Compounds for targeting the degradation of IRAK4 protein

Abstract

The present disclosure relates to a compound of formula (A): Formula (A), or a pharma- ceutically acceptable salt thereof, wherein DSM is a degradation signaling moiety covalently linked to a linker L, L is a linker that covalently links IRAK to DSM, and IRAK is an IRAK4 binding moiety represented by formula (I) covalently linked to linker L, in which all variables are as defined in the present application. The compounds described herein, or pharma- ceutically acceptable salts thereof, can activate selective ubiquitination of IRAK4 protein via the ubiquitin-proteasome pathway (UPP), resulting in degradation of IRAK4 protein. The present disclosure also provides methods of treating disorders responsive to modulation of IRAK4 activity and / or degradation of IRAK4 with at least one compound described herein. [Formula 1] TIFF2024525580000229.tif56121

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 219,167, filed July 7, 2021, and U.S. Provisional Patent Application No. 63 / 354,020, filed June 21, 2022. The entire contents of each of the foregoing applications are expressly incorporated herein by reference.

[0002] Specific agents that target the degradation of interleukin-1 receptor-associated kinase 4 (IRAK4) and methods for making and using such agents are provided. [Background technology]

[0003] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of nearly all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, nerve and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels, and secretory pathways, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection.

[0004] Covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases targets the protein for proteasomal degradation, where it is digested into small peptides and ultimately into its constituent amino acids that serve as building blocks for new proteins. There are over 600 E3 ubiquitin ligases that facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT domain E3s, U-box E3s, monomeric ring E3s, and multisubunit E3s.

[0005] It is known that the ubiquitin-proteasome pathway (UPP) can be harnessed for therapeutic intervention by using chimeric compounds capable of activating the ubiquitination of a target protein, the chimeric compounds comprising a target protein-binding element covalently linked to a ubiquitination recognition element. Such chimeric compounds capable of binding a target protein and a ubiquitin ligase can selectively degrade the target protein via the UPP. For example, the discovery that thalidomide binds to cereblon E3 ubiquitin ligase led to studies investigating the incorporation of thalidomide and certain derivatives into chimeric compounds for the targeted destruction of proteins.

[0006] Protein kinases are a large multigene family of over 500 proteins that play important roles in the development and treatment of many human diseases in oncology, neurology, and immunology. Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides, and other cellular metabolites, playing important roles in all aspects of eukaryotic cell physiology. In particular, protein kinases and lipid kinases are involved in signal transduction events that control cell activation, growth, differentiation, and survival in response to extracellular mediators or stimuli such as growth factors, cytokines, or chemokines. Protein kinases are generally classified into two groups: those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and / or threonine residues.

[0007] Kinases, such as those involved in orchestrating adaptive and innate immune responses, are important therapeutic targets for the development of anti-inflammatory drugs (Cohen, 2009. Current Opinion in Cell Biology 21, 1-8). Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events. Kinase targets of particular interest are members of the IRAK family.

[0008] Interleukin-1 receptor-associated kinase (IRAK) is critically involved in regulating intracellular signaling networks that control inflammation (Ringwood and Li, 2008. Cytokine 42, 1-7). IRAK is expressed in many cell types and can mediate signals from various cellular receptors, including toll-like receptors (TLRs).

[0009] IRAK1 was first identified by biochemical purification of IL-1-dependent kinase activity that coimmunoprecipitates with the IL-1 type 1 receptor (Cao et al., 1996, Science 271(5252):1128-31). IRAK2 was identified by searching human expressed sequence tag (EST) databases for sequences homologous to IRAK1 (Muzio et al., 1997, Science 278(5343):1612-5). IRAK3 (also called IRAKM) was identified using a mouse EST sequence encoding a polypeptide with significant homology to IRAK1 and screening a human phytohemagglutinin-activated peripheral blood leukocyte (PBL) cDNA library (Wesche et al., 1999, J. Biol. Chem. 274(27):19403-10). IRAK4 was identified by database searching for IRAK-like sequences and PCR of a universal cDNA library (Li et al., 2002. Proc. Natl. Acad. Sci. USA 99(8):5567-5572).

[0010] IRAK4 is the first protein kinase activated downstream of all toll-like receptors (TLRs) except for the interleukin-1 (IL-1) receptor and TLR3, and is thought to initiate signaling in the innate immune system through the rapid activation of IRAK1 and the slower activation of IRAK2.

[0011] Given that IRAK4 plays an important role in the signaling network that controls inflammation, there is a strong need to develop chimeric compounds that can activate the ubiquitination and degradation of IRAK4 protein. The object of the present disclosure is to provide new compounds, methods, compositions, and manufacturing methods useful for selectively degrading IRAK4 protein in vivo via the ubiquitin-proteasome pathway (UPP). Summary of the Invention

[0012] In a first aspect, the present disclosure provides a compound of formula (A): IRAK-L-DSM (A) or a pharmaceutically acceptable salt thereof, wherein DSM is a degradation signaling moiety covalently attached to linker L; L is a linker that covalently attaches IRAK to the DSM; IRAK is an IRAK4-binding moiety represented by formula (I) covalently attached to a linker, L; [ka] During the ceremony, A 1 are N, CH and CR 3 Selected from A 2 are N, CH and CR 4 Selected from, with the proviso that A 1 or A 2 can be N, B 1 and B 2 One of them is N and the other is C, R 1 teeth, i. 1 to 3 R 5 phenyl optionally substituted with ii. 5- or 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein 1 to 3 R 5 heteroaryl optionally substituted with iii. A 5- or 6-membered partially or fully saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from oxygen and nitrogen, and 1 to 3 R 5 a heterocycle optionally substituted with iv. 1 to 3 R 5 Partially or fully saturated C optionally substituted with 3-6 cycloalkyl, v. A 7-10 membered fused heterobicyclic ring system having 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein 1 to 3 R 5 heterobicyclic ring systems optionally substituted with vi. A 7- to 10-membered fused carbobicyclic ring system having 1 to 3 R 5 and selected from carbobicyclic ring systems optionally substituted with R 2 is hydrogen, C 1-4 alkyl, or halogen; R 3 and R 4 are halogens, C 1-4 Alkyl, nitrile and -OR 6 are independently selected from C 1-4 Alkyl is C 1-4 optionally substituted with alkoxy or at least one halogen; R 5 For each occurrence, CN, hydroxyl, C 1-4 Alkyl, oxo, halogen, -NR 8 R 9 , C 1-4 Alkoxy, -OC 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-4 Alkyl-C 3-6 Cycloalkyl, C(O)NR 10 R 11 , C 4-7 heterocycle and 5- or 6-membered heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; C 1-4 Alkyl is CN, halo, C 1-4optionally substituted with one or more substituents independently selected from alkoxy and hydroxyl; 3-6 Cycloalkyl and heteroaryl are C 1-4 optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkyl, hydroxyl, and halogen, or two R 5 The group, together with the intervening atoms, is phenyl, C 4-6 carbocycle, C 4-6 A heterocycle or a 7-membered bridged ring system optionally having one heteroatom selected from nitrogen and oxygen, can form a ring selected from phenyl, C 4-6 Carbocyclic and C 4-6 Each heterocycle contains 1-2 C 1-4 Alkyl, halogen or C 1-4 optionally substituted with haloalkyl; R 6 is hydrogen, C 1-5 Alkyl, C 3-6 cycloalkyl, a 4- to 7-membered partially or fully saturated heterocycle containing one or two heteroatoms selected from nitrogen and oxygen, a 5- to 10-membered spirocarbocycle, and a 4- to 10-membered heterocycle having one to two heteroatoms independently selected from nitrogen and oxygen; R 6 C represented by 1-5 Alkyl is halogen, hydroxyl, C 1-5 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 one to three substituents R independently selected from cycloalkyl, phenyl, a 4- to 7-membered partially or fully saturated heterocycle containing one or two heteroatoms selected from nitrogen and oxygen, and a 5- to 8-membered fully saturated bridged heterocyclic ring system having one to two heteroatoms independently selected from nitrogen and oxygen; 6a optionally substituted with R 6 C represented by 3-6 Cycloalkyl is a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, and C 1-4one to three substituents R independently selected from alkoxy; 6b optionally substituted with R 6 The 4-7 membered partially or fully saturated heterocycles, 5-10 membered spirocarbocycles and 5-10 membered spiroheterobicyclic ring systems represented by 1-4 one to three substituents R independently selected from alkoxy and oxo; 6c optionally substituted with R 6a C represented by 3-6 Cycloalkyl, phenyl, and 4- to 7-membered partially or fully saturated heterocycles are substituted with 1 to 3 R 7 and optionally substituted with Each R 7 is oxo, halogen, C 1-4 Haloalkyl, and C 1-4 alkyl; R 8 and R 9 are hydrogen and -C(O)C, respectively. 1-4 Alkyl, and C 1-4 alkyl, or R 8 and R 9 may combine to form a 4-6 membered saturated ring optionally containing one additional heteroatom selected from nitrogen or oxygen, the additional nitrogen being selected from C 1-4 optionally substituted with alkyl; R 10 and R 11 are hydrogen and C, respectively. 1-4 alkyl; -* denotes bond to linker L.

[0013] In another aspect, the present disclosure provides a method of treating a disorder responsive to modulation of IRAK4 activity and / or degradation of IRAK4 in a subject, the method comprising administering to the subject an effective amount of at least one compound described herein. The present disclosure also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder responsive to modulation of IRAK4 activity and / or degradation of IRAK4. Also provided are compounds described herein, or a pharmaceutically acceptable salt thereof, for use in treating a disorder responsive to modulation of IRAK4 activity and / or degradation of IRAK4. Methods of making the compounds described herein and any synthetic intermediates are also included in the present disclosure.

[0014] Other features or advantages will be apparent from the following detailed description of several embodiments, and from the appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0015] The compounds described herein or pharmaceutically acceptable salts thereof can activate selective ubiquitination of the IRAK4 protein via the ubiquitin-proteasome pathway (UPP), resulting in degradation of the IRAK4 protein. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof can modulate IRAK4 activity.

[0016] The compounds of the present disclosure, and pharmaceutical formulations thereof, may be useful in treating or preventing conditions and / or disorders mediated by IRAK4 function, such as, for example, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, Alzheimer's disease, ischemic stroke, cerebral ischemia, hypoxia, TBI (traumatic brain injury), CTE (chronic traumatic encephalopathy), epilepsy, Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

[0017] I. Definition Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the relevant art.

[0018] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The recitation of ranges of values, unless stated otherwise herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within that range, and each separate value is incorporated herein as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in any suitable order unless stated otherwise herein or clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely to better illustrate the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise stated.

[0019] As used herein, the term "alkyl" refers to a fully saturated, branched or unbranched hydrocarbon moiety. In some embodiments, alkyl contains 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In some embodiments, alkyl contains 6 to 20 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy or haloalkyl has the same definition as above. When indicated as "optionally substituted," the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0020] As used herein, the term "alkoxy" refers to an oxygen bridge (i.e., C 1~4 alkyl is as defined herein, 1~4 Alkoxy refers to a fully saturated, branched or unbranched alkyl moiety bonded via an alkyl group. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. Preferably, an alkoxy group has about 1 to 4 carbons, more preferably about 1 to 2 carbons.

[0021] As used herein, the term "aryl" refers to a carbocyclic (all carbon), aromatic monocyclic or bicyclic ring system containing 6 to 10 carbon atoms. Examples of 6-10 membered aryl groups include phenyl and naphthyl. In some embodiments, aryl is phenyl.

[0022] The term "bridged ring system," as used herein, is a ring system in which two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably 1 to 3) atoms selected from C, N, O, and S. In one embodiment, the bridged ring system has 6 to 8 ring members.

[0023] The term "fused ring system," as used herein, refers to a ring system having two ring structures that share two adjacent ring atoms. In one embodiment, the fused ring system has 8 to 12 ring members.

[0024] The term "spiro ring system," as used herein, is a ring system having two ring structures that share one ring atom. In one embodiment, the spiro ring system has 5 to 8 ring members.

[0025] The term "cycloalkyl" refers to a partially or fully saturated monocyclic, bicyclic, or spiro hydrocarbon group having 3 to 7 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms. In some embodiments, the cycloalkyl is a 3-6 membered fully saturated monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0026] As used herein, the term "carbocycle" or "carbocyclic ring" refers to a saturated or partially unsaturated (i.e., non-aromatic) monocyclic or bicyclic hydrocarbon group of 3 to 10, 3 to 8, 3 to 7, 3 to 5, 3 to 6, 4 to 6, 5 to 7, or 7 to 10 carbon atoms. 3- to 7-membered monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, and cycloheptatrienyl. Bicyclic carbocycles include, but are not limited to, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo-[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl, and spiro[3.3]heptanyl. 7-10 membered bicyclic carbocycles include, but are not limited to, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[3.3.2]decanyl, and decalinyl.

[0027] As used herein, the term "bridged carbocyclic ring" refers to a cyclic moiety joined at two non-adjacent ring atoms of a carbocyclic ring (e.g., bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, and bicyclo[3.2.1]octane).

[0028] As used herein, the term "fused bicyclic ring system" or "fused carbobicyclic ring system" refers to a carbon ring connected at two non-adjacent ring atoms of the carbocycle. Fused bicyclic ring systems include, but are not limited to, 1,2,3,4-tetrahydronaphthalene, (1S,5R)-1-methylbicyclo[3.1.0]hexane, bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane, and 2,3-dihydro-1H-indene.

[0029] As used herein, the term "spirocarbocyclic ring" means a bicyclic ring system in which both rings share one common carbon atom. Examples of spirocarbocyclic rings include spiro[2.5]octane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[3.4]octane, and the like.

[0030] "Halogen" or "halo" can be fluorine, chlorine, bromine or iodine (preferred halogens as substituents are fluorine and chlorine).

[0031] As used herein, the term "haloalkyl" or "halo-substituted alkyl" refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. A haloalkyl group can be a polyhaloalkyl including monohalo-alkyl, dihaloalkyl, or perhaloalkyl. A monohaloalkyl can have one iodine, bromo, chloro or fluoro within the alkyl group. A dihaloalkyl group and a polyhaloalkyl group can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically, a polyhaloalkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl group refers to an alkyl group in which all hydrogen atoms are replaced by halo atoms.

[0032] As used herein, the term "haloalkoxy" refers to a fully saturated branched or unbranched haloalkyl moiety bonded through an oxygen bridge (i.e., C 1~4 as defined herein for haloalkyl) --O-C 1~4 haloalkyl group).

[0033] As used herein, the term "heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring system having 1 to 4 heteroatoms independently selected from O, N and S, wherein N can be oxidized (e.g., N(O)) or quaternized, and S can optionally be oxidized to become sulfoxide and sulfone.

[0034] Examples of "5- to 6-membered heteroaryl" or "5- to 6-membered monocyclic heteroaryl" include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, etc. In some embodiments, the 5- to 6-membered heteroaryl is selected from pyrrolyl, pyridyl, pyrazolyl, thienyl, furanyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, and thiazolyl. In some embodiments, the 5-6 membered heteroaryl is chosen from pyridinyl, pyrimidinyl, 2H-1,2,3-triazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl, and thienyl.

[0035] Examples of 5-membered heteroaryls include, but are not limited to, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl. Examples of 8-10-membered bicyclic heteroaryls include imidazolethiazolyl, imidazopyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indazolyl, 2H-indazolyl, indolyl, isoindolyl, 2λ 2 Examples of 9- to 10-membered bicyclic heteroaryls include, but are not limited to, imidazopyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, 2H-indazolyl, indolyl, isoindolyl, 2λ-indazolyl ... 2-These include, but are not limited to, isoindolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, thienopyridinyl, and thieno[3,2-b]pyridinyl.

[0036] In some embodiments, the 5-membered heteroaryl is [ka] is selected from.

[0037] In some embodiments, the 6-membered heteroaryl is [ka] is selected from.

[0038] Examples of 9- to 10-membered heteroaryls include indolyl, indazolyl, benzofuranyl, quinoxalinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isothiazolo[4,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, imidazo[1,2-b]pyridazinyl, thieno[2,3-b]pyrazinyl, 1H-benzo[d]imidazolyl, benzo[d]thiazolyl, 1,6-naphthyridinyl, and 1,5-naphthyridinyl. In some embodiments, the 9- to 10-membered heteroaryl is selected from pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isothiazolo[4,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, imidazo[1,2-b]pyridazinyl, thieno[2,3-b]pyrazinyl, 1H-benzo[d]imidazolyl, benzo[d]thiazolyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, and 2H-indazolyl.

[0039] In some embodiments, heteroaryl is [ka] is an 8-9 membered bicyclic heteroaryl selected from:

[0040] The term "heterocycle" or "monocyclic heterocycle" refers to a monocyclic ring that is partially or fully saturated and contains 1 to 2 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Monocyclic heterocycles include, but are not limited to, octanyl, tetrahydrofuranyl, dihydrofuranyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiophorinyl, thiophorinyl 1,1 dioxide, tetrahydrothiopyran 1,1-dioxide, and 1,4-diazepanyl.

[0041] In some embodiments, the monocyclic heterocycle is [ka] is selected from.

[0042] The term "bicyclic heterocycle" refers to a bicyclic ring that is partially or fully saturated and contains 1 to 2 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Bicyclic heterocycles include 2,6-diazaspiro[3.3]heptane and pyrazolo[1,5-a]pyrimidine.

[0043] As used herein, the term "spiro bicyclic heterocycle" refers to a fully saturated bicyclic heterocyclic ring system having two ring structures that share one ring atom in common. In one embodiment, the spiro bicyclic heterocycle has 7 to 11 ring members.

[0044] The term "partially or fully saturated heterocycle" refers to a non-aromatic ring that is partially or fully saturated and can exist as a monocyclic, bicyclic (including fused heterocyclic) or spirocyclic ring. Unless otherwise specified, heterocyclic rings are generally 3- to 7-membered rings containing 1-3 heteroatoms (preferably 1, 2 or 3 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Partially saturated or fully saturated heterocyclic rings include groups such as epoxy, aziridinyl, azetidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, 1H-dihydroimidazolyl, hexahydropyrimidinyl, piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, oxazolidinyl, thiazolidinyl, 7-oxabicyclo[2.2.1]heptane, etc. Partially saturated heterocyclic rings include, but are not limited to, pyridin-2(1H)-one. Partially saturated heterocyclic rings also include groups in which a heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzofuranyl, indolinyl (or 2,3-dihydroindolyl), 2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydropyrido[3,4-b]pyrazinyl).

[0045] In some embodiments, the partially or fully saturated heterocycle is [ka] is selected from.

[0046] As used herein, the term "bridged heterocyclic ring system" refers to a 5- to 10-membered heterobicyclic moiety connected by two non-adjacent ring atoms of a heterocycle containing at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or a combination thereof) within the 5- to 10-membered cyclic ring system. Examples of "bridged heterocyclic ring systems" include, but are not limited to, 2-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[4.1.0]heptane, 2-oxabicyclo[2.2.1]heptane, 2-oxabicyclo[2.2.2]octane, 8-oxabicyclo[3.2.1]octane, and 2,6-dioxabicyclo[3.2.1]octane.

[0047] As used herein, "fused heterobicyclic ring system" refers to two ring systems that share two adjacent ring atoms and at least one of the rings contains a ring atom that is a heteroatom selected from O, N, and S. Examples of fused heterobicyclic ring systems include 1,3-dihydroisobenzofuran, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine, pyrazolo[1,5-a]pyrimidine, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, 6,7-dihydro-5H-cyclopenta[b]pyridine, 2-oxabicyclo[2.1.0]pentane, indolin-2-one, 2,3-dihydrobenzofuran, 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline, 3,4-dihydroquinolin-2(1H)-one, chroman, isochroman, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine, and the like. and 3-azabicyclo[3.1.0]hexane, or 3-azabicyclo[3.1.0]hexane. Partially saturated heterocyclic rings also include groups in which a heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzofuranyl, indolinyl (or 2,3-dihydroindolyl), 2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydropyrido[3,4-b]pyrazinyl, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, etc. In some embodiments, "fused heterobicyclic ring system" refers to a fused bicyclic heteroaryl.

[0048] In some embodiments, the term "7-10 membered fused heterobicyclic ring system" is limited to 7-10 membered bicyclic heteroaryls such as pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyridine, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, isothiazolo[4,33-b]pyridine, pyrrolo[1,2-a]pyrimidine, pyrido[3,2-d]pyrimidine, imidazo[1,2-b]pyridazine, thieno[2,3-b]pyrazine, 1H-benzo[d]imidazole, benzo[d]thiazole, 1,6-naphthyridine, and 1,5-naphthyridine.

[0049] As used herein, the term "spiroheterobicyclic ring system" refers to a bicyclic ring system in which both rings share one common atom. Examples of spiroheterobicyclic ring systems include oxaspiro[2.4]heptanyl, 5-oxaspiro[2.4]heptanyl, 4-oxaspiro[2.4]heptane, 4-oxaspiro[2.5]octanyl, 6-oxaspiro[2.5]octanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[bicyclo[2.1.1]hexane-2,3'-oxetan]-1-yl, oxaspiro[bicyclo[3.2.0]heptane-6,1'-cyclobutan]-7-yl, 2,6-diazaspiro[3.3]heptanyl, and -oxa-6-azaspiro[3.3]heptane. , 2,2,6-diazaspiro [3.3] heptane, 3-azaspiro [5.5] undecanyl, 3,9-diazaspiro [5.5] undecanyl, 7-azaspiro [3.5] nonane, 2,6-diazaspiro [3.4] octane, 8-azaspiro [4.5] decane, 1,6-diazaspiro [3.3] heptane, 5-azaspiro [2.5] octane, 4,7-diazaspiro [2.5] octane, 5-oxa-2-azaspiro [3.4] octane, 6-oxa-1-azaspiro [3.3] heptane, 3-azaspiro [5.5] undecanyl, 3,9-diazaspiro [5.5] undecanyl, and the like.

[0050] As used herein, "hydroxyl" or "hydroxy" refers to an --OH group.

[0051] The term "oxo" (=O) refers to an oxygen atom connected by a double bond to a carbon or sulfur atom. Examples include carbonyl, sulfinyl, or sulfonyl groups (--C(O)--, --S(O)--, or --S(O)--), such as a ketone, aldehyde, or part of an acid, ester, amide, lactone, or lactam group.

[0052] As used herein, groups / variables (e.g., L, Z) 1 , Z 2 When a group / variable is defined as a "bond," it means that the two moieties attached to that group / variable are directly connected to one another. For example, when L in formula (A) is a bond, it means that the IRAK moiety and the DSM moiety are directly connected. IRAK-L-DSM (A)

[0053] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "optionally substituted" refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Specific substituents are listed in the definitions and descriptions of the compounds and their examples. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions.

[0054] Unless otherwise specified, the term "compounds of the disclosure" refers to compounds of Formula (A) and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitution), and inherently formed moieties (e.g., polymorphs, solvates, and / or hydrates). Where moieties capable of forming salts are present, salts, particularly pharmaceutically acceptable salts, are also included.

[0055] The compounds and intermediates described herein can be isolated and used as the compounds themselves. Alternatively, if moieties capable of forming salts are present, the compounds or intermediates can be isolated and used as their corresponding salts. As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the present disclosure. "Salt" specifically includes "pharmaceutically acceptable salts."

[0056] The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and that are typically not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0057] Pharmaceutically acceptable acid addition salts include, for example, acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl Salts such as sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate can be formed using inorganic and organic acids.

[0058] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0059] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0060] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0061] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0062] Salts can be synthesized from compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable when feasible. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa. (1985), and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0063] In some embodiments, the present disclosure provides deuterated compounds, where any or more positions occupied by hydrogen can include enrichment with deuterium above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3500 times (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 times (60% deuterium incorporation), at least 4500 times (67.5% deuterium incorporation), at least 5000 times (75% deuterium), at least 5500 times (82.5% deuterium incorporation), at least 6000 times (90% deuterium incorporation), at least 6333.3 times (95% deuterium incorporation), at least 6466.7 times (97% deuterium incorporation), at least 6600 times (99% deuterium incorporation), or at least 6633.3 times (99.5% deuterium incorporation) greater than the natural abundance of deuterium, which is 0.015%. In one embodiment, hydrogen is present at its natural abundance at all positions.

[0064] Isotopically labeled compounds of formula (A) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, substituting the appropriate isotopically labeled reagent for the previously used unlabeled reagent.

[0065] Pharmaceutically acceptable solvates according to the present disclosure include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0066] Those skilled in the art will recognize that the compounds of the present disclosure may contain chiral centers and therefore may exist in different stereoisomeric forms. As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure. It is understood that substituents may be attached at chiral centers of carbon atoms. Therefore, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0067] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to designate racemic mixtures where appropriate. In designating the stereochemistry of the compounds of this disclosure, single stereoisomers in which the relative and absolute configuration of the two chiral centers are known are designated using the conventional RS system (e.g., (1S,2S)), and single stereoisomers in which the relative configuration is known but the absolute configuration is unknown are designated with an asterisk (e.g., (1R * ,2R * )), and racemates are designated by two letters (e.g., (1RS,2RS) for a racemic mixture of (1R,2R) and (1S,2S), and (1RS,2SR) for a racemic mixture of (1R,2S) and (1S,2R)).

[0068] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When compounds are pure enantiomers, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. Alternatively, resolved compounds can be defined by their respective retention times relative to the corresponding enantiomers / diastereomers via chiral HPLC.

[0069] Certain compounds described herein may contain one or more asymmetric centers or axes and therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0070] Unless otherwise specified, the compounds of the present disclosure are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R) and (S) stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., CHIRALPAK®, available from DAICEL Corp., using an appropriate solvent or mixture of solvents to achieve good resolution). and CHIRALCEL® The compounds may be separated by chiral SFC or HPLC chromatography columns such as (e.g., HCl ...

[0071] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0072] As used herein, "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. This term includes mammals, such as humans. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., a human; male or female (male or female)), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. Preferably, the subject is a human.

[0073] The phrase "pharmaceutically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with other ingredients contained in the formulation and / or the mammal being treated therewith.

[0074] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to the management and care of a patient for the purpose of combating the disease, condition, or disorder, and includes the administration of a compound of the present disclosure to prevent the onset of symptoms or complications, alleviate symptoms or complications, or eliminate the disease, condition, or disorder.

[0075] As used herein, the term "stroke" has its meaning commonly accepted in the art. The term can broadly refer to the development of neurological deficits associated with impaired blood flow, regardless of cause. Possible causes include, but are not limited to, thrombosis, hemorrhage, and embolism. The term "ischemic stroke" more specifically refers to a type of stroke that is limited in extent and caused by an obstruction to blood flow.

[0076] As used herein, a subject is "in need of" a treatment if such subject (preferably a human) would benefit biologically, medically, or in quality of life from such treatment.

[0077] As used herein, the term "co-administered" refers to the presence of two active agents in the blood of an individual. Co-administered active agents can be delivered simultaneously or sequentially.

[0078] The terms "combination therapy" or "in combination with" or "pharmaceutical combination" refer to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule with a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple or separate containers (e.g., capsules, powder, and liquid) for each active ingredient. The powder and / or liquid can be reconstituted or diluted to the desired dose before administration. Furthermore, such administration also encompasses the use of each type of therapeutic agent administered before, simultaneously, or sequentially with respect to each other without specific time limitations. In each case, the therapeutic regimen provides the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0079] II. Compounds of the Present Disclosure The compounds of the present disclosure include a degradation signaling moiety (DSM) capable of binding to an E3 ligase (e.g., a cereblon protein), an IRAK4 binding or targeting moiety, and optionally a linker that covalently attaches the DSM to the IRAK4 binding or targeting moiety.

[0080] In a first embodiment, the compound of the present disclosure comprises: Formula (A): IRAK-L-DSM (A) or a pharmaceutically acceptable salt thereof, wherein the IRAK, L, and DSM moieties of Formula (A) are as described in the first aspect above. In some embodiments, the DSM, IRAK, and linker moieties in Formula (A) are as described below.

[0081] A. IRAK4 Binding or Targeting Moieties In a second embodiment of the present disclosure, for a compound of formula (A): IRAK is a compound of formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions of the other variables are as defined in the first embodiment.

[0082] In a third embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, IRAK is an IRAK4 binding moiety represented by formula (I), (IA) or (IB), wherein R 1 is 1 to 3 R 5 phenyl optionally substituted with 1 to 2 nitrogen atoms, 5- or 6-membered heteroaryl (the heteroaryl is 5 and 9-10 membered bicyclic heteroaryl having 1, 2 or 3 nitrogen atoms (the ring system is optionally substituted with 1-3 R 5 and optionally substituted with ), the definitions of the other variables being as defined in the first embodiment.

[0083] In a fourth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, IRAK is an IRAK4 binding moiety represented by formula (I), (IA) or (IB), wherein R 1 is 1 to 2 R 5 oxazole optionally substituted with one to two R 5 phenyl optionally substituted with one to two R 5 pyrazole optionally substituted with one to two R 5 pyridine optionally substituted with one to two R 5 pyrimidine optionally substituted with, and one to two R 5 In some embodiments, R is selected from pyrazolo[1,5-a]pyrimidine optionally substituted with R, and the definitions of the other variables are as defined in the first embodiment. 1 is 1 to 2 R 5 oxazole optionally substituted with one to two R 5 phenyl optionally substituted with one to two R 5pyrazole optionally substituted with one to two R 5 pyrimidine optionally substituted with, and one to two R 5 wherein the definitions of the other variables are as defined in the first embodiment.

[0084] In a fifth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, IRAK is an IRAK4 binding moiety represented by formula (I), (IA) or (IB), wherein R 1 is the following formula: [ka] wherein m is 0, 1, or 2, and the other variables are as defined in the first embodiment. 1 is represented by formula (C1), (C2), (C3), (C5), (C7) or (C8), and the definitions of the other variables are as defined in the first embodiment.

[0085] In a sixth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, IRAK is an IRAK4 binding moiety represented by formula (I), (IA) or (IB), wherein R 1 is the following formula: [ka] and the definitions of the other variables are as defined in the first embodiment. 1 is represented by formula (C1a), (C1c), (C1e), (C2), (C3a), (C3b), (C5a), (C7a) or (C8a), and the definitions of the other variables are as defined in the first embodiment.

[0086] In a seventh embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, IRAK is an IRAK4 binding moiety represented by formula (I), (IA) or (IB), wherein R 1 is the following formula: [ka] and the definitions of the other variables are as defined in the first embodiment. In some embodiments, R 1 is represented by formula (C3b), and the definitions of the other variables are as defined in the first embodiment.

[0087] In an eighth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, IRAK is an IRAK4 binding moiety represented by formula (I), (IA) or (IB), wherein R 2 is hydrogen, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0088] In a ninth embodiment of the present disclosure, for compounds of formula (A), or a pharmaceutically acceptable salt thereof, IRAK is represented by the following formula: [ka] and wherein the other variables are as defined in the first embodiment. In some embodiments, the IRAK4 binding moiety is represented by formula (IA-1) or (IB-2), and the other variables are as defined in the first embodiment.

[0089] In a tenth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, IRAK is an IRAK4 binding moiety represented by one of formulas (I), (IA), (IB), (IA-1) or (IB-2), wherein R 3 is C 1-4 Alkyl or -OR 6and C 1-4 The alkyl is optionally substituted with at least one halogen, and R 6 is C 1-5 Alkyl, C 3-6 cycloalkyl or a 4- to 7-membered fully saturated heterocycle containing one or two heteroatoms selected from nitrogen and oxygen, R 6 C represented by 1-5 The alkyl is optionally substituted with 1 to 3 halogens, and R 6 C represented by 3-6 Cycloalkyl is a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, and C 1-4 one to three substituents R independently selected from alkoxy; 6b In some embodiments, R 3 is C 1-4 Alkyl or -OR 6 and C 1-4 The alkyl is optionally substituted with at least one halogen, and R 6 is C 1-5 alkyl, and the definitions of the other variables are as defined in the first, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0090] In an eleventh embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, IRAK is an IRAK4 binding moiety represented by one of formulas (I), (IA), (IB), (IA-1) or (IB-2), wherein R 3 is —CF 3 or —O—CH(CH 3 ) 2 , and the definitions of the other variables are as defined in the first, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0091] In a twelfth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, IRAK is an IRAK4 binding moiety represented by one of formulas (I), (IA), (IB), (IA-1) or (IB-2), wherein R 3is -O-CH(CH3)2, and the definitions of the other variables are 1, 3, 4, 5, 6, 7, Or as defined in the eighth embodiment.

[0092] In a thirteenth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, IRAK is an IRAK4 binding moiety represented by one of formulas (I), (IA), (IB), (IA-1) or (IB-2), wherein R 5 For each occurrence, C 1-4 Alkyl, halogen, C 1-4 Haloalkyl and C 3-4 cycloalkyl, wherein the C 3-4 The cycloalkyl is optionally substituted with one halo, and the other variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, tenth, eleventh, or twelfth embodiment. In some embodiments, R 5 For each occurrence, C 1-4 Alkyl, halogen and C 1-4 haloalkyl, and the definitions of the other variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, tenth, eleventh, or twelfth embodiment.

[0093] In a fourteenth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, IRAK is an IRAK4 binding moiety represented by one of formulas (I), (IA), (IB), (IA-1) or (IB-2), wherein R 5 is, for each occurrence, -CH3, -CHF2, -CF3, F, cyclopropyl, and [ka] and the definitions of the other variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, tenth, eleventh, or twelfth embodiment. In some embodiments, R 5is, for each occurrence, independently selected from -CH, -CHF, -CF and F, and the definitions of the other variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, tenth, eleventh or twelfth embodiment.

[0094] In a fifteenth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, IRAK is of the following formula: [ka] wherein R 5 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-4 is cycloalkyl, and the C 3-4 The cycloalkyl is optionally substituted with one halo, and the other variables are as defined in the first embodiment. In some embodiments, the IRAK4 binding moiety represents formula (IA-1a) or (IIB-2a), and R 5 is C 1-3 Alkyl or C 1-3 haloalkyl, and the definitions of the other variables are as defined in the first embodiment.

[0095] In a sixteenth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, IRAK is an IRAK4 binding moiety represented by one of formulas (IA-1a) or (IIB-2a), wherein R 5 is CH3, CHF2, CF3, cyclopropyl, or [ka] and the definitions of the other variables are as defined in the fifteenth embodiment. In some embodiments, R 5 is CH3, CHF2, or CF3, and the definitions of the other variables are as defined in the fifteenth embodiment.

