 2H), 3.37 - 3.35 (m, 1H), 3.19 - 3.14 (m, 1H), 3.13 (s, 3H), 3.11 - 3.05 (m, 1H), 2.85 - 2.74 (m, 1H), 2.65 - 2.53 (m, 5H), 2.34 - 2.33 (m, 1H), 2.32 (s, 3H), 2.13 - 2.06 (m, 7H). 1.98 - 1.85 (m, 1H). 1.83 - 1.66 (m, 2H), 1.50 (s. 6H),

[1377] 1.40 - 1.23 (m, 2H).

[1378] A-l C-58

[1379] \ / =\ 1 H 0 ^NH4

[1380] ° / n°— / =\ k / N\_ / NH

[1381] S=N N^O

[1382] Compound 7

[1383] 7V-(5-(4-((l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-177-benzo[d]imidazol-4-yl)piperidin-4-yl)oxy)piperidine- l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide

[1384] LC-MS (ES+):m / z 859.3 [M + H]+.

[1385] ‘H NMR (400 MHz, DMSO-c / <.) 5 12.12 (s, 1H), 11.10 (s, 1H), 10.38 (s, 1H), 9.19 (s, 1H), 8.83 (d, J= 1.6 Hz, 1H), 8.73 (s, 1H).

[1386] 8.14 (d. J= 8.0 Hz. 1H), 8.00 (dd, J= 8.4. 2.3 Hz. 1H), 7.02 - 6.94 (m, 2H), 6.92 - 6.85 (m, 2H), 6.84 (s, 1H), 5.38 - 5.30 (m, 1H), 4.11 - 3.73 (m, 3H), 3.64 (s, 5H), 3.17 - 2.95 (m, 6H), 2.92 - 2.83 (m, 1H), 2.80 - 2.70 (m, 2H), 2.64 (br s, 1H), 2.32 (s,

[1387]

[1388] 3H), 2.11 (s, 3H), 2.04 - 1.78 (m, 6H), 1.50 (s, 10H). A-l C-4 0

[1389] HN-A

[1390] X X x°0M \ NAX / VN'X /

[1391] O N -XUH0

[1392] X I X H A

[1393] Compound 8

[1394] 6'-acetamido-A-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2, 3-dihydro-177-benzo[d]imidazol-5-yl)piperidin-l-yl)-2- oxoethyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2- yl)amino)-[2,3,-bipyridine]-5-carboxamide

[1395] LC-MS (ES+): / n / z 817.3 [M + H]+.

[1396] 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 11.10 (s, 1H), 10.41 (s, 1H), 9.27 - 9.24 (m. 1H), 9.21 (s, 1H), 8.94 - 8.87 (m, 1H), 8.79 (s, 1H), 8.42 - 8.36 (m, 1H), 8.23 (d, J= 8.3 Hz, 1H), 7.12 (d, J= 1.0 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.98 - 6.92 (m, 2H), 6.86 (s, 1H), 5.40 - 5.31 (m, 1H), 4.60 - 4.51 (m, 1H), 4.31 - 4.20 (m, 2H), 4.12 - 4.02 (m, 1H). 3.35 (s, 3H), 3.24 - 3.16 (m.

[1397] 1H), 3.13 (s, 3H), 2.96 - 2.83 (m. 2H), 2.76 - 2.71 (m, 1H), 2.66 - 2.60 (m, 1H), 2.33 (s, 3H), 2.11 (s, 3H), 2.05 - 1.96 (m, 1H), 1.92 - 1.79 (m, 2H), 1.77 - 1.65 (m, 1H), 1.51 (s, 6H), 1.31 - 1.21 (m, 1H), 0.98 - 0.94 (m, 1H).

[1398] A-l C-5

[1399]

[1400] o

[1401] Compound 9

[1402] 6'-acetamido-A^-(6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2, 3-dihydro-l / 7-benzo[d]imidazol-5-yl)piperidin-l-yl)-6- oxohexyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2- y l)amino)- [2.3 '-bipyridine] -5-carboxamide

[1403] LC-MS (ES+): mz 873.3 [M + H]+.

[1404] 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 11.07 (br s, 1H), 10.38 (s, 1H), 9.31 - 9.08 (m, 2H), 8.81 - 8.67 (m, 2H), 8.42 (br s, 2H), 8.34 (dd, J= 8.6, 2.3 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 1.0 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.97 (s, 1H). 6.91 (dd, J= 8.1, 1.1 Hz, 1H), 6.83 (s, 1H), 5.33 (dd, J= 12.7, 5.4 Hz, 1H), 4.68 - 4.47 (m, 1H), 4.11 - 3.91 (m, 1H), 3.18 - 3.05 (m, 5H), 3.00 - 2.85 (m, 2H), 2.83 - 2.70 (m, 2H), 2.65 - 2.58 (m, 2H). 2.41 - 2.35 (m, 3H). 2.33 - 2.30 (m, 4H), 2.11 (s. 3H), 2.05 - 1.93 (m, 2H), 1.86 - 1.72 (m, 3H), 1.65 - 1.54 (m, 5H), 1.53 - 1.48 (m, 7H) and 1.44 - 1.36 (m, 2H).

[1405]

[1406] Compound 10

[1407] 6'-acetamido-JV-(10-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2, 3 -dihydro- 17 / -ben zo| d | imidazol-4-y l)piperidin- 1 -yl)- 10- oxodecyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2- y l)amino)- [2,3 '-bipyridine] -5-carboxamide LCMS (ES+): m,'z 929.4 [M + H]+

[1408] 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 11.22 - 10.99 (m. 1H), 10.37 (s, 1H), 9.20 (s, 2H). 8.76 (s, 1H), 8.73 - 8.67 (m.

[1409] 1H), 8.33 (dd, J = 8.6, 2.3 Hz, 1H), 8.19 (d, J= 8.3 Hz, 1H), 7.03 - 6.94 (m, 4H), 6.84 (s, 1H), 5.37 (br dd, J= 12.4, 5.4 Hz, 1H), 4.62 - 4.52 (m, 1H), 4.06 - 3.92 (m, 1H), 3.62 (s, 3H), 3.55 - 3.45 (m, 1H), 3.24 - 3.14 (m. 1H), 3.13 (s, 3H), 2.95 - 2.80 (m, 2H). 2.77 - 2.70 (m, 1H). 2.67 - 2.58 (m. 3H). 2.37 - 2.34 (m, 1H), 2.32 (s, 3H), 2.11 (s, 3H), 2.04 - 1.96 (m, 1H), 1.91 - 1.79 (m, 2H), 1.70 - 1.61 (m, 1H), 1.60 - 1.53 (m, 4H),

[1410] 1.51 (s, 6H), 1.39 - 1.25 (m, 12H).

[1411]

[1412] C-2

[1413] O

[1414] Compound 11

[1415] 6'-acetamido-Ar-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2, 3-dihy dro-17 / -benzo[d]imi dazol-4-yl)piperidin-l-yl)-2- oxoethyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2- y l)amino)- [2,3 '-bipyridine] -5-carboxamide LCMS (ESI): m'z 817.3 [M + H]+.

[1416] ‘H NMR (400 MHz, DMSO-d6) 5 12.25 (s, 1H), 11.11 (s, 1H), 10.41 (s, 1H), 9.26 (d. J = 1.9 Hz. 1H), 9.21 (s, 1H), 8.95 - 8.88 (m, 1H), 8.79 (s, 1H), 8.42 - 8.36 (m, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.07 - 6.95 (m, 4H), 6.86 (s, 1H), 5.43 - 5.36 (m, 1H), 4.61 - 4.52 (m, 1H), 4.31 - 4.23 (m, 2H), 4.12 - 4.03 (m, 1H), 3.65 (s, 3H), 3.62 - 3.53 (m, 1H), 3.30 - 3.24 (m, 2H), 3.13 (s, 3H). 2.96 - 2.76 (m. 2H), 2.66 - 2.59 (m. 1H), 2.33 (s, 3H), 2.11 (s, 3H), 2.05 - 1.97 (m, 1H), 1.96 - 1.85 (m, 2H), 1.84 - 1.72 (m,

[1417] 1H), 1.66 - 1.55 (m, 1H), 1.51 (s, 6H).

