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 P60975

[0002] TYK2 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 IFNa and IFNp. 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 / p, 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 Summary 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] Summary of the Invention

[0010] SMU / 15.01.2025The 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-Goutières 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 Summary 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. 1H-benzoimidazolyl, benzooxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, 1H-indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), 1H-pyrazolyl, pyrazolo[1,5-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-1H-benzimidazolyl, 1H-indazolyl, indolinyl, 2,3-dihydro-1,3-benzoxazolyl, 1H-pyrazolo[3,4-b]pyridyl, 1H-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, 1H-indazolyl, benzoxazolyl, pyridinyl, 1,3-dihydrobenzimidazol-2-one, 3H-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 12 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[5.5]undecanyl, 8-aza-bicyclo[3.2.1]octyl, 2,7-diazaspiro[3.5]nonyl, 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 oxopiperazinyl, 2-oxabicyclo[2.1.1]hexanyl, 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, 2-azaspiro[3.4]octyl, 1,2,3,3a,4,5,6,6a-octahydropyrrolo[3,4-c]pyrrolyl, l-oxa-8-azaspiro[4.5]decanyl, 2-azaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 3-azaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, 6-azaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 3,9-diazaspiro[5.6]dodecanyl, tetrahydrofuranyl, oxetanyl, piperazinyl, piperidyl, pyrrolidinyl, morpholinyl and azetidinyl.

[0022] The term “Ci-6-alkoxy”, alone or in combination w ith 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 Terminology7, 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 itencompasses a product comprising one or more active ingredients, and an optional carrier compnsing inert ingredients, as well as any product that results, directly or indirectly, from combination, 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 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 * / 2(Emax) 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 particularinhibitor would occupy 50% of the receptors if no competing ligand (e.g. a radioligand) was present. 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.

[0039] 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.

[0040] In general, the nomenclature used in this Application is based on AUTONOMTM2000, a Beilstein Institute computerized system for the generation of IUPAC systematic nomen-clature. Chemical structures shown herein were prepared using Biovia Draw 2024C, 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.

[0041] The invention also provides pharmaceutical compositions, methods of using, and methods of preparing the aforementioned compounds.

[0042] All separate embodiments may be combined.

[0043] One embodiment (embodiment 1) of the invention provides a compound of formula I, T-L-B I,

[0044] wherein

[0045] T is a target ligand

[0046]

[0047] T, wherein

[0048] a is -C(CH3F F), -C(heterocyclyl, OCH3), -C((CH3)2, OCH3) or -C(CH3)2OH,

[0049] b is N or CH,

[0050] c is H, -CO-C1-3-alkyl, -CO-C3-6-cycloalkyl, heterocyclyl or -Ci-3-alkyl, and

[0051] d is heteroaryl,e is absent, C1-3-alkyl, -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-heterocyclyl- or -N(CH3)-SO2-(CH2)I-2, -C3-6-cycloalkyl, heteroaryl, optionally substituted by =0. heteroaryl-heterocyclyl, or heteroaryl-heteroaryl, L is a linker selected from the group consisting of

[0052]

[0053] wherein

[0054] L1 is absent or selected from the group consisting of -CO-CH2-, -N-(CH2)1-5-CO-, -CO-(CH2)1-8-CO-, -heteroaryl-(CH2)0-1- and -(CH2)0-1-heteroaryl-,

[0055] 11 is CH orN,

[0056] 12 is CH orN,

[0057] c) -CO-(CH2)O-2-,

[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] l3 is selected from the group consisting of CH and N,

[0061] 14 is absent or -CO-,

[0062]

[0063] , wherein

[0064] L3 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-, and -(CH2)i-2- CO-(CH2)I-2-,

[0065] L4 is absent, -C3-6-cycloalkyl or heterocyclyl,L5 is absent or is selected from the group consisting of -(CH2)i-2-, -CO-, and -(CH2)I-2- CO-(CH2)I-2-,

[0066] , wherein l5 is -CH- or -N-, 16 is -O- or -CH2-, L6 is absent or heterocyclyl,

[0067] , wherein L7 is selected from the group consisting of - (CH2)I-2-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-, and

[0068] 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

[0069]

[0070] wherein e is a bicyclic heteroaryl, optionally substituted by Ci-3-alkyl, or aryl, optionally substituted by halogen or -O-Ci-3-alkyl.

[0071] 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

[0072] T1

[0073]

[0074] a), wherein

[0075] T1 is H, -CO-Ci-3-alkyl. -CO-C3-6-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.

[0076] F

[0077] F

[0078] , wherein

[0079] tl is H or -CH3, and

[0080] T3 is absent, -N(CH3)-C3-6-cycloalkyl or -C3-6-cycloalkyl,

[0081] T5

[0082] N

[0083]

[0084] , wherein

[0085] T4 is heteroaryl, and

[0086] T5 is absent. -CO- or heteroaryl,

[0087] , and

[0088]

[0089] , wherein

[0090] 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

[0091] , 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)1-2,

[0092]

[0093] b), wherein

[0094] tl is H or -CH3, and

[0095] T3 is absent or -cyclohexyl,

[0096]

[0097] , wherein

[0098] T4 is pyridinyl or pyrazolyl, and

[0099] T5 is absent, -CO- or a 5-membered heteroaryl,d)

[0100]

[0101] 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

[0102]

[0103] a), wherein

[0104]

[0105] T1 is H, -CO-CH3, -CO-CH2CH3,. ethyl or methyl, and

[0106] T2 is absent, Ci-3-alkyl, -CO-, -N(CH3)-, -N(CH3)-CO-(CH2)I-S-CO-, -N(CH3)-CO- (CH2)I-2. -N(CH3)-(CH2)I-2, -N(CH3)-SO2-(CH2)I-2. oxazolyL or -N(CH3)-CO-(CH2)1.2

[0107]

[0108] -N3> CN-i-

[0109]

[0110] tl is H or -CH3, and

[0111] T3 is absent or -cyclohexyl,

[0112]

[0113] T4 is pyridinyl, and

[0114] T5 is absent. -CO-, oxazolyl or pyrazolyl.

[0115]

[0116] t2 is -C(CH3,F,F) or -C(CH3)2OH.

[0117] 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

[0118] a), wherein

[0119] T1 is H, -CO-CH3. -CO-CH2CH3,. ethyl or methyl, and T2 is absent, Ci-3-alkyl, -CO-, -N(CH3)-, -N(CH3)-CO-(CH2)I.8-CO-, -N(CH3)-CO- (CH2)I-2. -N(CH3)-(CH2)I-2, -N(CH3)-SO2-(CH2)1-2, oxazolyl, or -N(CH3)-CO-(CH2)1-2-N> CN+

[0120]

[0121] T4 is pyridinyl, and

[0122] T5 is absent, -CO-, oxazolyl or pyrazolyl.

[0123] 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

[0124]

[0125]

[0126] 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

[0127]

[0128] 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

[0129]

[0130] wherein C1 is a bicyclic heteroaryl, optionally substituted by C1-C3-alkyl, and

[0131]

[0132] wherein C2 is a aryl, optionally substituted by halogen or -O-C1-3-alkyl.

[0133] 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

[0134]

[0135] wherein Cl is selected from the group consisting of

[0136] N-N

[0137] N

[0138] N

[0139]

[0140] , each optionally substituted by methyl, and

[0141]

[0142] wherein C2 is a phenyl, optionally substituted by F and -OCH3.

[0143] 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

[0144]

[0145] 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

[0146]

[0147] 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

[0148] , 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-,

[0149] . B

[0150] c) -CO-(CH2)O-2-.

[0151]

[0152] a. L2 is selected from the group consisting of a bond, -(CH2)I-2-, -CO-, and - (CH2)I.2-CO-(CH2)I-2-,

[0153] b. l1 is selected from the group consisting of CH and N,

[0154] c. 12 is absent or -CO-,

[0155]

[0156] , wherein

[0157] a. L3 is absent or is selected from the group consisting of -(CH2)i-2-, -CO-, and - (CH2)i.2-CO-(CH2)i-2-,

[0158] b. L4 is absent, C3-6cycloalkyl or heterocyclyl,

[0159] c. L5 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-, and - (CH2)I.2-CO-(CH2)I-2-,

[0160]

[0161] a. l3 is -CH- or -N-,

[0162] b. l4 is -O- or -CH2-,

[0163] c. L6 is absent or heterocyclyl,

[0164] g). wherein L7 is selected from the group consisting of - (CH2)I-2-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-, and

[0165]

[0166] , wherein L8 is selected from the group consisting of - (CH2)I.2-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-.

[0167] 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

[0168] , wherein LI is absent or selected from the group consisting of

[0169] -CO-CH2-, -N-(CH2)1-5-CO-, -CO-(CH2)1-8-CO-, and -heteroaryl-(CH2)0-1-, and

[0170] _ j—L5— L4— L3-Z^N-j- -4— L5-L4— L3^°Al-i-

[0171]

[0172] ( °‘1 6or O0-1 B. wherein

[0173] a) L3 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-, and - (CH2)i-2-CO-(CH2)i-2-,

[0174] b) L4 is absent, C3-6cycloalkyl or heterocyclyl,

[0175] c) L5 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-, and - (CH2)I.2-CO-(CH2)I-2-.

[0176] 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

[0177]

[0178]

[0179] 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

[0180]

[0181] 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

[0182] T-L-B

[0183]

[0184] wherein

[0185] T is a target ligand selected from the group consisting of

[0186]

[0187]

[0188] L is a linker selected from the group consisting of

[0189]

[0190] B is a CRBN binder selected from the group consisting of

[0191]

[0192] 17. A further embodiment of the invention provides a compound of formula I according to any of embodiments 1-1 wherein T is

[0193]

[0194] T, wherein

[0195] ais -C(CH3;F, F), -SO2CH3, -C(heterocyclyl, OCH3), -C((CH3)2, OCH3) or -C(CH3)2OH, b is N or CH,

[0196] c is H, -CO-C1-3-alkyl, -CO-C3-6-cycloalkyl, optionally substituted by -OCH3, heterocyclyl or -Ci-3-alkyl, and

[0197] d is heteroaryl -O-heterocyclyl,

[0198] 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, heteroaryl-heterocyclyl, or heteroarylheteroaryl,

[0199] 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

[0200] 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,

[0201] 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,

[0202] 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,

[0203] 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,

[0204] 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-[[l-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidylJoxy]piperidine-l-carbonyl]-2-pyndylJ-4-tt6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide.

[0205] 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,

[0206] 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,

[0207] 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,

[0208] 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,

[0209] 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-((lr,4r)-4-(4-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-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,

[0210] N-(5-(4-((lr,4r)-4-(4-(l-(2.6-dioxopiperidin-3N-(5-(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, 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-l-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3,-bipyridin]-6,-yl)acetamide.N-(6-(4-((lr,4r)-4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-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.

[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-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imi dazol-4-yl)piperi din-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-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperi din-1 -y l)-6-oxohexyl)-4'-((6-(2 -hydroxypropan-2 -yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,

[0218] 6-[6-acetamido-4-[[6-(l J -difluoroethyl)-4-methy 1-2 -pyridyl] amino] -3 -pyridyl] -~{N}- [6- [4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-6-oxo-hexyl|pyridine-3-carbo\amide.

[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-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-rnethoxyphenyl)piperazin-l -yl)methyl)piperi dine- l-carbonyl)pyri din-2-yl)acetamide.N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-10-[4-tl-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-ylJ-l-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-(1-(4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-3-yl)-4-((6-(2-methoxypropan-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-(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)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0237] 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)piperidin-1-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0238] N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazine-1-carbonyl]-4-hydroxy-1-piperidyl]-N-methyl-acetamide,

[0239] N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(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)piperidin-1-yl)-N-methylacetamide,

[0240] N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)cyclohexyl)pyridin-2-yl)acetamide,

[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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperidin-1-yl)oxazol-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((2-(l, 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 ty pe 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goutières 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 ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goutières 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 I,

[0273] wherein

[0274] T is a targeting ligand selected from the group consisting of

[0275] 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, a’ n Cvs-alkyl. -Q-Cvs-alkyl. -O-C3.ft-cy ckalkyl or Csn-.: n

[0276] a”' is Cs-j-alkyl, -()-(>.. s-dkyl or Halogen, b is N or CH.

[0277]

[0278] c is H, -CO-Ci-3-alkyl, -CO-Cs-e-cycloalkyl, H y heterocyclyl or -Ci-3-alkyl, and

[0279] d is absent or selected from the group consisting of -O-heterocyclyl, C4-6-cycloalkenyl, C3-6-cycloalkyl, aryl, aryl substituted by 1-2 halogen, heteroaryl and heteroaryl substituted by 1-2 halogen,

[0280] e is absent, -(CH2)I-3-, -CO-, -N(CH3)-, -N(CH3)-CO-(CH2)I.8-CO-, -N(CH3)-CO-, -N(CH3)-CO- (CH2)I.2, -N(CH3)-(CH2)I.2, -N(CH3)-CO-(CH2)i.2-heterocyclyl-, -N(CH3)-SO2-(CH2)I-2, -C3-6- cycloalkyl, heteroaryl, optionally substituted by =0, heteroaryl-heterocyclyl,

[0281]

[0282] or heteroarylheteroaryl,

[0283] L is a linker selected from the group consisting of

[0284]

[0285] wherein

[0286] L1 is absent or selected from the group consisting of -CO-(CH2)1-3-, -(CH2)1-3-CO-, -N-(CH2)1-9-CO-, -CO-(CH2)1-8-CO-, -(heterocyclyl,

[0287]

[0288] -heterocyclyl-(CH2)1-2-, -O-(CH2)1-2-, -C3-6-cycloalkyl-(CH2)0-1-, -aryl-(CH2)0-1-, -(CH2)0-1-aryl-, heteroaryl-(CH2)0-1- and -(CH2)0-1-heteroaryl-,

[0289] 11 is CH orN,

[0290]

[0291] c) -CO-(CH2)o-2-.

[0292]

[0293] L2 is selected from the group consisting of a bond, -(CH2)1-2-, -CO-, -O- and -(CH2)0-2-CO-(CH2)1-2-,

[0294] l3 is selected from the group consisting of CH and N,

[0295] l4 is absent, –CH2N(H,CH3)-, –(CH2)1-2- or –CO-,

[0296]

[0297] L3 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-,

[0298]

[0299] and - (CH2)I-2-CO-(CH2)I-2-,L4 is absent, -Ca-e-cycloalkyl or heterocyclyl.

[0300] L5 is absent or is selected from the group consisting of -(CH2)I-2-,

[0301]

[0302] -CO-, and -(CH2)I-2-CO-(CH2)I-2-,

[0303]

[0304] l5 is -CH- or -N-,

[0305] l6 is -O-, -CF2- or -CH2-,

[0306] L6 is absent, -(CH2)1-2-, -O-, -C3-6-cycloalkyl or -(CH2)0-2-heterocyclyl, optionally substituted by halogen,

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

[0308]

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

[0310]

[0311] B is a CRBN binder selected from the group consisting ofH

[0312] O.. N.,0

[0313] O

[0314] /

[0315]

[0316] wherein e is selected from the group consisting of a -(CH2)0-1-heteroaryl, optionally substituted by C1-3-alkyl, halogen or =O and -(CH2)0-1-aryl, optionally substituted by halogen or -O-C1-3-alkyl. Aspect 2 is a compound according to aspect 1 or a pharmaceutically acceptable salt thereof wherein

[0317] T is a targeting ligand selected from the group consisting of

[0318] a a a

[0319] H H N N,

[0320]

[0321] T, wherein a is –C(C1-3-alkyl,F,F) or –C(heterocyclyl,OCH3),

[0322] a' is (’i.'s-olky L

[0323] b is N or CH,

[0324] c is -CO-Ci-3-alkyl,

[0325] d is absent or selected from the group consisting of C3-6-cycloalkyl, -O-heterocyclyl, C4-6-cycloalkenyl, or heteroaryl,

[0326] e is absent or-CO-. and

[0327] L is a linker selected from the group consisting of

[0328] H J

[0329]

[0330] , wherein

[0331] L1 is absent or selected from the group consisting of -(CH2)1-8-, -(CH2)1-8-CO-, aryl-(CH2)0-1- or -C3-6-cycloalkyl-(CH2)0-1-,

[0332] 11 is CH orN,

[0333] 12 is CH orN,b)

[0334]

[0335] wherein

[0336] L2 is a bond or -(CH2)I-2-,

[0337] l3 is selected from the group consisting of CH and N,

[0338] 14 is absent or

[0339]

[0340] 15 is -CH-,

[0341] 16 is -CH2-,

[0342] L6 is absent, –(CH2)1-2- or–(CH2)0-2-heterocyclyl, optionally substituted by halogen, and B is a CRBN binder

[0343]

[0344] wherein e is selected from the group consisting of a

[0345]

[0346] heteroaryl, optionally substituted by Ci-3-alkyl, halogen or -(CH2)0-1aryl, optionally substituted by halogen or -O-Ci-3-alkyl.

[0347] Aspect 3 is a compound according to any one of aspects 1-2 or a pharmaceutically acceptable salt thereof wherein

[0348] T is a targeting ligand selected from the group consisting of

[0349]

[0350] T, whereina is -C(C‘,..3-afks 4, F. F) or -C(heterocyclyl, OCH3),

[0351]

[0352] a' is

[0353] b is N or CH,

[0354] c is -CO-Ci-3-alkyl,

[0355] d is absent or selected from the group consisting of C3-6-cycloalkyl, -O–heterocyclyl, C4-6-cycloalkenyl, or heteroaryl,

[0356] e is absent or-CO- Aspect 4 is a compound according to any one of aspects 1-3 or a pharmaceutically acceptable salt thereof wherein

[0357] T is a targeting ligand selected from the group consisting of

[0358]

[0359] and T, wherein a is –C(CH3,F,F) or –C(heterocyclyl,OCH3),

[0360] a' is C1-3-alkyl,

[0361] b is N or CH,

[0362] c is -CO- CH3,

[0363] d is absent or selected from the group consisting of -O–pyrrolidyl, cyclohexyl, cyclohexenyl, or 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,

[0364] e is absent or-CO-.

[0365] Aspect 5 is a compound according to any one of aspects 1 -4 or a pharmaceutically acceptable salt thereof wherein T is a targeting ligandT, wherein

[0366]

[0367] a is

[0368] a’ is C;..?-alkyL

[0369] b is CH,

[0370] c is -CO-Ci-3-alkyl,

[0371] d is heteroaryl, and

[0372] e is -CO-.

[0373] 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

[0374]

[0375]

[0376] L

[0377] wherein means the site of the targeting ligand T attached to L.

[0378] Aspect 7 is a compound according to any one of aspects 1-6 or a pharmaceutically acceptable

[0379]

[0380] wherein means the site attached to L.

[0381] Aspect 8 is a compound according to any one of aspects 1-7 or a pharmaceutically acceptable salt thereof wherein B is a CRBN binder

[0382]

[0383] wherein e is selected from the group consisting of a heteroaryl, optionally substituted by C1-3-alkyl. halogen or:::O and -(CH? A>-iaryl, optionally substituted by halogen or -O-Ci-3-alkyl.Aspect 9 is a compound according to any one of aspects 1-8 or a pharmaceutically acceptable salt thereof wherein B is a CRBN binder selected from the group consisting of

[0384] and

[0385]

[0386] wherein e is selected from the group consisting of a 2.3-dihydro- 1 / / -benzimidazolyl, optionally substituted by CH3, F or =0 and

[0387]

[0388] , optionally substituted by F or -O-CH3.

[0389] 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

[0390]

[0391] wherein e is selected from the group consisting of a heteroaryL optionally substituted by C1-3-alkyl and = < H? ary I. optionally substituted by halogen.

[0392] 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

[0393]

[0394]

[0395] CRBN binder B attached to L.

[0396] 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

[0397] L

[0398]

[0399] wherein means the site of the CRBN binder B attached to L.

[0400] Aspect 13 is a compound according to any one of aspects 1-12 or a pharmaceutically acceptable

[0401] L

[0402] means the site attached to

[0403]

[0404] Aspect 14 is a compound according to any one of aspects 1-13 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting of

[0405] L is a linker selected from the group consisting of

[0406]

[0407] LI is absent or selected from the group consisting of

[0408]

[0409] aryl-(CH2)0-1- or -C3-6-cycloalkyl-(CH2)0-1-11 is CH orN,

[0410] 12 is CH orN,

[0411]

[0412] L2 is a bond or -(CH2)I-2-,

[0413] l3 is selected from the group consisting of CH and N,

[0414] 14 is absent or and

[0415]

[0416] 15 is -CH-,

[0417] l6 is -CH2-,

[0418] L6 is absent,

[0419]

[0420] ; 2- or’fCHzKs-heterocyclyl, optionally substituted by halogen

[0421] 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

[0422] wherein

[0423] L1 is -C3-6-cycloalkyl-(CH2)0-1-,

[0424] 11 is N,

[0425] 12 is CH, and

[0426]

[0427] or, wherein15 is -CH-,

[0428] 16 is -CH2-,

[0429] L6 is –(CH2)0-2-heterocyclyl, optionally substituted by halogen.