[0096] B. Degradation Signaling Moiety (DSM) The degradation signaling moiety (DSM) in the compound of formula (A) or a pharmaceutically acceptable salt thereof may be a suitable moiety that binds to an E3 ubiquitin ligase (e.g., a cereblon protein), such as those described in WO2020 / 210630 entitled "Tricyclic Degraders of Ikaros and Aiolos"; WO2020 / 181232 entitled "Heterocyclic Compounds for Medical Treatment"; WO2020 / 132561 entitled "Targeted Protein Degradation"; WO2019 / 204354 entitled "Spirocyclic Compounds"; WO2019 / 099868 entitled "Degraders and Degrons for Targeted Protein Degradation"; WO2018 / 237026 entitled "N / O-Linked Degrons and Degronimers for Protein Degradation"; The degronimer may be a degron or an E3 ubiquitin ligase binding or targeting moiety described in WO2017 / 197051 entitled "Degronimers for Target Protein Degradation"; WO2017 / 197055 entitled "Heterocyclic Degronimers for Target Protein Degradation"; WO2017 / 197036 entitled "Spirocyclic Degronimers for Target Protein Degradation"; WO2017 / 197046 entitled "C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation"; and WO2017 / 197056 entitled "Bromodomain Targeting Degronimers for Target Protein Degradation."Other degradation signaling moieties or E3 ubiquitin ligase binding or targeting moieties that can be used include those described in WO2015 / 160845, WO2016 / 105518, WO2016 / 118666, WO2016 / 149668, WO2016 / 197032, WO2016 / 197114, WO2017 / 007612, WO2017 / 011371, WO2017 / 011590, WO2017 / 030814, WO2017 / 046036, WO2017 / 176708, WO2017 / 176957, WO2017 / 18041 7, WO2018 / 053354, WO2018 / 071606, WO2018 / 102067, WO2018 / 102725, WO2018 / 118598, WO2018 / 119357, WO2018 / 119441, WO2018 / 119448, WO2018 / 140809, WO2018 / 144649, WO2018 / 119448, WO2018 / 226542, WO2019 / 023553, WO2019 / 195201, WO2019 / 199816, and WO2019 / 099926. The entire teachings of the above-referenced PCT publications are incorporated herein by reference.

[0097] In a seventeenth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is is a degradation signaling moiety of formula (D): [ka] During the ceremony, [ka] represents a bond to the linker L, and Y represents a bond to the linker L. D1 or N and Z 1 is the bond, -NR D2 -, -O-, and -CH2-; G 1 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and partially saturated 4- to 11-membered heterocycle; G 1Each of the 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and partially saturated 4- to 11-membered heterocycle represented by the formula D3 optionally substituted with G 2 Het1, [ka] wherein *- represents a bond to the linker L; [ka] is G 1 Het1 represents a bond to a 4- to 7-membered monocyclic heterocycle or a 7- to 11-membered bicyclic heterocycle, each of which is optionally joined to one or more R D5 optionally substituted with R D1 is H, C 1-6 alkyl or halogen; R D2 is H or C 1-3 alkyl, and R D3 For each occurrence, H, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; R D4 is H or C 1-3 alkyl, and R D5 For each occurrence, H, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 and alkoxy, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0098] In an eighteenth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), wherein Het1 is a 4-7 membered monocyclic saturated heterocycle containing one or two nitrogen atoms, or a 7-11 membered spiro bicyclic saturated heterocycle containing one or two heteroatoms selected from N and O, each of which is joined to one or two RD5 and the definitions of the other variables are as defined in the seventeenth embodiment.

[0099] In a nineteenth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), wherein Het1 is piperidine, piperazine, 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 5-azaspiro[3.4]octane, or 9-oxa-9-azaspiro[5.5]undecane, each of which is selected from the group consisting of one or two R D5 and the definitions of the other variables are as defined in the seventeenth embodiment.

[0100] In a twentieth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (DI) or (D-II): [ka] During the ceremony, [ka] represents a bond to the linker L, and Z 1 is the bond, -NR D2 - and -O-, G 1 is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and partially saturated 4- to 11-membered heterocycle; G 1 Each of the 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and partially saturated 4- to 11-membered heterocycle represented by the formula D3 optionally substituted with R D2 is H or C 1-3 alkyl, and R D3 For each occurrence, H, halogens and C 1-4 alkyl; R D4 is C 1-3 alkyl, and R D5is halogen, n is 0, 1 or 2, and the definitions of the other variables are as defined in the seventeenth embodiment.

[0101] In a twenty-first embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), and 1 is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, or a partially saturated 4- to 11-membered heterocycle; G 1 Each of the 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and partially saturated 4- to 11-membered heterocycle represented by the formula D3 and optionally substituted with, the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.

[0102] In a twenty-second embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), wherein: 1 is selected from phenyl, pyrazole, pyridinyl and pyrimidinyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, indazolyl, and indolyl, each of which may be selected from one or two R D3 and optionally substituted with, the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.

[0103] In a twenty-third embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), and 1 is the following formula: [ka] wherein o is 0, 1 or 2; [ka] is G 2 represents a bond to Z 1 and the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.

[0104] In a twenty-fourth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), and 1 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; G 1 Each of the 6- to 10-membered aryl and 5- to 10-membered heteroaryl represented by the formula: D3 and optionally substituted with, the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.

[0105] In a twenty-fifth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), wherein: 1 is selected from phenyl, pyrazole, pyridinyl and pyrimidinyl, indazolyl, and indolyl, each of which may be selected from one or two R D3 and optionally substituted with, the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.

[0106] In a twenty-sixth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), and 1 is the following formula: [ka] wherein o is 0, 1 or 2; [ka] is G 2 represents a bond to Z 1 and the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth or twentieth embodiment.

[0107] In a twenty-seventh embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), and R D1 is H, —CH or F, and the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth or twenty-sixth embodiment.

[0108] In a twenty-eighth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), wherein R D2 is hydrogen, and the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh embodiment.

[0109] In a twenty-ninth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), and R D3 is, for each occurrence, independently selected from H, Cl, F, and —CH3, and the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment.

[0110] In a thirtieth embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), and R D4is —CH3, and the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, or twenty-ninth embodiment.

[0111] In a thirty-first embodiment of the present disclosure, for a compound of formula (A), or a pharmaceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI) or (D-II), wherein R D5 is independently for each occurrence F or OH, and the definitions of the other variables are as defined in the seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, or thirtieth embodiment.

[0112] In a thirty-second embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, DSM represents any one of the following attached to L: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiment.

[0113] C. Linker In a thirty-third embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, L is a bond, C 1-8 alkyl or represented by formula (L-1), (L-2) or (L-3), [ka] In the formula, Z 2 is a bond or C optionally substituted with one or more halogens 1-4 alkyl, and Het2 is one or more R L1 and G is a 4- to 7-membered heterocycle optionally substituted by 3 is C 3-7 cycloalkyl or 4- to 7-membered heterocycle, G 3 C represented by 3-7 The cycloalkyl and 4- to 7-membered heterocycle each may be one or more R L3 and optionally substituted with Z 3 is C 1-4 Alkyl or [ka] where: [ka] is G 3 represents the bond connected to the DSM, and -* represents the bond connected to the C 1-4 Alkyl is optionally substituted with one or more halogens, and Z 4 is R L4 C optionally substituted by 1-4 alkyl, and R L1 For each occurrence, H, halogen, C 1-4 Alkyl and C 1-4haloalkyl; R L2 is H or C 1-4 alkyl, and R L3 For each occurrence, H, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; R L4 , halo, -OR L5 , or halogen, C 3-7 C optionally substituted by cycloalkyl, phenyl, 4- to 7-membered monocyclic saturated heterocycle, or 5- to 6-membered heteroaryl 1-4 alkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered monocyclic saturated heterocycle, and 5- to 6-membered heteroaryl are each selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 optionally substituted with 1 to 3 substituents independently selected from haloalkoxy; R L5 is H, C 1-4 Alkyl or C 1-4 is haloalkyl, [ka] represents binding to the IRAK4 binding moiety, -* represents binding to the degradation signaling moiety DSM, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, or thirty-second embodiment.

[0114] In a thirty-fourth embodiment of the present disclosure, for compounds of formula (A), or a pharmaceutically acceptable salt thereof, L is a bond, and the definitions of the other variables are as defined in the thirty-third embodiment.

[0115] In a thirty-fifth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, L is C1-8 alkyl, and the definitions of the other variables are as defined in the thirty-third embodiment.

[0116] In a thirty-sixth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, L is represented by formula (L-1), (L-2) or (L-3), and Het2 is selected from azetidinyl, piperidinyl and pyrrolidinyl, and the azetidinyl, piperidinyl and pyrrolidinyl represented by Het2 each may be selected from one or more R L1 and optionally substituted by G 3 is azetidinyl, cyclohexyl or piperidinyl, and G 3 The cyclohexyl and piperidinyl represented by each may be one or more R L3 and the definitions of the other variables are as defined in the thirty-third embodiment.

[0117] In a thirty-seventh embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, L is represented by formula (L-1), (L-2) or (L-3), and Z 2 is a bond or -CH2-, and Z 3 is -CH2-, -CH2-CH2-, [ka] and Z 4 is —CH(CH 2 Ph)— or —CH 2 —CH 2 —CH 2 —, and the definitions of the other variables are as defined in the thirty-third or thirty-sixth embodiment.

[0118] In a thirty-eighth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, L is represented by formula (L-1), (L-2) or (L-3), wherein R L1 is H and R L2 is H and R L3 is H and R L4is benzyl, and the definitions of the other variables are as defined in the thirty-third, thirty-sixth, or thirty-seventh embodiment.

[0119] In a thirty-ninth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, L is represented by formula (L-1) and Het2 is represented by the following formula: [ka] wherein: [ka] is Z 2 represents binding to, -* represents binding to the degradation signaling moiety DSM, and the definitions of the other variables are as defined in the thirty-third, thirty-seventh or thirty-eighth embodiment.

[0120] In a fortieth embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, L is represented by formula (L-2), and G 3 is the following formula: [ka] wherein: [ka] represents binding to the IRAK4 binding moiety, and -* represents binding to the Z 3 and the definitions of the other variables are as defined in the thirty-third, thirty-seventh or thirty-eighth embodiment.

[0121] In a forty-first embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, L is represented by the following formula (L-1), and Het2 is: [ka] where: [ka] is Z 2 represents binding to, -* represents binding to the degradation signaling moiety DSM, and the definitions of the other variables are as defined in the thirty-third, thirty-seventh or thirty-eighth embodiment.

[0122] In a forty-second embodiment of the present disclosure, for compounds of formula (A), or pharmaceutically acceptable salts thereof, L is represented by formula (L-3), and Z 4 is C optionally substituted by benzyl 1-4 alkyl, and R L2 is H, and the definitions of the other variables are as defined in the thirty-third embodiment.

[0123] In a forty-third embodiment of the present disclosure, for compounds of formula (A), or a pharmaceutically acceptable salt thereof, L is of the following formula: [ka] wherein: [ka] represents binding to the IRAK4 binding moiety, -* represents binding to the degradation signaling moiety DSM, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, or thirty-second embodiment.

[0124] In a forty-fourth embodiment of the present disclosure, the compound of formula (A), or a pharmaceutically acceptable salt thereof, is any one of the compounds of Examples 1 to 87, or a pharmaceutically acceptable salt thereof.

[0125] III. Pharmaceutical Compositions and Methods of Use Another aspect of the present disclosure is a pharmaceutical composition comprising at least one compound described herein (e.g., a compound described in any of the above embodiments, or a pharmaceutically acceptable salt thereof), and at least one pharmaceutically acceptable carrier.

[0126] The compounds of the present disclosure are typically used as pharmaceutical compositions (e.g., compounds of the present disclosure and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes, as understood by those skilled in the art, generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, butyric acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and the like, and combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Any conventional carrier is contemplated for use in therapeutic or pharmaceutical compositions, except insofar as it is incompatible with the active ingredient. For purposes of this disclosure, solvates and hydrates are considered to be pharmaceutical compositions comprising a compound of the present disclosure and a solvent (ie, a solvate) or water (ie, a hydrate).

[0127] Compounds of the present disclosure have been found to modulate IRAK4 activity and may be beneficial in the treatment of neurological, neurodegenerative and other additional diseases.

[0128] In some embodiments, a compound described herein (e.g., a compound described in any of the above embodiments, or a pharmaceutically acceptable salt thereof) can be used to cause degradation of IRAK4 protein. In some embodiments, a compound described herein (e.g., a compound described in any of the above embodiments, or a pharmaceutically acceptable salt thereof) can be used to modulate (e.g., decrease) the level of IRAK4 protein. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., a compound described in any of the above embodiments, or a pharmaceutically acceptable salt thereof) can be used to modulate (e.g., decrease) the activity of IRAK4 or otherwise affect the properties and / or behavior of IRAK4, such as stability, phosphorylation, kinase activity, interactions with other proteins, etc.

[0129] In some embodiments, the present disclosure provides methods for reducing IRAK4 protein levels and / or IRAK4 enzymatic activity. In some embodiments, such methods comprise contacting a cell with an effective amount of a compound described herein (e.g., a compound described in any of the above embodiments, or a pharmaceutically acceptable salt thereof).

[0130] One aspect of the present disclosure includes a method of treating a disorder responsive to degradation of IRAK4 and / or inhibition of IRAK4 activity in a subject, comprising administering to the subject an effective amount of at least one compound described herein (e.g., a compound described in any of the above embodiments or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein.

[0131] One embodiment of the present disclosure includes a method of treating autoimmune diseases, cancer, cardiovascular diseases, diseases of the central nervous system, skin diseases, eye diseases and conditions, and bone diseases in a subject, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, thereby treating the autoimmune disease, cancer, cardiovascular diseases, diseases of the central nervous system, skin diseases, eye diseases and conditions, and bone diseases in the subject.

[0132] In one embodiment, the cardiovascular disease is selected from stroke and atherosclerosis. In one embodiment, the central nervous system disease is a neurodegenerative disease. In one embodiment, the skin disease is selected from rash, contact dermatitis, psoriasis, hidradenitis suppurativa, and atopic dermatitis. In one embodiment, the bone disease is selected from osteoporosis and osteoarthritis.

[0133] In one embodiment, the present disclosure provides a method of treating autoimmune disorders, inflammatory disorders, and cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound described herein (e.g., a compound described in any of the above embodiments or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein.

[0134] The term "autoimmune disorder" includes diseases or disorders involving an inappropriate immune response to natural antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, type 1 diabetes mellitus, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic lupus erythematosus, lupus erythematosus cutaneous (CLE), neuromyelitis optica (NMO), mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis.

[0135] In one embodiment, the autoimmune disease is selected from rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, systemic sclerosis, and Sjogren's syndrome, hi one embodiment, the autoimmune disease is type 1 diabetes.

[0136] The term "inflammatory disorder" includes diseases or disorders involving acute or chronic inflammation, such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. In some embodiments, the present disclosure provides methods of treating rheumatoid arthritis or lupus. In some embodiments, the present disclosure provides methods of treating multiple sclerosis. In some embodiments, the present disclosure provides methods of treating systemic lupus erythematosus or atopic dermatitis.

[0137] One embodiment of the present disclosure includes a method of treating an inflammatory disease in a subject, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating the inflammatory disease in the subject.

[0138] In one embodiment, the inflammatory disease is a lung disease or airway disease, hi one embodiment, the lung disease or airway disease is selected from adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, interstitial lung disease, asthma, chronic cough, and allergic rhinitis.

[0139] In one embodiment, the inflammatory disease is selected from transplant rejection, CD14-mediated sepsis, non-CD14-mediated sepsis, inflammatory bowel disease, Behcet's syndrome, ankylosing spondylitis, sarcoidosis, and gout, hi one embodiment, the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

[0140] One embodiment of the present disclosure includes a method of treating an ischemic fibrotic disease, the method comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating the ischemic fibrotic disease in the subject. In one embodiment, the ischemic fibrotic disease is selected from stroke, acute lung injury, acute kidney injury, ischemic heart injury, acute liver injury, and ischemic skeletal muscle injury.

[0141] One embodiment of the present disclosure includes a method of treating post-organ transplant fibrosis, the method comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating post-organ transplant fibrosis in the subject.

[0142] One embodiment of the present disclosure includes a method of treating hypertensive or diabetic end-organ disease, the method comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating the hypertensive or diabetic end-organ disease in the subject.

[0143] One embodiment of the present disclosure includes a method of treating hypertensive kidney disease, comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating the hypertensive kidney disease in the subject.

[0144] One embodiment of the present disclosure includes a method of treating idiopathic pulmonary fibrosis (IPF), comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating IPF in the subject.

[0145] One embodiment of the present disclosure includes a method of treating scleroderma or systemic sclerosis, the method comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating scleroderma or systemic sclerosis in the subject.

[0146] One embodiment of the present disclosure includes a method of treating cirrhosis, comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating cirrhosis in the subject.

[0147] One embodiment of the present disclosure includes a method of treating a fibrotic disorder in which tissue injury and / or inflammation is present, comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, thereby treating the fibrotic disorder in the subject in which tissue injury and / or inflammation is present, such as, for example, pancreatitis, peritonitis, burns, glomerulonephritis, complications of drug toxicity, and post-infectious scarring.

[0148] Scarring of internal organs is a major global health problem, resulting either from subclinical organ damage over a period of time or as a sequelae of acute severe injury or inflammation. All organs can be affected by scarring, and currently, few therapies specifically target scarring progression. Growing evidence suggests that scarring itself leads to further decline in organ function, inflammation, and tissue ischemia. This may be directly attributable to the deposition of fibrous matrix, which impairs functions such as contractility and relaxation of the heart and vasculature, or to poor lung expansion and contraction, or to increased space between the microvasculature and vital cells in nutrient-deprived organs, distorting normal tissue architecture. However, recent studies have shown that myofibroblasts themselves are inflammatory cells, producing injury-promoting cytokines, chemokines, and radicals. Myofibroblasts emerge as a result of migration from cells that normally nurse and maintain the microvasculature, known as pericytes. The result of this phenotypic transition is an unstable microvasculature, leading to abnormal vascularization or rarefaction.

[0149] The present disclosure relates to methods and compositions for treating, preventing, and / or reducing scarring in organs. More specifically, the present disclosure relates to methods and compositions for treating, preventing, and / or reducing scarring in kidneys. Some non-limiting examples of organs include kidney, heart, lung, stomach, liver, pancreas, hypothalamus, stomach, uterus, bladder, diaphragm, pancreas, intestine, colon, etc.

[0150] It is contemplated that the disclosure, methods, and compositions described herein can be used as anti-fibrotic agents or to treat, prevent, and / or reduce the severity and damage from fibrosis. It is further contemplated that the disclosure, methods, and compositions described herein can be used to treat, prevent, and / or reduce the severity and damage from fibrosis.

[0151] The compounds of the present disclosure (e.g., a compound described in any of the above embodiments or a pharmaceutically acceptable salt thereof) may be useful in the treatment of cancer, e.g., a cancer selected from solid tumor cancers and hematopoietic cancers.

[0152] The term "cancer" includes diseases or disorders involving abnormal growth and / or proliferation of cells, such as glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability-high colorectal cancer). In some embodiments, the present disclosure provides methods of treating leukemia or lymphoma.

[0153] Examples of solid tumor cancers include central nervous system cancer, brain cancer, breast cancer, head and neck cancer, lung cancer, esophageal and gastroesophageal junction cancer, stomach cancer, colon cancer, rectal cancer, anal cancer, hepatobiliary cancer, pancreatic cancer, non-melanoma skin cancer, melanoma, kidney cancer, prostate cancer, bladder cancer, uterine cancer, cervical cancer, ovarian cancer, bone cancer, neuroendocrine cancer, mesothelioma cancer, testicular cancer, thymoma and thymic cancer, and thyroid cancer.

[0154] Examples of hematopoietic cancers include B-cell neoplasms (including rare B-cell malignancies), Hodgkin's lymphoma, non-Hodgkin's lymphoma, post-transplant lymphoproliferative disorder, hairy cell leukemia, histiocytic neoplasms, and dendritic neoplasms.

[0155] Examples of B-cell neoplasms include chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), Waldenstrom's hypergammaglobulinemia, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, Richter's syndrome, and precursor B-lymphoblastic lymphoma. These include primary and secondary multiple myeloma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, and acute lymphoblastic leukemia.

[0156] In some embodiments, the cancer is selected from chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), and Waldenstrom's hypergammaglobulinemia. In one embodiment, the cancer is chronic lymphocytic leukemia (CLL). In another embodiment, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0157] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the subject is a primate. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the subject is a human.

[0158] According to the present disclosure, an "effective dose" or "effective amount" of a compound or pharmaceutical composition is an amount effective to treat or reduce the severity of one or more of the above-listed diseases, disorders, or conditions. The effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject can be 10 μg to 500 mg.

[0159] The formulation can be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., the compound of the present disclosure or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compound of the present disclosure is typically formulated into a pharmaceutical dosage form to provide an easily controllable dosage of the drug and provide patients with a simple and easy-to-use product.

[0160] Pharmaceutical compositions (or formulations) for application can be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution can include a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container can also include a tamper-evident assembly to prevent inadvertent access to the contents of the package. In addition, the container has disposed thereon a label that describes the contents of the container. The label can also include appropriate warnings.

[0161] Pharmaceutical compositions containing the compounds of the present disclosure will generally be formulated for parenteral or oral administration or alternatively for use as suppositories.

[0162] For example, oral pharmaceutical compositions of the present disclosure may be configured in a solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in a liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization, and / or may contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0163] Typically, the pharmaceutical composition is a tablet or gelatin capsule, which comprises an active ingredient together with a) diluent, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricant, such as silica, talcum, stearic acid, its magnesium salt or calcium salt and / or polyethylene glycol; in the case of tablets, further c) binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired, d) disintegrant, such as starch, agar, alginic acid or its sodium salt, or effervescent mixture; and / or e) absorbent, colorant, flavoring and sweetener. Tablets can be film-coated or enteric-coated according to methods known in the art.

[0164] Compositions suitable for oral administration include the compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, in order to provide a pharmaceutically simple and palatable preparation.

[0165] Tablets can contain active ingredients in a mixture with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture.These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc.Tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0166] Parenteral compositions (e.g., intravenous (IV) preparations) are aqueous, isotonic solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents, or emulsifiers, solution promoters, salts for regulating osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically useful substances. The compositions generally contain about 0.1 to 75%, or about 1 to 50%, of the active ingredient, prepared according to conventional mixing, granulating, or coating methods, respectively.

[0167] The compounds and compositions according to the disclosed methods may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the aforementioned diseases, disorders or conditions.

[0168] Administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal includes any suitable delivery method. Administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal includes administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally. Administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal also includes administering a compound that metabolizes a compound described herein or a pharmaceutically acceptable salt thereof to a mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.

[0169] The compounds of the present disclosure or pharmaceutical compositions thereof used in subjects (e.g., humans) are typically administered orally or parenterally at a therapeutic dose of about 100 mg / kg or less, about 75 mg / kg or less, about 50 mg / kg or less, about 25 mg / kg or less, about 10 mg / kg or less, about 7.5 mg / kg or less, about 5.0 mg / kg or less, about 3.0 mg / kg or less, about 1.0 mg / kg or less, about 0.5 mg / kg or less, about 0.05 mg / kg or less, or about 0.01 mg / kg or less, but preferably about 0.0001 mg / kg or more. When administered intravenously by infusion, the dosage may depend on the infusion rate at which the IV formulation is administered. Generally, the therapeutically effective dosage of the compound, pharmaceutical composition, or combination thereof depends on the species, body weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, pharmacist, clinician or veterinarian having ordinary skill in the art can readily determine the effective amount of each of the active ingredients required to prevent, treat or inhibit the progress of the disorder or disease.

[0170] Thus, the compounds described herein, or pharmaceutically acceptable salts thereof, may be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with the patient's food. For oral therapeutic administration, the compounds described herein, or pharmaceutically acceptable salts thereof, may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, or the like. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the compositions and preparations may, of course, vary and may conveniently be about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions may be such that an effective dosage level will be obtained.

[0171] Tablets, troches, pills, capsules, etc. may contain: a binder such as tragacanth, acacia, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; or a sweetening or flavoring agent such as sucrose, fructose, lactose, or aspartame.

[0172] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically, or intranasally. The active compound may be administered intravenously or intraperitoneally by infusion or injection. A solution of the active compound or its salt can be prepared in water, optionally mixed with a nontoxic surfactant. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compound is administered parenterally. In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the compound is administered systemically.

[0173] Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage.

[0174] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent containing various other ingredients as listed above, as needed, followed by filtration sterilization.For sterile powders for preparing sterile injectable solutions, the preferred preparation method can be vacuum drying and freeze-drying technology, which can obtain a powder of the active ingredient and any additional desired ingredients present in a solution previously sterile-filtered.

[0175] Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols or glycols or blends of water and alcohols / glycols, in which the compounds described herein or pharmaceutically acceptable salts thereof can be dissolved or dispersed at effective levels, optionally with the use of nontoxic surfactants.

[0176] Useful dosages of the compounds described herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; see, for example, U.S. Patent No. 4,938,949, incorporated by reference in its entirety.

[0177] The amount of the compound described herein or a pharmaceutically acceptable salt thereof required for treatment will vary not only depending on the particular salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be left to the discretion of the attending physician or clinician. Generally, however, the dosage may range from about 0.1 to about 10 mg / kg body weight per day.

[0178] The compounds described herein, or pharmaceutically acceptable salts thereof, can be conveniently administered in unit dosage form, for example, containing 0.01 to 10 mg, or 0.05 to 1 mg of active ingredient per unit dosage form. In some embodiments, dosages of 5 mg / kg or less may be suitable.

[0179] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

[0180] The disclosed methods may include kits containing a compound described herein or a pharmaceutically acceptable salt thereof, and instructional materials that can describe administering a compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, to a cell or a subject. This should be construed to include other embodiments of kits known to those of skill in the art, such as kits that include a solvent (e.g., sterile) for dissolving or suspending a compound described herein or a pharmaceutically acceptable salt thereof or a composition prior to administering the compound described herein or a pharmaceutically acceptable salt thereof or a composition to a cell or a subject. In some embodiments, the subject may be a human. [Example]

[0181] IV. Working Examples A. Abbreviations and acronyms used herein include the following: ACN: means acetonitrile (CH3CN); AcOH: means acetic acid; Aq. or aq.: means aqueous; Ar: means argon; br:means wide area; tBuXPhos Pd G3: [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II); °C: means degrees Celsius; CAN: means cerium ammonium nitrate [(NH4)2Ce(NO3)6]; CDCl3: means deuterochloroform; CDI: means 1,1′-carbonyldiimidazole; CH2Cl2: means methylene chloride; CaCl2: means calcium chloride; Cs2CO3: means cesium carbonate; d: means double line; dd: means double double line; δ: means chemical shift; D2O: means heavy water; DCM: dichloromethane; Dess-Martin Periodinane: 3-Oxo-1λ 5 ,2-benzoiodoxol-1,1,1(3H)-triyl triacetate; DIPEA: diisopropylethylamine; DMF: dimethylformamide; DMSO: means dimethyl sulfoxide; DMSO-d6: hexadeuterodimethyl sulfoxide; ESI: electrospray ionization; Et: means ethyl; Et3N: means triethylamine; EtOH: ethanol; EtOAc: means ethyl acetate; g: means grams; h: means time; HATU: means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HBr: means hydrogen bromide; HCl: means hydrochloric acid; HPLC: means high pressure liquid chromatography; 1 1H NMR: means proton nuclear magnetic resonance; H2O: means water; IPA: means isopropyl alcohol; K2CO3: means potassium carbonate; KOH: means potassium hydroxide; L: means liter; LC: means liquid chromatography; LC-MS: means liquid chromatography mass spectrometry; LDA: means lithium diisopropylamide; m: means multiplet; M: means mole; mins: means minutes; mL: means milliliter; μL: means microliter; mmol: means millimole; m / z: mass-to-charge ratio; mg: means milligram; Me: means methyl; MeCN: means acetonitrile; MeOH: means methanol; MHz: means megahertz; Min(s): minute(s); MS m / z: means mass spectrum peak; MTBE: means tert-butyl methyl ether; M / V: means mass-volume ratio; N2 or N2: means nitrogen; NH4Cl: means ammonium chloride; Na: means sodium; NaH: means sodium hydride; NaHCO3: means sodium bicarbonate; NaOH: means sodium hydroxide; NaOCN: means sodium cyanate; Na2SO4: means sodium sulfate; NH4Cl: means ammonium chloride; NMP: N-methyl-2-pyrrolidone; 2-Picoline borane complex: 2-methylpyridine-borane complex; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd-PEPPSI-IHeptCl: means dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); Pd(t-Bu3P)2: means bis(tri-tert-butylphosphine)palladium(0); PE or Pet Ether: means petroleum ether; Psi: means pounds per square inch; q: means quartet; R f : means retention factor; RT: means room temperature; s: means single line; sat.: means saturated; soln.: means solution; SFC: stands for supercritical fluid chromatography; t: means triple line; TEA: means triethylamine; TFA: means trifluoroacetic acid; THF: means tetrahydrofuran; TLC: means thin layer chromatography; μmol: means micromolar; UPLC: stands for ultra-high performance liquid chromatography; V: volume; XPhos: means 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0182] B. General Method The compounds of the examples were analyzed or purified according to one of the purification methods mentioned below unless otherwise stated.

[0183] When preparative TLC or silica gel chromatography is used, one skilled in the art can select any combination of solvents to purify the desired compound. Silica gel column chromatography was performed using 20-40 μM (particle size), 100-200 mesh, 250-400 mesh, or 400-632 mesh silica gel on a Teledyne ISCO Combiflash® RF, Biotage® Isolera One 3.3.0, Biotage® Flash Isolera Prime, Grace Reveleris X2 with ELSD purification, Gilson-281 with ELSD purification system, or by using pressurized nitrogen (approximately 10-15 psi) to pass the solvent through the column ("flash chromatography").

[0184] Unless otherwise noted, reactions were carried out under a nitrogen atmosphere. Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum.

[0185] C. Analysis method NMR Equipment specifications: Bruker AVANCE III 400 Bruker AVANCE III HD 400 Bruker AVANCE NEO 400 Bruker AVANCE DRX 500 Varian UNITYplus 400 LC / MS Equipment specifications: Agilent 1200 Series LC / MSD system equipped with DAD and Agilent LC\MS G6110A mass spectrometer. Agilent (Degasser: 1200; Pump: 1260; Hip-ALS: 1200; TCC: 1200; DAD: 1100) A series LC / MS system equipped with DAD\ELSD and Agilent LC\MS G6110A, mass spectrometer. Agilent (Degasser: 1200; Pump: 1260; Hip-ALS: 1100; TCC: 1260; DAD: 1100) A series LC / MS system equipped with a DAD and an Agilent LC\MS G1956A mass spectrometer. Agilent (Degasser: 1200; Pump: 1200; Hip-ALS: 1100; TCC: 1200; DAD: 1200) A series LC / MS system equipped with a DAD and an Agilent LC\MS G1956A mass spectrometer. Agilent 1200 Series LC / MSD system equipped with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6130A, G6120B mass spectrometers. Agilent Technologies 1260 Infinity LC / MSD system equipped with a DAD\ELSD Alltech 3300 and an Agilent LC\MSD G6120B mass spectrometer. Agilent Technologies 1260 Infinity II LC / MSD system equipped with a DAD\ELSD G7102A 1290 Infinity II and an Agilent LC\MSD G6120B mass spectrometer. Agilent 1260 Series LC / MSD system equipped with DAD\ELSD and Agilent LC\MSD (G6120B) mass spectrometer. UHPLC Agilent 1290 Series LC / MSD system equipped with DAD\ELSD and Agilent LC\MSD (G6125B) mass spectrometer. Agilent 1290 Infinity II-6130 Quadrupole MS (single quadrupole type) A SHIMADZU LC-20AD series LC / MS system equipped with an SPD-M20A and a SHIMADZU LC\MS LCMS-2020 mass spectrometer. SHIMADZU LC-20AD series LC / MS system equipped with SPD-M20A\ELSD and SHIMADZU LC\MS LCMS-2020 mass spectrometer A SHIMADZU LC-20AD series LC / MS system equipped with an SPD-M40 and a SHIMADZU LC\MS LCMS-2020 mass spectrometer. A SHIMADZU LC-20AB series LC / MS system equipped with an SPD-M20A and a SHIMADZU LC\MS LCMS-2020 mass spectrometer. A SHIMADZU LC-20AB series LC / MS system equipped with an SPD-M20A\ELSD and a SHIMADZU LC\MS LCMS-2020 mass spectrometer. Waters Acquity UPLC H-Class-SQ Detector 2 Ultima 3000 Dionex UHPLC-Thermo LCQ Fleet Ion Trap HPLC Equipment specifications: SHIMADZU LC-20AD series LC system with SPD-M20A SHIMADZU LC-20AB series LC system with SPD-M40 SHIMADZU LC-20AB series LC system with SPD-M20A Waters Acquity HPLC (binary / quaternary pump) Agilent 1260 Infinity II LC system with PDA detector Preparative HPLC Equipment specifications: Shimadzu Nexera Prep-Pump-LC-20 AP with autosampler and autofraction collector Gilson 331 / 332 HPLC Pump System Waters-MS prep-QDA SFC Equipment specifications: Waters 150 / 200 Purification System Waters Investigator Waters UPC2 Sepiatec Screening System

[0186] D. LC-MS method Method 1 0.1% formic acid solution (aqueous phase) 100% acetonitrile (organic phase) Mode: Gradient %B (5 to 95 in 3.7 minutes) Run Time: 4.8 minutes Column: Acquity UPLC BEH / X-Bridge BEH C18, 1.7μm / 2.5μm, 2.1 x 50mm Flow rate: 0.5mL / 0.6mL / min Temperature: 40℃ Method 2 10mM ammonium acetate solution (aqueous phase) 100% acetonitrile (organic phase) Mode: Gradient %B (5 to 95 in 3.7 minutes) Run Time: 4.8 minutes Column: Acquity UPLC BEH / X-Bridge BEH C18, 1.7μm / 2.5μm, 2.1 x 50mm Flow rate: 0.5mL / 0.6mL / min Temperature: 40℃ Method 3 0.1% TFA aqueous solution (aqueous phase) 100% acetonitrile (organic phase) Mode: Gradient %B (5 to 95 in 3.7 minutes) Run Time: 4.8 minutes Column: Acquity UPLC BEH / X-Bridge BEH C18, 1.7μm / 2.5μm, 2.1 x 50mm Flow rate: 0.5mL / 0.6mL / min Temperature: 40℃ Method 4 10mM ammonium bicarbonate solution (aqueous phase) 100% acetonitrile (organic phase) Mode: Gradient %B (5 to 95 in 3.7 minutes) Run Time: 4.8 minutes Column: Acquity UPLC BEH / X-Bridge BEH C18, 1.7μm / 2.5μm, 2.1 x 50mm Flow rate: 0.5mL / 0.6mL / min Temperature: 40℃ Method 5 Mobile phase: A: 0.0375% TFA (v / v) in HO B: 0.01875% TFA (v / v) in ACN Column: Kinetex EVO C18 30*2.1mm, 5μm Flow rate: 1.5mL / min Temperature: 50℃ Gradient: 5 to 95% B, 0 to 60% B, 30 to 90% B, or 50 to 100% B in 1.55 min Method 6 Mobile phase: A: 0.025% NH3H2O ​​in H2O (v / v) B: ACN Column: Kinetex EVO C18 30*2.1mm, 5μm Flow rate: 1.5mL / min Temperature: 50℃ Gradient: 5 to 95% B, 0 to 60% B, 30 to 90% B, or 50 to 100% B in 1.55 min Method 7 Injection volume: 0.5μl Column temperature: 60℃ UV scan: 207 - 223 nM 246 - 262 nM 272 - 288 nM Agilent Poroshell 120 SB-C18 4.6×30mm 2.7μm UHPLC Guard Infinity Lab Poroshell 120 with SB-C18 4.6×5mm 2.7μm Mobile phase A: 0.1% FA in water Mobile phase B: 0.1% FA in acetonitrile Elution Details Time (min) Flow rate (mL / min) %A %B 0.00 3.00 99 1 0.01 3.00 99 1 1.5 3.00 0 100 1.73 3.00 0 100 1.74 3.00 99 1 Method 8 Injection volume: 0.5μl Column temperature: 60℃ UV scan: 207 - 223 nM 246 - 262 nM 272 - 288 nM Agilent Poroshell 120 SB-C18 4.6×30mm 2.7μm UHPLC Guard Infinity Lab Poroshell 120 with SB-C18 4.6×5mm 2.7μm Mobile phase A: 0.1% FA in water Mobile phase B: 0.1% FA in acetonitrile Elution Details Time (min) Flow rate (mL / min) %A %B 0.00 1.5 99 1 0.01 1.5 99 1 5.00 1.5 0 100 5.99 1.5 0 100 6.00 1.5 99 1

[0187] E. Synthesis of Degradation Signaling Moiety (DSM) [ka] The intermediate 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione was prepared according to the method described on page 267 of WO2018237026A1.