[1418]

[1419] Table 8: selected examplesSyn thesis of N- [5- [6- [4- [ [ 1- [l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl] -4-piperidyl] oxy] piperidine- l-carbonyl]-2-pyridyl]-4- [ [6-( 1-methoxy- l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide (Compound 12)

[1420]

[1421] To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 6-|6-acetamido-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]pyridine-2-carboxylic acid (A-2, 40 mg, 91.85 pmol) and 3-[3-methyl-2-oxo-5-[4-(4-piperidyloxy)-l-piperidyl]benzimidazol-l-yl]piperidine-2, 6-dione trifluoroacetate (C-57, 70.08 mg, 101.04 pmol) in anhydrous DMF (2 mL) was added DIPEA (59.36 mg, 459.27 pmol, 80.00 pL) and HATU (52.39 mg, 137.78 pmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase column chromatography [Column: RediSep® C18-120 g; Mobile phase A: 0.1 mM NH4HCO3 in water and Mobile phase B: MeCN] to afford A-[5-[6-[4-[[l-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]piperidine-l-carbonyl]-2-pyridyl] -4- [ [6-( 1 -methoxy- 1 -methyl-ethyl)-4-methy 1-2 -pyridyl] amino] -2 -pyridyl] acetamide (Compound 12, 18 mg, 20.21 pmol, 22.00% yield) as an off-white solid. LC-MS (ES+):m / z 859.3 [M + H]+.1H NMR (400 MHz. DMSO-d6) δ 12.08 (s, 1H). 11.06 (s. 1H), 10.38 (s, 1H), 9.19 (s, 1H), 8.76 (s, 1H), 8.18 (d, J= 7.8 Hz, 1H), 8.08 (t, J= 7.9 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.03 - 6.89 (m, 2H), 6.82 (d, J= 2.1 Hz, 1H), 6.61 (s, 2H), 5.35 - 5.23 (m, 1H), 4.18 - 4.06 (m, 1H), 3.84 - 3.69 (m, 1H), 3.63 - 3.53 (m, 2H), 3.47 - 3.35 (m, 3H), 3.30 (s, 3H), 3.12 (s, 3H),2.81 ( d, J= 10.1 Hz, 2H), 2.63 ( s, 2H), 2.32 (s, 3H), 2.11 (s, 3H), 2.05 - 1.69 (m, 6H), 1.62 - 1.53 (m, 2H). 1.51 (s, 6H). 1.46 - 1.37 (m. 1H), 1.00 - 0.91 (m. 2H).

[1422] The following compounds were prepared using the method described above, with the corresponding targeting ligand and CRBN binder intermediate as reactants.

[1423] Targeting CRBN Compound

[1424] ligand binder

[1425] Intermediate

[1426] A-2 C-70

[1427] HN N

[1428] 1 0

[1429] Compound 13

[1430] 7V-(6-(6-((l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-177-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-2,6- diazaspiro[3.3]heptane-2-carbonyl)-4'-((6-(2-methoxypropan-2- yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6,- yl)acetamide

[1431] LC-MS (ES+): m'z 870.3 [M + H]+.

[1432] ’H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 11.09 (s, 1H), 10.37 (s, 1H), 9.15 (s, 1H). 8.60 (s, 1H), 8.35 (s. 1H), 8.15 - 8.05 (m, 2H), 7.85 (dd,. / = 5.8, 3.0 Hz, 1H), 7.00 - 6.93 (m, 2H), 6.90 - 6.84 (m, 2H), 6.76 (s, 1H), 5.34 (br dd, J= 12.7, 5.3 Hz, 1H), 4.54 (s, 2H), 4.22 (s, 2H), 3.59 (s, 3H), 3.28 - 3.25 (m, 3H), 3.12 (s, 3H), 3.08 - 3.03 (m, 3H), 2.94 - 2.84 (m, 1H). 2.75 - 2.69 (m, 1H), 2.65 - 2.57 (m, 3H), 2.35 - 2.33 (m, 1H), 2.32 (s, 3H), 2.26 - 2.18 (m, 2H), 2.11 (s, 3H), 2.05 - 1.96 (m, 1H), 1.75 - 1.65 (m, 2H), 1.50 (s, 6H), 1.36 - 1.23 (m, 3H).

[1433]

[1434] A-2 C-71 V o0HNX H I

[1435] y Y y o Y^rN°N^k<NV^M^ zx 1 1

[1436] Compound 14

[1437] A-(6-(6-(( 1 -(1 -(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-lE7-benzo[d]imidazol-5-yl)piperidin-4-yl)methyl)-2,6- diazaspiro[3.3]heptane-2-carbonyl)-4'-((6-(2-methoxypropan-2- yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'- yl)acetarmde

[1438] LCMS (ES+): m / z 870.3 [M + H]+.

[1439] 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 11.06 (s, 1H), 10.38 (s, 1H), 9.14 (s, 1H), 8.60 (s, 1H), 8.36 (s, 1H), 8.14 - 8.06 (m, 2H), 7.85 (dd, J= 5.9, 2.8 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J= 8.6 Hz, 1H), 6.80 (d, J= 2.1 Hz, 1H), 6.76 (s, 1H), 6.61 (dd, J= 8.6, 2.0 Hz, 1H), 5.28 (dd, J= 12.9, 5.4 Hz, 1H), 4.54 (s, 2H), 4.22 (s, 2H), 3.58 - 3.46 (m, 3H), 3.28 - 3.23 (m, 5H), 3.13 (s, 4H), 3.07 - 3.01 (m, 2H). 2.94 - 2.82 (m, 1H), 2.65 - 2.57 (m, 3H), 2.33 - 2.31 (m, 3H), 2.21 - 2.16 (m, 2H), 2.11 (s, 3H), 2.01 - 1.95 (m, 1H), 1.71 - 1.65 (m, 2H), 1.51 (s, 6H) and 1.29 - 1.12 (m, 3H).

[1440] A-2 C-56 / H o

[1441] N=< (

[1442] NH / \ / L

[1443] / =<

[1444] < )

[1445] — N—7N=\ / — \1

[1446] 0 VN / — /

[1447] 0x'

[1448] Compound 15

[1449] jV-(6-(4-((4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihy dro- 177-benzo [d] imi dazol -4-y l)piperazin- 1 - yl)methyl)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2- yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-

[1450]

[1451] yl)acetamide

[1452] LCMS (ES+): mz 858.2 [M + H]+.

[1453] ‘H NMR (400 MHz, DMSO-d6) 5 12.12 (s, 1H), 11.09 (br s, 1H), 10.38 (s, 1H), 9.20 (s, 1H), 8.77 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.08 (t, J = 7.9 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.02 - 6.84 (m, 4H), 6.60 (s, 1H). 5.40 - 5.30 (m, 1H), 4.65 - 4.56 (m.

[1454] 1H), 3.71 - 3.63 (m, 1H), 3.61 (s, 3H), 3.13 (s, 3H), 3.11 - 3.05 (m, 1H), 3.00 - 2.78 (m, 7H), 2.74 - 2.69 (m, 1H), 2.65 - 2.54 (m, 3H), 2.32 (s, 3H), 2.24 - 2.15 (m, 1H), 2.11 (s, 3H), 2.09 - 2.05 (m, 2H), 2.02 - 1.95 (m, 1H), 1.95 - 1.81 (m, 2H), 1.69 - 1.60 (m, 1H), 1.51 (s, 6H). 1.23 - 1.13 (m, 1H), 1.09 - 0.95 (m.

[1455] 1H).

[1456] A-2 C-58

[1457] HN^, N.

[1458] T l

[1459] I H ^I

[1460] ^

[1461] H I T H l VN

[1462] 10

[1463] Compound 16

[1464] jV-(6-(4-((l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-177-benzo[d]imidazol-4-yl)piperidin-4- yl)oxy)piperidine-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)- 4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide LC-MS (ES+): m / z 859.3 [M + H]+.

