Compounds for targeting the degradation of IRAK4 protein

Abstract

The present disclosure relates to a compound of formula (A): IRAK-L-DSM(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 the DSM, and IRAK is an IRAK4 binding moiety represented by formula (I) covalently linked to a linker L, where all variables are as defined herein. 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 a method of treating a disorder responsive to modulation of IRAK4 activity and / or degradation of IRAK4 with at least one compound described herein. [Formula 1] TIFF2024527570000473.tif43101

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 219,160, filed July 7, 2021, and No. 63 / 354,017, filed June 21, 2022. The entire contents of each of the foregoing applications are expressly incorporated herein by reference.

[0002] Provided are specific agents that target the degradation of interleukin-1 receptor associated kinase 4 (IRAK4), as well as methods of making and using such agents. [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, neuronal and muscular degeneration, neuronal 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 function as building blocks for new proteins. There are over 600 E3 ubiquitin ligases that facilitate the in vivo ubiquitination of various proteins and can be classified 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 exploited for therapeutic intervention by using chimeric compounds capable of activating 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 to 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 to target proteins for destruction.

[0006] Protein kinases are a large multigene family of more than 500 proteins that play a key role 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 and play a key role 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. In general, protein kinases are 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 the regulation of 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 the 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 a variety of cellular receptors, including toll-like receptors (TLRs).

[0009] IRAK1 was first identified by biochemical purification of an 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 by screening a human phytohemagglutinin-activated peripheral blood leukocyte (PBL) cDNA library with a mouse EST sequence encoding a polypeptide with significant homology to IRAK1 (Wesche et al., 1999. J. Biol. Chem. 274(27): 19403-10). IRAK4 was identified by database searches for IRAK-like sequences and PCR of a general cDNA library (Li et al., 2002. Proc. Natl. Acad. Sci. USA 99(8):5567-5572).

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

[0011] Considering that IRAK4 plays an important role in the signaling network that controls inflammation, there is a high 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 methods of manufacture that are 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 pharma- ceutically 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 covalently attached to a linker L, Formula (I); [ka] and wherein the IRAK4 binding site is represented by During the ceremony, A 1 are N, CH and CR 3 Selected from A 2 are N, CH and CR 4 is 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. a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5 said heteroaryl optionally substituted with iii. A 5- or 6-membered partially or completely saturated heterocycle having 1 to 2 heteroatoms independently selected from oxygen and nitrogen, and having 1 to 3 R 5 said 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 1-3 R 5 said heterobicyclic ring system optionally substituted with vi. A 7-10 membered fused carbobicyclic ring system having 1-3 R 5 The carbobicyclic ring system optionally substituted with is selected from 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 Heterocycles and 5- or 6-membered heteroaryls having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur (see C 1-4Alkyl is CN, halo, C 1-4 Optionally substituted with one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) substituents independently selected from alkoxy, hydroxyl, and 3-6 Cycloalkyl and the 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 ring selected from a heterocycle or a 7-membered bridged ring system optionally having one heteroatom selected from nitrogen and oxygen (such as the phenyl, C 4-6 Carbocyclic rings and the 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 4-7 membered partially or fully saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, a 5-10 membered spirocarbocyclic ring, and a 4-10 membered heterocycle having 1-2 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 1 to 3 substituents R independently selected from cycloalkyl, phenyl, a 4-7 membered partially or fully saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, and a fully saturated 5-8 membered bridged heterocyclic ring system having 1 to 2 heteroatoms independently selected from nitrogen and oxygen; 6a and optionally substituted with R 6 C represented by 3-6Cycloalkyl is halogen, C 1-4 Alki, C 1-4 Haloalkyl and C 1-4 1 to 3 substituents R independently selected from alkoxy 6b and optionally substituted with R 6 The 4-7 membered partially or fully saturated heterocycles, 5-10 membered spiro carbocyclic rings, and 5-10 membered spiro heterobicyclic ring systems represented by 1-4 1 to 3 substituents R independently selected from alkyl and oxo 6c and optionally substituted with R 6a The C represented by 3-6 Cycloalkyl, the phenyl, and the 4- to 7-membered partially or completely saturated heterocycle each have 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 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, said additional nitrogen being selected from C 1-4 optionally substituted with alkyl; R 10 and R 11 are hydrogen and C 1-4 alkyl, [ka] represents a bond to the linker L.

