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 autoin fl ammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease. Aicardi-Goiuteieres syndrome (AGS). Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity' and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

Description

[0001] Case P60974

[0002] DEGRADERS

[0003] Background Art

[0004] The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is responsible for transmitting signals from cytokines and growth factors. Tyrosine kinase 2 (TYK2) is a part of this pathway and was the first identified member of the JAK family. TYK2 controls the phosphorylation of STAT proteins, leading to the activation of STAT-dependent transcription. It mediates the downstream signaling of cytokine receptors for p40-containing cytokines such as IL-12 and IL-23, as well as type I interferons like 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-infl ammatoiy proteins like ty rosine 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 pathw ay 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 w ell 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 / 14.01.2025The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0011] T-L-B I

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

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

[0014] Detailed Description 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. IH-benzoimidazolyl, benzooxazinyl. benzoxazolyl. benzothiazinyl. benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, IH-indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), IH-pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl, 6,7-dihydro-5H-[l]pyrindinyl, l,3-dihydrobenzimidazol-2-one, 3 / / - 1,3-benzo\azol-2-one and the like. Particular "heteroaryl" are pyridinyl, oxazolyl and pyrazinyl. Specific "heteroaryl" are 2,3-dihydro-IH-benzimidazolyl. IH-indazolyl. indolinyl, 2,3-dihydro-l,3-benzoxazolyl, 1H-pyrazolo[3,4-b]pyridyl, IH-pyrazolo|4.5-c|pyridyl or 1,2,3,4-tetrahydroquinoxalyl, pyrimidinyl, benzimidazol-5-yl, 6, 8-dihydro-5H-imidazo[ 1,2-a] pyrazinyl, pyrazolo[l,5-a]pyridinyl, indazolyl, indolyl, IH-indazolyl, benzoxazolyl, pyridinyl, l,3-dihydrobenzimidazol-2-one, 377-1,3-benzoxazol-2-one.

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

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

[0021] The term “heterocyclyl”, alone or in combination with other groups, refers to a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 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|5.5Jundecanyl, 8-aza-bicyclo|3.2.1]octyl, 2,7-diazaspiro|3.5Jnonyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1] octyl, 9-aza-bicyclo[3.3.1]nonyl. 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. Particular heterocyclyl are “5-membered heterocyclyl” having 5 ring atoms. Specific heterocyclyl are 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, l,2,3,3rz,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 ‘A (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-Ci-3-alkyl, -CO-C3-6-cycloalkyl, heterocyclyl or -Ci-3-alkyl, and

[0051] d is heteroaryl,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)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] LI is absent or selected from the group consisting of -CO-CH2-, -N-(CH2)I-5-CO-, -CO- (CH2)I-8-CO-, -heteroaryl-(CH2)o-i- and -(CH2)o-i-heteroaryl-,

[0055] l1 is CH or N,

[0056] l2 is CH or N,

[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)I-8-CO-, -N(CH3)-CO- (CH2)I-2, -N(CH3)-(CH2)I-2, -N(CH3)-CO-(CH2)i-2-7-membered N-heterocyclyl-, 5- membered heteroaryl, or -N(CH3)-SO2-(CH2)I-2,

[0092]

[0093] b), wherein

[0094] t1 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(CH3FF) 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)1-8-CO-, -N(CH3)-CO- (CH2)I-2. -N(CH3)-(CH2)I-2, -N(CH3)-SO2-(CH2)I-2. oxazolyl. or -N(CH3)-CO-(CH2)I.2 -N> CN4-

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

[0131]

[0132] wherein C2 is a aryl, optionally substituted by halogen or -O-Ci-s-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)I-5-CO-, -CO-(CH2)I-8-CO-. and -heteroaryl-(CH2)0-i-,

[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. 11 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. 13 is -CH- or -N-,

[0162] b. 14 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)I-5-CO-, -CO-(CH2)I-8-CO-, and -heteroaryl-(CH2)o-i-, 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 1-16 wherein T is

[0193]

[0194] T, wherein

[0195] a is -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 -C1-3-alkyl, and

[0197] d is heteroaryl -O-heterocyclyl,

[0198] e is absent, Ci-3-alkyl, -N(CH3)-, -N(CH3)-CO-(CH2)1-8-CO-, -N(CH3)-CO-(CH2)I.2, -N(CH3)-(CH2)I-2, -N(CH3)-CO-(CH2)i-2-heterocyclyl- or -N(CH3)-SO2-(CH2)I-2, -C3-6-cycloalkyl, heteroaryl, optionally substituted by =0, heteroaryl-heterocyclyl, or heteroarylheteroaryl,

[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-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-methyl-4-oxo-butanamide,

[0201] N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-methyl-10-oxo-decanamide,

[0202] N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-methyl-6-oxo-hexanamide,

[0203] N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-methyl-4-oxo-butanamide,

[0204] N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-methyl-6-oxo-hexanamide,N-[5-[6-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]piperidine-1-carbonyl]-2-pyridyl]-4-[[6-(1-methoxy-1-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide.

[0205] N-(5-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)oxy)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

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

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

[0211] N-(6-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide.

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

[0213] N-(6-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)oxy)piperidine-1-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0214] N-(6-(2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0215] N-(6-(6-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(6-(6-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-4'-((6-(2-methoxypropan-2-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, 6'-acetamido-N-(6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-6-oxohexyl)-4'-((6-((S)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridine]-5-carboxamide,

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

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

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

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

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

[0221] N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]-N-methyl-acetamide,

[0222] N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-methyl-acetamide,

[0223] N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-1-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)-N-methylpiperidine-4-carboxamide,

[0224] (1r,4r)-N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)-N-methylcyclohexane-1-carboxamide,

[0225] (1r,4r)-N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-4-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)phenyl)-N-methylcyclohexane-1-carboxamide,

[0226] N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenoxy)-N-methylacetamide,

[0227] N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-3-(2,6-dioxopiperidin-3-yl)-N,1-dimethyl-1H-indazole-7-carboxamide,

[0228] N-(6'-acetamido-4'-((2-(1,1-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-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-N-methyl-6-oxohexanamide,

[0230] N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl-methyl-amino]-2-pyridyl]-2-pyridyl]acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[6-t[l-tl-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-ylJ-4-piperidyl]methylJ-2.6-diazaspiro[3.3]heptan-2-yl]-N-methyl-acetamide,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0257] N-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4-(4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-l-yl)methyl)piperidine-l-carbonyl)cyclohexyl)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-(l, 1 -difluoroethyl)pyrimidin-4-yl)amino)-5-(4-(4-(3-(2,6-dioxopiperidin-3-yl)- 1 - methyl-lH-indazol-7-yl)piperidin-l-yl)oxazol-2-yl)-|2,3'-bipyridinJ-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 type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury’, glutamate neurotoxicity’ and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

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

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

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

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

[0272] T-L-B I,

[0273] wherein

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

[0275]

[0276]

[0277] a is -C(Ci-3-alkyl FF), -C(heterocyclyl, OCH3), -C(heterocyclyl, F), -heterocyclyl, -C(C3-6-cycloalkyl, H), -C(C3-6-cycloalkyl, OCH3), -C(C3-6-cycloalkyl substituted by 1-2 halogen, H), -SO2CH3, -C((CH3)2, OCH3) or-C(CH3)2OH,

[0278] a' is Ci-3-alkyl, -O-Ci-3-alkyl, -O-C3-6-cycloalkyl or C3-6-cycloalkyl, and when attached to L, a' is absent or -O-,

[0279] a” is Ci-3-alkyl, -O-Ci.3-alkyl or halogen,

[0280] b is N or CH.

[0281] c is H, -CO-Ci.3-alkyl, -CO-C3.6-cycloalkyl, -CO-N(H, CH3), -CO-NH2, SO2-Ci-3-alkyl, heterocyclyl or -Ci.3-alkyl, and

[0282] d is selected from the group consisting of C3-6-cycloalkyl, aryl, aryl substituted by 1-2 halogen, heteroaryl and heteroaryl substituted by 1 -2 halogen,

[0283] 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, -O- or heteroarylheteroaryl,

[0284] L is a linker selected from the group consisting of

[0285]

[0286] wherein

[0287] 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-, -(CH₂)₁₋₈-, -(CH₂)₁₋₈-CO-, -(CH2)o-i-heterocyclyl, heterocyclyl-(CH2)o-i -heterocyclyl-(CH2)i-2-O-(CH2)i-2-, -hcteroaryl-iCFLjo-i- and - (CH2)o-i-heteroaryl-,

[0288] l1 is CH or N,

[0289] l2 is CH or N,

[0290] . B

[0291]

[0292] b)

[0293]

[0294] T B

[0295] c) -CO-(CH2)O-2-.

[0296]

[0297] L2 is selected from the group consisting of a bond, -(CH2)I-2-, -CO-, -O- and -(CH2)O-2- CO-(CH2)I-2-,

[0298] l3 is selected from the group consisting of CH and N,

[0299] 14 is absent, -CH2N(H, CH3)-, -(CH2)I-2- or -CO-,

[0300]

[0301] , wherein

[0302] L3 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-, -O-, and - (CH2)I-2-CO-(CH2)I-2-,L4 is absent, -Ca-e-cycloalkyl or heterocyclyl.

[0303] L5 is absent or is selected from the group consisting of -(CH2)I-2-, CH2N(H, CH3)-, heterocyclyl-CO-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-,

[0304]

[0305] , wherein l5 is -CH- or -N-,

[0306] 16 is -O-, -CF2-, or -CH2-,

[0307] L6 is absent, -(CH2)I-2-, -O-, -Cs-e-cycloalkyl or -(CH2)o-2-heterocyclyl, optionally substituted by halogen,

[0308] g). wherein L7 is selected from the group consisting of - (CH2)I-2-. -CO-, and -(CH2)I.2-CO-(CH2)I-2-. and

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

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

[0313]

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

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

[0316]

[0317] and T, wherein a is -C(Ci-3-alkyl. F. F), -C(heterocyclyl, OCH3), -heterocyclyl or -C((CHs)2, OCH3)

[0318] a’ is Ci-3-alkyl,

[0319] b is N or CH,

[0320] c is -CO-Ci-3-alkyl, -CO-C3-6-cycloalkyl, -CO-N(H, CH3) or SO2-Ci-3-alkyl,

[0321] d is heteroaryl, and

[0322] e is absent, -(CH2)1-3-, -N(CH3)-, -N(CH3)-CO- or -O-,

[0323] L is a linker selected from the group consisting of

[0324]

[0325] wherein

[0326] LI is absent or selected from the group consisting of -(CH2)1-3-CO-, -(CH2)I-S-, -(CH2)I-S- C0-, -heterocyclyl-(CH2)i-2 and -heterocyclyl-(CH2)i-2-O-(CH2)i-2-.

[0327] l1 is CH or N,

[0328] l2 is CH or N,

[0329]

[0330]

[0331] L2 is selected from the group consisting of –(CH2)1-2–, –CO–, –O– and –(CH2)0-2–CO–(CH2)1-2–,

[0332] l3 is selected from the group consisting of CH and N,

[0333] l4 is absent, –CH2N(H,CH3)-, or –(CH2)1-2-,

[0334] -4— L5-L4— L3- / ^\l4- T ■ '

[0335] d

[0336]

[0337] )0-1 B, wherein

[0338] L3 is absent or is selected from the group consisting of–(CH2)1-2–, –CO– and –O–, L4 is absent or heterocyclyl,

[0339] L5 is absent or is selected from the group consisting of CH2N(H, CH3)- and heterocyclyl- CO-,

[0340]

[0341] , wherein l5 is -CH- or -N-,

[0342] l6 is -O-, -CF2-, or -CH2-,

[0343] L6 is absent, -(CH2)I-2-, -O-, -C3-6-cycloalkyl or -(CH2)o-2-heterocyclyl, optionally substituted by halogen, and

[0344]

[0345] f), wherein L9 is selected from the group consisting of -(CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-, and

[0346] B is a CRBN binder selected from the group consisting of

[0347]

[0348] wherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by C1-3-alkyl, halogen or =O and -(CH2)0-1aryl, optionally substituted by halogen or -O-C1-3-alkyl.

[0349] Aspect 3 is a compound according to any one of aspects 1-2 or a pharmaceutically acceptable salt thereof wherein

[0350] T is a target ligand selected from the group consisting of

[0351]

[0352] and T, wherein a is –C(C1-3-alkyl,F,F), –C(heterocyclyl,OCH3), –heterocyclyl or –C((CH3)2,OCH3)

[0353] a’ is Ci-3-alkyl,

[0354] b is N or CH,

[0355] c is -CO-Ci-3-alkyl, -CO-C3-6-cycloalkyl, -C0-N(H, CH3) or SO2-Ci-3-alkyl,

[0356] d is heteroaryl, and

[0357] e is absent, -(CH2)1-3-, -N(CH3)-, -N(CH3)-CO- or -O-.

[0358] Aspect 4 is a compound according to any one of aspects 1-3 or a pharmaceutically acceptable salt thereof wherein T is a target ligand

[0359]

[0360] T, wherein a is –C(C1-3-alkyl,F,F) or –C(heterocyclyl,OCH3),

[0361] a’ is Ci-3-alkyl.

[0362] b is N or CH,

[0363] c is -CO-Ci-3-alkyl,

[0364] d is heteroaryl, and

[0365] e is absent, -(CH2)1-3-, -N(CH3)-CO- or -O-.

[0366] Aspect 5 is a compound according to any one of aspects 1-4 or a pharmaceutically acceptable salt thereof wherein T is selected from the group consisting of

[0367]

[0368]

[0369]

[0370] 

[0371]

[0372] L

[0373] wherein means the site of the target ligand T attached to L.

[0374] 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

[0375]

[0376] L wherein means the site of the target ligand T attached to L.

[0377] Aspect 7 is a compound according to any one of aspects 1-6 or a pharmaceutically acceptable salt thereof wherein T is selected from the group consisting of

[0378]

[0379] means the site attached to L.

[0380] Aspect 8 is a compound according to any one of aspects 1-7 or a pharmaceutically acceptable

[0381]

[0382]

[0383] salt thereof wherein T is wherein means the site attached to L.

[0384] 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

[0385]

[0386] wherein e is selected from the group consisting of a heteroaryl, optionally substituted by C1-3-alkyl, halogen or =O and -(CH2)0-1aryl, optionally substituted by halogen or -O-C1-3-alkyl.

[0387] Aspect 10 is a compound according to any one of aspects 1-9 or a pharmaceutically acceptable salt thereof wherein B is a CRBN binder selected from the group consisting of

[0388]

[0389] wherein e is selected from 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, each optionally substituted by CH3, F or =O and phenyl, optionally substituted by F or -O-CH3.

[0390] Aspect 11 is a compound according to any one of aspects 1-10 or a pharmaceutically acceptable salt thereof wherein B is a CRBN binder

[0391]

[0392] wherein e is selected from the group consisting of a heteroaryl, optionally substituted by C1-3-alkyl and -(CH2)0-1aryl, optionally substituted by halogen.

[0393] Aspect 12 is a compound according to any one of aspects 1-11 or a pharmaceutically acceptable salt thereof wherein B is a CRBN binder selected from the group consisting of

[0394]

[0395] wherein e is selected from 1H-indazolyl, optionally substituted by CH3and phenyl, optionally substituted by 2 F.

[0396] Aspect 13 is a compound according to any one of aspects 1-12 or a pharmaceutically acceptable salt thereof wherein B is selected from the group consisting of

[0397]

[0398]

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

[0400] Aspect 14 is a compound according to any one of aspects 1-13 or a pharmaceutically acceptable salt thereof wherein B is selected from the group consisting of

[0401] and

[0402] L

[0403]

[0404] means the site of the CRBN binder B attached to L.

[0405] Aspect 15 is a compound according to any one of aspects 1-14 or a pharmaceutically acceptable

[0406]

[0407]

[0408]

[0409] salt thereof wherein B is and wherein means the site attached to L.

[0410] 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 ofL is a linker selected from the group consisting of

[0411]

[0412] wherein

[0413] LI is absent or selected from the group consisting of -(CH2)1-3-CO-, -(CH2)I-S-, -(CH2)1-8-CO-, -heterocyclyl-(CH2)1-2and -heterocyclyl-(CH2)1-2-O-(CH2)1-2-,

[0414] l1 is CH or N,

[0415] l2 is CH or N,

[0416] . B

[0417] b)

[0418]

[0419]

[0420] L2 is selected from the group consisting of -(CH2)I-2-, -CO-, -O- and -(CH2)o-2-CO- (CH2)l-2-,

[0421] l3 is selected from the group consisting of CH and N,

[0422] 14 is absent, -CH2N(H, CH3)-, or-(CH2)i-2-,

[0423] -i— L5-L4— L3-Z^N-i- T ■ ■

[0424] d

[0425]

[0426] )0-1 B, wherein

[0427] L3 is absent or is selected from the group consisting of -(CH2)I-2-, -CO- and -O-, L4 is absent or heterocyclyl,

[0428] L5 is absent or is selected from the group consisting of CH2N(H, CH3)- and heterocyclyl- CO-,

[0429]

[0430] l5 is -CH- or -N-,

[0431] l6 is -O-, -CF2-, or -CH2-,

[0432] L6 is absent, -(CH2)I-2-, -O-, -C3-6-cycloalkyl or -(CH2)o-2-heterocyclyl, optionally substituted by halogen, and

[0433]

[0434] , wherein L9 is selected from the group consisting of -(CH2)I-2-, - CO-, and -(CH2)I-2-CO-(CH2)I-2-.

[0435] 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

[0436] a

[0437]

[0438] ) wherein

[0439] LI is absent or selected from the group consisting of -(CH2)I-8- and -heterocyclyl-(CH2)i-2, l1 is CH or N,

[0440] l2 is CH or N,

[0441] b

[0442]

[0443] ), whereinL2 is-(CH2)i-2-,

[0444] 13 is N,

[0445] 14 is-(CH2)i-2-,

[0446] -4— L5-L4— L3- / ^\l4- T ■ ■

[0447] c

[0448]

[0449] )0-1 B, wherein

[0450] L3 IS-(CH2)I-2-,

[0451] L4 is heterocyclyl,

[0452] L5 is heterocyclyl-CO-,

[0453]

[0454] l5 is -CH- or -N-,

[0455] 16 is -CH2-.

[0456] L6 is-(CH2)i-2- or -(CH2)o-2-heterocyclyl.

[0457] Aspect 18 is a compound according to any one of aspects 1-17 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting of

[0458]

[0459] o o

[0460]

[0461]

[0462]

[0463]

[0464] 

[0465]

[0466]

[0467] T

[0468] site attached to the CRBN binder B and means the site attached to the target ligand T. Aspect 19 is a compound according to any one of aspects 1-18 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting of

[0469]

[0470] B T

[0471]

[0472]

[0473]

[0474] o

[0475]

[0476] andwherein means the site attached to the CRBN binder B

[0477]

[0478] T

[0479] and means the site attached to the target ligand T.

[0480] Aspect 20 is a compound according to any one of aspects 1-19 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting of

[0481]

[0482] attached to the target ligand T.Aspect 21 is a compound according to any one of aspects 1-20 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting of

[0483]

[0484] T

[0485] site attached to the CRBN binder B and means the site attached to the target ligand T. Aspect 22 is a compound according to any one of aspects 1-21 or a pharmaceutically acceptable

[0486]

[0487] T

[0488] attached to the CRBN binder B and means the site attached to the target ligand T.

[0489] Aspect 23 is a compound according to any one of aspects 1-22 or a pharmaceutically acceptable salt thereof wherein Tis a target ligand selected from the group consisting of

[0490]

[0491] and T, wherein a is –C(C1-3-alkyl,F,F), –C(heterocyclyl,OCH3), –heterocyclyl or –C((CH3)2,OCH3)a’ is Ci-3-alkyl,

[0492] b is N or CH,

[0493] c is -CO-C1-3-alkyl, -CO-C3-6-cycloalkyl, -CO-N(H, CH3) or SO2-C1-3-alkyl,

[0494] d is heteroaryl, and

[0495] e is absent, -(CH2)1-3-, -N(CH3)-, -N(CH3)-CO- or -O-,

[0496]

[0497] wherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by C1-3-alkyl, halogen or =O and -(CH2)0-1aryl, optionally substituted by halogen or -O-C1-3-alkyl, and

[0498] L is a linker selected from the group consisting of

[0499]

[0500] wherein

[0501] L1 is absent or selected from the group consisting of -(CH2)1-3-CO-, -(CH2)1-8-, -(CH2)1-8-CO-, -heterocyclyl-(CH2)1-2 and -heterocyclyl-(CH2)1-2-O-(CH2)1-2-.

[0502] l1 is CH or N,

[0503] l2 is CH or N,

[0504]

[0505]

[0506] L2 is selected from the group consisting of –(CH2)1-2–, –CO–, –O– and –(CH2)0-2–CO–(CH2)1-2–,

[0507] l3 is selected from the group consisting of CH and N,

[0508] l4 is absent, –CH2N(H,CH3)-, or –(CH2)1-2-,

[0509] -4— L5-L4— L3- / ^\l4- T ■ '

[0510] d

[0511]

[0512] )0-1 B, wherein

[0513] L3 is absent or is selected from the group consisting of–(CH2)1-2–, –CO– and –O–, L4 is absent or heterocyclyl,

[0514] L5 is absent or is selected from the group consisting of CH2N(H, CH3)- and heterocyclyl- CO-,

[0515]

[0516] , wherein l5 is -CH- or -N-,

[0517] l6 is -O-, -CF2-, or -CH2-,

[0518] L6 is absent, –(CH2)1-2–, –O–, –C3-6–cycloalkyl or –(CH2)0-2–heterocyclyl, optionally substituted by halogen, and

[0519]

[0520] , wherein L9 is selected from the group consisting of –(CH2)1-2–, –CO–, and –(CH2)1-2–CO–(CH2)1-2–.

[0521] Aspect 24 is a compound according to any one of aspects 1-23 or a pharmaceutically acceptable salt thereof wherein Tis a target ligand selected from the group consisting of

[0522] a

[0523] H H N N

[0524]

[0525] and T, wherein a is -C(Ci-3-alkyl F F) or -C(heterocyclyl, OCH3),

[0526] a’ is Ci-3-alkyl.

[0527] b is N or CH,

[0528] c is -CO-Ci-3-alkyl,

[0529] d is heteroaryl,

[0530] e is absent, -(CH2)i-3-, -N(CH3)-C0- or -O-,

[0531] H

[0532]

[0533] wherein e is selected from the group consisting of a heteroaryl, optionally substituted by C1-3-alkyl and -(CH2)o-iaryl, optionally substituted by halogen, and

[0534] L is a linker selected from the group consisting of

[0535]

[0536] , wherein

[0537] L1 is absent or selected from the group consisting of –(CH2)1-8– and –heterocyclyl–(CH2)1-2,l1 is CH or N,

[0538] l2 is CH or N,

[0539] L2 is–(CH2)1-2–, l3 is N, l4 is–(CH2)1-2–,

[0540] wherein L3 is–(CH2)1-2–, L4 is heterocyclyl, L5 is heterocyclyl-CO–, and

[0541]

[0542]

[0543] . wherein

[0544] l5 is -CH- or -N-,

[0545] 16 is -CH2-,

[0546] L6 is-(CH2)1-2- or -(CH2)0-2-heterocyclyl.

[0547] Aspect 25 is a compound according to any one of aspects 1-24 or a pharmaceutically acceptable salt thereof wherein

[0548] T is a target ligand selected from the group consisting of

[0549]

[0550]

[0551]

[0552] 5 wherein means the site of the target ligand T attached to L.o o

[0553]

[0554] o O

[0555]

[0556]

[0557]

[0558]

[0559]

[0560] T

[0561] the site attached to the CRBN binder B and means the site attached to the target ligand T, and B is a CRBN binder selected from the group consisting of

[0562]

[0563]

[0564] the CRBN binder B attached to L.

[0565] Aspect 26 is a compound according to any one of aspects 1-25 or a pharmaceutically acceptable salt thereof wherein

[0566] T is a target ligand selected from the group consisting of

[0567]

[0568] L

[0569] wherein means the site of the target ligand T attached to L

[0570] B is a CRBN binder selected from the group consisting ofand

[0571] L

[0572]

[0573] means the site of the CRBN binder B attached to L. and

[0574] L is a linker binder selected from the group consisting of

[0575]

[0576] and

[0577] N • B wherein means the site attached to the CRBN binder B and

[0578]

[0579] means the site attached to the target ligand T.

[0580] Aspect 27 is a compound of formula I according to any of aspects 1-25, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

[0581] 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,

[0582] 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-y 1J - 1 -piperidyl] -N -methyl-6-oxo-hexanamide,

[0583] 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,

[0584] 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-4-yl)piperidin-l-yl)-N-methyl-4-oxobutanamide.

[0585] 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-4-yl]-l-piperidyl]-N-methyl-10-oxo-decanamide,N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-N-methylacetamide,

[0586] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]arnino]-5-[2-[[l-[l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl]acetamide,

[0587] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]morpholin-2-yl] -2 -pyridyl] -2-py ridy 1] acetamide,

[0588] N-(4-((6-(l, 1 -difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(2-((l -(1 '-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-[l,4'-bipiperidine]-4-carbonyl)piperidin-4-yl)oxy)pyrimidin-4-yl)pyridin-2-yl)acetamide,

[0589] N-(4-((6-( 1, 1 -difluoroethyl)-4-methylpy ridin-2-yl)amino)-5-(2-(( 1 -( 1 -(( 1 -(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)piperidine-4-carbonyl)pyrrolidin-3-yl)oxy)pyrimidin-4-yl)pyridin-2-yl)acetamide.

[0590] N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(2-((l-(l-((l-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)azetidine-3-carbonyl)piperidin-4-yl)oxy)pyrimidin-4-yl)pyridin-2-yl)acetamide,

[0591] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-3.9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[9-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-3-azaspiro[5.5]undecan-3-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[3-(2.6-dioxo-3-piperidyl)-l -methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[3-(2,6-dioxo-3-piperidyl)-l -methyl-indazol-7-yl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0592] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((8-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((8-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro- 1-methyl- lH-indazol-6-yl)-2, 8-diazaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((9-(3-(2,6-dioxopiperidin-3-yl)-l-methyl- lH-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0593] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(((3aR,6aR)-5-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0594] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((8-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro- l-methyl-lH-indazol-6-yl)-4.4-difluoro-2,8-diazaspiro[4.5]decan-2-yl)methyl)-[2, 3'-bipyridin]-6'-yl)acetamide,

[0595] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(((3aR,6aS)-5-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0596] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((9-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2, 3-dihydrobenzo[d]oxazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0597] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((8-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide

[0598] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-(((5s,8s)-8-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-lH-indazol-6-yl)-2-azaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0599] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-(((5r,8r)-8-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-lH-indazol-6-yl)-2-azaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0600] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((6-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide 5

[0601] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((9-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0602] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((8-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2, 3-dihydrobenzo[d]oxazol-6-yl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0603] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-3-azaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-3,9-diazaspiroL5.5]undecan-3-yl)methyl)-|2,3'-bipyridin]-6'-yl)acetamide,

[0604] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperazin-l-yl)ethyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0605] N-(5-((2-(l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperidin-4-yl)-2-azaspiro[3.4]octan-6-yl)oxy)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0606] N-(5-((2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0607] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((2-(l-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l -methyl- lH-indazol-6-yl)piperidin-4-yl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2, 3'-bipyridin]-6'-yl)acetamide,

[0608] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-3,3-difluoro-l-piperidyl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,

[0609] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl] acetamide.

[0610] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,

[0611] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]pyrrolidin-l-yl]methyl]-2-pyridyl]-2-pyridyl] acetamide,

[0612] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl] acetamide,

[0613] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl] acetamide.

[0614] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazine-l-carbonyl)piperidin-l-yl)methyl)-[2,3,-bipyridin]-6,-yl)acetamide,N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)oxy)piperidin-1-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0615] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-2-oxopiperazin-l-yl)methyl)piperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0616] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)-3,3-difluoropiperidin-1-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0617] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(r-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-[4,4'-bipiperidin]-l-yl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0618] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl] acetamide.

[0619] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((4-((4-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-lH-indazol-7-yl)piperazin-l-yl)methyl)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0620] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperazin-l-yl)methyl)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0621] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((4-((l-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-lH-indazol-6-yl)piperidin-4-yl)oxy)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0622] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((3-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-3-fluoroazetidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0623] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((4-((l-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-lH-indazol-7-yl)piperidin-4-yl)oxy)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0624] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperazin-l-yl)methyl)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0625] N-[5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]-2-pyridyl]-4-[(4-methyl-6-methylsulfonyl-2-pyridyl)amino]-2-pyridyl] acetamide.N-[5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]-1-piperidyl]methyl]-2-pyridyl]-4-[[6-methyl-2-(2-oxabicyclo[2.1.1]hexan-1-yl)pyrimidin-4-yl]amino]-2-pyridyl]acetamide,

[0626] N-(4'-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-((4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0627] N-(5-(((5r,8r)-8-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-2-azaspiro[4.5]decan-2-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0628] N-(5-((2-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0629] N-(5-((8-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l -methyl- lH-indazol-6-yl)-2, 8-diazaspiro[4.5]decan-2-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,

[0630] N-(5-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0631] N-(5-((9-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-3.9-diazaspiro[5.5]undecan-3-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0632] N-(5-((9-(3-(2,6-dioxopiperidin-3-yl)-l -methyl- lH-indazol-6-yl)-3-azaspiro[5.5]undecan-3-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0633] N-(5-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-3-azaspiro[5.5]undecan-3-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0634] N-(5-((4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-1-yl)methyl)-3,3-difluoropiperidin-1-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0635] N-(5-((4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-3.3-difluoropiperidin-l-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0636] N-(5-((4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperi din-1 -yl)methyl)-4'-((6-((R)-3-methoxytetrahy drofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,N-(5-((4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperazin-l-yl)methyl)-3,3-difluoropiperidin-l-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,

[0637] N-(5-((4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-3-fluoropiperidin-l-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,

[0638] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((ln4r)-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide,

[0639] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((ls,4s)-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide,

[0640] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((ln4r)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide formate,

[0641] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((1s,4s)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide,

[0642] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((lr,4r)-4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide formate,

[0643] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((ls,4s)-4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide formate,

[0644] N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]-4-piperidyl]oxy]-1-piperidyl]-N-methyl-acetamide,

[0645] N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-N-methylacetamide,

[0646] 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)oxy)phenyl)piperidin-l-yl)-N-methylacetamide,

[0647] N-(6'-acetamido-4'-((2-(1,1-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-1-yl)methyl)piperidin-1-yl)-N-methylacetamide,N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]-1-piperidyl]-N-methyl-acetamide,

[0648] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]-N-methyl-acetamide formate,

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

[0650] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,7-diazaspiro[3.4]octan-2-yl]-l-piperidyl] -N-methyl-acetamide,

[0651] 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)oxy)phenyl)piperidin-l-yl)methyl)piperidin-l-yl)-N-methylacetamide,

[0652] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[2-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]-2,7-diazaspiro[3.4]octan-7-yl]-N-methyl-acetamide,

[0653] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((5s,8s)-8-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)-2-azaspiro[4.5]decan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0654] N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((5r,8r)-8-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-2-azaspiro[4.5]decan-2-yl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0655] N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-4-fluoro- 1 -piperidyl] -2-pyridyl] -4-[ [6-[(3R)-3 -methoxy tetrahydrofur an-3 -yl] -4-methy 1-2-pyridyl] amino] -2-pyridyl] acetamide,

[0656] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-l-piperidyl]-2-pyridyl]-2-pyridyl] acetamide.

[0657] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)piperidin-l-yl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0658] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-[2,3'-bipyridin]-6'-yl)acetamide,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methoxy]-1-piperidyl]-2-pyridyl]-2-pyridyl]acetamide.

[0659] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]oxymethyl]-l-piperidyl]-2-pyridyl]-2-pyridyl] acetamide,

[0660] N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-1-piperidyl]methyl]-4-fluoro-1-piperidyl]-2-pyridyl]-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0661] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[(6S)-2-[l-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]-2,6-difluoro-phenyl]-4-piperidyl]-2-azaspiro[3.4]octan-6-yl]oxy]-2-pyridyl]-2-pyridyl] acetamide,

[0662] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[l-[3-(2.6-dioxo-3-piperidyl)-l -methyl-indazol-7-yl]-4-piperidyl]oxy]-2-pyridyl]-2-pyridyl]acetamide.

[0663] 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)oxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[[9-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undecan-3-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide,

[0664] N- [4-[[6-( 1, 1 -difluoroethyl)-4-methyl-2 -pyridyl] amino] -5- [5 -[ [9- [4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undecan-3-yl]methyl]-2-pyridyl]-2-py ridyl] acetamide,

[0665] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[[l-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-4-piperidyl]oxy]-2-pyridyl]-2-pyridyl]acetamide,

[0666] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]-2-pyridyl]-2-pyridyl] acetamide,

[0667] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[[3-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-py ridyl] acetamide.