[1465] 1H NMR (400 MHz, DMSO-d6) δ 12.08 (br s, 1H), 11.09 (s, 1H). 10.38 (s, 1H), 9.19 (s, 1H), 8.76 (s, 1H), 8.19 - 8.16 (m, 1H), 8.08 (t, J= 7.9 Hz, 1H), 7.56 (d, J = 7.1 Hz, 1H), 6.99 - 6.94 (m, 2H), 6.90 - 6.84 (m, 2H), 6.61 (s, 1H), 5.35 (dd, J = 12.6, 5.5 Hz, 1H), 4.16 - 4.04 (m, 1H), 3.84 - 3.72 (m, 1H), 3.62 (s, 3H), 3.59 - 3.41 (m, 3H), 3.30 - 3.22 (m, 2H), 3.12 (br s, 3H), 3.09 - 3.02 (m, 1H), 2.94 - 2.84 (m, 1H), 2.79 - 2.69 (m, 2H), 2.65 - 2.57 (m. 2H), 2.33 (s, 3H), 2.11 (s, 3H), 2.06 - 1.88 (m, 4H), 1.84 - 1.68 (m, 2H), 1.67 - 1.54 (m, 2H), 1.51 (s,

[1466]

[1467] 6H), 1.46 - 1.35 (m, 1H).

[1468] A-2 C-82 0

[1469] HNA

[1470] 0=\ /

[1471] x T >°

[1472] ,-k? J

[1473] A A JAX o

[1474] H A

[1475] f l

[1476] Compound 17

[1477] JV-(6-(4-((lr.4r)-4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2, 3 -dihydro- 1 / / -benzo [d]imidazol -5 - yl)phenyl)cyclohexyl)piperazine- 1 -carbonyl)-4'-((6-(2- methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide

[1478] LC-MS (ES+): m / z 919.3 [M + H]+.

[1479] XH NMR (400 MHz, DMSO-6) 5 11.94 (s, 1H), 11.13 (s, 1H), 10.39 (s, 1H), 9.16 (s, 1H), 8.75 (s, 1H), 8.22 - 8.14 (m, 1H), 8.09 (t, J= 7.9 Hz, 1H), 7.63 - 7.54 (m, 3H), 7.47 (d, J= 1.5 Hz, 1H), 7.34 - 7.25 (m. 3H), 7.18 (d. J= 8.3 Hz. 1H), 6.99 (s, 1H), 6.66 (s, 1H), 5.40 (dd, J= 12.9, 5.2 Hz, 1H), 3.74 (br s, 2H), 3.44 - 3.38 (m, 5H), 3.13 (s, 3H), 2.97 - 2.88 (m, 1H), 2.81 - 2.70 (tn, 1H), 2.65 - 2.60 (m, 1H), 2.58 - 2.53 (m, 2H), 2.47 - 2.41 (m, 3H), 2.33 (s. 3H), 2.11 (s, 3H), 2.08 - 2.00 (m, 1H), 1.88 - 1.72 (m, 4H), 1.52 (s, 6H), 1.48 - 1.39 (m, 2H),

[1480] 1.36 - 1.20 (m, 3H).

[1481]

[1482] A-2 C-80 0 HN^Y cr y o. Y T M_ / N\ hN / \AN^z^o / 0NH

[1483] O _ xj N= /

[1484] — 0 X /

[1485] Compound 18

[1486] A-(6-(4-(6-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5- methoxyphenyl)-2.6-diazaspiro[3.4]octan-2-yl)piperidine-l- carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2- Xi

[1487] yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide

[1488] LC-MS (ES+): m / z 863.4 [M + H]+.

[1489] z

[1490] ¹H NMR (400 MHz, DMSO-d₆ 5 12.06 (s, 1H). 10.85 (br s, 1H). 10.38 (s. lH), 9.18 (s. 1H), 8.75 (s, 1H), 8.17 (d, J= 7.8

[1491] 0

[1492] Hz, 1H), 8.07 (t, J= 7.9 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H), 6.97 (s, 1H), 6.61 (s, 1H), 6.54 (d, J= 15.1 Hz, 1H), 6.36 (d, J= 8.5

[1493] XmY

[1494] O

[1495] Hz, 1H), 4.89 (d, J= 6.6 Hz, 1H), 4.26 - 4.15 (m, 2H), 3.78 (s, 3H), 3.65 - 3.55 (m. 1H), 3.29 - 3.26 (m. 2H), 3.21 -1

[1496] 3.14 (m, 3H), 3.12 (s, 3H), 3.09 - 3.02 (m, 3H), 2.86 - 2.75 (m, 1H), 2.34 (s, 3H), 2.30 - 2.24 (m, 1H), 2.21 - 2.13 (m, 1H), 2.11 (s, 3H), 2.03 - 1.97 (m, 2H), 1.95 - 1.84 (m, 1H), 1.81 - 1.73 (m, 1H), 1.61 - 1.53 (m, 1H), 1.51 (s, 7H), 1.37 - 1.22 (m, 2H).

[1497] 1.19 - 1.06 (m, 2H).

[1498] A-2 C-81

[1499]

[1500] Compound 19

[1501] jV-(6-(2-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5- rnethoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-6- carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide

[1502] LC-MS (ES+): m / z 863.4 [M + H]+.

[1503] 1H NMR (400 MHz, DMSO-6) δ 11.85 (d, J= 15.6 Hz, 1H), 10.85 (d, J=4.8 Hz, 1H), 10.37 (d, J= 8.3 Hz, 1H), 9.17 (d, J = 16.0 Hz, 1H), 8.72 (d, J= 14.4 Hz, 1H), 8.20 - 8.06 (m, 2H). 7.69 (d,.7= 7,5 Hz. 1H), 6.96 (d, J=2.5 Hz, 1H), 6.68 - 6.47 (m, 3H), 5.10- 5.04 (m, 1H), 4.30-4.19 (m, 1H), 3.81 - 3.74 (m, 3H), 3.71 - 3.60 (m, 4H), 3.16- 3.09 (m, 6H), 3.06- 2.97 (m, 3H), 2.90 - 2.73 (m, 3H), 2.66 - 2.61 (m, 1H), 2.31 (s, 3H), 2.17-2.12 (m, 1H), 2.11 (s, 3H), 2.08 - 2.04 (m, 1H), 2.01 - 1.84 (m, 3H). 1.76 - 1.65 (m, 1H), 1.60 - 1.53 (m. 1H), 1.50 (s, 6H), 1.37 - 1.27 (m, 1H), 1.21 - 1.12 (m, 1H). A-4 C-l O HNY

[1504] HOJ l| £ >=o

[1505] H T | |

[1506] Y H O

[1507] Compound 20

[1508] 6'-acetamido-jV-(6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2, 3-dihydro-lL7-benzo[d]imidazol-4-yl)piperi din-l-yl)-6- oxohexyl)-4'-((6-(2-hydroxypropan-2-yl)-4-methylpyridin-2- yl)amino)-[2,3'-bipyridine]-5-carboxamide

[1509] LC-MS (ES+): m / z 859.4 [M + H]+.

[1510]

[1511] A-3 C-7

[1512] H T

[1513] fX'XT^NL^FH \ / N, / k °^N^° i xi

[1514] H XJ

[1515] Compound 21

[1516] A-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5- t4-[t4-[4-t(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro- phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2- py ridyl] -2-pyridyl] acetamide

[1517] LC-MS (ES+): m / z 831.3 [M + H]+.