[0013] In another aspect, the present disclosure provides a method for treating a disorder responsive to modulation of IRAK4 activity and / or degradation of IRAK4 in a subject, 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 pharma- ceutically 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 is a compound described herein, or a pharma- ceutically acceptable salt thereof, for use in treating a disorder responsive to modulation of IRAK4 activity and / or degradation of IRAK4. Methods for making the compounds described herein and any synthetic intermediates are also included in the present disclosure.

[0014] Other features or advantages will become apparent from the following detailed description of several embodiments, and from the appended claims. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows the pharmacokinetic profile of Compound 48 following dosing of 5 mg / kg IV and 10 mg / kg PO in male beagle dogs. [Diagram 2] 1 shows the pharmacokinetic profile of Compound 169 following dosing of 5 mg / kg IV and 10 mg / kg PO in male beagle dogs. [Diagram 3] FIG. 1 shows IRAK4 degradation following 10 mg / kg PO administration of vehicle, Compound 48, and Compound 169 in PBMCs of male beagle dogs. [Figure 4] FIG. 1 shows the pharmacokinetic profile of Compound 48 after dosing at 5 mg / kg IV and 10 mg / kg PO in male cynomolgus monkeys. [Diagram 5] 1 shows the pharmacokinetic profile of Compound 169 following dosing of 5 mg / kg IV and 10 mg / kg PO in male cynomolgus monkeys. [Figure 6] 1 shows IRAK4 degradation following 10 mg / kg PO dosing of vehicle, Compound 48, and Compound 169 in PBMCs of male cynomolgus monkeys. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The compounds described herein or pharma- ceutically acceptable salts thereof can activate selective ubiquitination of IRAK4 protein via the ubiquitin-proteasome pathway (UPP), leading to degradation of IRAK4 protein. In some embodiments, the compounds described herein or pharma- ceutically acceptable salts thereof can modulate IRAK4 activity.

[0017] The disclosed compounds, 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).

[0018] I. Definition Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the relevant art.

[0019] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The recitation of ranges of values ​​is intended to serve merely as a shorthand method of individually referring to each separate value falling within the range, unless otherwise stated herein, 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 are independently combinable. All methods described herein can be performed in any suitable order unless otherwise stated herein or clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely to better illustrate the present disclosure, and does not pose limitations on the scope of the present disclosure unless otherwise stated.

[0020] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. In some embodiments, an alkyl contains 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In some embodiments, an alkyl contains 6-20 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 group or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally 1-3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0021] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., --O--C 1-4 Alkyl group, C 1-4Alkyl refers to an alkyl group as defined herein. 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 1-4 carbons, more preferably about 1-2 carbons.

[0022] 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.

[0023] As used herein, the term "bridged ring system" is a ring system in which two non-adjacent ring atoms 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.

[0024] The term "fused ring system," as used herein, is 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.

[0025] 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.

[0026] The term "cycloalkyl" refers to a partially or fully saturated monocyclic or bicyclic or spirohydrocarbon 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).

[0027] As used herein, the terms "carbocycle" and "carbocyclic ring" refer to a saturated or partially unsaturated (i.e., non-aromatic) monocyclic or bicyclic hydrocarbon group having, for example, 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. Examples of 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.

[0028] As used herein, the term "bridged carbocyclic ring" refers to a cyclic moiety connected at two non-adjacent ring atoms of a carbocycle (e.g., bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, and bicyclo[3.2.1]octane).

[0029] As used herein, the term "fused bicyclic ring system" or "fused carbobicyclic ring system" refers to a carbocycle 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.

[0030] As used herein, the term "spirocarbocyclic ring" refers to 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, etc.

[0031] "Halogen" or "halo" can be fluorine, chlorine, bromine or iodine (preferred halogens as substituents are fluorine and chlorine).

[0032] As used herein, the term "haloalkyl" or "halo-substituted alkyl" refers to an alkyl group, as defined herein, in which at least one of the hydrogen atoms is replaced by a halo atom. The haloalkyl group may be a monohalo-alkyl, dihaloalkyl, or polyhaloalkyl, including perhaloalkyl. The monohaloalkyl may have one iodo, bromo, chloro, or fluoro in the alkyl group. The dihaloalkyl and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups in the alkyl. Typically, the 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 have been replaced with halo atoms.