[0430] 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

[0431]

[0432]

[0433] and, wherein means the site attached

[0434]

[0435] T

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

[0437] 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

[0438]

[0439] B T

[0440] wherein means the site attached to the CRBN binder B and means the site attached to the targeting ligand T.Aspect 18 is a compound according to any one of aspects 1-17 or a pharmaceutically acceptable

[0441]

[0442]

[0443] salt thereof wherein L is wherein means the site attached to

[0444]

[0445] T

[0446] the CRBN binder B and means the site attached to the targeting ligand T.

[0447] Aspect 19 is a compound according to any one of aspects 1-18 or a pharmaceutically acceptable salt thereof wherein

[0448] T is a targeting ligand selected from the group consisting of

[0449]

[0450] and T, wherein a is –C(C1-3-alkyl,F,F) or –C(heterocyclyl,OCH3),

[0451] a' is C1-3-alkyl,

[0452] b is N or CH,

[0453] c is -CO-Ci-3-alkyl,

[0454] d is absent or selected from the group consisting of C3-6-cycloalkyl, -O–heterocyclyl, C4-6-cycloalkenyl, or heteroaryl,

[0455] L

[0456] e is absent or-CO-, wherein means the site of the targeting ligand T attached to L.

[0457] L is a linker selected from the group consisting of

[0458] FF

[0459] a

[0460]

[0461] )TorT, wherein

[0462] LI is absent or selected from the group consisting

[0463]

[0464] of -(CH2)1-8-, -(CH2)1-8-CO-, or -C3-6-cycloalkyl-(CH2)0-1-,11 is CH orN,

[0465] 12 is CH orN,

[0466]

[0467] L2 is–(CH2)1-2-,

[0468] l3 is selected from the group consisting of CH and N,

[0469] 14 is absent or and

[0470]

[0471] 15 is -CH-,

[0472] l6 is -CH2-,

[0473] L6 is absent,

[0474]

[0475] or–(CH2)0-2-heterocyclyl, optionally substituted by halogen,

[0476]

[0477] B T

[0478] wherein means the site attached to the CRBN binder B and means the site attached to the targeting ligand T, and B is a CRBN binder selected from the group consisting of

[0479]

[0480] wherein e is selected from the group consisting of a 2,3-dihydro-1H-benzimidazolyl, optionally substituted by CH3, F or =O and

[0481]

[0482] , optionally substituted by F or -O-CH3.

[0483]

[0484] wherein means the site of the CRBN binder B attached to L.Aspect 20 is a compound according to any one of aspects 1-19 or a pharmaceutically acceptable salt thereof wherein

[0485]

[0486] T is a targeting ligand T, wherein a is –C(C1-3-alkyl,F,F),

[0487] a' is C1-3-alkyl,

[0488] b is CH,

[0489] c is -CO-Ci-3-alkyl,

[0490] d is heteroaryl, and

[0491]

[0492] L

[0493] e is -CO-, wherein means the site of the targeting ligand T attached to L

[0494] B is a CRBN binder selected from the group consisting of

[0495]

[0496] wherein e is selected from the group consisting of a heteroaryl, optionally substituted by C1-3-alkyl and aryl, optionally substituted by halogen.

[0497] L

[0498] w herein means the site of the CRBN binder B attached to L, and

[0499] L is a linker selected from the group consisting of

[0500] F

[0501] 12'

[0502] I B

[0503] ' ^L1

[0504] a

[0505]

[0506] ), whereinL1 is -C3-6-cycloalkyl-(CH2)0-1-,

[0507] 11 is N,

[0508] 12 is CH, and

[0509] ' B

[0510] b) or, wherein

[0511] 15 is -CH-,

[0512] 16 is -CH2-,

[0513]

[0514] B

[0515] L6 is–(CH2)0-2-heterocyclyl, optionally substituted by halogen, wherein means the

[0516]

[0517] T

[0518] site attached to the CRBN binder B and means the site attached to the targeting ligand T.

[0519] Aspect 21 is a compound of formula I according to any of aspects 1-20, or a pharmaceutically acceptable salt thereof, T is a targeting ligand selected from the group consisting of

[0520]

[0521]

[0522] B is a CRBN binder selected from the group consisting of

[0523]

[0524]

[0525]

[0526] T

[0527] to the CRBN binder B and means the site attached to the targeting ligand T.

[0528] Aspect 22 is a compound of formula I according to any of aspects 1-21. or a pharmaceutically acceptable salt thereof. T is

[0529]

[0530] L

[0531] wherein means the site attached to L, B is selected from the group consisting ofL

[0532]

[0533] wherein means the site of the CRBN binder B attached to L, and L is selected from the group consisting of

[0534]

[0535] B T wherein means the site attached to the CRBN binder B and means the site attached to the targeting ligand T.

[0536] Aspect 23 is a compound of formula I according to any of aspects 1-22, or a pharmaceutically acceptable salt thereof, selected from the group consisting ofN-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[10-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidylJ-10-oxo-decanoyl]pyrrolidin-3-ylJoxy-2-pyridyl] acetamide.

[0537] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]acetyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide, N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-6-oxo-hexanoyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide,

[0538] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]acetyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide, N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[1-[2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]-1-piperidyl]acetyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide,

[0539] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0540] N-(4-((6-( 1, 1 -difluoroethyl)-4-methylpy ridin-2-yl)amino)-5-(( 1 -(( 1 s,4s)-4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0541] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0542] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((ls,4s)-4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0543] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((6R)-2-(4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperi din-1 -yl)spiro[3.4]octane-6-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0544] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((2s,4s)-2-(4-(4-((2,6-dioxopiperidin-3-y l)amino)-2,6-difluorophenyl)-3,3-difluoropiperi din-1 -yl)spiro[3.4]octane-6-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0545] N-(4-((6-(l,1 -difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l -(8-(l -(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)-8-azaspiro[4.5]decan-2-yl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[10-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-10-oxo-decanoyl]pyrrolidin-3-yl]oxy-2-pyridyl] acetamide,

[0546] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[10-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-10-oxo-decanoyl]pyrrolidin-3-yl]oxy-2-pyridyl] acetamide,

[0547] 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,

[0548] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-6-oxo-hexanoyl]pyrrolidin-3-yl]oxy-2-pyridyl] acetamide,

[0549] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino] -2,6-difluoro-pheny l]piperazin- 1 -y 1] acetyl] py rrolidin-3-yl] oxy-2-py ridyl] acetamide,

[0550] 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 clohexyl] -2-pyri dyl] acetamide,

[0551] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[10-[4-[4-[(2,6-dioxo-3-piperidyl)amino] phenyl]-! -piperidyl]- 10-oxo-decanoyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide, N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,3-difluoro-l-piperidyl]methyl]cyclohexanecarbonyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide,

[0552] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[7-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-l-piperidyl]-7-oxo-heptanoyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide, N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[8-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-8-azaspiro[4.5]decane-3-carbonyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide,

[0553] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[8-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-8-azaspiro[4.5]decane-3-carbonyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide,

[0554] N-[5-[l-[[3-[3-(2,6-dioxo-3-piperidyl)-5-fluoro-l-methyl-indazol-6-yl]-3-azaspiro[5.5]undecan-9-yl]methyl]pyrrolidin-3-yl]oxy-4-[[6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-2-py ridyl] amino] -2-pyri dyl] acetamide,N-[5-[1-[[3-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-3-azaspiro[5.5]undecan-9-yl]methyl]pyrrolidin-3-yl]oxy-4-[[6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0555] N-[5-[l-[l-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-4-piperidyl]pyrrolidin-3-yl]oxy-4-[[6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0556] {N}-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[(3~{R})-l-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]cyclohexanecarbonyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide,

[0557] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]ethyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide,

[0558] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[l-[[3-[4-[(2,6-dioxo-3-piperidyl)amino]-2.6-difluoro-phenyl]-3-azaspiro[5.5]undecan-9-yl]methyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide,

[0559] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[3-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undecane-9-carbonyl]pyrrolidin-3-yl]oxy-2-pyridy 1] acetamide,

[0560] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[3-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3-azaspiro[5.5]undecan-9-yl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide, N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(7-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidine-4-carbonyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-2-yl)pyridin-2-yl)acetamide,

[0561] 6-acetamido-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-N-(6-(4-(l-(2,6-dioxopiperi din-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-6-oxohexyl)ni cotinamide,

[0562] 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)cyclohex-l-en-l-yl)pyridin-2-yl)acetamide,

[0563] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(8-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-8-azaspiro[4.5]decane-2-carbonyl)pyrrolidin-3-yl)oxy)pyri din-2-yl)acetamide,

[0564] N-(4-((6-(l,1 -difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l -(1 -(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperidine-4-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide, N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperidin-4-yl)methyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((l-(3-(2,6-dioxopiperidin-3-yl)- 1-methyl-lH-indazol-6-yl)piperidin-4-yl)methyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide, N-(4-((6-( 1, 1 -difluoroethy l)-4-methylpy ridin-2-yl)amino)-5-(((3 S)- 1 -(( 1 s,4R)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0565] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,3r)-3-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclobutane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0566] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(3-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-3-azaspiro[5.5]undecane-9-carbonyl)pyrrolidin-3-yl)oxy)pyridin- 2-yl)acetamide,

[0567] N-(4-((6-( 1, 1 -difluoroethyl)-4-methylpyridin-2-yl)arnino)-5-(((3R)- 1 -((lr,4R)-4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0568] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(((3S)-l-((lr,4S)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0569] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(((3R)-l-((ls,4S)-4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0570] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)benzoyl)pyrrolidin-3-yl)oxy)pyri din-2-yl)acetamide,

[0571] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(4-(4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyri din-2 -yl)acetamide.

[0572] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((ls,4s)-4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0573] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide, and

[0574] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(2-(l-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)-2-azaspiro[3.4]octan-6-yl)pyrrolidin-3-yl)oxy)pyri din-2 -yl)acetamide.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 of

[0575] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(3-(2,6-di oxopiperi din-3 -yl)- 1 -methyl-lH-indazol-7-yl)piperazin- 1 -yl)methyl)cyclohexane-l -carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0576] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((ls,4s)-4-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperi din-1 -yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0577] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,

[0578] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((ls,4s)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide, and

[0579] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((6R)-2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)spiro[3.4]octane-6-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide.

[0580] Aspect 25 is a process for the preparation of a compound according to any one of aspects 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 (I’)

[0581]

[0582] O

[0583]

[0584] wherein X is H or Ci-3alkyl and Y is H or halogen.

[0585] Aspect 26 is a compound of formula I according to aspects 1-24, or a pharmaceutically acceptable salt thereof, when manufactured according to a process of aspect 25.

[0586] Aspect 27 is a pharmaceutical composition comprising a compound in accordance with any one of aspects 1-26 and a pharmaceutically acceptable excipient.

[0587] Aspect 28 is a compound or pharmaceutically acceptable salt according to any one of aspects 1-26 for use as therapeutically active substance.

[0588] Aspect 29 is the use of a compound according to any one of aspects 1-26 as therapeutically active substance for the therapeutic and / or prophylactic treatment of autoimmune disorders like type I diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinflammatoiy 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-Goutières 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.

[0589] Aspect 30 is the use of a compound according to any one of aspects 1-26 as therapeutically active substance for the therapeutic and / or prophylactic treatment of inflammatory bowel disease.

[0590] Aspect 31 is a compound of formula I according to aspects 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 erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinfl ammatoty 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 (SAV1), 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-Goutières 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.

[0591] Aspect 32 is a compound of formula I according to aspects 1-26 for the use as therapeutically active substance for the therapeutic and / or prophylactic treatment of inflammatory bowel disease.

[0592] Aspect 33 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 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-Goutières 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 and wherein the method comprises administering a therapeutically effective amount of a compound according to any one of aspects 1-26 or a pharmaceutically acceptable salt thereof, to the subject.

[0593] Aspect 34 is a method of preventing or treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is inflammatory bowel disease and wherein the method comprises administering a therapeutically effective amount of a compound according to any one of aspects 1-26 or a pharmaceutically acceptable salt thereof, to the subject.

[0594] 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.

[0595] 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 known 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.

[0596] 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.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.

[0597] Example 1: Synthesis of Targeting Ligands

[0598] Synthesis of 2-chloro-6-(l,l-difluoroethyl)-4-methylpyridine

[0599]

[0600] Step-1:

[0601] To a solution of 6-chloro-4-methyl-2-pyridinecarboxylic acid (1, 10.0 g, 58.28 mmol) in DCM (100 mL) was added EDCI (11.17 g. 58.28 mmol), DMAP (0.71 g, 5.83 mmol), triethylamine (16.25 mL, 116.56 mmol) and N, O-dimethylhydroxylamine hydrochloride (2, 6.03 g, 61.77 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h, then the mixture was concentrated in vacuo to afford the crude material, which was purified by normal phase flash column chromatography (Stationary Phase: Silica gel; Eluent: Gradient from 50% to 100% EtOAc in Petroleum Ether) to afford 6-chloro-A^-methoxy-N,4-dimethylpicolinamide (3, 11.7 g, 54.51 mmol, 93.52% yield) as a white solid. LC-MS (ES+): m / z 214.9 [M + H]+.

[0602] Step-2:

[0603] To a solution of 6-chloro-A-methoxy-N.4-dimethylpicol inamide (3, 11.7 g, 54.51 mmol) in THF (100 mL) was slowly added methylmagnesium bromide (72.68 mL, 218.03 mmol) at -60 °C under a N2 atmosphere, and the resulting reaction mixture was allowed to warm to 0 °C and stirred for 3 h under N2. The reaction mixture was quenched by the addition of saturated aqueous NH4CI solution (150 mL) at 0 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na₂SO₄, filtered, and the filtrate concentrated in vacuo to afford the crude material, which was purified by normal phase flash column chromatography (Stationary Phase: Silica gel; Eluent: Gradient from 0% to 75% EtOAcin Petroleum Ether) to afford l-(6-chloro-4-methylpyridin-2-yl)ethan-l-one (4, 8.4 g, 49.53 mmol, 90.86% yield) as a colorless liquid. LC-MS (ES+): m / z 170.1 [M + H]+.

[0604] Step-3:

[0605] To a solution of l-(6-chloro-4-methylpyridin-2-yl)ethan-l-one (4, 8.0 g, 47.17 mmol) in DCE (100 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (34.78 mL, 188.67 mmol) at 0 °C. The resulting reaction mixture was stirred at 75°C for 4 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO₃ solution (150 mL) at 0 °C under a N2 atmosphere. The mixture was extracted with DCM (100 mL x 3) and the combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate concentrated in vacuo to afford the crude material, which was purified by normal phase flash column chromatography (Stationary Phase: Silica Gel; Eluent: Gradient from 0% to 5% EtOAc in Petroleum Ether) to afford 2-chloro-6-(l,l-difluoroethyl)-4-methylpyridine (5, 6.2 g, 32.36 mmol, 68.6% yield) as yellow' liquid. 'H NMR (400 MHz, CHLOROFORM-d) 8 7.39 (s, 1H), 7.22 (s, 1H), 2.41 (s, 3H), 1.99 (t, J= 18.8 Hz, 3H) ppm.

[0606] Synthesis of A-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(pyrrolidin-3-yloxy)pyridin-2-yl)acetamide (A-l)

[0607] DPPA, Et3N NaH, DMF, t-BuOH, 90 °C, 16h 25 °C, 16h Step-2 Step-1

[0608] HCI, 1,4-dioxane Pd2(dba)3, Xantphos 25 °C, 2h Cs2CO3, 1,4-Dioxane Step-4

[0609] 100 °C, 16h

[0610]

[0611] Step-3

[0612] Pd2(dba)3, Xantphos Cs2CO3, 1,4-Dioxane 120 °C, 16h Step-5

[0613]

[0614] Step-1:To a solution of benzy l 3-hydroxypyrrolidine-l-carboxylate (2, 8.95 g. 40.45 mmol) in DMF (100 mL) was added NaH (3.24 g, 80.91 mmol) at 0 °C and the resulting reaction mixture was stirred at 0 °C under a N2 atmosphere for 1.5 h. Then 2-bromo-5 -fluoroisonicotinic acid (1, 8.9 g, 40.45 mmol) was added and the resulting reaction mixture was allowed to warm to 25 °C and stirred for 14.5 h. The reaction mixture was quenched by the addition of saturated aqueous NH4CI solution (30 mL) under a N2 atmosphere and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo to afford the crude material, which was purified by reversed phase combi-flash (Column: Phenomenex Synergi C18 (150 mm x 25 mm x 10 pm); Eluent: mobile phase A: water (0.1%FA). Mobile phase B: ACN; Gradient from 75%-85% mobile phase B over 20 min) to afford 5-((l-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)-2-bromoisonicotinic acid (3, 13.5 g, 32.05 mmol, 79.22% yield) as a white solid. LC-MS (ES+): m / z 422.9 [M + H]+.

[0615] Step-2:

[0616] To a solution of 5-((l-((benzyloxy)carbonyl)pyrrolidin-3-yl)oxy)-2-bromoisonicotinic acid (3, 5.0 g, 11.87 mmol) and TEA (1.82 mL, 13.06 mmol) in f-BuOH (50 mL) at 5-10°C was added DPPA (3593.12 mg, 13.06 mmol). The resulting reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was concentrated in vacuo to afford the crude material, which was purified by normal phase flash column chromatography (Column: Silica Gel; Eluent: Gradient from 50% to 100% EtOAc in Petroleum Ether) to afford benzyl 3-((6-bromo-4-((tert-butoxycarbonyl)amino)pyridin-3-yl)oxy)pyrrolidine-l-carboxylate (4, 4.7 g, 9.55 mmol, 80.42% yield) as a white solid. 'H NMR (400 MHz, DMSO-cL) 5 8.14 - 7.99 (m, 2H), 7.42 - 7.28 (m, 5H), 5.16 - 5.03 (m, 3H), 3.67 - 3.64 (m 2H). 3.55 - 3.49 (m, 2H). 2.21 - 2.08 (m, 2H). 1.48 (s, 9H) ppm.

[0617] Step-3:

[0618] To a solution of benzyl 3-((6-bromo-4-((tert-butoxycarbonyl)amino)pyridin-3-yl)oxy)pyrrolidine-l-carboxylate (4, 4.1 g, 8.33 mmol) and acetamide (1.48 g, 24.98 mmol) in 1.4-di oxane (50 mL) was added Xantphos (0.96 g. 1.67 mmol). Cs₂CO₃ (5.43 g. 16.65 mmol) and Pd₂(dba)₃ (0.76 g, 0.83 mmol). The resulting reaction was stirred at 100 °C for 16 h under a N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the crude material, which was purified by normal phase flash column chromatography (Stationary Phase: Silica gel; Eluent: Gradient from 50% to 100% EtOAc in Petroleum Ether) to afford benzyl 3-((6-acetamido-4-((tert-butoxycarbonyl)amino)pyridin-3-yl)oxy)pyrrolidine-l-carboxylate (5, 3.85 g, 8.19 mmol) as ayellow solid. LC-MS (ES+): m / z 471.2 [M + H]+.

[0619] Step-4:A solution of benzyl 3-((6-acetamido-4-((tert-butoxycarbonyl)amino)pyridin-3-yl)oxy)pyrrolidine-l -carboxylate (5, 4.6 g. 9.78 mmol) in HCl / l,4-di oxane (50.0 mL, 100.0 mmol) was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to afford benzyl 3-((6-acetamido-4-aminopyridin-3-yl)oxy)pyrrolidine-1-carboxylate (6, 3.9 g, 9.59 mmol, 98.05% yield) as a yellow solid, which was used without further purification. LC-MS (ES+): m / z 371.2 [M + H]+.