[1518] XH NMR (400 MHz. DMSO-d6) δ 12.41 (s, 1H), 10.81 (s, 1H), 10.46 (s, 1H), 9.29 (s, 1H), 8.83 (d,.7= 1.8 Hz, 1H), 8.77 (s, 1H), 8.15 (d, J= 8.6 Hz, 1H), 7.98 (dd, J= 8.4, 2.2 Hz, 1H), 7.13 - 7.09 (m, 2H), 6.36 - 6.29 (m, 2H). 6.26 (d, J= 7.6 Hz, 1H), 4.58 - 4.44 (m. 1H), 4.36 - 4.28 (m, 1H), 3.75 - 3.64 (m, 1H), 3.22 - 3.10 (m, 1H), 3.01 - 2.92 (m, 4H), 2.90 - 2.80 (m, 1H), 2.78 - 2.70 (m, 1H), 2.62 - 2.57 (m, 1H), 2.45 - 2.43 (m, 3H), 2.37 (s, 3H), 2.26 - 2.20 (m, 2H), 2.18 - 2.02 (m, 8H), 1.94 - 1.82 (m, 3H), 1.80 - 1.69 (m, 1H), 1.22 - 1.09 (m. 2H).

[1519] A-3 C-59

[1520] N=\ r^C / y X / — ( / — \N\ X — N— N= / 0

[1521] 0

[1522] Compound 22

[1523] JV-[4-[[6-(l, 1 -difluoroethyl)-4-methyl-2 -pyridyl] amino]-5-[5- [4-[[4-[3-(2,6-dioxo-3-piperidyl)-l -methyl -indazol-7- yl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2- pyridyl]acetamide

[1524] LC-MS (ES+): m'z 834.3 [M + H]+.

[1525]

[1526] ’H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.88 (s, 1H),

[1527] 10.45 (s, 1H), 9.29 (s, 1H). 8.84 (d, J= 1.8 Hz, 1H). 8.78 (s, 1H), 8.18 - 8.12 (m, 1H), 7.99 (dd, J= 8.4, 2.2 Hz, 1H), 7.40 (dd,.7= 7.3, 1.7 Hz, 1H), 7.12 - 7.09 (m, 2H), 7.06 - 6.99 (m, 2H), 4.59 - 4.45 (m, 1H), 4.38 - 4.31 (m, 1H), 4.25 (s, 3H), 3.77 - 3.62 (m, 1H). 3.22 - 3.06 (m, 3H), 2.99 - 2.77 (m. 5H), 2.65 - 2.56 (m, 4H), 2.37 (s, 3H), 2.32 - 2.25 (m, 3H), 2.18 - 2.06 (m, 7H), 1.99 - 1.83 (m, 2H), 1.82 - 1.70 (m, 1H), 1.25 - 1.13 (m, 2H).

[1528] A-5 C-7 LF

[1529] FH T

[1530] n H |

[1531] Il i i THs XX XJ H

[1532] Compound 23

[1533] jV-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[5-[4-[[4-[4- [(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin- l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2- pyridyl]acetamide

[1534] LC-MS (ES’): m / z 817.3 [M + H]+.

[1535] 1H NMR (400 MHz, DMSO-6) δ 12.43 (s, 1H), 10.82 (s, 1H), 10.49 (s, 1H), 9.28 (s. 1H), 8.83 - 8.76 (m, 2H), 8.36 (s, 1H), 8.15 (d. J= 8.0 Hz. 1H), 7.98 (dd, J= 8.4. 2.3 Hz. 1H), 7.87 (t,.7= 7.9 Hz, 1H), 7.31 - 7.21 (m, 2H), 6.32 (d, J= 12.3 Hz, 2H), 6.26 (d, J= 8.0 Hz, 1H), 4.57 - 4.42 (m, 1H), 4.38 - 4.26 (m, 1H), 3.75 - 3.61 (m, 2H), 3.01 - 2.91 (m, 4H), 2.88 - 2.69 (m, 3H), 2.62 - 2.58 (m. 1H), 2.46 - 2.39 (m. 4H), 2.24 - 2.18 (m, 3H), 2.15 - 2.04 (m, 6H), 1.85 (br s, 3H), 1.77 - 1.68 (m,

[1536] 1H), 1.19 - 1.09 (m, 2H).

[1537]

[1538] A-5 C-13 LF

[1539] H T

[1540] n H i

[1541] o, N.

[1542] |f ^| ( ff y 1 H MYNJ O^N^O O.oXT Compound 24

[1543] A-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[5-[4-[[4-[4- [(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazin-l- yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2- pyridyl]acetamide

[1544] LC-MS (ES’): mJz 782.3 [M + H]+.

[1545] 1H NMR (400 MHz, DMSO-6) δ 12.41 (s, 1H), 10.90 (s, 1H), 10.48 (s, 1H), 9.27 (s, 1H). 8.81 (d, J = 1.8 Hz, 1H), 8.78 (s, 1H). 8.19- 8.11 (m, 1H), 7.98 (dd. J= 8.4. 2.2 Hz, 1H). 7.88 (t, J= 7.8 Hz, 1H), 7.26 (t, J = 7.4 Hz, 2H), 6.91 (br s, 4H), 5.03 (brdd, J= 10.2, 5.1 Hz, 1H), 4.58-4.46 (m, 1H), 3.78 - 3.63 (m, 1H), 3.26 - 3.10 (m, 2H), 3.09 - 2.91 (m, 4H), 2.90 - 2.75 (m, 1H), 2.71 - 2.64 (m, 2H), 2.63 - 2.53 (m, 3H), 2.31 - 2.23 (m, 1H), 2.25 - 2.01 (m, 9H), 1.97 - 1.80 (m, 2H), 1.79- 1.68 (m, 1H), 1.29 - 1.10 (m, 2H).

[1546] A-6 C-7

[1547] H T T T T

[1548] iHI F XI N XT H

[1549] Compound 25

[1550] JV-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro- phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2- pyridyl]-4-[(4-methyl-6-methylsulfonyl-2-pyridyl)amino]-2- pyridyl]acetamide

[1551]

[1552] LC-MS (ES+): m / z 845.2 [M + H]+.

[1553] ‘HNMR (401 MHz. DMSO-O d 12.68 (s, 1H), 10.82 (s, 1H), 10.57 (s, 1H), 9.25 (s, 1H), 9.20 - 9.07 (m, 1H), 8.88 - 8.78 (m, 2H), 8.28 - 8.11 (m, 1H), 8.00 (dd, J= 8.4, 2.2 Hz, 1H), 7.46 (s, 1H), 7.29 (s, 1H), 6.46 - 6.24 (m, 3H), 4.62 - 4.43 (m, 1H), 4.39 - 4.21 (m, 1H). 3.84 - 3.54 (m, 2H), 3.50 - 3.41 (m. 4H), 3.23 - 2.94 (m, 7H), 2.84 - 2.63 (m, 2H), 2.57 - 2.53 (m, 1H), 2.46 - 2.40 (m, 4H), 2.24 - 2.09 (m, 4H), 2.06 - 1.66 (m, 5H),

[1554] 1.38 - 1.14 (m, 2H).

[1555]

[1556] Table 9: selected examples

[1557] Synthesis of A-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6- dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]azetidine-l-carbonyl]-2- pyridyl]-2-pyridyl]acetamide (Compound 26)

[1558]

[1559] To a 20 mL screw-cap vial containing a well-stirred solution of 3-[4-[4-(azetidin-3- ylmethyl)piperazin-l-yl]-3,5-difluoro-phenoxy]piperidine-2, 6-dione trifluoroacetate (C-41, 60 mg, 95.85 pmol) and 6-[6-acetamido-4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-3- pyridyl]pyridine-3-carboxylic acid (A-3, 44.53 mg, 95.85 pmol) in anhydrous DMF (9.78 pL) were added A / V-di isopropyl ethyl amine (12.39 mg, 95.85 pmol, 16.70 pL) and HATU (36.45 mg, 95.85 pmol) at room temperature under nitrogen atmosphere. The contents were stirred at roomtemperature for 1 h. After completion of the reaction as indicated by LCMS, the reaction mixture was purified by reverse-phase column chromatography [Column: Cl 8; Mobile phase A: 0.1% ammonium bicarbonate in water and Mobile phase B: CH3CN] to afford A-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl] piperazin- 1 -y 1] methyl] azetidine- 1 -carbonyl] -2 -pyridyl] -2-py ridy 1] acetamide (Compound 26. 22 mg, 25.84 pmol. 26.96% yield) as a pure fluffy white solid. LC-MS (ES+): m / z 804.2 [M + H]+.1H NMR (401 MHz, DMSO-6) δ 12.51 (s, 1H), 10.97 (s, 1H), 10.46 (s, 1H), 9.31 (s, 1H), 9.07 (s, 1H), 8.79 (s, 1H), 8.17 (s, 2H), 7.13 (d, J = 6.6 Hz, 2H), 6.79 (br d, J= 11.1 Hz, 2H), 5.28 - 5.17 (m, 1H), 4.59 - 4.49 (m, 1H), 4.24 - 4.10 (m, 2H), 3.83 - 3.72 (m, 1H), 3.09 - 2.98 (m, 4H), 2.98 - 2.90 (m, 1H), 2.72 - 2.65 (m, 3H), 2.61 - 2.52 (m, 4H), 2.38 (s, 3H), 2.24 - 2.05 (m, 9H)

[1560] Synthesis of A-[4-[[6-(l,l-difluoroethyl)-4-methyI-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-3-hydroxy-azetidine-l-carbonyl] -2-pyridyl]-2-pyridyl] acetamide (Compound 27)

[1561] [156...