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

[0034] Examples of "5-6 membered heteroaryl" or "5-6 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 5-6 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 selected from pyridinyl, pyrimidinyl, 2H-1,2,3-triazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl, and thienyl.

[0035] Examples of 5-membered heteroaryl include, but are not limited to, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadizolyl, 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 heteroaryl include imidazole thiazolyl, imidazopyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indazolyl, 2H-indazolyl, indolyl, isoindolyl, 2λ 2 Examples of 9-10 membered bicyclic heteroaryls include, but are not limited to, imidazopyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, 2H-indazolyl, indolyl, isoindolyl, 2λ-indazolyl ... 2-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 9-10 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- to 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, oxtanyl, 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, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, tetrahydro-thiopyran 1,1- dioxide, 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 1-2 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Bicyclic heterocycles include, but are not limited to, 2,6-diazaspiro[3.3]heptane.

[0043] 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 spirocycle. Unless otherwise specified, heterocyclic rings are generally 3-7 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, and the like. 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).

[0044] In some embodiments, the partially or fully saturated heterocycle is [ka] is selected from.

[0045] As used herein, the term "bridged heterocyclic ring system" refers to a 5-10 membered heterobicyclic moiety connected at two non-adjacent ring atoms of a heterocycle containing at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or combinations thereof) in the 5-10 membered 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.

[0046] As used herein, the term "fused heterobicyclic ring system" refers to a bicyclic ring system that shares two adjacent ring atoms and at least one of the rings containing a ring atom that is a heteroatom selected from O, N, and S. Examples of fused heterobicyclic ring systems are 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 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine, 3,8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 7-oxabicyclo[2.2.1]heptane, 1H-pyrazole, 2,5-diazabicyclo[2.2.1]heptane, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine, 3-oxabicyclo[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, such as 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, and the like. In some embodiments, "fused heterobicyclic ring system" refers to a fused bicyclic heteroaryl.

[0047] 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[4,3-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.

[0048] 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'-oxetanyl]-1-yl, oxaspiro[bicyclo[3.2.0]heptane-6,1'-cyclobutane]-7-yl, 2,6-diazaspiro[3.3]heptanyl, -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.

[0049] As used herein, "hydroxyl" or "hydroxy" refers to an --OH group.

[0050] 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) 2 --), such as a ketone, an aldehyde, or part of an acid, ester, amide, lactone, or lactam group.

[0051] As used herein, when a group / variable (e.g., L, Z1, Z2, etc.) is defined as a "bond," this means that the two moieties attached to the group / variable are directly connected to each other. For example, when L in formula (A) is a bond, this means that the IRAK moiety and the DSM moiety are directly connected.

[0052] 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 replacing a hydrogen radical in a given structure with a radical of a specified substituent. Specific substituents are described in the definitions and descriptions of the compounds and examples thereof. Unless otherwise stated, an optionally substituted group may have a substituent at each substitutable position of the group, and when two or more positions in any given structure can be substituted with two or more substituents 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 substitutions), and inherently formed moieties (e.g., polymorphs, solvates and / or hydrates). If moieties capable of forming salts are present, salts are also included, particularly pharma- ceutically acceptable salts.

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

[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 to 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 by conventional chemical methods from compounds that contain a basic or acidic site. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable 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 a suitable acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. In general, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable where 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 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 least 3340 times more abundant (i.e., at least 50.1% deuterium incorporation), at least 3500 times more abundant (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 times more abundant (60% deuterium incorporation), at least 4500 times more abundant (67.5% deuterium incorporation), at least 5000 times more abundant (75% deuterium) than the natural abundance of deuterium, which is 0.015%. , replaced by deuterium at least 5500 times more abundant (82.5% deuterium incorporation), replaced by deuterium at least 6000 times more abundant (90% deuterium incorporation), replaced by deuterium at least 6333.3 times more abundant (95% deuterium incorporation), replaced by deuterium at least 6466.7 times more abundant (97% deuterium incorporation), replaced by deuterium at least 6600 times more abundant (99% deuterium incorporation), or replaced by deuterium at least 6633.3 times more abundant (99.5% deuterium incorporation).

[0064] In one embodiment, hydrogen is present at its natural abundance at all positions.

[0065] 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 an appropriate isotopically labeled reagent for the unlabeled reagent previously used.