[0668] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[[3-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-py ridyl] acetamide,

[0669] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[9-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.6]dodecan-3-yl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[1-[3-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]propanoyl]pyrrolidin-3-yl]oxypyrimidin-4-yl]-2-pyridyl]acetamide.

[0670] 5-[5-[[3-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecan-9-yl] methyl] -2 -pyridyl] -4- [ [6- [(3R)-3 -methoxy tetrahy drofuran-3 -y 1] -4-methyl-2-py ridy 1] amino] -N-methyl-pyridine-2-carboxamide,

[0671] N-[5-[5-[[7-[3-(2,6-dioxo-3-piperidyl)-5-fluoro-1-methyl-indazol-6-yl]-2,7-diazaspiro[3.5]nonan-2-yl]methyl]-2-pyridyl]-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0672] N-[5-[5-[[3-[3-(2,4-dioxohexahydropyrimidin-l-yl)-5-fluoro-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0673] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[l-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]oxy]-l-piperidyl]cyclopropyl]-2-pyridyl]-2-pyridyl] acetamide.

[0674] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[l-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]pyrrolidin-3-yl]-l-piperidyl]-2-pyridyl]-2 -pyridyl] acetamide,

[0675] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[l-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]pyrrolidin-3-yl]-l-piperidyl]-2-pyridyl]-2 -pyridyl] acetamide,

[0676] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[8-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-2,8-diazaspiro[4.5]decan-2-yl]-2-pyridyl]-2-pyridyl]acetamide,

[0677] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[3-[l-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-4-piperidyl]pyrrolidin-l-yl]-2-pyridyl]-2-pyridyl]acetamide,

[0678] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[8-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-4,4-difluoro-2,8-diazaspiro[4.5]decan-2-yl]methyl]-2-pyridyl]-2-pyridyl] acetamide,

[0679] N-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[6-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-3-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[8-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-l-oxa-8-azaspiro[4.5]decan-3-yl]oxy]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-4-piperidyl]oxy]-2-pyridyl]-2-pyridyl]acetamide,

[0680] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl]methanesulfonamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenylJ-3,3-difluoro-l-piperidylJmethylJ-l-piperidyl]-2-pyridyl]-2-pyridyl] acetamide,

[0681] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl] acetamide,

[0682] N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[3-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecan-9-yl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]morpholin-2-yl]-2-pyridyl]-2-pyridyl] acetamide,

[0683] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]-4-piperidyl]oxy]pyrimi din-4-yl] -2-pyridyl] acetamide.

[0684] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]-4-piperidyl]oxy]pyrimi din-4-yl] -2-pyridyl] acetamide,

[0685] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[8-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-8-azaspiro[4.5]decan-3-yl]morpholin-2-yl]-2-pyridyl]-2-pyridyl] acetamide.

[0686] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[8-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-8-azaspiro[4.5]decan-3-yl]piperazin-l-yl]-2-pyridyl]-2-pyridyl] acetamide,

[0687] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]acetyl]morpholin-2-yl]-2-pyridyl]-2-pyridyl] acetamide.

[0688] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[3-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-l-yl]propanoyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl] acetamide,

[0689] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]propanoyl]morpholin-2-yl]-2-pyridyl]-2-pyridyl] acetamide.

[0690] N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[1-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]propanoyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl]acetamide ,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[2-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,7-diazaspiro[3.5]nonan-7-yl]-2-pyridyl]-2-pyridyl]acetamide,

[0691] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]piperazin-l-yl]-2-pyridyl]-2-pyridyl] acetamide,

[0692] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[l-[[l-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]morpholin-2-yl]-2-pyridyl] -2 -pyridyl] acetamide,

[0693] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[l-[[l-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]piperazin-l-yl]-2-pyridyl] -2 -pyridyl] acetamide,

[0694] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[l-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-4-carbonyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl] acetamide.

[0695] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-l-yl]acetyl]morpholin-2-yl]-2-pyridyl]-2-pyridyl] acetamide,

[0696] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[3-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-l-yl]propanoyl]piperazin-l-yl]-2-pyridyl]-2-pyridyl] acetamide.

[0697] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]propanoyl]piperazin-l-yl]-2-pyridyl]-2-pyridyl] acetamide,

[0698] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]oxy]-3,3-difluoro-l-piperidyl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,

[0699] N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide,

[0700] N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-1-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide,

[0701] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-l-piperidyl]methyl]-l-piperidyl]-N-methyl-acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[4-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]phenyl]-2-pyridyl] acetamide.N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-3-methoxy-benzoyl]piperazin-1-yl]-N-methyl-acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]-3-oxo-piperazin-l-yl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,

[0702] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]piperazin-l-yl]-2-pyridyl] -2 -pyridyl] acetamide.

[0703] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperidine-4-carbonyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl] acetamide,

[0704] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-l-yl]acetyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl] acetamide.

[0705] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]acetyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl] acetamide,

[0706] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[4-(2,4-dioxohexahydropyrimidin- 1 -yl)phenyl] - 1 -piperidyl] -N-methyl-acetamide,

[0707] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[7-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperidine-4-carbonyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazin-2-yl]-2-pyridyl] acetamide,

[0708] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[4-[l-(2,6-dioxo-3-piperidyl)indolin-4-yl]-l-piperidyl]methyl]-l -piperidyl] -N-methyl-acetamide

[0709] N-[5-[6-[[(6S)-2-[l-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]-2,6-difluoro-phenyl]-4-piperidyl]-2-azaspiro[3.4]octan-6-yl]oxy]-2-pyridyl]-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-py ridyl] amino] -2-pyridyl] acetamide,

[0710] N-[5-[6-[[(6R)-2-[1-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]-2,6-difluoro-phenyl]-4-piperidyl]-2-azaspiro[3.4]octan-6-yl]oxy]-2-pyridyl]-4-[[6-(1-methoxy-1-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0711] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[4-[(2, 6-dioxo-3-piperidyl)amino] -2, 6-difluoro-phenyl]piperazin-l-yl] -N-methyl-acetamide, N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[4-[4-[(2,4-dioxohexahydropyrimidin-l-yl)methyl]phenyl]-l-piperidyl]methyl]-l-piperidyl]-N-methyl-acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-[l-[[l-[4-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-ylJphenylJcyclohexylJ-4-piperidyl]methyl]pyrazol-4-yl]-2-pyridyl]amino]-5-(2-pyridyl)-2 -pyridyl] acetamide,

[0712] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[3-(2,6-dioxo-3-piperidyl)indazol-l-yl]-l-piperidyl]-N-methyl-acetamide,

[0713] N-[4-[[6-(l,l-difluoroethyl)-4-[l-[2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperazin-l-yl]acetyl]azetidin-3-yl]oxy-2-pyridyl]amino]-5-(2-pyridyl)-2-pyridyl] acetamide.

[0714] N-[5-[l-[[l-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]-4-hydroxy-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrazol-3-yl]-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl -2-pyridyl] amino] -2 -pyridyl] acetamide,

[0715] N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-2,7-diazaspiro[3.5]nonan-2-yl]-N-methyl-acetamide.

[0716] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-l-yl]methyl]-l-piperidyl]acetyl]-methyl-amino]-2-pyridyl]-2-pyridyl]cyclopropanecarboxamide,

[0717] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-l-yl]methyl]-2-pyridyl]-2 -pyridyl] acetamide,

[0718] N-[5-[6-[4-[4-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]phenyl]cyclohexyl]piperazine-l-carbonyl]-2-pyridyl]-4-[[6-(l -methoxy- 1 -methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,

[0719] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-l-[[l-[l-(2.6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl]-N-methyl-piperidine-4-carboxamide,

[0720] N-[5-[6-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]piperidine-1-carbonyl]-2-pyridyl]-4-[[6-(1-methoxy-1-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide.

[0721] N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-1-yl]-N-methyl-acetamide

[0722] N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[7-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonan-2-yl]-N-methyl-acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[l4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperazin-l-yl]methylJ-l-piperidyl]-N-methyl-acetamide.

[0723] 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-[4-[l-(2,6-dioxo-3 -piperi dyl)-3 -methyl-2-oxo-benzimidazol-5-y 1] - 1 -piperidyl] -N -methyl -acetamide, N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((9-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-7-fluoro-l-methyl-lH-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0724] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-(6-((4-(4-((2,6-di ox opiperi din-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)-[2,3,-bipyridin] -6'-y l)acetamide.

[0725] N-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperi din-1-yl)methyl)piperidin-l-yl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)amino)-[2,3'-bipyridin] -6'-y l)acetamide,

[0726] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((7-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-pyrazolo[4.3-c]pyridin-6-yl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-[2.3'-bipyridin]-6'-yl)acetamide,

[0727] N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((6-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-pyrazolo[3,4-b]pyridin-6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide, and

[0728] N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-(3-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)pyrrolidin-l-yl)-[2,3'-bipyridin]-6'-yl)acetamide.

[0729] Aspect 28 is a compound of formula I according to any of aspects 1-27, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

[0730] N-[4-[[6-(l,l-difhioroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl]acetamide,

[0731] N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]morpholin-2-yl] -2 -pyridyl] -2-py ridyl] acetamide,

[0732] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[4-[(2,6-dioxo-3-piperidyl)amino]- 2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[9-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undecan-3-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[3-(2,6-dioxo-3-piperidyl)-l -methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-3,3-difluoro-l-piperidyl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,

[0733] N-(5-(((5r,8r)-8-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-2-azaspiro[4.5]decan-2-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin] -6'-y l)acetamide,

[0734] N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((5s,8s)-8-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)-2-azaspiro[4.5]decan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide,

[0735] N-(4'-((2-(l,l-difluoroethyl)pyri mi din-4-yl)amino)-5-((5r,8r)-8-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-2-azaspiro[4.5]decan-2-yl)-[2,3'-bipyridin] -6'-y l)acetamide,

[0736] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-l-piperidyl]-2-pyridyl]-2-py ridyl] acetamide,

[0737] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[(6S)-2-[l-[4-[[(3R)-2,6-di oxo-3-piperidyl]amino]-2,6-difluoro-phenyl]-4-piperidyl]-2-azaspiro[3.4]octan-6-yl]oxy]-2-pyridyl]-2-py ridyl] acetamide, and

[0738] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[l-[3-(2,6-dioxo-3-piperidyl)-l -methyl-indazol-7-yl]-4-piperidyl]oxy]-2-pyridyl]-2-pyridyl]acetamide.

[0739] Aspect 29 is a compound of formula I according to any of aspects 1-28, or a pharmaceutically acceptable salt thereof, that is selected from the group consisting of N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide,

[0740] N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-3,3-difluoro-l-piperidyl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenylJ-l-piperidyl]methyl]-l-piperidylJ-2-pyridyl]-2-py ridyl] acetamide,

[0741] N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide and

[0742] N-[5-[5-[[(3aR,6aR)-5-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-l,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]methyl]-2-pyridyl]-4-[[2-(l,l-difluoroethyl)pyrimi din-4-yl] amino] -2-pyridyl] acetamide.

[0743] Aspect 30 is a compound of formula I according to any of aspects 1-29, or a pharmaceutically acceptable salt thereof, that is N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-l-piperidyl]-2-py ridyl] -2-pyri dy 1] acetami de.

[0744] Aspect 31 is a process for the preparation of a compound according to any one of aspects 1-30 or a pharmaceutically acceptable salt thereof comprising reacting a compound of formula (A) with a compound of formula (3’) to a compound of formula (4’) and further to a compound of formula (I’)

[0745]

[0746]

[0747] (I )

[0748] wherein Xi is CH or N and X2 is CH or N, and Xi and X2 cannot simultaneously be CH.

[0749] Aspect 32 is a compound of formula I according to aspects 1-30, or a pharmaceutically acceptable salt thereof, when manufactured according to a process of aspect 31.

[0750] Aspect 33 is a pharmaceutical composition comprising a compound in accordance with any one of aspects 1-32 and a pharmaceutically acceptable excipient.

[0751] Aspect 34 is a compound or pharmaceutically acceptable salt according to any one of aspects 1 -32 for use as therapeutically active substance.

[0752] Aspect 35 is the use of a compound according to any one of aspects 1-32 as therapeutically active substance for the therapeutic and / or prophylactic treatment of autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinfl ammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS). Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

[0753] Aspect 36 is the use of a compound according to any one of aspects 1-32 as therapeutically active substance for the therapeutic and / or prophylactic treatment of inflammatory bowel disease.

[0754] Aspect 37 is a compound of formula I according to aspects 1-32 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 lupuserythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinfl ammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

[0755] Aspect 38 is a compound of formula I according to aspects 1-32 for the use as therapeutically active substance for the therapeutic and / or prophylactic treatment of inflammatory bowel disease.

[0756] Aspect 39 is a method of preventing or treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is an autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinfl ammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease and wherein the method comprises administering a therapeutically effective amount of a compound according to any one of aspects 1-32 or a pharmaceutically acceptable salt thereof, to the subject.

[0757] Aspect 40 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 1-32 or a pharmaceutically acceptable salt thereof, to the subject.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.

[0758] 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 the 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.

[0759] 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 w eight, 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.

[0760] 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.

[0761]

[0762] Synthesis of 4-chloro-2-(l,l-difluoroethyl)pyrimidine

[0763] O

[0764] t-BuOK, BnOH 1. Pd(PPh3)2CI2, DMF DAST DMF / THF 2. HCI, Acetone / H2O DCM Step-1 Step-2 / 3 Step-4

[0765] OBn 2 OBn 4

[0766] TFA POCI3Step-5 Step-6

[0767]

[0768] SStep-1:

[0769] A 500 mL three-neck round-bottom flask containing a well-stirred solution of potassium tert-butoxide (1 M, 67.12 mL) and benzyl alcohol (14.52 g, 134.25 mmol, 13.89 mL) in THF (50 mL) was heated under reflux temperature for 30 minutes. The reaction mixture was cooled to 0 °C and added dropwise to 2,4-dichloropyrimidine (1, 10 g, 67.12 mmol) in DMF (50 mL), while maintaining the temperature below -78 °C. After stirring for one hour, the reaction mixture was warmed up to room temperature and stirred for 16 h. The reaction mixture was then diluted with water (150 mL) under cooling and then extracted with DCM (250 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude was purified by column chromatography (EtOAc in pet ether, 0% to 10%) to afford 4-benzyloxy-2-chloro-pyrimidine (2, 13 g, 57.15 mmol, 85% yield) as an off-white solid. LC-MS (ES+): m / z 221.1 [M + H]+.

[0770] Step-2 and Step-3:

[0771] To a stirred solution of 4-benzyloxy-2-chloro-pyrimidine (2, 10 g, 43.96 mmol) in DMF (100 mL) were added tributyl (1 -ethoxy vinyl)stannane (3, 15.88 g, 43.96 mmol, 14.85 mL) and bis(triphenylphosphine)palladium (II) di chloride (1.54 g, 2.20 mmol) and the reaction mixture was heated at 100 °C for 3 h and then stirred at room temperature for 16 h. The reaction mixture was quenched with aqueous KF solution (50 mL) and extracted with EtOAc (2 x 250 mL). The separated organic layers were washed with water (150 mL), brine (150 mL), dried over Na2SO4, filtered, and the filtrate, concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica gel) using a gradient of EtOAc in petroleum ether (0-30%) to afford (4-(benzyloxy)-2-(l -ethoxy vinyl)pyrimidine (3a, 7 g) as a pale yellow semisolid. The compound 3a was dissolved in acetone (30 mL), water (30 mL) and acidified with 4 M HC1 in 1,4-dioxane (109.90 mL), stirred at room temperature for 1 h, and extracted with EtOAc (2 x 250 mL). The separated organic layers were washed with water (150 mL), brine(150 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford l-(4-benzyloxypyrimidin-2-yl)ethanone (4. 6 g, 17.09 mmol, 39% yield) as a pale yellow semi-solid, which was used without further purification. LC-MS (ES+): m / z 229.0 [M + H]+. Step-4:

[0772] To a 250 mL single-neck round-bottom flask containing a well-stirred solution of l-(4-benzyloxypyrimidin-2-yl)ethanone (4, 6 g, 17.09 mmol) in DCM (50 mL) was added N-ethyl-N-(trifluoro-sulfanyl)ethanamine (4.13 g, 25.63 mmol, 3.39 mL) and the reaction was stirred at 25 °C for 3 h. The mixture was quenched with aq. NaHCO3 (100 mL) and extracted with DCM (100 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel. EtOAc in pet ether) to give 4-benzyloxy-2-(l,l-difluoroethyl)pyrimidine (5, 2.5 g, 9.40 mmol, 55% yield) as a yellow oil. LC-MS (ES+): m / z 251.2 [M + H]+.

[0773] Step-5:

[0774] In a 50 mL single-neck round-bottom flask, a solution of 4-benzyloxy-2-(l,l -difluoroethyl) pyrimidine (5, 2.5 g, 9.40 mmol) in TFA (10.72 g, 94.04 mmol, 7.20 mL) was stirred at 100 °C for 16 h. The reaction mixture was monitored by LCMS. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure and the resulting crude was triturated with MTBE (10 mL) and dried under reduced pressure to give 2-(l,l-difluoroethyl)pyrimidin-4-ol (6. 1.6 g, 9.29 mmol. 99% yield) as a brown solid, which was used without further purification. UP LC-MS (ES’): m / z 159.0 [M - H] ’.

[0775] Step-6:

[0776] In a 100 mL single-neck round-bottom flask, a solution of 2-(l,l-difluoroethyl)pyrimidin-4-ol (6, 1.6 g. 9.29 mmol) in phosphorus oxychloride (28.50 g, 185.86 mmol. 17.32 mL) was stirred at 100 °C for 3 h. Then the mixture was evaporated to dryness. The resulting residue was diluted with DCM (50 mL), added slowly into water, and then extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The crude was purified by column chromatography using a gradient of 0% to 30% EtOAc in pet ether to give 4-chloro-2-(l,l-difluoroethyl)pyrimidine (7, 1.3 g, 6.12 mmol, 66% yield) as a yellow liquid. LC-MS (ES+): m / z 179.1 [M + H]+.

[0777] Synthesis of 2-bromo-6-(l,l-difluoroethyl)-4-methyl-pyridine

[0778]

[0779] To a 250 mL single-neck round-bottom flask containing a well stirred solution of 1-(6-bromo-4-methyl-2-pyridyl)ethanone (1, 2 g, 9.24 mmol) in 1,2-DCE (70 mL) was added N-ethyl-N-(trifluoro-sulfanyl)ethanamine (7.44 g, 46.18 mmol, 6.10 mL) at 0 °C. The resulting reaction mixture was stirred at 55 °C for 24 h. The reaction mixture was cooled and then neutralized with 10% aqueous NaOH solution. The aqueous layer was extracted with EtOAc (3 x 200 mL) and the combined organic layers were dried over anhydrous Na2SO4. filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel: Eluent: 5% EtOAc in pet ether) to afford 2-bromo-6-(l,l-difluoroethyl)-4-methyl-pyridine (2, 1 g, 3.76 mmol, 40.67% yield) as a light brown syrupy liquid. LC-MS (ES+): m / z 238.1 [M+ H]+.

[0780] Synthesis of 2-chloro-6-(l,l-difluoroethyl)-4-methyl-pyridine

[0781]

[0782] To a 500 mL single-neck round-bottom flask containing a well stirred solution of 1-(6-chloro-4-methyl-2-pyridyl)ethanone (1, 10 g, 58.96 mmol) in 1,2-DCE (100 mL) was added N-ethyl-N-(trifluoro-sulfanyl)ethanamine (47.52 g. 294.80 mmol, 38.95 mL) at 0 °C. The resulting reaction mixture was stirred at 55 °C for 16 h. After completion of the reaction indicated by TLC, the reaction mixture was cooled and neutralized with 10% aqueous NaOH solution. Aqueous layer was extracted with Ethyl acetate (3 × 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (Stationary Phase: 230-400 mesh silica gel, 50 g snap cartridge; Eluent: 0-5% ethyl acetate in petroleum ether, flow rate = 20 mL / min) to afford 2-chloro-6-(l,l-difluoroethyl)-4-methyl-pyridine (2, 4 g, 20.06 mmol, 34.02% yield) as a light-yellow liquid. LC-MS (ES+): m / z 192.2 [M + H]+

[0783] Synthesis of 2-chloro-4-methyl-6-(methylsulfonyl)pyridine

[0784] MeSNa mCPBA

[0785] DMF DCM

[0786] Step-1 Step-2

[0787]

[0788] SStep-1:

[0789] To a solution of 2,6-dichloro-4-methylpyridine (1. 5.0 g, 30.86 mmol) in DMF (50 mL) was added sodium methanethiolate (2.16 g, 30.86 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. Then the reaction mixture was concentrated to afford the crude residue, whichwas purified on normal phase column chromatography (Stationary Phase: Silica Gel; Eluent: Gradient from 10 / 1 to 5 / 1 Petroleum / EtOAc) to afford 2-chloro-4-methyl-6-(methylthio)pyridine (2, 4.0 g, 23.03 mmol, 74.63% yield) as a colorless liquid. LC-MS (ES+): m / z 173.9 [M+ H]+ 1H NMR (400 MHz, CHLOROFORM-d): δ 6.90 (s, 1H), 6.83 (s, 1H), 2.54 (s, 3H), 2.27 (s, 3H) ppm.

[0790] Step-2:

[0791] To a solution of 2-chloro-4-methyl-6-(methylthio)pyridine (2, 1.9 g, 10.94 mmol) in DCM (30 mL) was added 3-chlorobenzenecarboperoxoic acid (5.55 g, 27.35 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 2 h, then quenched by the addition of saturated Na₂SO₃ aqueous solution (50 mL) at 0 °C under a N2 atmosphere. The resulting reaction mixture was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to afford the crude residue, which was purified by Prep-HPLC (Column: Phenomenex luna C18 (150 x 40 mm) x 15 um; Mobile Phase: [A: H2O modified with 0.225% Formic Acid; B: MeCN]; Gradient: B%: 20.00% -50.00% over 15.00 min; flow rate: 60.00 mL / min) and lyophilized to afford 2-chloro-4-methyl-6-(methylsulfonyl)pyridine (3, 1200.0 mg, 5.83 mmol, 53.33% yield) as an off-white solid. LC-MS (ES+): m / z 205.9 [M+ H]+. 'H NMR (400 MHz, CHLOROFORM-<7): 5 7.83 (s, 1H), 7.39 (s, 1H), 3.23 (s, 3H), 2.48 (s, 3H) ppm.

[0792] Synthesis of 2-(2-oxabicyclo[2.1.1]hexan-l-yl)-4-chloro-6-methylpyrimidine

[0793]

[0794] SStep-1:

[0795] To a solution of 2-oxabicyclo[2.1.1]hexane-l-carboxylic acid (1, 2.2 g, 17.17 mmol) in DCM (30 mL) was added DMF (0.13 mL, 1.72 mmol) and oxalyl chloride (1.76 mL, 20.6 mmol) under a N2 atmosphere. The resulting reaction mixture was stirred at 20°C for 1 h. Then the reaction mixture was concentrated in vacuo to afford the crude residue. The crude residue was dissolved in DCM (20 mL) and cooled to 0°C, then NHs / MeOH (26.4 mL, 184.8 mmol) was slowly added into mixture, and the resulting reaction was stirred at 0°C for 2 h. The reaction mixture wasfiltered, and the filter cake was washed with MeOH (2 mL). The filtrate was concentrated in vacuo to afford a residue, which was triturated with MeCN (2 mL) to afford 2-oxabicyclo[2.1.1]hexane-l-carboxamide (2, 2.18 g, 17.15 mmol, 99.86% yield) as a white solid. ’H WIR (400 MHz, DMSO4) 57.30 - 7.13 (m, 2H), 3.16 (s, 2H), 2.88 (t, J= 2.8 Hz, 1H), 2.04 - 1.99 (m, 2H), 1.50 - 1.47 (m, 2H) ppm.

[0796] Step-2:

[0797] To a solution of 2-oxabicyclo[2.1.1]hexane-l-carboxamide (2, 2.18 g, 17.15 mmol) in DCM (20 mL) was added trimethyloxonium tetrafluoroborate (7608.4 mg, 51.44 mmol), and the resulting reaction mixture was stirred at 20°C for 12 h. The reaction mixture was poured into a saturated sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to afford methyl 2-oxabicyclo[2.1.1]hexane-l-carbimidate (3, 2.4 g, 17.0 mmol, 99.15% yield) as a yellow oil, which was used without further purification. 'll NMR (400 MHz, DMSO-< A) 5 3.75 -3.74 (m, 2H), 3.69 - 3.61 (m, 3H). 2.94 - 2.88 (m. 1H), 2.05 - 2.00 (m, 2H), 1.53 - 1.46 (m, 2H) ppm. Step-3:

[0798] A solution of methyl 2-oxabicyclo[2.1.1]hexane-l-carbimidate (3, 2.4 g, 17.0 mmol) in NHs / MeOH (20.0 mL, 140.0 mmol) was stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to afford 2-oxabicyclo[2. l.l]hexane-l-carboximidamide (4, 2140.0 mg, 16.96 mmol, 99.78% yield) as an off-white gum, which was used without further purification. Step-4:

[0799] To a solution of 2-oxabicyclo[2.1.1]hexane-l-carboximidamide (4, 2.14 g, 16.96 mmol) in methanol (20 mL) was added sodium methoxide (1832.77 mg, 33.93 mmol) and methyl acetoacetate (5, 1969.7 mg, 16.96 mmol). The resulting reaction mixture was stirred at 20 °C for 12 h. Then H2O (10 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were concentrated in vacuo to afford the crude residue, which was purified by reversed phase column chromatography (CombiFlash; Column: Phenomenex Synergi C18 150 mm × 25 mm × 10 μm; Mobile Phase: A: water modified with 0.1% Formic Acid, B: MeCN; Gradient: B%: 12%-30% over 20 min) to afford 2-(2-oxabicyclo[2.1.1]hexan-l-yl)-6-methylpyrimidin-4(3H)-one (6, 1120.0 mg, 5.83 mmol, 34.35% yield) as a white solid. LC-MS (ES+): m / z 193.1 [M + H]+. 'H NMR (400 MHz, METHANOL- 4) 5 6.18 (s, 1H), 3.95 (s, 2H), 3.04 (t, J= 3.2 Hz, 1H). 2.36 - 2.31 (m. 2H), 2.29 (s, 3H), 1.83 - 1.76 (m, 2H) ppm.

[0800] Step-5:

[0801] To a solution of 2-(2-oxabicyclo[2.1.1]hexan-l-yl)-6-methylpyrimidin-4(3H)-one (6, 1000 mg, 5.2 mmol) in DCM (15 mL) was added dimethylformamide (0.04 mL, 0.52 mmol) andphosphorus oxychloride (1.94 mL, 20.81 mmol). The resulting reaction mixture was stirred at 20°C for 1 h. Then the reaction mixture was poured into a saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed by brine (20 mL x 3). dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo to afford 2-(2-oxabicyclo[2.1.1]hexan-l-yl)-4-chloro-6-methylpyrimidine (7, 1030.0 mg. 4.89 mmol, 93.04% yield) as an orange solid, which was used without further purification. LC-MS (ES+): m / z 210.9 [M + H]+.

[0802] Synthesis of 2-bromo-6-[(3J?)-3-methoxytetrahydrofuran-3-yI]-4-inethyl-pyridine and 2-bromo-6-[(35)-3-methoxytetrahydrofuran-3-yl]-4-methyl-pyridine

[0803]

[0804] SStep-1:

[0805] In a 500 mL three-neck round-bottom flask, a well-stirred solution of 2,6-dibromo-4-methyl-pyridine (1, 10 g, 39.85 mmol) in DCM (100 mL) was cooled to -78°C before the dropwise addition of n-BuLi in hexane (2.5 M, 15.94 mL). The reaction was stirred at this temperature for about 15 min, then tetrahydrofuran-3-one (2, 3.43 g, 39.85 mmol) was added in one portion. The reaction was then stirred for 40 min at -78 °C. Upon completion of the reaction, the reaction mixture was poured into a mixture of saturated aqueous NH4CI (110 mL) and DCM (80 mL) and stirred for about 30 min. The separated organics were dried over NazSCh, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (Stationary Phase: silica gel; Eluent: 0-50% EtOAc in hexane) to afford 3-(6-bromo-4-methyl-2-pyridyl)tetrahydrofuran-3-ol (3, 11 g, 30.68 mmol, 76.99% yield) as a brown solid. LC-MS (ES+): m'z 260.0 [M + H]+.

[0806] Step-2:

[0807] To a 500 mL two-neck round-bottom flask containing a well-stirred solution of 3-(6-bromo-4-methyl-2-pyridyl)tetrahydrofuran-3-ol (3, 11 g, 30.68 mmol) in THF (100 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil) (3.07 g, 76.71 mmol) and then lodomethane (6.53 g, 46.03 mmol, 2.87 mL). The resulting mixture was stirred at 25 °C for 16 h under N2 atmosphere. The reaction was quenched with saturated aq. NH4CI (100 mL), andthe resulting mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (Stationary Phase: silica gel; Eluent: 0-20% ethyl acetate in petroleum ether) to yield 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-pyridine (4, 8 g, 28.73 mmol, 93.62% yield) as a colorless liquid. LC-MS (ES+): m / z 272.0 [M + H]+.

[0808] Step-3:

[0809] The enantiomeric mixture of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methyl-pyridine (4, 8 g, 27.52 mmol) was separated by SFC [Column Name: YMC Cellulose-SC, Flowrate: 3 mL / min, Co-Solvent: 10%, Co-Solvent Name: 0.5% Isopropylamine in IP A, Injected Volume: 2 µL, Temperature: 35 °C, Outlet Pressure: 100 bar].

[0810] The early-eluting isomer 2-bromo-6-[(37?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-pyri dine (5, 3 g, 10.25 mmol, 37.25% yield) was obtained as a white solid. UPLC-MS (ES+): m / z 272.1 [M + H]+. SFC RT = 3.17 min. [a]25 0= + 2.40, c = 1, CH3OH (Literature value [a]250= + 5.6, c = 0.2, CH3OH).

[0811] The late-eluting isomer 2-bromo-6-[(35’)-3-methoxytetrahydrofuran-3-yl]-4-methyl-pyridine (6, 3.5 g, 12.26 mmol, 44.56% yield) was obtained as a white solid. LCMS (ES+): m / z 272.1 [M + H]+. SFC RT = 4.09 min. [a]25 0= - 2.60, c = 1, CH3OH (Literature value [a]250= - 3.5, c = 0.2, CH3OH).

[0812] Note: Stereocenters are assigned by matching the SOR values in literature (W02022109580A14). According to literature, first fraction was R and second fraction was.

[0813] Synthesis of A-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-(methylamino)-2-pyridyl]-2-pyridyl] acetamide (A- 1)

[0814]

[0815]

[0816] SStep-1:

[0817] To a 500 mL three-neck round-bottom flask containing a well-stirred solution of tert-butyl V-(6-bromo-3-pyridyl)carbamate (1, 5 g, 18.31 mmol) in anhydrous THF (100 mL) was added NaH (60% dispersion in oil) (1.46 g, 36.61 mmol) and iodomethane (36.61 mmol. 2.28 mL) dropwise at 0 °C under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 4 h. Upon completion of the reaction as indicated by LCMS, the reaction was quenched with ice cold water (200 mL) and extracted with ethyl acetate (2 x 300 mL). The organic layers were dried over anhydrous Na₂SO₄. filtered and concentrated under reduced pressure to give / e / v-butyl 2V-(6-bromo-3-pyridyl)-7V-methyl-carbamate (2, 5.2 g. 17.67 mmol, 97% yield) as a yellow solid, which was used without further purification. LC-MS (ES+): m / z 287.0 | M + H]+.

[0818] Step-2:

[0819] To a 250 mL single-neck round-bottom flask containing a well-stirred suspension of terf-butyl JV-(6-bromo-3-pyridyl)-JV-methyl-carbamate (2, 6 g, 20.06 mmol) and 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (3, 13.44 g, 20.06 mmol) in 1,4-dioaxne (100 mL) and water (25 mL) was added potassium carbonate (2.77 g, 20.06 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 5 minutes before Pd(dppf)Cl2 (733.86 mg, 1.00 mmol) was added. The reaction mixture was purged with nitrogen gas for another 5 min and then stirred at 100 °C for 2 h. Upon completion of the reaction, the reaction mixture was filtered through a pad of Celite and the filtrate concentrated under reduced pressure. The crude was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 50% EtOAc in pet ether to afford tert-buty l JV-[6-(4-amino-6-chloro-3-pyridyl)-3-pyridyl]-7V-methyl-carbamate (4, 3 g, 7.93 mmol, 40% yield) as a yellow solid. LCMS (ES1): m / z 335.3 [M + H].