Claims

The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.Experimental PartThe following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.1A. L. Croxford et al., Cytokine Growth Factor Rev., 25 (4) (2014), pp. 415-4212Compendium of Chemical Terminology, 2nd, A. D. McNaught and A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).3Biochem. Pharmacol. (1973) 22:30994W020221095805US105081136WO20222717277WO20232836108WO20230191669WO202112758610WO202112758611WO202513760512WO201823702613WO202226125014W0202203202615W0202203202616WO2021255212CLAIMS1. A compound of formula I or a pharmaceutically acceptable salt thereofT-L-B I,whereinT is a targeting ligand selected from the group consisting ofandT, whereina is -C(Ci.3-alkyl FF), -C(heterocyclyl, OCH3), -C(heterocyclyl, F), -heterocyclyl, -C(C3.6-cycloalkyl, H), -C(C3-6-cycloalkyl, OCH3), -C(C3.6-cycloalkyl substituted by 1-2 halogen, H), -SO2CH3, -C((CH3)2, OCH3) or-C(CH3)2OH,a’ is Ci.3-alkyl, -O-Ci-3-alkyl, -O-C3.6-cycloalkyl or C3.6-cycloalkyl,a” is Ci-3-alkyl, -O-Ci-3-alkyl or halogen,b is N or CH,c is H. -CO-Ci-3-alkyl, -CO-C3-6-cycloalkyl. CO-N(H. CH3). -CO-NH2, SO2-Ci-3-alkyl, heterocyclyl or -Ci-3-alkyl. andd is selected from the group consisting of C3.6-cycloalkyl, aryl, aryl substituted by 1-2 halogen, heteroaryl and heteroaryl substituted by 1-2 halogen,e is absent Ci-3-alkyl, -N(CH3)-, -N(CH3)-CO-(CH2)I-8-CO-, -N(CH3)-CO-(CH2)I-2, -N(CH3)-(CH2)I-2, -N(CH3)-CO-(CH2)i-2-heterocyclyl- or -N(CH3)-SO2-(CH2)i-2, -C3-6-cycloalkyl, heteroaryl, optionally substituted by =0. heteroarvl-heterocyclvl. or heteroaryl-heteroaryl, L is a linker selected from the group consisting ofwhereinLI is absent or selected from the group consisting of -CO-(CH2)i-3-. -(CH2)I-3-CO-, -N- (CH2)I-9-CO-, -CO-(CH2)I-8-CO-, -(CH2)I-8-, -(CH2)I-8-CO-, -(CH2)o-i-heterocyclyl, - heterocyclyl-(CH2)o-2-0-(CH2)i-2-, -heteroaryl-(CH2)o-i- and -(CH2)o-i-heteroaryl-, 11 is CH or N,12 is CH or N,c) -CO-(CH2)O-2-.L2 is selected from the group consisting of a bond, -(CH2)I-2-, -CO-, -O-, -C3-6- cycloalkyl and -(CH2)O-2-CO-(CH2)I-2-,13 is selected from the group consisting of CH and N,14 is absent, -CH2N(H, CH3)-, -(CH2)I-2- or -CO-,' ( / h-A ' ' \)-A '— j— L5— L4— L3-^ N-j- -^L5-L4— L3-Z N-j-e x)THu / 1B ° orT H0B, w Uherei •nL3 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-. -O-, and - (CH2)I.2-CO-(CH2)I.2-,L4 is absent, -C3-6-cycloalkyl or heterocyclyl,L5 is absent or is selected from the group consisting of -(CH2)I-2-, CH2N(H, CH3)-, heterocyclyl-CO-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-,or. wherein 15 is -CH- or -N-,16 is -O-, -CF2-, or -CH2-,L6 is absent, -(CH2)I-2-, -O-, -C3-6-cycloalkyl or -(CH2)o-2-heterocyclyl, optionally substituted by halogen,, wherein L7 is selected from the group consisting of -(CH2)I- 2-, -O-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-, and, wherein L8 is selected from the group consisting of - (CH2)I-2-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-, andwherein L9 is absent or selected from the group consisting of - (CH2)I-2-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-, andB is a CRBN binder selected from the group consisting ofwherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by Ci-3-alkyl, halogen or =0 and -(CH2)o-iaryl, optionally substituted by halogen or -O-Ci-3-alkyl.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein T is a targeting ligand selected from the group consisting ofwhereina is -C(Ci-3-alkyl FF), -C(heterocyclyl, OCH3), -C(heterocyclyLF), -heterocyclyl, -C(C3-6-cycloalkyL OCH3), -C(C3-6-cycloalkyl substituted by 1-2 halogen, H), -SO2CH3, or -C((CH3)2, OCH3).a’ is Ci-3-alkyl, -O-Cus-alkyl, -O-C3-6-cycloalkyl or C3-6-cycloalkyl,a’ ’ is halogen,b is N or CH,c is -CO-C1-3-alkyl,d is selected from the group consisting of aryl substituted by 1-2 halogen, heteroaryl and heteroaryl substituted by 1-2 halogen, ande is absent,L is a linker selected from the group consisting ofLI is absent or selected from the group consisting of -NH-(CH2)I-9-CO-, -(CH2)I-8 - (CH2)o-i-heterocyclyl and-heterocyclyl-(CH2)o-2-0-(CH2)i-2-,l1 is CH or N,12 is CH or N,L2 is selected from the group consisting of-(CH2)i-2-, -CO-, -O- and -C3-6-cycloalkyl, 13 is N,14 is absent or -(CH2)I-2-.15 is -CH- or -N-,16 is -CH2-,L6 is absent, or –(CH2)0-2-heterocyclyl, optionally substituted by halogen,wherein L7 is selected from the group consisting of -(CH2)I-2-, -O- and -CO-,f), wherein L9 is absent, andB is a CRBN binder selected from the group consisting ofwherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by C1-3-alkyl, halogen or =O and -(CH2)0-1aryl, optionally substituted by halogen or -O-C1-3-alkyl.

3. A compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof whereinT is a targeting ligand selected from the group consisting ofwhereina is -C(C1-3-alkyl,F,F), -C(heterocyclyl,OCH3), -C(heterocyclyl,F), -heterocyclyl, -C(C3-6-cycloalkyl, OCH3), -C(C3-6-cycloalkyl substituted by 1-2 halogen, H), -SO2CH3, or -C((CH3)2, OCH3).a’ is Ci-3-alkyl, -O-Ci-s-alkyl, -O-C3-6-cycloalkyl or C3-6-cycloalkyl,a’ ’ is halogen,b is N or CH,c is -CO-C1-3-alkyl,d is selected from the group consisting of aryl substituted by 1-2 halogen, heteroaryl and heteroaryl substituted by 1-2 halogen, ande is absent.