[0188] [ka] The intermediate 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was prepared according to the method described on page 268 of WO2018 / 237026A1.

[0189] [ka] The intermediate 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was prepared according to the method described on page 353 of WO2020 / 132561A1.

[0190] Synthesis of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione isomers 1 and 2 [ka] Step 1: To a stirred solution of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (2 g, 7.24 mmol) and 3-bromopiperidine-2,6-dione (4.17 g, 21.71 mmol) in DMF (20 mL) was added sodium bicarbonate (6.08 g, 72.37 mmol) and the reaction mixture was stirred for 16 h at 80° C. After consumption of the starting material, the reaction mixture was diluted with water, the precipitate was filtered, and the solid was dried under vacuum. SFC purification afforded tert-butyl 4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate (0.2 g, 491.39 μmol, 6.79% yield) and tert-butyl 4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate (0.2 g, 491.39 μmol, 6.79% yield). Preparative SFC conditions Column / Dimensions: Chiralcel - OJ-H (21*250)mm, 5μm % CO2: 70% Co-solvent ratio (%): 30% (ACN) Total flow rate: 60g / min Back pressure: 100 bar Temperature: 30℃ Ultraviolet light: 243nm Solubility: ACN Number of injections: 86 Total refining time: 10 hours Equipment Details: Make / Model: SFC-150-II The first eluting peak during the SFC separation was assigned as isomer 1 (elution time = 1.993 min) and the second eluting peak was assigned as isomer 2 (elution time = 2.905 min). Isomer 1: LC-MS (ES - ): m / z 386.39 [M - H] - Isomer 2: LC-MS (ES - ): m / z 386.39 [M - H] - Step 2: To a stirred solution of tert-butyl 4-[4-[[-2,6-dioxo-3-piperidyl]amino]phenyl]piperidine-1-carboxylate Isomer 1 (0.2 g, 516.17 μmol) in DCM (5 mL) at 0° C., TFA (1.48 g, 12.98 mmol, 1 mL) was added over 2 min. The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated and co-distilled with toluene (10 mL) and diethyl ether (2 × 50 mL) to give 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione Isomer 1 TFA salt (0.15 g, 358.76 μmol, 69.51% yield) as a gummy green solid. LC-MS(ES + ): m / z 288.28[M+H] + . Step 3: To a stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine-1-carboxylate isomer 2 (0.15 g, 387.13 μmol) in DCM (10 mL) at 0 °C, 4 N HCl in 1,4-dioxane (13.55 mg, 376.37 μmol, 1.5 mL) was added. The resulting reaction mixture was stirred from 0 °C to room temperature for 3 h. DCM was removed under reduced pressure. Ether was added to the crude residue, and the resulting mixture was stirred for 5 min to isolate the desired product as the HCl salt. The solid was filtered and washed with ether (2 × 10 mL) to give 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione isomer 2 HCl salt (0.13 g, 385.40 μmol, 99.56% yield), which was used directly in the next step without further purification. LC-MS(ES + ): m / z 288.20 [M+H] + .

[0191] Synthesis of 3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione [ka] Step 1: A solution of 1-bromo-2-fluoro-4-nitro-benzene (6 g, 27.27 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (8.43 g, 27.27 mmol) in dioxane (60 mL) and water (15 mL) was purged with argon gas for 10 minutes in a round-bottom flask, followed by the addition of granular potassium carbonate (11.31 g, 81.82 mmol). After purging the solution with argon gas for an additional 20 minutes, palladium triphenylphosphane (1.58 g, 1.36 mmol) was added, and the reaction was stirred at 90 °C for 16 hours. The reaction progress was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was diluted with water and extracted with ethyl acetate (2 x 150 ml). The combined organic layers were concentrated in vacuo and purified by normal phase column chromatography (Davisil silica, 5% ethyl acetate in PET ether) to give tert-butyl 4-(2-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.95 g, 18.27 mmol, 67.01% yield) as a pale yellow solid. LC-MS (ES) + ): m / z 267.15 [M-tBu+H] + . Step 2: To a stirred solution of tert-butyl 4-(2-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (3 g, 9.31 mmol) in methanol (70 mL), 10% palladium on carbon, type 487, dry (3 g, 28.19 mmol) was added at room temperature. The reaction mixture was stirred at this temperature under a hydrogen atmosphere for 6 hours, and the progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the compound tert-butyl 4-(4-amino-2-fluoro-phenyl)piperidine-1-carboxylate (2.5 g, 5.95 mmol, 63.88% yield) as a purple solid, which was carried on to the next step without purification. LC-MS (ES)+ ): m / z 239.30 [M-tBu+H] + . Step 3: In a sealed tube, a solution of tert-butyl 4-(4-amino-2-fluoro-phenyl)piperidine-1-carboxylate (2.5 g, 8.49 mmol) and 3-bromopiperidine-2,6-dione (4.08 g, 21.23 mmol) in DMF (40 mL) was stirred for 10 min. After that, sodium bicarbonate (3.57 g, 42.46 mmol) was added, and the reaction was heated at 60 °C for 16 h. The reaction progress was monitored by LC-MS and TLC. After completion of the reaction, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by column chromatography (Devisil silica, 0–30% ethyl acetate in PET ether) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (1.8 g, 3.64 mmol, 42.86% yield) as a brown solid. LC-MS(ES - ): m / z 404.3[MH] - . Step 4: To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate (100 mg, 246.63 μmol) in DCM (1 mL) was added HCl / dioxane (2 mL). The mixture was stirred at 25° C. for 0.5 h. After completion of the reaction, as confirmed by LC-MS, the solvent was removed and the residue was dissolved in MeCN (30 mL), adjusted to pH=7 with NaHCO3, and filtered. The filtrate was concentrated in vacuo and used directly in the next step. Compound 3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione (75 mg, 233.34 μmol, 94.61% yield) was obtained as a white solid. LC-MS (ES + ): m / z 306.2 [M+H] + .

[0192] Synthesis of 3-[3-(4-piperidyl)anilino]piperidine-2,6-dione [ka] Step 1: To a solution of 1-bromo-3-nitrobenzene (5 g, 24.75 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (8.42 g, 27.23 mmol) in water (15 mL) and dioxane (50 mL), sodium carbonate (7.87 g, 74.26 mmol) and palladium acetate (555.70 mg, 2.48 mmol) were added. The mixture was stirred at 90 °C for 12 h. After LC-MS showed the consumption of the reactants, the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1). The compound tert-butyl 4-(3-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (6.5 g, 16.87 mmol, 68.17% yield) was obtained as a yellow solid. LC-MS (ES + ): m / z 249.1 [M-tBu+H] + . Step 2: To a solution of tert-butyl 4-(3-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (4 g, 13.14 mmol) in methanol (50 mL), 10 wt% Pd / C (400 mg) was added. The mixture was stirred at 25 °C for 5 hours under a H atmosphere (15 psi), and the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. Compound tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate (3.5 g, 12.66 mmol, 96.35% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 6.91 (t, J =7.7 Hz, 1H), 6.51 - 6.22 (m, 3H), 4.92 (s, 2H), 4.03 (br d, J =12.1 Hz, 2H), 2.90 -2.64 (m, 2H), 2.49 - 2.43 (m, 1H), 1.68 (br d, J =12.6 Hz, 2H), 1.40 (s, 10H). Step 3: To a solution of tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate (2.5 g, 9.05 mmol) and 3-bromopiperidine-2,6-dione (1.74 g, 9.05 mmol) in MeCN (3 mL) was added NaHCO (2.28 g, 27.14 mmol), and the mixture was stirred at 90 °C for 12 h. After 73% of the desired product was detected by LC-MS, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (2.5 g, 6.45 mmol, 71.33% yield) was obtained as a yellow solid. LC-MS (ES + ): m / z 332.0 [M-tBu+H] + . Step 4: To a solution of tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine-1-carboxylate (160 mg, 412.93 μmol) in DCM (2 mL) was added 4 M HCl in dioxane (4 M, 1.03 mL) at 0 °C, and the reaction was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed under reduced pressure. The residue was washed with MTBE (10 mL × 2) and then dried under reduced pressure to give crude 3-[3-(4-piperidyl)anilino]piperidine-2,6-dione HCl salt (120 mg, 351.24 μmol, 85.06% yield) as a pale yellow solid. LC-MS (ES) + ): m / z 288.4 [M+H] + .

[0193] Synthesis of 3-((6-(piperidin-4-yl)pyridin-3-yl)amino)piperidine-2,6-dione [ka] Step 1: To a stirred solution of tert-butyl 4-(5-nitro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (10 g, 32.75 mmol) in ethyl acetate (100 mL), 10 wt% palladium on carbon, type 487, dry (3.49 g, 32.75 mmol) was added, and the reaction was stirred under a hydrogen atmosphere for 16 hours. The reaction progress was monitored by TLC and LC-MS. Upon completion, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to dryness. The resulting crude product was purified by column chromatography (silica gel 60-120 mesh, 0-30% ethyl acetate in PET ether) to give tert-butyl 4-(5-amino-2-pyridyl)piperidine-1-carboxylate (7 g, 23.47 mmol, 71.66% yield). LC-MS (ES) - ): m / z 276.24[MH] - . Step 2: To a stirred solution of tert-butyl 4-(5-amino-2-pyridyl)piperidine-1-carboxylate (6.5 g, 23.44 mmol) and 3-bromopiperidine-2,6-dione (13.50 g, 70.31 mmol) in DMF (40 mL) was added sodium bicarbonate (19.69 g, 234.35 mmol) in a sealed tube. The reaction mixture was stirred at 85° C. for 16 hours. The progress of the reaction was monitored by TLC and LC-MS. Upon completion of the reaction, the reaction mixture was poured into ice water and the product was extracted with ethyl acetate. The organic layer was washed with chilled brine solution, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh, 0-100% ethyl acetate in PET ether) to give tert-butyl 4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-pyridyl]piperidine-1-carboxylate (2.84 g, 6.40 mmol, 27.32% yield) as a pale green solid. LC-MS (ES) - ): m / z 387.28[MH] - . Step 3: To a stirred solution of tert-butyl 4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-pyridyl]piperidine-1-carboxylate (1 g, 2.57 mmol) in DCM (10 mL) was added TFA (5.92 g, 51.92 mmol, 4 mL) at 0 °C. The reaction mixture was stirred for 3 h, and the reaction progress was monitored by TLC and LC-MS. Upon completion of the reaction, the reaction mixture was evaporated to give the crude product, which was triturated with diethyl ether and concentrated in vacuo to give 3-[[6-(4-piperidyl)-3-pyridyl]amino]piperidine-2,6-dione (700 mg, 2.03 mmol, 78.74% yield) as a green solid. LC-MS (ES) + ): m / z 289.46 [M+H] + .

[0194] Synthesis of 3-[4-(4-piperidyl)phenoxy]piperidine-2,6-dione [ka] Step 1: A solution of 4-(4-piperidyl)phenol HBr salt (2.00 g, 7.75 mmol) in DCM (20 mL) was added to a 100 mL round-bottom flask. tert-Butoxycarbonyl tert-butyl carbonate (2.03 g, 9.30 mmol, 2.13 mL) and triethylamine (3.92 g, 38.74 mmol, 5.40 mL) were added, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction (as confirmed by TLC), the reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (silica gel 230-400 mesh, 0-80% ethyl acetate in PET ether) to give tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (1.8 g, 6.45 mmol, 83.22% yield) as a white solid. LC-MS (ES) + ): m / z 178.2 [M-Boc+H] + . Step 2: Sodium hydride (93.78 mg, 3.61 mmol) was added slowly to a stirred solution of tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (1.0 g, 3.61 mmol) in THF (10 mL) at 0° C. After the addition, the reaction mixture was heated at 70° C. for 30 minutes. After it was cooled back to 0° C., 3-bromopiperidine-2,6-dione (553.83 mg, 2.88 mmol) was added very slowly, and then the reaction mixture was heated at 70° C. for 2 hours. The progress of the reaction was monitored by TLC. Upon completion, the reaction was quenched with ammonium chloride, extracted with ethyl acetate, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh, 0-50% ethyl acetate in PET ether) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperidine-1-carboxylate (0.5 g, 1.05 mmol, 29.17% yield). LC-MS (ES) + ): m / z 411.41 [M+Na] + . Step 3: To a solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperidine-1-carboxylate (0.55 g, 1.42 mmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (161.44 mg, 1.42 mmol, 109.08 μL) at 0° C., and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo to give the crude product, which was triturated with diethyl ether (20 mL) to give 3-[4-(4-piperidyl)phenoxy]piperidine-2,6-dione TFA salt (0.5 g, 1.13 mmol, 80.02% yield) as a white solid. LC-MS (ES) + ): m / z 289.28 [M+H] + .

[0195] Synthesis of 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione [ka] Step 1: A solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (10 g, 29.39 mmol) in 1,4-dioxane (100 mL) was added to a 500 mL round-bottom flask, and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (11.19 g, 44.08 mmol) was added, followed by potassium acetate (8.65 g, 88.17 mmol) at room temperature under an argon atmosphere. The reaction mixture was degassed with argon for 20 minutes, after which cyclopentyl(diphenyl)phosphane, dichloromethane, dichloropalladium, and iron (2.40 g, 2.94 mmol) were added, and the reaction was heated to 100 °C for 6 hours while monitoring by TLC and LC-MS. After completion of the reaction, the volatiles were removed under reduced pressure, and the residue was extracted with ethyl acetate (200 mL × 3) and water (200 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh, 0-30% EtOAc in PET ether) to give tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (10 g, 24.27 mmol, 82.58% yield) as a pale yellow solid. LC-MS (ES) + ): m / z 332.41 [M-56+H] + . Step 2: A solution of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (10 g, 25.82 mmol) in 1,4-dioxane (120 mL) and water (30 mL) was added to a 500 mL round-bottom flask, followed by 2,6-dibenzyloxy-3-bromo-pyridine (10.04 g, 27.11 mmol) and anhydrous tribasic potassium phosphate (16.44 g, 77.46 mmol) at room temperature under an argon atmosphere. The reaction mixture was degassed with argon for 20 minutes, after which cyclopentyl(diphenyl)phosphane, dichloropalladium, and iron (1.89 g, 2.58 mmol) were added, and the reaction was heated to 110 °C for 16 hours while monitoring by TLC and LC-MS. Upon completion of the reaction, the catalyst was filtered off through a celite bed and washed with ethyl acetate (100 mL x 3). The filtrate was washed with water (100 mL) and brine solution (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 230-400 mesh, 0-40% ethyl acetate in PET ether) to give the desired product as a thick yellow liquid, which was triturated with PET ether to give pure tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]piperidine-1-carboxylate (7 g, 11.57 mmol, 44.80% yield) as a white solid. LC-MS (ES) + ): m / z 551.43 [M+H] + . Step 3: A solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]piperidine-1-carboxylate (14 g, 25.42 mmol) in ethyl acetate (420 mL) was added to 10 wt% palladium on carbon (14 g, 25.42 mmol), and the reaction was stirred under hydrogen pressure (70 psi) at room temperature for 16 hours. The reaction progress was monitored by TLC and LC-MS. After the reaction was complete, the catalyst was filtered off through Celite and washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure, and the residue was triturated with pentane (100 mL) and diethyl ether (100 mL), dried, and concentrated under reduced pressure to give tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-1-carboxylate (8.6 g, 23.05 mmol, 90.65% yield) as a white solid. LC-MS(ES - ): m / z 371.23[MH] - . Step 4: To a stirred solution of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-1-carboxylate (250 mg, 671.22 μmol) in DCM (5 mL) was added TFA (5.92 g, 51.92 mmol, 4 mL) at 0° C. The reaction was stirred for 2 hours and the reaction progress was monitored by LC-MS and TLC. Upon completion, the reaction mixture was concentrated in vacuo to give the crude product, which was triturated with diethyl ether to give the desired product, 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione TFA salt (250 mg, 404.22 μmol, 60.22% yield) as a brown liquid. LC-MS (ES) - ): m / z 371.23[MH] - .

[0196] Synthesis of 3-(3-fluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione [ka] These procedures were essentially identical to those for 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione, except that the synthesis began with tert-butyl 4-(4-bromo-2-fluoro-phenyl)piperidine-1-carboxylate instead of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate for step 3, and palladium hydroxide was used instead of palladium. LC-MS (ES) + ): m / z 291.37 [M+H] + .

[0197] Synthesis of 3-fluoro-3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione [ka] Step 1: To a stirred solution of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperidine-1-carboxylate (8.4 g, 22.55 mmol) in DMF (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.87 g, 45.11 mmol, 6.73 mL) and 2-(trimethylsilyl)ethoxymethyl chloride (5.64 g, 33.83 mmol, 5.99 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, it was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh, 0-50% EtOAc in PET ether) to give tert-butyl 4-(4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenyl)piperidine-1-carboxylate (6.2 g, 11.59 mmol, 51.40% yield) as a yellow gummy liquid. LC-MS (ES) - ): m / z 501.36[MH] - . Step 2: To a stirred solution of tert-butyl 4-(4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenyl)piperidine-1-carboxylate (6.0 g, 11.94 mmol) in THF (120 mL) was added bis(trimethylsilyl)amide (3.99 g, 23.87 mmol) and N-fluorobenzenesulfonimide (3.76 g, 11.94 mmol) at 0° C. The reaction mixture was stirred at −78° C. for 20 minutes. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the mixture was cooled to room temperature, quenched with NH4Cl solution (200 mL), and extracted with ethyl acetate (500 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give tert-butyl 4-(4-(3-fluoro-2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenyl)piperidine-1-carboxylate (1.34 g, 1.78 mmol, 14.88% yield) as a yellow gummy liquid. LC-MS (ES - ): m / z 519.29[MH] - . Step 3: To a solution of tert-butyl 4-[4-[3-fluoro-2,6-dioxo-1-(2-trimethylsilylethoxymethyl)-3-piperidyl]phenyl]piperidine-1-carboxylate (0.580 g, 1.11 mmol) in DCM (6 mL) was added TFA (1.27 g, 11.14 mmol, 858.13 μL) at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was triturated with diethyl ether (50 mL) to give 3-fluoro-3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione TFA salt (0.580 g, 1.00 mmol, 90.14% yield) as an off-white semi-solid. LC-MS (ES) + ): m / z 291.22 [M+H] + .

[0198] Synthesis of 1-(1-methyl-6-piperazin-1-yl-indazol-3-yl)hexahydropyrimidine-2,4-dione [ka] Step 1: To a stirred solution of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (0.5 g, 1.55 mmol) in toluene (10 mL) in a 100 mL round-bottom flask, tert-butyl piperazine-1-carboxylate (288.18 mg, 1.55 mmol) and sodium tert-butoxide (297.40 mg, 3.09 mmol) were added at room temperature. The reaction mixture was degassed with argon for 10 minutes, then Pd(t-BuP) (79.07 mg, 154.73 μmol) was added and then degassed again for 5 minutes. The reaction was stirred at 110 °C for 16 hours while monitoring the progress of the reaction by LC-MS. The reaction mixture was evaporated to a residue, which was poured into water (20 mL), and the resulting solution was extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and evaporated to give the crude product, which was triturated with diethyl ether (30 mL) to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperazine-1-carboxylate (0.310 g, 614.96 μmol, 39.74% yield) as a pale yellow solid. LC-MS (ES) + ): m / z 429.50 [M+H] + . Step 2: To a stirred solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperidine-1-carboxylate (0.3 g, 700.14 mmol) in DCM (10 mL) was added TFA (1.48 g, 12.98 mmol, 1 mL) at 0 °C, and stirring was continued at room temperature for 6 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the solvent was evaporated under vacuum to give the crude product. The crude was triturated with diethyl ether (20 mL), and the solid was filtered and dried to give 1-(1-methyl-6-piperazin-1-yl-indazol-3-yl)hexahydropyrimidine-2,4-dione (0.280 g, 591.28 μmol, 84.45% yield) as a pale yellow solid. LC-MS (ES + ): m / z 329.30 [M+H] + .

[0199] Synthesis of 1-(5-fluoro-1-methyl-6-piperazin-1-yl-indazol-3-yl)hexahydropyrimidine-2,4-dione [ka] Step 1: To a solution of 4-bromo-2,5-difluoro-benzonitrile (10 g, 45.87 mmol) in EtOH (30 mL) was added methylhydrazine sulfate (19.84 g, 137.62 mmol) and EtN (18.57 g, 183.49 mmol, 25.61 mL). The mixture was stirred at 80 °C for 12 hours. LC-MS showed that the starting material was completely consumed, and one major peak with the desired mass was detected. The mixture was cooled to 30 °C, and water (300 mL) was added. The mixture was filtered, and the filter cake was washed with water (5 mL × 2), then concentrated under vacuum at 40 °C to give 6-bromo-5-fluoro-1-methyl-indazol-3-amine (6.5 g, 25.30 mmol, 55.16% yield) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ = 7.46 (d, J = 8.4 Hz, 1H), 7.06 - 7.04 (m, 1H), 5.68 (s, 2H), 3.83 (d, J = 0.8 Hz, 3H).LC-MS (ES + ): m / z 245 [M+H] + . Step 2: To a solution of 6-bromo-5-fluoro-1-methyl-indazol-3-amine (22 g, 90.14 mmol) and acrylic acid (9.74 g, 135.21 mmol, 9.28 mL) in 2 M aqueous HCl (220 mL) was added tetrabutylammonium bromide (2.91 g, 9.01 mmol). The mixture was stirred at 100 °C for 12 h. LC-MS showed complete consumption, with one major peak having the desired mass detected. The entire reaction mixture was basified with a saturated solution of NaHCO3 until pH = 8. The solution was acidified with acetic acid until pH = 5. A white solid precipitated, which was filtered, washed with water (250 mL), and then dried under reduced pressure to give 3-[(6-bromo-5-fluoro-1-methyl-indazol-3-yl)amino]propanoic acid (28 g, 88.57 mmol, 98.26% yield) as a white solid. LC-MS (ES + ): m / z 318.2 [M+H] + . Step 3: To a solution of 3-[(6-bromo-5-fluoro-1-methyl-indazol-3-yl)amino]propanoic acid (26 g, 82.25 mmol) in AcOH (260 mL) was added NaOCN (11.36 g, 164.49 mmol). The mixture was stirred at 60° C. for 16 hours. HCl (260 mL) was added to the mixture. The mixture was stirred at 60° C. for an additional 3 hours. LC-MS showed complete consumption of the starting material, with one major peak having the desired mass. The reaction mixture was cooled to room temperature, stirred for 1 hour, filtered, and washed with water (250 mL). The cake was dried under vacuum to give 1-(6-bromo-5-fluoro-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (18 g, 47.63 mmol, 57.91% yield) as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ = 10.59 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 4.00 (s, 3H), 3.93 - 3.90 (m, 2H), 2.77 - 2.73 (m, 2H). Step 4: To a solution of 1-(6-bromo-5-fluoro-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (5 g, 14.66 mmol) and tert-butyl piperazine-1-carboxylate (8.19 g, 43.97 mmol) in dioxane (50 mL) was added Pd-PEPPSI-IHeptCl (427.40 mg, 439.71 μmol) and CsCO (14.33 g, 43.97 mmol) under N atmosphere at 25 °C. The reaction mixture was stirred at 100 °C under N for 16 h. LC-MS indicated complete consumption and the desired mass was detected. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to give a residue that was triturated with EtOAc:MTBE (1:5). The suspension was filtered and dried to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]piperazine-1-carboxylate (3.4 g, 6.85 mmol, 46.76% yield) as a grey solid. 1 H-NMR (400 MHz, DMSO-d6) δ = 10.53 (s, 1H), 7.38 (d, J = 12.8 Hz, 1H), 7.16 (d, J = 6.8 Hz, 1H), 3.94 (s, 3H), 3.89-3.87(m, 2H), 3.52 (br s, 4H), 3.06 - 2.98 (m, 4H), 2.75 - 2.73 (m, 2H), 1.43 (s, 9H). Step 5: A solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]piperazine-1-carboxylate (2.4 g, 5.38 mmol) in 4 M HCl / dioxane (30 mL) was stirred at 25 °C for 2 hours. TLC showed that the reactant was consumed and a new spot had formed. The reaction mixture was concentrated to a residue, which was triturated with MTBE (200 mL), filtered, and the filter cake was dried under vacuum to give 1-(5-fluoro-1-methyl-6-piperazin-1-yl-indazol-3-yl)hexahydropyrimidine-2,4-dione (2 g, 4.70 mmol, 87.47% yield) as a gray solid. 1 H-NMR (400 MHz, DMSO-d6) δ = 10.54 (s, 1H), 9.22 (br s, 2H), 7.41 (d, J = 12.4 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 3.97 (s, 3H), 3.91 - 3.88 (m, 2H), 3.31 (br s, 8H), 2.76 - 2.72 (m, 2H).

[0200] Synthesis of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione [ka] Step 1: To sodium hydride (60% dispersion in mineral oil) (53.51 g, 2.33 mol) was added THF (2300 mL) and the suspension was cooled to 5-10 °C. A solution of 2,6-dibenzyloxypyridin-3-amine (230 g, 750.76 mmol) in THF (1400 mL) was added over 20 min at 5-10 °C, resulting in an exotherm. This temperature was maintained for 30 min. To this solution was added 4-bromo-1-fluoro-2-nitrobenzene, 98% (247.75 g, 1.13 mol, 138.41 mL) in THF (1600 mL) over 20 min at 5-10 °C. The solution was allowed to warm to room temperature and maintained at this temperature for 16 h. Product formation was confirmed by TLC (20% EtOAc / pet ether). The reaction mass was quenched with 10% water in THF (5V) below 10°C, and an exotherm was observed. Saturated NaCl solution (10V) was added below 15°C and allowed to warm to room temperature. The layers were separated and the organic layer was concentrated under vacuum. The aqueous layer was removed, extracted with DCM (15V) and set aside. The organic layer was combined with the crude product, washed with water (5V) and completely concentrated under vacuum at 45°C. The crude product was poured into DCM (2.5V) at 45°C and held for 15 minutes until dissolved, then PET ether (10V) was added at 45°C and held at 45°C for 1 hour. Cooled to room temperature and held for 30 minutes. Filtration and washing with PET ether (2 x 3V) gave 2,6-dibenzyloxy-N-(4-bromo-2-nitrophenyl)pyridin-3-amine (400g, 686mmol, 91% yield). LC-MS (ES + ): m / z 506.32 [M+H] + . Step 2: A solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitrophenyl)pyridin-3-amine (50 g, 98.75 mmol) in ACN (450 mL) and water (50 mL) was cooled to 0-5 °C, and sodium borohydride (7.47 g, 197.49 mmol, 6.98 mL) was added portionwise over 60 h, while maintaining room temperature for 4 h. TLC was used to monitor the progress of the reaction. Sodium borohydride (7.47 g, 197.49 mmol, 6.98 mL) was added at 0-5 °C, and this temperature was maintained for 2 h. The reaction was then quenched with 10% NH4Cl solution (5 V), and water (5 V) followed by DCM (10 V) was added, followed by stirring at room temperature for 15 min. The aqueous layer was extracted with DCM (10V) and the combined organic layers were washed with water (10V) and completely concentrated under vacuum at 40°C. The residue was stripped using Pet ether (3V) and the crude residue was taken up in 10% EtOAc in Pet ether (5V) and heated to 45°C. The temperature was maintained at 45°C for 30 minutes, cooled to room temperature and maintained for 30 minutes. The pure product was filtered and washed with Pet ether (3V). LC-MS (ES + ): m / z 476.33 [M+H] + . Step 3: To a stirred solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (200 g, 419.85 mmol) in DMF (800 mL) was added di(imidazol-1-yl)methanone (177.00 g, 1.09 mol) at 25-35 °C. An exotherm was observed. CDI was added in a single lot. An initial temperature of 25 °C was monitored, and a final temperature of 35 °C was observed over 15 min. The reaction was stirred at room temperature for 14 h. TLC indicated consumption of the starting material. The reaction was poured into water (420 mL) at room temperature. A precipitate formed (Note: slow addition required a minimum of 1 h on a bulk scale), and the mixture was stirred for 3 h. The solid was filtered and washed with water and PET ether (2 × 35 mL). The product was dried under vacuum at 50° C. for 7 hours to give 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (200 g, 391.43 mmol, 93.23% yield). LC-MS (ES + ): m / z 502.1 [M+H] + . Step 4: To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (108 g, 214.99 mmol) in DMF (1000 mL) was added sodium hydride (60% dispersion in mineral oil) (14.83 g, 644.96 mmol) in small portions at 0–28°C. The reaction mixture was stirred for 1 h, and then methyl iodide (stored over copper) (31.16 g, 214.99 mmol, 13.37 mL) was added dropwise over 30 min. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was diluted with ice-cold water to give a solid, which was filtered and dried in vacuo. The solid was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude compound was washed with pentane to give the product 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (95 g, 183.81 mmol, 85.50% yield) as a light brown solid. LC-MS (ES + ): m / z 516.14 [M+H]+ . Step 5: To a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (20 g, 38.73 mmol) in 1,4-dioxane (160 mL) and water (40 mL) was added sodium carbonate (12.32 g, 116.19 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (15.57 g, 50.35 mmol). The reaction was purged with nitrogen for 20 minutes, then charged with palladium(0) tetrakis(triphenylphosphine) (2.24 g, 1.94 mmol) and heated to 90-100 °C for 5 hours. TLC confirmed product formation. The reaction was cooled to room temperature, filtered through a celite bed, and washed with EtOAc. The filtrate was taken and completely distilled under vacuum at 45 °C. The crude product was dissolved in EtOAc (15 V) and partitioned with water (10 V). The organic layer was washed with water (5 V), brine (5 V), and then dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo at 45 °C and then purified by column chromatography (100-200 mesh silica gel, 0-30% ethyl acetate in PET ether) to give tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (21 g, 33.06 mmol, 99% yield). LC-MS (ES) + ): m / z 619.41 [M+H] + . Step 6: To a solution of tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (40 g, 64.65 mmol) in methanol (1600 mL) was added 10% palladium on carbon, type 487, dry (12.00 g, 112.76 mmol) and nickel (12.00 g, 204.45 mmol). Hydrogen gas (10 kg) was applied, and the reaction was maintained at 60-65 °C for 16 h. The reaction mass was cooled to room temperature, then filtered and washed with DCM and MeOH. The filtrate was taken and completely distilled under vacuum at 45 °C. To this crude residue was added IPA (3 V) and heated to 60 °C for 15 min. Pet ether (3V) was added, and the mixture was cooled to room temperature and stirred at this temperature for 1 hour. The solid was filtered and washed with pet ether to give tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (21 g, 44 mmol, 69% yield). LC-MS (ES) - ): m / z 441.18[MH] - . Step 7: To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (7.5 g, 16.95 mmol) in DCM (75 mL) was slowly added trifluoroacetic acid (55.87 g, 490.03 mmol, 37.75 mL) at 0-5 °C, and the temperature was maintained for 15 min. The reaction was allowed to warm to room temperature and maintained for 3 h. LC-MS followed the formation of the product. DCM and TFA were removed under vacuum at 40 °C, and the crude material was stripped with toluene (2 × 5 V). Upon addition of diethyl ether, solid formation was observed. The reaction was decanted after addition of diethyl ether (3 × 5 V) and then dried at 45 °C. The crude material was dissolved in MeOH (10V), stirred for 10 min, filtered through a sintered funnel, and washed with MeOH; a few undissolved particles were observed. The distilled filtrate was completely evaporated under vacuum at 45 °C to give 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione (7.72 g, 16.5 mmol, 97% yield). LC-MS (ES) - ): m / z 343.35[MH] - .