[0820] Step-3:

[0821] To two separate 40 mL screw-cap vials was evenly split the following reagents: a well-stirred solution of tert-butyl iV-[6-(4-amino-6-chloro-3-pyridyl)-3-pyridyl]-iV-methyl-carbamate (4, 1.5 g. 3.99 mmol) in 1,4-dioxane (20 mL). Then acetamide (5, 471.05 mg, 7.97 mmol) and cesium carbonate (2.60 g, 7.97 mmol) were added and the mixture was purged with N2 for 5 min.XantPhos (461.44 mg, 797.49 pmol) and Pd2(dba)3 (365.14 mg, 398.75 pmol) were added and the reaction mixture was stirred at 110 °C for 16 h. Upon completion of the reaction as indicated by LCMS, the reaction mixture was filtered through a pad of Celite, which was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure and the crude product was purified by reverse phase column chromatography [Column: C18 RediSep* R / gold (120 g HP Cl 8); Mobile phase A: 0.1% ammonium bicarbonate in MQ-water and Mobile phase B: acetonitrile; Flow rate: 10 mL / min] to afford tert-butyl A-[6-(6-acetamido-4-amino-3-pyridyl)-3-pyridyl]-A-methyl-carbamate (6, 500 mg, 1.34 mmol, 34% yield) as an off-white solid. UPLC-MS (ES+): m / z 358.3 [M + H]+.

[0822] Step-4:

[0823] To two separate 20 mL screw top vials was evenly split the following reagents: a well-stirred solution of tert-butyl A-[6-(6-acetamido-4-arnino-3-pyridyl)-3-pyridyl]-A-methyl-carbamate (6, 500 mg, 1.34 mmol) and 4-chloro-2-(l,l-difluoroethyl)pyrimidine (7, 428.25 mg, 2.01 mmol) in 1,4-dioxane (30 mL). Then Pd₂(dba)₃ (61.49 mg, 67.15 pmol) was added at ambient temperature under nitrogen atmosphere and the resulting mixture was degassed by bubbling nitrogen gas through the reaction mixture for 10 minutes. Subsequently XantPhos (77.71 mg, 134.30 pmol) and K3PO4 (570.15 mg, 2.69 mmol) were added to the reaction mixture and the reaction mixture was heated to 80 °C for 16 h. Upon completion of the reaction, the reaction mixture was fdtered through a pad of Celite and the filtrate concentrated under reduced pressure. The crude was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel: Eluent: 80% EtOAc in pet ether) to afford te / 7-butyl A-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-A-methyl-carbamate (8, 400 mg, 722.79 pmol, 54% yield) as a brown color solid. LC-MS (ES+): m / z 500.2 [M + H]+.

[0824] Step-5:

[0825] To a 100 mL single-neck round-bottom flask containing a well-stirred solution of terf-butyl A-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-A-methyl-carbamate (8, 400 mg, 722.79 pmol) in anhydrous DCM (5 mL) was added 4 M HC1 in 1,4-dioxane (1.81 mL). The resulting mixture was stirred while warming from 0 °C to room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude material was basified using saturated aqueous solution of sodium bicarbonate (100 mL) and then extracted with DCM (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford A-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-(methylamino)-2-pyridyl]-2-pyridyl]acetamide (A-l, 280 mg, 694.05 pmol, 96% yield) as an off-white solid. LC-MS (ES+): m z 400.1 [M + H]+.Synthesis of l-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-(methylainino)-2-pyridyl]-2-pyridyl]-3-methyl-urea (A-2)

[0826]

[0827] SStep-1:

[0828] To a 50 mL single-neck round-bottom flask containing well stirred solution of tert-butyl N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-N-methyl-carbamate (250 mg, 450.44 pmol) in THF (5 mL) and methanol (5 mL) was added lithium hydroxide, monohydrate (189.02 mg, 4.50 mmol) in water (3 mL) at 0 °C. The resulting reaction mixture was stirred at 50 °C for 5 h. The reaction mixture was then concentrated in vacuo and the crude was purified by reverse-phase column chromatography [Column: RediSep® column; Mobile phase A: 0.1% Formic acid in water and Mobile phase B: CH3CN] to afford tert-butyl N-[6-[6-amino-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-A-methyl-carbamate formate (150 mg, 291.96 pmol, 64.82% yield) as an off-white solid. LC-MS (ES+): m / z 458.1 [M + H]+.

[0829] Step-2:

[0830] To a 20 mL screw cap vial containing well stirred solution of / e / 7-butyl A-[6-[6-amino-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridylJ-3-pyridyl]-jV-methyl-carbamate (150 mg, 321.33 pmol) in THF (2 mL) were added TEA (325.15 mg, 3.21 mmol, 447.86 pL), 4-nitrophenyl chloroformate (97.15 mg, 481.99 pmol) and DMAP (39.26 mg, 321.33 pmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 4 h. Then methanamine hydrochloride (65.09 mg, 963.99 pmol, 72.40 pL) in DMF (2 mL) and TEA (325.15 mg, 3.21 mmol, 447.86 pL) was added and stirred at 70 °C for 16 h. Upon completion ofthe reaction, the reaction mixture was quenched with water (50 mL). and the aqueous layer was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography [Column: RediSep® column; Mobile phase A: 0.1% Formic acid in water and Mobile phase B: CH3CN] to afford te / 7-butyl A-[6-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-6-(methylcarbamoylamino)-3-pyridyl]-3-pyridyl]-A-methyl-carbamate (30 mg, 43.73 pmol, 13.61% yield) as an off-white solid. LC-MS (ES+): m / z 515.3 [M + H]+.

[0831] Step-3:

[0832] To a 10 mL single-neck round-bottom flask containing well stirred solution of tert-butyl V-[6-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-6-(methylcarbamoylamino)-3-pyridyl]-3-pyridyl]-A-methyl-carbamate (30 mg, 43.73 pmol) in DCM (1 mL) was added 4 N HC1 in 1,4-dioxane (0.2 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. The solvent was then removed from the reaction mixture and the obtained crude was triturated with MTBE (2 mL) to afford l-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-(methylamino)-2-pyridyl]-2-pyridylJ-3-methyl-urea hydrochloride (A-2, 20 mg, 42.58 pmol, 97.38% yield) as an off-white solid. UPLC-MS (ES+): m / z 415.0 [M + H]+.

[0833] Synthesis of / V-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-6-(morpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide (A-3)

[0834]

[0835] phthalimide, DMSO Step-3

[0836]

[0837] SStep-1:

[0838] To a solution of tert-butyl (2-acetamidopyridin-4-yl)carbamate (4a, 50.0 g, 198.97 mmol) in MeCN (500 mL) was added NBS (37.2 g, 208.92 mmol) at 20°C. Then the resulting reaction mixture was heated to 70°C and stirred for 2 h. The resulting reaction mixture was cooled to room temperature and diluted with H2O (1000 mL). The aqueous phase was extracted with EtOAc (800 mL x 3). The combined organic layers were washed with brine (500 mL x 3). dried over anhydrous Na₂SO₄. filtered, and concentrated in vacuo to afford a residue, which was triturated with MeCN (100 mL) at 25°C. Then the resulting suspension was filtered, and the filter cake was concentrated under reduced pressure to afford tert-butyl (2-acetamido-5-bromopyridin- 4-yl)carbamate (4b, 50.0 g, 151.43 mmol, 76.11% yield) as a white solid. MS (ES+): m z 332.0 [M + H]+.JH NMR (400 MHz, CHLOROFORM-ct) 5 9.05 (s, 1H), 9.14 (s, 1H), 8.46 (s, 1H), 8.21 (s, 1H), 7.13 (s, 1H), 2.20 (s, 3H), 1.55 (s, 9H) ppm.

[0839] Step-2:

[0840] To a solution of terf-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (4b, 10.0 g, 30.29 mmol) in 2-MeTHF (150 mL) was added B₂Pin₂ (11.5 g, 45.43 mmol), KOAc (8.92 g, 90.86 mmol), and XPhos Pd G3 (2.56 g. 3.03 mmol) under an N2 atmosphere at 20 °C. The resulting reaction mixture was heated to 90 °C and stirred for 16 h under an N2 atmosphere. The resulting reaction mixture was concentrated in vacuo to afford a residue. EtOAc (150 mL) was added, and the resulting mixture was stirred at 25 °C for 0.5 h. The resulting mixture was filtered, and the filtrate was concentrated in vacuo to afford the crude product. Then n-hexane (40 mL) was added, and the mixture was stirred at 25°C for 0.5 h. The resulting suspension was filtered, and the filtercake was washed with n-hexane (15 mL x 2) and collected to afford / c / 7 -butyl (2-acetamido-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)carbamate (4, 10.4 g, 27.57 mmol, 91.02% yield) as a yellow solid. MS (ES+): m / z 278.17 [M + H-C5H9O2]+. 'H NMR (400 MHz, DMSO-t / r,) 8 10.51 (s, 1H), 9.01 (s, 1H), 8.58 (s, 1H), 8.27 (s, 1H), 2.07 (s, 3H), 1.48 (s, 9H), 1.30 (s, 12H) ppm.

[0841] Step-3: (see Figure 1)

[0842] Solution 1 [2-bromo-6-chloropyridine (1, 11.0 g, 57.16 mmol), 4- ((benzyloxy)carbonyl)morpholine-2-carboxylic acid (2, 22.74 g, 85.74 mmol), phthalimide (8.41 g, 57.16 mmol), 2-terr-butyl-l,l,3,3-tetramethylguanidine (11.75 g, 68.59 mmol), [Ir(dF(CF3)ppy)2(dtbbpy)](PFe) (1.28 g, 1.14 mmol), and NiCl₂·dtppby (1.14 g, 2.86 mmol) in DMSO (300 mL)] was pumped by Pump 1 {SI, Pl, 20.096 mL / min} to flow reactor 1 {FLR1, FEP, Coils reactor, 3.175(l / 8”)mm, 20.096 mL, 40.0°C{ with a residence time of 1.0 min. The total reaction was reacted at 40 °C for 12 h. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (400 mL x 3). dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a residue, which was purified by normal phase column chromatography (Stationary Phase: Silica gel; Eluent: Gradient from 5 to 25% EtOAc in Petroleum ether) to afford the crude product, which was further purified by reversed phase chromatography [Combi-flash automated purification system; Column: Phenomenex Synergi C18 (150 mm x 25 mm) x 10 m; Mobile phase A: water (modified with 0.1%FA), Mobile Phase B: MeCN; Gradient from 60%-70% B over 20 min) to afford benzyl 2-(6-chloropyridin-2-yl)morpholine-4-carboxylate (3, 4.69 g, 14.09 mmol, 22.78% yield) as a yellow oil. MS (ES+): m / z 333.1 [M + H]+.

[0843] Step-4:

[0844] To a solution of benzyl 2-(6-chloropyridin-2-yl)morpholine-4-carboxylate (3, 2.03 g, 6.1 mmol) in 1,4-Di oxane (20 mL) was added terf-butyl (2-acetamido-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)carbamate (4, 2.3 g, 6.1 mmol), K2CO3 (1.68 g, 12.19 mmol), and Pd(dppf)Cl2 (446.11 mg, 0.61 mmol). The mixture was heated to 100°C and stirred for 12 h under an N2 atmosphere. The resulting reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (40 mL x 4). dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a residue, which was purified by normal phase column chromatography (Stationary Phase: Silica gel; Eluent: Gradient from 5 to 50% EtOAc in Petroleum ether) to afford benzyl 2-(6'-acetamido-4'-((fe / 7-butoxycarbonyl)amino)-[2,3'-bipyridin]-6-yl)morpholine-4-carboxylate (5, 3.08 g, 5.62 mmol, 92.25% yield) as an off-white solid. MS (ES+): m / z 548.3 [M + H]+. 'H NMR (400 MHz, CHLOROFORM-d) 8 11.66 (s, 1H), 9.17 (s, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 7.86 (t, J= 8.0 Hz,1H), 7.66 (d, J= 8.0 Hz, 1H), 7.46 - 7.30 (m, 6H), 5.28 - 5.13 (m, 2H), 4.58 (d, J=10.0 Hz, 1H), 4.47 (s, 1H), 4.16 - 4.03 (m, 2H), 3.83 - 3.71 (m, 1H), 3.34 - 3.10 (m, 2H), 2.23 (s, 3H). 1.48 (s, 9H) ppm.

[0845] Step-5:

[0846] To a solution of benzyl 2-(6'-acetamido-4'-((ferr-butoxycarbonyl)amino)-[2,3'-bipyridin]-6-yl)morpholine-4-carboxylate (5, 2.78 g, 5.08 mmol) in DCM (30 mL) was added TFA (10.0 mL). The resulting reaction mixture was stirred at 20°C for 0.5 h. The resulting mixture was brought to pH=8 by the addition of a saturated Na2CO3solution and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford benzyl 2-(6'-acetamido-4'-amino-[2,3'-bipyridin]-6-yl)morpholine-4-carboxylate (6, 2.27 g, 5.07 mmol, 99.92% yield) as an off-white gum. MS (ES+): m'z 448.2 [M + H]+.

[0847] Step-6:

[0848] To a solution of 2-chloro-6-(1,1-difluoroethyl)-4-methylpyridine (7, 1.17 g, 6.09 mmol) in 1,4-Dioxane (30 mL) was added benzyl 2-(6'-acetamido-4'-amino-[2,3'-bipyridin]-6-yl)morpholine-4-carboxylate (6, 2.27 g, 5.07 mmol), Cs2CO3(4.95 mg, 15.22 mmol), BINAP (631.74 mg, 1.01 mmol), and Pd2(dba)3(464.52 mg, 0.51 mmol). The resulting reaction mixture was heated to 100 °C and stirred for 12 h under N2. The resulting reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (40 mL x 4). dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a residue, which was triturated with Acetonitrile / THF (2 / 1, 8 mL). The resulting reaction mixture was filtered and washed with petroleum ether (3 mL). The filter cake was concentrated in vacuo to afford benzyl 2-(6'-acetamido-4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6-yl)morpholine-4-carboxylate (8, 2.05 g, 3.4 mmol, 65.78% yield) as an off-white solid. MS (ES+): m / z 603.2 [M + H]+. 'H NMR (400 MHz, DMSO-6) δ 12.57 -12.33 (m, 1H), 10.42 (s, 1H), 9.28 (s, 1H), 8.73 (s, 1H), 8.07 - 7.96 (m, 2H), 7.49 (d, J= 7.6 Hz, 1H), 7.44 - 7.19 (m, 5H), 7.10 (s, 1H), 7.07 - 6.97 (m, 1H), 5.23 - 4.97 (m, 2H), 4.78 (dd, J= 2.8, 12.0 Hz, 1H), 4.40 - 4.19 (m, 2H), 4.17 - 4.06 (m. 1H), 4.04 - 3.95 (m, 1H), 3.84 - 3.73 (m, 1H), 3.27 - 3.15 (m, 1H), 3.12 - 3.00 (m, 1H). 2.34 (s, 3H). 2.18 - 2.04 (m. 6H) ppm.

[0849] Step-7: (see Figure 2)

[0850] The fixed bed (named FLR1, volume 5 mL) was completely packed with granular 5% Pd / A12O3 catalyst (3.1 g). The H2back pressure regulator was adjusted to 1.5 Mpa. and the H2flow rate was 10 seem. Solution 1 [benzyl 2-(6'-acetamido-4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6-yl)morpholine-4-carboxylate (8, 1.8 g, 2.99 mmol) in DMF (72 mL) and Methanol (9 mL)] was pumped by Pump 1 {SI, Pl, 0.3 mL / min} to flow reactor 1 {FLR1,SS, Fixed bed, 6.350(l / 4")mm, 1.0 mL, 55.0°C}. The total reaction was reacted at 55°C for 1 h. The mixture was concentrated in vacuo to afford N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-6-(morpholin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide (9, 1.1 g, 2.35 mmol, 77.19% yield) as an off-white solid. MS (ES+): m / z 469.2 [M + H]+. 'H NMR (400 MHz, DMSO-6) 8 12.88 (s, 1H), 10.41 (s, 1H), 9.28 (s, 1H), 8.75 (s, 1H), 8.05 - 8.00 (m, 1H), 7.96 - 7.91 (m, 1H), 7.40 (d, J= 7.6 Hz, 1H), 7.11 (s, 1H), 7.04 (s, 1H), 4.66 (dd, J= 2.4, 10.4 Hz, 1H), 4.07 - 3.99 (m, 1H), 3.80 - 3.71 (m, 1H), 3.16 - 3.11 (m, 1H), 2.87 - 2.80 (m, 2H). 2.73 - 2.68 (m. 1H). 2.36 (s, 3H), 2.18 - 2.08 (m, 6H) ppm.

[0851] Synthesis of N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-(4-piperidyloxy)pyrimidin-4-yl]-2-pyridyl]acetamide (A-4)

[0852] Boe,

[0853] NaH, DMF Step-2

[0854] Pd2(dba)3, Xantphos Cs2CO3, dioxane Step-4

[0855] 5%Pd / Al2O3, H2MeOH, THF Step-5

[0856]

[0857] SStep-1:

[0858] To a solution of 4-bromo-2-chloropyrimidine (1, 1.0 g, 5.17 mmol), / e / V-butyl (2-acetamido-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4-yl)carbamate (2, 1.95 g, 5.17 mmol), and sodium carbonate (1.1 g, 10.34 mmol) in a mixture of water (4 mL) and 1,4-dioxane (20 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethanecomplex (421.86 mg, 0.52 mmol) in portions. The resulting reaction mixture was degassed and purged with N2 three times, and the reaction mixture was stirred at 80 °C for 1 h. Then the reaction mixture was cooled to 20 °C and filtered. The filtrate was concentrated in vacuo to afford a residue, which was purified by normal phase column chromatography (Stationary Phase: Silica Gel; Eluent: Gradient from 50 - 100% EtOAc in Petroleum Ether) to afford tert-butyl N-[2-acetamido-5-(2-chloropyrimidin-4-yl)-4-pyridyl]carbamate (3, 1.2 g, 3.3 mmol, 63.8% yield) as a light brown solid. MS (ES+): m / z 364.1 [M + H]+. 'H NMR (400 MHz. METHANOL-t / 4) 5 9.06 (s, 1H), 8.77 (s, 1H), 8.71 (d, J= 5.6 Hz, 1H), 7.97 (d, J= 5.6 Hz, 1H), 2.20 (s, 3H), 1.55 (s, 9H) ppm.

[0859] Step-2:

[0860] To a solution of tert-butyl N- [2-acetamido-5-(2-chloropyrimidin-4-yl)-4-pyridyl] carbamate (3, 2.9 g, 7.97 mmol) in DMF (50 mL) was added sodium hydride (0.38 g, 15.94 mmol) followed by benzy l 4-hydroxypiperidine-l -carboxylate (4, 1.81 mL, 11.96 mmol) at 0 °C under a N2 atmosphere. The resulting reaction mixture was warmed to 20 °C and stirred for 16 h. Then sodium hydride (765.26 mg, 31.89 mmol) was added at 20 °C and the reaction was stirred at 20 °C for another 2 h. The resulting reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to afford a residue, which was purified by normal phase column chromatography (Stationary' Phase: Silica gel; Eluent: Gradient from 0 to 100% EtOAc in Petroleum Ether) to afford benzyl 4-[4-[6-acetamido-4-(tert-butoxycarbonylamino)-3-pyridyl]pyrimidin-2-yl]oxypiperidine-l -carboxylate (5, 4.3 g, 7.64 mmol, 95.88% yield) as alight brown solid. MS (ES+): m / z 563.3 [M + H]+.

[0861] Step-3:

[0862] To a solution of benzyl 4-[4-[6-acetamido-4-(tert-butoxycarbonylamino)-3-pyridyl]pyrimidin-2-yl]oxypiperidine-l -carboxylate (5, 4.7 g, 8.35 mmol) in DCM (40 mL) was added trifluoroacetic acid (10.0 mL, 129.8 mmol). The resulting reaction mixture was stirred at 10 °C for 16 h. Then the reaction mixture was concentrated in vacuo to afford a residue, which was purified by reversed-phase HPLC (Column: Phenomenex Synergi C18 (150 mm * 25 mm) * 10 pm; Mobile phase A: water (modified with 0.1%NH3·H2O), Mobile Phase B: MeCN; Gradient from 75%-95% B over 21 min) to afford benzyl 4-[4-(6-acetamido-4-amino-3-pyridyl)pyrimidin-2-yl]oxypiperidine-l -carboxylate (6, 2.8 g, 6.05 mmol, 72.47% yield) as a light brown solid. MS (ES+): m / z 463.2 [M + H]+. 'H NMR (400 MHz. METHANOL- 4) 5 8.52 (s, 1H), 8.49 (d, J = 5.6 Hz. 1H), 7.50 (d. J = 5.6 Hz. 2H), 7.38 - 7.31 (m, 5H), 5.26 - 5.18 (m, 1H). 5.14 (s, 2H). 3.92 - 3.80 (m, 2H), 3.50 - 3.40 (m, 2H), 2.17 (s, 3H), 2.11 - 2.04 (m, 2H), 1.86 - 1.77 (m, 2H) ppm.

[0863] Step-4:To a solution of 2-chloro-6-(l,l-difluoroethyl)-4-methylpyridine (7, 956.99 mg, 4.99 mmol) in 1.4-dioxane (50 mL) was added cesium carbonate (4438.1 mg. 13.62 mmol), benzyl 4-[4-(6-acetamido-4-amino-3-pyridyl)pyrimidin-2-yl]oxypiperidine-l-carboxylate (6, 2.1 g, 4.54 mmol), and Xantphos (394.09 mg, 0.68 mmol), followed by Pd2(dba)3(415.78 mg, 0.45 mmol). The resulting reaction mixture was heated to 100 °C and stirred for 2 h under an N2 atmosphere. The resulting reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford a residue, which was purified by normal phase column chromatography (Stationary Phase: Silica gel; Eluent: 0 to 100% EtOAc in Petroleum Ether) to afford benzyl 4-[4-[6-acetamido-4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]pyrimi din-2 -yl]oxypiperi din e-l-carboxylate (8, 1.6 g, 2.29 mmol, 55.15% yield) as alight brown solid. MS (ES ): m / z 618.3 [M + H]+. Step-5: (See Figure 3)

[0864] Solution 1 [compound 8 (2.2 g, 3.56 mmol) in methanol (19 mL) and THF (19 mL)] was pumped by Pump 1 {SI, Pl, 0.3 mL / min} into flow reactor 1 {FLR1, SS, Fixed bed, 6.350(l / 4")mm, 1.0 mL, 55.0 °C}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular 5%Pd / Al2O3catalyst (WXSC1035, 1.5 g). The H2 back pressure regulator was adjusted to 1.5 MPa, and the flow rate of H2 set to 10 mL / min. The total reaction was reacted at 55 °C for 137 min. Then the reaction mixture was collected from the reactor output. The reaction was cooled to room temperature, the mixture was filtered, and the filter cake was concentrated in vacuo to afford a residue, which was triturated with MeCN (50 mL) and stirred for 10 min. Then the resulting mixture was filtered, and the filter cake was concentrated in vacuo to afford N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-(4-piperidyloxy)pyrimidin-4-yl]-2-pyridyl]acetamide (A-4, 1.0 g, 2.07 mmol, 58.06% yield) as a white solid. MS (ES+): m / z 484.2 [M + H]+.

[0865] Synthesis of N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-formyl-[2,3'-bipyridin]-6'-yl)acetamide (A-5)

[0866]

[0867]

[0868] SStep-1:

[0869] To a 250 mL multi-neck round-bottom flask containing a well stirred solution of 6-bromopyridine-3-carbaldehyde (1, 5 g, 26.88 mmol) in toluene (50 mL) were added 4-methylbenzenesulfonic acid: hydrate (511.32 mg, 2.69 mmol) and ethylene glycol (2. 8.34 g, 134.40 mmol, 7.50 mL) at room temperature. The resulting reaction mixture was stirred at 120 °C for 16 hours. Upon complete consumption of the starting material, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the obtained crude was purified by column chromatography (230-400 mesh silica gel) using a gradient of 10 to 15% ethyl acetate in pet ether to afford 2-bromo-5-(1,3-dioxolan-2-yl)pyridine (3, 4 g, 17.21 mmol, 64.03% yield) as a pale-yellow oily liquid. LC-MS (ES+): m'z 230.0 [M + H]+.

[0870] Step-2:

[0871] To a 100 mL multi-neck round bottom flask containing well stirred solution of 2-bromo-5-(1,3-dioxolan-2-yl)pyridine (3, 4 g, 17.21 mmol) in 1,4-dioxane (30 mL) and water (5 mL) were added Potassium carbonate, anhydrous, 99% (4.76 g, 34.43 mmol) and 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (4, 8.94 g, 17.21 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 10 minutes before bis(l-diphenylphosphanylcyclopenta-2,4-dien-l-yl)iron;dichloromethane;dichloropalladium (1.41 g, 1.72 mmol) was added at room temperature. The resulting reaction mixture was stirred at 100 °C for 2 hours. Upon complete consumption of the starting material, the reaction mixturewas filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (230-400 mesh silica gel) using a gradient of 35 to 40% ethyl acetate in pet ether to afford 6'-chloro-5-(l,3-dioxolan-2-yl)-[2,3'-bipyridin]-4'-amine (5, 1.8 g, 6.42 mmol, 37.28% yield) as an off-white solid. LC-MS (ES+): m / z 278.1 [M + H]+.

[0872] Step-3:

[0873] To a 20 mL screw capped reaction vial containing a well stirred solution of 6'-chloro-5-(l,3-dioxolan-2-yl)-[2,3'-bipyridin]-4'-amine (5, 1.51 g, 5.40 mmol) in 1,4-dioxane (5 mL) was added Cesium carbonate (3.52 g, 10.80 mmol) and acetamide (6, 478.29 mg, 8.10 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 10 minutes before (5-diphenylphosphanyl-9.9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (312.36 mg, 539.83 pmol)and (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one;palladium (247.17 mg, 269.92 pmol) were added at room temperature. The resulting reaction mixture was stirred at 110 °C for 16 h. Upon complete consumption of the starting material, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (230-400 mesh silica gel) using a gradient of 80 to 90% ethyl acetate in pet ether to afford N-[4-amino-5-[5-(1,3-dioxolan-2-yl)-2-pyridyl]-2-pyridyl]acetamide (7, 800 mg, 2.58 mmol, 47.87% yield) as a pale yellow solid. LC-MS (ES+): m / z 301.2 [M + H]+.

[0874] Step-4:

[0875] To a 40 mL screw-capped reaction vial containing a well-stirred solution of N-[4-amino-5-[5-(1,3-dioxolan-2-yl)-2-pyridyl]-2-pyridyl]acetamide (7, 700 mg, 2.26 mmol) in 1,4-dioxane (10 mL) were added Cesium carbonate (1.47 g, 4.52 mmol) and 4-chloro-2-(1,1-difluoroethyl)pyrimidine (8, 407.81 mg, 2.26 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 10 minutes before 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (130.82 mg, 226.10 pmol) and tris(dibenzylideneacetone)dipalladium(0) (103.52 mg, 113.05 pmol) were added at room temperature. The resulting reaction mixture was stirred at 90 °C for 12 h. Upon complete consumption of the starting material, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The obtained crude was purified by reverse-phase column chromatography (Column: RediSep® C18 column; Mobile phase A: 10 mM Ammonium bicarbonate in water and Mobile phase B: Acetonitrile) to afford N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-(1,3-dioxolan-2-yl)-2-pyridyl]-2-pyridyl]acetamide (9, 160 mg, 238.69 pmol, 10.56% yield) as a pale yellow solid. LC-MS (ES+): m / z 443.1 [M + H]+.

[0876] Step-5:To a 50 mL single-neck round bottom flask containing well stirred solution of / V-[4-[[2-(l,l- difluoroethyl)pyrimidin-4-yl]amino]-5-[5-(l,3-dioxolan-2-yl)-2-pyridyl]-2 -pyridyl] acetamide (9, 75.76 mg, 113.02 pmol) in acetone (5 mL) and water (1 mL) was added trifluoroacetic acid, 99% (64.43 mg, 565.08 pmol. 43.24 pL) at room temperature. The resulting reaction mixture was stirred at 60 °C for 2 h. Upon complete consumption of the starting material, the reaction mixture was concentrated under reduced pressure and the residue was co-distilled with toluene to afford N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-formyl-[2,3'-bipyridin]-6'-yl)acetamide (A- 5, 50 mg, 45.86 pmol, 40.58% yield) as a pale yellow solid, which was used without further purification. LC-MS (ES+): m / z 399.1 [M + H]+.

[0877] The following targeting ligands were prepared using the method described above, with the corresponding aldehyde 1 in Step-1 and bromide / chloride 8 in Step-4.

[0878] Aldehyde 1 in Step- Bromide / Chloride 8 Targeting Ligand

[0879] 1 in Step-4 co

[0880] N Br

[0881] HA

[0882] ■j J

[0883] A-6

[0884] LC-MS (ES+): m / z 412.2 [M + H]+

[0885] N Br O

[0886] X A JI

[0887] Cl

[0888] A ose

[0889] A-7

[0890] LC-MS (ES+): m / z 426.1 [M + H]+

[0891]

[0892] OT _ 1

[0893] ° / " Z—T1 >'0 Lts /

[0894] / / V> N^ Tr °Tvy

[0895] T H

[0896] BrHN\T\^N\Z / /

[0897] o T T Y

[0898] o

[0899] A-8

[0900] LC-MS (ES+): m / z 448.1 [M + H]+

[0901] O

[0902] f~\°

[0903] ^N^Br < T°

[0904] \=N

[0905] ry?'cl>=N C.

[0906] Np^NY_AN\^N

[0907] HN

[0908] / ^0

[0909] A-9

[0910] LC-MS (ES+): m / z 431.2 [M + H]+

[0911] °^n Br

[0912] N^ Br 0

[0913] LJ

[0914] '^N'^^NH

[0915] HJL

[0916] Cv

[0917] fr

[0918] A-10

[0919] LC-MS (ES+): m / z 398.1 [M + H]+

[0920] N

[0921] jl J

[0922] T T

[0923] •^N'X^55>^NH

[0924] " Y

[0925] A ll

[0926] UPLC-MS (ES+): m / z 413.3 [M +H]+

[0927]

[0928] Table 1: Preparation of A-6 to A-l 1Synthesis of N-(5-bromo-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide (A-12)

[0929]

[0930] SStep-1:

[0931] To a 250 mL round-bottom flask containing a well stirred solution of tert-butyl (6-bromopyridin-3-yl)carbamate (1, 6 g, 18.91 mmol) and 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (2, 11.53 g, 18.91 mmol) in water (12 mL) and 1,4-dioxane (48 mL) were added K2CO3 (3.92 g, 28.36 mmol) at ambient temperature. The reaction mixture was purged with nitrogen gas for 5 min before Pd(dppf)C12’ CH2CI2 (1.54 g, 1.89 mmol) was added and the mixture was stirred at 100 °C for 2 hours. Upon completion of reaction as indicated by UPLC, the reaction mixture was passed through a pad of C elite. which was subsequently washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure and the crude was purified by flash chromatography (Stationary Phase: 60-120 mesh silica gel, 120 g snap cartridge; Eluent: a gradient of 0-50% ethyl acetate in petroleum ether; flow rate = 30 mL / min) to afford tert-butyl N-[6-(4-amino-6-chloro-3-pyridyl)-3-pyridyl]carbamate (3, 3.0 g, 9.28 mmol, 49.10% yield) as an off-white solid. LC-MS (ES+): m z 321.1 [M + H]+.Step-2:

[0932] To a 250 mL round-bottom flask containing a well stirred solution of tert-butyl N-[6-(4-amino-6-chloro-3-pyridyl)-3-pyridyl]carbamate (3, 3 g, 9.26 mmol) and acetamide (4, 1.09 g, 18.52 mmol) in anhydrous 1,4-dioxane (50 mL) were added cesium carbonate (6.03 g, 18.52 mmol) at ambient temperature. The reaction mixture was purged with nitrogen gas for 5 min before Xantphos (1.07 g, 1.85 mmol) and Pd2(dba)3 (847.85 mg, 925.89 pmol) were added at ambient temperature. The reaction mixture was then stirred at 110°C for 16 hours. Upon completion of reaction as indicated by UPLC, the reaction mixture was filtered through a pad of celite, which was subsequently washed with ethyl acetate (300 mL) and the filtrate was concentrated under reduced pressure. The crude was purified by reversed-phase column chromatography [Column; RediSep® C18, 120 g gold; Mobile phase A: 0.1% formic acid in water and Mobile phase B: CH3CN, Flow rate: 15 mL / min] to afford tert-butyl N-[6-(6-acetamido-4-amino-3-pyridyl)-3-pyridyl]carbamate (5, 1.4 g, 3.31 mmol, 35.70% yield) as a light green solid. LC-MS (ES+): m / z 344.3 [M + H]+.