4. A compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof wherein T is a targeting ligandT is a targeting ligand selected from the group consisting ofwhereina is -C(C1-3-alkyl,F,F), or -C(heterocyclyl,OCH3),a’ is Ci-3-alkyl or -O-Ci-s-alkyl,a' ’ is halogen,b is N or CH,c is -CO-C1-3-alkyl,d is heteroaryl, ande is absent.

5. A compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof wherein T is a targeting ligandT is a targeting ligand selected from the group consisting ofwhereina is -C(CH3, F, F), or -C(tetrahydrofuranyl, OCH3),a is CH3or -O- CH3,a" is F.b is N or CH,c is -CO-CH3,d is pyridinyl, ande is absent.

6. A compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof wherein T is selected from the group consisting ofLmeans the site of the target ligand T attached to L.

7. A compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof wherein T is selected from the group consisting ofwhereinLmeans the site of the target ligand T attached to L.

8. A compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereofwherein T is wherein means the site attached to L.

9. A compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof wherein B is a CRBN binder selected from the group consisting ofwherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by Ci-3-alkyl or halogen and -(CH2)0-1aryl, optionally substituted by halogen.

10. A compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof wherein B is selected from the group consisting ofwherein e is selected from the group consisting of a 1H-indazolyl by CH3-alkyl and F and phenyl substituted by 2 F.

11. A compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof wherein B is selected from the group consisting ofattached to L.

12. A compound according to any one of claims 1-11 or a pharmaceutically acceptable salt thereof wherein B is selected from the group consisting ofLmeans the site of the CRBN binder B attached to L.

13. A compound according to any one of claims 1-12 or a pharmaceutically acceptable saltLthereof wherein B is and wherein means the site attached to L.

14. A compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting ofL2 is -(CH2)1-2-,13 is N,14 is absent.

15. A compound according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting ofL2 is -CH2-,13 is N,14 is absent.

16. A compound according to any one of claims 1-15 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting ofand wherein means the siteTattached to the CRBN binder B and means the site attached to the target ligand T.

17. A compound according to any one of claims 1-16 or a pharmaceutically acceptable saltthereof wherein L is selected from the group consisting ofB T wherein means the site attached to the CRBN binder B and means the site attached to the target ligand T.

18. A compound according to any one of claims 1-17 or a pharmaceutically acceptable saltthereof wherein L is wherein means the siteTattached to the CRBN binder B and means the site attached to the target ligand T.

19. A compound according to any one of claims 1-18 or a pharmaceutically acceptable salt thereof wherein T is a targeting ligand selected from the group consisting ofwhereina is –C(C1-3-alkyl,F,F), or –C(heterocyclyl,OCH3),a’ is Ci-3-alkyl or -O-Ci-3-alkyl,a” is halogen,b is N or CH,c is -CO-C1-3-alkyl,d is heteroaryl, ande is absent,wherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by Ci-3-alkyl or halogen and -(CH2)0-1aryl, optionally substituted by halogen, and L is selected from the group consisting ofL2 is –(CH2)1-2-,13 is N, and14 is absent.

20. A compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof wherein Tis a targeting ligand selected from the group consisting ofwhereina is –C(CH3,F,F), or –C(tetrahydrofuranyl,OCH3),a' is CH3or -O- CH3,a” is F,b is N or CH,C IS -CO-CH3,d is pyridinyl, ande is absent,B is selected from the group consisting ofwherein e is selected from the group consisting of a 1H-indozalyl by CH3-alkyl and F and phenyl substituted by 2 F, andL is selected from the group consisting ofL2 is -CH2-, 13 is N and 14 is absent.

21. A compound according to any one of claims 1-20 or a pharmaceutically acceptable salt thereof whereinLwherein means the site of the target ligand T attached to L,B is selected from the group consisting ofowherein means the site of the CRBN binder B attached to L, and L is selected from the group consisting ofand wherein means the siteTattached to the CRBN binder B and means the site attached to the target ligand T.

22. A compound according to any one of claims 1-21 or a pharmaceutically acceptable salt thereof whereinT is selected from the group consistingLmeans the site of the target ligand T attached to L,and whereinB Tmeans the site attached to the CRBN binder B and means the site attached toCRBN binder B attached to L.