[0201] Synthesis of 3-[3-methyl-2-oxo-4-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione [ka] Step 1: 2,6-Dibenzyloxypyridin-3-amine (50 g, 163.21 mmol) was dissolved in THF (500 mL) and cooled to -78 °C. Lithium bis(trimethylsilyl)amide (40.96 g, 244.81 mmol) was added dropwise, followed by stirring at -78 °C for 1 hour. 1-Fluoro-3-iodo-2-nitro-benzene (43.58 g, 163.21 mmol) was added dropwise as a solution in THF (500 mL) at -78 °C, followed by stirring at -78 °C for 1 hour. After the reaction was complete, as determined by TLC, it was quenched with 10% ammonium chloride solution (150 mL). The solvent was evaporated to give a black gummy solid. Pet ether was added and stirred vigorously for 15 minutes until a brown solid formed. The solid was filtered through a Buchner funnel and washed with pet ether (2 × 300 mL). The filter cake was dried under vacuum to give 2,6-dibenzyloxy-N-(3-iodo-2-nitro-phenyl)pyridin-3-amine (80 g, 144.57 mmol, 83% yield). LC-MS (ES + ): m / z 554.20 [M+H] + . Step 2: To a solution of 2,6-dibenzyloxy-N-(3-iodo-2-nitrophenyl)pyridin-3-amine (80 g, 144.57 mmol) in acetonitrile (720 mL) and water (80 mL) was added nickel(II) chloride hexahydrate, 98% (8.22 g, 28.91 mmol). The reaction was cooled to 0° C., and sodium borohydride (13.67 g, 361.44 mmol) was added in portions over 1 hour. The reaction mixture was stirred at room temperature for 30 minutes. Upon completion of the reaction as determined by TLC, the reaction mixture was filtered through Celite and washed with ethyl acetate. The organic layer was separated, washed with brine solution, and dried over anhydrous Na2SO4. The organic layer was evaporated to give a black gummy solid. To this crude residue was added PET ether and stirred until a brown solid was obtained. The solid was filtered through a Buchner funnel, washed with pet ether, and dried under vacuum to give N1-(2,6-dibenzyloxy-3-pyridyl)-3-iodo-benzene-1,2-diamine (36 g, 66 mmol, 45% yield). LC-MS (ES)+ ): m / z 524.23 [M+H] + . Step 3: A solution of N1-(2,6-dibenzyloxy-3-pyridyl)-3-iodo-benzene-1,2-diamine (5.58 g, 10.66 mmol) in DCM (120 mL) was cooled to 0 °C. Pyridine (8.43 g, 106.62 mmol, 8.62 mL) was added dropwise, and the solution was stirred at 0 °C for 30 minutes. Triphosgene (4.75 g, 15.99 mmol) was added dropwise as a solution at 0 °C. The reaction mixture was stirred at room temperature for 1 hour while being monitored by TLC. Upon completion, the reaction was quenched with saturated NaHCO3 solution added slowly at 0 °C, and effervescence was observed. The reaction mass was extracted with DCM, then washed with brine solution and dried over anhydrous Na2SO4. The organic layer was evaporated to give a light brown solid. Diethyl ether was added to the crude solid, and after thorough stirring, it was filtered through a Buchner funnel. The product was washed with diethyl ether and dried under vacuum to give 3-(2,6-dibenzyloxy-3-pyridyl)-7-iodo-1H-benzimidazol-2-one (5.1 g, 8.9 mmol, 83% yield). LC-MS (ES + ): m / z 550.55 [M+H] + . Step 4: A solution of 3-(2,6-dibenzyloxy-3-pyridyl)-7-iodo-1H-benzimidazol-2-one (47.82 g, 87.06 mmol) in DMF (410 mL) was added and cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil) (5.60 g, 243.75 mmol) was added portionwise, and the reaction mixture was then stirred at room temperature for 30 minutes. Iodomethane (18.53 g, 130.58 mmol, 8.13 mL) was added dropwise at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. Upon completion of the reaction as determined by TLC, the reaction mixture was slowly decanted into ice-cold water. An off-white solid precipitated, which was filtered through a Buchner funnel, washed with ice-cold water, and dried under vacuum. The solid was azeotroped with toluene (2 × 200 mL) to give a light brown solid. Pet ether was added and stirred well for 10 minutes. After that, the solid was filtered through a Buchner funnel and washed with pet ether (3 x 100 mL). The product was dried under vacuum to give 1-(2,6-dibenzyloxy-3-pyridyl)-4-iodo-3-methyl-benzimidazol-2-one as a light brown solid (47 g, 83 mmol, 95% yield). LC-MS (ES) + ): m / z 564.03 [M+H] + . Step 5: To a stirred solution of 1-(2,6-dibenzyloxy-3-pyridyl)-4-iodo-3-methyl-benzimidazol-2-one (25 g, 44.37 mmol) in dioxane (210 mL) and water (90 mL) was added potassium carbonate (18.40 g, 133.12 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (20.58 g, 66.56 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, and then palladium triphenylphosphine (5.13 g, 4.44 mmol) was added. The reaction was stirred at 100° C. for 4 hours and monitored by TLC and LC-MS. The reaction mass was filtered, concentrated under vacuum, and then purified by column chromatography (100-200 mesh silica gel, 10-20% EtOAc in PET ether) to give tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (20 g, 31.63 mmol, 71.27% yield) as a yellow solid. LC-MS (ES) + ): m / z 619.19 [M+H] + . Step 6: To a stirred solution of tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (21.00 g, 33.94 mmol) in 1,4-dioxane (600 mL), dihydroxypalladium (5.72 g, 40.73 mmol) was added. The reaction mixture was stirred at 60-65 °C under 150 psi of hydrogen gas for 12 h. TLC and LC-MS confirmed the reaction was complete (10% methanol in DCM, R fValue: 0.4). Upon completion, the reaction was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product, which was triturated with diethyl ether to give tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (10 g, 19.98 mmol, 58.86% yield). LC-MS (ES + ): m / z 441.54 [M+H] + . Step 7: A solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylate (10 g, 22.60 mmol) in DCM (150 mL) was cooled to 0° C. Trifluoroacetic acid (25.77 g, 225.99 mmol, 17.41 mL) was added and the reaction mixture was stirred at room temperature for 12 hours. TLC confirmed the reaction was complete (10% methanol in DCM, R f Value: 0.2). Upon completion, the reaction solvent was evaporated and diethyl ether (2 x 100 mL) was added to the crude mixture. The diethyl ether was removed and the product was dried under vacuum to give 3-[3-methyl-2-oxo-4-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione TFA salt (10.71 g, 22.39 mmol, 99.06% yield) as an off-white solid. LC-MS (ES + ): m / z 343.33 [M+H] + .

[0202] Synthesis of 3-[3-methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione [ka] Step 1: A solution of 2,6-dibenzyloxypyridin-3-amine (2 g, 6.53 mmol) in THF (50 mL) was cooled to −78° C. To this was added lithium bis(trimethylsilyl)azanide (1.09 g, 6.53 mmol, 6.5 mL) dropwise over 15 minutes at −78° C. The reaction was maintained at −78° C. for 1 hour, followed by the dropwise addition of 1-bromo-3-fluoro-2-nitro-benzene (1.44 g, 6.53 mmol). The reaction mixture was stirred for an additional 2 hours. Completion of the reaction was confirmed by TLC (20% EtOAc / Pet ether) and LC-MS. The reaction mixture was diluted with 10% ammonium chloride solution and concentrated under reduced pressure. The crude material was purified by column chromatography (pet ether and ethyl acetate) to give 2,6-dibenzyloxy-N-(3-bromo-2-nitro-phenyl)pyridin-3-amine (2.5 g, 4.08 mmol, 62.42% yield) as a yellow solid. LC-MS (ES + ): m / z 506.32 [M+H] + . Step 2: To a stirred solution of 2,6-dibenzyloxy-N-(3-bromo-2-nitro-phenyl)pyridin-3-amine (20 g, 39.50 mmol) in THF (65 mL) and methanol (65 mL) was added zinc (25.83 g, 394.99 mmol, 3.62 mL), followed by a suspension of ammonia hydrochloride (31.69 g, 592.48 mmol) in water (65 mL). The reaction mixture was stirred at room temperature for 2 hours, and the progress of the reaction was monitored by TLC. Upon completion of the reaction, the contents were passed through a Celite bed. The filtrate was concentrated in vacuo and extracted with EtOAc (250 mL). The organic layer was separated, dried over anhydrous Na2SO4, and then evaporated in vacuo. The crude material was purified by column chromatography using Davisil silica (elution solvent 0-70% EtOAc in hexanes) to give 3-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (15 g, 27.56 mmol, 69.78% yield) as a brown solid. LC-MS (ES) + ): m / z 398.46 [M-Br+H] + . Step 3: To a solution of 3-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (210 g, 440.84 mmol) in DMF (1.17 L) was added di(imidazol-1-yl)methanone (200.15 g, 1.23 mol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. TLC confirmed the consumption of the starting material (40% ethyl acetate in pet ether, R f Value: 0.4). Upon completion of the reaction, the mixture was poured into ice-cold water. An off-white solid precipitated and was filtered through a Buchner funnel. The wet solid was washed with water and dried under vacuum to give 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (220 g, 378.33 mmol, 85.82% yield). LC-MS (ES) - ): m / z 500.41[MH] - . Step 4: To a stirred solution of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (220 g, 437.93 mmol) in DMF (2200 mL) was added sodium hydride (28.19 g, 1.23 mol), a 60% dispersion in mineral oil, at 0°C. The reaction mixture was warmed to room temperature and maintained for 1 hour. The reaction mass was cooled again to 0°C and iodomethane (93.24 g, 656.90 mmol, 40.89 mL) was added dropwise at 0-5°C. The reaction mass was warmed to room temperature and maintained for 1 hour. The progress of the reaction was followed and confirmed by TLC (20% ethyl acetate:pet ether). R f Value: 0.3). Upon completion, the reaction was quenched in ice-cold water to precipitate an off-white solid, which was isolated by vacuum filtration and Buchner funnel, washing with water (1000 mL). The resulting wet solid was dried under vacuum to give 4-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one as an off-white solid (221 g, 420.66 mmol, 96.05% yield). LC-MS (ES + ): m / z 516.09 [M+H]+ . Step 5: In a sealed tube, a solution of 4-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (0.5 g, 968.27 μmol), tert-butyl N-methyl-N-(4-piperidyl)carbamate (207.50 mg, 968.27 μmol) in toluene (10 mL) was added to sodium 2-methylpropane-2-olate (279.16 mg, 2.90 mmol). The reaction was degassed with argon for 15 minutes, and then tBuXPhos Pd G3 (76.88 mg, 96.83 μmol) was added to the reaction mixture, which was degassed for an additional 5 minutes. The reaction mixture was then heated at 90° C. for 5 hours. The progress of the reaction was monitored by LC-MS. The reaction mixture was filtered through a celite bed, and the filtrate was concentrated to give the crude compound, which was purified by column chromatography (100-200 mesh silica gel, 0-70% ethyl acetate in PET ether) to give tert-butyl N-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methyl-carbamate (0.25 g, 307.80 μmol, 31.79% yield) as a yellow liquid. LC-MS (ES) analysis revealed that the elution was 0.25 g (307.80 μmol, 31.79% yield). + ): m / z 672.41 [M+Na] + . Step 6: tert-Butyl N-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methylcarbamate (0.415 g, 638.68 μmol) was solvated in ethanol (3 mL) and methanol (3 mL) and purged with nitrogen for 10 minutes. To this solution was added 10% palladium on carbon, type 487, dried (67.97 mg, 638.68 μmol), and the reaction mixture was stirred under a hydrogen atmosphere (rubber bladder) at room temperature for 5 hours. The progress of the reaction was monitored by TLC (10% methanol in DCM, Rf value: 0.3). After completion, the reaction mixture was filtered through a celite bed, washed with methanol (50 mL x 2), and the organic layer was concentrated to give the product tert-butyl N-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methyl-carbamate (0.3 g, 610.75 μmol, 95.63% yield) as a brown solid. LC-MS (ES) + ): m / z 672.41 [M+H] + . Step 7: To a stirred solution of tert-butyl N-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methyl-carbamate (0.3 g, 636.20 μmol) in DCM (50 mL) was added TFA (72.54 mg, 636.20 μmol, 49.01 μL) over 10 min. The reaction mixture was stirred at 25° C. for 4 h and the reaction was monitored by TLC (10% methanol in DCM, R f Value: 0.2). After completion of the reaction, the mixture was concentrated and co-distilled with toluene (10 ml) and diethyl ether (2 x 50 ml) to give the product 3-[3-methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione TFA salt (0.23 g, 447.87 μmol, 70.40% yield) as a brown solid. LC-MS (ES + ): m / z 372.28 [M+H] + .

[0203] Synthesis of 3-[3-methyl-5-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione [ka] Step 1: In a sealed tube, a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (1 g, 1.94 mmol) and tert-butyl N-methyl-N-(4-piperidyl)carbamate (622.52 mg, 2.90 mmol) in toluene (60 mL) was added to sodium 2-methylpropane-2-olate (558.30 mg, 5.81 mmol). The reaction was degassed with argon for 15 minutes, and then tBuXPhos Pd G3 (153.76 mg, 193.65 μmol) was added to the reaction mixture, which was degassed for an additional 5 minutes. The reaction mixture was then heated at 90° C. for 16 hours, and the reaction progress was monitored by LC-MS. The reaction mixture was filtered through a celite bed, and the filtrate was concentrated in vacuo and then purified by column chromatography (100-200 mesh silica gel, 0-70% ethyl acetate in PET ether) to give tert-butyl N-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]-N-methyl-carbamate (0.7 g, 1.02 mmol, 52.85% yield) as a yellow liquid. LC-MS (ES) + ): m / z 650.97 [M+H] + . Step 2: A stirred solution of tert-butyl N-[1-[1-(2,6-dibenzyloxy-3-pyridyl))-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]-N-methyl-carbamate (0.6 g, 923.39 μmol) in a mixture of ethanol (50 mL) and ethyl acetate (50 mL) was purged with hydrogen gas, followed by the addition of 10% palladium on carbon, type 487, dry (523.21 mg, 4.92 mmol) and concentrated HCl (254.14 mg, 7.06 mmol, 2 mL). The reaction mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 5 hours. The progress of the reaction was monitored by LC-MS. After complete consumption of the starting material, the reaction mixture was filtered through a Celite bed and washed with methanol (50 mL × 2). The filtrate was concentrated to give tert-butyl N-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]-N-methyl-carbamate (0.25 g, 334.01 μmol, 36.17% yield) as a yellow solid. LC-MS (ES + ): m / z 472.93 [M+H] + . Step 3: To a stirred solution of tert-butyl N-[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]-N-methyl-carbamate (0.32 g, 678.62 μmol) was added TFA (77.38 mg, 678.62 μmol, 52.28 μL) over 10 minutes at 0° C. The reaction mixture was stirred at 25° C. for 4 hours and the reaction was monitored by TLC (10% methanol in DCM, R f Value: 0.2). After completion, the reaction mixture was concentrated and co-distilled with toluene (10 ml) and diethyl ether (2 x 50 ml) to give the product 3-[3-methyl-5-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione TFA salt (0.25 g, 475.69 μmol, 70.10% yield) as an off-white solid. LC-MS (ES + ): m / z 372.28 [M+H] +.

[0204] Synthesis of 3-[3-[4-[4-(methylamino)-1-piperidyl]anilino]piperidine-2,6-dione [ka] Step 1: To a stirred solution of 1-fluoro-4-nitro-benzene (2 g, 14.17 mmol, 1.50 mL) in DMF (10 mL) was added tert-butyl N-methyl-N-(4-piperidyl)carbamate (3.04 g, 14.17 mmol) and granular potassium carbonate (3.92 g, 28.35 mmol), and the reaction was heated to 80° C. for 4 h. TLC (R f The reaction was checked for completion by HPLC (0.4 in 10% ethyl acetate in pet ether) and LC-MS. After completion, the reaction was concentrated in vacuo to give the crude product, which was purified by flash column chromatography (silica gel) to give tert-butyl N-methyl-N-[1-(4-nitrophenyl)-4-piperidyl]carbamate (2 g, 5.84 mmol, 41.23% yield). LC-MS (ES + ): m / z 336.28 [M+H] + . Step 2: To a stirred solution of tert-butyl N-methyl-N-[1-(4-nitrophenyl)-4-piperidyl]carbamate (2 g, 5.96 mmol) in ethanol (20 mL) was added 10% palladium on carbon, Form 487, dry (634.59 mg, 5.96 mmol), and the reaction was stirred under an atmosphere of H for 4 h. TLC (R f The reaction was checked for completion by HPLC (0.4% in 50% ethyl acetate in pet ether) and LC-MS. The reaction was filtered through a bed of celite and washed with methanol. The solvent was evaporated under vacuum and the residue was washed with pentane to give tert-butyl N-[1-(4-aminophenyl)-4-piperidyl]-N-methyl-carbamate (1.5 g, 4.67 mmol, 78.24% yield). LC-MS (ES + ): m / z 303.31 [M+H]+ . Step 3: tert-Butyl N-[1-(4-aminophenyl)-4-piperidyl]-N-methyl-carbamate (1 g, 3.27 mmol) was dissolved in DMF (10 mL) and 3-bromopiperidine-2,6-dione (1.26 g, 6.55 mmol) and sodium bicarbonate (1.10 g, 13.10 mmol) were added. The reaction was heated to 100° C. for 16 hours. The progress of the reaction was monitored by TLC (R f Monitoring by HPLC (0.4% in 50% ethyl acetate in PET ether) indicated consumption of the starting material. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous NaSO and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel, ethyl acetate and PET ether) to give tert-butyl N-[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]-N-methyl-carbamate (0.6 g, 1.35 mmol, 41.36% yield) as a pale yellow solid. LC-MS (ES) + ): m / z 417.56 [M+H] + . Step 4: To a stirred solution of tert-butyl N-[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]-N-methyl-carbamate (0.5 g, 1.20 mmol) in DCM (5 mL) was added 4 M HCl in dioxane (43.77 mg, 1.20 mmol) slowly at 0 °C, and the reaction was stirred at 0-25 °C for 2 h. TLC (R f The reaction was checked for completion by HPLC (0.4 in 50% ethyl acetate in PET ether) and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with pentane and diethyl ether to give 3-[4-[4-(methylamino)-1-piperidyl]anilino]piperidine-2,6-dione HCl salt (0.35 g, 823.28 μmol, 68.58% yield). LC-MS (ES + ): m / z 317.37 [M+H] + .

[0205] Synthesis of 3-[3-[[4-(methylamino)-1-piperidyl]methyl]anilino]piperidine-2,6-dione [ka] Step 1: To a stirred solution of 3-bromobenzaldehyde (5 g, 27.15 mmol) in a mixture of MeCN:MeOH (1:1 ratio, 20 mL) was added tert-butylmethyl(piperidin-4-yl)carbamate (6.95 g, 32.58 mmol), followed by sodium acetate (6.68 g, 81.45 mmol) and catalytic acetic acid (0.1 mL). The reaction was stirred at 100° C. for 3 hours. After 3 hours, the reaction mixture was cooled to 0° C., and sodium cyanoborohydride (1.68 g, 27.15 mmol) was added in portions and allowed to stir at room temperature for 16 hours. After complete consumption of the starting material, the reaction mixture was quenched with cold water. The solvent was evaporated under reduced pressure, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude compound, which was purified using column chromatography (silica gel 100-200 mesh, EtOAc and pet ether) to give tert-butyl (1-(3-bromobenzyl)piperidin-4-yl)(methyl)carbamate formate (5.5 g, 10.91 mmol, 40.20% yield). LC-MS (ES) + ): m / z 385.4 [M+H] + . Step 2: In a sealed tube, a solution of tert-butyl (1-(3-bromobenzyl)piperidin-4-yl)(methyl)carbamate (3 g, 7.85 mmol) in 1,4-dioxane (20 mL) was added to NaO tBu (2.26 g, 23.54 mmol) was added. This was purged with ammonia gas for 20 minutes, after which XPhos Pd G3 (1.25 g, 1.57 mmol) was added. The resulting reaction mixture was heated and stirred at 90° C. for 16 hours. The progress of the reaction was monitored by LC-MS and thin layer chromatography. After complete consumption of the starting material, the reaction mixture was filtered, and the filtrate was concentrated to dryness. The crude compound was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 2-[1-[(3-aminophenyl)methyl]-4-piperidyl]propanoate (2 g, 1.24 mmol, 15.82% yield). LC-MS (ES + ): m / z 320.38 [M+H] + . Step 3: To a stirred solution of tert-butyl N-[1-[(3-aminophenyl)methyl]-4-piperidyl]-N-methylcarbamate (2.0 g, 6.28 mmol) in DMF (20 mL) was added NaHCO (1.58 g, 18.84 mmol), and the solution was purged with argon gas for 15 minutes. 3-Bromopiperidine-2,6-dione (3.62 g, 18.84 mmol) was then added, and the resulting reaction mixture was heated at 90 °C with stirring for 16 hours. The progress of the reaction was monitored by LC-MS and thin-layer chromatography. After complete consumption of the starting material, the reaction mixture was concentrated to dryness and purified by preparative HPLC to give tert-butyl (1-(3-((2,6-dioxopiperidin-3-yl)amino)benzyl)piperidin-4-yl)(methyl)carbamate formate (0.4 g, 792.17 μmol, 12.61% yield). LC-MS (ES + ): m / z 320.38 [M+H] + . Step 4: A stirred solution of tert-butyl (1-(3-((2,6-dioxopiperidin-3-yl)amino)benzyl)piperidin-4-yl)(methyl)carbamate TFA salt (0.03 g, 55.09 μmol) in DCM (3 mL) was cooled to 0° C. and TFA (444.00 mg, 3.89 mmol, 0.3 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by LC-MS and thin layer chromatography (10% MeOH in DCM, R f Value: 0.3). After complete consumption of the starting material, the reaction mixture was concentrated to dryness to give 3-[3-[[4-(methylamino)-1-piperidyl]methyl]anilino]piperidine-2,6-dione TFA salt (0.023 g, 42.36 μmol, 76.89% yield) as a pale red solid. LC-MS (ES + ): m / z 331.51 [M+H] + .

[0206] Synthesis of 3-[3-[4-(methylamino)-1-piperidyl]anilino]piperidine-2,6-dione [ka] Step 1: To a stirred solution of tert-butyl N-methyl-N-(4-piperidyl)carbamate (5.30 g, 24.75 mmol) in dioxane (30 mL) was added sodium tert-butoxide (4.76 g, 49.50 mmol), Tris(dibenzylideneacetone)palladium(0) (1.13 g, 1.12 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (286.44 mg, 495.04 μmol) were added. The reaction was stirred for 15 minutes, after which 1-bromo-3-nitro-benzene (5.0 g, 24.75 mmol, 52.52 μL) was added. The reaction mixture was stirred at 100° C. for 16 hours while being monitored by TLC (mobile phase: 50% EtOAc:Pet ether, R f(Product): 0.5). After completion, the reaction mixture was quenched with ice, and the precipitated solid was filtered and dried under vacuum to give tert-butyl N-methyl-N-[1-(3-nitrophenyl)-4-piperidyl]carbamate (5.0 g, 14.61 mmol, 59.02% yield) as a yellow solid. LC-MS (ES + ): m / z 336.2 [M+H] + . Step 2: To a stirred solution of tert-butyl N-methyl-N-[1-(3-nitrophenyl)-4-piperidyl]carbamate (5.0 g, 14.91 mmol) in methanol (50 mL) was added palladium on carbon (5.00 g, 46.98 mmol) and the reaction mixture was stirred at room temperature for 16 h while being monitored by TLC (mobile phase: 50% EtOAc:Pet ether. R f (Product): 0.5). After completion, the reaction mixture was filtered through Celite and the organic layer was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (100-200 mesh silica gel, 0-50% EtOAc in pet ether) to give tert-butyl N-[1-(3-aminophenyl)-4-piperidyl]-N-methyl-carbamate (3.0 g, 9.53 mmol, 63.91% yield) as a yellow solid. LC-MS (ES + ): m / z 306.18 [M+H] + . Step 3: To a stirred solution of tert-butyl N-[1-(3-aminophenyl)-4-pyridyl]-N-methyl-carbamate (2.5 g, 8.19 mmol) and 3-bromopiperidine-2,6-dione (3.14 g, 16.37 mmol) in DMF (3 mL) was added sodium bicarbonate (2.75 g, 32.74 mmol). The reaction mixture was heated at 80° C. for 16 hours while being monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (100-200 mesh silica gel, 0-50% EtOAc in PET ether) to give tert-butyl N-[1-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]-N-methyl-carbamate (1.3 g, 2.90 mmol, 35.46% yield) as a yellow gummy liquid. LC-MS (ES) + ): m / z 417.53 [M+H] + . Step 4: To a stirred solution of tert-butyl N-[1-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]-N-methyl-carbamate (80 mg, 192.07 μmol) in DCM (5 mL) was added TFA (131.40 mg, 1.15 mmol, 88.79 μL) at 0° C. and stirred at room temperature for 2 hours while monitoring by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with diethyl ether (2×100 mL). The precipitated solid was filtered and dried under vacuum to give 3-[3-[4-(methylamino)-1-piperidyl]anilino]piperidine-2,6-dione TFA salt (72 mg, 159.15 μmol, 82.86% yield) as a blue solid. LC-MS (ES) + ): m / z 317.52 [M+H] + .

[0207] Synthesis of 3-[3-[4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione [ka] Step 1: A solution of (3-bromophenyl)boronic acid (1 g, 4.98 mmol), 2,6-dibenzyloxy-3-iodo-pyridine (2.08 g, 4.98 mmol), potassium carbonate (2.06 g, 14.94 mmol), cyclopentyl(diphenyl)phosphene; dichloropalladium; iron (364.35 mg, 497.94 μmol), and 2,6-dibenzyloxy-3-iodo-pyridine (2.08 g, 4.98 mmol) in dioxane:water (4:1 ratio, 5 mL) was stirred at 90 °C for 16 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound 2,6-dibenzyloxy-3-(3-bromophenyl)pyridine (1.500 g, 1.41 mmol, 28.35% yield). LC-MS (ES + ): m / z 446.2 [M+H] + . Step 2: A solution of 2,6-dibenzyloxy-3-(3-bromophenyl)pyridine (1.3 g, 2.91 mmol), tert-butyl N-methyl-N-(4-piperidyl)carbamate (749.02 mg, 3.50 mmol), sodium tert-butoxide (559.82 mg, 5.83 mmol), and tBuXPhos Pd G3 (462.52 mg, 582.52 μmol) in toluene (15 mL) was stirred for 16 h at 100° C. The reaction mixture was concentrated under reduced pressure, diluted with cold water, and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl N-[1-[3-[(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]-N-methyl-carbamate (0.9 g, 947.00 μmol, 32.51% yield). LC-MS (ES + ): m / z 580.3 [M+H] + . Step 3: To a stirred solution of tert-butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]-N-methylcarbamate (1.8 g, 3.10 mmol) in ethyl acetate:ethanol:THF = 1:5:4 (30 mL) was added 10% palladium on carbon (Type 487, 1.8 g). The reaction mixture was then stirred under H2 (1 atm) for 16 hours. The reaction mixture was passed through a bed of Celite, washed with methanol, and concentrated under reduced pressure to give the crude desired compound. The crude material was purified by reverse phase column chromatography (Column / dimensions: X-SELECT C18 (19 x 250 x 5 um) Mobile phase A: 0.1% FA in water (aqueous phase) Mobile phase B: ACN (organic phase) Gradient (time / %B): 0 / 20, 2 / 20, 10 / 50, 15 / 50, 15.1 / 98, 18 / 98, 18.1 / 20, 21 / 20. Flow rate: 16 ml / min. Solubility: ACN + THF + water) to give the compound tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]-N-methyl-carbamate (1.00 g, 2.48 mmol, 79.92% yield). LC-MS (ES) - ): m / z 400.3 [M - H] - . Step 4: A solution of tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]-N-methyl-carbamate (0.040 g, 99.63 μmol) and 20% 2,2,2-trifluoroacetic acid (11.36 mg, 99.63 μmol, 7.68 μL) in DCM (1 mL) was stirred at 0° C. for 4 hours and then at room temperature. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and triturated with diethyl ether to give 3-[3-[4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione TFA salt (27 mg, 64.16 μmol, 64.40% yield). LC-MS (ES) + ): m / z 302.3 [M+H] + .

[0208] Synthesis of 3-[4-[4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione [ka] Step 1: In a sealed tube, a solution of (4-bromophenyl)boronic acid (4 g, 19.92 mmol) and 2,6-dibenzyloxy-3-iodo-pyridine (8.31 g, 19.92 mmol) in dioxane and water (20 mL) was added to potassium carbonate (8.25 g, 59.75 mmol). After purging the reaction mixture with argon for 20 minutes, Pd(dppf)Cl (1.46 g, 1.99 mmol) was added and the reaction was stirred at 90 °C for 16 hours. The progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered and concentrated. It was then diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (60-120 mesh silica gel, 0-4% ethyl acetate in PET ether) to give 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine formate (7 g, 9.93 mmol, 49.83% yield) as an off-white solid. LC-MS (ES) + ): m / z 446.1 [M+H] + . Step 2: To a stirred solution of tert-butyl N-methyl-N-(4-piperidyl)carbamate TFA salt (1.47 g, 4.48 mmol) in toluene (20 mL) was added (CH3)3CONa (861.24 mg). After 10 min, 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (2 g, 4.48 mmol) was added, and the resulting reaction mixture was stirred with heating for 16 h. The reaction progress was monitored by LC-MS. The reaction crude was filtered and concentrated. The crude mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give tert-butyl N-[1-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]-N-methyl-carbamate (3 g, 3.83 mmol, 85.45% yield). LC-MS(ES + ): m / z 581.00 [M+H] + . Step 3: To a stirred solution of tert-butyl N-[1-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]-N-methyl-carbamate (3 g, 5.17 mmol) in EtOAc (10 mL) and EtOH (10 mL) under a hydrogen atmosphere, Pd / C (3.14 g, 25.87 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by LC-MS. After consumption of the starting material, the resulting crude product was filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column / dimensions: X-BRIDGE PHENYL-C18 (19*250*5um), mobile phase A: 5 mM ammonium acetate in water (aqueous phase) ACN (organic phase)) to obtain the compound tert-butyl N-[1-[4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]-N-methyl-carbamate (1.7 g, 4.21 mmol, 81.37% yield). LC-MS (ES) + ): m / z 402.5 [M+H] + . Step 4: To a solution of tert-butyl N-[1-[4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]-N-methyl-carbamate formate (0.05 g, 111.73 μmol) in DCM (2 mL) at 0° C., TFA (12.74 mg, 111.73 μmol, 8.61 μL) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give the crude product, which was triturated with diethyl ether (5 mL) to give 3-[4-[4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione formate (0.03 g, 84.15 μmol, 75.32% yield) as a light brown solid. LC-MS (ES) analysis revealed that the 3-[4-[4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione formate (0.03 g, 84.15 μmol, 75.32% yield) was obtained. + ): m / z 302.5 [M+H] + .

[0209] Synthesis of 3-[2-fluoro-3-(4-piperidyl)anilino]piperidine-2,6-dione [ka] Step 1: To a solution of 1-bromo-2-fluoro-3-nitrobenzene (4 g, 18.189 mmol) in 1,4-dioxane (40 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (6.18 g, 20.00 mmol) and cesium carbonate (14.81 g, 45.46 mmol). The reaction mixture was purged with dry argon gas for approximately 15 minutes, after which Pd(dppf)Cl (1.33 g, 1.82 mmol) was added. The reaction mixture was heated to 80 °C for 16 hours. Upon completion, the mixture was cooled to room temperature and the solvent was removed to give a crude mixture, which was further purified by column purification (ethyl acetate / petroleum ether) to give tert-butyl 4-(2-fluoro-3-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (4 g, 6.20 mmol, 34.13% yield). LC-MS (ES + ): m / z 223.4 [M+H-Boc] + . Step 2: To a solution of tert-butyl 4-(2-fluoro-3-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (4.3 g, 13.34 mmol) in ethanol (60 mL) was added Pd / C (4.3 g). The reaction mixture was stirred under a hydrogen atmosphere at 28 °C for 16 hours. Upon completion of the reaction, the reaction mixture was filtered through a Celite bed, and the filtrate was concentrated to obtain crude compound tert-butyl 4-(3-amino-2-fluoro-phenyl)piperidine-1-carboxylate (3.5 g, 9.27 mmol, 69.52% yield), which was used in the next step without further purification. LC-MS (ES) + ): m / z 295.4 [M+H] + . Step 3: To a solution of tert-butyl 4-(3-amino-2-fluoro-phenyl)piperidine-1-carboxylate (2.0 g, 6.79 mmol) in toluene (30 mL) was added 2,6-dibenzyloxy-3-bromo-pyridine (2.77 g, 7.47 mmol) and sodium tert-butoxide (1.96 g, 20.38 mmol). The reaction mixture was purged with dry argon gas, and then tert-butyl XPhos Pd G3 (539.47 mg, 679.43 μmol) was added. The reaction was heated to 90° C. for 16 hours. Upon completion of the reaction, the crude mixture was concentrated and purified by column chromatography over 100-200 silica mesh using ethyl acetate-pet ether as the eluent to give tert-butyl 4-[3-[(2,6-dibenzyloxy-3-pyridyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (1.8 g, 2.16 mmol, 31.77% yield). LC-MS (ES) - ): m / z 583.6 [M + H] - . Step 4: To a solution of tert-butyl 4-[3-[(2,6-dibenzyloxy-3-pyridyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (3.0 g, 5.14 mmol) in ethanol (20 mL) and DCM (20 mL) was added Pd / C (3.0 g, 24.70 mmol), and the reaction mixture was stirred under a hydrogen atmosphere at 28 °C for 16 hours. Upon completion of the reaction, the reaction mixture was filtered through a Celite bed and concentrated under reduced pressure to give tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (2 g, 4.20 mmol, 81.68% yield), which was used in the next step without further purification. LC-MS (ES) - ): m / z 404.3 [M + H] - . Step 5: A stirred solution of tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (1.1 g, 2.71 mmol) in DCM was cooled to 0 °C, and then HCl in dioxane (1.98 g, 54.26 mmol, 2.47 mL) was added. The reaction mixture was stirred at 28 °C for 2 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting crude material was washed with diethyl ether and pentane to give 3-[2-fluoro-3-(4-piperidyl)anilino]piperidine-2,6-dione HCl salt (1 g, 2.37 mmol, 87.35% yield). LC-MS (ES) + ): m / z 306.3 [M+H] + .