[0620] Step-5:

[0621] To a solution of benzyl 3-((6-acetamido-4-aminopyridin-3-yl)oxy)pyrrolidine-l-carboxylate (6, 3.9 g, 9.59 mmol) in 1,4-Dioxane (50 mL) was added 2-chloro-6-(l,l-difluoroethyl)-4-methylpyridine (7, 2.02 g, 10.54 mmol), Xantphos (1.11 g, 1.92 mmol), Cs₂CO₃ (6.25 g. 19.17 mmol) and Pd₂(dba)₃ (0.88 g, 0.96 mmol) under a N2 atmosphere. The resulting reaction mixture was stirred at 120 °C for 16 h under N2. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford the crude material, which was purified by normal phase flash column chromatography (Stationary' Phase: Silica gel; Eluent: Gradient from 50% to 100% EtOAc in Petroleum ether) to afford benzyl 3-((6-acetamido-4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)pyridin-3-yl)oxy)pyrrolidine-l-carboxylate (8, 3.8 g, 7.23 mmol, 75.43% yield) as a yellow solid. LC-MS (ES+): m / z 526.2 [M + H]+.

[0622] Step-6:

[0623] To a solution of benzyl 3-((6-acetamido-4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)pyridin-3-yl)oxy)pyrrolidine-l-carboxylate (8, 2.0 g, 3.81 mmol) in methanol (50 mL) was added Pd(OH)2 (534.4 mg, 0.38 mmol) under a N2 atmosphere. The resulting reaction mixture was purged and degassed with H2 3 times. Then the reaction mixture was stirred at 25 °C for 3 h under a H2 atmosphere (15 psi, generated from a balloon containing H2). The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford the crude material. A solution of petroleum ether and EtOAc (6 / 1, 20 mL) was added, and the resulting mixture was stirred at 25 °C for 0.5 h. The resulting solid was filtered, collected, and dried in vacuo to afford 7V-(4-((6-(l, 1 -difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(pyrrolidin-3-yloxy)pyridin-2-yl)acetamide (A-l, 1.32 g, 3.37 mmol, 82.33% yield) as an off-white solid. LC-MS (ES+): m / z 392.1 [M + H]+. 'H NMR (400 MHz. CD3OD) 5 9.07 (s. 1H), 7.81 (s. 1H), 7.07 (s, 1H), 7.03 (s, 1H), 5.07 (t,.7 = 4.8 Hz, 1H), 3.27 (d, J= 12.4 Hz, 1H), 3.16 (td, J= 12, 10.8 Hz, 1H), 3.04 (dd, J= 4.4, 12.4 Hz, 1H), 2.97 - 2.90 (m, 1H), 2.38 (s, 3H), 2.23 - 2.15 (m, 4H), 2.11 - 2.02 (m, 4H) ppm.

[0624] Example 2: Synthesis of CRBN Binders and Intermediates

[0625] 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (B-l)

[0626]

[0627] 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 WO20232836104.

[0628] 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (B-2)

[0629] O

[0630] o

[0631]

[0632] 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 WO20230191665.

[0633] Synthesis of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole

[0634]

[0635] Step-3

[0636] Step-1:

[0637] To a 500 mL multi-neck round-bottom flask containing a well-stirred solution of 7-bromo-l / / -indazole (1, 10 g, 50.75 mmol) in DMF (110 mL) was added potassium phosphate tribasic (16.16g, 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 was formed. The precipitate was filtered and dried under reduced pressure to afford 7-bromo-3-iodo-l / 7-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]+.

[0638] Step-2:

[0639] To a 250 mL single-neck round-bottom flask containing a well-stirred solution of7-bromo-3-iodo- 1 / / -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:

[0640] To a 500 mL single-neck round-bottom flask containing a well-stirred solution of7-bromo-3-iodo-l-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)C12'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]+.

[0641] Synthesis of 3-(l-methyl-7-piperazin-l-yl-indazol-3-yl)piperidine-2, 6-dione (B-3)

[0642]

[0643] Step-1:

[0644] 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 piperazine- 1 -carboxylate (2, 320.10 mg. 1.72 mmol) in 1.4-dioxane (10 mL) was added Cs₂CO₃ (1.68 g, 5.16 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes before Pd-PEPPSl-IHept-Cl (116.78 mg, 171.87 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: 25 to 30% Ethyl acetate in Petroleum ether) to afford tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl]piperazine-l-carboxylate (3, 600 mg, 968.86 pmol, 56% yield) as a yellow viscous oil. LC-MS (ES+): m / z 606.3 [M + H]+.

[0645] Step-2:

[0646] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl]piperazine-l -carboxylate (3, 600 mg, 968.76 pmol) in 1,4-dioxane (10 mL) was added palladium hydroxide on carbon (600 mg, 4.27 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 to afford ferf-butyl 4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperazine-l-carboxylate (4, 400 mg, 816.85 pmol, 84% yield) as an off-white solid. LC-MS (ES+): m / z 428.1 [M + H]+.

[0647] Step-3:

[0648] To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperazine-l -carboxylate (4, 200 mg, 408.43(imol) in DCM (5 mL) was added TF A (1.23 mmol, 93.77 pL) 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 product was triturated with MTBE (5 mL) to afford 3-(l-methyl-7-piperazin-l-yl-indazol-3-yl)piperidine-2, 6-dione trifluoroacetate (B-3, 180 mg, 379.04 pmol, 92% yield) as a pale-pink solid. LC-MS (ES+): m / z 328.2 [M + H]+.

[0649] 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione (B-4)

[0650] H

[0651]

[0652] Compound 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione was prepared using the method described on page 265 of WO20182370266.

[0653] 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (B-5)

[0654]

[0655] O

[0656] Compound 3-((3,5-difluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was prepared using the method described on page 167-168 of WO20220320267.

[0657] Synthesis of 2,6-dibenzyloxy- / V-(4-bromo-3,5-difluoro-phenyl)pyridin-3-amine and afford 2,6-dibenzyloxy- -[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] pyridin-3-amine

[0658] OBn

[0659]

[0660] Step-1:

[0661] 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-di oxane (80 mL) was added sodium tert-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 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 (60-120 mesh silica gel, 340 g snap cartridge; flow rate = 60 mL / min, a gradient of 0-20% ethyl acetate in petroleum ether) to afford 2,6-dibenzyloxy-jV-(4-bromo-3,5-difluoro-phenyl)pyridin-3-amine (3, 7 g, 13.14 mmol, 83.83% yield) as a gummy yellow oil. LC-MS (ES+): m / z 497.1 [M + H]+.

[0662] Step-2:

[0663] To a 40 mL screw-cap vial containing a well-stirred solution of 2,6-dibenzyloxy-jV-(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)Ch DCM (328.41 mg, 402.15 pmol) and the reaction mixture was stirred at 90 °C for 12 h. After completion of the reaction as indicated by LCMS, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with 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, filtered, and the filtrate concentrated in vacuo to afford 2,6-dibenzyloxy-jV-[3,5-difluoro-4-(4,4,5,5-tetramethyl-l,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]+Synthesis of 3-((4-(3,3-difluoropiperidin-4-yl)-3,5-difluorophenyl)amino)piperidine-2,6-dione (B-6)

[0664]

[0665] Step-1:

[0666] To a 250 mL multi-neck round-bottom flask containing a well-stirred solution of tert-butyl 3,3-difluoro-4-oxo-piperidine- 1 -carboxylate (1, 5 g, 21.26 mmol) in dichloromethane (50 mL) was added triethylamine (63.77 mmol, 8.89 mL) and trifluoromethanesulphonic anhydride (25.51 mmol, 4.19 mL) at -75 °C. The resulting reaction mixture was warmed to room temperature and stirred for 16 h. After completion of the reaction as indicated by the 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) and brine (300 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford the crude compound, which was purified by normal phase 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): 56.32 (s, 1H), 4.26 (s, 2H). 3.99 (t, J=8, 2H), 1.51 (s, 9H) ppm.

[0667] Step-2:

[0668] To a 40 mL vial containing a well-stirred solution of tert-butyl 3,3-difluoro-4-(tnfluoromethylsulfonyloxy)-2,6-dihydropyri dine- 1 -carboxylate (2, 2.5 g, 5.45 mmol) and 2,6-dibenzyloxy-N-[3,5-difluoro-4-(4,4,5,5-tetramethyl-l,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, 10.89 mmol) at room temperature. The reaction mixture was degassed by bubbling nitrogen gasthrough the reaction mixture for 2 min. Then, XPhos-Pd-G3 (460.92 mg, 544.53 pmol) was added, and the reaction mixture was heated to 80 °C and stirred for 4 h. After completion of the reaction as indicated by the UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate concentrated under reduced pressure to afford the crude compound, which was purified by normal phase flash column chromatography (Stationary' Phase: 230-400 mesh silica gel; Eluent: Gradient from 15 to 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-1-carboxylate (4, 820 mg, 1.15 mmol, 21% yield) as a pale yellow solid. LC-MS (ES+): m / z 636.2 [M + H]+.

[0669] Step-3:

[0670] 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 hydrogen atmosphere (bladder pressure) at room temperature for 16 h. After completion of the reaction as indicated 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- 1-carboxylate (5, 300 mg, 605.57 pmoL 52% yield) as a paleyellow solid.

[0671] LC-MS (ES’): mz 458.1 [M - H]’.

[0672] Step 4:

[0673] 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 trifluoro acetic acid (6.06 mmol, 463.40 pL) at 0 °C. The resulting 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 to afford the crude residue, which was triturated with MTBE (7 mL) and dried to afford 3-[4-(3,3-difluoro-4-piperidyl)-3,5-difluoro-anilino]piperidine-2, 6-dione trifluoroacetate (B-6, 250 mg, 516.49 pmol. 85% yield) as a pale-yellow solid. LC-MS (ES+): m / z 360.1 [M + H]+.

[0674] Synthesis of 3-[3,5-difluoro-4-(4-oxo-l-piperidyl)anilino]piperidine-2, 6-dione (B-7)Cs₂CO₃

[0675] DMF

[0676] Step-1

[0677]

[0678] 10% Pd / C, H2

[0679] 1,4-dioxane

[0680] Step-2

[0681]

[0682] NaHCO3, DMF

[0683]

[0684] Step-3

[0685] aqueous HCI acetone Step-4

[0686]

[0687] Step-1:

[0688] To a 40 mL vial containing a well-stirred solution of 1.4-dioxa-8-azaspiro[4.5]decane (1, 2 g, 13.97 mmol, 1.79 mL) and l,2,3-trifluoro-5-nitro-benzene (2, 2.47 g, 13.97 mmol) in DMF (5 mL) was added Cesium carbonate (13.65 g, 41.90 mmol) at room temperature and the reaction mixture was stirred at 90 °C for 2 h. Upon completion of the reaction, 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 (50 g column; 230-400 mesh silica gel) using a gradient of 10-30% ethyl acetate in pet ether to afford 8-(2,6-difluoro-4-nitro-phenyl)-l,4-dioxa-8-azaspiro[4.5]decane (3, 3.9 g, 12.73 mmol, 91.13% yield) as a yellow solid. LC-MS (ES+): m / z 301.0 [M + H]+.

[0689] Step-2:

[0690] To a 100 mL single-neck round-bottom flask containing a well stirred solution of 8-(2,6-difluoro-4-nitro-phenyl)-l,4-dioxa-8-azaspiro[4.5]decane (3, 3.9 g, 12.73 mmol) in 1,4-dioxane (5 mL) was added 10% Palladium on carbon, wet (3.5 g, 32.89 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature under hydrogen atmosphere for 16 h. Upon completion of the reaction, 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 (50 g column; 230-400 mesh silica gel) using a gradient of 20-30% ethyl acetate in pet ether to afford 4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3,5-difluoro-aniline (4, 2.8 g, 10.26 mmol, 80.57% yield) as a brown solid. LC-MS (ES+): m / z 271.0 [M + H]+. Step-3:To a 40 mL screw cap vial containing a well-stirred solution of 4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3,5-difluoro-aniline (4, 2.8 g, 10.26 mmol) and 3-bromopiperidine-2,6-dione (5, 5.91 g, 30.77 mmol) in DMF (4 mL) was added sodium bicarbonate (2.58 g, 30.77 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 16 h and concentrated in vacuo. The crude material was purified by reverse-phase column chromatography [Column: RediSep® C18, Mobile phase A: 10 mM HCOOH in water and Mobile phase B: MeCN] to afford 3-[4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3, 5-difluoro-anilino]piperidine- 2,6-dione (6, 2.2 g, 5.36 mmol, 52.31% yield) as an off-white solid. LC-MS (ES+): m / z 382.3 [M + H]+.

[0691] Step-4:

[0692] To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-[4-(1.4-dioxa-8-azaspiro[4.5]decan-8-yl)-3,5-difluoro-anilino]piperidine-2, 6-dione (6, 500 mg, 1.22 mmol) in anhydrous acetone (10 mL) was added hydrochloric acid, 36% w / w aq. soln. (12.5 M, 18.60 mL) at room temperature. The resulting reaction mixture was stirred at 80 °C for 16 h. Upon completion of the reaction, the reaction mixture was basified with 10% sodium bicarbonate solution, diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 3-[3,5-difluoro-4-(4-oxo-1-piperidyl)anilino]piperidine-2,6-dione (B-7, 220 mg, 417.41 pmol, 34.23% yield). LCMS (ES+): m / z 338.2 [M + H]+.

[0693] 2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)acetic acid (C-l)

[0694]

[0695] Compound 2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)acetic acid was prepared following the procedure on page 224-228 of WO20230597928.

[0696] Synthesis of 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl] acetic acid (C-2)4 M HCI in 1,4-dioxane DCM

[0697] Step-2

[0698]

[0699] Step-1:

[0700] To a 500 mL two-neck round-bottom flask containing a well-stirred solution of 3 -[3 -methyl -2-oxo-4-(4-piperidyl)benzimidazol-l-yl]piperidine-2, 6-dione hydrochloride (B-2, 10 g, 26.40 mmol) in DMSO (76.92 mL) was added DIPEA (10.23 g, 79.19 mmol, 13.79 mL) followed by tert-butyl 2-bromoacetate (2, 5.66 g, 29.04 mmol, 4.26 mL) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at 25 °C for 6 h, and the progress of the reaction was monitored by TLC and UPLC-MS. The reaction mixture was then quenched with ice water (400 mL). The precipitate was filtered and dried under reduced pressure to afford tertbutyl 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]acetate (3, 10.2 g, 22.24 mmol, 84.27% yield) as an off-white solid, which was used without further purification. UPLC-MS (ES+): m / z 457.2 [M + H]+.

[0701] Step-2:

[0702] To a 1000 mL single-neck round-bottom flask containing a well-stirred solution of terf-butyl 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]acetate (3, 20 g, 43.81 mmol) in anhydrous DCM (200.00 mL) was added 4 M HCI in 1,4-dioxane (109.52 mL) at 0 °C and the resulting suspension was stirred at 25 °C for 16 h. Upon completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the obtained solid was triturated with MTBE (20 mL) and dried under reduced pressure to afford 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl] acetic acid hydrochloride (C-2, 18.22 g, 41.65 mmol, 95.06% yield) as an off-white solid, which was used without further purification. 'H-NMR (400 MHz. DMSO- e): 6 11.10 (s, 1H), 7.12-6.94 (m, 3H), 5.40 (dd, J= 5.60, 12.60 Hz, 1H), 4.15 (s, 2H), 3.66-3.52 (m, 6H), 3.29-3.18 (m, 2H), 2.88 (t, J= 5.60 Hz, 1H), 2.76-2.62 (m, 2H), 2.22-1.93 (m, 5H) ppm.The following intermediate was prepared using the method above, with the corresponding CRBN binder in Step-1.

[0703] CRBN binder in Step-1 Intermediate MS

[0704] H H LC-MS (ES+): m^z f T TJ 402.3 [M + H]+.

[0705] X X L l

[0706] CE 'N' X)

[0707] HL / NHHOH

[0708] B-4 C-3

[0709]

[0710] Table 1: Preparation of C-3

[0711] Synthesis of 6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]- 6-oxo-hexanoic acid (C-4)

[0712] H

[0713]

[0714] Step-1:

[0715] To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 3-[3-methyl-2- oxo-5-(4-piperidyl)benzimidazol-l-yl]piperidine-2, 6-dione hydrochloride (B-l, 10 g, 26.33 mmol) in DMF (100 mL) were added DIPEA (17.02 g, 131.66 mmol, 22.93 mL), EDC hydrochloride (6.31 g, 32.92 mmol), hydroxybenzotriazole (6.05 g, 39.50 mmol), and 6-tert- butoxy-6-oxo-hexanoic acid (2, 5.86 g, 28.97 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 16 h. After completion of the reaction.the reaction mixture was quenched with ice water (200 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with cold brine (2 x 200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 0-20% methanol in dichloromethane) to afford tert-butyl 6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l -piperidyl] -6-oxo-hexanoate (3, 11 g, 20.74 mmol. 78.77% yield) as a brown solid. LCMS (ESI): m / z 527.2 [M + H]+

[0716] Step-2:

[0717] To a 50 mL round-bottom flask containing a well-stirred solution of tert-butyl 6-[4-[ 1 -(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-6-oxo-hexanoate (3, 0.5 g, 942.80 pmol) in anhydrous DCM (5 mL) was added 4.0 M HCl in 1,4-dioxane (4 M, 2.36 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 h. Upon completion of the reaction, excess solvents were removed under reduced pressure to afford 6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-6-oxo-hexanoic acid (C-4, 0.4 g, 821.05 pmol, 87.09% yield) as a light-pink solid. LCMS (ES+): m / z 471.2 [M + H]+

[0718] Synthesis of 4-[[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazoI-7-yl]piperazin-l-yl] methyl] cyclohexanecarboxylic acid (C-5)

[0719]

[0720] Step-1:

[0721] To a 20 mL screw-cap vial containing a well-stirred solution of 3-(l-methyl-7-piperazin-l-yl-indazol-3-yl)piperidine-2, 6-dione trifluoroacetate (B-3, 180 mg, 379.04 pmol) and methyl 4-formylcyclohexanecarboxylate (2, 96.77 mg, 568.56 pmol) in DMSO (2 mL) were added sodium acetate (155.47 mg, 1.90 mmol) and acetic acid (227.62 mg, 3.79 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h before MP-cyanoborohydride (350 mg, 700 pmol) was added and continued stirring at 70 °C for 2 h. After completion of thereaction as indicated by UPLC-MS, the reaction mixture was fdtered through a cotton funnel and the filtrate was concentrated under reduced pressure. The crude compound was purified by reverse-phase column chromatography [Column: RediSep R / GoldK C18-120 g; Mobile phase A: 10 mM Ammonium bicarbonate in water and Mobile phase B: Acetonitrile] to afford methyl 4- [[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperazin-l- yl]methyl]cyclohexanecarboxylate (3, 140 mg, 228.50 pmol, 60% yield) as an off-white solid. LC-MS (ES+): m / z 482.1 [M + H]+.

[0722] Step-2:

[0723] To a 20 mL screw-cap vial containing a well-stirred solution of methyl 4-[[4-[3-(2,6-dioxo-3- piperidyl)-l -methyl-indazol-7-yl]piperazin-l -yl]methyl]cyclohexanecarboxylate (3, 100 mg, 163.21 pmol) in THF (5 mL) was added 1.5 M HC1 in water (0.3 mL, 0.45 mmol) at room temperature. The resulting reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the residue was triturated with MTBE to afford 4-[[4-[3-(2,6-dioxo-3-piperidyl)-l- methyl-indazol-7-yl]piperazin-l-yl]methyl]cyclohexanecarboxylic acid (C-5, 100 mg. 117.42 pmol, 71% yield) as an off-white solid. LC-MS (ES+): m / z 468.2 [M + H]+.

[0724] The following intermediate was prepared using the method described above, with the corresponding CRBN binder as reactant in Step-1.

[0725] CRNB binder in Intermediate MS

[0726] Step-1

[0727] LC-MS fY° rXC i 'X"Fi H (ES+): m / z 500.2 [M + o s XI H Xj H]+.