[0933] Step-3:

[0934] To vials (40 mL x 2 ) containing a well stirred solution of tert-butyl A-[6-(6-acetamido-4-amino-3-pyridyl)-3-pyridyl]carbamate (5, 1.4 g, 3.30 mmol) and 4-chloro-2-( 1,1-difluoroethyl)pyrimidine (6, 884.57 mg, 4.95 mmol) in anhydrous 1,4-dioxane (40 mL) were added K3PO4 (2.10 g, 9.91 mmol) at ambient temperature. The reaction mixture was purged with nitrogen gas for 5 min before Xantphos (382.17 mg, 660.49 pmol) and Pd2(dba)? (302.41 mg, 330.25 pmol) was added at ambient temperature. The reaction mixture was then stirred at 90°C for 4 hours. Upon completion of reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite, which was subsequently washed with ethyl acetate (60 mL) and dichloromethane (50 mL). The filtrate was concentrated under reduced pressure and the obtained crude was purified by reverse-phase column chromatography [Column; RediSep® C18, 60 g gold; Mobile phase A: 0.1% formic acid in water and Mobile phase B: CHsCN, Flow rate: 15 mL / min] to afford tert-butyl N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]carbamate (7, 350 mg, 656.84 pmol, 19.89% yield) as an off-white solid. LC-MS (ES+): m / z 486.3 [M + H]

[0935] Step-4:

[0936] To a 100 mL round-bottom flask containing well stirred solution of tert-butyl N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]carbamate (7, 350 mg, 656.04 μmol) in anhydrous methanol (10 mL) were added 4.0 M HC1 in 1,4-dioxane (1.64 mL) at 0 °C and the mixture was stirred at ambient temperature for 2 hours. Upon completion of reaction mixture as indicated by UPLC, the reaction mixture was concentratedunder reduced pressure, and the crude material was co-distilled with methyl tert-butyl ether (10 mL x 2) and petroleum ether (10 mL x 2 times). The crude was then dissolved in methanol (10 mL) and MP-carbonate (2mmol / g) (700 mg, 656.04 pmol) was added and stirred for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford V-[5-(5-amino-2-pyridyl)-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-2-pyridyl]acetamide (8, 250 mg. 580.55 pmol, 88.49% yield) as a yellow solid. LC-MS (ES+): m / z 386.2 [M + H]+.

[0937] Step-5:

[0938] To a 100 mL round-bottom flask containing well stirred solution of jV-[5-(5-amino-2-pyridyl)-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-2-pyridyl]acetamide (8, 250 mg, 580.55 pmol) in anhydrous MeCN (5 mL) were added isoamyl nitrite (136.02 mg, 1.16 mmol, 155.45 pL) at ambient temperature and the mixture was stirred for 15 min before CuBr (166.56 mg, 1.16 mmol, 35.36 pL) was added. The reaction mixture was stirred at ambient temperature for 3 hours. Upon completion of the reaction as indicated by UPLC, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (50 mL x 2 times). The combined organic layer was washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by flash column chromatography (Stationary Phase: 60-120 mesh silica gel, 25 g snap cartridge, Eluent: a gradient of 0-100% ethyl acetate in petroleum ether; flow rate = 30 mL / min) to afford N-(5-bromo-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide (A- 12, 130 mg. 260.84 pmol, 44.93% yield) as a yellow solid. LC-MS (ES+): m / z 450.9 [M + H]+.

[0939] Synthesis of A-|5-(5-biomo-2-pyiidyl)-4-[[6-|(3 / ?)-3-methoxytetiahydiofiiian-3-yl|-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide (A- 13)

[0940] CS2CO3, dioxane

[0941] Pd(OAc)2, Xantphos Step-1

[0942] °- p^ / __ B-B' F NBS, MeCN o 5 b-'Y" Step-2 KOAc, dioxane

[0943] Pd(dppf)CI2«DCM

[0944]

[0945] Step-3Cs2CO3, dioxane Xantphos Pd G3 Step-6

[0946]

[0947] SStep-1:

[0948] To a 500 mL two-neck round-bottom flask containing a well stirred solution of / V-(4-bromo-2-pyridyl)acetamide (1, 11 g, 51.15 mmol) and tert-butyl carbamate (2, 8.99 g, 76.73 mmol) in dioxane (19.57 mL) was added CS2CO3 (50.00 g, 153.45 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 min before Xantphos (4.44 g, 7.67 mmol) and Pd(OAc)2 (1.15 g, 5.12 mmol) were added, 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 in vacuo. The crude product was purified by flash chromatography (Stationary Phase: 60-120 mesh silica gel; eluent: 0-100% ethyl acetate in petroleum ether) to afford te / 7-butyl jV-(2-acetamido-4-pyridyl)carbamate (3, 11 g, 42.59 mmol, 83.27% yield) as a white solid. LC-MS (ES+): m / z 252.1 [M + H].

[0949] Step-2:

[0950] In a 100 mL single-neck round-bottom flask, a well-stirred solution of tert-butyl 7V-(2-acetamido-4-pyridyl)carbamate (3, 2.5 g, 9.95 mmol) in acetonitrile (20 mL) was cooled to 0 °C before N-bromosuccinimide (1.77 g, 9.95 mmol) was added and the reaction mixture was stirred for 1 h at 70 °C. The reaction mixture was then diluted by water (20 mL) and extracted by ethyl acetate (2 x 50 mL). The organic phases were washed with brine (lOmL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 0-100% ethyl acetate in petroleum ether) to afford tert-butyl N-(2-acetamido-5-bromo-4-pyridyl)carbamate (4, 2.5 g, 5.30 mmol, 53.27% yield) as a white solid. LC-MS (ES+): m / z 330.0 [M + H]+.

[0951] Step-3:To a 100 mL round-bottom flask containing a well stirred solution of tert-butyl 7V-(2-acetamido-5-bromo-4-pyridyl)carbamate (4, 2 g. 6.06 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (5, 2.31 g, 9.09 mmol) in 1,4-dioxane (20 mL) was added Potassium acetate (2.97 g, 30.29 mmol) at room temperature. Nitrogen gas was purged through the mixture for 5 minutes before Pd(dppf)Cl2·DCM (247.33 mg, 302.87 pmol) was added and the reaction mixture was stirred at 90 °C for 6 h. Upon completion of the reaction, the reaction mixture was filtered through a pad of Cehte, and the Celite pad was washed with ethyl acetate (200 mL). The combined filtrate was concentrated under reduced pressure to afford [6-acetamido-4-(terLbutoxycarbonylamino)-3-pyridyl]boronic acid (6, 2.6 g, 5.99 mmol, 98.91% yield) as a brown solid. LC-MS (ES+): m / z 296.1 [M + H]+

[0952] Step-4:

[0953] To a 250 mL round-bottom flask containing a well stirred solution of 5-bromo-2-iodo-pyridine (7, 2.5 g, 8.81 mmol) and [6-acetamido-4-(terLbutoxycarbonylamino)-3-pyridyl]boronic acid (6, 3.82 g, 8.81 mmol) in a mixture of water (3 mL) and dioxane (30 mL) was added K2CO3 (2.43 g. 17.61 mmol) at room temperature. Nitrogen gas was purged through the mixture for 5 minutes before Pd(dppf)Cl2 DCM (719.15 mg, 880.62 pmol) was added and the reaction mixture was stirred at 60 °C for 2h. Upon completion of the reaction as indicated by UPLC, the reaction mixture was passed through a pad of Celite, and the Celite pad was washed with ethyl acetate (200 mL). The filtrate was diluted with water (150 mL) and extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 60-120 mesh silica gel, 50 g snap cartridge; flow rate = 30 mL / min; Eluent: 0-10% ethyl acetate in petroleum ether) to afford tert-butyl 7V-[2-acetamido-5-(5-bromo-2-pyridyl)-4-pyridyl (carbamate (8, 2 g, 4.47 mmol, 50.75% yield) as an white solid. LC-MS (ES+): m z 408.1 [M + 2H]+.

[0954] Step-5:

[0955] To a 100 mL single-neck round-bottom flask containing a stirred solution of tert-butyl 7V-[2-acetamido-5-(5-bromo-2-pyridyl)-4-pyridyl]carbamate (8, 2 g, 4.91 mmol) inDCM (30 mL) was added 4.0 M HC1 in 1,4-dioxane (4 M. 12.28 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as indicated by the UPLC-MS, the solvent was removed under reduced pressure and the crude product was washed with MTBE (20 mL) to afford JV-[4-amino-5-(5-bromo-2-pyridyl)-2-pyridyl]acetamide (9, 1.5 g, 4.60 mmol, 93.74% yield) as an off-white solid. LC-MS (ES+): m 'z 307.1 [M]+.

[0956] Step-6:To a 20 mL screw cap vial containing a well stirred solution of / V-|4-amino-5-(5-bromo-2- pyridyl)-2 -pyridyl] acetamide hydrochloride (9. 500 mg, 1.37 mmol) and 2-bromo-6-[(37?)-3- methoxytetrahydrofuran-3-yl]-4-methyl-pyridine (10, 489.17 mg, 1.78 mmol) in 1,4-di oxane (15 mL) was added CS2CO3 (1.43 g, 4.39 mmol) at room temperature. Nitrogen gas was purged through the mixture for 5 minutes before XantPhos Pd G3 (130.08 mg, 137.16 pmol) was added and the reaction mixture was stirred at 90 °C for 16 h. 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 THF (20 mL). The filtrate was concentrated under reduced pressure and the crude material was purified by reverse-phase column chromatography [Column: RediSep® Cl 8; Mobile phase A: 10 mM Formic acid in water and Mobile phase B: MeCN], the pure fractions were concentrated to get crude. the crude was triturated with MTBE(10 ml) to afford 7V-[5-(5- bromo-2-pyridyl)-4-[[6-[(3 )-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2- pyridyl] acetamide (A-13, 300 mg, 490.66 pmol, 35.77% yield) as a pale-yellow solid. LC-MS (ES+): m / z 500.1 [M + 2]+.

[0957] The following targeting ligand was prepared using the method described above, with the corresponding building blocks in Step-6.

[0958] Bromide in Step-6 Targeting ligand MS ^^. Br

[0959] F^ ^ LC-MS (ES+): m / z J Y 464.1 [M + 2]+.

[0960] 0

[0961] Br H Y

[0962] jl

[0963] F' i

[0964] F

[0965] A-14

[0966]

[0967] Table 2: Preparation of A-14

[0968] Synthesis of 2V-(5-chloro-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'- yl)acetamide (A-23)

[0969] TFA DCM Pd2(dba)3, Xantphos Step-1 K3PO4, dioxane Step-2

[0970]

[0971]

[0972] SStep-1:

[0973] A solution of / e / 7-butyl (2-acetamido-5-bromopyridin-4-yl)carbamate (1, 4.0 g, 12.11 mmol) in DCM (12 mL) and TFA (12.0 rnL, 12.11 mmol) was stirred at 20°C for 2 h. The reaction mixture was basified to pH = 9 by saturated NaHCOs aqueous solution and diluted with water (80 mL). The water phase was extracted with EtOAc (80 mL x 3). The combined organic phase was washed with brine (80 mL x 3), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford A-(4-amino-5-bromopyridin-2-yl)acetamide (2, 2.3 g, 10.0 mmol, 82.52% yield) as a white solid. MS (ES+): m / z 232.0 [M + H]+.

[0974] Step-2:

[0975] To a solution of 4-chloro-2-(l,l-difluoroethyl)pyrimidine (3, 1.0 g, 5.6 mmol) and A-(4-amino-5-bromopyridin-2-yl)acetamide (2, 1288.4 mg, 5.6 mmol) in 1,4-dioxane (18 mL) was added K3PO4 (2377.44 mg, 11.2 mmol), Xantphos (324.04 mg, 0.56 mmol) and Pd2(dba)3(512.81 mg, 0.56 mmol) at 20°C under N2 atmosphere. The mixture was stirred at 100 °C for 2 h. The reaction was cooled to room temperature. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was poured into water (60 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed by brine (40 mL x 4). dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (S1O2. Petroleum ether / Ethyl acetate = 0:1, R / = 0.4) to afford X-(5-bromo-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide (4, 1.2 g, 3.22 mmol, 57.58% yield) as a yellow solid. MS (ES+): m / z 374.1 [M + H]+.

[0976] Step-3:

[0977] To a solution of 2V-(5-bromo-4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)pyridin-2-yl)acetamide (4, 1.2 g, 3.22 mmol) and bis(pinacolato)diboron (5, 1801.33 mg, 7.09 mmol) in 2-methyltetrahydrofuran (2 mL) was added KOAc (1265.77 mg, 12.9 mmol) at 20°C, the mixture was stirred at 20°C for 0.5 h under N2. A solution of XPhos (153.71 mg. 0.32 mmol) and Pd(OAc)2 (36.19 mg, 0.16 mmol) in 2-methyltetrahydrofuran (15 mL) was added and the reaction was heated at 75 °C for 12 h. The mixture was filtered and the filtrate was concentratedin vacuum to give a residue. The residue was triturated with CH3CN (10 mL) at 25°C. Then the suspension were filtered and the filter cake were concentrated under reduced pressure to afford A^-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (6, 770.0 mg, 1.84 mmol, 56.96% yield) as purple solid. MS (ES+): m / z 338.1 [M + H]+.

[0978] Step-4:

[0979] To a solution of A-(4-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (6, 700.0 mg, 1.67 mmol) in 1,4-dioxane (7 mL) and water (1.5 mL) was added 2-bromo-5 -chloropyridine (7, 385.58 mg, 2.0 mmol), Pd(dppf)Cl2 (122.17 mg, 0.17 mmol) and K2CO3(461.52 mg, 3.34 mmol) under N2 at 20°C, the mixture was heated to 100 °C and stirred for 2 h under N2. The reaction was cooled to room temperature, the mixture was poured into water (60 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with brine (60 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (neutral condition, Phenomenex Synergi Cl 8 150 mm x 25 mm x 10 pm; mobile phase:

[0980] [water-MeCN]; B%: 50%-60%, 20 min) to afford 2V-(5-chloro-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide (A-23, 115.0 mg, 0.28 mmol, 17.01% yield) as ayellow' solid. MS (ES ): m / z 405.1 [M + H]+.

[0981] Synthesis of A-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-(5-hydroxy-2-pyridyl)-2-pyridyljacetamide (A-15)

[0982]

[0983] 20% Pd(OH)2 / C

[0984] dioxane, DMF

[0985] Step-4

[0986]

[0987] SStep-1:

[0988] To a 500 mL round-bottom flask containing a well stirred solution of 5-benzyloxy-2-bromo-pyridine (1, 7.5 g, 28.40 mmol) and 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (2, 12.05 g, 28.40 mmol) in anhydrous 1,4-dioxane (80 mL) and water (20 mL) were added K2CO3 (7.85 g, 56.79 mmol) at ambient temperature. The mixture was purged with N2 for 5 min before Pd(dppf)Cl2·DCM (2.32 g, 2.84 mmol) was added at ambient temperature and the reaction mixture was stirred for 90°C for 2 hours. After completion of reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite, which was subsequently washed with ethyl acetate (200 mL). The filtrate was then concentrated under reduced pressure, and the crude material was purified by flash column chromatography (Stationary Phase: 60-120 mesh silica gel, 340 g snap cartridge; Eluent: a gradient of 0-40% ethyl acetate in petroleum ether; flow7rate = 60 mL / min). The product was then triturated with pet-ether (150 mL) and dried over under vacuum to afford 5-(5-benzyloxy-2-pyridyl)-2-chloro-pyridin-4-amine (3, 6 g, 17.61 mmol, 62.01% yield) as an off-white solid. LCMS (ES+): m / z 312.0 [M + H]+.

[0989] Step-2:

[0990] To a 40 mL vial containing a well stirred solution of 5-(5-benzyloxy-2-pyridyl)-2-chloro-pyridin-4-amine (3, 1 g, 3.21 mmol) and acetamide (4, 947.35 mg, 16.04 mmol) in 1,4-dioxane (10 mL) was added CS2CO3 (2.09 g, 6.42 mmol) at room temperature. The mixture was purged with nitrogen gas for 2 min before XantPhos Pd G3 (304.19 mg, 320.75 pmol) was added. The reaction mixture was stirred at 110°C for 2 h and the reaction progress was monitored by LCMS and TLC. The reaction mixture was then filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase column chromatography [Column: X-bridge C8 (250x19)mm 5 microns, Mobile phase A: 0.1 % formic acid in water and Mobile phase B: MeCN] to afford X-[4-amino-5-(5-benzyloxy -2 -pyridyl)-2-pyridyl] acetamide (5, 1 g, 2.90 mmol, 90.35% yield) as a pale yellow7solid. LC-MS (ES+): m z 335.3 [M + H]+.

[0991] Step-3:To a 40 mL vial containing a well stirred solution of A-[4-amino-5-(5-benzyloxy-2-pyridyl)-2- pyridyl] acetamide (5, 1 g. 2.99 mmol) and 4-chloro-2-(l,l-difluoroethyl)pyrimi dine (6, 801.06 mg, 4.49 mmol) in dioxane (10 mL) was added CS2CO3 (1.95 g, 5.98 mmol) at room temperature. The mixture was purged with nitrogen gas for 2 min before XantPhos Pd G3 (283.62 mg, 299.07 pmol) was added. The reaction mixture was stirred at 110°C for 2 h and the reaction progress was monitored by LCMS and TLC. The reaction mixture was then filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was washed with MTBE and then dried under vacuum to afford A-[5-(5-benzyloxy-2- pyridyl)-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-2-pyridyl]acetamide (7, 1 g, 944.43 pmol, 31.58% yield) as a yellow solid. LC-MS (ES+): m / z 477.3 [M + H]+

[0992] Step-4:

[0993] To a 100 mL single-neck round-bottom flask containing a well stirred solution ofA-[5-(5- benzyloxy-2-pyridyl)-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-2-pyridyl]acetamide (7, 1 g, 2.10 mmol) in 1,4-di oxane (15 mL) and DMF (5 mL) was added 20 wt.% Palladium hydroxide on carbon, 50% water (147.37 mg. 209.87 pmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The reaction mixture was then filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase column chromatograph O \zy —= [Column: X-bridge C8 (250><19)mm 5 microns, Mobile phase A: 0.1 % formic acid in w &ater and Mobile phase B: MeCN ] to afford A-[4-[[2-(l,l-difluoroethyl)pyrimidin-4- 0— '

[0994] yl]amino]-5-(5-hydroxy-2-pyridyl)-2-pyridyl]acetamide (A-15, 770 mg, 1.72 mmol, 82.05% yield) as a white solid. LC-MS (ES+): m / z 387.1 [M + H]+.

[0995] The following targeting ligand was prepared using the method above, with the corresponding chloride 6 in Step-3.

[0996] Chloride 6 in Step-3 Targeting ligand MS

[0997] LC-MS (ES+): m / z 436.2 [M V IR) /

[0998] + H]+.

[0999] T H O

[1000] A-16

[1001]

[1002] Table 3: Preparation of A-16Syn thesis of N- [5- [5-(2-azaspiro [3.4] octan-6-yloxy)-2-pyridyl]-4- [ [6-[(3 / ?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide (A- 17)

[1003]

[1004] SStep-1:

[1005] To a 20 mL vial containing a well stirred solution of A-[5-(5-hydroxy-2-pyridyl)-4-[[6-[(37?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide (A-16, 150 mg, 344.45 pmol) and tert-butyl 6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (2, 117.44 mg, 516.68 pmol) in anhydrous THF (5 mL) were added triphenylphosphine (271.03 mg, 1.03 mmol) and diisopropylazodicarboxylate (208.95 mg, 1.03 mmol, 203.46 pL) at ambient temperature. The reaction mixture was stirred at 70 °C for 3 hours. Another portion of triphenylphosphine (271.03 mg, 1.03 mmol) and diisopropylazodicarboxylate (208.95 mg, 1.03 mmol, 203.46 pL) were added to the reaction mixture at ambient temperature and stirred at 70 °C for 3 hours. After completion of reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure and the crude product was purified by reverse-phase column chromatography [Column: RediSep® C18, 60 g gold; Mobile phase A: 0.1% formic acid in water and Mobile phase B: CH3CN, Flow rate: 15 mL / min] to afford tert-butyl 6-[[6-[6-acetamido-4-[[6-[(3A)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-3-pyridyl]-3-pyridyl]oxy]-2-azaspiro[3.4]octane-2-carboxylate (3, 40 mg, 57.39 pmol, 16.66% yield) as a pale-yellow solid. LC-MS (ES+): m / z 645.3 [M + H]+.

[1006] Step-2:

[1007] To a 25 mL round-bottom flask containing a well stirred solution of / c / 7-butyl 6-[[6-[6-acetamido-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-3-pyridyl]-3-pyndyl]oxy]-2-azaspiro[3.4]octane-2-carboxylate (3, 35 mg, 50.21 pmol) in DCM (3 mL) was added TFA (5.73 mg, 50.21 μmol, 3.84 μL) at 0 °C and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure, and the residue was co-distilled with toluene, washed with MTBE, and dried to afford Ar-[5-[5-(2-azaspiro[3.4]octan-6-yloxy)-2-pyridyl]-4-[[6-[(37?)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide trifluoroacetate (A-17, 30 mg, 40.08 pmol, 79.82% yield) as an off-white solid. LC-MS (ES+): m / z 545.2 [M + H]+

[1008] Synthesis of A-|5-[5-(2-azaspiro[3.4|octan-6-yloxy)-2-pyridyl|-4-|[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide (A- 18)

[1009]

[1010] SStep-1:To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 6-bromopyridin-3-ol (1. 1 g, 5.75 mmol) and tert-butyl 6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (2, 1.31 g, 5.75 mmol) in anhydrous tetrahydrofuran (20 mL) was added triphenylphosphine (2.26 g, 8.62 mmol) at 0 °C. After 5 minutes, diisopropylazodicarboxylate (1.74 g, 8.62 mmol, 1.70 mL) was added to the reaction mixture at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and UPLC. After complete consumption of the starting material, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (Column: RediSep® C18 column; Mobile phase A: 0.1% Formic acid in water and Mobile phase B: Acetonitrile) to afford tert-butyl 6-[(6-bromo-3-pyridyl)oxy]-2-azaspiro[3.4]octane-2-carboxylate (3, 1.5 g, 3.82 mmol, 66.53% yield) as a pale-yellow7solid. LC-MS (ES+): m / z 327.1 [M-Isobutene+ H]+.

[1011] Step-2:

[1012] To an 40 mL screw-capped reaction vial containing a well-stirred solution of fert-butyl 6-((6-bromo-3-pyridyl)oxy]-2-azaspiro[3.4]octane-2-carboxylate (3, 1.5 g, 3.69 mmol) in 1,4 dioxane (30 mL) and water (6 mL) were added 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (4, 1.88 g, 4.43 mmol) and sodium carbonate (781.90 mg, 7.38 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 5 minutes. Subsequently, Pd(dppf)Cl2·DCM (301.22 mg, 368.86 pmol) was added and the reaction mixture was stirred at 90°C for 2 hours. Upon the complete consumption of the starting material, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The obtained crude was purified by column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 35 to 40% ethyl acetate in petroleum ether) to afford tert-butyl 6-[[6-(4-amino-6-chloro-3-pyridyl)-3-pyridyl]oxy]-2-azaspiro[3.4]octane-2-carboxylate (5, 1 g, 2.20 mmol, 59.67% yield) as an off-white solid. LC-MS (ES+): m / z 431.3 [M + H]+.

[1013] Step-3:

[1014] To a 40 mL screw cap vial containing a well stirred solution of terf-butyl 6-[[6-(4-amino-6-chloro-3-pyridyl)-3-pyridyl]oxy]-2-azaspiro[3.4]octane-2-carboxylate (5, 450 mg, 990.48 pmol) and acetamide (6, 292.52 mg, 4.95 mmol) in 1,4-dioxane (15 mL) was added CS2CO3 (806.80 mg, 2.48 mmol) at room temperature. Nitrogen gas w as purged through the reaction mixture for 10 minutes before XantPhos Pd G3 (93.93 mg, 99.05 pmol) was added and the reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was then passed through a pad of Celite, and the filtrate w as concentrated under reduced pressure. The crude product w as purified by reverse-phase column chromatography [Column: RediSep® C18; Mobile phase A: lOmMFA in water and Mobile phase B: MeCN] to afford tert-butyl 6-[[6-(6-acetamido-4-amino-3-pyridyl)-3-pyridyl]oxy]-2-azaspiro[3.4]octane-2-carboxylate (7, 350 mg, 588.74 pmol, 59.44% yield). LC-MS (ES+): m / z 454.2 [M + H]+.

[1015] Step-4:

[1016] To a 20 mL screw-cap vial containing a well-stirred solution of tert-butyl 6-[[6-(6-acetamido-4-amino-3-pyridyl)-3-pyridyl]oxy]-2-azaspiro[3.4]octane-2-carboxylate (7, 200 mg, 382.64 pmol) and 2-chloro-6-(1,1-difluoroethyl)-4-methyl-pyridine (8, 120.78 mg, 573.96 pmol) in 1,4-dioxane (6 mL) was added cesium carbonate (374.01 mg, 1.15 mmol) and DIPEA 247.27 mg, 1.91 mmol. 333.24 pL) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes. Subsequently, Pd2(dba)3 (35.04 mg, 38.26 pmol) and XantPhos (22.14 mg. 38.26 pmol) were added and the reaction mixture was stirred at 110 °C for 16 h. After completion of the reaction as indicated by the UPLC-MS, the reaction mixture was passed through a pad of Celite and the fdtrate was concentrated under reduced pressure. The crude compound was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 80 to 90% ethyl acetate in petroleum ether) to afford / e / 7-butyl 6-[[6-[6-acetamido-4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-3-pyridyl]oxy]-2-azaspiro[3.4]octane-2-carboxylate (9, 100 mg, 124.86 pmol, 32.63% yield) as a pale-yellow solid. LC-MS (ES+): m / z 609.0 [M + H]+

[1017] Step-5:

[1018] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 6-[[6-[6-acetamido-4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-3-pyridyl]-3-pyridyl]oxy]-2-azaspiro[3.4]octane-2-carboxylate (9, 100 mg, 124.86 pmol) in anhydrous DCM (5 mL) was added trifluoroacetic acid (142.37 mg, 1.25 mmol, 95.55 pL) atO °C. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the crude product was triturated with MTBE (7 mL) and dried to afford N-[5-[5-(2-azaspiro[3.4]octan-6-yloxy)-2-pyridyl]-4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide trifluoroacetate (A-18, 75 mg. 100.42 pmol, 80% yield) as a pale-yellow solid. LC-MS (ES+): m / z 509.6 [M + H]+.

[1019] Synthesis of N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(2-(pyrrolidin-3-yloxy)pyrimidin-4-yl)pyridin-2-yl)acetamide (A-22)o

[1020]

[1021] SStep-1:

[1022] To a solution of 4-bromo-2-chloropyrimidine (1, 1.54 g, 7.95 mmol, 1 equiv), tert-butyl (2-acetamido-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-yl)carbamate (2, 3.0 g, 7.95 mmol, 1 equiv), sodium carbonate (1.69 g, 15.9 mmol, 2 equiv) in water (4 mL) and 1,4-dioxane (30 mL) was added Pd(dppf)Cl2 (649 mg, 0.8 mmol, 1 equiv) in portions under N2 atmosphere. The reaction mixture stirred at 80 °C for 1 h under N2 atmosphere. Then the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed by brine (40 mL x 4). dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo. The crude material was purified by column chromatography (Stationary Phase: Silica gel; Eluent: Gradient from 1 / 0 to 1 / 1 Petroleum / EtOAc) to afford tertbutyl (2-acetamido-5-(2-chloropyrimidin-4-yl)pyridin-4-yl)carbamate (3, 1.58 g, 4.34 mmol, 54.61% yield) as ayellow solid. LC-MS (ESI): m / z 364.1 [M + H]+.

[1023] Step-2:

[1024] To solution of tert-butyl (2-acetamido-5-(2-chloropyrimidin-4-yl)pyridin-4-yl)carbamate (3, 1.5 g, 4.12 mmol, 1 equiv) in DMF (30 mL) was added sodium hydride (330 mg, 8.25 mmol, 2 equiv) at 0 °C under an N2 atmosphere, and the reaction mixture was stirred for 0.5 h. Then asolution of benzyl 3-hydroxypyrrolidine-1-carboxylate (4, 958 mg, 4.33 mmol, 1.5 equiv) in DMF (7.5 mL) was added and the reaction mixture was stirred at 20°C for 12 h under N2 atmosphere. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo. The crude material was purified by column chromatography (Stationary Phase: Silica gel; Eluent: Gradient from 1 / 0 to 1 / 1 Petroleum / EtOAc) to afford benzyl 3-((4-(6-acetamido-4-((tert-butoxycarbonyl)amino)pyridin-3-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-carboxylate (5, 1.4 g, 2.55 mmol, 61.89% yield) as a yellow solid. LC-MS (ESI): m / z 549.3 [M + H]+.

[1025] Step-3:

[1026] To a solution of benzyl 3-((4-(6-acetamido-4-((tert-butoxycarbonyl)amino)pyridin-3-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-carboxylate (5, 1.3 g, 2.37 mmol, 1 equiv) in DCM (10 mL) was added TFA (5.0 mL) and the reaction mixture was stirred at 25°C for 1 h. The reaction mixture was poured into saturated sodium carbonate solution (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo to afford benzyl 3-((4-(6-acetamido-4-aminopyri din-3 -yl)pyrimi din-2 -yl)oxy)pyrrolidine-l -carboxylate (6, 1.05 g, 2.34 mmol, 98.8% yield) as an off-white solid, which was used without further purification. LC-MS (ESI): m / z 449.2 [M + H]+.

[1027] Step-4:

[1028] To a solution of 2-chloro-6-( 1, 1 -difluoroethyl)-4-methylpyridine (7, 487 mg, 2.54 mmol, 1.2 equiv) in 1,4-dioxane (20 mL) was added cesium carbonate (2.07 g, 6.35 mmol, 3 equiv), benzyl 3-((4-(6-acetamido-4-aminopyridin-3-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-carboxylate (6, 950 mg. 2.12 mmol), BINAP (264 mg, 0.42 mmol, 0.2 equiv) and Pd2(dba)3 (194 mg, 0.21 mmol, 0.1 equiv). The resulting reaction mixture was stirred at 100°C for 12 h under an N2 atmosphere. Then the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (40 mL x 4). dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo to afford the crude material, which was purified by column chromatography (Stationary Phase: Silica gel; Eluent: gradient from 20 / 1 / 0 to 0 / 10 / 1 petroleum ether / EtOAc / methanol) to yield partially purified material, which w as triturated with MeCN (5 mL) and filtered. The filter cake w as washed with petroleum ether (10 mL) and concentrated to afford benzyl 3-((4-(6-acetamido-4-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)pyridin-3-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-carboxylate (8, 670 mg, 1.11 mmol, 49.78% yield) as a brown solid, which was used without further purification. LC-MS (ESI): m / z 604.4 [M + H]+.Step-5: (see Figure 4)

[1029] Solution 1: benzyl 3-((4-(6-acetamido-4-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)pyridin-3-yl)pyrimidin-2-yl)oxy)pyrrolidine-1-carboxylate (8, 620 mg, 1.03 mmol) in DMF (14 mL), methanol (7 rnL), and THF (7 mL). The fixed bed (FLR1, volume 5 mL) was completely packed with granular catalyst [5% Pd / ALCh, WXSC1035, 2.4 g]. The H2 back pressure regulator was adjusted to 0.1 MPa. and the H2 flow rate was set to 9.000 mL / min. Solution 1 was pumped by Pump 1 {SI, Pl, 1 mL / min} to flow reactor 1 {FLR1, SS, Fixed bed, 6.350(l / 4")mm, 5.000 mL, 55.0°C}. The total reaction was performed at 55 °C for 90 min. Then the reaction mixture was collected from the reactor output and concentrated in vacuo to afford N-(4-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(2-(pyrrolidin-3-yloxy)pyrimidin-4-yl)pyridin-2-yl)acetamide (A-22, 475 mg, 1.01 mmol. 91.15% yield) as an off-white solid, which was used without further purification. LC-MS (ESI): m / z 470.2 [M + H]+.