[0210] Synthesis of 3-[4-(4-piperidyl)-3-(trifluoromethyl)anilino]piperidine-2,6-dione [ka] Step 1: To a stirred solution of 4-bromo-3-methyl-aniline (1.3 g, 6.99 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.16 g, 6.99 mmol) in DMF (20 mL) was added anhydrous tribasic potassium phosphate (3.71 g, 17.47 mmol), and the mixture was purged with nitrogen for 5 minutes. To the mixture was added cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; and iron (285.31 mg, 349.37 μmol), and the mixture was stirred at 110 °C for 3 hours. The progress of the reaction was monitored by TLC and UPLC. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give the crude product. The crude material was purified by column chromatography (230-400 mesh silica, 30% ethyl acetate in PET ether) to give tert-butyl 4-(4-amino-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.5 g, 5.16 mmol, 73.84% yield) as a pale yellow solid. LC-MS (ES) + ): m / z 289.2 [M+H] + . Step 2: To a stirred solution of tert-butyl 4-(4-amino-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (800 mg, 2.77 mmol) and 3-bromopiperidine-2,6-dione (2.66 g, 13.87 mmol) in DMF (15 mL), sodium bicarbonate (1.17 g, 13.87 mmol, 539.45 μL) was added and the reaction mixture was stirred at 80° C. for 16 hours. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give the crude product. The crude material was purified by column chromatography (silica 230-400, 50% ethyl acetate in pet ether) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (800 mg, 1.70 mmol, 61.14% yield) as a pale green solid. LC-MS (ES) + ): m / z 400.3 [M+H] + . Step 3: To a stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 1.25 mmol) in ethyl acetate (20 mL), 10% palladium on carbon, type 487, dry (133.20 mg, 1.25 mmol) was added and stirred at room temperature for 16 hours. The reaction progress was monitored by LC-MS. The reaction mixture was filtered through Celite and concentrated to give the crude product tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-methyl-phenyl]piperidine-1-carboxylate (400 mg, 898.34 μmol, 71.77% yield) as a pale green solid. LC-MS (ES) + ): m / z 346.2 [M - (C(CH3)3+ H] + . Step 4: To a stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (200 mg, 498.13 μmol) in DCM (5 mL) was added HCl in dioxane (498.13 μmol, 5 mL), and the reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by UPLC. The reaction mixture was concentrated to give the crude product, 3-[3-methyl-4-(4-piperidyl)anilino]piperidine-2,6-dione HCl salt (150 mg, 372.07 μmol, 74.69% yield), as an off-white solid. LC-MS(ES + ): m / z 302.2 [M+H] + .

[0211] Synthesis of 3-[4-(2-piperazin-1-ylethyl)anilino]piperidine-2,6-dione [ka] Step 1: To a stirred solution of tert-butyl 4-[2-(4-aminophenyl)ethyl]piperazine-1-carboxylate (1 g, 3.27 mmol) in DMF (10 mL) was added sodium bicarbonate (687.65 mg, 8.19 mmol, 318.35 μL), and the reaction mixture was stirred at 0° C. for 10 minutes. To the suspension was added 3-bromopiperidine-2,6-dione (943.03 mg, 4.91 mmol), and the reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the layers were separated, and the organic layer was concentrated under reduced pressure. The crude material was washed with diethyl ether and dried to afford tert-butyl 4-[2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl]piperazine-1-carboxylate (1 g, 1.70 mmol, 52.06% yield) as a pale yellow semisolid. The crude compound was carried on to the next step without purification. LC-MS (ES - ): m / z 415.3 [M - H] - . Step 2: A stirred solution of tert-butyl 4-[2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl]piperazine-1-carboxylate (150 mg, 360.13 μmol) in DCM (5 mL) was cooled to 0° C., then trifluoroacetic acid (821.27 mg, 7.20 mmol, 554.91 μL) was added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated, triturated with diethyl ether, filtered, and dried to give 3-[4-(2-piperazin-1-ylethyl)anilino]piperidine-2,6-dione (110 mg, 253.79 μmol, 70.47% yield). LC-MS (ES) + ): m / z 317.5 [M+H] + .

[0212] Synthesis of 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione [ka] Step 1: To a mixture of 1-bromo-4-iodo-benzene (1 g, 3.53 mmol) and tert-butyl piperazine-1-carboxylate (724.19 mg, 3.89 mmol) in toluene (30 ml), sodium 2-methylpropan-2-olate (339.70 mg, 3.53 mmol) was added, and the entire solution was degassed with nitrogen for 15 minutes, followed by the addition of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (3.24 g, 3.53 mmol) and [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane (2.20 g, 3.53 mmol). After the addition, the reaction mixture was heated at 100 °C for 12 hours. The reaction mixture was diluted with ethyl acetate (60 mL), washed with water / brine, and separated. After evaporation of the organic layer, the residue was purified by column chromatography to give tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (460 mg, 1.19 mmol, 33.56% yield). LC-MS (ES + ): m / z 341.1 [M+H] + . Step 2: To a stirred solution of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (20 g, 58.61 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (29.77 g, 117.22 mmol) in dioxane (100 mL) was added potassium acetate (11.50 g, 117.22 mmol, 7.33 mL). The reaction mixture was degassed with nitrogen for 15 minutes, after which cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; and iron (4.79 g, 5.86 mmol) were added. After the addition, the reaction mixture was stirred in a sealed tube at 100 °C for 12 minutes. Upon completion of the reaction, the reaction mixture was filtered through a bed of Celite, which was washed several times with ethyl acetate. The combined organic layers were washed with water / brine and separated. It was then concentrated in vacuo to give tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (18 g, 38.94 mmol, 66.44% yield). The crude material obtained was used directly in the next step. LC-MS (ES + ): m / z 389.2 [M+H] + . Step 3: To a stirred solution of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (12.3 g, 31.68 mmol) in DMF (80 mL) and water (10 mL) was added sodium carbonate (6.71 g, 63.35 mmol), and the resulting solution was degassed with argon for 15 minutes, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.32 g, 3.17 mmol). The reaction mixture was then heated at 100 °C for 5 hours. After complete consumption of the starting material, the reaction mixture was filtered through a Celite bed, and ice-cold water was added to the filtrate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water / brine, separated, dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by column chromatography eluting with 1% methanol in dichloromethane to give tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]piperazine-1-carboxylate (11.5 g, 13.55 mmol, 42.78% yield) as an off-white solid. LC-MS (ES) + ): m / z 552.7[M+H] + . Step 4: A stirred solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]piperazine-1-carboxylate (22 g, 39.88 mmol) in ethyl acetate (120 mL) and ethanol (120 mL) was degassed with argon for 20 minutes, after which 10% palladium on carbon (8.49 g, 7.98 mmol) was added, and the reaction mixture was stirred under an atmosphere of hydrogen (balloon) at room temperature for 16 hours. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by column chromatography eluting with 2% methanol in dichloromethane to give tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazine-1-carboxylate (13.2 g, 33.58 mmol, 84.20% yield) as an off-white solid. LC-MS (ES) + ): m / z 374.2 [M+H] + . Step 5: To a stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)phenyl]piperazine-1-carboxylate (13.1 g, 35.08 mmol) in DCM (50 mL) was added 4 M HCl in dioxane (35.08 mmol, 20 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. Evaporation followed by lyophilization afforded 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione hydrochloride (10.8 g, 34.39 mmol, 98.03% yield) as an off-white solid. LC-MS (ES) + ): m / z 274.4 [M+H] + .

[0213] Synthesis of 3-(4-piperazin-1-ylphenoxy)piperidine-2,6-dione [ka] Step 1: To a stirred solution of 4-bromophenol (8 g, 46.24 mmol) in ACN (100 mL), bromomethylbenzene (9.49 g, 55.49 mmol, 6.59 mL) and potassium carbonate, anhydrous powder 325 mesh (15.98 g, 115.60 mmol, 6.98 mL) were added at room temperature under a N atmosphere, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with cold water and then extracted with EtOAc. The organic layer was washed with brine solution, then dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The resulting crude was purified by column chromatography using 100-200 silica gel. The product was eluted with 0-30% EtOAc in PET ether to give 1-benzyloxy-4-bromobenzene (10 g, 36.86 mmol, 79.72% yield) as an off-white solid. LC-MS (ES) analysis revealed that the product was eluted with 0-30% EtOAc in PET ether to give 1-benzyloxy-4-bromobenzene (10 g, 36.86 mmol, 79.72% yield) as an off-white solid. + ): m / z 263.3 [M+H] + . Step 2: A stirred solution of sodium tert-butoxide (456.52 mg, 4.75 mmol) in a mixture of THF (2.5 mL) and toluene (2.5 mL) was purged with argon for 5 minutes in a microwave vial. To this solution, 1-benzyloxy-4-bromo-benzene (0.5 g, 1.90 mmol) and tert-butyl piperazine-1-carboxylate (460.09 mg, 2.47 mmol) were added and purged with argon for 10 minutes. To this reaction mixture, tBuXPhos Pd G2 (149.51 mg, 190.02 μmol) was added and microwaved at 100° C. for 30 minutes. Evaporation followed by column chromatography (230-400 silica gel, 0-30% ethyl acetate and PET ether as eluent) afforded tert-butyl 4-(4-benzyloxyphenyl)piperazine-1-carboxylate (0.650 g, 1.61 mmol, 84.48% yield) as a yellow solid. LC-MS (ES) + ): m / z 369.2 [M+H] + . Step 3: To a stirred solution of tert-butyl 4-(4-benzyloxyphenyl)piperazine-1-carboxylate (0.65 g, 1.76 mmol) in ethyl acetate (10 mL), 10% palladium on carbon, type 487, dry (0.65 g, 6.11 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was filtered through Celite with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure and dried to give tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,3-difluoro-piperidine-1-carboxylate (0.460 g, 922.91 μmol, 46.48% yield) as a colorless dark liquid. LC-MS (ES) - ): m / z 277.3 [M - H] - . Step 4: To a stirred solution of tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (0.4 g, 1.44 mmol) in THF (20 mL), sodium hydride (60% dispersion in mineral oil) (330.38 mg, 14.37 mmol) (NaH washed with hexane) was added at room temperature under argon gas. The reaction mixture was then stirred at 70° C. for 30 minutes. After that, 3-bromopiperidine-2,6-dione (1.38 g, 7.19 mmol) in THF was added and refluxed at 70° C. for 4 hours under argon. The reaction mixture was poured onto ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 0-40% ethyl acetate in PET ether to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazine-1-carboxylate (0.25 g, 618.96 μmol, 43.07% yield) as an off-white solid. LC-MS (ES) - ): m / z 388.3 [M - H] - . Step 5: To cold hydrochloric acid in dioxane (808.84 μmol, 5.0 mL) was added tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazine-1-carboxylate (315.0 mg, 808.84 μmol), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give a white solid, which was then washed with pentane and ether to give 3-(4-piperazin-1-ylphenoxy)piperidine-2,6-dione hydrochloride (265.0 mg, 793.07 μmol, 98.05% yield) in the form of the HCl salt as a white solid. LC-MS (ES) + ): m / z 290.1 ​​[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.97 (br s, 2H), 6.94 (m, 4H), 5.06 (m, 1H), 3.23 (m, 8H), 2.66-2.61 (m, 2H), 2.15-2.10 (m, 2H);

[0214] Synthesis of 3-[4-(4-piperidyloxy)anilino]piperidine-2,6-dione [ka] Step 1: To a 100 mL sealed tube containing a well-stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol) and 1-fluoro-4-nitro-benzene (1.40 g, 9.94 mmol, 1.05 mL) in tertiary butanol (30 mL), potassium tert-butoxide (1.23 g, 10.93 mmol) was added and stirred at 90 °C for 1 hour. After completion of the reaction, the reaction mixture was poured into ice-cold water, and the solid precipitate was filtered and dried to give tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (2.5 g, 7.06 mmol, 71.02% yield). LC-MS (ES) + ): m / z 223.0 [M-COOtBu+H] + . 1 H NMR (300 MHz, CDCl3): δ 8.22 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 4.65-4.60 (m, 1H), 3.76-3.68 (m, 2H), 3.44-3.36 (m, 2H), 2.03-1.95 (m, 2H), 1.86-1.70 (m, 2H), 1.43 (s, 9H) ppm. Step 2: To a solution of tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (2.5 g, 7.76 mmol) in ethanol (50 mL) was added 10% palladium on carbon, type 487, dry (500 mg, 4.70 mmol). After degassing the solution, the reaction was stirred under an atmosphere of hydrogen (hydrogen bladder) at room temperature for 16 hours. After completion of the reaction, the catalyst was filtered through a bed of Celite, and the resulting filtrate was evaporated to dryness under reduced pressure to give tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (2 g), which was used without further purification. LC-MS (ES) + ): m / z 193.1 [M+H-Boc] + . Step 3: At room temperature, 3-bromopiperidine-2,6-dione (3.94 g, 20.52 mmol), tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (5 g, 17.10 mmol), NaHCO (5.93 g, 34.20 mmol), and DMF (50 mL) were added to a 150 mL sealed tube. The mixture was purged with nitrogen, and the stirred reaction was sealed and heated at 40 °C overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenoxy]piperidine-1-carboxylate (8.2 g), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 6.77 (d, J = 8.9 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.47 (d, J = 7.3 Hz, 1H), 4.24 (ddt, J = 35.6, 11.7, 5.6 Hz, 2H), 3.66 - 3.58 (m, 2H), 3.30 (s, 1H), 3.15 (t, J = 10.6 Hz, 2H), 2.73 (ddd, J = 17.3, 12.8, 5.4 Hz, 1H), 2.63 - 2.53 (m, 1H), 2.16 - 2.07 (m, 1H), 1.83 (dd, J = 12.7, 7.0 Hz, 3H), 1.49 (ddd, J = 12.8, 8.3, 3.9 Hz, 2H), 1.41 (s, 8H). Step 4: To an oven-dried round-bottom flask containing a solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenoxy]piperidine-1-carboxylate (600 mg, 1.49 mmol) in 1,4-dioxane (3 mL) was added hydrogen chloride (4.0 M in dioxane) (10 mL). The reaction mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure to give 3-[4-(4-piperidyloxy)anilino]piperidine-2,6-dione (510 mg, 78.43% yield) as a brown gummy solid, which was used without further purification. LC-MS (ES) + ): m / z 304.0 [M+H] + .

[0215] Synthesis of 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetic acid [ka] Step 1: To a solution of 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione (2.5 g, 8.10 mmol, HCl salt) in DMF (30 mL) was added tert-butyl 2-bromoacetate (1.74 g, 8.91 mmol, 1.31 mL) and TEA (2.46 g, 24.29 mmol, 3.39 mL) at room temperature under an inert atmosphere and stirred for 24 hours. The reaction mixture was quenched with water (100 mL) and the solid was filtered. The solid was air-dried to give tert-butyl 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetate (2.37 g, 5.83 mmol, 71.96% yield) as a white solid. LC-MS (ES) + ): m / z 387.2 [M+H] + . Step 2: tert-Butyl 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetate (2.43 g, 6.29 mmol) was added to a solution of 4 M HCl in dioxane (4 M in dioxane, 50.00 mL) at room temperature under an inert atmosphere and stirred for 24 hours. The resulting mixture was evaporated to dryness and dried under vacuum to give 2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetic acid (2.15 g, 5.51 mmol, 87.62% yield, HCl salt). LC-MS (ES) + ): m / z 331.0 [M+H] + .

[0216] Synthesis of 4-[(2,6-dioxo-3-piperidyl)oxy]benzoic acid [ka] Step 1: To a solution of tert-butyl 4-hydroxybenzoate (8.09 g, 41.66 mmol) in dry THF (150 mL) was added sodium hydride (4.17 g, 104.16 mmol) (60% dispersion in mineral oil) in small portions at 0° C. under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 30 minutes. 3-Bromopiperidine-2,6-dione (10 g, 52.08 mmol) was then added at 0° C., and the reaction was stirred at room temperature for 24 hours. The reaction mixture was evaporated in vacuo and quenched with saturated ammonium chloride solution (50 mL) at 0° C., followed by extraction with ethyl acetate (3×150 mL). The combined organic layers were washed with ice-cold brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was triturated with MTBE (2 x 30 mL) and filtered to give tert-butyl 4-[(2,6-dioxo-3-piperidyl)oxy]benzoate (5.65 g, 18.50 mmol, 44.41% yield) as gray crystals. LC-MS (ES) - ): m / z 304.0 [MH] - . Step 2: To a solution of tert-butyl 4-[(2,6-dioxo-3-piperidyl)oxy]benzoate (2.1 g, 6.88 mmol) in DCM (40 mL) was added TFA (29.78 g, 261.18 mmol, 20 mL) at room temperature and stirred overnight. The resulting mixture was evaporated to dryness, triturated with MTBE (5 mL), and filtered to give 4-[(2,6-dioxo-3-piperidyl)oxy]benzoic acid (1.6 g, 6.10 mmol, 88.68% yield) as a gray solid. LC-MS (ES) - ): m / z 248.2 [MH] - .

[0217] F. Synthesis of Representative Compounds Synthesis of tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-acetylpiperidine-1-carboxylate (50 g, 219.97 mmol) in THF (500 mL) was added dropwise LDA (2 M, 131.98 mL) at −78° C. After stirring the solution at −78° C. for 1 h, chlorotrimethylsilane (47.80 g, 439.95 mmol, 55.84 mL) was added at this temperature. The reaction was stirred at −78° C. for an additional 1 h. After consumption of the reactants as indicated by TLC, the reaction mixture was poured into aqueous sodium bicarbonate (200 mL), and the aqueous phase was extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting residue was then dissolved in THF (500 mL), and sodium bicarbonate (27.72 g, 329.96 mmol) and N-bromosuccinimide (58.73 g, 329.96 mmol) were added at 0 °C. The solution was stirred at 25 °C for 2 h. After TLC showed complete conversion, the reaction mixture was poured into aqueous sodium bicarbonate (2 L), and the aqueous phase was extracted with ethyl acetate (500 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (28 g, 64.31 mmol, 29.24% yield) as a yellow oil. LC-MS (ES) + ): m / z 249.9 [M-tBu+H] + .

[0218] Synthesis of 5-bromo-4-isopropoxy-pyridin-2-amine [ka] Step 1: To a suspension of 2-aminopyridin-4-ol (40 g, 363.26 mmol) in DMF (500 mL) was added cesium carbonate (118.36 g, 363.26 mmol) and 2-iodopropane (61.75 g, 363.26 mmol, 36.32 mL). The mixture was stirred at 120 °C for 16 hours. After consumption of the reactants as evidenced by TLC, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (300 mL × 4). The combined organic layers were washed with brine 300 (150 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product 4-isopropoxypyridin-2-amine (29 g, 183.73 mmol, 50.58% yield) as a yellow solid. LC-MS (ES) + ): m / z 153.1 [M+H] + . Step 2: To a solution of 4-isopropoxypyridin-2-amine (29 g, 190.55 mmol) in acetonitrile (300 mL) was added 1-bromopyrrolidine-2,5-dione (30.52 g, 171.49 mmol). The mixture was stirred at 25 °C for 2 hours. After consumption of the reactants as indicated by TLC, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL × 5). The combined organic layers were washed with brine (150 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (250 g silica, 10-50% ethyl acetate in PET ether as eluent at 100 mL / min). Compound 5-bromo-4-isopropoxy-pyridin-2-amine (42 g, 181.75 mmol, 95.38% yield) was obtained as an orange solid. LC-MS (ES) + ): m / z 230.9 [M+H] + .

[0219] Synthesis of N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: A solution of 5-bromo-4-isopropoxy-pyridin-2-amine (2.5 g, 10.82 mmol) and tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (4.97 g, 16.23 mmol) in ethanol (30 mL) was stirred at 90 °C for 16 h. The solvent was concentrated under reduced pressure, and the material was purified by reverse-phase column chromatography (0–40% acetonitrile in 0.1% formic acid in water) to give tert-butyl 4-(6-bromo-7-isopropoxy-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (3.4 g, 6.52 mmol, 60.22% yield) as a brown solid. LC-MS (ES) + ): m / z 438.8 [M+H] + Step 2: To a stirred solution of tert-butyl 4-(6-bromo-7-isopropoxy-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (5.0 g, 11.41 mmol) in toluene (50 mL) was added 6-(trifluoromethyl)pyridine-2-carboxamide (3.25 g, 17.11 mmol). The reaction mixture was purged with argon gas for 10 minutes. Sodium 2-methylpropan-2-olate (1.53 g, 15.97 mmol) was added to the reaction mixture and purged with argon gas for 10 minutes. tBuXPhos Pd G3 (906.08 mg, 1.14 mmol) was then added to the reaction mixture and purged with argon gas for an additional 10 minutes. The reaction mixture was stirred at 100° C. for 32 hours. After completion of the reaction, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 x 500 mL). The organic layer was dried over anhydrous sodium NaSO and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography to give tert-butyl 4-[7-isopropoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (3.9 g, 6.62 mmol, 58.07% yield) as a yellow solid. LC-MS (ES) + ): m / z 548.32 [M+H]+ Step 3: To a stirred solution of tert-butyl 4-[7-isopropoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (5.0 g, 9.13 mmol) in DCM (50 mL) was added trifluoroacetic acid (10.41 g, 91.31 mmol, 7.03 mL) dropwise at 0 °C, and the reaction mixture was stirred for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and triturated with diethyl ether to give N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide trifluoroacetate (6.15 g, 8.56 mmol, 93.71% yield) as an off-white solid. LC-MS (ES) + ): m / z 448.33 [M+H] +

[0220] Synthesis of N-[2-(azetidin-3-yl)-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: To a stirred solution of methyl 1-benzhydrylazetidine-3-carboxylate (40 g, 142.17 mmol) in THF, sodium 2-chloroacetate (24.84 g, 213.26 mmol) and TEA (21.58 g, 213.26 mmol, 29.72 mL) were added at 0°C, and the resulting reaction mixture was stirred at room temperature for 30 minutes. Then, tert-butyl magnesium chloride (33.23 g, 284.35 mmol) was added at -5°C, the cooling bath was removed, and the mixture was stirred for 1 hour. The reaction mixture was quenched with ammonium chloride, extracted with ethyl acetate, and concentrated to give 1-(1-benzhydrylazetidin-3-yl)-2-chloroethanone (38 g, 50.70 mmol, 35.66% yield) as an off-white solid. LC-MS (ES) + ): m / z 300.10 [M+H]+ Step 2: To a stirred solution of 1-(1-benzhydrylazetidin-3-yl)-2-chloro-ethanone (25 g, 83.39 mmol) and 5-bromo-4-isopropoxypyridin-2-amine (9.64 g, 41.70 mmol) in ethanol at 0° C., sodium bicarbonate (4.20 g, 50.03 mmol, 1.95 mL) was added, and the reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was concentrated and purified by preparative HPLC to give 2-(1-benzhydrylazetidin-3-yl)-6-bromo-7-isopropoxy-imidazo[1,2-a]pyridine (7 g, 11.75 mmol, 28.19% yield). LC-MS (ES) + ): m / z 476.21 [M+H] + Step 3: A stirred solution of 2-(1-benzhydrylazetidin-3-yl)-6-bromo-7-isopropoxy-imidazo[1,2-a]pyridine (6.0 g, 12.59 mmol), 6-(trifluoromethyl)picolinamide (3.59 g, 18.89 mmol), and sodium tert-butoxide (1.69 g, 17.63 mmol) in toluene was degassed for 30 min. To this mixture was added XPhos Pd G3 (1.01 mmol), degassed again for 20 min, and then the reaction mixture was stirred at 100 °C for 16 h. After consumption of the starting material, standard workup followed by reverse-phase purification afforded N-[2-(1-benzhydrylazetidin-3-yl)-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (2 g, 2.83 mmol, 22.51% yield). LC-MS (ES) + ): m / z 586.88[M+H] + Step 4: To a stirred solution of N-[2-(1-benzhydrylazetidin-3-yl)-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (1.5 g, 2.56 mmol) in methanol was added 20 wt% palladium hydroxide on carbon, 50% water (359.72 mg, 2.56 mmol), followed by hydrochloric acid, 36% w / w in water (93.39 mg, 2.56 mmol, 116.74 μL), and the resulting reaction mixture was stirred under hydrogen balloon pressure at room temperature for 24 hours. The reaction mixture was filtered through a bed of celite and concentrated to give N-[2-(azetidin-3-yl)-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (0.9 g, 1.87 mmol, 72.89% yield). LC-MS (ES + ): m / z 420.32 [M+H] + .

[0221] Example 1 Synthesis of N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]acetyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: A stirred solution of glyoxylic acid, 50% w / w aqueous solution (0.031 g, 418.72 μmol, 23.13 μL) in methanol and 3-[4-(4-piperidyl)phenoxy]piperidine-2,6-dione (100.61 mg, 348.93 μmol) was stirred at 0° C. for 10 minutes. Sodium cyanoborohydride (43.85 mg, 697.86 μmol) was then added at 0° C., and the resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of the starting material, the reaction mixture was concentrated to give 2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]acetic acid (0.09 g, 148.10 μmol, 42.45% yield), which was used without further purification. LC-MS (ES) + ): m / z 345.41 [MH] - Step 2: To a stirred solution of N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (0.05 g, 111.74 μmol) and 2-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]acetic acid (38.71 mg, 111.74 μmol) in THF was added TEA (11.31 mg, 111.74 μmol, 15.57 μL) and T3P (53.30 mg, 167.62 μmol) at 0° C., and the resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of the starting material, the reaction mixture was concentrated and purified by preparative HPLC to give N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]acetyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (37 mg, 46.60 μmol, 41.70% yield). LC-MS (ES) + ): m / z 776.59 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.45 (s, 1H), 9.44 (s, 1H), 8.43 (q, J = 8.1 Hz, 2H), 8.24 (d, J = 7.3 Hz, 1H), 7.70 (s, 1H), 7.14 (d, J = 10.3 Hz, 3H), 6.92 (d, J = 8.5 Hz, 2H), 5.13 (q, J = 5.3 Hz, 1H), 4.88 (m, 1H), 4.38 (d, J = 12.8 Hz, 1H), 4.18 (d, J = 12.9 Hz, 1H), 3.14 (m, 1H), 2.92 (m, 3H), 2.75 (d, J = 10.9 Hz, 2H), 2.64 (m, 1H), 2.38 (t, J = 21.6 Hz, 2H), 2.07 (m, 6H), 1.74 (m, 6H), 1.63 (m, 6H), 1.40 (d, J = 5.9 Hz, 1H). TLC Rf: 0.1 (10% methanol in DCM) Preparative HPLC conditions: Column / Dimensions: X-Bridge C18 (19*250*5um) Mobile phase A: 5 mM AA in water (aqueous phase) Mobile phase B: 100% acetonitrile Gradient (time / B(%)): 0 / 10, 2 / 10, 2.5 / 25, 22 / 63, 22.1 / 95, 24 / 95, 24 / 95, 24.1 / 10, 26.5 / 10 Flow rate: 17ml / min Solubility: CAN+THF+DMSO

[0222] Example 2 The compound of Example 2 was prepared essentially following the synthesis of Example 1. [ka] N-[2-[1-[2-[4-[3-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 776.59 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.45 (s, 1H), 9.45 (s, 1H), 8.43 (q, J = 8.0 Hz, 1H), 8.25 (d, J = 7.0 Hz, 1H), 8.14 (s, 1H), 7.70 (s, 1H), 7.13 (s, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.68 (t, J = 8.1 Hz, 1H), 6.52 (t, J = 6.5 Hz, 1H), 5.51 (d, J = 6.2 Hz, 1H), 4.88 (m, 1H), 4.38 (t, J = 12.3 Hz, 2H), 4.06 (s, 1H), 3.16 (m, 5H), 2.83 (m, 4H), 2.03 (m, 2H), 1.71 (m, 5H), 1.52 (m, 5H), 1.40 (m, 6H), 1.25 (t, J = 5.4 Hz, 1H).

[0223] Example 3 The compound of Example 3 was prepared essentially following the synthesis of Example 1. [ka] N-[2-[1-[2-[4-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 775.12 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.44 (s, 1H), 9.44 (s, 1H), 8.43 (q, J = 8.1 Hz, 2H), 8.24 (d, J = 7.1 Hz, 1H), 8.17 (s, 1H), 7.70 (s, 1H), 7.13 (s, 1H), 6.98 (t, J = 7.7 Hz, 1H), 6.56 (s, 1H), 6.47 (q, J = 7.1 Hz, 2H), 5.74 (d, J = 7.5 Hz, 1H), 4.88 - 4.34 (m,2H), 4.17 (d, J = 12.8 Hz, 1H), 3.32 (s, 3H), 2.93 (s, 3H), 2.73 (m, 2H), 2.50 (s, 1H), 2.35 (t, J = 9.9 Hz, 1H), 2.00 -1.86 (m, 6H), 1.67 (m, 5H), 1.40 (m, 7H).

[0224] Example 4 The compound of Example 4 was prepared essentially following the synthesis of Example 1. [ka] N-[2-[1-[2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]acetyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 760.09 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.45 (s, 1H), 9.45 (s, 1H), 8.43 (m, 5H), 8.24 (d, J = 7.0 Hz, 1H), 7.70 (s, 1H), 7.34-7.12 (m, 5H), 4.88 (t, J = 5.9 Hz, 1H), 4.39 (d, J = 14.2 Hz, 1H), 4.18 (d, J = 12.7 Hz, 1H), 3.80 (q, J = 5.4 Hz, 1H), 3.10-2.67 (m, 11H), 2.06 (q, J = 19.3 Hz, 6H), 1.70 (d, J = 40.3 Hz, 2H), 1.40 (d, J = 5.9 Hz, 6H).

[0225] Example 5 The compound of Example 5 was prepared essentially following the synthesis of Example 1. [ka] N-[2-[1-[2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-1-yl]acetyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 761.55[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.44 (s, 1H), 9.44 (s, 1H), 8.45 (t, J = 14.1 Hz, 1H), 8.39 (m, 2H), 8.24 (d, J = 7.1 Hz, 1H), 7.69 (s, 1H), 7.34 (q, J = 8.0 Hz, 1H), 7.08 (t, J = 17.8 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.71 (s, 1H), 4.88 (t, J = 6.0 Hz, 1H), 4.43 (t, J = 21.5 Hz, 1H), 4.15 (d, J = 13.9 Hz, 1H), 3.72 (q, J = 5.3 Hz, 1H), 3.58 (q, J = 19.3 Hz, 1H), 3.15 (m, 8H), 2.90 (s, 1H), 2.76 (s, 1H), 2.57 (m, 5H), 2.07 (m, 8H), 1.40 (d, J = 5.9 Hz, 3H).

[0226] Example 6 The compound of Example 6 was prepared essentially following the synthesis of Example 1. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazin-1-yl]acetyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 777.69 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.44 (s, 1H), 9.44 (s, 1H), 8.44 (t, J = 8.0 Hz, 2H), 8.24 (d, J = 7.1 Hz, 1H), 7.69 (s, 1H), 7.13 (s, 1H), 6.89 (m, 4H), 5.02 (m, 1H), 4.94 (m, 1H), 4.40 (d, J = 13.1 Hz, 1H), 4.15 (d, J = 12.2 Hz, 1H), 3.11 (m, 5H), 2.91 (s, 1H), 2.67 (m, 6H), 2.08 (m, 4H), 1.43 (m, 5H), 0.94 (m, 6H).

[0227] Example 7 The compound of Example 7 was prepared essentially following the synthesis of Example 1. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 793.23 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.54 (s, 1H), 9.63 (d, J = 100.7 Hz, 1H), 8.47 (t, J = 7.8 Hz, 2H), 8.30 (d, J = 7.1 Hz, 1H), 8.10 (s, 1H), 7.37 (s, 1H), 7.21-6.95 (m, 3H), 6.49 (t, J = 9.9 Hz, 3H), 6.12 (d, J = 6.5 Hz, 1H), 5.09 (s, 1H), 4.40 (m, 4H), 3.77-3.34 (m, 3H), 3.16 (m, 4H), 2.93 (t, J = 11.8 Hz, 2H), 2.74 (m, 1H), 2.60 (m, 1H), 2.09 (m, 5H), 1.89 (d, J = 14.3 Hz, 2H), 1.46 (d, J = 5.8 Hz, 6H).

[0228] Example 8 The compound of Example 8 was prepared essentially following the synthesis of Example 1. [ka] N-[2-[1-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]propanoyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 807.42[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.45 (s, 1H), 9.44 (s, 1H), 8.40 (m, 3H), 8.24 (d, J = 7.2 Hz, 1H), 7.69 (s, 1H), 7.12 (s, 1H), 6.97 (t, J = 8.7 Hz, 1H), 6.43 (t, J = 6.9 Hz, 2H), 5.98 (d, J = 7.7 Hz, 1H), 4.88 (m, J = 5.9 Hz, 1H), 4.41 (d, J = 12.7 Hz, 1H), 4.29 (m, J = 6.0 Hz, 1H), 3.96 (m, 4H), 3.18 (m, 3H), 2.93 (m, 2H), 2.71 (m, 5H), 2.50 (m, 4H), 1.96 (m, J = 9.8 Hz, 1H), 1.51 (m, 11H).

[0229] Example 9 The compound of Example 9 was prepared essentially following the synthesis of Example 1. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 775.48[M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.45 (s, 1H), 9.44 (s, 1H), 8.43 (q, 2H), 8.26 (t, 2H), 7.70 (s, 1H), 7.13 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 5.64 (d, J = 7.5 Hz, 1H), 4.88 (m, 1H), 4.38 (d, J = 12.8 Hz, 1H), 4.22 (m, J = 7.5 Hz, 2H), 3.17 (m, 5H), 2.91 (s, 3H), 2.73 (m, 2H), 2.56 (t, 3H), 2.32 (m, 1H), 2.04 (m, 4H), 1.85 - 1.4 (m, 6H).

[0230] Example 10 The compound of Example 10 was prepared essentially following the synthesis of Example 1. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]acetyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 776.56[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 14.20 (s, 1H), 10.77 (s, 1H), 10.56 (s, 1H), 9.79 (s, 1H), 8.47 (q, J = 8.1 Hz, 2H), 8.31 (t, J = 4.2 Hz, 1H), 8.15 (s, 1H), 7.45 (s, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 6.97 (s, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 5.12 (t, J = 6.0 Hz, 1H), 4.44 (q, J = 16.6 Hz, 3H), 4.23 (q, J = 5.3 Hz, 1H), 3.47 (m, 4H), 3.30 (m, 5H), 3.05 (m, 2H), 2.95 (d, J = 12.3 Hz, 1H), 2.72 (m, 1H), 2.50 (d, J = 1.6 Hz, 1H), 2.11 (q, J = 9.3 Hz, 3H), 1.87 (m, 1H), 1.69 (m, 6H), 1.48 (d, J = 6.0 Hz, 1H).