[0728] X I FX'' T" T

[0729] 1 F C-6

[0730] H

[0731] B-6

[0732]

[0733] Table 2: Preparation of C-6

[0734] Synthesis of (lr,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin- l-yl)inethyl)cyclohexane-l-carboxylic acid (C-7) and (l,4v)-4-((4-(4-((2,6-dioxopiperidin-3- yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carboxylic acid (C-8)NaOAc, CH3COOH MP-CNBH3, DMSO Step-1

[0735]

[0736] C-8

[0737] Step-1:

[0738] To a 20 mL glass-vial containing a well-stirred solution of 3-(3,5-difluoro-4-piperazin-l-yl-anilino)piperidine-2, 6-dione (B-5, 300 mg, 925 pmol) and methyl 4-formylcyclohexanecarboxylate (2, 157.44 mg, 925 pmol) in DMSO (5 mL) were added acetic acid (55.55 mg, 925 pmol) and sodium acetate (379.40 mg, 4.62 mmol) at room temperature and stirred for 1 h. Then MP-CNBH3 (600 mg, 1.2 mol) was added and stirring was continued at 70 °C for 2 h. After completion of the reaction as indicated by the UPLC-MS, the reaction mixture was passed through a cotton contained funnel and the filtrate was concentrated under reduced pressure. The crude residue was purified by reverse-phase column chromatography [Column: RediSep R Gold® C18-100 g; Mobile phase A: 0.1% Ammonium bicarbonate in water; Mobile Phase B: Acetonitrile] to afford methyl 4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]cyclohexanecarboxylate (3. 200 mg, 296.53 pniol. 32% yield) as a pale yellow solid. LC-MS (ES+): m / z 479.3 [M + H]+.

[0739] Step-2:

[0740] To an 8 mL screw-cap vial containing a well-stirred solution of methyl 4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]cyclohexanecarboxylate (3, 200 mg, 417.95 pmol) in THF (2 mL) was added 1.5 N HCl in water (557.26 μL, 835.89 μmol) at room temperature. The resulting mixture was stirred at 70 °C for 5 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC [Column: RediSep R / Gold K C18-60 g; Mobile phase A: 0.1% Ammonium bicarbonate in water; Mobile Phase B: Acetonitrile].The early-eluting isomer (lr,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l -carboxylic acid (arbitrarily assigned as / ram-isomer) (C-7, 50 mg, 93.35 pmol, 22% yield) was obtained as a pale-yellow solid. LC-MS (ES+): m / z 465.1 [M + H]+

[0741] The late-eluting isomer (ls,4s)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carboxylic acid (arbitrarily assigned as cis-isomer) (C-8, 30 mg, 59.95 pmol. 14% yield) was obtained as a pale-yellow solid. LC-MS (ES+): m / z 465.1 [M + H]+.

[0742] Synthesis of 2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]acetic acid (C-9)

[0743]

[0744] Step-1:

[0745] To a 20 mb screw-capped vial containing well-stirred solution of 3-(3,5-difluoro-4-piperazin-l-yl-anilino)piperidine-2, 6-dione (B-5. 1.0 g, 3.08 mmol), tert-butyl 4-formylpiperidine-l-carboxylate (2, 657.59 mg, 3.08 mmol) in DMSO (20 mL) were added Sodium acetate, anhydrous (758.81 mg, 9.25 mmol, 496.60 pL) and Acetic acid (555.48 mg, 9.25 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 h. Then MP-CNBH3 (2.0 g, 4.00 mmol) was added and stirred at room temperature for 2 h. After complete consumption of the starting material as indicated by UPLC-MS, the reaction mixture was was filtered by and the filtrate was purified by reverse phase columnchromatography [Column: RediSep R Gold® C18-30g, Mobile phase A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile] to afford tert-butyl 4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carboxylate (3, 1.3 g, 2.36 mmol, 76.39% yield) as an off-white solid. LC-MS (ES+): m / z 522.3 [M + H]+

[0746] Step-2:

[0747] To a 50 mL round-bottom flask containing well stirred solution of tert-butyl 4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carboxylate (3, 650 mg, 1.25 mmol) in DCM (10 mL) was added TFA (710.46 mg, 6.23 mmol, 476.82 pL) at 0°C. The reaction mixture was stirred at 25°C for 2 h, then washed with hexane and MTBE, and the solid part was dried under reduced pressure to get 3-[3,5-difluoro-4-[4-(4-piperidylmethyl)piperazin-l-yl]anilino]piperidine-2, 6-dione trifluoroacetate (4, 550 mg, 662.77 pmol, 53.18% yield) as a pale green free solid. LC-MS (ES+): m / z 522.2 [M + H]+.

[0748] Step-3:

[0749] To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-[3,5-difluoro-4-[4-(4-piperidylmethyl)piperazin-l-yl]anilino]piperidine-2, 6-dione (4, 250 mg, 593.14 pmol) in DMF (3 mL) were added TEA (180.06 mg, 1.78 mmol, 248.02 pL) and tert-butyl 2-bromoacetate (115.70 mg, 593.14 pmol, 86.99 pL) at room temperature. The resulting reaction mixture was stirred at 70°C for 16 h. After completion of the reaction as indicated by the UPLC-MS, reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude compound was purified by reverse-phase column chromatography [Column: RediSep® C 18-120 g; Mobile phase A: 0.1 mM NH4HCO3 in water and Mobile phase B: MeCN] to afford tert-butyl 2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]acetate (5, 130 mg, 157.47 pmol, 26.55% yield) as an off-white solid. LC-MS (ES+): m / z 536.2 [M + H]+.

[0750] Step-4:

[0751] To a 25 mL round-bottom flask containing a well stirred solution of tert-butyl 2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]acetate (5, 50 mg. 93.35 pmol) in DCM (2 mL) was added TFA (31.93 mg, 280.05 pmol, 21.43 pL) at 0°C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was then washed with hexane and MTBE and the solid precipitate was dried under reduced pressure to afford 2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]acetic acid (C-9, 85 mg, 58.25 pmol, 62.40% yield). LC-MS (ES+): m / z 480.2 [M + H]+Example 3: Synthesis of Protein DegradersSynthesis of N- [4- [ [6-(l,l-difluoroethyl)-4-methyl-2-py ridyl] amino]-5- [ 1- [ 10- [4- [ l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-10-oxo-decanoyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide (Compound 1)

[0752]

[0753] Compound 1

[0754] To an 8 mL screw-capped reaction vial containing a well-stirred solution of 10-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-10-oxo-decanoic acid (C-3, 30 mg, 56.97 pmol) in N,N-dimethylformamide (1 mL), was added N,N-diisopropylethylamine (22.09 mg, 170.90 pmol, 29.77 pL) and HATU (32.49 mg, 85.45 pmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 5 mins. Then N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-pyrrolidin-3-yloxy-2-pyridyl]acetamide (A-1, 22.30 mg. 56.97 pmol) was added and continued stirring at room temperature for 0.5 h. The reaction was monitored by UPLC. After complete consumption of the starting materials, the reaction mixture was directly purified by reverse-phase column chromatography (Column: RediSep® Cl 8 column; Mobile phase A: 10 mM Ammonium bicarbonate in water and Mobile phase B: Acetonitrile) to afford N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[1-[10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-10-oxo-decanoyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide (Compound 1, 27 mg, 28.15 μmol, 49.42% yield) as an off-white solid. LC-MS (ES+): m / z 900.3 [M + H]+.1H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H), 10.12 (s, 1H), 9.09 (s, 1H), 8.33 (d, J= 5.6 Hz. 1H), 7.95 (d, J= 6.8 Hz. 1H), 7.18 - 6.88 (m, 5H). 5.34 (dd. J = 12.7. 5.3 Hz, 1H). 5.13 - 4.99 (m, 1H), 4.61 - 4.49 (m, 1H), 4.03 - 3.92 (m, 1H), 3.76 - 3.50 (m, 4H), 3.33 (s, 2H), 3.15 - 2.72 (m, 4H), 2.65 - 2.58 (m, 1H), 2.35 - 2.32 (m, 4H), 2.29 - 2.24 (m, 2H), 2.20 - 2.14 (m, 2H), 2.11 - 2.09 (m, 2H), 2.06 - 2.04(m, 3H), 2.02 - 1.95 (m, 1H), 1.84 - 1.75 (m, 2H), 1.66 - 1.56 (m, 1H), 1.53 - 1.44 (m, 4H), 1.31 - 1.20 (m. 8H), 1.01 - 0.91 (m, 5H).

[0755] The following compounds were prepared using the method described above, using the corresponding targeting ligand and CRBN binder intermediate.

[0756] Targeting CRBN Compound MS ligand binder

[0757] intermediate

[0758] A-l C-l 0

[0759] HN'A

[0760] ° V

[0761] ^~NH d \

[0762] " Q-NZO

[0763] Compound 2

[0764] A-[4-[[6-(l.l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5- [l-[2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-l-piperidyl]acetyl]pyrrolidin-3- yl] oxy-2-py ridyl] acetamide

[0765] LC-MS (ES+): m / z 774.3 [M + H]+.

[0766] 1H NMR (400 MHz, DMSO-d6) δ 11.08 (br s, 1H), 10.12

[0767] (s, 1H), 9.10 (brs, 1H), 8.39 - 8.30 (m, 1H), 7.97 (d, J =

[0768] 10.5 Hz, 1H), 7.18 - 6.80 (m, 5H), 5.40 - 5.27 (m, 1H),

[0769] 5.15 - 5.01 (m, 1H), 4.02 - 3.57 (m, 4H), 3.22 - 3.12 (m, 2H), 3.09 - 3.03 (m, 1H). 3.00 - 2.85 (m, 3H). 2.78 - 2.70

[0770] (m, 1H), 2.65 - 2.58 (m, 1H), 2.32 - 2.24 (m, 4H), 2.19 - 2.00 (m, 10H), 1.78 - 1.50 (m, 5H), 1.37 - 1.22 (m, 1H),

[0771] 0.94 (t, J = 7.3 Hz, 1H).

[0772] A-l C-4 O

[0773] ° \o==i\ —

[0774] / ^NvHd \

[0775] Y \ ip >=o O-NYO F,-AV

[0776] V- J o

[0777] Compound 3

[0778]

[0779] Targeting CRBN Compound MS ligand binder

[0780] intermediate

[0781] 7V-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5- [l-[6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5 -y 1] - 1 -piperidyl] -6-oxo- hexanoyl] pyrrolidin-3-yl] oxy -2 -pyridyl] acetamide

[0782] LC-MS (ES+): m / z 844.3 [M + H]+.

[0783] 1H NMR (400 MHz, DMSO-d6) δ 11.07 (bs, 1H), 10.12 (s, 1H), 9.09 (s, 1H), 8.34 (s, 1H), 7.95 (d, J = 13 Hz, 1H), 7.16 – 6.90 (m, 5H), 5.37 – 5.26 (m, 1H), 5.15 – 5.01 (m, 1H), 4.56 (br d, J = 13.9 Hz, 1H), 4.04 – 3.88 (m, 1H), 3.77 – 3.61 (m, 3H), 3.56 – 3.46 (m, 1H), 3.33 (s, 3H), 3.15 – 3.06 (m, 1H), 2.97 – 2.88 (m, 1H), 2.82 – 2.70 (m, 2H), 2.63 – 2.57 (m, 2H), 2.39 – 2.30 (m, 7H), 2.24 – 2.18 (m, 2H), 2.12 – 2.08 (m, 2H), 2.05 – 2.01 (m, 4H), 1.99 – 1.86 (m, 1H), 1.82 – 1.71 (m, 2H), 1.60 – 1.46 (m, 6H).

[0784] A-l C-2

[0785] x i r LNX

[0786] L-' / N A )JX / / °

[0787] H

[0788] Compound 4

[0789] 7V-[4-[[6-(l.l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5- [ 1 -[2-[4- [ 1 -(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]-l-piperidyl]acetyl]pyrrolidin-3- yl]oxy-2-pyridyl] acetamide

[0790] LC-MS (ES+): m / z 774.2 [M + H]+.

[0791] 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 10.12 (s, 1H), 9.11 (br d, J = 16.4 Hz, 1H), 8.40 – 8.26 (m, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 14.5 Hz, 1H), 7.03 (d, J = 7.1 Hz, 1H), 6.97 – 6.78 (m, 3H), 5.41 – 5.32 (m, 1H), 5.16 – 5.04 (m, 1H), 4.18 – 4.03 (m, 1H), 3.85 – 3.64 (m, 3H), 3.54 (s, 3H), 3.22 – 2.99 (m, 4H), 2.99 – 2.87 (m,

[0792]

[0793] Targeting CRBN Compound MS ligand binder

[0794] intermediate

[0795] 2H), 2.71 - 2.67 (m, 2H), 2.62 - 2.56 (m, 1H), 2.35 - 2.29 (m, 3H), 2.24 - 2.15 (m, 2H), 2.12 - 2.01 (m, 7H), 1.95 - 1.83 (m, 1H), 1.81 - 1.72 (m, 2H), 1.66 - 1.47 (m, 2H).

[0796] A-l C-9 F

[0797] F~Y^

[0798] rl

[0799] / \ —

[0800] N

[0801] / )=0 \-N

[0802] 0 Compound 5

[0803] jV-[4-[[6-(l.l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5- tl-t2-t4-Lt4-|4-t(2,6-dioxo-3-piperidyl)aminoJ-2,6- difluoro-phenyl]piperazin- 1 -y l]methy 1] - 1 - piperidyl]acetyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide

[0804] LCMS (ES+): m / z 853.3 [M + H]+.

[0805] JHNMR (400 MHz, DMSO-d6) 5 10.81 (s, 1H), 10.13 (d,.7 = 2.4 Hz, 1H), 9.11 (br d, J= 10.4 Hz, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 8.41 - 8.22 (m. 1H), 7.94 (d, J= 4.1 Hz, 1H), 7.15 (d,.7= 16.8 Hz, 1H), 7.06 (s, 1H), 6.32 (br d, J = 11.6 Hz, 2H), 6.25 (br d, J= 7.8 Hz, 1H), 5.18 - 5.03 (m, 1H), 4.37 - 4.27 (m, 1H), 4.18 - 4.09 (m, 1H), 3.83 - 3.49 (m. 4H), 3.17 - 3.01 (m, 2H), 2.98 - 2.79 (m, 6H), 2.62 - 2.57 (m, 1H). 2.42 - 2.34 (m. 4H), 2.20 - 1.95 (m.

[0806] 12H), 1.94 - 1.81 (m, 2H), 1.68 - 1.53 (m, 2H), 1.48 - 1.28 (m, 2H), 1.15 - 0.99 (m, 1H), 0.89 - 0.73 (m, 1H).

[0807]

[0808] Table 3: Preparation of Compound 2-5Synthesis of / V-(4-((6-(l,l-difliioioethyl)-4-methylpyridin-2-yl)amino)-5-((l-((l / ',4 / )-4-((4-(3- (2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 6)

[0809]

[0810] To an 8 mL screw-cap vial containing a well-stirred solution of A-[4-[[6-(l,l-difhroroethyl)-4-methyl-2-pyridyl]amino]-5-pyrrolidin-3-yloxy-2-pyridyl]acetamide (A-l, 45 mg, 114.97 pmol) and 4-[[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperazin-l-yl]methyl]cyclohexanecarboxylic acid (C-6, 97.91 mg, 114.97 pmol) in DMF (1 mL) were added HATU (65.57 mg, 172.45 pmol) and DIPEA (44.58 mg, 344.90 pmol, 60.08 pL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was purified by reverse-phasecolumn chromatography [Column: RediSep Rf Gold® C18-60 g; Mobile phase A: 10 mM Ammonium bicarbonate in water and Mobile phase B: Acetonitrile] to yield a mixture of isomers, which were further purified by preparative HPLC [Column: X-Select C18 (19 x 250) 5 micron; Mobile phase A: 0.1% Formic acid in water and Mobile phase B: Acetonitrile] to afford A-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(3-(2,6- dioxopiperidin-3-yl)-l-methyl-17 / -indazol-7-yl)piperazin-l-yl)methyl)cyclohexane-l- carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 6, early-eluting isomer arbitrarily assigned as trans, 20 mg, 23.64 pmol, 20% yield) and A-(4-((6-(l,l-difluoroethyl)-4- methylpyridin-2-yl)amino)-5-((l-((l.s',4v)-4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-17 / - indazol-7-yl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide formate (4, early-eluting isomer arbitrarily assigned as cis, 5 mg. 5.47 pmol, 4% yield) as a white solids.

[0811] Synthesis of / V-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lv,4')-4-((4-(4- ((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l- yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 7)

[0812]

[0813]

[0814] To an 8 mL pressure sustained vial containing a well-stirred suspension of 4-[[4-[4-[(2.6-dioxo- 3-piperidyl)amino]-2,6-difluoro-phenyl]-3,3-difluoro-l-piperidyl]methyl]cyclohexanecarboxylic acid (C-6, 60 mg, 96.23 pmol) and jV-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-pyrrolidin-3-yloxy-2-pyridyl]acetamide (A-l, 37.67 mg, 96.23 pmol) in DMF (3 mL) were added DIPEA (62.18 mg, 481.14 pmol. 83.80 pL) andHATU (54.88 mg, 144.34 pmol) at room temperature. The resulting mixture was stirred at room temperature for Ih. After completion of the reaction as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by reverse-phase Prep-HPLC [Column: X SELECT C18 (150 x 19) mm, 5 pm; Mobile phase A: 0.1% Ammonium bicarbonate in water and Mobile Phase B: Acetonitrile, Flow rate: 25 mL / min],

[0815] The early-eluting peak X-(4-((6-( 1, 1 -difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(( 1 -(( lr,4r)- 4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperi din-1-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (3, arbitrarily assigned as trans. 1.5 mg, 1.65 pmol. 1.71% yield) was obtained as an off-white solid. LCMS (ES+): m / z 873.2 [M + H]+.

[0816] The early-eluting peak N-(4-((6-(l, 1 -difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((ls,4s)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperi din-1-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 7, arbitrarily assigned as cis, 23 mg. 25.30 pmol, 26.29% yield) was obtained as an off-white solid.LCMS (ES+): m / z 873.2 [M + H]+. ‘HNMR (400 MHz, DMSO-d6 5 10.87 (s, 1H), 10.14 (s, 1H), 9.09 (d. J= 10.1 Hz, 1H), 8.38 - 8.34 (m, 1H), 7.99 - 7.94 (m, 1H), 7.17 - 7.10 (m, 1H), 7.06 (s, 1H), 6.50 (d, J = 7.5 Hz, 1H), 6.36 (d, J = 12.8 Hz, 2H), 5.13 - 5.03 (m, 1H), 4.45 - 4.31 (m, 1H), 3.85 - 3.60 (m, 3H), 3.57 - 3.49 (m, 1H), 3.27 - 3.16 (m, 1H), 3.13 - 3.06 (m, 1H), 2.97 -2.86 (m, 1H), 2.80 - 2.69 (m, 1H), 2.65 - 2.55 (m, 1H), 2.45 - 2.37 (m, 2H), 2.34 (s, 4H), 2.29 -2.17 (m, 4H). 2.16 - 2.08 (m, 4H). 2.06 - 2.01 (m, 4H), 1.95 - 1.87 (m, 1H), 1.80 - 1.63 (m. 4H), 1.58 - 1.39(m, 4H), 1.36 - 1.27 (m, 1H), 0.96 - 0.86 (m, 1H).

[0817] Synthesis of 7V-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yI)amino)-5-((l-((lr,4r)-4-((4-(4- ((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 8) and V-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((ls,4s)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 9)

[0818]

[0819]

[0820] Step-1:

[0821] To an 8 mL vial containing a well-stirred solution of(lr,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l -carboxylic acid (C-7, 50 mg, 107.64 pmol) and A-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-pyrrolidin-3-yloxy-2-pyridyl] acetamide (A-l, 42.13 mg, 107.64 pmol) in anhydrous DMF (3 mL) were added DIPEA (41.72 mg, 322.92 pmol, 56.22 pL) and HATU (61.39 mg. 161.46 pmol) at room temperature. The 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 compound was purified by reverse phase prep-HPLC [Column: X-SELECT Cl 8, 5 micron; Mobile phase A: 0.1% Ammonium bicarbonate in water; Mobile phase B: Acetonitrile] to afford N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr.4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin- 1-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 8, 8 mg, 9.15 pmol, 8% yield) as an off-white solid. LC-MS (ES+): m / z 838.3 [M + H]+and1H NMR (400 MHz, DMSO-d6) 5 10.82 (s, 1H), 10.14 (s, 1H), 9.09 (d, J = 10.0 Hz, 1H). 8.37 (d, J = 7.9 Hz. 1H), 7.96 (d. J= 4.5 Hz. 1H), 7.21 - 7.03 (m, 2H), 6.32 (d, J= 11.8 Hz, 2H), 6.26 (d, J = 7.9 Hz, 1H), 5.13 - 5.03 (m, 1H), 4.36-4.28 (m, 1H), 3.87 - 3.62 (m, 3H), 3.59 - 3.44 (m, 2H), 2.95 (br s, 4H), 2.81 - 2.68 (m, 1H), 2.58 – 2.51 (m, 1H), 2.42 - 2.32 (m, 8H), 2.16 - 2.03 (m, 10H), 1.92 - 1.67 (m, 5H), 1.63 - 1.46 (m, 1H), 1.39 - 1.19 (m, 2H), 0.98 - 0.82 (m, 2H).