[1030] Synthesis of 6-((6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)(methyl)amino)-6-oxohexanoic acid (A-19)

[1031]

[1032] SStep-1:

[1033] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 6-tert-butoxy-6-oxo-hexanoic acid (2, 176.22 mg, 871.31 pmol) and 1-methyl imidazole (429.23 mg. 5.23 mmol, 414.71 pL) in anhydrous MeCN (1.8 mL) and DMF (0.2 mL) were added TCFH (733.42 mg, 2.61 mmol) and N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-(methylamino)-2-pyridyl]-2-pyridyl]acetamide (A-l, 200 mg, 435.66 pmol) at ambient temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h and monitored byLCMS. Thereafter, the solvent was evaporated under reduced pressure and the crude material was purified by reverse-phase prep-HPLC (Column: RediSep® C18 (250 x 19) mm, mobile phase: 0.1% ammonium bicarbonate in water: MeCN) and the pure fractions were lyophilized to afford tert-butyl 6-[[6-[6-acetamido-4-[[2-(l, 1 -difluoroethyl)pyrimidin-4- yl]amino]-3-pyridyl]-3-pyridyl]-methyl-amino]-6-oxo-hexanoate (3, 160 mg, 270.83 pmol, 62.17% yield) as an off-white solid. LC-MS (ES+): m / z 584.2 [M + H]+.

[1034] Step-2:

[1035] To a 50 mL single-neck round bottom flask containing a well-stirred solution of fert-butyl 6-[[6- [6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-methyl- amino] -6-oxo-hexanoate (3, 160 mg, 271.41 pmol) in anhydrous DCM (3 mL) was added 4.0 M HC1 in 1,4-dioxane (4 M, 678.51 pL) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h. After completion of the reaction as indicated by LCMS, the reaction mixture was concentrated under reduced pressure and the residue was codistilled with MTBE (2 x 20 mL) to afford 6-((6'-acetamido-4'-((2-(l,l-difluoroethyl)pyrimi din- 4-yl)amino)-[2.3'-bipyridin]-5-yl)(methyl)amino)-6-oxohexanoic acid (A-19, 130 mg. 236.48 pmol, 87.13% yield) as a brown solid. LCMS (ES‘): m / z 526.0 |M - HJ".

[1036] The following targeting ligands were prepared using the method described above, using the corresponding acid as a building block in Step-1.

[1037] Acid 2 in Step-1 Targeting ligand MS

[1038] OH LC-MS (ES+):

[1039] O^OH

[1040] r0m / z 584.3 [M + H]+.

[1041] Y Y I I

[1042] 1 0 A J

[1043] 1

[1044] A-20

[1045] 0 LC-MS (ES+):

[1046] m / z 500.2 [M + 1 0

[1047] H I H]+.

[1048] T n |

[1049] 1 0

[1050] A-21

[1051]

[1052] Table 4: Preparation of A-20 and A-21

[1053] Example 2: Synthesis of CRBN Binders and Intermediates

[1054] References for the Synthesis of Building Blocks

[1055] Building Block Reference

[1056] OBn Compound was prepared using the method described on page 308-311 of WO2022271727

[1057] WO20222717275.

[1058] f T >°

[1059] Br'^ N

[1060] 5-bromo-l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl- benzimidazol-2-one

[1061] OBn Compound was prepared using theNmethod described on page 181-183 of WO20222717276.

[1062] f T >°

[1063] BrX

[1064] 4-bromo-l-(2,6-dibenzyloxy-3-pyridyl)-3-methyl- benzimi dazol -2 -one

[1065]

[1066] Table 5: Preparation of building blocks

[1067] 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6- dione (B-l)

[1068]

[1069] Compound 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2,6-dione was prepared using the method described on page 119-122 of WO20232836107.3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (B-2)

[1070] O

[1071] O

[1072]

[1073] H

[1074] Compound 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-177-benzo[d]imidazol-l-yl)piperidine-2, 6-dione was prepared using the method described on page 167-170 of WO20230191668.

[1075] Synthesis of 3-[6-(2,8-diazaspiro [4.5] decan-8-yl)-2-oxo-l,3-benzoxazol-3-yl] piperidine-2,6-dione (B-3)

[1076]

[1077] SStep-1:

[1078] To a 40 mL screw-cap vial containing a well-stirred solution of 6-bromo-3H-l,3-benzoxazol-2-one 1 (700 mg, 3.11 mmol) and terLbutyl 2,8-diazaspiro[4.5]decane-2-carboxylate 2 (1.49 g, 6.21 mmol) and in Toluene (12 mL) was added sodium / c / 7-butoxide (597.21 mg, 6.21 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes. Subsequently, RuPhos (115.99 mg, 248.58 pmol) and Pd2(dba)3 (113.81 mg, 124.29 pmol) was added and continued stirring at 110 °C for 3 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 wasconcentrated under reduced pressure. The crude material was purified by flash column chromatography (230-400 mesh silica gel; 30- 40% Di chloro methane in ethyl acetate) to affordd tert-butyl 8-(2-oxo-3H-l,3-benzoxazol-6-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate 3 (250 mg, 590.65 pmol, 19% yield) as a pale yellow solid.

[1079] LC-MS (ES+): m'z 374.0 [M + H]+

[1080] Step-2:

[1081] To a 40 mL screw-cap vial containing a well-stirred solution of tert-butyl 8-(2-oxo-3H-l,3-benzoxazol-6-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate 3 (250 mg, 589.11 pmol) and 3-bromopiperidine-2, 6-dione 4 (339.35 mg, 1.77 mmol) in anhydrous acetonitrile (12 mL) was added cesium carbonate (959.72 mg, 2.95 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction as indicated by UPLC-MS. the reaction mixture was quenched with water (20 mL). Aqueous layer was extracted with DCM (2 X 150 mL). Combined organic layers were dried over anhydrous Na2SO4. filtered and filtrate was concentrated under reduced pressure. The crude material was purified by reversed-phase column chromatography [Column: RediSep Rf Gold C18-330 g; Mobile phase A: 10 rnM Ammonium bi carbonate in water and Mobile phase B: Acetonitrile] to afford tert-butyl 8-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate 5 (100 mg, 124.59 pmol, 21% yield) as a pale yellow solid.

[1082] LC-MS (ES+): m'z 485.3 [M + H]+

[1083] Step-3:

[1084] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 8-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (5, 100 mg, 123.83 pmol) in anhydrous DCM (5 mL) was added 4M HC1 in 1,4-di oxane (45.15 mg, 1.24 mmol, 309.57 pL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure to get crude residue was triturated with MTBE (5 mL) and dried to afford 3-[6-(2,8-diazaspiro[4.5]decan-8-yl)-2-oxo-l,3-benzoxazol-3-yl]piperidine-2, 6-dione 6 (60 mg, 91.22 pmol, 73.67% yield, Hydrochloric acid salt) as a pale yellow solid.

[1085] LC-MS (ES+): m / z 385.0 [M + H]+

[1086] Synthesis of 3- [6-(3,9-diazaspiro [5.5]undecan-3-yl)-2-oxo- 1,3-benzoxazol-3-yl] piperi dine-2, 6-dione (B-4)

[1087]

[1088] Step-1:

[1089] To a 40 mL screw-cap vial containing a well-stirred solution of 6-bromo-3H-1,3-benzoxazol-2-one (1, 1 g, 4.67 mmol) and terf-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2, 2.38 g, 9.35 mmol) in toluene (15 mL) was added sodium terLbutoxide (898.09 mg, 9.35 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 min. Then, RuPhos (174.43 mg. 373.80 pmol) and Pd2(dba)3 (171.15, 186.90 pmol) were added and continued stirring at 120 °C for 3 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (230-400 mesh silica gel; 20 to 25% Ethyl acetate in DCM) to afford tert-butyl 9-(2-oxo-3H-l,3-benzoxazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (3, 370 mg, 868.97 pmol, 18% yield) as an off-white solid.

[1090] LC-MS (ES+): m / z 388.0 [M + H]+.

[1091] Step-2:

[1092] To a 40 mL screw-cap vial containing a well-stirred solution of tert-butyl 9-(2-oxo-3H-l,3-benzoxazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (3, 370 mg, 868.97 pmol) and 3-bromopiperidine-2, 6-dione (4, 834.25 mg, 4.34 mmol) in DMF (5 mL) was added K2CO3 (360.30 mg, 2.61 mmol) at room temperature. The resulting reaction mixture was stirred 100 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched by addition of ice-cold water. Aqueous layer was extracted with EtOAc (3 X 50 mL). Organic layer was dried over anhydrous sodium sulfate, fdtered, and the filtrate was concentrated to get the crude compound which was purified by flash column chromatography (230-400 mesh silica gel; 20 to 25% Ethyl acetate in DCM) to afford terf-butyl 9-[3-(2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (5, 120 mg, 208.92 pmol. 24% yield) as a pale yellow solid.

[1093] LC-MS (ES+): m / z 499.2 [M + H]+.

[1094] Step-3:

[1095] To a 25 mL single-neck round bottom flask containing well stirred solution of te / 7-butyl 9-[3- (2,6-dioxo-3-piperidyl)-2-oxo-l,3-benzoxazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (5, 60 mg, 103.50 pmol) in DCM (2 mL) was added TFA (653.39 pmol, 0.05 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure. The crude material was triturated with MTBE (20 mL) to afford 3-[6- (3,9-diazaspiro[5.5]undecan-3-yl)-2-oxo-l,3-benzoxazol-3-yl]piperidine-2.6-dione (B-4. 60 mg, 70.25 pmol, 67% yield. Trifluoroacetic acid salt) as an off-white sold.

[1096] LC-MS (ES+): m / z 399.2 [M + H]+

[1097] References for the Synthesis of Building Blocks

[1098] Building Block Reference Compound was prepared using the method described on page 270-272 of XX?

[1099] WO20211275869.

[1100] OBn

[1101] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo4- methyl-lFf-indazole

[1102]

[1103] Table 6: Preparation of building block

[1104] Synthesis of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole

[1105]

[1106] Step-3SStep-1:

[1107] To a 500 mL multi-neck round-bottom flask containing a well-stirred solution of 7 -bromo- 1H-indazole (1, 10 g, 50.75 mmol) in DMF (110 mL) was added potassium phosphate tribasic (16.16 g, 76.13 mmol) and iodine (19.32 g, 76.13 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was quenched by the addition of an aqueous sodium sulfite solution, at which point a precipitate was formed. The precipitate was filtered and dried under reduced pressure to afford 7-bromo-3-iodo-l / V-inda / ole (2, 15 g, 45.99 mmol, 90% yield) as an off-white solid, which was used without further purification. LC-MS

[1108]

[1109] (ES+): 322.9 [M + H]+.

[1110] Step-2:

[1111] To a 250 mL single-neck round-bottom flask containing a well-stirred solution of7-bromo-3-iodo- 177-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-methyl-indazole (2 g, 5.61 mmol, 25% yield) as an off-white solid. LC-MS (ES+): m / z 336.9 [M + H]+Step-3:

[1112] 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(dppl)C12'DCM (569.54 mg, 697.42 ymol) 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]+

[1113] Synthesis of 6-bromo-3-(2,6-dibenzyIoxy-3-pyridyl)-5-fluoro-l-methyl-indazole and 3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)ind azole

[1114] l2, NaOH dioxane / H20 Step-1

[1115] B2pin2, KOAc Pd(dppf)CI2-DCM dioxane Pd(dppf)CI2«DCM Step-4 Na2CO3, dioxane / H20

[1116]

[1117] Step-3 SStep-1:

[1118] To a 500 mL single-neck round-bottom flask containing a well stirred solution of 6-bromo-5-fluoro-lH-indazole (1, 7 g, 32.55 mmol) in 1,4 dioxane (70 mL) and water (7 mL) was added sodium hydroxide, pellets, 98% (3.91 g, 97.66 mmol) and iodine (9.92 g, 39.07 mmol) under nitrogen atmosphere at room temperature, the resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (500 mL). The organic layer was washed with 10 % sodium bicarbonate solution (250 mL), sodium thiosulfate solution (250 mL) and brine (100 mL). The organic layer was then dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford 6-bromo-5-fluoro-3-iodo-177-indazole (2, 10 g, 27.54 mmol, 84.60% yield) as a brown solid. LC-MS (ES‘): m / z 340.8 [M - H]’.

[1119] Step-2:

[1120] To a 500 mL single-neck round-bottom flask containing a well stirred solution of 6-bromo-5-Huoro-3-iodo-lL7-indazole (2, 10 g, 29.33 mmol) in anhydrous N, A-dimethy 1 formamide (100 mL) was added potassium hydroxide, flake, 85% (4.94 g, 88.00 mmol) followed by iodomethane (5.00 g. 35.20 mmol, 2.19 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After complete consumption of the starting material, the reaction mixture was diluted with ice cold water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and thefiltrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (60-120 mesh silica gel) using a gradient of 0-10% ethyl acetate in petroleum ether to afford 6-bromo-5-fluoro-3-iodo-l-methyl-indazole (3, 4.5 g, 12.60 mmol, 42.97% yield) as an off-white solid. LC-MS (ES+): m / z 357.0 [M + H]+.

[1121] Step-3:

[1122] To a250 mL sealed tube containing a well-stirred solution of 6-bromo-5-fluoro-3-iodo-l-methyl -indazole (3, 4.5 g, 12.68 mmol) and 2.6-dibenzyloxy-3-(4.4.5.5-telramethyl-l.3,2-dioxaborolan-2-yl)pyridine (4, 5.82 g, 13.95 mmol) in a mixture of 1,4-di oxane (50 mL) and water (5 mL) was added sodium carbonate (4.03 g, 38.03 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was purged with nitrogen gas for 10 min before bis(l-dipheny Iphosphanylcy cl openta-2,4-di en-1-yl)iron;dichloromethane;dichloropalladium (1.04 g, 1.27 mmol) was added. The resulting mixture was heated at 80 °C for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature, poured into water (200 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh) using a gradient of 0-100% ethyl acetate in petroleum ether to afford 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-indazole (5, 5.3 g, 8.81 mmol, 69.48% yield) as a off white solid. LC-MS (ES+): m / z 520.1 [M + H]+.

[1123] Step-4:

[1124] To a 250 mL single-neck round-bottom flask containing a well stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-indazole (5, 1.8 g, 2.99 mmol) in dry 1,4-dioxane (30 mL) was added 4.4.5.5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.28 g, 8.97 mmol) and potassium acetate (880.76 mg, 8.97 mmol) under nitrogen atmosphere. The reaction mixture was degassed by bubbling nitrogen gas into the reaction mixture for 10 minutes. Subsequently, Pd(dppf)C12 CH2CI2 (244.29 mg, 299.15 pmol) was added, and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was then filtered through a pad of Celite and the Celite pad was washed with dichloromethane (200 mL). The filtrate was concentrated under reduced pressure and the crude was purified by flash column chromatography (100 g, silica gel 230-400 mesh) using a gradient of 0-100% ethyl acetate in pet ether to afford 3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-6-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazole (6, 1.7 g, 1.96 mmol, 66.0% yield) as a brown gummy liquid. LC-MS (ES+): m / z 566.3 [M + H]+.3-(l-methyl-6-(piperazin-l-yl)-l / / -indazol-3-yl)piperidine-2.6-dione (B-5)

[1125]

[1126] Compound 3-(l-methyl-6-(piperazin-l-yl)-177-indazol-3-yl)piperidine-2, 6-dione was prepared using the method described on page 301-303 of WO202513760510.

[1127] Synthesis of 3-(l-methyl-7-piperazin-l-yl-indazol-3-yl)piperidine-2, 6-dione (B-6)

[1128]

[1129] SStep-1:

[1130] To a 40 mL screw-capped vial containing well-stirred solution of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (1, 500 mg, 829.36 pmol) and ferf-butyl piperazine-1 -carboxylate (2, 154.47 mg, 829.36 pmol) in 1,4-di oxane (5 mL) was added sodium te / 7-butoxide (199.26 mg, 2.07 mmol) at room temperature. Nitrogen gas was purged through the reaction mixture for 10 minutes. Then RuPhos Pd G3 (69.36 mg. 82.94 pmol) was added and the reaction mixture was stirred at 90 °C for 5 h. Reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography (230-400 mesh silica gel; eluent of 25 to 30% EtOAc in pet ether) to afford tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl]piperazine-l-carboxylate (3, 550 mg, 293.38 pmol, 35.37% yield) as a yellow viscous oil. LC-MS (ES+): m / z 606.2 | M + HJ+.

[1131] Step-2:

[1132] To a 100 mL single-neck round-bottom flask containing a well-stirred suspension of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl]piperazine-l-carboxylate (3, 550 mg, 293.38 pmol) in ethanol (5 mL) and 1,4-di oxane (20 mL) was added 20 wt.% Palladiumhydroxide on carbon, 50% water (412.02 mg, 586.75 pmol) at room temperature and the resulting suspension was stirred at room temperature under hydrogen atmosphere for 5 h with 1 atm of hydrogen pressure. After completion of the reaction as indicated UPLC, the reaction mixture was filtered through a pad of Celite, which was subsequently washed with a mixture of ethanol and 1,4-dioxane (1:9). The combined filtrate was concentrated under reduced pressure to afford tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperazine-l -carboxylate (4, 140 mg, 289.17 pmol, 98.57% yield) as a light-brown solid. LC-MS (ESI): m / z 428.3 [M + H]+Step-3:

[1133] To a 50 mL single neck round bottom flask containing well stirred solution of tert-butyl 4-[3- (2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]piperazine-l -carboxylate (4, 140 mg, 289.17 pmol) in DCM (3 mL) was added 4.0 M HC1 in 1,4-dioxane (4 M. 72.29 pL) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. After completion of reaction indicates UPLC, the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with MTBE (5 mL x 3) and dried over under reduced pressure to afford 3-(l-methyl-7-piperazin-l-yl-indazol-3-yl)piperidine-2, 6-dione hydrochloride (B-6, 110 mg, 278.14 pmol, 96.19% yield) as a light-brown solid. UPLC-MS (ES+): m / z 328.2 [M + HJ+Synthesis of 3- [6-(3,9-diazaspiro [5.5]undecan-3-yl)-l-methyl-indazol-3-yl] piperidine-2,6- dione (B-7)

[1134]

[1135] SStep-1:

[1136] To a 40 mL screw-cap vial containing a well-stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-l-methyl-indazole (1, 1 g, 1.90 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3- carboxylate (2, 579.51 mg, 2.28 mmol) in 1,4-dioxane (10 mL) was added cesium carbonate(1.24 g, 3.80 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes. Then, XPhos (90.43 mg, 189.85 pmol) and Pd2(dba)s (173.85 mg, 189.85 pmol) were added and the reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 20 to 25% Ethyl acetate in Petroleum ether) to afford terf-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (3, 1.1 g, 1.51 mmol, 79% yield) as a pale yellow solid. LC-MS (ES+): m / z 674.3 [M + H]+

[1137] Step-2:

[1138] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (3, 800 mg, 1.13 mmol) in dry 1,4-dioxane (10 mL) was added 20% Palladium hydroxide on carbon (791.95 mg, 1.13 mmol). 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 filtered and washed withTHF (180 mL), 1,4-dioxane (180 mL) and the filtrate was concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography [Column: RediSep Rf Gold® C18-120 g, Mobile phase A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile] to afford tert-butyl 9-[3-(2.6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (4, 570 mg, 1.09 mmol, 97% yield) as a pale yellow solid.

[1139] LC-MS (ES+): m / z 496.3 [M + H]+

[1140] Step-3:

[1141] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (4, 70 mg, 134.18 pmol) in anhydrous DCM (5 mL) was added 4 M HC1 in 1,4-dioxane (670.89 pL, 2.68 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure to afford 3-[6-(3,9-diazaspiro[5.5]undecan-3-yl)-l-methyl-indazol-3-yl]piperidine-2, 6-dione hydrochloride (B-7, 50 mg, 108.24 pmol, 80% yield, Hydrochloric acid salt) as a pale yellow solid.

[1142] LC-MS (ES+): m / z 396.3 [M + H]+

[1143] The following CRBN binders were prepared using the method described above, with the corresponding amine 2 in SStep-1:00

[1144] Br - somide 1 in Step- Amine 2 in Step- CRBN binder MS X / S’ 1 1

[1145] \ / o _

[1146] LC-MS (ES+): m / z (^N-BocHN

[1147] ' Jz1 382.2 [M + H]+. XX?^" o\- 03 ZJ HN^ XX?

[1148] O= / 'i

[1149] N=Z

[1150] OBnHNV

[1151] 0

[1152] B-8

[1153] / \. -Boc LC- HN V N HN^

[1154] MS (ES+): m / z 382.5 XX?

[1155] [M + H]+. BnO~~ / z ~^. XX?

[1156] N=Z

[1157] OBn0==\ \

[1158] nN ~Y

[1159] C # o

[1160] JI / \ 0

[1161] B-9 ' J 1z

[1162] Boc HN" A _ LC-MS ^Ny^N (ES+): m / z 340.0 [M XX + H]+. N?

[1163] H (5 eq. TFA and ° A \

[1164] HN-Z DCM were used in 0 Step-2 for B-10 deprotection) OBn H

[1165] N HNX~''XLC-MS N (ES+): m / z 414.2 [M + H]+. ]X°Bn

[1166] XXN^IXT (5 eq. TFA and i

[1167] Boc DCM were used in Step-2 for deprotection)

[1168]

[1169]

[1170] Synthesis of 3- [7-(3,9-diazaspiro [5.5]undecan-3-yl)-l-methyl-indazol-3-yl] piperidine-2,6- dione (B-13)

[1171]

[1172] SStep-1:

[1173] To an 8 mL screw-cap vial containing a well-stirred solution of 7-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-l-methyl-indazole (1, 500 mg, 819.37 pmol) and tert-butyl 3,9- diazaspiro[5.5]undecane-3-carboxylate (2, 625.26 mg, 2.46 mmol) in 1,4-dioxane was added NaOtBu (236.23 mg, 2.46 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 min. Then, RuPhos Pd G3 (68.53 mg, 81.94 pmol) was added and the reaction mixture was stirred at 110 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica; Eluent: 20% ethyl acetate in petroleum ether) to afford tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl]-3,9-diazaspiro[5.5]undecane- 3-carboxylate (3, 400 mg, 415.53 pmol, 50% yield) as off-white solid. LC-MS (ES+): m / z 674.1 [M + H]+Step-2:

[1174] To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (3, 417.14 mg, 433.34 nmol) in 1,4-di oxane (2 mL) was added 20% palladium hydroxide on carbon (304.29 mg, 433.34 pmol) at room temperature and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. After completion of the reaction as indicated UPLC-MS, the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with THF (50 mL). The filtrate was concentrated under reduced pressure to afford / c / 7-butyl 9-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (4, 290 mg, 427.15 pmol, 98% yield) as a brown solid. LCMS (ES+): m / z 496.1 [M + H]

[1175] Step-3:

[1176] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (4, 150 mg, 283.33 nmol) in anhydrous DCM (4.94 mL) was added 4 M HC1 in 1.4-dioxane (1.42 mmol, 354.16 pL) at 0 °C and the reaction mixture was stirred at room temperature for 3 h. After completion of reaction mixture as indicated by UPLC-MS, the reaction mixture was concentrated under reduced pressure and the crude product was triturated with methyl tert-butyl ether (10 mL) to afford 3-[7-(3,9-diazaspiro[5.5]undecan-3-yl)-l-methyl-indazol-3-yl]piperidine-2, 6-dione hydrochloride (B-13. 120 mg, 269.47 pmol. 95% yield) as an off-white solid. LC-MS (ES ): m / z 396.1 [M + H]+.

[1177] Synthesis of 3-[6-(4,4-difluoro-2,8-diazaspiro[4.5]decan-8-yl)-5-fluoro-l-methyl-indazol-3-yl]piperidine-2, 6-dione (B-14)

[1178]

[1179] SStep-1:To a 20 mL screw-cap vial containing a well-stirred solution of 6-bromo-3-(2.6-dibenzyloxy-3-pyridyl)-5 -fluoro- 1-methyl-indazole (1, 400 mg, 651.96 pmol) and / e / 7-butyl 4,4-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (2, 270.23 mg, 977.94 pmol) in 1,4-di oxane (5 mL) was added CS2CO3 (637.26 mg, 1.96 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 5 minutes before Pd-PEPPSI-IHeptCl (63.49 mg, 65.20 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: 50 to 55% Ethyl acetate in Petroleum ether) to afford tert-butyl 8-|3-(2.6-dibenzyloxy-3-pyridyl)-5-fluoro-l-methyl-indazol-6-yl]-4,4-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (3. 440 mg, 560.95 pmol, 86% yield) as a brown solid. LC-MS (ES+):

[1180]

[1181] 714.3 [M+ H]+.

[1182] Step-2:

[1183] To 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 8-[3-(2,6-dibenzyloxy-3-pyridyl)-5-fluoro-1-methyl-indazol-6-yl]-4,4-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (3, 440 mg, 560.95 pmol) in 1,4-di oxane (10 mL) was added 20 wt.% palladium hydroxide (440 mg, 3.13 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. After completion of the reaction as indicated by UPLC-MS, the reaction mixture w as passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase PREP HPLC [Column: RediSep Rf Gold® C18-120 g; Mobile phase A: 10 mM Ammonium bicarbonate in water and Mobile phase B: Acetonitrile] to afford te / 7-butyl 8-[3-(2,6-dioxo-3-piperidyl)-5-fluoro-l-methyl-indazol-6-yl]-4,4-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (4, 210 mg, 388.19 pmol, 69% yield) as an off-white solid. LCMS (ES+): m / z 536.0 [M + H]+.

[1184] Step-3:

[1185] To a 50 mL single-neck round bottom flask containing a w ell stirred solution of tert-butyl 8-[3-(2,6-dioxo-3-piperidyl)-5-fluoro-l-methyl-indazol-6-yl]-4,4-difluoro-2,8-diazaspiro[4.5]decane-2-carboxylate (4. 70 mg. 129.40 pmol) in DCM (3 mL) was added TFA (3.92 mmol, 0.3 mL) 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 product was triturated with MTBE (20 mL) to afford 3-[6-(4,4-difluoro-2.8-diazaspiro[4.5]decan-8-yl)-5-fluoro-l-methyl-indazol-3-yl]piperidine-2,6-dione trifluoroacetate (B-14, 65 mg, 105.28 pmol, 81% yield) as an off white solid. LC-MS (ES+): m / z 436.3 [M + H]+.Synthesis of 3-[6-|(3a / ?,6a / ?)-2,3,3a,4,6,6a-hexahydro-l / / -pyrrolo[3,4-c|pyrrol-5-yl|-l- methyl-indazol-3-yl]piperidine-2, 6-dione (B-15)

[1186]

[1187] SStep-1:

[1188] To a 40 mL screw-cap reaction-vial containing a well-stirred mixture of 6-bromo-3-(2,6- dibenzyloxy-3-pyridyl)-l-methyl-indazole (1, 500 mg, 977.45 pmol) and tert-butyl (3aS,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (2, 311.25 mg, 1.47 mmol) in 1,4-dioxane (10 mL) was added cesium carbonate (796.18 mg, 2.44 mmol) at room temperature. Nitrogen gas was purged through the reaction mixture for 5 minutes before XPhos (93.19 mg, 195.49 pmol) and tris(dibenzylideneacetone)dipalladium(0) (89.51 mg, 97.74 pmol) were added and the reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 45-50% Ethyl acetate in Petroleum ether) to afford tert-butyl (3a5,6a5)-2-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl- indazol-6-yl]-l,3,3a,4,6,6a-hexahydropyrrolo[3.4-c]pyrrole-5-carboxylate (3, 620 mg. 903.07 pmol, 92% yield) as an off-white solid. LC-MS (ES+): m / z 632.0 [M + H]+

[1189] Step-2:

[1190] To a 100 mL single neck round bottom flask containing a well stirred solution of / c / 7-butyl (3a5,6aS)-2-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-l,3.3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (3, 450 mg. 712.29 pmol) in 1,4-dioxane (5 mL) and THF (5 mL) was added 20 wt.% palladium hydroxide (500.16 mg, 712.29 pmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reducedpressure. The crude material was purified by reverse-phase prep-HPLC [Column: RediSep R / ' Gold® Cl 8-120 g; Mobile phase A: 10 mM Ammonium bicarbonate in water and Mobile phase B: Acetonitrile] to afford tert-butyl (3aS,6aS)-2-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (4, 180 mg, 392.92 pmol, 55% yield) as an off-white solid. LC-MS (ES+): m / z 454.3 [M + H]+.

[1191] Step-3:

[1192] To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (3aS,6aS)-2-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (4, 60 mg, 130.97 pmol) in DCM (3 mL) was added TFA (3.92 mmol, 0.3 mL) 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. The crude material was triturated with MTBE (20 mL) to afford 3-[6-[(3a7?,6a / ?)-2,3,3a,4,6,6a-hexahydro-lE7-pyrrolo[3,4-c]pyrrol-5-yl]-l- methyl-indazol-3-yl]piperidine-2, 6-dione trifluoroacetate (B-15, 55 mg, 112.96 pmol, 86% yield) as an off-white sold. LC-MS (ES+): m / z 354.1 [M + H]+

[1193] The following CRBN binder was prepared using the method described above, with the corresponding amine in Step-1.

[1194] Amine in Step-1 CRBN binder MS BocN'"%s; O LC-MS (ES+): m / z 354.0 [M + H]+

[1195] JOCN

[1196] B-16

[1197]

[1198] Table 8: Preparation of B-16

[1199] Synthesis of 3-[6-(3-azaspiro[5.5]undecan-9-yl)-l-methyl-indazol-3-yl]piperidine-2, 6-dione (B-17)

[1200] OBn

[1201] Pd(OAc)2, PdCI2(dppf)-DCM

[1202] 1,4-dioxane Step-1

[1203]

[1204]

[1205] SStep-1:

[1206] To a 40 mL pressure capped vial containing a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1, 500 mg, 949.27 pmol) in 1,4-di oxane (10 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2, 409.79 mg, 1.61 mmol) and potassium acetate (279.48 mg, 2.85 mmol) and the mixture was purged with N2 for 5 min. Then 1, T-bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (77.48 mg, 94.93 pmol) was added and the reaction mixture was purged with N2 for another 5 min. The reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (Stationary' Phase: 60-120 mesh silica gel; Eluent: 0-100% ethyl acetate in petroleum ether) to afford 3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazole (3, 500 mg, 804.25 pmol, 84.72% yield) as a pale-yellow solid. LC-MS (ES+): m / z 548.2 [M + H]+

[1207] Step-2:

[1208] To a 40 mL screw-cap vial containing a well-stirred solution of 3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazole (3, 450 mg, 723.76 pmol) and tert-butyl 9-(trifluoromethylsulfonyloxy)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (4, 479.05 mg, 1.09 mmol) in 1,4- dioxane (10 mL) and water (2 mL) was added sodium carbonate (230.14 mg, 2.17 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes. Then, Pd(dppl)C12'DCM (59.11 mg, 72.38 pmol) were added andthe reaction mixture was stirred at 80 °C for 2 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 was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 20 to 25% ethyl acetate in petroleum ether) to afford tert-butyl 9-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-3- azaspiro[5.5]undec-9-ene-3-carboxylate (5. 400 mg, 494.01 pmol, 68% yield) as a pale yellow solid. LC-MS (ES+): m / z 671.3 [M + H]+

[1209] Step-3:

[1210] To a 50 mL single-neck round-bottom flask containing a well-stirred suspension of / e / V-butyl 9- [3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-3-azaspiro[5.5]undec-9-ene-3- carboxylate (5. 400 mg. 494.01 pmol) in THF (10 mL) and in ethanol (10 mL) was added 20 wt.% palladium hydroxide on carbon (520.32 mg, 741.01 pmol). 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 filtered and washed with THF (100 mL), ethanol (100 mL) and the filtrate was concentrated under reduced pressure to afford tertbutyl 9-|3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3-azaspirot5.5Jundecane-3- carboxylate (6, 200 mg, 376.85 pmol, 76% yield) as a pale-yellow solid. LC-MS (ES+): m / z 495.3 [M + H]+

[1211] Step-4:

[1212] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-[3- (2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3-azaspiro[5.5]undecane-3-carboxylate (6, 200 mg, 376.85 pmol) in anhydrous DCM (5 mL) was added trifluoroacetic acid (3.77 mmol, 288.39 pL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure to afford 3-[6-(3-azaspiro[5.5]undecan-9-yl)-l-methyl-indazol-3-yl]piperidine-2,6- dione trifluoroacetate (B-17, 150 mg, 289.89 pmol, 77% yield) as a pale-yellow solid. LC-MS (ES+): zn / z 395.3 [M + H]+

[1213] The following CRBN binder was prepared using the method described above, with the corresponding bromide 1 and inflate 4 in Step-1.