[0231] Example 11 Synthesis of N-[2-[1-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-pyridyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: To a stirred solution of N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide trifluoroacetate (0.5 g, 890.51 μmol) in a mixture of dioxane (2 mL) and water (8 mL), N-ethyl-N-isopropyl-propan-2-amine (230.18 mg, 1.78 mmol, 310.22 μL) was added followed by 2-chloroacetic acid (120.2 μL, 1.8 mmol) at room temperature. The reaction mixture was stirred at 65° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give 2-[4-[7-isopropoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]acetic acid (170 mg, 332.95 μmol, 37.39% yield) as an off-white solid. LC-MS (ES + ): m / z 506.37 [M + H] + Step 2: To a stirred solution of 2-[4-[7-isopropoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]acetic acid (20.0 mg, 39.57 μmol) in DMF (2.0 mL) was added N-ethyl-N-isopropyl-propan-2-amine (25.57 mg, 197.83 μmol, 34.46 μL) dropwise at 25° C., followed by the addition of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (25.18 mg, 79.13 μmol). After 5 minutes, a solution of 3-[[6-(4-piperidyl)-3-pyridyl]amino]piperidine-2,6-dione (15.92 mg, 39.57 μmol) in DMF (1.0 mL) was added at room temperature and stirred for 16 hours. After consumption of the starting material, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-[2-[1-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-pyridyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide trifluoroacetate (15.9 mg, 17.85 μmol, 45.11% yield) as an off-white solid. LC-MS (ES) + ): m / z 776.47[M+H] + . 1H NMR (401 MHz, DMSO) δ 10.87 (s, 1H), 10.55 (s, 1H), 9.74 (s, 1H), 8.47 (q, J = 8.3 Hz, 1H), 8.30 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.44-6.97 (m, 7H), 5.09 (d, J = 5.6 Hz, 1H), 4.44 (m, 4H), 3.71 (m, 4H), 3.20 (m, 4H), 2.91 (d, J = 58.7 Hz, 1H), 2.75 (m, 3H), 2.28-2.00 (m, 7H), 1.73 (d, J = 15.8 Hz, 1H), 1.47 (d, J = 5.9 Hz, 6H).

[0232] Example 12 The compound of Example 12 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-(3-fluoro-2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 778.14[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 10.52 (s, 1H), 9.62 (s, 1H), 8.45 (m, 2H), 8.20 (q, J = 25.6 Hz, 1H), 7.54 (m, 4H), 7.18-6.52 (m, 2H), 4.96 (m,1H), 4.55 (d, J = 11.9 Hz, 1H), 4.36 (d, J = 13.9 Hz, 1H), 3.77 (s, 1H), 3.62 (s, 1H), 2.26 (m, 3H), 2.03 (m, 2H), 1.89 - 1.45 (m, 12H), 1.28 (m, 7H), 0.89 (m, 2H).

[0233] Example 13 The compound of Example 13 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[3-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 792.97[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.80 (d, J = 5.9 Hz, 1H), 10.44 (s, 1H), 9.43 (d, J = 5.1 Hz, 1H), 8.44 (m, 2H), 8.24 (t, J = 4.2 Hz, 2H), 7.67 (s, 1H), 7.13 (s, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.68 (t, J = 8.2 Hz, 1H), 6.49 (t, J = 6.7 Hz, 1H), 5.51 (d, J = 7.1 Hz, 1H), 4.87 (m, 1H), 4.47 (t, J = 24.9 Hz, 1H), 4.37 (q, J = 5.7 Hz, 1H), 4.23 (s, 1H), 3.09 (m, 5H), 2.87- 2.50 (m, 3H), 2.03 (m, 6H), 1.72 (m, 5H), 1.40-1.14 (m, 8H).

[0234] Example 14 The compound of Example 14 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-[[2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-6-isopropoxy-imidazo[1,2-a]pyridin-7-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Isomer 2. Example 14 was prepared essentially following the synthesis of Example 11 using 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione Isomer 2. LC-MS (ES) + ): m / z 775.74[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.47 (s, 1H), 9.50 (s, 1H), 8.45 (t, J = 7.8 Hz, 1H), 8.26 (d, J = 7.1 Hz, 1H), 7.78 (s, 1H), 7.15 (t, J = 25.5 Hz, 3H), 6.96 (d, J = 6.7 Hz, 1H), 6.62 (d, J = 7.9 Hz, 2H), 5.71 (d, J = 7.2 Hz, 1H), 4.92 (s, 1H), 4.51 (d, J = 11.1 Hz, 1H), 4.27 (s, 3H), 3.76 (s, 1H), 3.54 (d, J = 26.8 Hz, 1H), 3.04 (d, J = 98.4 Hz, 3H), 2.72 (m, 1H), 2.20 (d, J = 12.8 Hz, 2H), 2.05 (q, J = 14.0 Hz, 3H), 1.85 (m, 4H), 1.57 (d, J = 7.3 Hz, 4H), 1.41 (d, J = 5.9 Hz, 1H), 1.24 (s, 6H), 1.24 (s, 1H).

[0235] Example 15 The compound of Example 15 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-[[2,6-dioxo-3-piperidyl]amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-6-isopropoxy-imidazo[1,2-a]pyridin-7-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Isomer 1. Example 15 Example 15 was prepared essentially following the synthesis of Example 11 using 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione Isomer 1. LC-MS (ES) + ): m / z 775.12 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.44 (q, J = 7.3 Hz, 2H), 8.26 (t, J = 16.6 Hz, 3H), 7.67 (s, 1H), 7.07 (s, 3H), 6.97 (d, J = 8.1 Hz, 2H), 6.63 (d, J = 8.1 Hz, 2H), 5.67 (d, J = 8.1 Hz, 1H), 4.86 (d, J = 5.9 Hz, 1H), 4.47 (s, 1H), 4.25 (t, J = 5.6 Hz, 1H), 4.02 (s, 2H), 3.47 (m, 6H), 3.12 (d, J = 11.7 Hz, 1H), 2.71 (m, 3H), 2.08 (m, 3H), 1.81 (m, 2H), 1.65-1.74 (m, 5H), 1.42 (m, 3H).

[0236] Example 16 The compound of Example 16 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 818.26 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.4 Hz, 2H), 8.24 (d, J = 7.3 Hz, 1H), 7.67 (s, 1H), 7.12 (s, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.5 Hz, 2H), 5.62 (d, J = 7.2 Hz, 1H), 4.87 (m, 1H), 4.24 (t, J = 7.6 Hz, 1H), 3.58 - 3.13 (m, 4H), 3.13 (s, 2H), 2.81 (m, 2H), 2.59 - 2.50 (m, 2H), 2.43 - 2.31 (m, 9H), 2.11 (m, 3H), 1.94 (d, J = 11.6 Hz, 3H), 1.65 (m, 3H), 1.40 (m, 7H).

[0237] Example 17 The compound of Example 17 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES - ): m / z 773.31 [M - H] - . 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.44 (s, 1H), 9.42 (d, J = 3.8 Hz, 1H), 8.43 (m, J = 6.0 Hz, 2H), 8.24 (t, J = 4.2 Hz, 1H), 7.66 (s, 1H), 7.12 (s, 1H), 7.00 (t, J = 7.7 Hz, 1H), 6.48 (m, 3H), 5.76 (d, J = 7.5 Hz, 1H), 4.87 (m, J = 5.8 Hz, 1H), 4.50 (d, J = 12.6 Hz, 1H), 4.22 (m, 1H), 3.04 (t, J = 6.3 Hz, 1H), 2.91 (s, 1H), 2.63 (m, J = 7.1 Hz, 1H), 2.14 (d, J = 10.9 Hz, 1H), 1.95 (d, J = 14.0 Hz, 1H), 1.66 (m, 14H), 1.40 (d, J = 5.9 Hz, 7H), 1.26 (m, 2H), 0.87 (m, 1H).

[0238] Example 18 The compound of Example 18 was prepared essentially following the synthesis of Example 11. [ka] N-(2-(1-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)-7-isopropoxyimidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)picolinamide. LC-MS (ES + ): m / z 833.83 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1 H) 10.44 (s, 1 H) 9.44 - 9.40 (m, 1 H) 8.47 - 8.36 (m, 3 H) 8.26-8.22 (m, 1 H) 7.39 (s, 1 H) 7.16 (d, J=7.2 Hz, 1 H) 7.17-7.09 (m, 2 H) 4.91 - 4.82 (m, 1 H) 3.95 (s, 3 H) 3.92 - 3.87 (m, 2 H) 3.82 - 3.78 (m, 2 H) 3.70-3.65 (m, 2 H) 3.25- 3.20 (m, 4 H) 3.18 - 3.12 (m, 4 H) 3.10 - 2.95 (m, 2 H) 2.16 - 2.14 (m, 2 H) 2.17 - 2.14 (m, 2 H) 1.98- 1.94 (m, 2 H) 1.75 - 1.62 (m, 2 H) 1.40(d, J=6.0 Hz, 6 H).

[0239] Example 19 The compound of Example 19 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 804.61[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.46 (s, 1H), 9.47 (s, 1H), 8.45 (m, 1H), 8.25 (d, J = 7.3 Hz, 1H), 8.14 (s, 2H), 7.75 (s, 1H), 7.14 (s, 1H), 6.94 (d, J = 8.2 Hz, 2H), 6.60 (d, J = 8.3 Hz, 2H), 5.66 (d, J = 7.4 Hz, 1H), 4.90 (m, 1H), 4.26 (m, J = 5.8 Hz, 1H), 3.51 (m, 10H), 2.49-2.78 (m, 9H), 2.10 (q, J = 5.9 Hz, 3H), 1.87 (m, 3H), 1.41 (m, 6H), 1.26 (d, J = 6.5 Hz, 1H).

[0240] Example 20 The compound of Example 20 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 792.97[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.44 (s, 1H), 9.44 (s, 1H), 8.43 (q, J = 8.4 Hz, 2H), 8.24 (d, J = 7.2 Hz, 1H), 8.19 (s, 1H), 7.67 (s, 1H), 7.13 (s, 1H), 7.01 (d, J = 8.2 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H), 5.77 (d, J = 7.3 Hz, 1H), 4.88 (t, J = 6.1 Hz, 1H), 4.29 (d, J = 4.5 Hz, 1H), 3.56 (m, 2H), 3.33 (s, 2H), 3.15 (d, J = 12.7 Hz, 2H), 2.86 (d, J = 10.9 Hz, 2H), 2.70 - 2.50 (m, 3H), 2.40 (m, 2H), 2.25 (s, 1H), 2.12 (t, J = 11.1 Hz, 3H), 1.92 (d, J = 7.8 Hz, 3H), 1.65 (d, J = 10.8 Hz, 2H), 1.40 (m, 8H).

[0241] Example 21 The compound of Example 21 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 776.01 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 14.23 (s, 1H), 10.92 (s, 1H), 10.55 (s, 1H), 9.63 (d, J = 41.6 Hz, 1H), 8.47 (q, J = 8.4 Hz, 1H), 8.30 (d, J = 7.2 Hz, 1H), 8.14 (s, 1H), 7.42 (s, 1H), 7.15 (q, J = 17.1 Hz, 3H), 6.97 (d, J = 8.3 Hz, 1H), 5.14 (m, 2H), 4.43 (m, 1H), 3.75 (d, J = 13.6 Hz, 2H), 3.65 (d, J = 10.9 Hz, 3H), 3.20 (t, J = 12.2 Hz, 4H), 2.71 (m, 4H), 2.18 (m, 6H), 1.86 (d, J = 11.8 Hz, 2H), 1.62 (d, J = 9.9 Hz, 1H), 1.47 (d, J = 5.9 Hz, 6H), 1.19 (t, J = 17.8 Hz, 1H).

[0242] Example 22 The compound of Example 22 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)phenyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 761.05[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.44 (s, 1H), 9.42 (s, 1H), 8.44 (t, J = 8.1 Hz, 2H), 8.24 (d, J = 7.1 Hz, 1H), 8.16 (s, 1H), 7.67 (s, 1H), 7.06-7.12 (t, J = 11.5 Hz, 3H), 6.93 (d, J = 8.6 Hz, 2H), 4.87 (m, 1H), 3.74 (q, J = 5.1 Hz, 3H), 3.60 (s, 2H), 3.15 (t, J = 26.8 Hz, 2H), 2.91 (d, J = 10.9 Hz, 2H), 2.63 (m, 2H), 2.50 (m, 2H), 2.43 (m, 1H), 2.15 (t, J = 11.7 Hz, 3H), 1.99 (m, 3H), 1.66 (d, J = 10.0 Hz, 2H), 1.40 (d, J = 6.0 Hz, 6H), 1.23 (s, 1H).

[0243] Example 23 The compound of Example 23 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 775.46[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.41 (m, J = 11.2 Hz, 2H), 8.23-8.46 (d, J = 7.1 Hz, 2H), 7.66 (s, 1H), 7.14 (s, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 8.2 Hz, 2H), 5.66 (d, J = 7.3 Hz, 1H), 4.87 (m, J = 5.9 Hz, 1H), 4.49 (d, J = 11.8 Hz, 1H), 4.25 (q, J = 10.5 Hz, 2H), 2.83 (m, J = 24.4 Hz, 9H), 2.13 (q, J = 10.3 Hz, 10H), 1.96 (t, J = 13.6 Hz, 1H), 1.76 (m, J = 10.5 Hz, 7H), 1.40 (d, J = 5.9Hz, 1H).

[0244] Example 24 The compound of Example 24 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 793.44[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 14.11 (s, 1H), 10.80 (s, 1H), 10.52 (s, 1H), 9.65 (s, 1H), 8.46 (q, J = 8.1 Hz, 1H), 8.29 (d, J = 6.7 Hz, 1H), 7.99 (s, 2H), 7.08 (m, J = 27.8 Hz, 2H), 6.46 (t, J = 6.6 Hz, 1H), 6.06 (s, 1H), 5.04 (s, 4H), 4.43 (q, J = 29.9 Hz, 2H), 3.69 (m, 8H), 3.08 (m, J = 24.6 Hz, 1H), 2.74 (m, J = 8.3 Hz, 2H), 2.60 (s, 7H), 1.44-1.50 (m, 7H), 1.24 (s, 1H).

[0245] Example 25 The compound of Example 25 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-[(2,4-dioxohexahydropyrimidin-1-yl)methyl]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 775.46[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 10.20 (s, 1H), 9.68 (s, 1H), 8.46 (q, J = 8.3 Hz, 1H), 8.29 (d, J = 7.1 Hz, 1H), 8.06 (s, 1H), 7.36-6.96 (m, 7H), 5.05 (s, 1H), 4.55-4.33 (m, 5H), 3.70 (q, J = 20.2 Hz, 1H), 3.64 (q, J = 20.2 Hz, 2H), 3.36 (m, 6H), 2.82 (t, J = 11.4 Hz, 2H), 2.50 (s, 2H), 2.27 (d, J = 13.9 Hz, 2H), 2.03 (t, J = 17.1 Hz, 2H), 1.88 (t, J = 11.3 Hz, 2H), 1.64 (d, J = 10.4 Hz, 1H), 1.46 (d, J = 5.7 Hz, 6H).

[0246] Example 26 The compound of Example 26 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 816.28[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.53 (d, J = 6.7 Hz, 2H), 9.70 (s, 1H), 8.47 (q, J = 8.4 Hz, 2H), 8.29 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.39 (s, 1H), 7.23-6.90 (m, 5H), 5.06 (s, 1H), 4.40 (s, 2H), 3.91 (m, 5H), 3.73 (s, 2H), 3.62 (t, J = 13.0 Hz, 4H), 3.36 (m, 4H), 2.74 (t, J = 6.5 Hz, 2H), 2.29 (t, J = 14.0 Hz, 2H), 2.04 (t, J = 13.6 Hz, 2H), 1.46 (d, J = 5.9 Hz, 6H).

[0247] Example 27 The compound of Example 27 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 776.34[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.56 (s, 1H), 9.77 (s, 1H), 8.47 (m, 2H), 8.30 (q, J = 2.9 Hz, 1H), 8.19 (d, J = 11.7 Hz, 1H), 7.47 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 6.97 (s, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 8.7 Hz, 2H), 5.11 (t, J = 5.9 Hz, 1H), 4.39 (s, 2H), 4.23 (q, J = 5.2 Hz, 1H), 3.53 (m, 3H), 3.18 (m, 4H), 3.01 (m, 4H), 2.70 (m, 1H), 2.58 (q, J = 7.3 Hz, 1H), 2.27 (m, 3H), 2.06 (m, 2H), 1.87 (m, 1H), 1.47 (d, J = 6.0 Hz, 6H).

[0248] Example 28 The compound of Example 28 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 777.13 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.44 (s, 1H), 9.42 (s, 1H), 8.43 (m, 2H), 8.24 (q, J = 2.9 Hz, 1H), 7.66 (s, 1H), 7.12 (s, 1H), 6.92 (m, 3H), 5.03 (q, J = 5.1 Hz, 1H), 4.87 (m, 1H), 3.74 (s, 2H), 3.60 (s, 2H), 3.31 (s, 1H), 3.20 (s, 2H), 3.02 (d, J = 35.1 Hz, 2H), 2.90 (d, J = 11.2 Hz, 2H), 2.63 (m, 3H), 2.13 (m, 4H), 1.90 (m, 6H), 1.66 (m, 2H), 1.40 (m, 4H).

[0249] Example 29 The compound of Example 29 was prepared essentially following the synthesis of Example 11. [ka] N-[2-[1-[2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 760.00 [M+H] +. 1H NMR (401 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.55 (s, 1H), 9.70 (d, J = 37.2 Hz, 1H), 8.47 (q, J = 8.5 Hz, 2H), 8.30 (d, J = 7.1 Hz, 1H), 8.15 (s, 1H), 7.44 (s, 1H), 7.10 (m, 6H), 5.10 (t, J = 5.7 Hz, 1H), 4.54 (d, J = 13.0 Hz, 1H), 4.38 (q, J = 17.1 Hz, 2H), 3.80 (m, 2H), 3.66 (d, J = 9.9 Hz, 2H), 3.21 (q, J = 10.3 Hz, 4H), 2.81 (q, J = 10.8 Hz, 2H), 2.67 (m, 1H), 2.5 (m, 1H), 2.23 (m, 4H), 2.05 (m, 2H), 1.89 (t, J = 8.2 Hz, 2H), 1.69 (m, 1H), 1.47 (m, 5H).

[0250] Example 30 Synthesis of N-[2-[1-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-3-oxo-propyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: To a solution of N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide trifluoroacetate (1.0 g, 1.78 mmol), anhydrous potassium carbonate (738.44 mg, 5.34 mmol) in acetonitrile (10 mL) stirred at 0° C. for 10 minutes, tert-butyl 3-bromopropanoate (446.85 mg, 2.14 mmol) was added and stirred at 80° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was washed with diethyl ether and then dried to give tert-butyl 3-[4-[7-isopropoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]propanoate (0.600 g, 979.81 μmol, 55.01% yield) as a pale yellow semi-solid. It was used without further purification. LC-MS (ES) + ): m / z 576.83 [M+H] + . Step 2: To a solution of tert-butyl 3-[4-[7-isopropoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]propanoate (0.500 g, 868.63 μmol) in DCM (5 mL) stirred at 0° C. for 10 min, TFA (1.98 g, 17.37 mmol, 1.34 mL) was added and stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure, co-distilled with toluene (twice), and washed with diethyl ether to give 3-[4-[7-isopropoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]propanoic acid trifluoroacetate (0.420 g, 643.06 μmol, 74.03% yield) as a light brown solid. LC-MS (ES) + ): m / z 520.37[M+H] + . Step 3: To a stirred solution of 3-[4-[7-isopropoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]propanoic acid trifluoroacetate (30.0 mg, 47.35 μmol) in DMF (2.0 mL) was added N-ethyl-N-isopropyl-propan-2-amine (30.60 mg, 236.77 μmol, 41.24 μL) dropwise at 25° C., followed by the addition of N,N,N′,N′-tetramethyl-1-(3-oxido-2,3-dihydrotriazolo[4,5-b]pyridin-3-ium-1-yl)methanediamine; hexafluorophosphate (36.20 mg, 94.71 μmol). After 5 minutes, a solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione HCl salt (19.01 mg, 58.70 μmol) in DMF (1.0 mL) was added at room temperature and stirred for 16 hours. After consumption of the starting material, the mixture was concentrated, and the residue was purified by preparative HPLC to give N-[2-[1-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-3-oxo-propyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide trifluoroacetate salt (43.0 mg, 44.46 μmol, 93.90% yield) as a green solid. LC-MS (ES) + ): m / z 789.45[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.55 (s, 1H), 9.75 (s, 1H), 9.33 (s, 1H), 8.47 (q, J = 8.5 Hz, 2H), 8.30 (d, J = 7.2 Hz, 1H), 8.16 (s, 1H), 7.47 (s, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 6.96 (t, J = 6.6 Hz, 2H), 6.62 (d, J = 8.4 Hz, 2H), 5.09 (t, J = 5.9 Hz, 1H), 4.53 (d, J = 12.1 Hz, 1H), 4.27 (q, J = 5.2 Hz, 1H), 3.83 (q, J = 37.6 Hz, 2H), 3.44 (t, J = 26.5 Hz, 2H), 3.12 (t, J = 12.3 Hz, 4H), 2.92 (d, J = 4.6 Hz, 2H), 2.67 (m, 4H), 2.30 (m, 4H), 2.07 (s, 1H), 1.83 (m, 4H), 1.47 (d, J = 5.9 Hz, 6H). Mobile phase (A): 10 mM AA in water Mobile phase (B): Acetonitrile Flow rate: 17ml / min Column: SUNFIRE 5μm (19×150mm) Gradient Time B(%): 0 / 10, 2.5 / 10, 26 / 38.9, 26.10 / 100, 28.10 / 100, 28.20 / 10, 30.20 / 10 Solubility: ACN+THF Number of injections: 5

[0251] Example 31 The compound of Example 31 was prepared essentially following the synthesis of Example 30. [ka] N-[2-[1-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]-3-oxo-propyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 807.34[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.2 Hz, 2H), 8.24 (d, J = 7.2 Hz, 1H), 7.66 (s, 1H), 7.12 (s, 1H), 6.97 (t, J = 8.6 Hz, 1H), 6.45 (t, J = 6.1 Hz, 2H), 6.02 (d, J = 7.8 Hz, 1H), 4.88 (t, J = 6.0 Hz, 1H), 4.53 (d, J = 12.8 Hz, 1H), 4.31 (t, J = 4.2 Hz, 1H), 4.01 (d, J = 12.8 Hz, 1H), 3.09 (t, J = 12.3 Hz, 1H), 2.92 (t, J = 16.1 Hz, 3H), 2.70 (m, 1H), 2.50 (t, J = 1.9 Hz, 7H), 2.08 (t, J = 10.5 Hz, 3H), 1.92 (q, J = 13.2 Hz, 2H), 1.73 (m, 8H), 1.40 (d, J = 5.9 Hz, 6H).

[0252] Example 32 The compound of Example 32 was prepared essentially following the synthesis of Example 30. [ka] N-[2-[1-[3-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]-3-oxo-propyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES+ ): m / z 774.50 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.56 (s, 1H), 9.77 (s, 1H), 9.30 (s, 1H), 8.47 (m, J = 5.0 Hz, 2H), 8.30 (q, J = 2.9 Hz, 1H), 8.19 (s, 1H), 7.48 (s, 1H), 7.22-6.97 (m, 4H), 5.11 (m, 1H), 4.56 (d, J = 13.5 Hz, 1H), 3.92 (m, 1H), 3.832 (m, 1H), 3.42 (t, J = 12.2 Hz, 3H), 3.16 (t, J = 11.0 Hz, 4H), 2.92 (t, J = 5.4 Hz, 2H), 2.81 (s, 1H), 2.67 (m, 2H), 2.31 (m, 2H), 2.17 (m, 2H), 2.04 (m, 1H), 1.86 (m, 4H), 1.62 (s, 1H), 1.47 (m, 7H).

[0253] Example 33 The compound of Example 33 was prepared essentially following the synthesis of Example 30. [ka] N-[2-[1-[3-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperazin-1-yl]-3-oxo-propyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 791.45[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.56 (s, 1H), 9.77 (s, 1H), 9.30 (s, 1H), 8.47 (q, J = 8.3 Hz, 2H), 8.30 (d, J = 7.2 Hz, 1H), 8.18 (s, 1H), 7.48 (s, 1H), 6.94 (m, 5H), 5.08 (m, 2H), 3.68 (m, 3H), 3.14 (m, 6H), 3.02 (s, 1H), 2.94 (t, J = 6.9 Hz, 3H), 2.68 (m, 3H), 2.31 (t, J = 8.0 Hz, 2H), 2.14 (m, 3H), 1.84 (m, 2H), 1.47 (d, J = 6.0 Hz, 6H).

[0254] Example 34 The compound of Example 34 was prepared essentially following the synthesis of Example 30, except starting from N-[2-(azetidin-3-yl)-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. [ka] N-[2-[1-[3-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-3-oxo-propyl]azetidin-3-yl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 761.50 [M+H] + . 1H NMR (401 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.45 (s, 1H), 9.44 (s, 1H), 8.43 (q, J = 8.2 Hz, 2H), 8.25 (d, J = 7.2 Hz, 1H), 7.75 (s, 1H), 7.16 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.5 Hz, 2H), 5.66 (d, J = 7.5 Hz, 1H), 4.88 (m, J = 5.8 Hz, 1H), 4.52 (d, J = 13.5 Hz, 1H), 4.26 (m, 1H), 3.96 (d, J = 12.6 Hz, 1H), 3.61 (s, 4H), 3.18 (s, 2H), 3.07 (t, J = 12.5 Hz, 1H), 2.67 (m, 5H), 2.36 (m, 2H), 2.10 (m, 2H), 1.90 (s, 4H), 1.73 (q, J = 10.7 Hz, 1H), 1.41 (d, J = 6.0 Hz, 6H).

[0255] Synthesis of N-[2-[4-(hydroxymethyl)cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: In a sealed tube, a stirred solution of methyl 4-(hydroxymethyl)cyclohexanecarboxylate (10 g, 58.06 mmol) and bromomethylbenzene (17.28 g, 101.03 mmol, 12 mL) in DIPEA (16.32 g, 126.31 mmol, 22 mL) was stirred at 130 °C for 8 h. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic extracts were washed with water, brine solution, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography on silica (100-200 mesh) using 0-10% EtOAc in PET ether as the eluent to give 4-(benzyloxymethyl)cyclohexanecarboxylate (11.5 g, 43.84 mmol, 75.49% yield) as a yellow liquid. 1 H NMR (400 MHz, DMSO-d6) δ 7.31-7.26 (m, 5H), 4.56 (s, 2H), 3.65 (s, 3H), 3.26 (d, J=6.4 Hz 2H), 2.27- 2.23 (m, 1H), 2.21-1.97 (m, 2H), 2.01-1.97 (m, 2H), 1.89 (m, 1H), 1.56 (m, 2H), 1.01 (m, 2H). Step 2: To a stirred solution of methyl 4-(benzyloxymethyl)cyclohexanecarboxylate (11.5 g, 43.84 mmol) in THF (170 mL) was added sodium chloroacetate (20.42 g, 175.36 mmol) and TEA (17.74 g, 175.36 mmol, 24.44 mL). The reaction mixture was then cooled to −10° C. and tert-butylmagnesium chloride solution (2.0 M in THF) (20.49 g, 175.36 mmol, 161 mL) was added slowly. The temperature was allowed to rise to 25° C. and stirred for 4 h. After complete consumption of the starting material, the reaction mixture was quenched with saturated cold ammonium chloride and extracted twice with ethyl acetate, and the ethyl acetate layer was washed with brine, dried over anhydrous NaSO, and concentrated to give 1-[4-(benzyloxymethyl)cyclohexyl]-2-chloro-ethanone (11 g, 39.18 mmol, 89.36% yield) as a yellow liquid. 1 H NMR (400 MHz, DMSO-d6) δ 7.36-7.26 (m, 5H), 4.56 (s, 2H), 3.65 (s, 3H), 3.28 (d, J=6.4 Hz 2H), 2.27- 2.23 (m, 1H), 2.21-1.97 (m, 1H), 2.01-1.97 (m, 2H), 1.89 (m, 1H), 1.56 (m, 2H), 1.01 (m, 2H). Step 3: In a sealed tube, a stirred solution of 5-bromo-4-isopropoxy-pyridin-2-amine (6 g, 25.96 mmol) and 1-[4-(benzyloxymethyl)cyclohexyl]-2-chloro-ethanone (9.75 g, 34.72 mmol) in ethanol (5 mL) and DIPEA (15.58 g, 120.57 mmol, 21 mL) was added and then heated to 95° C. for 16 h. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic extracts were washed with water, brine solution, dried over anhydrous NaSO, filtered, concentrated under reduced pressure, and purified by flash column chromatography on silica 100-200 mesh using 0-5% MeOH in DCM as eluent to give 2-[4-(benzyloxymethyl)cyclohexyl]-6-bromo-7-isopropoxy-imidazo[1,2-a]pyridine (5 g, 10.06 mmol, 38.73% yield) as a brown liquid. LC-MS (ES) + ): m / z 457.30 [M + H] + Step 4: In a sealed tube, a solution of 2-[4-(benzyloxymethyl)cyclohexyl]-6-bromo-7-olate (2.10 g, 21.86 mmol) in toluene (280 mL) and 2-methylpropan-2-olate (2.10 g, 21.86 mmol) was added. Isopropoxy-imidazo[1,2-a]pyridine (5 g, 10.93 mmol), 6-(trifluoromethyl)pyridine-2-carboxamide (3.25 g, 17.09 mmol) were degassed with argon for 15 minutes. tBuXPhos Pd G3 (1.74 g, 2.19 mmol) was added to the reaction mixture, which was then degassed again for 5 minutes. The reaction mixture was then heated at 90 °C for 5 hours. The reaction mixture was filtered through a Celite bed, the filtrate was concentrated, and the crude compound was purified by silica gel column chromatography (mesh 100-200). The product was eluted with 10% methanol in DCM column chromatography to give N-[2-[4-(benzyloxymethyl)cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (4 g, 6.04 mmol, 55.22% yield). LC-MS (ES) analysis revealed that the elution was 10% methanol in DCM. + ): m / z 565.22 [M+H] + . Step 5: To a stirred solution of N-[2-[4-(benzyloxymethyl)cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (4 g, 7.06 mmol) in a mixture of methanol (50 mL) and ethanol (50 mL), purging with hydrogen gas was added 10% palladium on carbon (4 g, 37.59 mmol) and concentrated HCl (254.14 mg, 7.06 mmol, 2 mL), and the reaction mixture was stirred under a hydrogen atmosphere (rubber bladder filled with hydrogen gas at 1 atmosphere pressure) at room temperature for 5 hours. After complete consumption of the starting material, the reaction mixture was filtered through a Celite bed and washed with methanol (50 mL × 2). The filtrate was concentrated to give N-[2-[4-(hydroxymethyl)cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (2.8 g, 5.35 mmol, 75.74% yield). LC-MS (ES) + ): m / z 477.30 [M+H] + .

[0256] Example 35 Synthesis of N-[2-[4-[[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: To a stirred solution of N-[2-[4-(hydroxymethyl)cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (1 g, 2.10 mmol) in DCM (25 mL) was added Dess-Martin periodinane (2.67 g, 6.30 mmol) at 0-5 °C, and the reaction temperature was raised to 25 °C and stirred for 8 h. After completion of the reaction, the reaction was quenched with saturated, cold sodium bicarbonate and extracted twice with DCM. The DCM layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to give N-[2-(4-formylcyclohexyl)-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (0.7 g, 811.42 μmol, 38.66% yield) as a yellow solid. LC-MS (ES) + ): m / z 475.34 [M+H] + . Step 2: To a stirred solution of N-[2-(4-formylcyclohexyl)-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (0.1 g, 210.76 μmol) and 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione trifluoroacetate (52.93 mg, 136.99 μmol) in methanol (5 mL), the reaction mixture was cooled to 20° C. and sodium cyanoborohydride (35 mg, 556.95 μmol) was added, followed by stirring at 25° C. for 16 hours. After completion of the reaction, methanol was evaporated and the residue was purified by HPLC to give N-[2-[4-[[4-[4-(2,6-dioxo-3-piperidyl)phenyl]-1-piperidyl]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide formate (18.3 mg, 22.85 μmol, 10.84% ​​yield) as a white solid. LC-MS (ES) + ): m / z 731.34[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (d, J = 6.2 Hz, 1H), 10.47 (s, 1H), 9.50 (s, 1H), 8.44 (m, 2H), 8.26 (d, J = 6.9 Hz, 1H), 8.13 (s, 1H), 7.73 (s, 1H), 7.12 (d, J = 24.4 Hz, 2H), 6.52 (m, 4H), 5.90 (s, 1H), 4.93 (s, 1H), 4.31 (m, 1H), 3.60 (s,1H), 3.07 (m, 7H), 2.50 (m, 4H), 2.10 (t, J = 11.4 Hz, 3H), 1.94 -1.71 (m, 9H), 1.42 (m, 8H), 1.15 (t, J = 11.6 Hz, 2H). Preparative HPLC conditions: Column / Dimensions: X SELECT C18 (19*250, 5um) Mobile phase A: 0.05% TFA in water Mobile phase B: 100% acetonitrile Gradient (time / B(%)) 0 / 10, 4 / 10, 26 / 38.3, 26.10 / 95, 28 / 95, 28.1 / 10, 30. Flow rate: 16ml / min Solubility: water + ACN + THF

[0257] Example 36 The compound of Example 36 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 775.16[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.5 Hz, 1H), 8.23 ​​(t, J = 6.6 Hz, 2H), 7.66 (d, J = 29.2 Hz, 1H), 7.12 (d, J = 13.3 Hz, 1H), 6.76-6.53 (m, 9H), 5.36 (m, 1H), 4.87 (m, 1H), 4.18 (m, 1H), 3.34 (m, 2H), 2.67 (m, 2H), 2.58-2.38 (m, 3H), 2.23 (m, 5H), 2.08 (m, J = 7.1 Hz, 2H), 1.82 (m, 5H), 1.56 (d, J = 5.9 Hz, 9H), 1.00 (t, J = 11.3 Hz, 2H).

[0258] Example 37 The compound of Example 37 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 801.45[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.2 Hz, 1H), 8.27 (t, J = 14.0 Hz, 3H), 7.63 (s, 1H), 7.11 (s, 1H), 7.01 (m, 3H), 5.37 (q, J = 5.9 Hz, 1H), 4.87 (m, J = 6.0 Hz, 1H), 3.59 (s, 3H), 3.35 (s, 2H), 2.99 (m, 2H), 2.89 (m, 1H), 2.64 (q, J = 10.9 Hz, 1H), 2.58 (q, J = 10.9 Hz, 2H), 2.19 (m, 5H), 1.99 (m, 2H), 1.79 (m, 4H), 1.58 (m, 1H), 1.40 (m, 8H), 1.05 (m, 2H).

[0259] Example 38 The compound of Example 38 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[4-[3-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 764.39 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.2 Hz, 2H), 8.22-8.19 (m, 3H), 7.63 (s, 1H), 7.11 (s, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.67 -6.55 (m, 3H), 5.48 (d, J = 5.4 Hz, 1H), 4.87 (m, 1H), 4.37 (t, J = 8.3 Hz, 1H), 2.97 (d, J = 9.7 Hz, 2H), 2.75 (q, J = 5.8 Hz, 2H), 2.50 (t, J = 1.6 Hz, 2H), 2.18 (m, 8H), 1.90 (d, J = 11.1 Hz, 2H), 1.66 (m, 4H), 1.40 (m, 6H), 1.03 (q, J = 11.1 Hz, 2H).