[0822] Step-2:

[0823] To a 20 mL vial containing a well-stirred solution of (1s,4s)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l -carboxylic acid (C-8, 50 mg, 107.64 pmol) andX-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-pyrrolidin-3-yloxy- 2-pyridyl] acetamide (A-l, 42.13 mg, 107.64 pmol) in anhydrous DMF (3 mL) were added DIPEA (13.91 mg, 107.64 pmol) and HATU (40.93 mg, 107.64 pmol) at room temperature. The 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 reducedpressure. The crude compound was purified by reverse-phase prep-HPLC [Column: X-SELECT C18, 5 micron; Mobile phase A: 0.1% Trifluoroacetic acid water in water; Mobile phase B: Acetonitrile] to afford X-(4-((6-( 1, 1 -difluoroethyl)-4-methylpyridin-2-y l)amino)-5-(( 1 -(( 15,4s)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide trifluoroacetate (Compound 9. 7 mg, 7.18 pmol, 7% yield) as an off-white solid. LC-MS (ES+): m / z 838.2 [M + H] ’. 'H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.95 (b s, 1H), 9.10 (s, 1H), 8.63 – 8.43 (s, 1H), 7.94 (s, 1H), 7.23 – 7.06 (t, 2H), 6.39 (t, 3H), 5.17 - 5.06 (m, 1H), 4.39 - 4.30 (m, 1H), 3.86 - 3.65 (m, 3H), 3.54-3.48 (m, 4H), 3.20 - 3.06 (m, 6H), 2.76 - 2.68 (m, 1H), 2.60 (br s, 2H), 2.41 - 2.20 (m, 6H), 2.16 - 1.99 (m, 9H), 1.95 - 1.81 (m, 1H), 1.67 - 1.45 (m, 8H).

[0824] Synthesis of / V-(4-((6-(l,l-difluoioethyl)-4-methylpyiidin-2-yl)amino)-5-((l-((6 / ?)-2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)spiro[3.4]octane-6-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 10) and N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((2s,4s)-2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)spiro[3.4]octane-6-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 11)

[0825]

[0826] MP-CNBH3, DMSO Step-2

[0827]

[0828] Step-1:

[0829] To a 20 mL screw-cap vial containing a well-stirred solution of A-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-pyrrolidin-3-yloxy-2-pyridyl]acetamide (A-l, 50 mg, 127.74 pmol) and 2-oxospiro[3.4]octane-7-carboxylic acid (2. 21.48 mg. 127.74 pmol) in anhydrous DMF (3 mL) were added DIPEA (49.53 mg, 383.23 pmol, 66.75 pL) and HATU (97.14 mg, 255.48 pmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC [Column: RediSep Rf Gold® C18-30 g; Mobile phase A: 10 mM Ammonium bicarbonate in water; Mobile phase B: Acetonitrile] to afford A-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-(2-oxospiro[3.4]octane-7-carbonyl)pyrrolidin-3-yl]oxy-2-pyridyl] acetamide (3, 50 mg, 89.65 pmol, 70% yield) as a pale-yellow solid. LC-MS (ES+): m / z 542.2 [M + H]+.

[0830] Step-2:

[0831] To an 8 mL screw-cap vial containing a well-stirred solution of A-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-(2-oxospiro[3.4]octane-7-carbonyl)pyrrolidin-3-yl]oxy-2-pyridyl] acetamide (3, 50 mg. 92.32 pmol) and 3-[4-(3,3-difluoro-4-piperidyl)-3,5-difluoro-anilino]piperidine-2,6-dione trifluoroacetate (B-6, 43.70 mg, 92.32 pmol) in DMSO (3 mL) were added sodium acetate (75.73 mg, 923.21 pmol) and acetic acid (55.44 mg, 923.21 pmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h before MP-cyanoborohydride (100 mg. 200 pmol) was added and stirring was continued at 70 °C for 2h. After completion of the reaction as indicated by the UPLC-MS, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC [Column: X SELECT C18 (150 x 19) mm, 5 pm; Mobile phase A: 0.1% Ammonium bicarbonate in water and Mobile Phase B: Acetonitrile],

[0832] The early-eluting fraction (arbitrarily assigned as / rara-isomer) / V-(4-((6-(l.l-dilluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((6A)-2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluoropheny l)-3,3 -difluoropiperidin- 1 -yl )spiro[3.4] octane-6-carbony l)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 10, 5 mg, 5.56 pmol, 6% yield) was obtained as an off-white solid. LC-MS (ES+): m / z 885.3 [M + H]+. and 'H NMR (401 MHz, DMSO- s): 5 10.84 (s, 1H), 10.19 (d, 1H), 9.16 - 9.05 (m, 1H), 8.41 - 8.29 (m, 1H), 8.04 - 7.90 (m, 1H), 7.28 - 7.02 (m, 2H). 6.51 (d, J = 7.9 Hz. 1H), 6.36 (d, J = 12.6 Hz, 2H). 5.17 - 5.04 (m, 1H), 4.41 – 4.34 (m, 1H), 3.71 (br s, 3H), 3.60 - 3.52 (m, 1H), 3.25 - 3.13 (m, 1H), 3.09 - 2.97 (m, 1H), 2.90 - 2.69 (m, 3H), 2.59 (1H), 2.37 - 1.59 (m, 28H) ppm.

[0833] The late-eluting fraction (arbitrarily assigned as c / .s-isomer) A-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((6S)-2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2.6-difluorophenyl)-3,3-difluoropiperidin-l-yl)spiro[3.4]octane-6-carbonyl)pyrrolidm-3-yl)oxy)pyridin-2-yl)acetamide (Compound 11, 6 mg, 6.68 pmol, 7% yield) was obtained as an off-white solid. LC-MS (ES+): m / z 885.3 [M + H]+. 'H NMR (401 MHz, DMSO-d6): 5 10.84 (s, 1H), 10.14 (br s, 1H), 9.17 - 9.07 (d, 1H), 8.36 (d, J= 7.6 Hz, 1H), 8.00 - 7.86 (m, 1H), 7.07 (s, 2H), 6.51 (d. J = 8.0 Hz, 1H). 6.36 (d, J = 13.4 Hz, 2H), 5.12 - 5.02 (m. 1H), 4.43 - 4.33 (m, 1H), 3.81 - 3.59 (m, 3H), 3.59 - 3.44 (m, 2H), 3.29 - 3.15 (m, 2H), 3.09 - 2.96 (m, 1H), 2.92 -2.83 (m, 1H), 2.81 - 2.72 (m, 2H), 2.66 - 2.55 (m, 1H), 2.44 - 2.32 (m, 4H), 2.29 - 2.15 (m, 3H), 2.13 - 2.03 (m, 7H), 1.96 - 1.83 (m, 4H), 1.83 - 1.70 (m, 4H), 1.69 - 1.58 (m, 4H) ppm.

[0834] Synthesis of N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(8-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)-8-azaspiro[4.5]decan-2-yl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide (Compound 12)

[0835] MP-CNBH3, NaOAc CH3COOH, DMSO Step-1

[0836]

[0837]

[0838] Step-1:

[0839] To a 20 mL screw-cap vial containing a well-stirred solution of A-[4-[[6-(l,l-difhroroethyl)-4-methyl-2-pyridyl]amino]-5-pyrrolidin-3-yloxy-2-pyridyl]acetamide (A-l, 100 mg, 255.48 pmol) and tert-butyl 3-oxo-8-azaspiro[4.5]decane-8-carboxylate (2, 64.72 mg, 255.48 pmol) in DMSO (4 mL) were added acetic acid (153.42 mg. 2.55 mmol) and sodium acetate (104.79 mg, 1.28 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Then MP-CNBH3 (200 mg, 408.77 pmol) was added and the reaction mixture was stirred at 70 °C for 1 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered through a cotton funnel, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase column chromatography [Column: RediSep R / Gold® Cl 8-30 g, Mobile phase A: 10 mM Ammonium bicarbonate in water and Mobile phase B: Acetonitrile] to afford tert-butyl 3-[3-[[6-acetamido-4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]oxy]pyrrolidin-l-yl]-8-azaspiro[4.5]decane-8-carboxylate (3, 120 mg, 181.77 pmol, 71% yield) as an off-white solid. LC-MS (ES+): m / z 629.3 [M + H]+.

[0840] Step-2:

[0841] To a 25 mL single-neck round-bottom flask containing well-stirred solution of tert-butyl 3-[3-[[6-acetamido-4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]oxy]pyrrolidin-l-yl]-8-azaspiro[4.5]decane-8-carboxylate (3, 120 mg, 181.77 pmol) in DCM (3 mL) was added TFA (727.08 pmol, 55.64 μL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as indicated by UPLC-MS, solvent was removed from the reaction mixture and the residue was co-distilled with toluene to affordA-[5- [l-(8-azaspiro[4.5]decan-3-yl)pyrrolidin-3-yl]oxy-4-[[6-(l,l-difluoroethyl)-4-methyl-2- pyridyl]amino]-2-pyridyl]acetamide trifluoroacetate (4. 100 mg, 149.38 pmol, 82% yield) as a brown solid. LC-MS (ES+): m / z 529.3 [M + H]+.

[0842] Step-3:

[0843] To a 20 mL glass-vial containing a well-stirred solution of A-[5-[l-(8-azaspiro[4.5]decan-3- yl)pyrrolidin-3-yl]oxy-4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide (4, 100 mg. 181.60 pmol) in DMSO (3 mL) were added 3-[3, 5-difluoro-4-(4-oxo-l- piperidyl)anilino]piperidine-2, 6-dione (B-7, 73.80 mg, 181.60 pmol), acetic acid (109.05 mg, 1.82 mmol) and sodium acetate (74.49 mg, 908.00 pmol) and the reaction mixture was stirred at room temperature for 1 h. Then MP-CNBH₃ (200 mg, 399.52 pmol) was added and the reaction mixture was stirred at 70 °C for 1 h. After completion of the reaction as indicated by the UPLC- MS, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase column chromatography [Column: RediSep R / Gold® C18-30 g; Mobile phase A: 0.1% ammonium bicarbonate in water and Mobile phase B: Acetonitrile] to afford N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[1-[8-[1-[4- [(2.6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]-8-azaspiro[4.5]decan-3- yl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide (Compound 12, 3 mg, 3.48 pmol, 2% yield) as an off-white solid. LCMS (ES+): m / z 850.3 [M + H]+and1H NMR (401 MHz, DMSO-6) 8 10.81 (s, 1H), 10.10 (d, J= 4.0 Hz, 1H), 9.12 (d, J= 5.6 Hz. 1H), 8.40 (s, 1H), 7.86 (d, J= 6.5 Hz, 1H), 7.14 (d. J = 5.8 Hz, 1H), 7.07 (s. 1H), 6.31 (d, J= 11.5 Hz, 2H), 6.23 (d. J = 7.9 Hz. 1H), 4.94 - 4.83 (m, 1H), 4.37 - 4.24 (m, 1H), 3.00 - 2.88 (m, 7H), 2.86 - 2.71 (m, 4H), 2.44 - 2.40 (m, 2H), 2.37 - 2.31 (m, 7H), 2.30 - 2.23 (m, 2H), 2.08 - 2.01 (m, 6H), 1.83 - 1.59 (m, 6H), 1.55 - 1.33 (m, 10H).

[0844] Compound

[0845] Number Structure

[0846] 13 N-[4-[[6-(1,1- difluoroethyl)-4-methyl-2- pyridyl]amino]-5-[1-[10-0ANH

[0847] / / \ A /

[0848] \\ ACF A, —

[0849] [4-[l-(2.6-di o KA AN F A. A / vxo-3- yo A ANH? O 'NA NH piperidyl)-3-methyl-2-oxo- V 0

[0850]

[0851] Compound

[0852] Number Structure benzimidazol-4-y 1] - 1 - piperidyl] -10-oxo- decanoy 1] py rrolidin-3 - yl]oxy-2- pyridyl]acetamide

[0853] 14 N-[4-[[6-(1,1- difluoroethyl)-4-methyl-2- pyridyl]amino]-5-[1-[10- [4-[1-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-1- piperidyl]-10-oxo- decanoyl]pyrrolidin-3- yl]oxy-2-

[0854] N VNH oF

[0855] pyridyl]acetamide \ —10

[0856] 15 N-[4-[[2-(1,1- difluoroethyl)pyrimidin-4- yl]amino]-5-[4-[4-[[4-[4- [(2,6-dioxo-3- piperidyl)amino]-2-fluoro-

[0857] 5 -methoxy - 'r pheny IJpiperazin- 1 - 0 XI N A A N A [ ] HN AJ yl]methyl]piperidine-l - carbonyl] cyclohexyl] -2- X^NH py ri dy 1] acetamide

[0858] 16 N-[4-[[6-(1,1- difluoroethyl)-4-methyl-2- pyridyl]amino]-5-[1-[6-[4- [1-(2,6-dioxo-3-piperidyl)-

[0859] XNH / A. /

[0860] 3-methyl-2-oxo- A XX VF

[0861] benzimidazol-4-y 1] - 1 - / HUI rNHpiperidyl] -6-oxo- °X i nzo o

[0862]

[0863] Compound

[0864] Number Structure hexanoyl]pyrrolidin-3- yl]oxy-2- py ri dy 1] acetamide

[0865] 17 N-[4-[[6-(1,1- difluoroethyl)-4-methyl-2- pyridyl]amino]-5-[1-[2-[4- [4-[(2,6-dioxo-3- piperidyl)amino]-2,6- difluoro-phenyl]piperazin- / / \ i

[0866] C ) OO -Z=—.

[0867] HF V

[0868] l-yl]acetyl]pyrrolidin-3- O^. N. X) / k / N. 0 HN— yl]oxy-2- Z ri T X

[0869] Hjfl ri-H M / py ri dy 1] acetamide \ 18 7V 0 ’ 0

[0870] -L4-LL2-(1,1- difluoroethyl)pyrimidin-4- yl]amino]-5-[4-[4-[[4-[4- b 0O

[0871] [(2,6-dioxo-3- piperidyl)amino] -2-fluoro- 5-methoxy- phenyl]piperazin- 1 - ^ 00 O yl]methyl]piperidine-l - carbonyl] cyclohexyl] -2- pyridyljacetamide

[0872] 19 N-[4-[[6-(1,1- difluoroethyl)-4-methyl-2- pyridyl]amino]-5-[1-[10- [4-[4-[(2,6-dioxo-3- piperidyl)amino]phenyl]- 1-piperidyl]-10-oxo- decanoyl]pyrrolidin-3- ° / y~NH / 0 \ / HZH f l I I yl]oxy-2-N> ANH OrO N O pyridyl]acetamide oH ¥

[0873] ' 0

[0874]

[0875] O Compound z — Number Structure \ / °= 20 JV-[4-[[6-(l,l- z difluoroethyl)-4-methyl-2- Xv o pyridyl]amino]-5-[l-[4- [[4-[4-[(2, 6-di oxo-3- piperidyl)amino] -2,6- difluoro-phenyl]-3,3- difluoro-1- \ _ _ F

[0876] piperidyl] methyl] cyclohex

[0877] 0N X VNHF anecarbonyl]pyrrolidin-3- yl]oxy-2- T XI XJ pyridyl]acetamide H 21 N-[4-[[6-(1,1- difluoroethyl)-4-methyl-2- pyridyl]amino]-5-[1-[7-[4- [4-[(2,6-dioxo-3- piperidyl)amino]phenyl]- 1-piperidyl]-7-oxo- heptanoyl]pyrrolidin-3-

[0878] yl]oxy-2- X X X J

[0879] pyridyl]acet amide H

[0880] 32 N-(4-((2-(1,1- difluoroethyl)pyrimidin-4- yl)amino)-5-(7-(l-(4-((2,6- dioxopiperidin-3- y l)amino)-2-fluoro-5 - methoxyphenyl)piperidine- 4-carbonyl)-5,6,7,8- tetrahydroimidazo[l,2- a]pyrazin-2-yl)pyridin-2- yl)acetamide

[0881]

[0882] Compound

[0883] Number Structure

[0884] 33 6-acetamido-4-((2-(1,1- difluoroethyl)pyrimidin-4- yl)amino)-N-(6-(4-(1-(2,6-

[0885] dioxopiperidin-3-yl)-3- \ N

[0886] methyl-2-oxo-2,3-dihydro- 177-benzo[d]imidazol-5- yl)piperidin-l-yl)-6- Q oxohexyl)ni cotinamide 0 34 7V-(4-((2-(l,l- ZI

[0887] difluoroethyl)pyrimidin-4- yl)amino)-5-(4-(4-((4-(4- ((2,6-dioxopiperidin-3- \, F

[0888] yl)amino)-2-fluoro-5- N^ / T

[0889] / / V

[0890] \ N _ p~~ methoxyphenyl)piperazin- ON\N—

[0891] 1 -yl)methyl)piperidine-l - o

[0892] carbony l)cy clohex- 1 -en- 1 - o v yl)pyridin-2-yl)acetamide o °

[0893] / \

[0894] 35 N-(4-((6-(1,1- difluoroethyl)-4- methylpyridin-2- yl)amino)-5-((1-(8-(3-(2,6- dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)- 8-azaspiro[4.5]decane-2- carbonyl)pyrrolidin-3- yl)oxy)pyridin-2- yl)acetamide

[0895]

[0896] Compound

[0897] Number Structure 36 JV-(4-((6-(l,l- 0

[0898] difluoroethyl)-4- HNU

[0899] oU /

[0900] methylpyridin-2- y l)amino)-5-((l -( 1 -(3-(2,6- tjCN

[0901] dioxopiperi din-3 -y 1)- 1 - methyl- 177-indazol-7 - yl)piperidine-4- X

[0902] °N£X°

[0903] carbonyl)pyrrolidin-3- o yl)oxy)pyridin-2- X ^A HN^ yl)acetamideF

[0904] 37 7V-(4-((6-(l,l- difluoroethyl)-4- methylpyridin-2- o y l)amino)-5-(( 1 -(( 1 -(3- O=\ 7 (2,6-dioxopiperidin-3-yl)- 1 -methyl- 177-indazol-7- HN

[0905] yl)piperidin-4- y l)methy l)py rrolidin-3 - yl)oxy)pyridin-2-N

[0906] yl)acetamide F F

[0907] 38 N-(4-((6-(1,1- difluoroethyl)-4- methylpyridin-2- yl)amino)-5-((1-((1-(3- (2,6-dioxopiperidin-3-yl)- 1-methyl-1H-indazol-6- 0

[0908] \ HN-X, yl)piperidin-4- \

[0909] yl)methyl)pyrrolidin-3- >NH V -Lu yl)oxy)pyridin-2-0N UNH£ yl)acetamide

[0910]

[0911] Compound

[0912] Number Structure

[0913] 39 N-(4-((6-(1,1- difluoroethyl)-4- methylpyridin-2- yl)amino)-5-(((3S)-1- ((1s,4R)-4-((4-(4-((2,6- dioxopiperidin-3- yl)amino)-2,6- difluorophenyl)piperazin- 1-yl)methyl)cyclohexane-hf o...01 -carbonyl)pyrrolidin-3- kA A A o HNA^Y yl)oxy)pyridin-2- H / — ( V' \ — \ y ' / l)acetamide xHN^ /

[0914] 0 40 N-(4-((6-(1,1- difluoroethyl)-4- methylpyridin-2- yl)amino)-5-((1-((1r,3r)-3- ((4-(4-((2,6- dioxopiperidin-3- yl)amino)-2,6- difluorophenyl)piperazin- 1-yl)methyl)cyclobutane-rAy'N'A. _ 1 -carbonyl)pyrrolidin-3- A A A J F °MJNA N HF~7~^ k \ / yl)oxy)pyridin-2- \ o yl)acetamide

[0915] 41 7V-(4-((6-(l,l- difluoroethyl)-4- methylpyridin-2- yl)amino)-5-((l -(3-(4- o

[0916] ((2,6-dioxopiperidin-3-oyl)amino)-2.6-Hk ' A^M difluorophenyl)-3- L ^AN A^A-F FAA^( HNA azaspiro[5.5]undecane-9-

[0917]

[0918] Compound

[0919] Number Structure carbonyl)pyrrolidin-3- yl)oxy)pyridin-2- yl)acetamide

[0920] 42 N-(4-((6-(1,1- difluoroethyl)-4- methylpyridin-2- yl)amino)-5-(((3R)-1- ((1r,4R)-4-((4-(4-((2,6- dioxopiperidin-3- yl)amino)-2,6- difluorophenyl)piperazin- 1-yl)methyl)cyclohexane-HF