[1214] Bromide 1 in Step-1 Triflate 4 in Step-2 CRBN binder MS

[1215]

[1216]

[1217] Synthesis of 3-(l-methyl-6-((5r,8r)-2-azaspiro[4.5]decan-8-yl)-LH-indazol-3-yl)piperidine- 2,6-dione (B-19) and 3-(l-methyl-6-((5s,8s)-2-azaspiro[4.5]decan-8-yl)-LH-indazol-3- yl)piperidine-2, 6-dione (B-20)

[1218]

[1219] SStep-1:To a 250 mL round-bottom flask containing a well-stirred suspension of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (1. 5 g. 9.99 mmol) in 1.4-dioxane (50 mL), was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (5.07 g, 19.98 mmol) and potassium acetate (2.45 g, 24.98 mmol) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 min before Pd(dppf)Cl₂·CH₂Cl₂ (408.01 mg, 499.61 pmol) was added to the mixture. The resulting mixture was heated at 80 °C for 16 h. The reaction mixture treated with ethyl acetate (250 mL) and filtered through a pad of celite (6 g) and the celite was washed with ethyl acetate (2 x 100 mL). The filtrate was concentrated under reduced pressure and the crude material was purified by flash column chromatography (silica gel, 100-200 mesh) using a gradient of 0-100% ethyl acetate in petroleum ether to afford 3-(2.6-dibenzyloxy-3-pyridyl)-l-methyl-6-(4,4.5.5-tetramethyl-l,3,2-dioxaborolan-2-yl) indazole (2, 5 g, 7.86 mmol, 79% yield) as a brown gum. LC-MS (ES+): m / z 548.2 [M + H]+. Step-2:

[1220] To a 500 mL three-neck round-bottom flask containing a well-stirred solution of tert-butyl 8-oxo-2-azaspiro[4.5]decane-2-carboxylate (3, 5 g, 19.74 mmol) in tetrahydrofuran (100 mL), cooled to -78 °C, was added lithium diisopropylamide (2.0 M in tetrahydrofuran, 14.80 mL, 29.6 mmol) under nitrogen atmosphere. The resulting mixture was stirred at -78 °C under nitrogen atmosphere for 1 h before A. A-bis(trifluoromethylsul fonyl)-5-chloro-2-pyridylamine (9.30 g. 23.68 mmol) in tetrahydrofuran (20 mL) was added at -78 °C under nitrogen atmosphere. The reaction mixture was warmed up to room temperature gradually and stirred at this temperature for 16 h. The reaction mixture was then treated with aqueous ammonium chloride (250 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 0-100% ethyl acetate in petroleum ether) to afford tert-butyl 8-(trifluoromethylsulfonyloxy)-2-azaspiro[4.5]dec-7-ene-2-carboxylate (4, 6 g, 15.57 mmol, 79% yield) as an off-white solid. LC-MS (ES+): m / z 330.1 [M - COOtBu + H]+.

[1221] Step-3:

[1222] To a 250 mL sealed tube containing a well-stirred solution of tert-butyl 8-(trifluoromethylsulfonyloxy)-2-azaspiro[4.5]dec-7-ene-2-carboxylate (4, 3 g, 7.78 mmol) and 3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazole (2, 4.99 g, 8.56 mmol) in a mixture of 1,4-dioxane (30 mL) and water (5 mL) was added sodium carbonate (1.65 g, 15.56 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was purged with nitrogen gas for 10 min before Pd(dppf)Cl₂·CH₂Cl₂ (635.49 mg, 778.18 pmol) was added. The resulting mixture was heated at 80 °C for 16 h. After completion of thereaction as indicated by TLC, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic phases were washed with brine solution (100 mL) and dried over anhydrous sodium sulfate. The solution was fdtered, and the fdtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Stationary' Phase: 100-200 mesh silica gel; Eluent: 0-100% ethyl acetate in petroleum ether) to afford tert-butyl 8-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-2-azaspiro[4.5]dec-7-ene-2-carboxylate (5, 3 g, 4.12 mmol, 53% yield) as a brown gum. LC-MS (ES+): m'z 657.5 [M + H]+.

[1223] Step-4:

[1224] To a 100 mL tiny clave containing a well-stirred solution of tert-butyl 8-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]-2-azaspiro[4.5]dec-7-ene-2-carboxylate (5, 2 g, 3.05 mmol) in methanol (40 mL) was added acetic acid (914.29 mg, 15.23 mmol) followed by 20% palladium hydroxide on carbon (wetted with ca. 55% water) (0.5 g, 3.56 mmol) and 10% palladium on carbon (0.5 g, 4.70 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50 °C under hydrogen atmosphere for 16 h. After complete consumption of the starting material as indicated by TLC and UPLC, the reaction mixture was filtered through a pad of Celite, which was washed repeatedly with methanol (50 mL). The combined filtrate was concentrated under reduced pressure to afford tert-butyl 8-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-2-azaspiro[4.5]decane-2-carboxylate (6, 0.7 g, 1.17 mmol, 39% yield) as a brown solid and a mixture of diastereomers. The crude product was carried to the next step without purification. LC-MS (ES+): m / z 481.1 [M + H]+.

[1225] Step-5:

[1226] To a 100 mL single-neck round-bottom flask containing a w ell-stirred solution of tert-butyl 8-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-2-azaspiro[4.5]decane-2-carboxylate (6, 940 mg, 1.41 mmol) in dichloromethane (10 mL) was added 4.0 M hydrogen chloride solution in 1,4-dioxane (3.5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to afford 3-[6-(2-azaspiro [4.5]decan-8-yl)-l-methyl-indazol-3-yl]piperidine-2, 6-dione hydrochloride (7, 590 mg, 1.39 mmol, 98% yield) as an off-white solid and a mixture of diastereomers. LC-MS (ES+): m / z 381.1 [M + H]+.

[1227] Step-6:

[1228] The diastereomeric 3-[6-(2-azaspiro[4.5]decan-8-yl)-l-methyl-indazol-3-yl]piperidine-2, 6-dione (3 g, 7.88 mmol) was separated by preparative HPLC chromatography. Reverse phase preparative HPLC method: Column / dimensions: X-SELECT C18 (250*19mm)5; Mobile phase: A:0.1% TFA in water B: acetonitrile; Flow rate: 20 mL / min.The early-eluting isomer was concentrated under reduced pressure to afford 3-(l-methyl-6-((5r,8r)-2-azaspiro[4.5]decan-8-yl)-lH-indazol-3-yl)piperidine-2.6-dione trifluoroacetate (B-19, 710 mg, 1.42 mmol, 18.07% yield) as an off-white solid. LC-MS (ES+): m / z 381.2 [M + H]+. The late-eluting isomer was concentrated under reduced pressure to afford 3-(l-methyl-6-((5s, 8s)-2-azaspiro[4.5]decan-8-yl)-177-indazol-3-yl)piperidine-2, 6-dione trifluoroacetate (B-20, 250 mg, 269.06 pmol, 3.41% yield) as an off-white solid. LC-MS (ES+): m / z 381.1 [M + H]+. Synthesis of 3- [l-methyl-6-(4-oxocyclohexyl)indazol-3-yl]piperidine-2, 6-dione (B-21)

[1229]

[1230] SStep-1:

[1231] To a 100 mL three-neck round-bottom flask containing a well-stirred suspension of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (1, 2 g, 4.00 mmol) and 2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2, 1.28 g, 4.80 mmol) in acetonitrile (9.67 mL) was added potassium carbonate (1.10 g, 7.99 mmol) and the resulting mixture was degassed by bubbling nitrogen gas for 10 min. Subsequently, Pd(dppf)C12'CH2C12 (652.81 mg, 799.38 pmol) was added, and the reaction mixture was stirred at 85 °C for 1 h. The reaction mixture was then diluted with ethyl acetate (50 mL) and filtered through a pad of celite (3 g), which was washed with ethyl acetate (2 x 50 mL). The combined filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (100-200 mesh silica gel) using a gradient of 0-100% ethyl acetate: pet ether to afford 3-(2,6-dibenzyloxy-3-pyridyl)-6-(l,4-di oxaspiro [4.5]dec-7-en-8-yl)-l-methyl-indazole (3, 3 g, 3.36 mmol, 84.08% yield) as a brown liquid. LC-MS (ES+): m / z 560.2 [M + H]+.

[1232] Step-2:To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 3-(2,6-dibenzyloxy-3-pyridyl)-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-methyl-indazole (3, 2.5 g, 4.47 mmol) in 1,4-dioxane (50 mL) was added 10% palladium hydroxide on carbon (wetted with ca.

[1233] 55% water)(1.25 g, 8.93 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, which was washed with a mixture of ethyl acetate (200 mL) and di chloromethane (100 mL). The combined filtrate were concentrated under reduced pressure and the crude product was purified by flash column chromatography (100-200 mesh silica gel, 100g SNAP) using a gradient of 65-70% ethyl acetate in petroleum ether to afford 3-[6-(l,4-dioxaspiro[4.5]decan-8-yl)-l-methyl-indazol-3-yl]piperidine-2, 6-dione (4, 1.7 g, 4.27 mmol, 95.53% yield) as an off-white solid. LCMS (ES+): m / z 384.3 [M + H]+.

[1234] Step-3:

[1235] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3-[6-(1,4-dioxaspiro[4.5]decan-8-yl)-1-methyl-indazol-3-yl]piperidine-2,6-dione (4, 1.7 g, 4.43 mmol) in tetrahydrofuran (60 mL) was added aqueous hydrochloric acid (6 N, 7.39 mL) dropwise at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. After completion of the reaction as indicated by UPLC, the reaction mixture was quenched slowly with 10% aqueous sodium bicarbonate solution (100 ml) at 0 °C and stirred for 20 min until pH = 7-8. The mixture was extracted with dichloromethane (2 x 100 mL) and the separated organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was triturated with pet ether and the obtained solid was dried under vacuum to afford 3-[l-methyl-6-(4-oxocyclohexyl)indazol-3-yl]piperidine-2, 6-dione (B-21, 1.58 g, 3.97 mmol, 89.51% yield) as an off-white solid. LC-MS (ES+): m / z 341.2 [M + H]+.

[1236] Synthesis of 3-[l-methyl-7-(4-oxo-l-piperidyl)indazol-3-yl]piperidine-2, 6-dione (B-22)

[1237] Pd-PEPPSI-IHept-CI CS2CO3, dioxane

[1238]

[1239] Step-1TFA DCM

[1240] Step-3

[1241]

[1242] SStep-1:

[1243] 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, 500 mg, 999.23 µmol) and l,4-dioxa-8-azaspiro[4.5]decane (2, 286.15 mg, 2.00 mmol) in anhydrous 1,4-dioxane (10 mL) was added Cs2CO3(651.14 mg, 2.00 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 min. Then, [l,3-bis[2,6-bis(l-ethylpropyl)phenyl]imidazol-2-ylidene]-dichloro-palladium;3-chloropyridine (39.55 mg, 49.96 pmol) was added and the reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: 30% ethyl acetate in petroleum ether) to afford 8-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-7-yl]-l,4-dioxa-8-azaspiro[4.5]decane (3, 450 mg, 775.78 pmol, 77% yield) as a white solid. LC-MS (ES+): m / z 563.3 [M + H]+.

[1244] Step-2:

[1245] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 8-[3-(2,6-dibenzy loxy-3-pyridyl)-l-methyl-indazol-7-yl]-l,4-dioxa-8-azaspiro[4.5]decane (3, 450 mg, 775.78 pmol) in DMF (1 mL) and 1,4-dioxane (5 mL) was added 20 wt.% palladium hydroxide on carbon (54.47 mg, 77.58 pmol) at room temperature. The resulting reaction mixture was stirred at room temperature under hydrogen atmosphere for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by reversephase column chromatography [Column: X-bridge C8 (250 x 19) mm 5 microns, Mobile phase A: 0.1 % Formic acid in water and Mobile phase B: Acetonitrile] to afford 3-[7-(1.4-dioxa-8-azaspiro[4.5]decan-8-yl)-l-methyl-indazol-3-yl]piperidine-2, 6-dione (4, 200 mg, 494.55 pmol, 63% yield) as a white solid. LC-MS (ES+): m / z 385.5 [M + H]+.

[1246] Step-3:

[1247] To a 10 mL single-neck round-bottom flask containing a well-stirred solution of 3-[7-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-l-methyl-indazol-3-yl]piperidine-2,6-dione (4, 200 mg, 520.25 pmol) in DCM (5 mL) was added TFA (5.20 mmol, 398.13 pL) at 0 °C and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as indicated byUPLC-MS, the reaction mixture was concentrated under reduced pressure, and the residue was triturated with MTBE to afford 3-[l-methyl-7-(4-oxo-l-piperidyl)indazol-3-yl]piperidine-2,6- dione trifluoroacetate (B-22, 150 mg, 244.28 pmol, 46% yield) as an off-white solid. LC-MS (ES+): m / z 341.1 [M + H]+

[1248] The following CRBN binder was prepared using the method described above, with the corresponding bromide 1 and amine 2 in Step-1.

[1249] Bromide 1 in Step-1 Amine 2 in Step-1 CRBN binder MS

[1250] LC-MS (ES+): m / z 359.3 [M + H]+.

[1251] B-23

[1252]

[1253] Table 10: Preparation of B-23

[1254] Synthesis of 3-[5-fhioro-l-methyl-6-(4-oxocyclohexyl)indazol-3-yl]piperidine-2, 6-dione (B- 24)

[1255]

[1256] SStep-1:

[1257] To a 40 mL vial containing a well-stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-5- fluoro-l-methyl-indazole (1, 500 mg, 884.11 pmol) and 2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2, 235.30 mg, 884.11 pmol) in anhydrous THF (10 mL) and water (2 mL) was added K3PO4 (375.34 mg, 1.77 mmol) at room temperature. Themixture was purged with nitrogen gas for 10 min before XPhos Pd G3 (74.84 mg, 88.41 pmol) was added at room temperature. The reaction mixture was heated at 90 °C for 6 h. After completion of the reaction as indicated by UPLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (Stationary Phase: 230-400 mesh silica gel, 100 g snap cartridge; Eluent: 0-20% ethyl acetate in petroleum ether; flow rate = 30 mL / min) to afford 3-(2,6-dibenzyloxy-3-pyridyl)-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-fluoro-l-methyl-indazole (3, 200 mg, 341.49 pmol, 38.63% yield) as an off-white solid. LCMS (ES+): m / z 578.2 [M + H]+

[1258] Step-2:

[1259] To a 25 mL single-neck round-bottom flask containing a well-stirred suspension of 3-(2,6-dibenzyloxy-3-pyridyl)-6-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-fluoro-l-methyl-indazole (3, 200 mg, 341.49 pmol) in 1,4-dioxane (5 mL) and DMF (1 mL) was added 10% Pd(OH)2 on carbon (wetted with ca. 55% water) (959.15 mg, 682.98 pmol) at room temperature and the resulting suspension was stirred at room temperature under hydrogen atmosphere (1 atm pressure) for 5 h. After completion of the reaction as indicated by UPLC, the reaction mixture was filtered through a pad ofCelite and the Celite pad was washed with DMF and THF (1:9). The combined filtrate was concentrated under reduced pressure to afford 3-[6-(1,4-dioxaspiro[4.5]decan-8-yl)-5-fluoro-l-methyl-indazol-3-yl]piperidine-2,6-dione (4, 100 mg, 175.20 pmol, 51.30% yield) as a light brown solid. LC-MS (ES+): m / z 402.2 [M + H]+

[1260] Step-3:

[1261] In a 25 mL single-neck round-bottom flask, a suspension of 3-[6-(1,4-dioxaspiro[4.5]decan-8-yl)-5-fluoro-l-methyl-indazol-3-yl]piperidine-2,6-dione (4, 100 mg, 175.20 µmol) in TFA (2.98 g, 26.14 mmol, 2 mL) was stirred at room temperature for 2 h. The reaction mixture was then evaporated under reduced pressure, and the residue was triturated with MTBE and dried to yield a crude product, which was purified by reverse-phase column chromatography (Column: RediSep® C18 column; Mobile phase A: 10 mM ammonium bicarbonate in water and Mobile phase B: Acetonitrile) to afford 3-[5-fluoro-l-methyl-6-(4-oxocyclohexyl)indazol-3-yl]piperidine-2, 6-dione (B-24, 40 mg, 107.07 pmol, 61.11% yield) as a white solid. LC-MS (ES+): m / z 358.0 [M + H]+Synthesis of 2,6-dibenzyloxy-N-(4-bromo-3,5-difluoro-phenyl)pyridin-3-amine and afford 2,6-dibenzyloxy-N-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridin-3-amine

[1262]

[1263] SStep-1:

[1264] To five 40 mL vial containing a well stirred solution of 2-bromo-l,3-difluoro-5-iodo-benzene (1, 5 g. 15.68 mmol) and 2,6-dibenzyloxypyridin-3-amine (2. 5.31 g, 15.68 mmol) in anhydrous 1,4-dioxane (80 mL) was added sodium / e / 7-butoxide (3.77 g, 39.20 mmol) at ambient temperature. The mixture was purged with N2 for 5 min before Xantphos (1.81 g, 3.14 mmol) and Pd(dba)2 (901.58 mg, 1.57 mmol) were added to the reaction mixture at ambient temperature. Stirred reaction mixture for 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-N-(4-bromo-3,5-difluoro-phenyl)pyridin-3-amine (3, 7 g, 13.14 mmol, 83.83% yield) as a yellow gummy. LC-MS (ES+): m / z 497.1 [M + H]+.

[1265] Step-2:

[1266] To a 40 mL screw-cap vial containing a well-stirred solution of 2,6-dibenzyloxy-N-(4-bromo-3,5-difluoro-phenyl)pyridin-3-amine (3, 2.14 g, 4.02 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4, 1.02 g, 4.02 mmol) in 1,4-dioxane (20 mL) was added potassium acetate (1.18 g, 12.06 mmol) at room temperature. The reaction mixture was purged with N2 for 5 min before Pd(dppf)Cl2·DCM (328.41 mg, 402.15 pmol) and the reaction mixture was stirred at 90 °C for 12 h. After completion of the reaction indicated by LCMS, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure and the cruderesidue was quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine solution (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2,6-dibenzyloxy-N-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridin-3-amine (5, 1.5 g, 1.99 mmol, 49.43% yield) as a brown gummy solid. LC-MS (ES+): m / z 544.2 [M + H]+

[1267] 3-((3,5-difluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (B-25)

[1268]

[1269] Compound 3-((3,5-difluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dionewas prepared using the method described on page 254-255 of WO202226125011.

[1270] 3-((3,5-difluoro-4-(piperazin-l-yl)phenyl)amino)piperidine-2, 6-dione (B-26)

[1271]

[1272] O

[1273] Compound 3-((3,5-difluoro-4-(piperazin-l-yl)phenyl)amino)piperidine-2, 6-dione was prepared using the method described on page 167-168 of W0202203202612.

[1274] Synthesis of 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3,5-difluoro-anilino]piperidine-2,6-dione (B-27)

[1275]

[1276] SStep-1:To a 40 mL vial containing a well stirred solution of l,2,3-trifluoro-5-nitro-benzene (1, 696.16 mg. 3.93 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2, 1 g, 3.93 mmol) in anhydrous DMF (10 mL) was added CS2CO3 (3.84 g, 11.79 mmol) at ambient temperature. The reaction mixture was stirred at 90°C for 2 hours and the progress was monitored by LCMS. After completion of reaction as indicated by LCMS, the reaction mixture was poured into ice-water (10 mL) and stirred for 5-10 min. The precipitate was filtered and dried under vacuum to afford tert-butyl 9-(2,6-difluoro-4-nitro-phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (3, 1.3 g, 2.85 mmol, 72.54% yield) as a pale-yellow solid. LC-MS (ES+): m / z 412.2 [M + H]+.

[1277] Step-2:

[1278] To a 100 mL single-neck round-bottom flask containing a well stirred solution of tert-butyl 9-(2,6-difluoro-4-nitro-phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (3, 1 g, 2.19 mmol) in anhydrous 1,4-dioxane (10 mL) were added 10% Palladium on carbon wet (902.60 mg, 8.48 mmol) at ambient temperature. The reaction mixture was stirred at this temperature for 1 hour under hydrogen atmosphere. After completion of reaction as indicated by UPLC, the reaction mixture was filtered through a pad of Celite, which was subsequently washed with THF (10 mL). The filtrate was concentrated under reduced pressure to afford / e / ' / -butyl 9-(4-amino-2,6-difluoro-phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (4, 800 mg, 1.99 mmol, 90.84% yield) as an off-white solid. LC-MS (ES+): m / z 382.3 [M + H]+.

[1279] Step-3:

[1280] To a 20 mL vial containing well stirred solution of tert-butyl 9-(4-amino-2,6-difluoro-phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (4, 500 mg, 1.25 mmol) and 3-bromopiperidine-2,6-dione (5, 717.29 mg, 3.74 mmol) in anhydrous DMF (5 mL) were added NaHCCL (313.82 mg, 3.74 mmol) to the reaction mixture at room temperature. Stirred reaction mixture at 90°C for 16 hours. After completion of reaction as indicated by UPLC, the reaction mixture was passed through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase column chromatography [Column: RediSep® C18, 30 g Gold; Mobile phase A: 0.1% NH4HCO3 in water and Mobile phase B: CH3CN, Flow rate: 15 mL / min] to afford tert-butyl 9-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (6, 280 mg, 559.88 pmol, 44.96% yield) as an off-white solid. LC-MS (ES+): m / z 493.4 [M + H]+.

[1281] Step-4:

[1282] To a 50 mL round-bottom flask containing a well stirred solution of tert-butyl 9-[4-[(2.6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (6, 280 mg, 559.88 pmol) in DCM (5 mL) was added TFA (1.28 g, 11.20 mmol, 856.90 pL) to the reactionmixture at 0 °C and stirred reaction mixture at room temperature for 3 hours. After completion of reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure to give the crude compound, which was co-distilled with toluene (3 mL) and methyl / e / 7-butyl ether (10 mL) to afford 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3,5-difluoro-anilino]piperidine-2,6-dione trifluoroacetate (B-27, 280 mg, 523.38 pmol, 93.48% yield) as an off-white solid. LC-MS (ES+): m / z 393.2 [M + H]+.

[1283] Synthesis of 3-[4-(3-azaspiro[5.5]undecan-9-yl)-3,5-difluoro-anilino]piperidine-2, 6-dione (B-28)

[1284]

[1285] SStep-1:

[1286] To a 250 mL three-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1, 1 g, 3.74 mmol) in THF (20 mL) was added 2.0 M lithium diisopropylamide in THF (5.61 mmol, 2.81 mL) at -78 °C. The resulting mixture was stirred at same temperature under nitrogen atmosphere for 1 h. Then 1,1,1 -trifl uoro-A-phenyl-A-(trifluoromethylsulfonyl)methanesulfonamide (2, 2.00 g, 5.61 mmol) in THF (20 mL) was added at -78 °C and the reaction mixture was slowly warmed to room temperature and stirred at for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was quenched with aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and thefiltrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 5 to 10 % Ethyl acetate in Petroleum ether) to afford / crt-butyl 9-(trifluoromethylsulfonyloxy)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (3, 760 mg, 1.90 mmol, 50% yield) as a pale-yellow solid. LC-MS (ES+): m / z 300.0 [M - COOtBu + H]+.

[1287] Step-2:

[1288] To a 100 mL sealed tube containing a well-stirred solution of 2,6-dibenzyloxy-A-[3,5-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyridin-3-amine (3, 850 mg, 1.24 mmol) and tert-butyl 9-(trifluoromethylsulfonyloxy)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (4, 720 mg, 1.80 mmol) in 1,4-di oxane (20 mL) was added K3PO4 (527.23 mg. 2.48 mmol) at room temperature. The mixture was purged with nitrogen gas for 2 minutes before Pd(dppf)Cl2·DCM (101.42 mg, 124.19 pmol) was added and the reaction mixture was stirred at 90 °C for 4 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 and the crude was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica; Eluent: 20 to 30 % Ethyl acetate in Petroleum ether) to afford tert-butyl 9-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undec-9-ene-3-carboxylate (5, 680 mg, 735.21 µmol, 59% yield) as an off-white solid. LC-MS (ES+): m / z 668.3 [M + H]+. Step-3:

[1289] To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undec-9-ene-3-carboxylate (5, 680 mg, 735.21 pmol) in 1,4-di oxane (20 mL) was added 20% palladium hydroxide on carbon (516.25 mg, 3.68 mmol) at room temperature. The reaction mixture was stirred at room temperature under hydrogen atmosphere 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; Eluent: 50 to 60 % Ethyl acetate in Petroleum ether) to afford tert-butyl 9-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undecane-3-carboxylate (6, 170 mg, 327.02 µmol, 44% yield) as an off-white solid.

[1290] LC-MS (ES’): m / z 490.1 [M - H]’.

[1291] Step-4:

[1292] To a 10 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undecane-3-carboxylate (6, 50 mg, 96.18 pmol) in DCM (3 mL) was added trifluoroacetic acid (2.61 mmol, 0.2 mL) at roomtemperature. The reaction mixture was stirred at this temperature for 1 h. After completion of the reaction as indicated by UPLC-MS. the solvent was removed from the reaction mixture and the crude product was triturated with MTBE (10 rnL) to afford 3-[4-(3-azaspiro[5.5]undecan-9-yl)-3, 5-difluoro-anilino]piperidine-2, 6-dione trifluoroacetate (B-28, 7, 45 mg, 66.77 pmol, 69% yield) as an off-white solid. LC-MS (ES+): m / z 392.3 [M + H]+.

[1293] Synthesis of 3- [4-(2,6-diazaspiro [3.4] octan-6-yl)-3,5-difluoro-anilino] piperidine-2, 6-dione (B-29)

[1294] H2, Pd / C CS2CO3, DMF EtOAc Step-1 Step-2

[1295]

[1296] SStep-1:

[1297] To a 40 mL screw-cap vial containing a well-stirred solution of tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate (1, 700 mg, 3.30 mmol) and l,2,3-trifluoro-5-nitro-benzene (2, 583.91 mg, 3.30 mmol) in DMF (3 mL) was added CS2CO3 (3.22 g, 9.89 mmol) at room temperature. The resulting reaction mixture was stirred at 90 °C for 2 h. After completion of the reaction as indicated by the UPLC-MS, the reaction mixture was passed through a pad of Celite and the fdtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (Stationary Phase: 230-400 silica gel; Eluent: 25 to 30% ethyl acetate in petroleum ether) to afford tert-butyl 7-(2,6-difluoro-4-nitro-phenyl)-2,7-diazaspiro[3.4]octane-2-carboxylate (3, 1.1 g. 2.79 mmol, 84% yield) as a yellow solid. LC-MS (ES+): m / z 270.1 [M + H-Boc]+

[1298] Step-2:To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 7- (2,6-difluoro-4-nitro-phenyl)-2,7-diazaspiro[3.4]octane-2-carboxylate (3, 1.1 g, 2.79 mmol) in dioxane (8 mL) was added 10% palladium on carbon (1 g, 9.40 mmol) at room temperature. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 3 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 was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 silica gel; Eluent: 30-40% ethyl acetate in petroleum ether) to afford tert-butyl 7-(4-amino-2,6-difluoro-phenyl)-2,7-diazaspiro[3.4]octane-2-carboxylate (4, 980 mg, 2.77 mmol, 99% yield) as an off- white solid. LC-MS (ES+): m / z 340.2 [M + H]+

[1299] Step-3:

[1300] To a 40 mL screw-cap vial containing a well-stirred solution of tert-butyl 7-(4-amino-2,6- difluoro-phenyl)-2,7-diazaspiro[3.4]octane-2-carboxylate (4, 980 mg, 2.77 mmol) and 3- bromopiperidine-2, 6-dione (5, 1.60 g, 8.32 mmol) in DMF (3 mL) was added sodium bicarbonate (698.63 mg. 8.32 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction as indicated by the UPLC-MS, the reaction mixture was purified by reverse-phase column chromatography [Column: RediSep Rf Gold® C18-120 g; Mobile phase A: 10 mM Ammonium bicarbonate in water and Mobile phase B: Acetonitrile] to afford tert-butyl 7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,7- diazaspiro[3.4]octane-2-carboxylate (6, 700 mg, 1.51 mmol, 54% yield) as an off-white solid. LC-MS (ES+): m / z 451.1 [M + H]+.

[1301] Step-4:

[1302] To a 10 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 7-[4- [(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,7-diazaspiro[3.4]octane-2-carboxylate (6, 80 mg, 172.26 pmol) in DCM (1 mL) was added 4 M HC1 in 1,4-di oxane (0.5 mL, 2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction as indicated by the UPLC-MS, the solvent was removed from the reaction mixture and the crude product was triturated with MTBE (10 mL) to afford 3-[4-(2,6-diazaspiro[3.4]octan-6- yl)-3.5-difluoro-anilino]piperidine-2, 6-dione hydrochloride (B-29, 70 mg. 99.53 pmol, 57% yield) as an off-white solid. LC-MS (ES+): m / z 351.2 [M + H]+.

[1303] The following CRBN binder was prepared using the method described above, with the corresponding amine 1 in Step-1.

[1304] Amine 1 in Step-1 CRBN binder MS

[1305]

[1306]

[1307] Synthesis of 3-[3,5-difluoro-4-(4-oxo-l-piperidyl)anilino]piperidine-2, 6-dione (B-31)

[1308] NaHCO3, DMF Step-3 aqueous HCI acetone Step-4

[1309]

[1310] SStep-1:

[1311] To a 40 mL vial containing a well-stirred solution of l,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]+.

[1312] Step-2:

[1313] 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-di oxane (5 mL) was added 10% Palladium on carbon, wet (3.5 g, 32.89 mmol) at room temperature. Theresulting 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]+

[1314] Step-3:

[1315] 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-(1,4-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]+.

[1316] Step-4:

[1317] To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 3-[4-(l,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. (1.5 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-l-piperidyl)anilino]piperidine-2, 6-dione (B-31, 220 mg, 417.41 pmol, 34.23% yield). LCMS (ES+): m / z 338.2 [M + H]+.

[1318] Synthesis of afford 3-[3,5-difluoro-4-(4-oxocyclohexyl)anilino]piperidine-2,6-dione (B-32)

[1319]

[1320]

[1321] SStep-1:

[1322] To a 40 mL screw-cap vial containing a well-stirred solution of 2.6-dibenzyloxy- / V-(4-bromo-3,5-difluoro-phenyl)pyridin-3-amine (1, 500 mg, 1.01 mmol) and 2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2, 294.33 mg, 1.11 mmol) in 1,4-dioxane (10 mL), were added water (1 mL) and K2CO3 (416.84 mg, 3.02 mmol) at room temperature. Nitrogen gas was purged into the reaction mixture for 2 minutes. Then, Pd(dppf)Cl2·DCM (82.10 mg, 100.54 pmol) was added and the reaction mixture was stirred at 90 °C for 2 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was passed through a pad of Celite. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: 0-10% ethyl acetate in petroleum ether) to afford 2,6-dibenzyloxy-2V-[4-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-3,5-difluoro-phenyl]pyridin-3-amine (3, 500 mg, 856.99 pmol, 85% yield) as a yellow solid. LC-MS (ES+): m / z 557.2 [M + H]+.

[1323] Step-2:

[1324] To a 50 mL single-neck round bottom flask containing a well-stirred solution of2,6-dibenzyloxy-7V-[4-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-3,5-difluoro-phenyl]pyridin-3-amine (3, 500 mg, 856.99 pmol) in 1,4-dioxane (5 mL) and DMF (1 mL) was added 20% palladium hydroxide on carbon (60.18 mg, 85.70 pmol) at room temperature. The resulting reaction mixture was stirred at room temperature under hydrogen atmosphere for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude compound w as purified by reverse-phase column chromatography [Column: X-bridge C8 (250 x 19) mm 5 microns, Mobile phase A: 0.1 % Formic acid in water and Mobile phase B: Acetonitrile] to afford 3-[4-(l,4-dioxaspiro[4.5]decan-8-yl)-3,5-difluoro-anilino]piperidine-2, 6-dione (4, 200 mg, 299.70 pmol, 34% yield) as a white solid. LC-MS (ES‘): m / z 379.0 [M - H]‘

[1325] Step-3:

[1326] To a 10 mL single-neck round bottom flask containing a well-stirred solution of3-[4-(l,4-dioxaspiro[4.5]decan-8-yl)-3,5-difluoro-anilino]piperidine-2, 6-dione (4a, 50 mg, 74.92pmol) inDCM (1 mL) was added TFA (3.75 mmol, 286.68 pL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 6 h. After completion of the reaction as indicated by UPLC-MS,the solvent was removed from the reaction mixture and the residue was triturated with MTBE (2 ml) to afford 3-[3,5-difluoro-4-(4-oxocyclohexyl)anilino]piperidine-2, 6-dione trifluoroacetate (B-32, 30 mg, 57.69 pmol, 77% yield) as an off-white solid. LC-MS (ES‘): m / z 335.1 [M - H]'.

[1327] 3-((5-fluoro-2-methoxy-4-(piperazin-l-yl)phenyl)amino)piperidine-2, 6-dione (B-33)

[1328]

[1329] Compound 3-((5-fluoro-2-methoxy-4-(piperazin-l -yl)phenyl)amino)piperidine-2, 6-dione was prepared using the method described on page of 165-167 of W0202203202613.