[0066] Pharmaceutically acceptable solvates according to the present disclosure include those in which the solvent of crystallization may be isotopically substituted, e.g., D 2 O, d 6 -Acetone, d 6 -Contains DMSO.

[0067] 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 a substituent may be bonded at a chiral center of a carbon atom.Therefore, the present disclosure includes the enantiomers, diastereomers, or racemates of the compounds.

[0068] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. 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 the present disclosure, single stereoisomers with known relative and absolute configurations of the two chiral centers are designated using the conventional RS system (e.g., (1S,2S)), single stereoisomers with known relative configurations but unknown absolute configurations are designated using 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).

[0069] "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. If the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds of unknown absolute configuration may be designated (+) or (-) depending on the way (dextrorotatory or levorotatory) they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, resolved compounds may be defined by their respective retention times relative to the corresponding enantiomer / diastereomer via chiral HPLC.

[0070] Certain compounds described herein contain one or more asymmetric centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0071] 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., separated on chiral SFC or HPLC chromatography columns such as CHIRALPAK® and CHIRALCEL® available from DAICEL Corp., using a suitable solvent or solvent mixture to achieve good separation). When the compound contains a double bond, the substituent may be in the E or Z configuration. When the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0072] 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.

[0073] As used herein, "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. The 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), 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.

[0074] The phrase "pharmacologically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with other ingredients included in the formulation and / or with the mammal being treated therewith.

[0075] 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, alleviating symptoms or complications, or eliminating the disease, condition, or disorder.

[0076] As used herein, the term "stroke" has its meaning as commonly accepted in the art. The term may refer broadly to the occurrence of neurological abnormalities associated with poor 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 scope and caused by an obstruction in blood flow.

[0077] As used herein, a subject is "in need of" a treatment if such a subject (preferably a human) would benefit biologically, medically, or in quality of life from such treatment.

[0078] As used herein, the term "co-administration" refers to the presence of two active agents in the blood of an individual. Co-administered active agents can be delivered simultaneously or sequentially.

[0079] The term "combination therapy" or "in combination with" or "pharmaceutical combination" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration includes substantially simultaneous co-administration of these therapeutic agents, such as in a single capsule with a fixed ratio of active ingredients. Alternatively, such administration includes co-administration in multiple containers or separate containers (e.g., capsules, powders, and liquids) for each active ingredient. The powders and / or liquids can be reconstituted or diluted to the desired dose before administration. Furthermore, such administration also includes the use of each type of therapeutic agent administered before each other, simultaneously, or sequentially, without specific time restrictions. In either case, the treatment regimen provides the beneficial effect of the drug combination in treating the condition or disorder described herein.

[0080] II. Compounds of the Present Disclosure The compounds of the disclosure include a degradation signaling moiety (DSM) capable of binding to an E3 ligase (e.g., a cereblon protein), an IRAK binding or targeting moiety, and optionally a linker that covalently attaches the DSM to the IRAK binding or targeting moiety.

[0081] In a first embodiment, the compound of the present disclosure has formula (A): IRAK-L-DSM(A) or a pharma- ceutically 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 of formula (A) are as described below.

[0082] A. IRAK4 Binding or Targeting Sites In a second embodiment of the present disclosure, for a compound of formula (A), IRAK is represented by formula (IA) or (IB): [ka] or a pharma- ceutically acceptable salt thereof, wherein the other variables are as defined in the first embodiment.

[0083] In a third embodiment of the present disclosure, for a compound of formula (A), IRAK is represented by formula (IA) or (IB): [ka] or a pharma- ceutically acceptable salt thereof, wherein the other variables are as defined in the first embodiment.

[0084] In a fourth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), or (IC), wherein R 1 1 to 3 R 5 phenyl optionally substituted with 5 a 5- or 6-membered partially or fully saturated heterocycle having 1 to 2 heteroatoms independently selected from the heteroaryl, oxygen and nitrogen, optionally substituted with 1 to 3 R 5 and 9-10 membered bicyclic heteroaryl having 1, 2 or 3 nitrogen atoms, each of which is optionally substituted with 1-3 R 5 and wherein the definitions of the other variables are as defined in the first, second, or third embodiment.