[0921] CK. N..0 9 1 -carbonyl)pyrrolidin-3- kA A A? o HN-A^X. yl)oxy)pyridin-2- H F / v A / H\NA / yl)acetamide \ o 43 7V-(4-((6-(l,l- difluoroethyl)-4- methylpyridin-2- y l)amino)-5-(((3S)- 1 - ((lr,4< S)-4-((4-(4-((2,6- dioxopiperidin-3- yl)amino)-2,6- difluorophenyl)piperazin-HF f-A

[0922] 1 -yl)methyl)cyclohexane- l-carbonyl)pyrrolidin-3- kA N A A F r F o N-V HNA VA / / ylH / v A?H\NNA / )oxy)pyridin-2- \ O yl)acetamide

[0923] 44 7V-(4-((6-(l,l-HF

[0924] difluoroethyl)-4- kA A Aco methylpyridin-2- HNAAM H F A / / A A / yl)amino)-5-(((37?)-l- / \_ / HNA \ o ((B,4S)-4-((4-(4-((2,6-

[0925]

[0926] xo- Compound Z Number Structure dioxopiperidin-3- yl)amino)-2,6- l / ° " difluorophenyl)piperazin- 1 -yl)methyl)cyclohexane- 1 -carbonyl)pyrrolidin-3- yl)oxy)pyridin-2- yl)acetamide

[0927] 45 AA-(4-((6-(l,l- O ZI

[0928] difluoroethyl)-4- methylpyridin-2- o

[0929] yl)amino)-5-((l -(4-((4-(4- ((2,6-dioxopiperidin-3- yl)amino)-2,6- difluorophenyl)piperazin- 1- yl)methyl)benzoyl)pyrrolid

[0930] in-3-yl)oxy)pyridin-2- yl)acetamide

[0931] 46 jy-(4-((6-(l,l- difluoroethyl)-4- methylpyridin-2- y l)amino)-5-(( 1 -(4-(4-(4- ((2,6-dioxopiperidin-3- yl)amino)-2,6- 0

[0932] di fl uoropheny l)piperazin- 1 -yl)cyclohexane-l - u HF1 1 1 HN^\\ carbonyl)pyrrolidin-3- O^N- X) J y, O I T \ Y \ yl)oxy)pyridin-2- H F

[0933] yl)acetamide

[0934]

[0935] Compound

[0936] Number Structure

[0937] 47 N-(4-((6-(1,1- difluoroethyl)-4- methylpyridin-2- yl)amino)-5-((1-((1s,4s)-4- ((4-(3-(2,6-dioxopiperidin- 3-yl)-1-methyl-1H- indazol-6-yl)piperazin-1- 0 'X HNA y l)methy l)cy clohexane- 1 - carbony 1 )py rroli din-3 - O-HNo

[0938] yl)oxy)pyridin-2- yl)acetamide \A AAv-N-A 48 N-(4-((6-(1,1- difluoroethyl)-4- methylpyridin-2- yl)amino)-5-((1-((1r,4r)-4- ((4-(3-(2,6-dioxopiperidin- 3-yl)-1-methyl-1H- indazol-6-yl)piperazin-1- o \ _ HNA yl)methyl)cyclohexane-l - KNH oXj carbonyl)pyrrolidin-3-N

[0939] NH F J

[0940] T~NHu? JT / N yl)oxy)pyridin-2- yl)acetamide

[0941] 49 7V-(4-((6-(l,l- difluoroethyl)-4- methylpyridin-2- y l)amino)-5-(( 1 -(2-( 1 -(4- ((2,6-dioxopiperidin-3- \ J L if yl)amino)-2,6- rT THdifluorophenyl)piperidin- J i

[0942] H F i I | r> 4-yl)-2-azaspiro[3.4]octan- O^N^° F T T r ¥

[0943] 6-yl)pyrrolidin-3- H

[0944] yl)oxy)pyridin-2-

[0945]

[0946] Compound

[0947] Number Structure

[0948] yl)acetamide

[0949]

[0950] Table 4: other representative compounds

[0951] Compound

[0952] Number Structure

[0953] 22 2V-[4-[[6-(l,l- difluoroethyl)-4-methyl-2- pyridyl]amino]-5-[l-[8-[3- (2,6-dioxo-3-piperidyl)-l- methyl-indazol-7-yl]-8- azaspiro[4.5]decane-3- ^ F OZy- carbonyl]pyrrolidin-3- r z

[0954] yl]oxy-2- pyridyl]acetamide

[0955] 23 2V-[4-[[6-(l,l- difluoroethyl)-4-methyl-2- ’Zf—. pyridyl]amino]-5-[l-[8-[3- X X \< 1=

[0956] (2,6-dioxo-3-pipendyl)-l- X 0

[0957] methyl-indazol-6-yl]-8-HN o J J zI / \ azaspiro[4.5]decane-3- O carbonyl]pyrrolidin-3- yl]oxy-2- py ri dy 1] acetami de

[0958] 24 JV-[5-[l-[[3-[3-(2,6-dioxo- O \ /

[0959] 3-piperidyl)-5-fluoro-l- / NH

[0960] methyl-indazol-6-yl]-3- azaspiro[5.5]undecan-9- yl]methyl]pyrrolidin-3- yl]oxy-4-[[6-(3- methoxytetrahydrofuran-3- F XX? yl)-4-methyl-2- pyridyl]amino]-2-HN~T\ pyridyl]acetamide 0

[0961]

[0962] Compound

[0963] Number Structure

[0964] 25 JV-[5-[l-[[3-[3-(2,4- dioxohexahydropyrimidin- 1 -y l)-5-fluoro- 1 -methyl- 0 \ _ /

[0965] indazol-6-yl]-3- / ^~NH

[0966] azaspiro[5.5]undecan-9- yl]methyl]pyrrolidin-3- yl]oxy-4-[[6-(3- methoxytetrahydrofuran-3- XX? yl)-4-methyl-2- -A pyridyl]amino]-2-HNY

[0967] pyridyl]acetamide 0 26 7V-[5-[l-[l-[3-(2,6-dioxo- 3-piperidyl)-l-methyl- indazol-7-yl]-4- piperidyl]pyrrolidin-3- °? N

[0968] yl]oxy-4-[[6-(3- / / N _ methoxytetrahydrofuran-3- yl)-4-methyl-2- pyridyl]amino]-2-<( / N~ Xy0pyridyl]acetamide

[0969] 27 N-[4-[[6-(l.l- difluoroethyl)-4-methyl-2- pyridyl]amino]-5-[(3R)-l - [4-[[4-[4-[(2,6-dioxo-3- piperidyl)amino]-2.6- di fluoro-phenyl] piperazin- 1- H 1 fAoy 1] methyl] cy clohexanecarb

[0970] L A. o HNX 'Nonyl]pyrrolidin-3-yl]oxy- H FA^ / A /

[0971] / \_ / HNA\ 2-pyridyl]acetamide \ 0

[0972]

[0973] Compound

[0974] Number Structure

[0975] 28 JV-[4-[[6-(1,1- difluoroethyl)-4-methyl-2- pyridyl]amino]-5-[l-[2-[4- [4-[(2,6-dioxo-3- piperidyl)amino]-2,6- di fluoro-phenyl] piperazin- l-yl]ethyl]pyrrolidin-3-HF

[0976] O?>, N^, O / kHN— < A 'Nyl]oxy-2- i r ii 4F\

[0977] I. A JL A A \ / pyridyljacetamideH\ b 29 2V-[4-[[2-(l,l- difluoroethyl)pyrimidin-4- yl]amino]-5-[l-[[3-[4- [(2,6-dioxo-3- piperidyl)amino]-2,6- difluoro-phenyl]-3- azaspiro[5.5]undecan-9- yl]methyl]pyrrolidin-3- H f

[0978] 0,N<; °1HNZZ / Nnyl]oxy-2- pyri dy 1] acetamide HHRN= /

[0979] 30 2V-[4-[[6-(l,l- difluoroethyl)-4-methyl-2- pyndylJamino]-5-[l-t3-|4- [(2,6-dioxo-3- piperidyl)amino]-2,6- difluoro-phenyl]-3- o

[0980] azaspiro [5.5 ]undecane-9- <"''1 0 carbonyl]pyrrolidin-3- Hiiu-- /

[0981] °< Y-NV0HN—Oyl]oxy-2- VI N XZ FF- \A — / CH / HN^ \ py ri dy 1] acetamide HF? W

[0982]

[0983] Compound

[0984] Number Structure

[0985] 31 A-[4-[[6-(l,l-F

[0986] difluoroethyl)-4-methyl-2- >-NH yf \

[0987] pyridyl]amino]-5-[l-[3-[3-0

[0988] (2,6-dioxo-3-piperidyl)-l- methyl-indazol-6-yl]-3- azaspiro[5.5]undecan-9- y 1] pyrrolidin-3-yl] oxy-2- pyridyl]acetamide

[0989] HNA

[0990] o

[0991]

[0992] Table 5: further compounds

[0993] Pharmacological Tests

[0994] The compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are associated with modulation of TYK2 protein via degradation. The compounds were investigated in accordance with the test given hereinafter.

[0995] Example 4: HTRF Total TYK2 Degradation Assay in HEL92.1.7 Cells

[0996] TYK2 degradation of selected compounds of the invention was quantified in a homogenous time resolved fluorescence (HTRF) assay directed against the TYK2 protein and using HEL92.1.7 cells, which is a human erythroblast cell line isolated from the bone marrow of a patient with erythroleukemia.

[0997] For each compound tested, a stock solution of test compounds was prepared by dissolving neat compound in DMSO (Catalog No. D8418, Sigma- Aldrich, Inc., St. Louis, MO, USA) to generate a 10 mM stock solution that was stored at -20 °C. These compound stock solutions were serially diluted (half log titration) in DMSO to generate a 10-point dilution series (10000, 3161, 1000, 317, 100, 32, 10, 3.2, 1, 0.3 pM) in an acoustic ready 384-well low dead volume microplate (Catalog No. 001-16128, Beckman Coulter Life Sciences, Indianapolis, IN, USA). Using an Echo 650 Acoustic Liquid Handler (Beckman Coulter Life Sciences), 12.5 nL of serially diluted compound solutions were dispensed in duplicate to each 384-well CELLSTAR* TC Plate (Item No. 784080, Greiner Bio-One North America Inc., Monroe, NC, USA). DMSO (12.5 nL) was transferred to all control w ells.

[0998] HEL92.1.7 cells were obtained from ATCC® (Catalog No. TIB-180, American Type Culture Collection, Manassas, VA, USA). The cells were maintained in complete mediumconsisting of phenol red free RPMI-1640 (Product No. 17-105-CV, Coming, Glendale, AZ, USA) supplemented with 10% fetal bovine serum (FBS; Catalog No. 16000044, Gibco™, Thermo Fisher Scientific, Waltham, MA, USA) and 2 mM final GlutaMAX (Catalog No. 35050061, Thermo Fisher Scientific) at 37 °C in an atmosphere of 5% CO2 in air and routinely sub-cultured to maintain cell density under 2xl06cells / mL. Cells were spun down by centrifugation at 1200 rpm for 10 minutes at room temperature. The cell pellet was resuspended in complete medium for plate-based assays. Using an electronic repeating pipette, 12.5 uL of HEL92.1.7 cell suspension was dispensed into 384-well CELLSTAR® TC Plates to a final cell density of 20,000 cells / well, to columns 1-22 of each plate. The final compound dose response concentrations after cell dispensing were 10000, 3161, 1000, 317, 100, 32, 10, 3.2, 1, 0.3 and 0 nM. Complete medium without cells was dispensed into columns 23-24 of each plate, serving as plate background. Plates were spun briefly at 1000 rpm, covered with the plate’s clear plastic lid, and cells were incubated at 37°C in an atmosphere of 5% CO2 in air for 6 hours or 24 hours. The final concentration of DMSO was 0.1% for all samples.

[0999] TYK2 degradation was quantified using HTRF Total TYK2 Detection Kit assay reagents (Part No. 64TYK2TPEH, Revvity, Inc., Waltham, MA, USA) directed against the TYK2 protein. Following 6-hour or 24-hour incubation, cells were lysed by adding 4 pL of HTRF Lysis Buffer No. 4 with Blocking Reagent (prepared according to the manufacturer’s instructions) to columns 1-24 of the assay plate, covered with the plate’s clear plastic lid, follow ed by incubation at room temperature for 30 minutes. Lastly, 4 pL of detection antibody mix (each antibody diluted 1:40 in HTRF Detection Buffer according to the manufacturer’s instructions) were then added to columns 1-24 of the plate. Plates were covered with the clear plastic lid and incubated for 16 hours. Time-resolved Forster resonance energy transfer (FRET) signal was measured on a PHERAstar® microplate reader (BMG Labtech Inc., Cary, NC, USA). Column 23 (no cells) was used as plate background or positive control (P). Percent responses of signal (T) were calculated by normalizing to the DMSO treated N controls on the same microtiter plate after background (i.e. P controls) signal subtraction:

[1000] Response% = 100 x (Signal [T] - Average [P]) / ( Average [N] - Average [P]) Curve fit and DC50 determination were performed by 4 parametric logistic fit analysis using Scinamic* data analysis software (version 1.5.202412012129, Scinamic, LLC, Lancaster, MA, USA). The fit was performed through minimization of the root mean squared error between observed and calculated values of the 4-parameter logistic equation using the simplex optimizer of the Apache Commons Math library. Boundary conditions for the fit parameters were set as: top was constrained to be between 80% and 120% response, bottom to be between 0% and 80% response, Hill slope between -3 and -0.3, inflection point unrestricted. DC50S were computed asthe concentrations where the fitted curves cross the 50% response level. Emax, or maximum effect of each compound, represents the amount of residual protein remaining in the cell following compound treatment. IP, or inflection point of the dose-response curve, is the concentration of compound at which 50% of the observed degradation response is achieved. Mean and standard deviations were computed from replicates of the experiment. The right side of the degradation ‘“Hook effect” was not incorporated into the fit to facilitate DCso determination from the left side of the degradation response curve.

[1001] Table 6 shows the activity of selected compounds in this HTRF total TYK2 degradation assay with HEL92.1.7 cells follow ing 6 hours of incubation, and Table 7 and Table 8 following 24 hours of incubation. The experiment was conducted at least once for each compound identified in the Tables below, where if the experiment was conducted multiple times, then the data shown in the table is the average of the two or more experiments. In the tables below, “NA” is used for DC50 when Emax is greater than 50%.

[1002] HTRF HTRF HTRF HEL92.1.7 HEL92.1.7 HEL92.1.7

[1003] tTYK2 tTYK2 tTYK2 Compound 6 hours 6 hours 6 hours

[1004] Number DC50 (nM) Emax (%) IP (nM)

[1005] 5 107.09 20.18 85.77 6 18.45 12.47 14.03 48 17.05 28.41 9.91

[1006]

[1007] Table 6: HTRF Total TYK2 Degradation Assay in HEL92.1.7 Cells After 6 Hours

[1008] HTRF HTRF HTRF HEL92.1.7 HEL92.1.7 HEL92.1.7

[1009] tTYK2 tTYK2 tTYK2

[1010] Compound 24 hours 24 hours 24 hours

[1011] Number DC50 (nM) Emax (%) IP (nM)

[1012] 1 827.33 31.17 413.91

[1013] 2 1220.84 24.62 718.67

[1014] 3 1188.30 27.83 607.35

[1015] 4 2077.23 39.53 1057.18

[1016] 5 72.93 19.47 58.28

[1017] 6 21.60 17.09 14.47

[1018] 7 147.25 28.57 57.63

[1019]

[1020] HTRF HTRF HTRF HEL92.1.7 HEL92.1.7 HEL92.1.7 tTYK2 tTYK2 tTYK2 Compound 24 hours 24 hours 24 hours Number DC50 (nM) Emax (%) IP (nM)

[1021] 8 18.01 15.11 12.16

[1022] 9 17.44 15.38 11.92

[1023] 10 19.45 15.89 14.25

[1024] 11 90.39 28.04 59.82

[1025] 12 408.38 35.33 251.13

[1026] 13 790.61 43.04 147.42

[1027] 14 486.67 45.06 152.37

[1028] 15 NA 51.15 358.17

[1029] 16 NA 54.53 591.91

[1030] 17 NA 55.97 2205.75

[1031] 18 NA 62.68 2869.11

[1032] 19 NA 63.98 37.98

[1033] 20 NA 70.35 39142.09

[1034] 21 NA 74.31 367.34

[1035] 32 37.05 43.83 7.68

[1036] 33 NA 78.67 4288.95

[1037] 34 NA 79.42 1918.17

[1038] 40 44.87 26.89 25.61

[1039] 41 NA 71.39 40.52

[1040] 43 8.3 13.44 5.94

[1041] 45 23.03 25.57 10.56

[1042] 46 190.62 43.52 26.63

[1043] 47 22.67 17.12 16.57

[1044] 48 11.81 15.13 8.28

[1045] 49 NA 80.7 489.45

[1046]

[1047] Table 7: HTRF Total TYK2 Degradation Assay in HEL92.1.7 Cells After 24 Hours HTRF HTRF HTRF HEL92.1.7 HEL92.1.7 HEL92.1.7 tTYK2 tTYK2 tTYK2 Compound 24 hours 24 hours 24 hours Number DC50 (nM) Emax (%) IP (nM)

[1048]

[1049] 1 2118.23 41.03 740.44

[1050] 35 44.4 31.25 26.21

[1051] 36 NA 50.9 41.22

[1052] 37 72.32 36.38 28.4

[1053] 38 NA 55.38 14.64

[1054] 39 14.08 15.41 12.3

[1055] 42 9.45 8.06 6.97

[1056] 43 8.98 6.54 9.1

[1057] 44 14.85 16.5 8.29

[1058]

[1059] Table 8: HTRF Total TYK2 Degradation Assay in HEL92.1.7 Cells After 24 Hours Example 5: Phosphorylated TYK2 Detection in HEL92.1.7 Cells via HTRF

[1060] TYK2 binding of selected compounds of the invention was quantified in a homogenous time resolved fluorescence (HTRF) assay to detect phosphorylated TYK2 protein (pTYK2) using HEL92.1.7 cells, which is a human erythroblast cell line isolated from the bone marrow of a patient with erythroleukemia.

[1061] For each compound tested, a stock solution of test compound was prepared by dissolving neat compound in DMSO (Catalog No. D8418, Sigma- Aldrich. Inc., St. Louis, MO, USA) to generate a lOmM stock solution that was stored at -20 °C. These compound stock solutions were serially diluted (half log titration) in DMSO to generate an 10-point dilution series (10000, 3161, 1000, 317, 100, 32, 10, 3.2, 1, 0.3 pM) in an acoustic ready 384-well low dead volume microplate (Catalog No. 001-16128), Beckman Coulter Life Sciences, Indianapolis, IN, USA). Using an Echo 650 Acoustic Liquid Handler (Beckman Coulter Life Sciences). 12.5 nL of serially diluted compound solutions were dispensed in duplicate to each 384-well CELLSTAR® TC Plate (Item No. 784080, Greiner Bio-One North America Inc., Monroe, NC, USA). DMSO (12.5 nL) was transferred to all control wells.

[1062] HEL92.1.7 cells were obtained from ATCC® (Catalog No. TIB-180, American Type Culture Collection, Manassas, VA, USA). The cells were maintained in complete medium consisting of phenol red free RPMI-1640 (Product No. 17-105-CV, Coming, Glendale, AZ, USA) supplemented with 10% fetal bovine serum (FBS; Catalog No. 16000044, Gibco™, Thermo Fisher Scientific, Waltham, MA, USA) and 2 mM final GlutaMAX (Catalog No. 35050061, Thermo Fisher Scientific) at 37 °C in an atmosphere of 5% CO2 in air and routinely sub-cultured to maintain cell density under 2xl06cells / mL.

[1063] Cells were spun dow n by centrifugation at 1200 rpm for 10 minutes at room temperature. The cell pellet was resuspended in complete medium for plate-based assays. Using an electronicrepeating pipette, 10.5 pL of HEL92.1.7 cell suspension was dispensed into 384-well CELLSTAR* TC Plates to a final cell density of 40,000 cells / well, to columns 1-22 of each plate. The final compound dose response concentrations after cell dispensing were 10000, 3161, 1000, 317, 100, 32, 10, 3.2, 1, 0.3 and 0 nM. Complete medium without cells was dispensed into columns 23-24 of each plate, serving as plate background. Plates were spun briefly at 1000 rpm, covered with the plate's clear plastic lid, and cells were incubated at 37 °C in an atmosphere of 5% CO2 in air for 1 hour. The final concentration of DMSO was 0.1% for all samples.