[1330] Synthesis of 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-5-fluoro-2-methoxy-anilino]piperidine- 2, 6-dione (B-34)

[1331] TFA, DCM Step-4

[1332]

[1333] SStep-1:

[1334] To a 20 mL vial containing a well stirred solution of l-bromo-2-fluoro-5-methoxy-4-nitro-benzene (1, 700 mg, 2.80 mmol) in 1,4-di oxane (14 mL) was added / c / 7-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2, 1.07 g, 4.20 mmol) and Cesium carbonate (1.82 g.5.60 mmol) at room temperature and nitrogen gas was purged through the mixture for 10 minutes. Then Pd2(dba)s (128.19 mg, 139.99 pmol) and Xantphos (162.00 mg, 279.98 pmol) were added and the reaction mixture was stirred at 90 °C for 16 h. After the completion of the reaction as indicated by LC-MS, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel) to afford tert-butyl 9-(2-fluoro-5-methoxy-4-nitro-phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (3, 600 mg, 1.15 mmol, 40.90% yield) as ayellow solid. LC-MS (ES+): m / z 368.2 [M -isobutene + H]+. Step-2:

[1335] To a 25 mL single-neck round-bottom flask containing a well-stirred suspension of tert-butyl 9-(2-fluoro-5-methoxy-4-nitro-phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (3, 600 mg, 1.13 mmol) in THF (5 mL), water (10 mL) and ethanol (15 mL) were added iron powder (443.09 mg, 7.93 mmol) and NH4CI (303.15 mg, 5.67 mmol) at ambient temperature under nitrogen atmosphere. The resulting suspension was heated at 80 °C for 2 h and the reaction mixture was then cooled to ambient temperature. After complete consumption of the starting material as indicated by TLC, the reaction mixture was filtered through a pad of Celite and Celite bed was washed with EtOAc (100 mL). The combined filtrate was diluted with water (80 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (Stationary Phase: 100 g silica-gel; Eluent: 0-40% EtOAc / pet ether) to afford tert-butyl 9-(4-amino-2-fluoro-5-methoxy-phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (4, 400 mg, 932.16 pmol, 82.24% yield) as an yellow gummy solid. LC-MS (ES+): m / z 394.4 [M + H]+.

[1336] Step-3:

[1337] To a 25 mL single-neck round-bottom flask containing a well-stirred suspension of tert- butyl 9-(4-amino-2-fluoro-5-methoxy-phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (4, 200 mg, 508.27 pmol) and 3-bromopiperidine-2, 6-dione (5, 195.18 mg, 1.02 mmol) in DMF (4 mL) were added NaHCO3(128.09 mg, 1.52mmol) at ambient temperature under nitrogen atmosphere. The resulting suspension was heated at 90°C for 16 h and the reaction mixture was cooled to ambient temperature. After complete consumption of the starting material as indicated by TLC, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (Stationary Phase: 100 g silica-gel; Eluent: 0-40% EtOAc / pet ether) to afford tert-butyl 9-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (6, 150 mg, 221.88 pmol, 43.65% yield) as a brown gum. LC-MS (ES+): m / z 505.1 [M + H]+.

[1338] Step-4:

[1339] To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 9-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (6, 150 mg, 297.27 pmol) in DCM (2 mL) was added TFA (33.90 mg. 297.27 pmol, 22.75 pL) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction as indicated by the UPLC-MS, the solvent was removed under reduced pressure. The crude compound was purified by reverse-phase column chromatography [Column: RediSep® C18-50 g; Mobile phase A: 0.1 mM NH4HCO3in water and Mobile phase B: MeCN] to afford 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-5-fluoro-2-methoxy-anilino]piperidine-2,6-dione (B-34, 110 mg, 265.27 pmol, 89.23% yield) as a brown gum. LC-MS (ES+): m / z 405.1 [M + H]+.

[1340] Synthesis of 3-(2-methoxy-4-piperazin-l-yl-anilino)piperidine-2, 6-dione (B-35)

[1341]

[1342] SStep-1:

[1343] To a 40 mL screw-cap vial containing a well-stirred solution of 4-fluoro-2-methoxy-1-2 nitrobenzene (1, 1 g, 5.84 mmol) and tert-butyl piperazine- 1 -carboxylate (2, 1.63 g, 8.77 mmol) in anhydrous DMF (12 mL) was added K2CO3 (2.42 g, 17.53 mmol) at room temperature. The resulting suspension was heated at 80 °C for 16 h. After complete consumption of the starting material as indicated by UPLC-MS, the reaction mixture was quenched with water, and the aqueous layer was extracted with ethyl acetate (2 x 400 mL). The combined organic layers were washed with saturated NaCl solution (350 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (Stationary Phase: 230-400 mesh silica; Eluent: 15 to20% Ethyl acetate in Petroleum ether) to afford tert-butyl 4-(3-methoxy-4-nitro-phenyl)piperazine-l -carboxylate (3, 1.9 g. 5.59 mmol, 96% yield) as a pale-yellow solid. LC-MS (ES+): m / z 238.2 [M- COO'Bu + H]+.

[1344] Step-2:

[1345] To a 50 mL single-neck round-bottom flask containing a well-stirred suspension of tert-butyl 4-(3-methoxy-4-nitro-phenyl)piperazine-l-carboxylate (3, 950 mg, 2.79 mmol) inTHF (7 mL) and ethanol (7 mL) was added 10% Palladium on carbon (1.49 g, 1.40 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 filtered through a pad of Celite, and the Celite pad was washed with THF (200 mL) and ethanol (200 mL). The filtrate was concentrated under reduced pressure, and the crude residue was purified by column chromatography (Stationary Phase: 230-400 mesh silica; Eluent: 30 to 40% ethyl acetate in petroleum ether) to afford tert-butyl 4-(4-amino-3-methoxy-phenyl)piperazine-l -carboxylate (4, 1.3 g, 2.72 mmol, 97% yield) as a pale-yellow solid. LC-MS (ES+): m / z 308.1 [M + H]+.

[1346] Step-3:

[1347] To a 40 mL screw-cap vial containing a well-stirred suspension of terf-butyl 4-(4-amino-3-methoxy-phenyl)piperazine-l -carboxylate (4, 1.3 g, 2.72 mmol) and 3-bromopiperidine-2,6-dione (5, 1.57 g, 8.15 mmol) in anhy drous DMF (15 mL) was added sodium bicarbonate (2.28 g, 27.18 mmol) at room temperature. The reaction mixture was heated at 80 °C for 16 h. After completion of the reaction as indicated by UPLC-MS, the reaction mixture was diluted with water (200 mL) and was extracted with EtOAc (2 x 300 mL). The combined organic layer was dried over sodium sulfate and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (Stationary Phase: 60-120 mesh silica; Eluent: 40-50% Ethyl acetate in Petroleum ether) to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-3-methoxy-phenyl]piperazine-l-carboxylate (6, 1.1 g, 2.44 mmol, 90% yield) as a pale-yellow solid. LC-MS (ES+): m / z 419.3 [M + H]+.

[1348] Step-4:

[1349] 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]-3-methoxy-phenyl]piperazine-l -carboxylate (6, 500 mg, 1.11 mmol) in anhydrous DCM (5 mL) was added 4 M HC1 in 1,4-dioxane (2.78 mL, 11.11 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure and the crude residue was triturated with MTBE (5 mL) and dried to afford 3-(2-methoxy-4-piperazin-l-yl-anilino)piperidine-2, 6-dione hydrochloride (B-35, 350 mg, 539.65 pmol, 48% yield) as a pale-yellow solid. LC-MS (ES+): m / z 319.2 [M + H]+.

[1350] 3-(4-(piperidin-4-yI)phenoxy)piperidine- 2, 6-dione (B-36)

[1351]

[1352] Compound 3-(4-(piperidin-4-yl)phenoxy)piperidine-2, 6-dione was prepared using the method described on page 555 of WO202125521214.

[1353] Synthesis of 3-[3,5-difluoro-4-(4-piperidyl)phenoxy]piperidine-2,6-dione (B-37)

[1354]

[1355] SStep-1:

[1356] To two 40 mL screw-cap reaction vials containing a well-stirred solution of 4-bromo-3,5-difluoro-phenol (1, 3 g, 14.35 mmol) in 1,4-dioxane (30 mL) was added tert-butyl 4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-277-pyridine-l-carboxylate (2, 4.44 g, 14.35 mmol), K3PO4 (7.62 g, 35.89 mmol) and water (3 mL) at room temperature. The reaction mixture was purged with nitrogen gas for 5 minutes. Then Pd(dppf)Cl2 DCM (1.17 g, 1.44 mmol) was added, and the reaction mixture was stirred at 90 °C for 10 h. Progress of the reaction was monitored by UPLC.

[1357] After the starting material was consumed, the reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (Stationary Phase: 230-400 mesh silica gel: Eluent: 10-15% Ethyl acetate in Pet ether) to afford tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)-3,6-dihydro-277-pyndine-l -carboxylate (3, 3.85 g, 11.02 mmol, 76.78% yield) as a pale yellow solid. LC-MS (ES‘): m / z 310.0 [M - H]+.

[1358] Step-2:To a 100 mL round-bottom flask containing a well stirred solution of tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)-3,6-dihydro-2 / f-pyridine-l -carboxylate (3, 1 g. 2.89 mmol) in THF (10 mL) was added 20% Pd(OH)2 on carbon (wetted with ca. 55% water) (738.15 mg, 2.89 mmol) at room temperature and the reaction mixture was stirred at 25°C for 16 hours under H2 atmosphere. The reaction progress was monitored by TLC and LCMS. The reaction mixture was then filtered through a pad of Celite, which was subsequently washed with a mixture of THF (200 mL) and dioxane (100 mL). The filtrate was concentrated under reduced pressure, and the residue was triturated with DCM and MTBE. The obtained crude was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 20% EtOAc in pet ether) to afford tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)piperidine-l-carboxylate (4, 900 mg, 2.83 mmol, 97.99% yield) as a pale-yellow solid. LCMS (ES ): m / z 312.3 [M - H]’.

[1359] Step-3:

[1360] To a 40 mL pressure-cap vial containing a well-stirred solution of tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)piperidine-l-carboxylate (4, 1.4 g, 4.29 mmol) and 3-bromopiperidine-2, 6-dione (5, 3.29 g, 17.16 mmol) in MeCN (10 mL) was added CS2CO3 (3.49 g, 10.72 mmol) and the reaction mixture was stirred at 70°C for 1 h. The reaction mixture was then filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 30% Ethyl acetate in pet ether) to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperidine-l-carboxylate (6, 900 mg, 1.80 mmol, 41.93% yield) as a yellow solid. LC-MS (ES+): m z 325.0 [M-tBuCOO + H]+.

[1361] Step-4:

[1362] To a 50 mL round-bottom flask containing a well stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2.6-difluoro-phenyl]piperidine-l-carboxylate (6, 1 g, 1.98 mmol) in DCM (10 mL) was added 4.0 M HCl in 1,4-dioxane (4 M, 4.20 mL) at 0°C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was then concentrated under reduced pressure and diluted with MTBE. The obtained precipitate was washed with MBTE 2-3 times and dried under reduced pressure to afford 3-[3,5-difluoro-4-(4-piperidyl)phenoxy]piperidine-2, 6-dione hydrochloride (B-37, 900 mg, 1.67 mmol. 84.40% yield) as a white solid. LC-MS (ES ): m / z 325.1 [M + H]+.Synthesis of 3-(3,5-difluoro-4-piperazin-l-yl-phenoxy)piperidine-2, 6-dione (B-38)

[1363] Boc Boc

[1364]

[1365] SStep-1:

[1366] To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 1,2,3-trifluoro-5-nitro-benzene (1, 5 g, 28.24 mmol) and tert-butyl piperazine- 1 -carboxylate (2, 5.26 g, 28.24 mmol) in DMF (50 mL) was added Et3N (11.8 mL, 84.71 mmol) and the resulting reaction mixture was stirred at 100 °C for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to afford the crude residue. The crude residue was purified by flash silica gel column chromatography (Stationary phase: 230-400 mesh silica gel; Eluent: 35 % ethyl acetate in petroleum ether) to afford tert-butyl 4-(2,6-difluoro-4-nitro-phenyl)piperazine-l -carboxylate (3, 7 g, 18.78 mmol, 66% yield) as a yellow solid. LC-MS (ES+): m / z 244.1 [M-COOtBu + H]+

[1367] Step-2:

[1368] To 25 mL round-bottomed flask containing a well-stirred solution of tert-butyl 4-(2,6-difluoro-4-nitro-phenyl)piperazine-l -carboxylate (3, 7 g, 20.39 mmol) in THF (80 mL) was added 20% Pd(OH)2 on carbon (5.73 g, 8.16 mmol), and the resulting reaction mixture was stirred under a H2 atmosphere with bladder pressure for 16 h. Upon completion of reaction as determined by UPLC-MS, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to afford thecrude residue, which was triturated with methyl terf-buty 1 ether to afford tert-butyl 4-(4-amino-2.6-difluoro-phenyl)piperazine-l-carboxylate (4, 6.1 g, 19.38 mmol, 95% yield) as a brown solid, which was used without further purification.

[1369] Step-3:

[1370] To a 100 mL single-neck round-bottom flask containing a well-stirred solution of terf-butyl 4-(4-amino-2,6-difluoro-phenyl)piperazine-l -carboxylate (4, 1.01 g, 3.19 mmol) in anhydrous acetonitrile (10 mL) was added isoamyl nitrite (1.50 g, 12.77 mmol, 1.71 mL) at room temperature. Then CuBr (915.61 mg, 6.38 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 3 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was quenched by the addition of saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layer was washed with water (60 mL) and brine solution (40 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude compound, which was purified by flash chromatography (Stationary Phase: 60-120 mesh silica gel; Eluent: 40 % ethyl acetate in petroleum ether) to afford tert-butyl 4-(4-bromo-2,6-difluoro-phenyl)piperazine-l-carboxylate (5, 200 mg, 450.66 pmol, 14% yield) as a yellow solid. LC-MS (ES+): m / z 277.0 [M-COOtBu + H]+.

[1371] Step-4:

[1372] To a 20 mL vial containing a well-stirred solution of terf-butyl 4-(4-bromo-2,6-difluoro-phenyl)piperazine-l -carboxylate (5, 170 mg, 383.06 pmol) in 1,4-di oxane (2.01 mL) was added bis(pinacolato)diboron (2.43 g, 9.58 mmol) and potassium acetate (75.19 mg, 766.12 pmol) under nitrogen atmosphere. The resulting reaction mixture was degassed with nitrogen for 2 min. Then Pd(dppf)C12 DCM (15.64 mg, 19.15 pmol) was added to the reaction mixture, and the resulting reaction mixture was heated to 90 °C for stirred for 16 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with DCM (50 mL) and ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (6, 200 mg. 138.91 pmol, 36% yield) as a brown solid, which was used without further purification. LC-MS (ES+): m / z 425.5 [M + H]+.

[1373] Step-5:

[1374] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)phenyl]piperazine-l-carboxylate (6, 600 mg, 424.24 pmol) in anhydrous ethyl acetate (6 mL) was added H₂O₂ solution (4.24 mmol, 130.00 pL) at 0 °C. The resulting reaction mixture was allowed to warm to ambient temperatureand stirred for 3 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was quenched by the addition of a saturated Na₂S₂O₃ solution (20 mL) and extracted with ethyl acetate (2 x 70 mL). The combined organic layer was washed with water (20 mL) and brine solution (20 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford the crude residue. The crude residue was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 35% ethyl acetate in petroleum ether) to afford fert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)piperazine-l-carboxylate (7, 155 mg, 400.56 pmol, 94% yield) as an off-white solid. LC-MS (ES‘): m / z 313.0 [M - H]‘. Step-6:

[1375] To a 50 mL two-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)piperazine-l -carboxylate (7, 200 mg, 521.75 pmol) in DMF (3 mL) was cooled to 0-5°C. Then NaH (60% dispersion in oil, 62.61 mg, 1.57 mmol) was added at 0-5 °C and the resulting reaction mixture was stirred for 15 min. Then, 3-bromopiperidine-2,6-dione 8 (200.36 mg, 1.04 mmol) was added, and the resulting reaction mixture was warmed to ambient temperature and stirred for 3 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was quenched by the addition of an ice cold aqueous 1.5 N HC1 solution and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with water (20 mL), brine (20 mL), dried over sodium sulfate, fdtered, and the fdtrate concentrated under reduced pressure to afford the crude residue, which was purified by flash column chromatography (Stationary Phase: 230-400 mesh silica gel; Eluent: 60% ethyl acetate in petroleum ether) to afford tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazine-l -carboxylate (9, 125 mg, 195.98 pmol, 38% yield) as a white solid. LC-MS (ES+): m / z 370.1 [M-isobutene + H]+.

[1376] Step-7:

[1377] To a 25 mL round-bottom flask containing a well-stirred solution of fert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazine-l-carboxylate (9, 125 mg, 196.86 pmol) in DCM (5 mL) was added 4 M HC1 in 1,4-dioxane (2.01 mL, 8.04 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 h. Upon completion of the reaction as determined by UPLC-MS, the reaction mixture was concentrated under reduced pressure to afford the crude residue, which was triturated with methyl fert-butyl ether to afford 3-(3, 5-difluoro-4-piperazin-l-yl-phenoxy)piperidine-2, 6-dione hydrochloride (B-38, 95 mg, 192.38 pmol, 98% yield) as an off-white solid, which was used without further purification.

[1378] 3Synthesis of 10-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l- piperidyl]-10-oxo-decanoic acid (C-l)

[1379]

[1380] SStep-1:

[1381] To a 40 mL screw-capped glass vial containing a well-stirred solution of 10-re / 7-butoxy- 10-oxo- decanoic acid (2, 124.53 mg, 482.02 pmol) and 3-[3-methyl-2-oxo-4-(4-piperidyl)benzimidazol- l-yl]piperidine-2, 6-dione trifluoroacetate (B-2, 200 mg, 438.20 pmol) in anhydrous DMF (5.19 mL) was added DIPEA (283.16 mg, 2.19 mmol, 381.62 pL) and HATU (216.60 mg, 569.66 pmol) at ambient temperature under nitrogen atmosphere. The contents were stirred at this temperature for 2 h. Upon completion of the reaction, the reaction mixture was quenched with ice (10 g) and ice-cold water (20 mL). The resulting precipitate was filtered and washed with water (3 x 10 mL) and pet ether (2 x 10 mL) to afford fe / 7-butyl 10-[4-[l-(2,6-dioxo-3- piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-10-oxo-decanoate (3, 200 mg, 299.25 pmol. 68.29% yield) as an off white solid, which was used without further purification. LC-MS (ES+): m / z 527.3 [M-isobutene+ H]+.

[1382] Step-2:

[1383] To a 50 mL single-neck round-bottom flask containing a well-stirred solution of / c / 7-butyl 10-[4- [1 -(2.6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l -piperidyl]-! 0-oxo-decanoate (3, 130 mg, 223.09 pmol) in anhydrous DCM (4 mL) was added a 4.0 M hydrogen chloride solution in 1,4-di oxane (5 mL) at 0 °C under nitrogen atmosphere. The contents were stirred for 2 h at ambient temperature. After consumption of the starting material as in dicated by UPLC, excesssolvent was removed under reduced pressure and the crude product was washed with pet ether (2 x 10 mL) and MTBE (10 mL) to afford 10-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl]-10-oxo-decanoic acid (C-l, 110 mg, 150.98 pmol, 67.68% yield) as an off-white solid, which was used without further purification. LC-MS (ES+): m / z 527.3 [M + H]⁺.

[1384] Synthesis of 2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-l-piperidyl] acetic acid (C-2)

[1385]

[1386] SStep-1:

[1387] To a 500 mL two-neck round-bottom flask containing 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) were 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. The reaction mixture was then quenched with ice water (400 mL), and the precipitate was filtered and dried under reduced pressure to afford / ert-butyl 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. UPLC-MS (ESI) m / z 457.2 [M + H]+.

[1388] Step-2:

[1389] To a 1000 mL single-neck round-bottom flask containing a well stirred solution of tert-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 HC1 in 1,4-dioxane (4 M, 109.52 mL) at 0 °C and the resulting suspension was stirred at 25 °C for 16 h. After completion of the reaction, the reaction mxture 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-1, 18.22 g, 41.65 mmol, 95.06% yield) as an off-white solid. UPLC-MS (ESI): m / z 401.3 [M + H]+.

[1390] Synthesis of 1- [ [ 1- [4- [(2,6-dioxo-3-piperidyl)amino] -2,6-difluoro-phenyl]-4-piperidyl] methyl] pi peridine-4-carboxylic acid (C-3)

[1391] Pd / Al₂O₃, H₂ NaBH(OAc)₃, AcOH MeOH, THF MeOH Step-2 Step-1

[1392] DIEA, DMF Step-3

[1393]

[1394] SStep-1:

[1395] To a solution of tert-butyl piperidine-4-carboxylate (1, 5.0 g, 26.99 mmol) in methanol (100 rnL) was added acetic acid (162.07 mg, 2.7 mmol) and benzy l 4-formylpiperidine-l-carboxylate (2, 10.01 g, 40.48 mmol), followed by sodium cyanoborohydride (8.6 g. 136.85 mmol) at 0 °C. The resulting reaction mixture was warmed to 20 °C and stirred for 1 h. Then the reaction mixture was concentrated in vacuo to yield a residue, which was diluted by the addition of a saturated NaHCO₃ aqueous solution (100 mL) and H2O (100 mL), and the mixture was extracted withEtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (Combi-flash Automated purification system; Column: Phenomenex Synergi C18 (150 mm * 25 mm) * 10 pm; Mobile Phase A: water (modified with 0.1% Formic Acid), Mobile Phase B: MeCN; Gradient: 70%-100% B over 20 min) to afford benzyl 4-[(4-tert-butoxy carbonyl- l-piperidyl)methyl]piperi dine- 1 -carboxylate benzyl 4-((4-(tert-butoxycarbonyl)piperidin-l-yl)methyl)piperidine-l-carboxylate (3, 6.0 g, 14.4 mmol, 53.37% yield) as light yellow oil. LC-MS (ES+): m / z 417.3 [M + H]+. 'H NMR (400 MHz, METHANOL-d₄): 5 7.41 - 7.26 (m, 5H), 5.10 (s, 2H), 4.13 (d, J = 13.2 Hz, 2H), 2.86 (d, J = 11.2 Hz, 3H), 2.29 - 2.13 (m, 3H). 2.08 - 1.98 (m. 3H), 1.87 - 1.62 (m, 7H), 1.51 - 1.33 (m, 9H), 1.16 - 0.99 (m, 2H) ppm.

[1396] Step-2: (see Figure 5)

[1397] The fixed bed (named FLR1, volume 5 mL) was completely packed with granular 5% Pd / Al₂O₃ cataly st (3.4 g). The H2 back pressure regulator was adjusted to 1.5 MPa. and the flow rate of H2 was set to 20 mL / min. Solution 1 [benzyl 4-((4-(tert-butoxycarbonyl)piperidin-l-yl)methyl)piperidine-l -carboxylate (3, 5.0 g, 12.0 mmol) in THF (50 mL) and Methanol (50 mL)] was pumped by Pump 1 {SI, Pl, 0.3 mL / min} to flow reactor 1 {FLR1, SS, Fixed bed, 6.35(l / 4")mm, 5 mL, 50.0 °C}. The total reaction was reacted at 50 °C for 330 min. Then the reaction mixture was collected from the reactor output and concentrated in vacuo to afford tertbutyl l-(4-piperidylmethyl)piperidine-4-carboxylate (4, 3.2 g, 11.33 mmol, 94.39% yield) as a pink solid. 'H NMR (400 MHz, METHANOL-d₄): 83.04 (d, J= 12.0 Hz, 2H), 2.85 (s, 2H), 2.66 - 2.55 (m, 2H), 2.20 - 2.14 (m, 2H), 2.03 - 1.96 (m, 2H), 1.85 - 1.66 (m, 8H), 1.53 - 1.40 (m, 9H), 1.21 - 1.05 (m, 2H) ppm.

[1398] Step-3:

[1399] To a solution of tert-butyl l-(4-piperidylmethyl)piperidine-4-carboxylate (4, 3.18 g, 11.27 mmol) in DMF (20 mL) was added / V. A-diisopropylethylamine (2.24 mL, 12.88 mmol) and 1,2,3-trifluoro-5-nitrobenzene (5, 1.9 g, 10.73 mmol). The resulting reaction mixture was stirred at 10 °C for 2 h. The reaction mixture was directly purified by reverse-phase HPLC [Column: Phenomenex Synergi Cl 8 (150 mm * 25 mm) * 10 pm; Mobile Phase A: water (Modified with 0.1% FA), Mobile phase B: MeCN; gradient: 100% B, 20 min) to afford tert-butyl l-[[l-(2,6-difluoro-4-nitro-phenyl)-4-piperidyl]methyl]piperidine-4-carboxylate (6, 3.0 g, 6.83 mmol, 63.62% yield) as a yellow solid. LC-MS (ES⁺): m / z 440.4 [M + H]. 'H NMR (400 MHz, DMSO-de): 8 8.01 - 7.90 (m, 2H), 3.46 (d, J= 12.4 Hz, 2H), 3.13 (t, J= 11.6 Hz, 2H), 2.74 (d, J = 11.2 Hz, 2H), 2.19 - 2.06 (m, 3H), 1.91 (t, J= 10.4 Hz, 2H), 1.79 - 1.67 (m, 5H), 1.57 - 1.46 (m, 2H), 1.39 (s, 9H), 1.21 - 1.11 (m, 2H) ppm.Step-4:

[1400] To a solution of tert-butyl l-[[l-(2,6-difluoro-4-nitro-phenyl)-4-piperidyl]methyl]piperidine-4-carboxylate (6, 3.0 g, 6.83 mmol) in Methanol (100 mL) was added 5% Pd / SiO₂ catalyst (2.0 g) under N2. The resulting reaction mixture was stirred at 10 °C for 2 h under a H2 atmosphere (15 psi). The resulting reaction mixture was filtered, and the filter cake was concentrated in vacuo to afford a residue, which was purified by normal phase column chromatography (Stationary Phase: Silica Gel, Eluent: Gradient from 0 - 100% EtOAc in Petroleum ether) to afford tert-butyl 1-[[1-(4-amino-2,6-difluoro-phenyl)-4-piperidyl]methyl]piperidine-4-carboxylate (7, 1.8 g, 4.4 mmol, 64.39% yield) as a yellow solid. LC-MS (ES+): m / z 410.3 [M + H]+.JH NMR (400 MHz, CHLOROFORM-d): 56.15 (d, J= 10.4 Hz, 2H), 3.11 - 2.97 (m, 6H), 2.55 - 2.26 (m, 5H), 2.04 -1.95 (m, 2H). 1.95 - 1.83 (m. 2H), 1.83 - 1.67 (m, 3H), 1.45 (s, 10H) ppm.

[1401] Step-5:

[1402] To a solution of tert-butyl 1-((1-(4-amino-2,6-difluorophenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (7, 1.7 g, 4.15 mmol) in 1,4-Dioxane (30 mL) was added cesium carbonate (4.06 g, 12.45 mmol), 2,6-bis(benzyloxy)-3-iodopyridine (8, 1.73 g, 4.15 mmol) and RuPhosPdG3 (0.35 g, 0.42 mmol). The resulting reaction mixture was heated to 100 °C and stirred for 16 h under N2. The resulting reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford a residue, which was purified by normal phase column chromatography (Stationary Phase: Silica gel; Eluent: Gradient from 0 - 50% EtOAc in Petroleum ether) to afford tert-butyl l-[[l-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2,6-difluoro-phenyll-4-piperidyl]methyl]piperidine-4-carboxylate (9, 2.0 g, 2.86 mmol, 68.94% yield) as a light brown oil. LC-MS (ES+): m / z 699.4 [M + H]+. Step-6: (see Figure 6)

[1403] Solution 1 [tert-butyl l-((l-(4-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (9, 1.5 g, 2.15 mmol) in THF (38 mL)] was pumped by Pump 1 {SI, Pl, 0.3 mL / min} to flow reactor 1 {FLR1, SS, Fixed bed, 6.350(l / 4")mm, 1.0 mL, 70.0 °C}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular 5% Pd(OH)₂ / Al₂O₃ (WXSC1007, 1.5 g) catalyst. The H2 back pressure regulator was adjusted to 2 MPa, and the flow rate of H2 to 15 mL / min. The total reaction was reacted at 70 °C for 126 min. Then the reaction mixture was collected from the reactor output and concentrated in vacuo to afford a residue, which was purified by normal phase column chromatography (Stationary Phase: Silica gel; Eluent: Gradient from 0 - 66% EtOAc in Petroleum ether) to afford tert-butyl l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carboxylate (10, 386.0 mg, 0.74 mmol, 34.54% yield) as a light brown solid. LC-MS (ES+): m / z 521.3 [M + H]+.

[1404] Step-7:To a solution of tert-butyl l-((l-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6- difluorophenyl)piperidin-4-yl)methyl)piperidine-4-carboxylate (10, 60.0 mg, 0.12 mmol) in DCM (0.400 mL) was added trifluoroacetic acid (0.4 mL, 5.19 mmol), and the resulting reaction mixture stirred at 20 °C for 1 h. The resulting mixture was concentrated in vacuo to give a residue. MeOH (5 mL) and strong alkali phenylethlene anion exchange resin (100 mg) were added, and the resulting mixture was stirred at 20 °C for 0.5 h. The mixture was filtered, and the filtrate was concentrated in vacuo to afford l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro- phenyl]-4-piperidyl]methyl]piperidine-4-carboxylic acid (C-3, 50.0 mg, 0.11 mmol, 93.4% yield) as a green oil. LC-MS (ES⁻): m / z 465.2 [M + H]+.

[1405] The following intermediate was prepared using a similar method as described above, with the corresponding amine 1 and ketone 2 as a reactant in Step-1.

[1406] Amine 1 in Aldehyde / Ketone Intermediate MS

[1407] Step-1 2 in Step-1

[1408] O LC-MS (ES+): m z 451.2

[1409] [M + H]+.

[1410] 0 o / k o (NaBH₃CN was used as Cbz JL A a reducing agent in F^Y^ F

[1411] Step-1; XPhos Pd G4 was used as a catalyst in 0 Step-5)

[1412] Ho $Y

[1413] C-4

[1414] 01 LC-MS (ES+): m / z 437.3 Y

[1415] Cbz [M + H]+.

[1416] HklY HN-VH

[1417] A. 0 (NaBH₃CN was used as Jl A a reducing agent in F'''' Y' T

[1418] Step-1; XPhos Pd G4 was used as a catalyst inr9 Step-5)

[1419] OH

[1420] C-26

[1421]

[1422] Table 12: Preparation of C-4 and C-26Syn thesis of 3- [5-fluoro-2-methoxy-4- [4-(4-piperidylmethyl)piperazin-l-yl] anilino] piperidine-2, 6-dione (C-5)

[1423] MP-CNBH3, AcOH DMSO

[1424]

[1425] SStep-1:

[1426] To a 20 mL screw cap vial containing a well-stirred solution of 3-(5-fluoro-2-methoxy-4-piperazin-l-yl-anilino)piperidine-2, 6-dione (B-33, 300 mg, 891.90 pmol) and tert-butyl 4-formylpiperidine-1 -carboxylate (2, 190.22 mg, 891.90 gmol) in DMSO (6 mL) was added acetic acid (160.68 mg, 2.68 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. Then MP-CNBH3 (500 mg, 1 mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 4 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 to afford t...