23. A compound of formula I according to any of claims 1-22, or a pharmaceutically acceptable salt thereof, selected from the group consisting ofN-(5-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)oxy)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carbonyl)-4-hydroxypiperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-(4-((1r,4r)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)phenyl)cyclohexyl)piperazine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-(4-(6-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-2,6-diazaspiro[3.4]octan-2-yl)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)oxy)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,6'-acetamido-N-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-2-oxoethyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,6'-acetamido-N-(6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-6-oxohexyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,6'-acetamido-N-(10-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-10-oxodecyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,6'-acetamido-N-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-2-oxoethyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,N-[5-[6-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]piperidine-1-carbonyl]-2-pyridyl]-4-[[6-(1-methoxy-1-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,N-(6-(6-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(6-(6-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(6-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(6-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)oxy)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(6-(4-((1r,4r)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)phenyl)cyclohexyl)piperazine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(6-(4-(6-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-2,6-diazaspiro[3.4]octan-2-yl)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(6-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,6'-acetamido-N-(6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-6-oxohexyl)-4'-((6-(2-hydroxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[4-[[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7-yl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[6-(1,1-difluoroethyl)-2-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[6-(1,1-difluoroethyl)-2-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-4-[(4-methyl-6-methylsulfonyl-2-pyridyl)amino]-2-pyridyl]acetamide,N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]azetidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-1-piperidyl]methyl]-3-hydroxy-azetidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidin-1-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)pyrrolidin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2S)-2-((6-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)morpholine-4-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-1-yl)methyl)-4-hydroxypiperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-6-yl)piperidin-l-yl)methyl)-3-hydroxypyrrolidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((6-(3-(2,6-dioxopiperidin-3-yl)- l-methyl-1H-indazol-6-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)phenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((l-(3-(2.6-dioxopiperidin-3-yl)- 1-methyl-1H-indazol-6-yl)pynolidin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)phenyl)piperidin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide, A^-(4,-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-1H-indazol-6-yl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((6-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-4-fluoropiperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((6-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-l / 7-indazol-7-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)pyrrolidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperidin-4-yl)methoxy)piperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methoxy)piperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((4-(3-(2,6-dioxopiperidin-3-yl)- l-methyl-l / / -indazol-7-yl)piperazin-l-yl)methyl)pyrrolidine-l-carbonyl)-|2,3'-bipyridinJ-6'-yl)acetamide.N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-7-yl)piperazin-l-yl)methyl)azetidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(3-(2-(4-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-1H-indazol-7-yl)piperazin-l-yl)ethyl)azetidine-l-carbonyl)-f2,3'-bipyridin]-6'-yl)acetamide.N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((6-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1 7-indazol-6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperazin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((l-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(6-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-l / 7-indazol-7-yl)piperazin-l-yl)methyl)-3-azabicyclo[3.1.1]heptane-3-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-3,3-difluoropiperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(5-((2,6-dioxopiperi din-3-yl)oxy)pyridin-2-yl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.2V-(4'-((6-(l,l-difluoropropyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,(> S')-A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide.(7?)-A^-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin- 3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-|2,3'-bipyridin]-6'-yl)acetamide.2V-[4-[[4-(cyclopropoxy)-6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridy 1] acetamide,7V-[4-[[2-(l, 1 -difluoroethyl )-4-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2, 6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl]acetamide, jV-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-4-[[6-[(37?)-3-methoxytetrahydrofuran-3-yl]-4-methyl -2-pyridyl] amino] -2 -pyridyl] acetamide,7V-[5-[5-[2-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-26-difluoro-phenyl]piperazin-l-yl]methyl]morpholine-4-carbonyl]-2-pyridyl]-4-[[6-[(37?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide.jV-[5-[5-[4-[[4-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-7-yl]-l-piperidyl]methyl]piperidine-l-carbonyl]-2-pyridyl]-4-[[6-[(3?)-3-methoxytetrahydrofuran-3-yl]- 4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-4-fluoro-piperidine-l-carbonyl]-2-pyridyl]-4-[[6-[(3A)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide.jV-[5-[5-[4-[[4-[3-(2,6-dioxo-3-piperidyl)pyrazolo[l,5-a]pyridin-7-yl]piperazin-l-yl]methyl]-4-fluoro-piperidine-l-carbonyl]-2-pyridyl]-4-[[6-[(3?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,2V-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2.6-difluorophenyl)cyclohexyl)methyl)piperazine- 1-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin] -6'-y l)acetamide,jV-(5-(2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[i7]oxazol-7-yl)-6-azaspiro|3.4|octane-6-carbonyl)-4'-((6- )-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6,-yl)acetamide,jV-(5-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-l#-indazol-6-yl)piperazin-l-yl)methyl)pyrrolidine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin- 2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,A^-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)cyclohexyl)methyl)piperazine-l-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran- 3-yl)-4-methylpyndin-2-yl)amino)-[2,3,-bipyridin]-6,-yl)acetamide.A^-(5-((27?)-2-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)morpholine-4-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,2V-(5-((2< S)-2-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)morpholine-4-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,A^-(5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)pyrazolo[L5-a]pyridin-6-yl)piperazin-l-yl)methyl)piperi dine- l-carbonyl)-4'-((6-((J?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide.Ar-(5-(4-((6-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-7-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,A-(5-(4-((l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-l / 7-indazol-7-yl)pyrrolidin-3-yl)methyl)piperazine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,jV-(5-(4-((l-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,JV-(5-((3R)-3-((4-(3-(2.6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-7-yl)piperazin-l-yl)methyl)pyrrolidine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,jV-(5-((31S')-3-((4-(3-(2,6-dioxopiperidin-3-yl)-l -methyl- 1H-indazol-7-yl)piperazin- 1-yl)methyl)pyrrolidine-l-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,JV-(5-(4-((l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-6-yl)pyrrolidin-3-yl)methyl)piperazine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,A^-(5-(4-((6-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-(( )-3-methoxytetrahydrofuran-3-yl)-4-methylpyndm-2-yl)arnino)-|2,3'-bipyridin]-6'-yl)acetamide. 2V-(5-(4-((4-(3-(2,6-dioxopiperidin-3-yl)benzo[<7|isoxazol-7-yl)piperidin-l-yl)methyl)piperidine- 1-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin] -6'-y l)acetamide,jV-(5-(3-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)pyrrolidine-l-carbonyl)-4'-((6-((A)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin- 2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,A^-(5-(3-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-3-hydroxypyrrolidine-1 -carbonyl)-4'-((6-(( / )-3-methoxytetrahydroluran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide.2V-(5-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-7-yl)piperazin-l-yl)methyl)pyrrolidine-l-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin- 2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,7V-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidin-l-yl)methyl)piperidine-l-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2 -yl)amino)-[2.3'-bipyridin] -6'-y l)acetamide,Ar-(5-(4-((4-(4-(((7?)-2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-4'-((6-((J?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,7V-(5-(4-((4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperi dine- l-carbonyl)-4'-((6-((J?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide+l,jV-(5-((2r,4s')-2-(4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[< |oxazol-7-yl)-3,3-difluoropiperidin-l-yl)-6-azaspiro[3.4]octane-6-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran- 3-yl)-4-methylpyri din-2 -yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,JV-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2.6-difluorophenyl)piperidin-l-yl)methyl)-4- H uoropipendine- 1 -carbonyl )-4'-((6-(( / ?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,jV-(5-(4-((4-(4-(((7?)-2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3,-bipyridin]-6,-yl)acetamide,JV-(5-(4-((4-(4-(((5)-2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4- H uoropiperi dine- 1 -carbonyl )-4'-((6-((7 )-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl),jV-(5-((2y4r)-2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)-6-azaspiro[3.4]octane-6-carbonyl)-4'-((6-((7?)-3-methoxytetrahydrofuran-3-yl)-4-methylpyndm-2-yl)amino)-|2 '-bipyridin]-6'-yl)acetamide.V-(5-((27-,- / x)-2-(4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)-6-azaspiro[3.4]octane-6-carbonyl)-4'-((6-((?)-3-methoxytetrahydrofuran- 3-yl)-4-methylpyri din-2 -yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,6'-acetamido-A^-(6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-177-benzo|«'|imidazol-4-yl)piperidin-l-yl)-6-oxohexyl)-4'-((6-((X)-3-methoxytelrahydrofuran-3-yl)- 4-methylpyridin-2-yl)amino)-[2.3'-bipyridine]-5-carboxamide,jV-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridylJ-4-t[6-(3-methoxyoxetan-3-yl)-4-methyl-2-py ridyl] amino] -2-pyridyl] acetamide.2V-(4'-((4-cyclopropyl-6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,A^-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-(CR)-3-fluorotetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide.Ar-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-((<S,)-3-fluorotetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,A-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperidine-l-carbonyl)-4'-((6-(l-fluorocyclobutyl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin] -6'-y l)acetamide,jV-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-4'-((6-(l -methoxy cyclopropyl)-4-methylpyridin-2-yl)amino)-P^'-bipyridinJ-b'-y^acetamide,2V-(4'-((6-(2,2-difluorocyclopropyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l -carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,jV-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-4'-((6-((J?)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6,-yl)acetamide,jV-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-4- H uoropiperi dine- 1 -carbonyl )-4'-((6-((7 )-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]pyrrolidine-l-carbonyl]-2-pyridyl]-2-pyridy 1] acetamide.2V-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-4-fluoro-piperidine-l-carbonyl]-2-pyridyl] -2-pyridyl] acetamide,jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino] -2,6-difluoro-pheny 11 pi perazi n- 1 -yl] methyl] -4-hy droxy -piperidine- 1 -carbonyl] -2-pyridyl] -2-pyridyl] acetamide,A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)-2-oxopiperazin-l-yl)methyl)piperidine-l-carbonyl)-|2,3'-bipyridin]-6'-yl)acetamide.2V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,A^-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[2-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]morpholine-4-carbonyl]-2-pyridyl]-2-pyridy 1] acetamide,Ar-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((l-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)piperidin-4-yl)oxy)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide, 7V-[4-[[2-(l, 1 -difluoroethyl )pyrimidin-4-yl]amino]-5-[5-[4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]phenoxy]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl]acetamide.Ar-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,2V-[4-f[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-f4-[fl-[4-f(2.6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methoxy]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]oxymethyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridy 1] acetamide,-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperazine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4,7-diazaspiro[2.5]octan-4-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,jV-[4-[[2-(l,l-dilluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,A-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[2-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,6-diazaspiro[3.3]heptan-6-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl]acetamide.A^-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]- 2.6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonylJ-2-pyridylJ-2-pyridyl] acetamide,2V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide, A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyndin]-6'-yl)acetamide, 2V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(9-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-l / / -indazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide, A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-(l-(4-((2,6-dioxopiperidin-3-yl)amino)- 26-difluorophenyl)piperidin-4-yl)pyrrolidine-l-carbonyl)-|23'-bipyridin]-6'-yl)acetamide. 2V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-(l-(4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)cyclopropyl)piperidine-l-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)piperazin-l-yl)methyl)azetidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.2V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(6-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)piperazin-l-yl)methyl)-3-azabicyclo[3.1.1]heptane-3-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)piperazin-l-yl)methyl)-6-azabicyclo[3.1.1]heptane-6-carbonyl)-[2,3'-bipyridin] -6'-y l)acetamide,jV-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(3-(2-(4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)ethyl)azetidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,A^-(4'-((2-(l,l-difluoroethyl)-5-fluoropyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2.3'-bipyridin]-6'-yl)acetamide,jV-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluoropheny l)piperazin- 1 -yl)methy l)piperidine- 1 -carbony l)-3 -fl uoro-[2, 3 -bipyridin] -6'-yl)acetamide,(7?)-7V-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.(5)-V-(4'-((2-(l,l -difl uoroethyl)pyrimi din-4-yl)amino)-5-(4-((4-(4-((2,6-di ox opiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin- 1 -yl)methyl)piperidine- 1 -carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.2V-(4'-((2-(l,l -difl uoroethyl)pyrimidin-4-yl)amino)-5-((25,4r)-2-(4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)-6-azaspiro[3.4]octane-6-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,A^-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((2r,45')-2-(4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)-6-azaspiro[3.4]octane-6-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,jV-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine- 1 -carbonyl] -2 -pyridyl] -4-[[6-methyl-2-(2-oxabicyclo[2.1.1 ]hexan- 1 -yl)pyrimidin-4-yl] amino] -2 -pyridyl] acetami de,4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2.6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-iV-methyl-pyridine-2-carboxamide,N-(4'-((6-(1,1-difluoroethyl)-4-methoxypyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide,2V-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-hydroxy-4-piperidyl]methyl]piperidine-l-carbonyl]-2-py ridyl] -2 -pyridyl] acetamide,7V-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[4-[[4-[l-(2,6-dioxo-3-piperidyl)indolin-5-yl]piperazin-l-yl]methyl]-4-fluoro-piperidine-l-carbonyl]-2-pyridyl]-2-py ridyl] acetamide,V-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[ rac}-(2 R})-2-[[6-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-2-azaspiro[3.3]heptan-2-yl]methyl]morpholine-4-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,jV-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-l-piperidyl]methyl]-3-hydroxy-pyrrolidine-l-carbonyl]-2-pyridyl] -2 -pyridyl] acetamide,V-[5-[5-[2-[3-(2.6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-6-azaspiro[3.4]octane-6-carbonyl]-2-pyridyl]-4-[[4-methyl-6-[ rac}-(3 R})-3-methoxytetrahydrofuran-3-yl]-2-py ridyl] amino] -2-pyridyl] acetamide,jV-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)oxy]-3-fluoro-2-pyridyl]piperazin-l-yl]methyl]-4-fluoro-pipendine-l-carbonyl]-2-pyridyl] -2-pyridyl] acetamide,jV-[5-[5-[4-[[4-[3-(2,6-dioxo-3-piperidyl)pyrazolo[l,5-a]pyridin-7-yl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-4-t|4-methyl-6-| / rac}-(3 / R})-3-methoxy tetrahy drofuran-3 -y 1] -2-pyridyl] amino] -2-pyridyl] acetamide.JV-[5-[5-[4-[[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-4-methoxy-benzoyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-4-[[6-[(3)rR})-3-methoxytetrahydrofuran-3-yl]-4-methyl -2-pyridyl] amino] -2-pyridyl] acetamide,Af-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[6-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3-pyridyl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[5-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2-pyridyl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]phenyl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-py ridyl] acetamide,JV-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-fluoro-phenyl]-2-py ridyl] acetamide,jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]piperidine-l-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,7V-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-di fluoro-phenyl] piperazine- 1 -carbonyl] -2-pyridyl] -2 -pyridyl] acetamide,jV-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[7-[4-[(2,6-dioxo-3-piperidyl)amino]- 2-fluoro-phenyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2-pyridyl]-2-pyridyl]acetamide, 6-[6-acetamido-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-jV-[6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-6-oxo-hexyl] pyridine-3 -carboxamide,6-[6-acetamido-4-[[6-(l,1 -difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-jV-[6-[4-[l -(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-6-oxo-hexyl]pyridine- 3-carboxamide,JV-[5-[5-[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperidine-l-carbonyl]-2-pyridyl]-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2 -pyridyl] acetamide,6-[6-acetamido-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-^V-[10-|4-[ l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l -piperidyl]- 10-oxo-decyl] pyridine-3 -carboxamide.JV-[5-[5-[9-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]-3,9-diazaspiro[5.5]undecane-3-carbonyl]-2-pyridyl]-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl] amino] -2-pyridyl] acetamide,]N}-[4-[[2-(l,l-difluoroethyl)-5-fluoro-pyrimidin-4-yl]amino]-5-[5-[~{rac}-(3~{a}~{S},6~{a}~{S})-2-[3-(2,6-dioxo-3-piperidyl)-5-fluoro-l-methyl-indazol-6-yl]-1.3.3~{a},4,6,6~{a}-hexahydropyrrolo[3,4-c]pyrrole-5-carbonyl]-2-pyridyl]-2-py ridyl] acetamide,{N}-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[5-[(3~{R})-3-hydroxy-3-[[4-[l-methyl-3-[(3~{R})-3-methyl-2,6-dioxo-3-piperidyl]indazol-6-yl]-l-piperidyl]methyl]pyrrolidine-l-carbonyl] -2-pyridyl] -2-pyridyl] acetamide,{N]-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[5-[(3~{S})-3-hydroxy-3-[[4-[l-methyl-3-[(3~{R})-3-methyl-2,6-dioxo-3-piperidyl]indazol-6-yl]-l-piperidyl]methyl]pyrrolidine-l-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,{N}-[4-[[2-(l,l-difluoroethyl)-5-fluoro-pyrimidin-4-yl]amino]-5-[5-[9-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carbonyl]-2-pyridyl]-2-pyridyl] acetamide,{N}-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[6-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-3-pyridyl]-2-pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]cyclohexyl]-2-pyridyl]acetamide,6-[6-acetamido-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-N-[6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-6-oxo-hexyl] pyridine-2-carboxami de,6-[6-acetamido-4-[[6-(l -methoxy- l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-N-[2-|4-tl-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-2-oxo-ethyl] pyridine-2-carboxamide.andN-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[4-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-l-yl]methyl]piperidine-l-carbony 1] cy clohexen- 1 -y 1] -2-pyridyl] acetamide.