[1064] After compound incubation, the cells were stimulated with IFNa. 2 pL of IFNa (Catalog No. 592706, BioLegend, Inc., San Diego, CA, USA) in complete medium was dispensed into the 384-well CELLSTAR® TC Plates to a final concentration of 150 ng / mL. Plates were spun briefly at 1000 rpm, covered with the plate’s clear plastic lid. and the cells were incubated at 37 °C in an atmosphere of 5% CO2 in air for 15 minutes to stimulate TYK2 phosphorylation.

[1065] Phosphorylated TYK2 was quantified using HTRF Human Phospho-TYK2 (Tyrl054 / 1055) Detection Kit assay reagents (Part No. 64TYK2Y10PEH, Revvity, Inc., Waltham, MA, USA) directed against the phosphorylated TYK2 protein. Following IFNa stimulation, cells were lysed by adding 4 pL of HTRF Lysis Buffer No. 4 with Blocking Reagent (prepared according to the manufacturer’s instructions) to columns 1-24 of the assay plate, covered with the clear plastic lid, followed by incubation at room temperature for 30 minutes. Lastly, 4 pL of detection antibody mix (each antibody diluted 1:40 in HTRF Detection Buffer according to the manufacturer’s instructions) were then added to columns 1-24. Plates were covered with the clear plastic lid and incubated for 16 hours. Time-resolved FRET signal was measured on a PHERAstar® microplate reader (BMG Labtech Inc., Cary, NC, USA). Column 23 (no cells) was used as plate background or positive control (P). Percent responses of signal (T) were calculated by normalizing to the DMSO treated N controls on the same microtiter plate after background (i.e. P controls) signal subtraction:

[1066] Response% = 100 x (Signal [T] - Average [P]) / (Average [N] - Average [P]) Curve fit and IC50 determination were performed by 4 parametric logistic fit analysis using Scinamic® data analysis software (version 1.5.202412012129, Scinamic, LLC, Lancaster, MA, USA). The fit was performed through minimization of the root mean squared error between observed and calculated values of the 4-parameter logistic equation using the simplex optimizer of the Apache Commons Math library'. Boundary conditions for the fit parameters were set as: top was constrained to be between 80% and 120% response, bottom to be between 0% and 80% response. Hill slope between -3 and -0.3. inflection point unrestricted. IC50s were computed as the concentrations where the fitted curves cross the 50% response level. Emax, or maximum effect of each compound, represents the amount of residual pTYK2 protein remaining in the cellfollowing compound treatment. IP, or inflection point of the dose-response curve, is the concentration of compound at which 50% of the observed inhibition response is achieved. Mean and standard deviations were computed from replicates of the experiment.

[1067] The results are shown in Table 9 and Table 10. The experiment was conducted at least once for each compound identified in the Table below, where if the experiment was conducted multiple times, then the data shown in the table is the average of the two or more experiments. In the tables below, ”N A“ is used for IC50 when Emax is greater than 50%.

[1068] HTRF HTRF HTRF HEL92.1.7 HEL92.1.7 HEL92.1.7

[1069] pTYK2 pTYK2 pTYK2

[1070] 1 hour 1 hour 1 hour

[1071] Compound + 150 ng / mL IFNa + 150 ng / mL IFNa + 150 ng / mL IFNa

[1072] Number IC50 (nM) Emax (%) IP (nM)

[1073] 1 7915.50 41.24 4183.68

[1074] 2 NA 83.97 1287.59

[1075] 3 NA 90.86 3453.02

[1076] 4 NA 62.50 1673.22

[1077] 5 1730.58 18.33 1247.87

[1078] 13 NA 55.92 2439.06

[1079] 14 NA 57.71 3754.91

[1080] 15 NA 87.79 60.75

[1081] 16 NA 74.15 3021.46

[1082] 17 NA 93.58 2718.45

[1083] 18 NA 94.12 1137.55

[1084] 19 NA 60.41 2027.74

[1085] 21 9990.01 43.52 2478.06

[1086] 32 104.41 9.60 84.31

[1087] 33 NA 93.58 26531.18

[1088] 34 NA 88.94 99996.91

[1089]

[1090] Table 9: HTRF pTYK2 Assay in HEL92.1.7 Cells After 1 Hour

[1091] HTRF HTRF HTRF HEL92.1.7 HEL92.1.7 HEL92.1.7

[1092] pT YK2 pTYK2 pTYK2

[1093] 1 hour 1 hour 1 hour

[1094] Compound + 150 ng / mL IFNa + 150 ng / mL IFNa + 150 ng / mL IFNa

[1095] Number IC50 (nM) Emax (%) IP (nM)

[1096] 6 319.37 15.78 162.57

[1097]

[1098] HTRF HTRF HTRF

[1099] HEL92.1.7 HEL92.1.7 HEL92.1.7

[1100] pTYK2 pTYK2 pTYK2

[1101] 1 hour 1 hour 1 hour

[1102] Compound + 150 ng / mL IFNa + 150 ng / mL IFNa + 150 ng / mL IFNa

[1103] Number IC50 (nM) Emax (%) IP (nM)

[1104] 7 NA 54.16 434.56

[1105] 8 NA 56.87 50114.60

[1106] 9 588.79 20.28 325.05

[1107] 10 NA 52.90 230.25

[1108] 11 NA 55.88 283.79

[1109] 12 NA 75.88 244.41

[1110] 20 2060.83 31.78 1484.32

[1111] 35 1956.59 24.8 1507.86

[1112] 36 1663.64 18.22 1418

[1113] 37 44.08 6.03 37.3

[1114] 38 1421.83 22.84 480.93

[1115] 40 1312.01 19.55 797.44

[1116] 41 1050.22 38.61 324.21

[1117] 42 799.66 21.16 186.84

[1118] 43 388.6 15.82 239.46

[1119] 45 537.71 8.5 353.16

[1120] 46 684.9 -4.44 765.57

[1121] 47 1051.19 19.15 776.69

[1122] 48 692.21 18.56 408.91

[1123] 49 NA 52.27 2402.93

[1124]

[1125] Table 10: HTRF pTYK2 Assay in HEL92.1.7 Cells After 1 Hour

[1126] Example 6: Phosphorylated STAT1 Detection in JURKAT Cells via HTRF Assay Selected compounds of the invention were evaluated for the capacity to inhibit the TYK2 pathway using a homogenous time resolved fluorescence (HTRF) assay to detect phosphorylated STAT1 protein (pSTATl) in the JURKAT. Clone E6-1 cell line, which is a clone of the JURKAT-FHCRC cell line derived from the JURKAT cell line which was established from peripheral blood of a human patient with acute T-cell leukemia.

[1127] For each compound tested, a stock solution of test compound was prepared by dissolving neat compound in DMSO (Catalog No. D8418, Sigma- Aldrich, Inc., St. Louis, MO, USA) togenerate a 10 mM stock solution that was stored at -20 °C. Compound stock solutions were serially diluted (half log titration) in DMSO to generate an 10-point dilution series (10000. 3161, 1000, 317, 100, 32, 10, 3.2, 1, 0.3 pM) in an acoustic ready 384-well low dead volume microplate (Catalog No. 001-16128, Beckman Coulter Life Sciences, Indianapolis, IN, USA). Using an Echo 650 Acoustic Liquid Handler (Beckman Coulter Life Sciences), 12.5 nL of serially diluted compound solutions were dispensed in duplicate to each 384-well CELLSTAR® TC Plate (Item No. 784080, Greiner Bio-One North America Inc., Monroe, NC, USA). DMSO (12.5 nL) was transferred to all control wells.

[1128] The JURKAT, Clone E6-1 cell line was obtained from ATCC® (Catalog No. TIB-152, American Type Culture Collection, Manassas, VA, USA). The cells were maintained in complete medium consisting of phenol red free RPMI-1640 (Product No. 17-105-CV, Coming, Glendale, AZ, USA) supplemented with 10% fetal bovine serum (FBS; Catalog No. 16000044, Gibco™, Thermo Fisher Scientific, Waltham, MA, USA) and 2 mM final GlutaMAX (Catalog No. 35050061, Thermo Fisher Scientific) at 37 °C in an atmosphere of 5% CO2 in air and routinely sub-cultured to maintain cell density under 2x106cells / mL.

[1129] Cells were spun down by centrifugation at 1200 rpm for 10 minutes at room temperature. The cell pellet was resuspended in complete medium for plate-based assays. Using an electronic repeating pipette, 10.5 pL of JURKAT cell suspension was dispensed into 384-well CELLSTAR® TC Plates to a final cell density of 40,000 cells / well, to columns 1-22 of each plate. The final compound dose response concentrations after cell dispensing were 10000, 3161. 1000, 317, 100, 32, 10, 3.2, 1, 0.3 and 0 nM. Complete medium without cells was dispensed into columns 23-24 of each plate, serving as plate background. Plates were spun briefly at 1000 rpm, covered with the plate's clear plastic lid, and cells were incubated at 37 °C in an atmosphere of 5% CO2 in air for 24 hours. The final concentration of DMSO was 0.1% for all samples.

[1130] After compound incubation, the cells were stimulated with IFNa. 2 pL IFNa (Catalog No.

[1131] 592706, BioLegend, Inc., San Diego, CA, USA) in complete medium was dispensed into 384-well CELLSTAR® TC Plates to a final concentration of 150 ng / rnL. Plates were spun briefly at 1000 rpm, covered with the plate’s clear plastic lid, and cells were incubated at 37 °C in an atmosphere of 5% CO2 in air for 15 min to stimulate downstream activation of the TYK2 pathway.

[1132] Phosphorylated STAT1 was quantified using HTRF Human and Mouse Phospho-STATl (Tyr701) Detection Kit assay reagents (Part No. 63ADK026PEH, Revvity, Inc., Waltham, MA, USA) directed against the phosphorylated STAT1 protein. Following IFNa stimulation, cells were lysed by adding 4 pL of HTRF Lysis Buffer No. 4 with Blocking Reagent (prepared according to the manufacturer’s instructions) to columns 1-24 of the assay plate, covered withthe plate's clear plastic lid, followed by incubation at room temperature for 30 minutes. Lastly, 4 pL of detection antibody mix (each antibody diluted 1:80 in HTRF Detection Buffer) were then added to columns 1-24. Plates were covered with the clear plastic lid and incubated for 16 hours. Time-resolved FRET signal was measured on a PHERAstar® microplate reader (BMG Labtech Inc., Cary, NC, USA). Column 23 (no cells) was used as plate background or positive control (P). Percent responses of signal (T) were calculated by normalizing to the DMSO treated N controls on the same microtiter plate after background (i.e. P controls) signal subtraction: Response% = 100 x (Signal [T] - Average [P]) / (Average [N] - Average [P])

[1133] Curve fit and IC50 determination were performed by 4 parametric logistic fit analysis using Scinamic® data analysis software (version 1.5.202412012129, Scinamic, LLC, Lancaster, MA, USA). The fit was performed through minimization of the root mean squared error between observed and calculated values of the 4-parameter logistic equation using the simplex optimizer of the Apache Commons Math library. Boundary conditions for the fit parameters were set as: top was constrained to be between 80% and 120% response, bottom to be between 0% and 80% response, Hill slope between -3 and -0.3, inflection point unrestricted. IC50s were computed as the concentrations where the fitted curves cross the 50% response level. Emax, or maximum effect of each compound, represents the amount of residual pSTAT1 protein remaining in the cell following compound treatment. IP, or inflection point of the dose-response curve, is the concentration of compound at which 50% of the observed degradation response is achieved. Mean and standard deviations were computed from replicates of the experiment.

[1134] The results are shown in Table 11. The experiment was conducted at least once for each compound identified in the Table below, where if the experiment was conducted multiple times, then the data shown in the table is the average of the two or more experiments. In the tables below, ”N A" is used for IC50 when Emax is greater than 50%.

[1135] HTRF HTRF HTRF JURKAT JURKAT JURKAT pSTAT1 pSTAT1 pSTAT1

[1136] 24 hours 24 hours 24 hours

[1137] Compound + 150 ng / mL IFNa + 150 ng / mL IFNa + 150 ng / mL IFNa

[1138] Number IC50 (nM) Emax (%) IP (nM)

[1139] 1 1347.96 30.31 439.11

[1140] 2 NA 54.66 238.98

[1141] 3 NA 77.91 876.93

[1142] 4 NA 51.10 412.48

[1143] 6 34.65 23.68 10.90

[1144] 8 270.91 22.83 100.78

[1145]

[1146] HTRF HTRF

[1147] HTRF JURKAT JURKAT JURKAT pSTAT1 pSTAT1 pSTAT1

[1148] 24 hours 24 hours 24 hours

[1149] Compound + 150 ng / mL IFNa + 150 ng / mL IFNa + 150 ng / mL IFNa

[1150] Number IC50 (nM) Emax (%) IP (nM)

[1151] 9 149.18 24.98 61.93

[1152] 10 593.85 37.69 118.71

[1153] 13 4138.55 30.15 2120.10

[1154] 14 NA 58.50 2549.58

[1155] 15 NA 68.67 860.94

[1156] 16 NA 71.69 922.78

[1157] 18 NA 61.95 4999.71

[1158] 19 3994.63 37.28 1683.53

[1159] 21 7883.04 42.59 1593.36

[1160] 34 6872.94 22.14 5980.37

[1161] 47 208.82 18.52 58.23

[1162] 48 73.09 25.51 32.96

[1163]

[1164] Table 11: HTRF pSTAT1 Pathway Inhibition Assay in JURKAT Cells After 24 Hours Example 7: IL-23-Induced STAT3 Phosphorylation in Human Peripheral Blood Mononuclear Cells Flow Cytometry Assay

[1165] Selected compounds were tested to determine their effect on IL-23-induced STAT3 phosphory lation in a human peripheral blood mononuclear cell (PBMC) flow cytometry7assay.

[1166] After obtaining informed consent, human PBMCs were isolated from venous blood collected from healthy donors using BD Vacutainer® blood collection tubes with sodium hepann (Catalog No. 367874, BD Biosciences, San Diego, CA, USA). The collected blood was diluted with serum-free RPMI-1640 medium (Catalog No. 11875093, Gibco™, Thermo Fisher Scientific, Waltham, MA, USA ) at a 1:1 ratio and layered on top of Lymphoprep® density7gradient medium (Catalog No. 18061, STEMCELL Technologies. Inc., Cambridge. MA. USA) at a 2:1 ratio of diluted blood to Lymphoprep® before centrifugation at 430 x g for 30 minutes with brakes off. The PBMC layer was carefully collected from the interface and resuspended in complete medium, which consisted of RPMI-1640 plus 10% heat-inactivated fetal bovine serum (h.i. FBS; Catalog No. 10082147, Gibco™, Thermo Fisher Scientific, Waltham, MA, USA).

[1167] Red blood cell lysis was performed by adding 2-3 mL of red blood cell lysis buffer (Catalog No. R7757, Sigma-Aldrich Corp., St. Louis, MO, USA) to the collected PBMC layer and incubating for 5 minutes at room temperature. After centrifugation at 350 x g for 10 minutesat room temperature, the PBMC pellet was resuspended in complete medium and counted using a hemocytometer. For cryopreservation, PBMCs were mixed with freezing medium consisting of 90% h.i. FBS + 10% DMSO (Catalog No. D2650, Sigma-Aldrich Corp., St. Louis, MO, USA), aliquoted into cryovials (Catalog No. 523193, Tarsons Products Limited, Kolkata, West Bengal, India), and stored in a Mr. Frosty® freezing container (Catalog No. 5100-0001, Thermo Fisher Scientific, Waltham, MA, USA) at -80 °C overnight before transferring to liquid nitrogen storage.

[1168] For each compound tested, a 10-point half-log dilution series was prepared with a top concentration of 1 mM in DMSO. Test compound or DMSO was dispensed into a 96-well clear round-bottom plate (Product No. 3799, Coming, Glendale, AZ, USA) at 0.1 pL per well using the Echo 650 Acoustic Liquid Handler (Beckman Coulter Life Sciences, Indianapolis, IN, USA). Cryopreserved human PBMCs were thawed and resuspended in RPMI-1640 + 10% fetal bovine serum (FBS; Catalog No. 16000044, Gibco™, Thermo Fisher Scientific, Waltham, MA, USA) at 1 million cells / mL. Treatment of cells with compound was initiated by dispensing 99 pL of cells (-100,000 cells) into each well of the 96-well round-bottom plate (final top concentration of compound: 1 pM; final concentration of DMSO: 0.1%). The cells were incubated with the compound at 37 °C in an atmosphere of 5% CO2 in air for 6 hours. At the end of the compound treatment, the cells were stimulated with the addition of 1 pL of 30 pg / mL carrier-free recombinant human IL-23 (Catalog No. 574106, BioLegend, Inc., San Diego, CA, USA) in phosphate-buffered saline (PBS; Product No. 21-040-CV, Coming, Glendale, AZ, USA) or left unstimulated by adding 1 pL PBS, where the final IL-23 concentration for stimulated cells was 300 ng / mL. Cells were incubated at 37 °C in an atmosphere of 5% CO2 in air for 30 minutes. The stimulation was stopped by adding 100 pL warm BD Phosflow™ Lyse / Fix Buffer (Catalog No. 558049, BD Biosciences, San Diego, CA, USA) and incubating at 37 °C in an atmosphere of 5% CO2 in air for 10 minutes. Cells were washed twice with Stain Buffer (Catalog No. 554656, BD Biosciences) and stored at 4 °C until the next day.

[1169] Cells were blocked with 100 pg / mL human immunoglobulin G (IgG; Catalog No. 56834, Sigma-Aldrich Corp., St. Louis, MO, USA) in Stain Buffer at room temperature for 10 minutes, then stained with Brilliant Violet 421™ anti-human CD3 antibody (Catalog No. 300434, BioLegend, Inc.. San Diego, CA, USA) and Alexa Fluor® 647 anti-human CD161 antibody (Catalog No. 339910, BioLegend) diluted in Stain Buffer at room temperature for 30 minutes before washing twice with Stain Buffer. Cells were permeabilized with ice-cold Perm Buffer III (Catalog No. 558050, BD Biosciences, San Diego, CA, USA) on ice for 30 minutes before washing twice with Stain Buffer. Cells were stained with PE mouse anti-STAT3 (pY705) antibody (Catalog No. 562072, BD Biosciences) diluted in Stain Buffer at room temperature for30 minutes before washing twice with Stain Buffer and then resuspended in Stain Buffer for analysis on the NovoCyte flow cytometer (Agilent Technologies, Inc., Santa Clara. CA, USA).

[1170] Data analysis was performed using NovoExpress flow cytometry software (version 1.6.1, Agilent Technologies, Inc., Santa Clara, CA, USA) and Scinamic software (version 1.5.202412012129, Scinamic, LLC, Lancaster, MA, USA). Using NovoExpress, the lymphocyte population was gated for CD3+ / CD161highcells. The median fluorescence intensity (MFI) corresponding to the pSTAT3 signal was determined for this subpopulation for each sample. The MFI values were then imported into Scinamic and the normalized pSTAT3 response for each sample was calculated using the equation 100%*(S-N) / (P-N), where S is the pSTAT3 MFI for the sample, N is the average pSTAT3 MFI for the DMSO-treated unstimulated cells across the 96-well round-bottom plate corresponding to the expected minimum pSTAT3 signal, and P is the average pSTAT3 MFI for the DMSO-treated IL-23-stimulated cells across the 96-well roundbottom plate corresponding to the expected maximum pSTAT3 signal. A logistic curve fit was performed to determine the IC50 and IP values for each compound tested. IC50 values were computed as the concentrations where the fitted curves cross the 50% response level. IP, or inflection point of the dose-response curve, is the concentration of compound at which 50% of the observed degradation response is achieved. Averages and standard deviations were computed from replicates of the experiment.

[1171] For each compound identified inTable 12, the assay was conducted three times using PBMCs from a different donor for each assay, and the data shown in the table for each compound is the average of the three assays.

[1172] The results are shown in the Table below.