[0260] Example 39 The compound of Example 39 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[4-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 746.37[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (m, 2H), 8.27- 8.23 ​​(m, 3H), 7.62 (s, 1H), 7.11 (s, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.57 (s, 1H), 6.47 (t, J = 10.0 Hz, 3H), 5.71 (d, J = 7.6 Hz, 1H), 4.87 (m,1H), 4.34 (m, 1H), 2.94 (d, J = 10.9 Hz, 2H), 2.74 (q, J = 5.8 Hz, 1H), 2.50 (d, J = 1.8 Hz, 1H), 2.33 (t, J = 1.8 Hz, 2H), 2.10 - 2.07 (m, 5H), 1.90 -1.55 (m, 5H), 1.63-1.55 (m, 4H), 1.40 (d, J = 6.0 Hz, 6H), 1.02 (d, J = 11.4 Hz, 2H).

[0261] Example 40 The compound of Example 40 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[[1-[4-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 760.29 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.77 (d, J = 4.9 Hz, 1H), 10.45 (s, 1H), 9.45 (s, 1H), 8.43 (q, J = 8.0 Hz, 2H), 8.25 (t, J = 4.3 Hz, 1H), 8.13 (s, 2H), 7.66 (s, 1H), 7.08 (m, 3H), 6.91 (t, J = 8.8 Hz, 2H), 6.52 (m, 5H), 4.89 (m, 1H), 3.76 (m, 1H), 2.89 (m, 3H), 2.63 (m, 3H), 2.02 -1.72 (m, 9H), 1.41 (m, 9H), 1.16 (m, 2H).

[0262] Example 41 The compound of Example 41 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[4-[4-(2,6-dioxo-3-piperidyl)-2-fluoro-phenyl]-1-piperidyl]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 749.36[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (m, 2H), 8.24 (t, J = 4.2 Hz, 2H), 7.63 (s, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.11 (s, 1H), 7.03 (t, J = 8.2 Hz, 2H), 4.87 (m, 1H), 3.86 (q, J = 5.6 Hz, 1H), 2.96 (d, J = 11.0 Hz, 2H), 2.69 (m, 6H), 2.20 (m, 3H), 1.98 (m, 6H), 1.72 -1.57 (m, 5H), 1.40 (m,6H), 1.02 (m, 2H).

[0263] Example 42 The compound of Example 42 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 830.10[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 14.04 (s, 1H), 11.10 (s, 1H), 10.56 (s, 1H), 9.78 (s, 1H), 9.01 (s, 1H), 8.47 (q, J = 8.3 Hz, 2H), 8.30 (d, J = 7.2 Hz, 1H), 8.12 (s, 1H), 7.41 (s, 1H), 7.06 (m, 4H), 5.37 (q, J = 5.9 Hz, 1H), 5.12 (m, 1H), 3.66 (s, 3H), 3.26 (m, 4H), 2.84 (m, 8H), 2.50 (m, 2H), 2.13-1.90 (m, 8H), 1.47 (m, 6H), 1.25 (m, 3H).

[0264] Example 43 The compound of Example 43 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[[1-[3-(2,6-dioxo-3-piperidyl)phenyl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 760.12 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.78 (d, J = 7.8 Hz, 1H), 10.44 (s, 1H), 9.42 (s, 1H), 8.42- 8.24(m, 4H), 7.66 (d, J = 27.9 Hz, 1H), 7.13 (q, J = 7.6 Hz, 2H), 6.81 (t, J = 8.2 Hz, 3H), 6.59 (d, J = 7.3 Hz, 1H), 4.87 (m, 1H), 3.73 (q, J = 7.9 Hz, 3H), 2.63 (m, 4H), 2.44 (m, 2H), 2.22 (m, 6H), 2.04 (t, J = 9.6 Hz, 2H), 1.88 (d, J = 10.6 Hz, 2H), 1.74 (m, 2H), 1.40 (m, 11H), 0.99 (m, 2H).

[0265] Example 44 The compound of Example 44 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[[1-[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 775.16[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.75 (d, J = 7.7 Hz, 1H), 10.44 (s, 1H), 9.42 (s, 1H), 8.41 (m, 2H), 8.35-8.24 (m, 3H), 7.66 (d, J = 28.2 Hz, 1H), 7.12 (d, J = 12.4 Hz, 1H), 6.90 (t, J = 7.9 Hz, 1H), 6.26-6.10 (m, 3H), 5.60 (d, J = 7.5 Hz, 1H), 4.87 (t, J = 6.0 Hz, 1H), 4.29 (q, J = 5.5 Hz, 1H), 3.66 (d, J = 10.4 Hz, 1H), 2.73 (m, 2H), 2.59 (q, J = 10.0 Hz, 3H), 2.37 (d, J = 34.5 Hz, 1H), 2.21 (m, 5H), 2.08 (t, J = 16.5 Hz, 3H), 1.87 (t, J = 11.0 Hz, 3H), 1.76 (t, J = 19.1 Hz, 3H), 1.40 (m, 10H), 0.99 (m, 1H).

[0266] Example 45 The compound of Example 45 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 831.10[M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.97 (s, 1H), 11.07 (s, 1H), 10.55 (s, 1H), 9.76 (s, 1H), 8.94 (s, 1H), 8.48 (t, J = 8.2 Hz, 2H), 8.30 (d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.39 (s, 1H), 7.21-6.96 (m, 9H), 6.87 (s, 1H), 6.68 (d, J = 8.2 Hz, 1H), 5.30 (t, J = 6.4 Hz, 1H), 5.11 (s, 1H), 3.79 (d, J = 11.3 Hz, 2H), 3.35-3.17 (m, 5H), 2.07 (m, 7H), 1.87 (t, J = 13.6 Hz, 4H), 1.47 (m, 7H), 1.19 (t, J = 18.0 Hz, 2H).

[0267] Example 46 The compound of Example 46 was prepared essentially following the synthesis of Example 35. [ka] N-[2-[4-[[[1-[[3-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]-4-piperidyl]-methyl-amino]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 787.49 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.80 (d, J = 6.2 Hz, 1H), 10.47 (s, 1H), 9.50 (s, 1H), 8.44 (m, 2H), 8.26 (d, J = 6.9 Hz, 1H), 8.13 (s, 1H), 7.73 (s, 1H), 7.12 (d, J = 24.4 Hz, 2H), 6.52 (m, 4H), 5.90 (s, 1H), 4.93 (s, 1H), 4.31 (m, 1H), 3.60 (s,1H), 3.07 (m, 7H), 2.50 (m, 4H), 2.10 (t, J = 11.4 Hz, 3H), 1.94 -1.71 (m, 9H), 1.42 (m, 8H), 1.15 (t, J = 11.6 Hz, 2H).

[0268] Example 47 Synthesis of N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: A stirred solution of N-[2-[4-(hydroxymethyl)cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (1 g, 2.10 mmol) in DCM (70 mL) was cooled to 0-5 °C, and TEA (1.09 g, 10.76 mmol, 1.50 mL) was added. Methanesulfonyl chloride (2.04 g, 17.84 mmol, 1.38 mL) was added dropwise, and the reaction mixture was stirred at 0-5 °C for 2 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was concentrated, and the crude material was purified by silica gel column chromatography (0-10% methanol / DCM) to give 4-[7-isopropoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]imidazo[1,2-a]pyridin-2-yl]cyclohexyl]methyl methanesulfonate (0.7 g, 1.19 mmol, 56.53% yield). LC-MS (ES) + ): m / z 555.63 [M + H] + Step 2: To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione trifluoroacetate (123.45 mg, 270.47 μmol) in DMF (5 mL) at 25° C. was added cesium carbonate (88.13 mg, 270.47 μmol) and the mixture was stirred for 15 minutes, after which a solution of [4-[7-isopropoxy-6-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]imidazo[1,2-a]pyridin-2-yl]cyclohexyl]methyl methanesulfonate (0.1 g, 180.32 μmol) in DMF (0.5 mL) was added dropwise and the reaction mixture was stirred at 90° C. for 4 hours. DMF was evaporated and the residue was purified by HPLC to give N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidyl]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (18.8 mg, 21.19 μmol, 11.75% yield) as a white solid. LC-MS (ES) + ): m / z 801.42[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.3 Hz, 2H), 8.24 (d, J = 7.2 Hz, 1H), 7.63 (s, 1H), 7.11 (s, 1H), 7.00 (m, 3H), 5.37 (q, J = 5.9 Hz, 1H), 4.88 (m, 1H), 3.59 (s, 3H), 3.17 (d, J = 5.2 Hz, 1H), 2.92 (m, 1H), 2.66 (m, 4H), 2.19 (d, J = 6.7 Hz, 2H), 2.05 (m, 5H), 1.91 (d, J = 13.6 Hz, 2H), 1.79-1.57 (m, 5H), 1.40 (m, 8H), 1.23-1.07 (m, 3H). Preparative HPLC conditions: Mobile phase (A): 0.1% TFA in HO Mobile phase (B): 100% acetonitrile Flow rate: 16ml / min Column: SUNFIRE C18 5μm (19×150mm) Gradient time B percentage (%): 0 / 15, 2 / 15, 10 / 35, 16 / 35, 16.1 / 100

[0269] Example 48 The compound of Example 48 was prepared essentially following the synthesis of Example 47. [ka] N-[2-[4-[[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]methyl]cyclohexyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 764.12 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.43 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.2 Hz, 1H), 8.24 (d, J = 7.1 Hz, 1H), 8.14 (s, 1H), 7.62 (s, 1H), 7.10 (s, 1H), 7.00 (t, J = 8.8 Hz, 1H), 6.45 (t, J = 8.5 Hz, 2H), 5.99 (d, J = 7.4 Hz, 1H), 4.87 (t, J = 5.9 Hz, 1H), 4.30 (t, J = 12.0 Hz, 1H), 3.30 (s, 2H), 2.50 (m, 4H), 2.29- 2.07 (m, 7H), 1.88 (q, J = 9.3 Hz, 3H), 1.65 -1.60 (m, 5H), 1.40 (m, 8H), 1.35-1.04 (m, 2H).

[0270] Synthesis of methyl 2-(1-tert-butoxycarbonyl-4-piperidyl)-6-isopropoxy-indazole-5-carboxylate [ka] Step 1: To a solution of 2-fluoro-4-hydroxybenzaldehyde (20.00 g, 142.74 mmol) in DMF (200 mL) was added potassium carbonate (39.46 g, 285.49 mmol) and 2-iodopropane (26.69 g, 157.02 mmol, 15.70 mL). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (2000 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic layers were washed with brine (1000 mL) and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give 2-fluoro-4-isopropoxybenzaldehyde (22 g, 120.62 mmol, 84.50% yield) as a colorless oil. LC-MS (ES) + ): m / z 183.1 [M+H] + . Step 2: To a solution of 2-fluoro-4-isopropoxy-benzaldehyde (40 g, 219.55 mmol) in acetic acid (800 mL) was added dropwise a solution of molecular bromine (38.59 g, 241.50 mmol) in acetic acid (40 mL) at 20° C. The reaction mixture was stirred at 50° C. for 16 hours. After consumption of the reactants as indicated by TLC and LC-MS, the mixture was filtered and concentrated under reduced pressure to give 5-bromo-2-fluoro-4-isopropoxy-benzaldehyde (50 g, 147.46 mmol, 67.16% yield) as a yellow oil, which was used in the next step without purification. LC-MS (ES) + ): m / z 260.9 [M+H] + . Step 3: To a solution of 5-bromo-2-fluoro-4-isopropoxybenzaldehyde (50 g, 124.48 mmol) in ethanol (500 mL) was added hydroxylamine hydrochloride (8.65 g, 124.48 mmol, 5.18 mL) and potassium carbonate (18.92 g, 136.93 mmol). The reaction mixture was stirred at 100° C. for 2 hours. After consumption of the reactants as indicated by LC-MS, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give (£)-5-bromo-2-fluoro-4-isopropoxybenzaldehyde oxime (50 g, 139.44 mmol) as a yellow oil, which was used without further purification. LC-MS (ES) + ): m / z 276.0 [M+H] + . Step 4: To a solution of (E)-5-bromo-2-fluoro-4-isopropoxy-benzaldehyde oxime (50 g, 181.09 mmol) in DMA (500 mL) was added hydrazine hydrate (96.97 g, 1.94 mol, 94.15 mL). The reaction mixture was stirred at 140 °C for 16 h. After the consumption of the reactants was confirmed by LC-MS, the reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (1000 mL × 3). The combined organic layers were washed with aqueous NaCl (1000 mL × 2), dried over Na2SO4, filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 5-bromo-6-isopropoxy-1H-indazole (17 g, 48.65 mmol, 26.86% yield) as a yellow oil. LC-MS (ES) + ): 254.9 m / z [M+H] + . Step 5: To a solution of 5-bromo-6-isopropoxy-1H-indazole (14 g, 54.88 mmol) in DMF (150 mL) were added dicesium carbonate (35.76 g, 109.76 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (19.93 g, 71.34 mmol). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL*3). The combined organic layers were washed with brine (200 mL*2), dried over Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (Biotage Isolera One, 1.D. 95 mm x H 365 mm Welch Ultimate XB_C18 20-40 μm; 120A; mobile phase, MeCN / HO, gradient B%, 30-80% in 30 min; 80% in 25 min). The compound tert-butyl 4-(5-bromo-6-isopropoxy-2H-indazol-2-yl)piperidine-1-carboxylate (2.1 g, 4.75 mmol, 8.66% yield) was obtained as a white solid. LC-MS (ES) + ): m / z 438.2 [M+H] + . Step 6: A vial was charged with tert-butyl 4-(5-bromo-6-isopropoxy-2H-indazol-2-yl)piperidine-1-carboxylate (7, 1.5 g, 3.42 mmol), diacetoxypalladium (153.65 mg, 684.37 μmol), Xantphos (791.98 mg, 1.37 mmol), and dicesium carbonate (2.23 g, 6.84 mmol). The vial was evacuated, backfilled with N2, and sealed with a septa-equipped screw cap. A solution of 6-(trifluoromethyl)picolinamide (715.63 mg, 3.76 mmol) in dioxane (45 mL) was added via syringe at 20 °C. The vial was sealed and heated at 100 °C for 16 h. LC-MS confirmed complete consumption of the reactants and the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (120 g silica, 0-70% ethyl acetate / petroleum ether gradient elution) to afford tert-butyl 4-(6-isopropoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)piperidine-1-carboxylate (762.98 mg, 1.34 mmol, 39.09% yield) as a yellow solid. LC-MS (ES) + ): m / z 548.1 [M+H] +

[0271] Example 49 Synthesis of N-(2-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)-6-isopropoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide [ka] Step 1: A solution of tert-butyl 4-[6-isopropoxy-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazol-2-yl]piperidine-1-carboxylate (650 mg, 1.19 mmol) in HCl / dioxane (10 mL) was stirred at 20° C. for 2 hours. The reaction mixture was concentrated. The crude product, N-[6-isopropoxy-2-(4-piperidyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide hydrochloride (580 mg, 1.11 mmol, 93.90% yield), was used in the next step without further purification. LC-MS (ES) + ): 448.0 [M+H] + Step 2: To a solution of N-[6-isopropoxy-2-(4-piperidyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide hydrochloride (180 mg, 371.97 μmol) in DMF (3 mL) was added TEA (112.92 mg, 1.12 mmol, 155.53 μL) and tert-butyl 2-bromoacetate (72.55 mg, 371.97 μmol, 54.55 μL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product, tert-butyl 2-[4-[6-isopropoxy-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazol-2-yl]-1-piperidyl]acetate (3, 200 mg, 327.64 μmol, 88.08% yield), was used in the next step without further purification. LC-MS (ES + ): 562.1 [M + H] + Step 3: To a solution of tert-butyl 2-[4-[6-isopropoxy-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazol-2-yl]-1-piperidyl]acetate (170 mg, 302.71 μmol) in DCM (3.5 mL) was added HCl (12 M, 252.26 μL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product, 2-[4-[6-isopropoxy-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazol-2-yl]-1-piperidyl]acetic acid hydrochloride (120 mg, 205.92 μmol, 68.03% yield), was used in the next step without further purification. LC-MS (ES) + ): 506.0 [M +H] + Step 4: To a solution of 2-[4-[6-isopropoxy-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazol-2-yl]-1-piperidyl]acetic acid hydrochloride (50 mg, 92.26 μmol) and 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione hydrochloride (29.88 mg, 92.26 μmol) in DMF (500 μL) was added HATU (52.62 mg, 138.39 μmol) and DIPEA (71.54 mg, 553.56 μmol, 96.42 μL). The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was directly purified by preparative HPLC (FA conditions). The compound N-(2-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)-6-isopropoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide formate (48.41 mg, 54.26 μmol, 58.81% yield) was obtained as a white solid. "FA Condition" Method Equipment: Gilson-281 Column: Shim-pack C18 150mm*25mm*10um Mobile phase: A for HO (0.225% FA v / v), B for acetonitrile Gradient: B 24% to 64% linear in 13 minutes Flow rate: 25ml / min Column temperature: room temperature Wavelength: 220nm / 254nm 1 H NMR (400MHz, DMSO-d6): δ= 10.77 (d, J = 8.0 Hz, 2H), 9.87 - 9.56 (m, 1H), 8.76 (s, 1H), 8.51 - 8.37 (m, 3H), 8.23 ​​(d, J =7.7 Hz, 1H), 7.22 (s, 1H), 6.97 (br d, J = 8.3 Hz, 2H), 6.63 (br d, J = 8.3 Hz, 2H), 5.71 (br d, J = 7.4 Hz, 1H), 4.96 - 4.65 (m,2H), 4.60 - 4.24 (m, 4H), 3.88 - 3.66 (m, 2H), 3.63 - 3.39 (m, 3H), 3.26 - 3.05 (m, 2H), 2.85 - 2.69 (m, 3H), 2.63 - 2.56 (m, 3H),2.45 - 2.35 (m, 2H), 2.15 - 2.07 (m, 1H), 1.94 - 1.75 (m, 3H), 1.67 - 1.53 (m, 1H), 1.42 (d, J = 6.0 Hz, 7H).LC-MS (ES + ): m / z 775.1 [M + H] +

[0272] Example 50 The compound of Example 50 was prepared essentially following the synthesis of Example 49. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-6-isopropoxy-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide 1H NMR (400MHz, DMSO-d6): δ= 10.78 (d, J = 15.9 Hz, 2H), 9.95 - 9.45 (m, 1H), 8.76 (s, 1H), 8.50 - 8.36 (m, 3H), 8.23 ​​(d, J = 7.7 Hz, 1H), 7.22 (s, 1H), 6.97 (t, J = 8.6 Hz, 1H), 6.53 - 6.42 (m, 2H), 6.06 (br d, J = 7.8 Hz, 1H), 4.94 - 4.81 (m, 1H), 4.75 -4.22 (m, 4H), 3.84 - 3.62 (m, 1H), 3.25 - 3.08 (m, 3H), 3.06 - 2.86 (m, 2H), 2.83 - 2.70 (m, 2H), 2.60 (br d, J = 3.5 Hz, 2H), 2.44- 2.36 (m, 2H), 2.14 - 2.02 (m, 2H), 1.95 - 1.60 (m, 5H), 1.49 (br dd, J = 2.8, 11.8 Hz, 2H), 1.42 (d, J = 6.0 Hz, 6H). LC-MS (ES + ): m / z 793.1 [M + H] +

[0273] Example 51 Synthesis of N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]-6-isopropoxy-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: To a solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (100 mg, 348.00 μmol), tert-butyl 2-bromoacetate (67.88 mg, 348.00 μmol, 51.04 μL) in DMF (1.5 mL) was added TEA (35.21 mg, 348.00 μmol, 48.50 μL). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (90 mg, 211.14 μmol, 60.67% yield) as a white solid. LC-MS (ESI) m / z 402.3 (M+H) + Step 2: To a solution of tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (100 mg, 249.07 μmol) in DCM (1 mL) was added a 37% aqueous solution of concentrated HCl (90.81 mg, 2.49 mmol, 113.52 μL). The mixture was stirred at 25 °C for 1 h and then concentrated under reduced pressure. The residue was dissolved in HO (1 mL) and MeCN (2 mL), and the resulting solution was concentrated under reduced pressure again to give 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid HCl salt (2, 50 mg, 115.19 μmol, 46.25% yield) as a green solid, which was used directly in the next step without further purification. LC-MS (ESI): m / z 297.0 (M+H) + Step 3: To a solution of N-[6-isopropoxy-2-(4-piperidyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (90 mg, 201.14 μmol) and 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid (76.81 mg, 201.14 μmol, HCl salt) in DMF (1 mL) was added HATU (114.72 mg, 301.71 μmol) and diisopropylethylamine (155.97 mg, 1.21 mmol, 210.21 μL). The mixture was stirred at 25° C. for 3 h. The reaction mixture was filtered and then purified by preparative HPLC (FA conditions) to give N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]-6-isopropoxy-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide formate (6.53 mg, 7.73 μmol, 3.84% yield) as a white solid. "FA Condition" Method Equipment: Gilson-281 Column: Shim-pack C18 150mm*25mm*10um Mobile phase: A for HO (0.225% FA v / v), B for acetonitrile Gradient: B 24% to 64% linear in 13 minutes Flow rate: 25ml / min Column temperature: room temperature Wavelength: 220nm / 254nm 1H NMR (400 MHz, DMSO-d6): δ = 10.85 - 10.69 (m, 2H), 8.73 (s, 1H), 8.48 - 8.36 (m, 3H), 8.31 (s, 1H), 8.22 (dd, J = 0.9, 7.6Hz, 1H), 7.20 (s, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 5.63 (d, J = 7.5 Hz, 1H), 4.84 (td, J = 6.0, 12.0 Hz,1H), 4.77 - 4.63 (m, 1H), 4.49 (br d, J = 13.1 Hz, 1H), 4.35 - 4.19 (m, 2H), 2.92 (br d, J = 7.9 Hz, 2H), 2.83 - 2.66 (m, 2H), 2.61- 2.53 (m, 1H), 2.39 - 2.28 (m, 2H), 2.23 - 2.02 (m, 6H), 1.98 - 1.78 (m, 2H), 1.77 - 1.52 (m, 4H), 1.40 (d, J = 6.0 Hz, 6H) LC-MS (ESI): m / z 775.2 (M+H) +

[0274] Example 52 The compound of Example 52 was prepared essentially following the synthesis of Example 41. [ka] N-(2-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetyl)piperidin-4-yl)-6-isopropoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide. 1H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 10.74 (s, 1H), 8.74 (s, 1H), 8.48 - 8.38 (m, 2H), 8.37 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.18 (s, 1H), 6.99 (br s, 1H), 6.52 - 6.43 (m, 2H), 6.08 (br d, J = 6.8 Hz, 1H), 4.84 (td, J = 6.0, 12.0 Hz, 1H), 4.75 (br t, J = 10.8 Hz, 1H), 4.51 (br d, J = 13.6 Hz, 1H), 4.32 (m, 1H), 4.06 - 3.80 (m, 1H), 3.62 - 3.41 (m, 2H), 3.26 - 3.12 (m, 1H), 3.08 - 2.80 (m, 3H), 2.79 - 2.63 (m, 2H), 2.63 - 2.58 (m, 1H), 2.57 - 2.53 (m, 1H), 2.29 - 2.03 (m, 5H), 2.02 - 1.64 (m, 6H), 1.41 (d, J = 5.6 Hz, 6H).LC-MS (ES + ): m / z 793.4.

[0275] Synthesis of tert-butyl 4-(6-amino-7-isopropoxyimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate [ka] Step 1: To a solution of tert-butyl 4-(6-bromo-7-isopropoxy-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (6 g, 13.69 mmol) in NMP (60 mL) was added 30% ammonium hydroxide (39.97 g, 342.19 mmol, 44.42 m) and copper oxide (391.71 mg, 2.74 mmol). The mixture was stirred at 90 °C for 16 h. After complete consumption of the reactants as confirmed by LC-MS, the reaction mixture was diluted with HO (150 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (150 mL × 2), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1). The compound tert-butyl 4-(6-amino-7-isopropoxyimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (3.5 g, 8.60 mmol, 62.82% yield) was obtained as a yellow oil. LC-MS (ES + ): m / z 375.2 [M+H] + .

[0276] Example 53 Synthesis of N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]pyrimidine-4-carboxamide [ka] Step 1: To a solution of tert-butyl 4-(6-amino-7-isopropoxy-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (100 mg, 267.04 μmol) and pyrimidine-4-carboxylic acid (49.71 mg, 400.56 μmol) in DMF (1 mL) was added HATU (152.30 mg, 400.56 μmol) and diisopropylethylamine (345.13 mg, 2.67 mmol, 465.14 μL). The mixture was stirred at 25° C. for 3 hours. After consumption of the reactants as indicated by LC-MS, the reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL×4). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give an oil, which was purified by preparative TLC (pet ether:ethyl acetate=0:1) to give tert-butyl 4-[7-isopropoxy-6-(pyrimidine-4-carbonylamino)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (70 mg, 121.34 μmol, 45.44% yield) as a yellow solid. LC-MS (ES + ): m / z 481.3 [M+H] + . Step 2: A solution of tert-butyl 4-[7-isopropoxy-6-(pyrimidine-4-carbonylamino)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (60 mg, 124.85 μmol) in dioxane / HCl (4 M, 1 mL) was stirred at 25° C. for 16 hours. After complete consumption of the reactant as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure to give N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]pyrimidine-4-carboxamide HCl salt (50 mg, 119.93 μmol, 96.06% yield) as a yellow solid, which was used in the next step without purification. LC-MS (ES) + ): m / z 381.3 [M+H] + Step 3: To a solution of N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]pyrimidine-4-carboxamide (52 mg, 124.73 μmol, HCl salt) and tert-butyl 2-bromoacetate (24.33 mg, 124.73 μmol, 18.29 μL) in DMF (1 mL) was added TEA (100.97 mg, 997.83 μmol, 139.08 μL), and the mixture was stirred for 3 h at 25° C. After complete consumption of the reactants as indicated by LC-MS, the reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL×4). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give tert-butyl 2-[4-[7-isopropoxy-6-(pyrimidine-4-carbonylamino)imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]acetate (60 mg, 108.21 μmol, 86.76% yield) as a yellow solid, which was used without further purification. LC-MS (ES) + ): m / z 495.3 [M+H] + Step 4: To a solution of tert-butyl 2-[4-[7-isopropoxy-6-(pyrimidine-4-carbonylamino)imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]acetate (45 mg, 90.99 μmol) in DCM (1 mL) was added HCl (80.00 mg, 2.19 mmol, 0.1 mL). The mixture was stirred for 16 h. After complete consumption of the reactant as indicated by LC-MS, the reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give 2-[4-[7-isopropoxy-6-(pyrimidine-4-carbonylamino)imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]acetic acid (25 mg, 56.21 μmol, 61.78% yield) as a white solid. LC-MS (ES) + ): m / z 439.3 [M+H] + Step 5: To a solution of 2-[4-[7-isopropoxy-6-(pyrimidine-4-carbonylamino)imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]acetic acid (20 mg, 45.61 μmol) in DMF (0.5 mL) was added HATU (26.01 mg, 68.42 μmol), diisopropylethylamine (47.16 mg, 364.90 μmol, 63.56 μL), and 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (15.73 mg, 54.73 μmol). The mixture was stirred at 25° C. for 3 hours. After complete consumption of the reactants as indicated by LC-MS, the reaction mixture was filtered and the filtrate was purified by preparative HPLC (TFA conditions) to give N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]pyrimidine-4-carboxamide TFA salt (6.8 mg, 7.97 μmol, 17.48% yield) as a green solid. "TFA condition" method Equipment: Gilson-281 Column: Phenomenex Synergi C18 150mm*25mm* 10um Mobile phase: A for HO (0.075% TFA v / v), B for acetonitrile Gradient: B: Linear 10% to 40% in 10 minutes Flow rate: 25ml / min Column temperature: room temperature Wavelength: 220nm / 254nm 1H NMR (400 MHz, DMSO-d6) δ = 10.79 (s, 1H), 10.50 (s, 1H), 9.72 (s, 2H), 9.49 (d, J = 0.9 Hz, 1H), 9.22 (d, J = 5.0 Hz, 1H),8.26 - 8.12 (m, 2H), 7.47 (s, 1H), 6.96 (br d, J = 8.4 Hz, 2H), 6.62 (br d, J = 8.4 Hz, 2H), 5.08 (td, J = 6.0, 11.9 Hz, 1H), 4.60 -4.17 (m, 4H), 3.76 - 3.63 (m, 2H), 3.23 - 3.11 (m, 4H), 2.60 (br s, 4H), 2.23 (br s, 3H), 2.14 - 1.95 (m, 3H), 1.94 - 1.73 (m, 3H),1.65 - 1.54 (m, 1H), 1.47 (d, J = 6.0 Hz, 6H).LC-MS (ES + ): m / z 708.0 [M+H] +

[0277] Example 54 The compound of Example 54 was prepared essentially following the synthesis of Example 53. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-3-(trifluoromethyl)benzamide LC-MS (ES + ): m / z 774.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ = 10.78 (s, 1H), 10.22 (s, 1H), 9.79 - 9.58 (m, 1H), 9.27 (s, 1H), 8.35 - 8.17 (m, 2H), 8.12 -8.02 (m, 2H), 7.85 (t, J = 7.8 Hz, 1H), 7.42 (s, 1H), 6.97 (br d, J = 8.3 Hz, 2H), 6.64 (br d, J = 8.2 Hz, 2H), 5.06 - 4.88 (m, 1H),4.61 - 4.22 (m, 4H), 3.46 - 3.29 (m, 3H), 3.18 (br t, J = 12.0 Hz, 4H), 2.87 - 2.56 (m, 4H), 2.39 - 2.17 (m, 3H), 2.16 - 1.95 (m,3H), 1.94 - 1.77 (m, 3H), 1.66 - 1.53 (m, 1H), 1.41 (d, J = 6.0 Hz, 6H).

[0278] Example 55 The compound of Example 55 was prepared essentially following the synthesis of Example 53. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]pyridine-2-carboxamide LC-MS (ES + ): m / z 707.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 10.77 (s, 1H), 10.60 (s, 1H), 9.77 (s, 1H), 9.73 - 9.59 (m, 1H), 8.79 (d, J = 4.5 Hz, 1H), 8.27- 8.09 (m, 3H), 7.80 - 7.71 (m, 1H), 7.45 (s, 1H), 6.96 (br d, J = 8.3 Hz, 2H), 6.63 (br d, J = 8.4 Hz, 2H), 5.07 (qd, J = 6.0, 11.8Hz, 1H), 4.59 - 4.22 (m, 4H), 3.79 - 3.60 (m, 3H), 3.24 - 3.12 (m, 4H), 2.81 - 2.54 (m, 4H), 2.36 - 2.18 (m, 3H), 2.15 - 1.96 (m,3H), 1.93 - 1.73 (m, 3H), 1.66 - 1.54 (m, 1H), 1.48 (d, J = 6.0 Hz, 6H)

[0279] Example 56 The compound of Example 56 was prepared essentially following the synthesis of Example 53. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]benzamide. LC-MS (ES + ): m / z 706.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ = 10.77 (s, 1H), 9.82 (s, 1H), 9.75 - 9.60 (m, 1H), 9.37 (s, 1H), 8.13 - 8.04 (m, 1H), 7.96 (d, J= 7.3 Hz, 2H), 7.71 - 7.55 (m, 3H), 7.41 (s, 1H), 6.96 (br d, J = 8.3 Hz, 2H), 6.63 (br d, J = 8.3 Hz, 2H), 4.98 (quin, J = 5.9 Hz,1H), 4.61 - 4.21 (m, 4H), 3.48 - 3.28 (m, 3H), 3.27 - 3.09 (m, 4H), 2.84 - 2.55 (m, 4H), 2.37 - 2.17 (m, 3H), 2.15 - 1.97 (m, 3H),1.94 - 1.73 (m, 3H), 1.66 - 1.50 (m, 1H), 1.42 (d, J = 6.0 Hz, 6H)

[0280] Example 57 The compound of Example 57 was prepared essentially following the synthesis of Example 53. [ka] N-(2-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)-7-isopropoxyimidazo[1,2-a]pyridin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LC-MS (ES + ): 747.86;[M + H] + :747.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1 H) 10.72 (s, 1 H) 9.82(s, 1 H) 9.61 - 9.78 (m, 1 H) 9.46 (dd, J=7.2, 1.51 Hz, 1 H) 8.94 (dd, J=4.0, 1.51 Hz, 1 H) 8.80 (s, 1 H) 8.17 - 8.26 (m, 1 H) 7.50 (s, 1 H) 7.37 - 7.44 (m, 1 H) 6.97 (br d, J=8.4 Hz, 2 H) 6.63 (br d, J=8.4 Hz, 2 H) 5.04 - 5.16 (m, 1 H) 4.24 - 4.56 (m, 4 H) 3.76 - 3.88 (m, 2 H) 3.38-3.47 (m, 2 H) 3.14-3.25 (m, 3 H) 2.64 - 2.83 (m, 3 H) 2.56 - 2.63 (m, 1 H) 2.16 - 2.37 (m, 3 H) 1.95 - 2.15 (m, 3 H) 1.74 - 1.92 (m, 3 H) 1.56 (d, J=5.6 Hz, 6 H) 1.36 - 1.47 (m, 1 H).

[0281] Example 58 The compound of Example 58 was prepared essentially following the synthesis of Example 53. [ka] N-(2-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)-7-isopropoxyimidazo[1,2-a]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide. LC-MS (ESI): m / z 787.90; 788.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ= 10.81 - 10.74 (m, 1H), 9.68 (s, 1H), 9.61 - 9.57 (m, 1H), 9.19 (s, 1H), 8.75 (d, J = 5.1 Hz, 1H), 8.22 - 8.12 (m, 1H), 7.87 (s, 1H), 7.80 (d, J = 5.1 Hz, 1H), 7.45 (s, 1H), 6.97 (br d, J = 8.3 Hz, 2H), 6.69 - 6.58 (m, 2H), 5.17 - 5.07 (m, 1H), 4.58 - 4.48 (m, 1H), 4.45 - 4.32 (m, 2H), 4.31 - 4.26 (m, 1H), 3.80 - 3.71 (m, 2H), 3.69 - 3.65 (m, 2H), 3.20 - 3.13 (m, 4H), 2.77 - 2.67 (m, 4H), 2.62 (s, 3H), 2.37 - 2.22 (m, 3H), 2.14 - 1.98 (m, 3H), 1.92 - 1.78 (m, 3H), 1.65 - 1.57 (m, 1H), 1.54 - 1.50 (m, 6H)

[0282] Example 59 The compound of Example 59 was prepared essentially following the synthesis of Example 53. [ka] N-(2-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)-7-isopropoxyimidazo[1,2-a]pyridin-6-yl)-2,4-difluorobenzamide. LC-MS (ES + ): 741.82;[M+H] + : 742.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1 H) 9.79 (d, J=8.00 Hz, 1 H) 9.64 - 9.75 (m, 1 H) 9.62 (s, 1 H) 8.09 - 8.16 (m, 1 H) 7.94 - 8.02 (m, 1 H) 7.51-7.59 (m, 1 H) 7.45 (s, 1 H) 7.33 (td, J=8.4, 2.4 Hz, 1 H) 6.97 (br d, J=8.4 Hz, 2 H) 6.64 (br d, J=8.4 Hz, 2 H) 4.96 - 5.08 (m, 1 H) 4.52 (br d, J=12.8 Hz, 1 H) 4.25 - 4.44 (m, 3 H) 3.70 - 3.84 (m, 3 H) 3.08 - 3.27 (m, 4 H) 2.66 - 2.82 (m, 3 H) 2.53-2.62 (m, 1 H) 2.15 - 2.38 (m, 3 H) 1.95 - 2.15 (m, 3 H) 1.74 - 1.95 (m, 3 H) 1.52 - 1.65 (m, 1 H) 1.44 (d, J=6.0 Hz, 6 H).