[0085] In a fifth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), or (IC), wherein R 1 1 to 2 R 5 phenyl optionally substituted with 1 to 2 R 5pyrazole optionally substituted with one to two R 5 pyridine optionally substituted with one or two R 5 pyridone optionally substituted with one or two R 5 pyrimidine optionally substituted with, and one to two R 5 and wherein the definitions of the other variables are as defined in the first, second, or third embodiment.

[0086] In a sixth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), or (IC), wherein R 1 1 to 2 R 5 phenyl optionally substituted with 1 to 2 R 5 pyrazole optionally substituted with one to two R 5 pyridine optionally substituted with one or two R 5 pyrimidine optionally substituted with, and one to two R 5 and wherein the definitions of the other variables are as defined in the first, second, or third embodiment.

[0087] In a seventh embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), or (IC), wherein R 1 is expressed by the following formula: [ka] where m is 0, 1, or 2, and the other variables are as defined in the first, second, or third embodiment.

[0088] In an eighth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), or (IC), wherein R 1 is expressed by the following formula: [ka] where m is 0, 1, or 2, and the other variables are as defined in the first, second, or third embodiment.

[0089] In a ninth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), or (IC), wherein R 1 is expressed by the following formula: [ka] and the definitions of the other variables are as defined in the first, second, or third embodiment.

[0090] In a tenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), or (IC), wherein R 1 is expressed by the following formula: [ka] and the definitions of the other variables are as defined in the first, second, or third embodiment.

[0091] In an eleventh embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), or (IC), wherein R 1 is expressed by the following formula: [ka] and the definitions of the other variables are as defined in the first, second, or third embodiment.

[0092] In a twelfth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), or (IC), wherein R 1 is expressed by the following formula: [ka] and the definitions of the other variables are as defined in the first, second, or third embodiment.

[0093] In a thirteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), or (IC), wherein R 2 is hydrogen, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[0094] In a fourteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is represented by the following formula: [ka] and the definitions of the other variables are as defined in the first embodiment.

[0095] In a fifteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is represented by the following formula: [ka] and the definitions of the other variables are as defined in the first embodiment.

[0096] In a sixteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), (IC), (IA-1), (IA-2), (IA-3), (IA-4), (IB-1), (IB-2), (IB-3), (IB-4), (IC-1), (IC-2), (IC-3), or (IC-4), wherein 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 and alkyl, 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, or fifteenth embodiment.

[0097] In a seventeenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), (IC), (IA-1), (IA-2), (IA-3), (IA-4), (IB-1), (IB-2), (IB-3), (IB-4), (IC-1), (IC-2), (IC-3), or (IC-4), wherein R 3 -CF 3 or -O-CH(CH 3 ) 2 and the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.

[0098] In an eighteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), (IC), (IA-1), (IA-2), (IA-3), (IA-4), (IB-1), (IB-2), (IB-3), (IB-4), (IC-1), (IC-2), (IC-3), or (IC-4), wherein R 3 is -O-CH(CH 3 ) 2 and the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment.

[0099] In a nineteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), (IC), (IA-1), (IA-2), (IA-3), (IA-4), (IB-1), (IB-2), (IB-3), (IB-4), (IC-1), (IC-2), (IC-3), or (IC-4), wherein R 5 For each existence, C 1-4 Alkyl, halogen, C 1-4 Haloalkyl and C 3-4 cycloalkyl, 3-4 Cycloalkyl is optionally substituted with 1 halo, and 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, or eighteenth embodiment.

[0100] In a twentieth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), (IC), (IA-1), (IA-2), (IA-3), (IA-4), (IB-1), (IB-2), (IB-3), (IB-4), (IC-1), (IC-2), (IC-3), or (IC-4), wherein R 5 For each existence, C 1-4 Alkyl, halogen, and C 1-4 haloalkyl, 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, or eighteenth embodiment.

[0101] In a twenty-first embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), (IC), (IA-1), (IA-2), (IA-3), (IA-4), (IB-1), (IB-2), (IB-3), (IB-4), (IC-1), (IC-2), (IC-3), or (IC-4), wherein R 5 For each occurrence, -CH 3 , -CHF 2 , -CF 3 , F, cyclopropyl, and [ka] and the definitions of the other variables are as defined in the nineteenth or twentieth embodiment.