[1173] Flow Cytometry Flow Cytometry

[1174] pSTAT3 pSTAT3

[1175] 6 hours 6 hours

[1176] 300 ng / mL IL-23 300 ng / mL IL-23

[1177] 30 min 30 min

[1178] Compound Number

[1179] IC50 (nM) IP (nM)

[1180] 5 153.92 213.86

[1181] 9 38.44 30.51

[1182] 48 273.58 379.90

[1183]

[1184] Table 12: IL-23-induced STAT3 phosphorylation in human PBMCs

[1185] Pharmaceutical Compositions

[1186] The compounds of formula I and the pharmaceutically acceptable salts can be used as therapeutically active substances, e.g. in the form of pharmaceutical preparations. Thepharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

[1187] The compounds of formula I and the pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, com starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are. for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

[1188] The pharmaceutical preparations can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for vary ing the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[1189] Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also provided by the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and / or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

[1190] The dosage can vary' within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

[1191] The following examples illustrate the present invention without limiting it, but serve merely as representative thereof. The pharmaceutical preparations conveniently contain about 1 -500 mg, particularly 1-100 mg, of a compound of formula I. Examples of compositions according to the invention are:

[1192] ATablets of the following composition are manufactured in the usual manner:

[1193] ingredient mg / tablet

[1194] 5 25 100 500 Compound of formula I 5 25 100 500 Lactose Anhydrous DTG 125 105 30 150

[1195] Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450 Magnesium Stearate 1 1 1 1

[1196]

[1197] Total 167 167 167 831 Table 13: possible tablet composition

[1198] Manufacturing Procedure

[1199] 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

[1200] 2. Dry the granules at 50°C.

[1201] 3. Pass the granules through suitable milling equipment.

[1202] 4. Add ingredient 5 and mix for three minutes; compress on a suitable press.

[1203] Example B-l

[1204] Capsules of the following composition are manufactured:

[1205] ingredient mg / capsule

[1206] 5 25 100 500 Compound of formula I 5 25 100 500 Hydrous Lactose 159 123 148 - Com Starch 25 35 40 70 Talk 10 15 10 25 Magnesium Stearate 1 2 2 5

[1207]

[1208] Total 200 200 300 600 Table 14: possible capsule ingredient composition

[1209] Manufacturing Procedure

[1210] 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

[1211] 2. Add ingredients 4 and 5 and mix for 3 minutes.

[1212] 3. Fill into a suitable capsule.

[1213] The compound of formula I, lactose and com starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto andmixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules.

[1214] Example B-2

[1215] Soft Gelatin Capsules of the following composition are manufactured:

[1216] ingredient mg / capsule

[1217] Compound of formula I 5

[1218] Yellow wax 8

[1219] Hydrogenated Soya bean oil 8

[1220] Partially hydrogenated plant oils 34

[1221] Soya bean oil 110

[1222]

[1223] Total 165

[1224] Table 15: possible soft gelatin capsule ingredient composition

[1225] ingredient mg / capsule

[1226] Gelatin 75

[1227] Glycerol 85 % 32

[1228] Karion 83 8 (dry matter)

[1229] Titan dioxide 0.4

[1230] Iron oxide yellow 1.1

[1231]

[1232] Total 116.5

[1233] Table 16: possible soft gelatin capsule composition

[1234] Manufacturing Procedure

[1235] The compound of formula I is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

[1236] Example C

[1237] Suppositories of the follow ing composition are manufactured:

[1238] ingredient mg / supp.

[1239] Compound of formula I 15

[1240] Suppository' mass 1285

[1241]

[1242] Total 1300

[1243] Table 17: possible suppository compositionManufacturing Procedure

[1244] The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45°C. Thereupon, the finely powdered compound of formula I is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool; the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

[1245] Example D

[1246] Injection solutions of the following composition are manufactured:

[1247] ingredient mg / inj ection solution.

[1248] Compound of formula I 3

[1249] Polyethylene Glycol 400 150

[1250] acetic acid q.s. ad pH 5.0

[1251]

[1252] water for injection solutions ad 1.0 mL

[1253] Table 18: possible injection solution composition

[1254] Manufacturing Procedure

[1255] The compound of formula I is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 mL by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

[1256] Example E

[1257] Sachets of the following composition are manufactured:

[1258] ingredient mg / sachet Compound of formula I 50

[1259] Lactose, fine powder 1015

[1260] Microcrystalline cellulose (AVICEL PH 102) 1400

[1261] Sodium carboxymethyl cellulose 14

[1262] Polyvinylpvrrolidon K 30 10

[1263] Magnesium stearate 10

[1264] Flavoring additives 1

[1265]

[1266] Total 2500

[1267] Table 19: possible sachet composition

[1268] Manufacturing ProcedureThe 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.

[1269] Experimental Part

[1270] The 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.

[1271] 1A. L. Croxford et al., Cytokine Growth Factor Rev., 25 (4) (2014), pp. 415-421

[1272] 2Compendium of Chemical Terminology, 2nd, A. D. McNaught and A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).

[1273] 3Biochem. Pharmacol. (1973) 22:3099

[1274] 4WO2023283610

[1275] 5WO2023019166

[1276] 6WO2018237026

[1277] 7WO2022032026

[1278] 8WO2023059792

Claims

CLAIMS1. A compound of formula I or a pharmaceutically acceptable salt thereofT-L-B I,whereinis a targeting ligand selected from the group consisting ofa is -C(Ci.3-alkyl. F, F), -C(heterocyclyl, OCH3), -C(heterocydyLF), -heterocycIyL -C(C?.V- cydoalkyl, Hl -C(C3u-cydoaikyl, OCH<), -C(C^-cycloa11yl substituted by i-2 halogen, H), - SCbO fe, -C((CH3)2, OCH3) or -C(CH3)2OH, a' is C1-3-alkyl, -O-C1-3-alkyl, -O-C3-6-cycloalkyl or C3-6-cycloalkyl,a” is Cx-3-alkyI, ~O~C.3~aIky! or halogen,b is N or CH,c is H, -CO-C1-3-alkyl, -CO-C3-6-cycloalkyl,heterocyclyl or -Ci-3-alkyl, andd is absent or selected from the group consisting of -O-heterocyclyl, C4-6-cycloalkenylcycloalkyl, aryl, aryl substituted by 1-2 halogen, heteroaryl and heteroaryl substituted by 1-2 halogen,e is absent, -(CH2)1-3-, -CO-, -N(CH3)-, -N(CH3)-CO-(CH2)1-8-CO-, -N(CH3)-CO-, -N(CH3)-CO-(CH2)1-2, -N(CH3)-(CH2)1-2, -N(CH3)-CO-(CH2)1-2-heterocyclyl-, -N(CH3)-SO2-(CH2)1-2, -C3-6-cycloalkyl, heteroaryl, optionally substituted by =O, heteroaryl-heterocyclyl, -O- or heteroaryl-heteroaryl,L is a linker selected from the group consisting ofwhereinLI is absent or selected from the group consistingof -CO-(CH2)1-3-, -(CH2)1-3-CO-, -N-(CH2)1-9-CO-, -CO-(CH2)1-8-CO-, -(CH2)0-1-heterocyclyl,heterocyclyl-(CH2)0-1-, -heterocyclyl-(CH2)1-2-O-(CH2)1-2-, -C3-6-cycloalkyl-(CH2)0-1-, -aryl-(CH2)0-1-, -(CH2)0-1-aryl-, heteroaryl-(CH2)0-1- and -(CH2)0-1-heteroaryl-,11 is CH orN,l) -CO-(CH2)0-2-,m)L2 is selected from the group consisting of a bond, -(CH2)1-2-, -CO-, -O- and -(CH2)0-2-CO-(CH2)1-2-,l3 is selected from the group consisting of CH and N,l4 is absent, or -CO-., whereinL3 is absent or is selected from the group consisting of -(CH2)1-2-, -CO-, -O-, and -(CH2)1-2-CO-(CH2)1-2-,L4 is absent, -C3-6-cycloalkyl or heterocyclyl,L5 is absent or is selected from the group consisting of -(CH2)I-2-,(-CO-, and -(CH2)1-2-CO-(CH2)1-2-,l5 is -CH- or -N-,l6 is -O-, -CF2-, or -CH2-,L6 is absent,-(CH2)1-2-, -O-, -C3-6-cycloalkyl or -(CH2)0-2-heterocyclyl, optionally substituted by halogen,p), wherein L7 is selected from the group consisting of -(CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-, andq), wherein L8 is selected from the group consisting of -(CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-, andBB is a CRBN binder selected from the group consisting ofwherein e is selected from the group consisting of a -(CH2)0-1-heteroaryl, optionally substituted by C1-3-alkyl, halogen or =O and -(CH2)0-1-aryl, optionally substituted by halogen or -O-C1-3-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 ofand T, wherein a is –C(C1-3-alkyl,F,F) or –C(heterocyclyl,OCH3),a' is (’i.'s-alky Lb is N or CH,c is -CO-Ci-3-alkyl,d is absent or selected from the group consisting of C3-6-cycloalkyl, -O-heterocyclyl, C4-6-cycloalkenyl, or heteroaryl,e is absent or-CO-. andL is a linker selected from the group consisting ofd)TorT, whereinLI is absent or selected from the group consisting ofaryl- (CH2)O-I- or -C?.^cycloalkyL(CH2J< M-.11 is CH orN,12 is CH orN,e)whereinL2 is a bond or -(CH2)I-2-,l3 is selected from the group consisting of CH and N,14 is absent or15 is -CH-,16 is -CH2-,L6 is absent, or-(CH2)o->"heterocyclyl, optionally substituted by halogen, and B is a CRBN binderwherein e is selected from the group consisting of aheteroaryl, optionally substituted by Ci-3-alkyl, halogen or -(CH2)0-1aryl, optionally substituted by halogen or -O-Ci-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 ofand T, whereina is -C(C‘,..3-afks 4, F. F) or -C(heterocyclyl, OCH3),a' isb is N or CH,c is -CO-Ci-3-alkyl,d is absent or selected from the group consisting of C3-6-cycloalkyl, -O–heterocyclyl, C4-6-cycloalkenyl, or heteroaryl,e is absent or-CO- 4. A compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof whereinT is a targeting ligand selected from the group consisting ofand T, wherein a is –C(CH3,F,F) or –C(heterocyclyl,OCH3),a' is C1-3-alkyl,b is N or CH,c is -CO- CH3,d is absent or selected from the group consisting of -O–pyrrolidyl, cyclohexyl, cyclohexenyl, or 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,e is absent or-CO-.

5. A compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof wherein T is a targeting ligandT, whereina is –C(C1-3-alkyl,F,F),a’ Cra-alkykb is CH,c is -CO-Ci-3-alkyl,d is heteroaryl, ande is -CO-.

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 ofLwherein means the site of the targeting ligand T attached to L.A compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereofmeans the site attached to L.

8. A compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof wherein B is a CRBN binderwherein e is selected from the group consisting of a -(CH2)0-1-heteroaryl, optionally substituted by C1-3-alkyl, halogen or =O and -aryl, optionally substituted by halogen or -O-Ci-3-alkyl.

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 ofandwherein e is selected from the group consisting of a 2,3-dihydro-1H-benzimidazolyl, optionally substituted by CH3, F or =O and, optionally substituted by F or -O-CH3.

10. A compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof wherein B is a CRBN binderwherein e is selected from the group consisting of a heteroaryl, optionally substituted by C1-3-alkyl and -(CH2)0-1aryl, optionally substituted by halogen.

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 ofCRBN binder B attached 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 ofthe CRBN binder B attached to L.

13. A compound according to any one of claims 1-12 or a pharmaceutically acceptable saltLmeans the site attached to14. A compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting ofL is a linker selected from the group consisting ofLI is absent or selected from the group consisting ofaryl-(CH2)0-1- or -C3-6-cycloalkyl-(CH2)0-1-11 is CH orN,12 is CH orN,L2 is a bond or -(CH2)I-2-,l3 is selected from the group consisting of CH and N,14 is absent or and15 is -CH-,l6 is -CH2-,L6 is absent,; 2- or’fCHzKs-heterocyclyl, optionally substituted by halogen15. A compound according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting ofwhereinL1 is -C3-6-cycloalkyl-(CH2)0-1-,11 is N,12 is CH, andor, wherein15 is -CH-,16 is -CH2-,L6 is -(CH2)0-2-heterocyclyl, optionally substituted by halogen.

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 of5•Nv B 'and, wherein means the site attachedTo the CRBN binder B and means the site attached to the targeting ligand T.

17. A compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting ofB Twherein means the site attached to the CRBN binder B and means the site attached to the targeting ligand T.

18. A compound according to any one of claims 1-17 or a pharmaceutically acceptable saltthereof wherein L is wherein means the site attached toTthe CRBN binder B and means the site attached to the targeting ligand T.

19. A compound according to any one of claims 1-18 or a pharmaceutically acceptable salt thereof whereinT is a targeting ligand selected from the group consisting ofand T, wherein a is –C(C1-3-alkyl,F,F) or –C(heterocyclyl,OCH3),a' is C1-3-alkyl,b is N or CH,c is -CO-Ci-3-alkyl,d is absent or selected from the group consisting of C3-6-cycloalkyl, -O-heterocyclyl, C4-6-cycloalkenyl, or heteroaryl,Le is absent or-CO-, wherein means the site of the targeting ligand T attached to L.L is a linker selected from the group consisting ofFFd)TorT, whereinLI is absent or selected from the group consistingof, or -C3-6-cycloalkyl-(CH2)0-1-,11 is CH orN,12 is CH orN,L2 is–(CH2)1-2-,l3 is selected from the group consisting of CH and N,14 is absent or and15 is -CH-,l6 is -CH2-,L6 is absent,or–(CH2)0-2-heterocyclyl, optionally substituted by halogen,B Twherein means the site attached to the CRBN binder B and means the site attached to the targeting ligand T, and B is a CRBN binder selected from the group consisting ofwherein e is selected from the group consisting of a 2,3-dihydro-1H-benzimidazolyl, optionally substituted by CH3, F or =O and, optionally substituted by F or -O-CH3.wherein means the site of the CRBN binder B attached to L.

20. A compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof whereinT is a targeting ligand T, wherein a is –C(C1-3-alkyl,F,F),a' is C1-3-alkyl,b is CH,c is -CO-Ci-3-alkyl,d is heteroaryl, andLe is -CO-, wherein means the site of the targeting ligand T attached to LB is a CRBN binder selected from the group consisting ofwherein e is selected from the group consisting of a heteroaryl, optionally substituted by C1-3-alkyl and aryl, optionally substituted by halogen.Lwherein means the site of the CRBN binder B attached to L, andL is a linker selected from the group consisting ofF12'I B' ^L1c), whereinL1 is -C3-6-cycloalkyl-(CH2)0-1-,11 is N,12 is CH, and15 is -CH-,16 is -CH2-,BL6 is–(CH2)0-2-heterocyclyl, optionally substituted by halogen, wherein means theTsite attached to the CRBN binder B and means the site attached to the targeting ligand T.

21. A compound of formula I according to any of claims 1-20, or a pharmaceutically acceptable salt thereof, T is a targeting ligand selected from the group consisting ofB is a CRBN binder selected from the group consisting ofTto the CRBN binder B and means the site attached to the targeting ligand T.

22. A compound of formula I according to any of claims 1-21, or a pharmaceutically acceptable salt thereof. T isLwherein means the site attached to L, B is selected from the group consisting ofLwherein means the site of the CRBN binder B attached to L, and 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 targeting ligand T.

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-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[10-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidylJ-10-oxo-decanoyl]pyrrolidin-3-ylJoxy-2-pyridyl] acetamide.N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]acetyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide, N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-6-oxo-hexanoyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]acetyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide, N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[1-[2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]-1-piperidyl]acetyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-( 1, 1 -difluoroethyl)-4-methylpy ridin-2-yl)amino)-5-(( 1 -(( 1 s,4s)-4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((ls,4s)-4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((6R)-2-(4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperi din-1 -yl)spiro[3.4]octane-6-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((2s,4s)-2-(4-(4-((2,6-dioxopiperidin-3-y l)amino)-2,6-difluorophenyl)-3,3-difluoropiperi din-1 -yl)spiro[3.4]octane-6-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,1 -difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l -(8-(l -(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)-8-azaspiro[4.5]decan-2-yl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[10-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-10-oxo-decanoyl]pyrrolidin-3-yl]oxy-2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[10-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-l-piperidyl]-10-oxo-decanoyl]pyrrolidin-3-yl]oxy-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,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[6-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-6-oxo-hexanoyl]pyrrolidin-3-yl]oxy-2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino] -2,6-difluoro-pheny l]piperazin- 1 -y 1] acetyl] py rrolidin-3-yl] oxy-2-py ridyl] 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-carbony 1] cy clohexyl] -2-pyri dyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[10-[4-[4-[(2,6-dioxo-3-piperidyl)amino] phenyl]-! -piperidyl]- 10-oxo-decanoyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide, N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,3-difluoro-l-piperidyl]methyl]cyclohexanecarbonyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[7-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-l-piperidyl]-7-oxo-heptanoyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide, N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[8-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-8-azaspiro[4.5]decane-3-carbonyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[8-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-8-azaspiro[4.5]decane-3-carbonyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide,N-[5-[l-[[3-[3-(2,6-dioxo-3-piperidyl)-5-fluoro-l-methyl-indazol-6-yl]-3-azaspiro[5.5]undecan-9-yl]methyl]pyrrolidin-3-yl]oxy-4-[[6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-2-py ridyl] amino] -2-pyri dyl] acetamide,N-[5-[1-[[3-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-3-azaspiro[5.5]undecan-9-yl]methyl]pyrrolidin-3-yl]oxy-4-[[6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,N-[5-[l-[l-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-4-piperidyl]pyrrolidin-3-yl]oxy-4-[[6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,{N}-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[(3~{R})-l-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]cyclohexanecarbonyl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]ethyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[l-[[3-[4-[(2,6-dioxo-3-piperidyl)amino]-2.6-difluoro-phenyl]-3-azaspiro[5.5]undecan-9-yl]methyl]pyrrolidin-3-yl]oxy-2-py ridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[3-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undecane-9-carbonyl]pyrrolidin-3-yl]oxy-2-pyridy 1] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[l-[3-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3-azaspiro[5.5]undecan-9-yl]pyrrolidin-3-yl]oxy-2-pyridyl]acetamide, N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(7-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidine-4-carbonyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-2-yl)pyridin-2-yl)acetamide,6-acetamido-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-N-(6-(4-(l-(2,6-dioxopiperi din-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-6-oxohexyl)ni cotinamide,N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-(4-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)cyclohex-l-en-l-yl)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(8-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-8-azaspiro[4.5]decane-2-carbonyl)pyrrolidin-3-yl)oxy)pyri din-2-yl)acetamide,N-(4-((6-(l,1 -difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l -(1 -(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperidine-4-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide, N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperidin-4-yl)methyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((l-(3-(2,6-dioxopiperidin-3-yl)- 1-methyl-lH-indazol-6-yl)piperidin-4-yl)methyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide, N-(4-((6-( 1, 1 -difluoroethy l)-4-methylpy ridin-2-yl)amino)-5-(((3 S)- 1 -(( 1 s,4R)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,3r)-3-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclobutane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(3-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-3-azaspiro[5.5]undecane-9-carbonyl)pyrrolidin-3-yl)oxy)pyridin- 2-yl)acetamide,N-(4-((6-( 1, 1 -difluoroethyl)-4-methylpyridin-2-yl)arnino)-5-(((3R)- 1 -((lr,4R)-4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(((3S)-l-((lr,4S)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(((3R)-l-((ls,4S)-4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)benzoyl)pyrrolidin-3-yl)oxy)pyri din-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(4-(4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyri din-2 -yl)acetamide.N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((ls,4s)-4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide, andN-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-(2-(l-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)-2-azaspiro[3.4]octan-6-yl)pyrrolidin-3-yl)oxy)pyri din-2 -yl)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-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(3-(2,6-di oxopiperi din-3 -yl)- 1 -methyl-lH-indazol-7-yl)piperazin- 1 -yl)methyl)cyclohexane-l -carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((ls,4s)-4-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperi din-1 -yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((lr,4r)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide,N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((ls,4s)-4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)cyclohexane-l-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)acetamide, andN-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((l-((6R)-2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-3,3-difluoropiperidin-l-yl)spiro[3.4]octane-6-carbonyl)pyrrolidin-3-yl)oxy)pyridin-2-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 (I’)Owherein X is H or C1-3alkyl and Y is H or halogen.

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-Goutières 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 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-Goutières 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-Goutières 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 and wherein the method comprises administering a therapeutically effective amount of acompound according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof, to the subject.

34. A method of preventing or treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is inflammatory bowel disease 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.

35. The invention as hereinbefore described.

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