[0283] Example 60 The compound of Example 60 was prepared essentially following the synthesis of Example 53. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-1-methyl-pyrazole-3-carboxamide. LC-MS (ES + ): m / z 710.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 10.78 (s, 1H), 9.75 - 9.56 (m, 2H), 9.41 (s, 1H), 8.28 - 8.06 (m, 1H), 7.94 (d, J = 2.1 Hz,1H), 7.44 (s, 1H), 6.96 (br d, J = 8.3 Hz, 2H), 6.84 (d, J = 2.3 Hz, 1H), 6.63 (br d, J = 8.5 Hz, 2H), 5.05 (td, J = 6.0, 11.9 Hz,1H), 4.60 - 4.19 (m, 4H), 3.98 (s, 3H), 3.71 (br s, 3H), 3.28 - 3.08 (m, 4H), 2.86 - 2.54 (m, 4H), 2.38 - 2.16 (m, 3H), 2.14 - 1.95(m, 3H), 1.93 - 1.74 (m, 3H), 1.65 - 1.50 (m, 1H), 1.46 (d, J = 6.0 Hz, 6H).

[0284] Example 61 The compound of Example 61 was prepared essentially following the synthesis of Example 53. [ka] 3-(Difluoromethyl)-N-(2-(1-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)-7-isopropoxyimidazo[1,2-a]pyridin-6-yl)-benzamide. LC-MS (ES + ): 755.85;[M + H] + : 756. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1 H) 10.07(s, 1H) 9.49 - 9.89 (m, 1 H) 9.25 (s, 1 H) 8.10 - 8.18 (m, 2 H) 8.04 (br s, 1 H) 7.86 (br d, J=7.6 Hz, 1 H) 7.69 - 7.79 (m, 1 H) 7.37 (s, 1 H) 7.04 - 7.32 (m, 1 H) 6.96 (br d, J=8.4 Hz, 2 H) 6.63 (br d, J=8.4 Hz, 2 H) 4.89 - 5.02 (m, 1H) 4.52 (br d, J=12.96 Hz, 1 H) 4.24 - 4.46 (m, 3 H) 3.62 - 3.81 (m, 4 H) 3.17-3.25 (m, 3 H) 2.66 - 2.81 (m, 3 H) 2.55 - 2.62 (m, 1 H) 2.16 - 2.40 (m, 3 H) 1.98 - 2.15 (m, 3 H) 1.75 - 1.93 (m, 3 H) 1.52 - 1.65 (m, 1 H) 1.42 - 1.50 (m, 1 H) 1.40 (d, J=5.99 Hz, 6 H).

[0285] Example 62 Synthesis of N-[2-[1-[2-[4-[4-[(2,4-dioxohexahydropyrimidin-1-yl)methyl]phenyl]-1-piperidyl]ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: To a stirred solution of N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (1.0 g, 2.23 mmol) in ethanol, 2,2-dimethoxyacetaldehyde (232.66 mg, 2.23 mmol) and sodium cyanoborohydride (210.67 mg, 3.35 mmol) were added at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated and dried under vacuum to give crude N-[2-[1-(2,2-dimethoxyethyl)-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (1.0 g, 1.38 mmol, 61.83% yield). LC-MS (ES) + ): m / z 536.30 [M+H] + . Step 2: To a stirred solution of N-[2-[1-(2,2-dimethoxyethyl)-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (1.0 g, 1.87 mmol) in THF, 3 M HCl (68.08 mg, 1.87 mmol, 3 mL) was added at 0 °C, and the resulting mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was concentrated and dried under vacuum to give crude N-[7-isopropoxy-2-[1-(2-oxoethyl)-4-piperidyl]imidazo[1,2-a]pyridin-6-yl]-6(trifluoromethyl)pyridine-2-carboxamide HCl salt (0.8 g, 1.03 mmol, 55.14% yield). LC-MS (ES) + ): m / z 488.28 [M -H]-. Step 3: To a stirred solution of N-[7-isopropoxy-2-[1-(2-oxoethyl)-4-piperidyl]imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (0.05 g, 102.15 μmol) and 1-[[4-(4-piperidyl)phenyl]methyl]hexahydropyrimidine-2,4-dione TFA salt (29.35 mg, 73.13 μmol) in methanol, TEA was added for basification at 0° C. and stirred for 30 minutes. Then, 2-picoline borane complex (60 mg, 102.15 μmol) was added at 0° C., and the resulting mixture was stirred at 60° C. for 16 hours. The reaction mixture was concentrated and then purified by preparative HPLC to give N-[2-[1-[2-[4-[4-[(2,4-dioxohexahydropyrimidin-1-yl)methyl]phenyl]-1-piperidyl]ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamidogamic acid salt (11 mg, 12.77 μmol, 12.50% yield). LC-MS (ES) + ): m / z 761.18[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 10.18 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.4 Hz, 2H), 8.25 (t, J = 7.8 Hz, 3H), 7.66 (s, 1H), 7.23 (d, J = 37.7 Hz, 4H), 7.12 (s, 1H), 4.88 (t, J = 6.1 Hz, 1H), 4.47 (s, 2H), 2.98 (m, 8H), 2.67 (d, J = 14.5 Hz, 4H), 2.07 (m, 4H), 1.95 (d, J = 12.4 Hz, 2H), 1.65 (m, 6H), 1.40 (d, J = 5.9 Hz, 6H).

[0286] Example 63 The compound of Example 63 was prepared essentially following the synthesis of Example 62. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]-1-piperidyl]ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 762.11[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.54 (s, 1H), 9.71 (s, 1H), 8.47 (t, J = 8.1 Hz, 2H), 8.29 (d, J = 7.0 Hz, 1H), 8.09 (s, 1H), 7.36 (s, 1H), 7.19 (t, J = 10.3 Hz, 1H), 7.09 (s, 1H), 6.98 (t, J = 6.8 Hz, 1H), 5.17 (q, J = 5.3 Hz, 1H), 5.07 (s, 1H), 3.00 (m, 4H), 3.0 (m, 8H), 2.73-2.5 (m, 4H), 2.13 (m, 4H), 1.91 (m, 6H), 1.46 (d, J = 5.8 Hz, 6H), 1.14 (m, 1H).

[0287] Example 64 The compound of Example 64 was prepared essentially following the synthesis of Example 62. [ka] N-[2-[1-[2-[4-[4-(2,6-dioxo-3-piperidyl)-2-fluoro-phenyl]-1-piperidyl]ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 764.70[M+H] +. H NMR (401 MHz, DMSO) δ 10.83 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.5 Hz, 2H), 8.24 (d, J = 7.1 Hz, 1H), 7.66 (s, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.03 (t, J = 8.1 Hz, 2H), 4.88 (m, 1H), 3.86 (q, J = 5.5 Hz, 1H), 2.98 (m, 4H), 2.66 (m, 6H), 2.50 (m, 4H), 2.22 (q, J = 5.4 Hz, 3H), 2.05 (m, 5H), 1.89 (m, 3H), 1.69 (m, 1H), 1.40 (d, J = 5.9 Hz, 6H).

[0288] Example 65 The compound of Example 65 was prepared essentially following the synthesis of Example 62. [ka] N-[2-[1-[2-[4-[4-(2,6-dioxo-3-piperidyl)phenyl]piperazin-1-yl]ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 747.56[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.5 Hz, 1H), 8.24 (d, J = 7.3 Hz, 1H), 7.68 (d, J = 16.8 Hz, 1H), 7.08 (t, J = 16.8 Hz, 2H), 6.89 (d, J = 8.5 Hz, 1H), 4.88 (m, 1H), 3.72 (q, J = 5.2 Hz, 4H), 3.02 (t, J = 32.7 Hz, 2H), 2.58 (m, 9H), 2.01 (m, 10H), 1.62 (s, 6H), 1.40 (m, 3H), 1.24 (s, 1H).

[0289] Example 66 The compound of Example 66 was prepared essentially following the synthesis of Example 62. [ka] N-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 761.59[M + H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.6 Hz, 2H), 8.24 (d, J = 7.3 Hz, 1H), 7.68 (t, J = 9.3 Hz, 1H), 7.12 (s, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 5.63 (d, J = 7.2 Hz, 1H), 4.87 (q, J = 5.9 Hz, 1H), 4.26 (s, 1H), 4.13 (d, J = 3.9 Hz, 1H), 2.96 (m, 4H), 2.72 (d, J = 12.0 Hz, 1H), 2.59 (m, 6H), 2.45 (m, 4H), 2.30 (t, J = 10.1 Hz, 1H), 1.96 (m, 7H), 1.62 (d, J = 19.0 Hz, 6H), 1.40 (d, J = 5.9 Hz, 1H), 1.33 (m, 3H).

[0290] Example 67 The compound of Example 67 was prepared essentially following the synthesis of Example 62. [ka] N-[2-[1-[2-[4-[4-(2,6-dioxo-3-piperidyl)amino-2-fluoro-phenyl]-1-piperidyl]ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 777.53 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.43 (q, J = 8.5 Hz, 2H), 8.24 (d, J = 7.2 Hz, 1H), 7.66 (s, 1H), 7.12 (s, 1H), 6.99 (t, J = 8.9 Hz, 1H), 6.44 (t, J = 8.6 Hz, 1H), 5.99 (d, J = 7.6 Hz, 1H), 4.88 (m, 1H), 4.30 (t, J = 11.9 Hz, 1H), 2.96 (m, 7H), 2.67 (s, 1H), 2.58 (m, 3H), 2.50 (m, 4H), 2.00 (m, 6H), 1.65 (m, 6H), 1.40 (d, J = 5.9 Hz, 6H).

[0291] Example 68 Synthesis of N-[2-[1-[2-[4-[5-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide [ka] Step 1: To a stirred solution of 2-(4-nitrophenyl)ethanol (3.00 g, 17.95 mmol) in ethanol (30 mL) in a 25 mL round-bottom flask was added palladium on carbon (572.97 mg, 5.38 mmol). The resulting reaction mixture was stirred at room temperature under a hydrogen bladder atmosphere for 16 hours. Upon completion, the reaction mixture was filtered through a bed of Celite and washed with ethyl acetate. The collected filtrate was concentrated under reduced pressure to give 2-(4-aminophenyl)ethanol (2.3 g, 16.53 mmol, 92.13% yield) as an off-white solid. LC-MS (ES) analysis revealed that the 2-(4-aminophenyl)ethanol was soluble in water and eluted with hexane. + ): m / z 137.99 [M+H] + . Step 2: To a stirred solution of 2-(4-aminophenyl)ethanol (1.5 g, 10.93 mmol) in DMF (15 mL) in a 50 mL round-bottom flask was added sodium bicarbonate (2.30 g, 27.34 mmol, 1.06 mL) and 3-bromopiperidine-2,6-dione (2.73 g, 14.22 mmol). The resulting reaction mixture was stirred at 70° C. for 16 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and then washed with water and brine solution. The collected organic layer was dried over NaSO, filtered, and then concentrated under reduced pressure to provide the crude compound. The crude material was purified by flash column chromatography using 100-200 silica gel eluted with 50-60% EtOAc in PET ether to give 3-[4-(2-hydroxyethyl)anilino]piperidine-2,6-dione (1 g, 3.42 mmol, 31.29% yield) as an off-white solid. LC-MS (ES) + ): m / z 249.35 [M + H] + Step 3: To a stirred solution of 3-[4-(2-hydroxyethyl)anilino]piperidine-2,6-dione (0.4 g, 1.61 mmol) in DCM (10 mL) in a 25 mL round-bottom flask at 0 °C, N,N-diethylethanamine (326.06 mg, 3.22 mmol, 449.11 μL) and methanesulfonyl chloride (239.92 mg, 2.09 mmol, 162.11 μL) were added. The resulting reaction mixture was stirred at 70 °C for 16 h. Upon completion, the reaction mixture was diluted with dichloromethane and washed with water and brine solution. The collected organic layer was dried over Na SO , filtered, and then concentrated under reduced pressure to provide the crude compound. The crude compound was purified by flash column chromatography using neutral alumina eluting with 50-60% EtOAc in petroleum ether to give 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl methanesulfonate (0.17 g, 365.09 μmol, 22.66% yield) as an off-white solid. LC-MS (ES) + ): m / z 327.12 [M+H] + . Step 4: To a stirred solution of N-[7-isopropoxy-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (274.20 mg, 612.81 μmol) in DMF (4 mL) in a 25 mL round-bottom flask was added sodium bicarbonate (128.70 mg, 1.53 mmol, 59.58 μL) and 2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl methanesulfonate (0.2 g, 612.81 μmol), followed by stirring for 16 h at 75° C. Upon completion, the mixture was concentrated in a Genevac to remove the solvent. The residue was purified by preparative HPLC, and the fractions were lyophilized to give N-[2-[1-[2-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]ethyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide formate (22 mg, 28.93 μmol, 4.72% yield) as an off-white solid. LC-MS (ES) + ): m / z 678.38[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.41 (m, 2H), 8.24 (d, J = 7.2 Hz, 1H), 7.66 (s, 1H), 7.12 (s, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 5.62 (d, J = 7.3 Hz, 1H), 4.88 (m, 2H), 4.22 (m, 2H), 2.99 (d, J = 10.9 Hz, 2H), 2.74 (m, 1H), 2.58 (t, J = 8.7 Hz, 4H), 2.45 (m, 2H), 2.10 (m, 3H), 1.90 (m, 3H), 1.66 (q, J = 10.8 Hz, 2H), 1.41 (m, 6H), 1.26 (d, J = 19.3 Hz, 1H), 0.88 (t, J = 6.5 Hz, 1H). Preparative HPLC method: Column / Dimensions: SUNFIRE C8 (19*250*5um) Mobile phase A: 0.1% FA in water (aq) Mobile phase B: 100% acetonitrile Gradient (time / B(%)): 0 / 10, 2 / 10, 2.5 / 15, 17 / 43, 18 / 95, 21 / 95, 21.1 / 10, 23 / 10 Flow rate: 17ml / min Solubility: ACN+water+THF TLC pattern: 10% methanol in DCM R f Value: 0.3

[0292] Example 69 The compound of Example 69 was prepared essentially following the synthesis of Example 68. [ka] N-[2-[1-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]butyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 706.18[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.44 (s, 1H), 9.42 (s, 1H), 8.43 - 8.24 (m, 5H), 7.65 (s, 1H), 7.11 (s, 1H), 6.91 (d, J = 8.2 Hz, 2H), 6.60 (d, J = 8.3 Hz, 2H), 5.61 (d, J = 7.4 Hz, 1H), 4.88 (t, J = 6.0 Hz, 1H), 4.26 (m, 1H), 2.82- 2.59 (m, 5H), 2.44 (m, 2H), 2.30 (q, J = 7.6 Hz, 1H), 2.11 (m, 5H), 1.92 (m, 11H), 1.40 (d, J = 6.0 Hz, 1H).

[0293] Example 70 The compound of Example 70 was prepared essentially following the synthesis of Example 68. [ka] N-[2-[1-[6-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]hexyl]-4-piperidyl]-7-isopropoxy-imidazo[1,2-a]pyridin-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (ES + ): m / z 734.16[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.44 (s, 1H), 9.43 (s, 1H), 8.45 (m, 8H), 8.24 (d, J = 7.2 Hz, 1H), 7.65 (s, 1H), 7.11 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 5.61 (d, J = 7.4 Hz, 1H), 4.88 (t, J = 6.0 Hz, 1H), 4.24 (q, J = 5.2 Hz, 1H), 2.90 (d, J = 10.5 Hz, 2H), 2.74 (m, 1H), 2.59 (d, J = 3.9 Hz, 2H), 2.50 (s, 2H), 2.26 (t, J = 7.0 Hz, 2H), 2.09 (d, J = 4.0 Hz, 1H), 1.92 (m, 5H), 1.63 (d, J = 10.4 Hz, 2H), 1.40 (m, 5H), 1.26 (m, 5H).

[0294] Synthesis of 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetic acid [ka] Step 1: To a stirred solution of 3-[4-(4-piperidyl)anilino]piperidine-2,6-dione (0.15 g, 522.00 μmol) and tert-butyl 2-bromoacetate (101.82 mg, 522.00 μmol, 76.56 μL) in ACN (10 mL) was added N-ethyl-N-isopropyl-propan-2-amine (404.79 mg, 3.13 mmol, 545.54 μL), the reaction mixture was purged with nitrogen at room temperature for 5 minutes, and the reaction mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by column chromatography using silica to give tert-butyl 2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetate (...

Claims

1. A compound of formula (A), IRAK-L-DSM (A) or a pharmaceutically acceptable salt thereof, wherein DSM is a degradation signaling moiety covalently attached to linker L, L is a linker that covalently attaches IRAK to DSM, IRAK is an IRAK4-binding moiety represented by formula (I) that is covalently attached to linker L, 【Chemical 1】 wherein A １ is selected from N, CH and CR ３ and A ２ is selected from N, CH and CR ４ however, provided that only one of A １ or A ２ can be N B １ and B ２ one of them is N and the other is C, R １ is i. Phenyl optionally substituted by 1 to 3 Rs ５ and which is optionally substituted in the case of ii. A 5- or 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and having 1 to 3 Rs ５ wherein said heteroaryl is optionally substituted by iii. A 5- or 6-membered partially or fully saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclic ring may optionally be substituted with 1 to 3 R ５ groups; iv. 1 to 3 Rs ５ which may optionally be substituted and which is partially or fully saturated C ３－６ cycloalkyl v. a 7- to 10-membered fused hetero-bicyclic ring system having 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen, wherein 1 to 3 R ５ optionally substituted said hetero-bicyclic ring system, and vi. a condensed carbocyclic ring system of 7 to 10 members, said carbocyclic ring system optionally substituted with 1 to 3 R ５ selected from said carbocyclic ring system, optionally substituted with R ２ is hydrogen, C １－４ alkyl or halogen, and R ３ and R ４ each represents halogen, C １－４ alkyl, nitrile and -OR ６ independently selected from, said C １－４ alkyl being optionally substituted with C １－４ alkoxy or at least one halogen, R ５ is, for each occurrence, CN, hydroxyl, C １－４ alkyl, oxo, halogen, -NR ８ R ９ , C １－４ alkoxy, -O-C １－４ alkyl, C ３－６ cycloalkyl, -C １－４ alkyl-C ３－６ cycloalkyl, C(O)NR １０ R １１ , C ４－７ heterocycle, and independently selected from 5- or 6-membered heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, said C １－４ alkyl is optionally substituted with one or more substituents independently selected from CN, halo, C １－４ alkoxy, and hydroxyl, said C ３－６ cycloalkyl and said heteroaryl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of C １－４ alkyl, hydroxyl and halogen, or two R ５ groups together with intervening atoms can form a ring selected from phenyl, C ４－６ carbocycle, C ４－６ heterocycle, or a 7-membered bridged ring system optionally having 1 heteroatom selected from nitrogen and oxygen, said phenyl, said C ４－６ carbocycle and said C ４－６ heterocycle are each optionally substituted with 1 to 2 C １－４ alkyl, halogen or C １－４ haloalkyl, R ６ is hydrogen, C １－５ alkyl, C ３－６ ycloalkyl, a 4- to 7-membered partially or fully saturated heterocyclic ring containing one or two heteroatoms selected from nitrogen and oxygen, a 5- to 10-membered spirocarbocyclic ring, and a 4- to 10-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and the C ６ alkyl represented by R １－５ is optionally substituted with 1 to 3 substituents R １－５ independently selected from halogen, hydroxyl, C １－４ alkyl, C １－４ alkoxy, C ３－６ haloalkoxy, C ６ａ ycloalkyl, phenyl, a 4- to 7-membered partially or fully saturated heterocyclic ring containing one or two heteroatoms selected from nitrogen and oxygen, and a fully saturated 5- to 8-membered bridged heterocyclic ring system having 1 to 2 heteroatoms independently selected from nitrogen and oxygen, and the C ６ ycloalkyl represented by R ３－６ is optionally substituted with 1 to 3 substituents R １－４ independently selected from halogen, C １－４ alkyl, C １－４ haloalkyl, and C ６ｂ alkoxy, and the 4- to 7-membered partially or fully saturated heterocyclic ring, the 5- to 10-membered spirocarbocyclic ring and the 5- to 10-membered spiroheterobicyclic ring system represented by R ６ are optionally substituted with 1 to 3 substituents R １－４ independently selected from C ６ｃ alkyl and oxo, and the C ６ａ ycloalkyl, the phenyl, and the 4- to 7-membered partially or fully saturated heterocyclic ring represented by R ３－６ are optionally substituted with 1 to 3 R ７ s. Each R ７ is independently selected from oxo, halogen, C １－４ haloalkyl and C １－４ alkyl, R ８ and R ９ each independently is hydrogen, -C(O)C １－４ alkyl and C １－４ alkyl, or R ８ and R ９ may combine to form a 4- to 6-membered saturated ring optionally containing one additional heteroatom selected from nitrogen or oxygen, said additional nitrogen being optionally substituted with C １－４ alkyl, R １０ and R １１ are each independently selected from hydrogen and C １－４ alkyl, -* represents a bond to said linker L, said compound, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein IRAK is an IRAK4-binding moiety represented by formula (IA) or (IB): [Chemical 2]

3. (i) R １ is phenyl optionally substituted by 1 to 3 R ５ , 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms, said heteroaryl optionally substituted by 1 to 3 R ５ , 9- to 10-membered bicyclic heteroaryl having 1, 2 or 3 nitrogen atoms, said ring system being optionally substituted by 1 to 3 R ５ and being selected from said bicyclic heteroaryl, (ii) R1 is selected from oxazole optionally substituted with one or two R5, phenyl optionally substituted with one or two R5, pyrazole optionally substituted with one or two R5, pyridine optionally substituted with one or two R5, pyridone optionally substituted with one or two R5, pyrimidine optionally substituted with one or two R5, and pyrazolo[1,5-a]pyrimidine optionally substituted with one or two R5, (iii) R1 is selected from oxazole optionally substituted with one or two R5, phenyl optionally substituted with one or two R5, pyrazole optionally substituted with one or two R5, pyridine optionally substituted with one or two R5, pyrimidine optionally substituted with one or two R5, and pyrazolo[1,5-a]pyrimidine optionally substituted with one or two R5, (iv) R1 is represented by one of the following formulas: [Chemical 3] wherein m is 0, 1 or 2, (v) R1 is represented by one of the following formulas: 【Chemical Formula 4】 wherein m is 0, 1 or 2, (vi) R1 is represented by one of the following formulas: 【Chemical Formula 5】 (vii) R1 is represented by one of the following formulas: [Chemical Formula 6] (viii) R1 is represented by the following formula: 【Chemical Formula 7】 or, (ix) R1 is represented by the following formula: [Chemical Formula 8] The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

5. IRAK is the following formula: 【Chemical Formula 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an IRAK4 binding moiety represented by one of them.

6. R ３ is C １－４ alkyl or -OR ６ wherein the C １－４ alkyl is optionally substituted with at least one halogen and optionally R3 is -CF3 or -O-CH(CH3)2, R ６ is C １－５ alkyl, C ３－６ cycloalkyl, or a 4- to 7-membered fully saturated heterocyclic ring containing one or two heteroatoms selected from nitrogen and oxygen, and the C ６ alkyl represented by R １－５ is optionally substituted with 1 to 3 halogens, and the C ６ cycloalkyl represented by R ３－６ is optionally substituted with 1 to 3 substituents R １－４ independently selected from halogen, C １－４ alkyl, C １－４ haloalkyl, and C ６ｂ alkoxy, the compound according to claim 5, or a pharmaceutically acceptable salt thereof.

7. R ５ which, for each occurrence, is independently selected from the following, the compound according to claim 5, or a pharmaceutically acceptable salt thereof; (i) C １－４ alkyl, halogen, C １－４ haloalkyl, or C ３－４ cycloalkyl, provided that said C ３－４ cycloalkyl is optionally substituted with one halo (ii) C1-4 alkyl, halogen, or C1-4 haloalkyl, (iii) -CH3, -CHF2, -CF3, F, cyclopropyl, or 【Chemical 10】 or, (iv) -CH3, -CHF2, -CF3 or F.

8. IRAK is of the following formula: 【Chemical 11】 an IRAK4 binding moiety represented by one of them, wherein R ５ is C １－３ alkyl, C １－３ haloalkyl, C ３－４ cycloalkyl, and said C ３－４ cycloalkyl is optionally substituted with one halo Optionally, R5 is CH3, CHF2, CF3, cyclopropyl, or 【Chemical 12】 is, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. DSM is a decomposition signal transduction moiety of formula (D), 【Chemical 13】 wherein, 【Chemical Formula 14】 represents a bond to the linker L, Y is CR Ｄ１ or N, and Z １ is a bond, -NR Ｄ２ -, -O- and -CH ２ - and is selected from G １ is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and partially saturated 4- to 11-membered heterocyclic rings, and the 6- to 10-membered aryl, the 5- to 10-membered heteroaryl, and the partially saturated 4- to 11-membered heterocyclic ring represented by G １ are each optionally substituted with one or more R Ｄ３ s, G ２ is 【Chemical Formula 15】 is selected from, *- represents a bond to the linker L, 【Chemical 16】 represents the connection to G １ and represents the connection to Het １ is a 4- to 7-membered monocyclic heterocyclic ring or a 7- to 11-membered bicyclic heterocyclic ring, each of which is optionally substituted with one or more R Ｄ５ and is optionally substituted with R Ｄ１ is selected from H, C １－６ alkyl or halogen, and R Ｄ２ is H or C １－３ is alkyl, R Ｄ３ which, for each occurrence, is independently selected from H, halogen, C １－４ alkyl and C １－４ haloalkyl R Ｄ４ is H or C １－３ and is alkyl, R Ｄ５ which, for each occurrence, is independently selected from H, halogen, hydroxyl, C １－４ alkyl, C １－４ haloalkyl and C １－４ alkoxy, a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. (i) Het １ is a 4- to 7-membered monocyclic saturated heterocyclic ring containing one or two nitrogen atoms, or a 7- to 11-membered saturated spiro bicyclic heterocyclic ring containing one or two heteroatoms selected from N and O, each of which is optionally substituted with one or two R Ｄ５ and optionally substituted, or (ii) Het1 is piperidine, piperazine, 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 5-azaspiro[3.4]octane or 9-oxa-9-azaspiro[5.5]undecane, each of which is optionally substituted with one or two RD5, The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

11. DSM is a decomposition signal transduction moiety of formula (D-I) or (D-II), 【Chemical 17】 wherein, 【Chemical Formula 18】 represents a bond to the linker L, Z １ is selected from a bond, -NR Ｄ２ -, and -O-, G １ is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and partially saturated 4- to 11-membered heterocycles, and the 6- to 10-membered aryl, the 5- to 10-membered heteroaryl, and the partially saturated 4- to 11-membered heterocycle represented by G １ are each optionally substituted with one or more R Ｄ３ s, R Ｄ２ is H or C １－３ is alkyl, R Ｄ３ which, for each occurrence, is independently selected from H, halogen and C １－４ alkyl R Ｄ４ is C １－３ alkyl, and R Ｄ５ is a halogen, and n is 0, 1, or 2, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. G １ is (i) a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl or a partially saturated 4- to 11-membered heterocyclic ring, wherein G １ the 6- to 10-membered aryl, the 5- to 10-membered heteroaryl and the partially saturated 4- to 11-membered heterocyclic ring represented by Ｄ３ are each optionally substituted with one or two R (ii) selected from phenyl, pyrazolyl, pyridinyl and pyrimidinyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, indazolyl, and indolyl, each of which is optionally substituted with one or two RD3, (iii) the following formula: 【Chemical Formula 19】 represented by one of them, wherein, o is 0, 1 or 2, 【Chemical 20】 represents a bond to G2, -*- represents a bond to Z1, (iv) G1 is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, and the 6- to 10-membered aryl and the 5- to 10-membered heteroaryl represented by G1 are each optionally substituted with one or two RD3, (v) G1 is selected from phenyl, pyrazolyl, pyridinyl, pyrimidinyl, indazolyl, and indolyl, each of which is optionally substituted with one or two RD3, or, (vi) G1 is represented by one of the following formulas: 【Chemical 21】 wherein, o is 0, 1, or 2, 【Chemical 22】 represents a bond to G2, -* represents a bond to Z1, The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

13. (i) R Ｄ１ is H, -CH ３ or F, (ii) RD2 is H, (iii) RD3 is selected from H, Cl, F, and -CH3 for each occurrence, (iv) RD4 is -CH3, (v) RD5 is independently F or OH for each occurrence, (vi) G1 is selected from phenyl, pyrazolyl, pyridinyl, pyrimidinyl, indazolyl, and indolyl, each of which is optionally substituted with one or two RD3, or,

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein DSM represents any one of the following bonded to L. [[Chemical Formula 23-1]] 【Chemical Formula 23-2】 [[Chemical Formula 23-3]] 【Chemical Formula 23-4】 [[Chemical 23-5]] [Chemical 23-6] 【Chemical Formula 23-7】 [[Chemical 23-8]] 【Chemical Formula 23-9】

15. L is a bond, C １－８ is alkyl or has the formula (L-1), (L-2) or (L-3): 【Chemical 24】 represented by, wherein, Z ２ is C optionally substituted by a bond or one or more halogens １－４ alkyl, Het ２ is a 4- to 7-membered heterocyclic ring optionally substituted by one or more R Ｌ１ groups. G ３ is C ３－７ cycloalkyl or a 4- to 7-membered heterocyclic ring, and the C ３ cycloalkyl and the 4- to 7-membered heterocyclic ring represented by G ３－７ are each optionally substituted with one or more R Ｌ３ s, Z ３ is C １－４ alkyl or 【Chemical Formula 25】 wherein, 【Chemical 26】 is the bond connected to G ３ represents a bond connected to G, - * is a bond connected to the DSM, and the C １－４ alkyl is optionally substituted with one or more halogens Z ４ is C Ｌ４ alkyl optionally substituted by R １－４ and R Ｌ１ is, for each occurrence, independently selected from H, halogen, C １－４ alkyl and C １－４ haloalkyl R Ｌ２ is H or C １－４ is alkyl, R Ｌ３ which, for each occurrence, is independently selected from H, halogen, C １－４ alkyl and C １－４ haloalkyl; R Ｌ４ is halo, -OR Ｌ５ or halogen, C ３－７ alkyl optionally substituted by cycloalkyl, phenyl, a 4- to 7-membered monocyclic saturated heterocycle, or a 5- to 6-membered heteroaryl, and the C １－４ alkyl, the C ３－７ cycloalkyl, the phenyl, the 4- to 7-membered monocyclic saturated heterocycle, and the 5- to 6-membered heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from halogen, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxy and C １－４ haloalkoxy, R Ｌ５ is H, C １－４ alkyl or C １－４ haloalkyl, and 【Chemical 27】 represents a bond to the IRAK4 binding moiety, -* represents a bond to the degradation signal transduction site DSM, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. (i) L is represented by formula (L-1), (L-2), or (L-3), Het ２ is selected from azetidinyl, piperidinyl and pyrrolidinyl, and the azetidinyl, the piperidinyl and the pyrrolidinyl represented by Het ２ are each optionally substituted by one or more R Ｌ１ and G ３ is azetidinyl, cyclohexyl or piperidinyl, and the cyclohexyl and piperidinyl represented by G ３ are each optionally substituted by one or more R Ｌ３ in each case. (ii) Z2 is a bond or -CH2-, Z3 is -CH2-, -CH2-CH2-, 【Chemical formula 28】 wherein, Z4 is -CH(CH2Ph)- or -CH2-CH2-CH2-, or, (iii) RL1 is H, RL2 is H, RL3 is H, RL4 is benzyl, The compound according to claim 15, or a pharmaceutically acceptable salt thereof.

17. (i) L is represented by formula (L-1), and Het ２ is the following formula: 【Chemical Formula 29】 represented by one of the following, wherein, 【Chemical Formula 30】 represents the connection to Z ２ and represents the connection to -* represents a bond to the degradation signal transduction site DSM, (ii) L is represented by formula (L-2), G3 is represented by one of the following formulas: 【Chemical 31】 wherein, 【Chemical 32】 represents a bond to the IRAK4 binding moiety, -* represents a bond to Z3, (iii) L is represented by formula (L-1), Het2 is 【Chemical 33】 wherein, 【Chemical 34】 represents a bond to Z2, -* represents a bond to the degradation signal transduction site DSM, (iv) L is represented by formula (L-3), Z4 is C1-4 alkyl optionally substituted by benzyl, RL2 is H, or (v) L is represented by any one of the following formulas: 【Chemical 35】 wherein, 【Chemical 36】 represents a bond to the IRAK4 binding moiety, - * represents a bond to the degradation signal transduction site DSM, The compound according to claim 15, or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, selected from the compounds of any one of Examples 1 to 87, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition for treating an IRAK4-mediated disease, comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, optionally, (i) the IRAK4-mediated disease is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, ankylosing spondylitis, osteoporosis, neuromyelitis optica, systemic sclerosis, psoriasis, dermatomyositis, atopic dermatitis, hidradenitis suppurativa, type I diabetes, type II diabetes, inflammatory bowel disease, Crohn's disease, ulcerative colitis, hyper IgD syndrome, periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, IL-1 receptor antagonist deficiency, Alzheimer's disease, Parkinson's disease, multiple sclerosis and cancer, or (ii) the IRAK4-mediated disease is selected from the group consisting of autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases and / or disorders, cardiovascular diseases, allergies, asthma, hormone-related diseases, ischemic stroke, cerebral ischemia, hypoxia, traumatic brain injury, chronic traumatic encephalopathy, epilepsy, Parkinson's disease, and amyotrophic lateral sclerosis, The pharmaceutical composition.

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