24. A compound of formula I according to any of claims 1-23, or a pharmaceutically acceptable salt thereof, selected from the group consisting ofN-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]azetidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-1-piperidyl]methyl]-3-hydroxy-azetidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,7V-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(4-((4-(3-(26-dioxopiperidin-3-yl)-5-fluoro-l -methyl- 1H-indazol-6-yl)piperazin-l-yl)methyl)piperi dine-1 -carbonyl)-[2.3'-bipyridin] -6'-y l)acetamide,N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]piperidine-1-carbonyl]-2-pyridyl]-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[3-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]pyrrolidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]-4-fluoro-piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]-4-hydroxy-piperidine-1-carbonyl]-2-pyridyl]-2-pyridyl]acetamide,N-(4'-((2-(1,1-difluoroethyl)-5-fluoropyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide, andN-(4'-((6-(1,1-difluoroethyl)-4-methoxypyridin-2-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-[2,3'-bipyridin]-6'-yl)acetamide.

25. A process for the preparation of a compound according to any one of claims 1-24 or a pharmaceutically acceptable salt thereof comprising reacting a compound of formula (A) with a compound of formula (C) to a compound of formula (I’)wherein Xi is H or Ci-salkyl.

26. A compound of formula I according to claims 1-24, or a pharmaceutically acceptable salt thereof, when manufactured according to a process of claim 25.

27. A pharmaceutical composition comprising a compound in accordance with any one of claims 1-26 and a pharmaceutically acceptable excipient.

28. A compound or pharmaceutically acceptable salt according to any one of claims 1-26 for use as therapeutically active substance.

29. The use of a compound according to any one of claims 1-26 as therapeutically active substance for the therapeutic and / or prophylactic treatment of autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinflammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease,Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis. Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

30. The use of a compound according to any one of claims 1-26 as therapeutically active substance for the therapeutic and / or prophylactic treatment of inflammatory bowel disease.

31. A compound of formula I according to claims 1-26 for the use as therapeutically active substance for the therapeutic and / or prophylactic treatment of autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus ery thematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinflammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

32. A compound of formula I according to claims 1-26 for the use as therapeutically active substance for the therapeutic and / or prophylactic treatment of inflammatory bowel disease.

33. A method of preventing or treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is an autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinflammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus hostdisease and wherein the method comprises administering a therapeutically effective amount of a compound according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof, to the subject.

34. The invention as hereinbefore described.***

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