Claims

CLAIMS1. A compound of formula I or a pharmaceutically acceptable salt thereofT-L-B I,whereinis a target ligand selected from the group consisting ofa is -C(Ci-3-alkyl FF), -C(heterocyclyl, OCH3), -C(heterocyclyl, F), -heterocyclyl, -C(C3-6-cycloalkyl, H), -C(C3-6-cycloalkyl, OCH3), -C(C3-6-cycloalkyl substituted by 1-2 halogen, H), -SO2CH3, -C((CH3)2, OCH3) or -C(CH3)2OH,a' is C1-3-alkyl, -O-Ci-3-alkyl, -O-C3-6-cycloalkyl or Cs-e-cycloalkyl, and when attached to L, a' is absent or -0-,a’' is Ci-3-alkyl, -O-Ci-3-alkyl or halogen,b is N or CH,c is H, -CO-Ci-3-alkyl, -CO-Cs-6-cycloalkyl, -CO-N(H, CH3), -CO-NH2, SO2-Ci-3-alkyl, heterocyclyl or -Ci-3-alkyl, andd is selected from the group consisting of Cs-e-cycloalkyl, ary l, ary l substituted by 1-2 halogen, heteroaryl and heteroaryl substituted by 1-2 halogen,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, -O- or heteroarylheteroaryl,L is a linker selected from the group consisting ofwhereinL1 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-, -(CH₂)₁₋₈-, -(CH₂)₁₋₈-CO-, -(CH2)o-i-heterocyclyl, heterocyclyl-(CH2)o-i -heterocyclyl-(CH2)i-2-O-(CH2)i-2-, -hcteroaryl-iCFLjo-i- and - (CH2)o-i-heteroaryl-,l1 is CH or N,l2 is CH or N,. Bb)T Bc) -CO-(CH2)O-2-.L2 is selected from the group consisting of a bond, -(CH2)I-2-, -CO-, -O- and -(CH2)O-2- CO-(CH2)I-2-,l3 is selected from the group consisting of CH and N,14 is absent, -CH2N(H, CH3)-, -(CH2)I-2- or -CO-,, whereinL3 is absent or is selected from the group consisting of -(CH2)I-2-, -CO-, -O-, and - (CH2)I-2-CO-(CH2)I-2-,L4 is absent, -Ca-e-cycloalkyl or heterocyclyl.L5 is absent or is selected from the group consisting of -(CH2)I-2-, CH2N(H, CH3)-, heterocyclyl-CO-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-,, wherein l5 is -CH- or -N-,16 is -O-, -CF2-, or -CH2-,L6 is absent, -(CH2)I-2-, -O-, -Cs-e-cycloalkyl or -(CH2)o-2-heterocyclyl, optionally substituted by halogen,g). wherein L7 is selected from the group consisting of - (CH2)I-2-. -CO-, and -(CH2)I.2-CO-(CH2)I-2-. andh), wherein L8 is selected from the group consisting of - (CH2)I-2-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-. andi), wherein L9 is selected from the group consisting of -(CH2)I-2-, -CO-, and -(CH2)I-2-CO-(CH2)I-2-, andB is a CRBN binder selected from the group consisting ofwherein e is selected from the group consisting of a -(CH₂)₀₋₁heteroaryl optionally substituted by Ci-3-alkyl, halogen or =0 and -(CH2)0-1aryl, optionally substituted by halogen or -O-Ci-3-alkyl.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein T is a target ligand selected from the group consisting ofT, wherein a is -C(Ci-3-alkyl. FF), -C(heterocyclyl,OCH₃), -heterocyclyl or -C((CH₃)₂,OCH₃)a’ is Ci-3-alkyl,b is N or CH,c is -CO-Ci-3-alkyl, -CO-C3-6-cycloalkyl, -CO-N(H, CH3) or SO2-Ci-3-alkyl.d is heteroaryl, ande is absent, -(CH2)1-3-, -N(CH3)-, -N(CH3)-CO- or -O-,L is a linker selected from the group consisting ofwhereinLI is absent or selected from the group consisting of -(CH2)1-3-CO-, -(CH2)I-8-, -(CH2)1-8-CO-, -heterocyclyl-(CH2)1-2and -heterocyclyl-(CH2)1-2-O-(CH2)1-2-.l1 is CH or N,l2 is CH or N,L2 is selected from the group consisting of –(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, –CH2N(H,CH3)-, or –(CH2)1-2-,-4— L5-L4— L3- / ^\l4- T ■ 'd)0-1 B, whereinL3 is absent or is selected from the group consisting of–(CH2)1-2–, –CO– and –O–, L4 is absent or heterocyclyl,L5 is absent or is selected from the group consisting of CH2N(H, CH3)- and heterocyclyl- CO-,, wherein 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, andf), wherein L9 is selected from the group consisting of -(CH2)1-2-, -CO-, and -(CH2)1-2-CO-(CH2)1-2-, andB is a CRBN binder selected from the group consisting ofwherein e is selected from the group consisting of a -(CH2)0-1heteroaryl, optionally substituted by C1-3-alkyl, halogen or =O and -(CH2)0-1aryl, optionally substituted by halogen or -O-C1-3-alkyl.

3. A compound according to any one of claims 1 -2 or a pharmaceutically acceptable salt thereof whereinT is a target ligand selected from the group consisting ofand T, wherein a is –C(C1-3-alkyl,F,F), –C(heterocyclyl,OCH3), –heterocyclyl or –C((CH3)2,OCH3)a’ is Ci-3-alkyl,b is N or CH,c is -CO-Ci-3-alkyl, -CO-C3-6-cycloalkyl, -C0-N(H, CH3) or SO2-Ci-3-alkyl,d is heteroaryl, ande is absent, -(CH2)1-3-, -N(CH3)-, -N(CH3)-CO- or -O-.

4. A compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof wherein T is a target ligandT, wherein a is –C(C1-3-alkyl,F,F) or –C(heterocyclyl,OCH3),a’ is Ci-3-alkyl.b is N or CH,c is -CO-Ci-3-alkyl,d is heteroaryl, ande is absent, -(CH2)1-3-, -N(CH3)-CO- or -O-.

5. A compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof wherein T is selected from the group consisting of5 6. A compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof wherein T is selected from the group consisting of, wherein means the site of the target ligand T attached to L.

7. A compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereofwherein T is wherein means the site attached to L.A compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof wherein B is a CRBN binder selected from the group consisting ofwherein e is selected from the group consisting of a heteroaryl, optionally substituted by C1-3-alkyl, halogen or =0 and -(CH2)0-1aryl, 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 ofwherein e is selected from 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, each optionally substituted by CH3, F or =0 and phenyl, 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 a CRBN binder selected from the group consisting ofwherein e is selected from ITif-indazolyl, optionally substituted by CH3 and phenyl, optionally substituted by 2 F.

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 of13. A compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof wherein B is selected from the group consisting ofandLmeans the site of the CRBN binder B attached to L.

14. A compound according to any one of claims 1-13 or a pharmaceutically acceptable saltattached to L.

15. A compound according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting ofL is a linker selected from the group consisting ofwhereinLI is absent or selected from the group consisting of -(CH2)1-3-CO-, -(CH2)1-8-, -(CH2)1-8-CO-, -heterocyclyl-(CH2)1-2and -heterocyclyl-(CH2)1-2-O-(CH2)1-2-,l1 is CH or N,l2 is CH or N,L2 is selected from the group consisting of –(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, –CH2N(H,CH3)-, or –(CH2)1-2-,-4— L5-L4— L3- / ^\l4- T ■ 'd)0-1 B, whereinL3 is absent or is selected from the group consisting of–(CH2)1-2–, –CO– and –O–, L4 is absent or heterocyclyl,L5 is absent or is selected from the group consisting of CH2N(H, CH3)- and heterocyclyl- CO-,, wherein 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, and, wherein L9 is selected from the group consisting of -(CH2)1-2-, - CO-, and -(CH2)i-2-CO-(CH2)i-2-.

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 ofwhereinL1 is absent or selected from the group consisting of -(CH2)1-8- and -heterocyclyl-(CH2)1-2, l1 is CH or N,l2 is CH or N,, whereinL2 is–(CH2)1-2-,13 is N,l4 is-(CH2)1-2-,-i— L5-L4— L3-Z^N-i- T ■ ■c)0-1 B, whereinL3 is (CH2)I-2-,L4 is heterocyclyl,L5 is heterocyclyl-CO-,, wherein l5 is -CH- or -N-,16 is -CH2-,L6 is-(CH2)1-2- or -(CH2)0-2-heterocyclyl.

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 ofTsite attached to the CRBN binder B and means the site attached to the target ligand T.

18. A compound according to any one of claims 1-17 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting of'Tand means the site attached to the target ligand T.

19. A compound according to any one of claims 1-18 or a pharmaceutically acceptable salt thereof wherein L is selected from the group consisting ofandwherein means the site attached to the CRBN binder B andTmeans the site attached to the target ligand T.

20. A compound according to any one of claims 1-19 or a pharmaceutically acceptable saltthereof wherein L is wherein means the siteTattached to the CRBN binder B and means the site attached to the target ligand T.

21. A compound according to any one of claims 1-20 or a pharmaceutically acceptable salt thereof wherein Tis a target ligand selected from the group consisting ofand T, whereina is -C(Ci-3-alkyl. FF), -C(heterocyclyl, OCH3), -heterocyclyl or -CC CFh OCFF)a’ is Ci-3-alkyl,b is N or CH,c is -CO-Ci-3-alkyl, -CO-C3-6-cycloalkyl, -CO-N(H, CH3) or SO2-Ci-3-alkyl,d is heteroaryl, ande is absent, -(CH2)1-3-, -N(CH3)-, -N(CH3)-C0- or -0-,wherein e is selected from the group consisting of a -(CH2)o-iheteroaryl, optionally substituted by Ci-3-alkyl, halogen or =0 and -(CH2)o-iaryl, optionally substituted by halogen or -O-Ci-3-alkyl, andL is a linker selected from the group consisting ofwhereinLI is absent or selected from the group consisting of -(CH2)1-3-CO-, -(CH2)1-8-, -(CH2)I-8- CO-, -heterocyclyl-(CH2)1-2and -heterocyclyl-(CH2)1-2-O-(CH2)1-2-,l1 is CH or N,l2 is CH or N,L2 is selected from the group consisting of –(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, –CH2N(H,CH3)-, or –(CH2)1-2-,whereinL3 is absent or is selected from the group consisting of–(CH2)1-2–, –CO– and –O–, L4 is absent or heterocyclyl,L5 is absent or is selected from the group consisting of CH2N(H, CH3)- and heterocyclyl-j), wherein l5 is -CH- or -N-,16 is -O-, -CF2-, or -CH2-,L6 is absent, -(CH2)I-2-, -O-, -C3-6-cycloalkyl or -(CH2)o-2-heterocyclyl, optionally substituted by halogen, and, wherein L9 is selected from the group consisting of -(CH2)1-2-, - CO-, and -(CH2)I-2-CO-(CH2)I-2-.

22. A compound according to any one of claims 1-21 or a pharmaceutically acceptable salt thereof wherein Tis a target ligand selected from the group consisting ofaH H N Nand T, wherein a is –C(C1-3-alkyl,F,F) or –C(heterocyclyl,OCH3).a’ is Ci-3-alkyl.b is N or CH,c is -CO-Ci-3-alkyl,d is heteroaryl,e is absent, -(CH2)i-3-, -N(CH₃)-CO- or -O-,Hwherein e is selected from the group consisting of a heteroaryl, optionally substituted by C1-3-alkyl and -(CH2)0-1aryl, optionally substituted by halogen, andL is a linker selected from the group consisting of, whereinL1 is absent or selected from the group consisting of -(CH2)1-8- and -heterocyclyl-(CH2)1-2,l1 is CH or N,l2 is CH or N,L2 is–(CH2)1-2–, l3 is N, l4 is–(CH2)1-2–,-4— L5-L4— L3- / ^ N-r- T ■ ■ g)0-1 B, wherein L3 is–(CH2)1-2–, L4 is heterocyclyl, L5 is heterocyclyl-CO–, andorl5 is -CH- or -N-,16 is -CH2-,L6 is-(CH2)1-2- or -(CH2)0-2-heterocyclyl.

23. A compound according to any one of claims 1-22 or a pharmaceutically acceptable salt thereof whereinT is a target ligand selected from the group consisting of5 wherein means the site of the target ligand T attached to L.o oo OTthe site attached to the CRBN binder B and means the site attached to the target ligand T, and B is a CRBN binder selected from the group consisting ofthe CRBN binder B attached to L.

24. A compound according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof whereinT is a target ligand selected from the group consisting ofLwherein means the site of the target ligand T attached to LB is a CRBN binder selected from the group consisting ofandLmeans the site of the CRBN binder B attached to L. andL is a linker binder selected from the group consisting ofwherein means the site attached to the CRBN binder B andTmeans the site attached to the target ligand T.

25. A compound of formula I according to any of claims 1-24, or a pharmaceutically acceptable salt thereof, selected from the group consisting ofN-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-10-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]-N-methyl-10-oxo-decanamide,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-y 1J - 1 -piperidyl] -N -methyl-6-oxo-hexanamide,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-(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-4-yl)piperidin-l-yl)-N-methyl-4-oxobutanamide.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-4-yl]-l-piperidyl]-N-methyl-10-oxo-decanamide,N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-N-methylacetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]arnino]-5-[2-[[l-[l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl]acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]morpholin-2-yl] -2 -pyridyl] -2-py ridy 1] acetamide,N-(4-((6-(l, 1 -difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(2-((l -(1 '-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-[l,4'-bipiperidine]-4-carbonyl)piperidin-4-yl)oxy)pyrimidin-4-yl)pyridin-2-yl)acetamide,N-(4-((6-( 1, 1 -difluoroethyl)-4-methylpy ridin-2-yl)amino)-5-(2-(( 1 -( 1 -(( 1 -(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)piperidine-4-carbonyl)pyrrolidin-3-yl)oxy)pyrimidin-4-yl)pyridin-2-yl)acetamide.N-(4-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(2-((l-(l-((l-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)methyl)azetidine-3-carbonyl)piperidin-4-yl)oxy)pyrimidin-4-yl)pyridin-2-yl)acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-3.9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[9-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-3-azaspiro[5.5]undecan-3-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[3-(2.6-dioxo-3-piperidyl)-l -methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[3-(2,6-dioxo-3-piperidyl)-l -methyl-indazol-7-yl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((8-(4-((2,6-dioxopiperidin-3-yl)amino)- 2.6-difluorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((8-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro- 1-methyl- lH-indazol-6-yl)-2, 8-diazaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((9-(3-(2,6-dioxopiperidin-3-yl)-l-methyl- lH-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(((3aR,6aR)-5-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((8-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro- l-methyl-lH-indazol-6-yl)-4.4-difluoro-2,8-diazaspiro[4.5]decan-2-yl)methyl)-[2, 3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-(((3aR,6aS)-5-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((9-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2, 3-dihydrobenzo[d]oxazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((8-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamideN-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-(((5s,8s)-8-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-lH-indazol-6-yl)-2-azaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-(((5r,8r)-8-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-lH-indazol-6-yl)-2-azaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((6-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide 5N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((9-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((8-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2, 3-dihydrobenzo[d]oxazol-6-yl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-3-azaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((9-(3-(2,6-dioxopiperidin-3-yl)-5-Huoro-l-methyl-lH-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(2-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2,6-difluorophenyl)piperazin-l-yl)ethyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-((2-(l-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperidin-4-yl)-2-azaspiro[3.4]octan-6-yl)oxy)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-((2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((2-(l-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l -methyl- lH-indazol-6-yl)piperidin-4-yl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2, 3'-bipyridin]-6'-yl)acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-3,3-difluoro-l-piperidyl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl] acetamide.N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]pyrrolidin-l-yl]methyl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl] acetamide.N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazine-l-carbonyl)piperidin-l-yl)methyl)-[2,3,-bipyridin]-6,-yl)acetamide,N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)oxy)piperidin-1-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)-2-oxopiperazin-l-yl)methyl)piperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-3-methoxyphenyl)piperazin-1-yl)methyl)-3,3-difluoropiperidin-1-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-(r-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)-[4,4'-bipiperidin]-l-yl)-[2,3'-bipyridin]-6'-yl)acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl] acetamide.N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((4-((4-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-lH-indazol-7-yl)piperazin-l-yl)methyl)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((4-((4-(4-((2,6-dioxopiperi din-3-yl)oxy)-2,6-difluorophenyl)piperazin-l-yl)methyl)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((4-((l-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-lH-indazol-6-yl)piperidin-4-yl)oxy)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((3-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-3-fluoroazetidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((4-((l-(3-(2,6-dioxopiperi din-3-yl)-l-methyl-lH-indazol-7-yl)piperidin-4-yl)oxy)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperazin-l-yl)methyl)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-[5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]-2-pyridyl]-4-[(4-methyl-6-methylsulfonyl-2-pyridyl)amino]-2-pyridyl] acetamide.N-[5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]-1-piperidyl]methyl]-2-pyridyl]-4-[[6-methyl-2-(2-oxabicyclo[2.1.1]hexan-1-yl)pyrimidin-4-yl]amino]-2-pyridyl]acetamide,N-(4'-((6-(l,l-difluoroethyl)pyridin-2-yl)amino)-5-((4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-3,3-difluoropiperidin-l-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-(((5r,8r)-8-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-2-azaspiro[4.5]decan-2-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-((2-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-((8-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l -methyl- lH-indazol-6-yl)-2, 8-diazaspiro[4.5]decan-2-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,N-(5-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-((9-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-3.9-diazaspiro[5.5]undecan-3-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-((9-(3-(2,6-dioxopiperidin-3-yl)-l -methyl- lH-indazol-6-yl)-3-azaspiro[5.5]undecan-3-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)-3-azaspiro[5.5]undecan-3-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-((4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-1-yl)methyl)-3,3-difluoropiperidin-1-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-((4-((4-(4-((2.6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-3.3-difluoropiperidin-l-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(5-((4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-4-fluoropiperi din-1 -yl)methyl)-4'-((6-((R)-3-methoxytetrahy drofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,N-(5-((4-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)piperazin-l-yl)methyl)-3,3-difluoropiperidin-l-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2.3'-bipyridin]-6'-yl)acetamide,N-(5-((4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-3-fluoropiperidin-l-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyri din-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((ln4r)-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((ls,4s)-4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-l-methyl-lH-indazol-6-yl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((ln4r)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide formate,N-(4'-((6-(1,1-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((1s,4s)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((lr,4r)-4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide formate,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((2-((ls,4s)-4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)cyclohexyl)-2-azaspiro[3.4]octan-6-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide formate,N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]-4-piperidyl]oxy]-1-piperidyl]-N-methyl-acetamide,N-(6'-acetamido-4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-[2,3'-bipyridin]-5-yl)-2-(9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-N-methylacetamide,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)oxy)phenyl)piperidin-l-yl)-N-methylacetamide,N-(6'-acetamido-4'-((2-(1,1-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-1-yl)methyl)piperidin-1-yl)-N-methylacetamide,N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]-1-piperidyl]-N-methyl-acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]-N-methyl-acetamide formate,N-[6-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-6-(methylcarbamoylamino)-3-pyridyl]-3-pyridyl]-2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-1-yl]methyl]-1-piperidyl]-N-methyl-acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,7-diazaspiro[3.4]octan-2-yl]-l-piperidyl] -N-methyl-acetamide,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)oxy)phenyl)piperidin-l-yl)methyl)piperidin-l-yl)-N-methylacetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[2-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]-2,7-diazaspiro[3.4]octan-7-yl]-N-methyl-acetamide,N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((5s,8s)-8-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)-2-azaspiro[4.5]decan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((2-(l,l-difluoroethyl)pyrimidin-4-yl)amino)-5-((5r,8r)-8-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-2-azaspiro[4.5]decan-2-yl)-[2,3'-bipyridin] -6'-y l)acetamide,N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-4-fluoro- 1 -piperidyl] -2-pyridyl] -4-[ [6-[(3R)-3 -methoxy tetrahydrofur an-3 -yl] -4-methy 1-2-pyridyl] amino] -2-pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-l-piperidyl]-2-pyridyl]-2-pyridyl] acetamide.N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-(4-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)piperidin-l-yl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-(9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-[2,3'-bipyridin]-6'-yl)acetamide,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methoxy]-1-piperidyl]-2-pyridyl]-2-pyridyl]acetamide.N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]oxymethyl]-l-piperidyl]-2-pyridyl]-2-pyridyl] acetamide,N-[5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-1-piperidyl]methyl]-4-fluoro-1-piperidyl]-2-pyridyl]-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[(6S)-2-[l-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]-2,6-difluoro-phenyl]-4-piperidyl]-2-azaspiro[3.4]octan-6-yl]oxy]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[l-[3-(2.6-dioxo-3-piperidyl)-l -methyl-indazol-7-yl]-4-piperidyl]oxy]-2-pyridyl]-2-pyridyl]acetamide.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)oxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[[9-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undecan-3-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide,N- [4-[[6-( 1, 1 -difluoroethyl)-4-methyl-2 -pyridyl] amino] -5- [5 -[ [9- [4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undecan-3-yl]methyl]-2-pyridyl]-2-py ridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[[l-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-4-piperidyl]oxy]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[[3-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-py ridyl] acetamide.N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[5-[[3-[4-[(2,6-dioxo-3-piperidyl)oxy]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[9-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.6]dodecan-3-yl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[1-[3-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]propanoyl]pyrrolidin-3-yl]oxypyrimidin-4-yl]-2-pyridyl]acetamide.5-[5-[[3-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecan-9-yl] methyl] -2 -pyridyl] -4- [ [6- [(3R)-3 -methoxy tetrahy drofuran-3 -y 1] -4-methyl-2-py ridy 1] amino] -N-methyl-pyridine-2-carboxamide,N-[5-[5-[[7-[3-(2,6-dioxo-3-piperidyl)-5-fluoro-1-methyl-indazol-6-yl]-2,7-diazaspiro[3.5]nonan-2-yl]methyl]-2-pyridyl]-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,N-[5-[5-[[3-[3-(2,4-dioxohexahydropyrimidin-l-yl)-5-fluoro-l-methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-4-[[6-[(3R)-3-methoxytetrahydrofuran-3-yl]-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[l-[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]oxy]-l-piperidyl]cyclopropyl]-2-pyridyl]-2-pyridyl] acetamide.N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[l-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]pyrrolidin-3-yl]-l-piperidyl]-2-pyridyl]-2 -pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[l-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]pyrrolidin-3-yl]-l-piperidyl]-2-pyridyl]-2 -pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[8-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-2,8-diazaspiro[4.5]decan-2-yl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[3-[l-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-4-piperidyl]pyrrolidin-l-yl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[8-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-4,4-difluoro-2,8-diazaspiro[4.5]decan-2-yl]methyl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-2-pyridyl]amino]-5-[6-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]piperidine-l-carbonyl]-3-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[8-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-l-oxa-8-azaspiro[4.5]decan-3-yl]oxy]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]- 2.6-difluoro-phenyl]-4-piperidyl]oxy]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl]methanesulfonamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenylJ-3,3-difluoro-l-piperidylJmethylJ-l-piperidyl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]-l-piperidyl]methyl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[3-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecan-9-yl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]morpholin-2-yl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]-4-piperidyl]oxy]pyrimi din-4-yl] -2-pyridyl] acetamide.N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]-4-piperidyl]oxy]pyrimi din-4-yl] -2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[8-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-8-azaspiro[4.5]decan-3-yl]morpholin-2-yl]-2-pyridyl]-2-pyridyl] acetamide.N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[8-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-8-azaspiro[4.5]decan-3-yl]piperazin-l-yl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]acetyl]morpholin-2-yl]-2-pyridyl]-2-pyridyl] acetamide.N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[3-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-l-yl]propanoyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]propanoyl]morpholin-2-yl]-2-pyridyl]-2-pyridyl] acetamide.N-[4-[[6-(1,1-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[1-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]propanoyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl]acetamide ,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[2-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-2,7-diazaspiro[3.5]nonan-7-yl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-7-azaspiro[3.5]nonan-2-yl]piperazin-l-yl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[l-[[l-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]morpholin-2-yl]-2-pyridyl] -2 -pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[l-[[l-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]piperazin-l-yl]-2-pyridyl] -2 -pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[l-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-4-carbonyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl] acetamide.N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-l-yl]acetyl]morpholin-2-yl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[3-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-l-yl]propanoyl]piperazin-l-yl]-2-pyridyl]-2-pyridyl] acetamide.N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]propanoyl]piperazin-l-yl]-2-pyridyl]-2-pyridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]oxy]-3,3-difluoro-l-piperidyl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-1-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-1-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-l-piperidyl]methyl]-l-piperidyl]-N-methyl-acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[4-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-l-piperidyl]methyl]phenyl]-2-pyridyl] acetamide.N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-3-methoxy-benzoyl]piperazin-1-yl]-N-methyl-acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]-3-oxo-piperazin-l-yl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]piperazin-l-yl]-2-pyridyl] -2 -pyridyl] acetamide.N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperidine-4-carbonyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl] acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-l-yl]acetyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl] acetamide.N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]acetyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl] acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[4-(2,4-dioxohexahydropyrimidin- 1 -yl)phenyl] - 1 -piperidyl] -N-methyl-acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[7-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperidine-4-carbonyl]-6,8-dihydro-5H-imidazo[l,2-a]pyrazin-2-yl]-2-pyridyl] acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[4-[l-(2,6-dioxo-3-piperidyl)indolin-4-yl]-l-piperidyl]methyl]-l -piperidyl] -N-methyl-acetamideN-[5-[6-[[(6S)-2-[l-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]-2,6-difluoro-phenyl]-4-piperidyl]-2-azaspiro[3.4]octan-6-yl]oxy]-2-pyridyl]-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-py ridyl] amino] -2-pyridyl] acetamide,N-[5-[6-[[(6R)-2-[l-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]-2,6-difluoro-phenyl]-4-piperidyl]-2-azaspiro[3.4]octan-6-yl]oxy]-2-pyridyl]-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl-2-pyridyl] amino] -2-pyridyl] acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[4-[(2, 6-dioxo-3-piperidyl)amino] -2, 6-difluoro-phenyl]piperazin-l-yl] -N-methyl-acetamide, N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[[4-[4-[(2,4-dioxohexahydropyrimidin-l-yl)methyl]phenyl]-l-piperidyl]methyl]-l-piperidyl]-N-methyl-acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-[l-[[l-[4-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-ylJphenylJcyclohexylJ-4-piperidyl]methyl]pyrazol-4-yl]-2-pyridyl]amino]-5-(2-pyridyl)-2 -pyridyl] acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[3-(2,6-dioxo-3-piperidyl)indazol-l-yl]-l-piperidyl]-N-methyl-acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-[l-[2-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperazin-l-yl]acetyl]azetidin-3-yl]oxy-2-pyridyl]amino]-5-(2-pyridyl)-2-pyridyl] acetamide.N-[5-[l-[[l-[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]-4-hydroxy-piperidine-4-carbonyl]-4-piperidyl]methyl]pyrazol-3-yl]-4-[[6-(l-methoxy-l-methyl-ethyl)-4-methyl -2-pyridyl] amino] -2 -pyridyl] acetamide,N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[7-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-2,7-diazaspiro[3.5]nonan-2-yl]-N-methyl-acetamide.N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-l-yl]methyl]-l-piperidyl]acetyl]-methyl-amino]-2-pyridyl]-2-pyridyl]cyclopropanecarboxamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-l-yl]methyl]-2-pyridyl]-2 -pyridyl] acetamide,N-[5-[6-[4-[4-[4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]phenyl]cyclohexyl]piperazine-l-carbonyl]-2-pyridyl]-4-[[6-(l -methoxy- 1 -methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-l-[[l-[l-(2.6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]methyl]-N-methyl-piperidine-4-carboxamide,N-[5-[6-[4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]oxy]piperidine-1-carbonyl]-2-pyridyl]-4-[[6-(1-methoxy-1-methyl-ethyl)-4-methyl-2-pyridyl]amino]-2-pyridyl]acetamide.N-[6-[6-acetamido-4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-5-methoxy-phenyl]piperazin-1-yl]-N-methyl-acetamideN-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[7-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonan-2-yl]-N-methyl-acetamide,N-[6-[6-acetamido-4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-3-pyridyl]-3-pyridyl]-2-[4-[l4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperazin-l-yl]methylJ-l-piperidyl]-N-methyl-acetamide.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-[4-[l-(2,6-dioxo-3 -piperi dyl)-3 -methyl-2-oxo-benzimidazol-5-y 1] - 1 -piperidyl] -N -methyl -acetamide, N-(4'-((6-(l,l-difluoroethyl)-4-methylpyridin-2-yl)amino)-5-((9-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-7-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-(6-((4-(4-((2,6-di ox opiperi din-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)-2-azaspiro[3.3]heptan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide.N-(5-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperi din-1-yl)methyl)piperidin-l-yl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)amino)-[2,3'-bipyridin] -6'-y l)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((7-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-pyrazolo[4.3-c]pyridin-6-yl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-[2.3'-bipyridin]-6'-yl)acetamide,N-(4'-((6-(l,l-difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-((6-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-pyrazolo[3,4-b]pyridin-6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-[2,3'-bipyridin]-6'-yl)acetamide, andN-(4'-((6-(l,l -difluoroethyl)-4-methylpyri din-2 -yl)amino)-5-(3-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperidin-l-yl)methyl)pyrrolidin-l-yl)-[2,3'-bipyridin]-6'-yl)acetamide.

26. A compound of formula I according to any of claims 1-25, or a pharmaceutically acceptable salt thereof, selected from the group consisting ofN-[4-[[6-(l,l-difhioroethyl)-4-methyl-2-pyridyl]amino]-5-[2-[[l-[l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]-4-piperidyl]oxy]pyrimidin-4-yl]-2-pyridyl]acetamide,N-[4-[[6-(l,l-difluoroethyl)-4-methyl-2-pyridyl]amino]-5-[6-[4-[l-[[l-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-4-piperidyl]methyl]piperidine-4-carbonyl]morpholin-2-yl] -2 -pyridyl] -2-py ridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[4-[(2,6-dioxo-3-piperidyl)amino]- 2,6-difluoro-phenyl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide,N-[4-[[2-(1,1-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[9-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-3-azaspiro[5.5]undecan-3-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[3-[3-(2,6-dioxo-3-piperidyl)-l -methyl-indazol-6-yl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]-2-pyridyl]-2-pyridyl]acetamide, N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]piperazin-l-yl]methyl]-3,3-difluoro-l-piperidyl]methyl]-2-pyridyl] -2 -pyridyl] acetamide,N-(5-(((5r,8r)-8-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)-2-azaspiro[4.5]decan-2-yl)methyl)-4'-((6-((R)-3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-[2,3'-bipyridin] -6'-y l)acetamide,N-(4'-((2-(1,1-difluoroethyl)pyrimidin-4-yl)amino)-5-((5s,8s)-8-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperazin-1-yl)methyl)-2-azaspiro[4.5]decan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide,N-(4'-((2-(l,l-difluoroethyl)pyri mi din-4-yl)amino)-5-((5r,8r)-8-((4-(4-((2,6-dioxopiperi din-3-yl)amino)-2,6-difluorophenyl)piperazin-l-yl)methyl)-2-azaspiro[4.5]decan-2-yl)-[2,3'-bipyridin] -6'-y l)acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2,6-difluoro-phenyl]-l-piperidyl]methyl]-l-piperidyl]-2-pyridyl]-2-py ridyl] acetamide,N-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[(6S)-2-[l-[4-[[(3R)-2,6-di oxo-3-piperidyl]amino]-2,6-difluoro-phenyl]-4-piperidyl]-2-azaspiro[3.4]octan-6-yl]oxy]-2-pyridyl]-2-py ridyl] acetamide, andN-[4-[[2-(l,l-difluoroethyl)pyrimidin-4-yl]amino]-5-[5-[[l-[3-(2,6-dioxo-3-piperidyl)-l -methyl-indazol-7-yl]-4-piperidyl]oxy]-2-pyridyl]-2-pyridyl]acetamide.

27. A process for the preparation of a compound according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof comprising reacting a compound of formula (A) with a compound of formula (3’) to a compound of formula (4’) and further to a compound of formula (Dwherein Xi is CH or N and X2 is CH or N, and Xi and X2 cannot simultaneously be CH.

28. A compound of formula I according to claims 1-26, or a pharmaceutically acceptable salt thereof, when manufactured according to a process of claim 27.

29. A pharmaceutical composition comprising a compound in accordance with any one of claims 1-27 and a pharmaceutically acceptable excipient.

30. A compound or pharmaceutically acceptable salt according to any one of claims 1-28 for use as therapeutically active substance.

31. The use of a compound according to any one of claims 1-28 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-associatedvasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

32. The use of a compound according to any one of claims 1-28 as therapeutically active substance for the therapeutic and / or prophylactic treatment of inflammatory’ bowel disease.

33. A compound of formula I according to claims 1-28 for the use as therapeutically active substance for the therapeutic and / or prophylactic treatment of autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinflammatory syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes; neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease.

34. A compound of formula I according to claims 1-28 for the use as therapeutically active substance for the therapeutic and / or prophylactic treatment of inflammatory bowel disease.

35. A method of preventing or treating a disease or disorder in a subject in need thereof, wherein the disease or disorder is an autoimmune disorders like type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, lupus nephritis, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, proteasome-associated autoinflammatory’ syndromes (PRAAS), ISG15 deficiency, and inflammatory bowel disease; inflammatory disorders like rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, STING-associated vasculopathy with onset in infancy (SAVI), and inflammatory bowel disease; proliferative disorders like hematological cancer, polycythemia vera, myelofibrosis, essential thrombocythemia, and thrombocytosis; endocrine disorders like polycystic ovary syndrome, Crouzon's syndrome, and type 1 diabetes;neurological disorders like Alzheimer's disease, Aicardi-Goiuteieres syndrome (AGS), Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia; and / or disorders associated with transplantation like transplant rejection and graft versus host disease and wherein the method comprises administering a therapeutically effective amount of a compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof, to the subject.

36. 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 1-28 or a pharmaceutically acceptable salt thereof, to the subject.

37. The invention as hereinbefore described.

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