[0102] In a twenty-second embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (I), (IA), (IB), (IC), (IA-1), (IA-2), (IA-3), (IA-4), (IB-1), (IB-2), (IB-3), (IB-4), (IC-1), (IC-2), (IC-3), or (IC-4), wherein R 5 For each occurrence, -CH 3 , -CHF 2 , -CF 3 and F, with the definitions of the other variables being as defined in the nineteenth or twentieth embodiment.

[0103] In a twenty-third embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is represented by the following formula: [ka] [ka] wherein R is an IRAK4 binding site represented by one of the formulas: 5 is C 1-3 Alkyl or C 1-3 Haloalkyl or C 3-4 cycloalkyl, 3-4 The cycloalkyl is optionally substituted with 1 halo, and the other variables are as defined in the first embodiment.

[0104] In a twenty-fourth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is represented by the following formula: [ka] wherein R is an IRAK4 binding site represented by one of the formulas: 5 is C 1-3 Alkyl or C 1-3haloalkyl, and the other variables are as defined in the first embodiment.

[0105] In a twenty-fifth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (IA-1a), (IA-2a), (IA-3a), (IA-4a), (IB-1a), (IB-2a), (IB-3a), (IB-4a), (IC-1a), (IC-2a), (IC-3a), or (IC-4a), wherein R 5 is CH 3 , CHF 2 , C.F. 3 , cyclopropyl, or [ka] and the other variables are as defined in the twenty-third or twenty-fourth embodiment.

[0106] In a twenty-sixth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, IRAK is an IRAK4 binding site represented by one of formulas (IA-1a), (IA-2a), (IA-3a), (IA-4a), (IB-1a), (IB-2a), (IB-3a), (IB-4a), (IC-1a), (IC-2a), (IC-3a), or (IC-4a), wherein R 5 is CH 3 , CHF 2 , or CF 3 and the other variables are as defined in the twenty-third or twenty-fourth embodiment.

[0107] B. Degradation signaling site (DSM) The decomposition signaling moiety (DSM) in the compound of formula (A) or a pharma- ceutically 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, for example, 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", WO2018 / 237026, entitled "Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation", WO2019 ... The degronimer may be a binding site or targeting site for a degron or an E3 ubiquitin ligase as described in WO2017 / 197051 entitled "Heterocyclic Degronimers for Target Protein Degradation", WO2017 / 197055 entitled "Spirocyclic Degronimers for Target Protein Degradation", WO2017 / 197036 entitled "C3-Carbon Linked Glutarimide 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 sites or E3 ubiquitin ligase binding sites or targeting sites that can be used are 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 / 1 80417, 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 PCT publications are incorporated herein by reference.

[0108] In a twenty-seventh embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a compound of formula (D): [ka] is a degradation signaling moiety of [ka] represents a bond to the linker L, and Y represents a CR D1 or N and Z 1 is a bond, -NR D2 -, -O-, and -CH 2 - selected from, 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 6-10 membered aryl, 5-10 membered heteroaryl, and partially saturated 4-11 membered heterocycles represented by the formula D3 and optionally substituted with G 2 Het 1 , *-NR D4 -C 4-6 Cycloalkyl-**, *-NR D4 -Het 1 -**, *-NR D4 -Het 1 -C 1-4 Alkyl-**, *-C 1-4 Alkyl-C(R D1 )=Het 1 -**, *-C(O)-C 1-4 Alkyl-Het 1 -**, *-Het 1 -C 1-6 Alkyl-**, *-Het 1 -O-**, *-C(O)-C 1-4 Alkyl-Het 1 -C(O)-**, *-C(O)-Het 1 -C(O)-**, *-C(O)-phenyl-C 1-4 Alkyl-NHC(O)-**, *-C(O)-C 1-6 Alkyl-NR D4 -**, *-NR D4 -Cycloalkyl-**, *-O-Het 1 -**, or *-NR D4 -C 1-4 Alkyl-Het 1 -**, where *- represents a bond to the linker L and **- represents a bond to G 1 represents a bond to Het 1 is a 4-7 membered monocyclic heterocycle or a 7-11 membered bicyclic heterocycle, each of which contains one or more (e.g., 1-6, 1-3, or 1, 2, 3, 4, 5, or 6) R D5 and optionally substituted with R D1 , H, C 1-6 alkyl, or halogen; R D2 is H or C1-3 is alkyl, R D3 For each occurrence, H, halogen, C 1-4 Alkyl, and C 1-4 haloalkyl; R D4 is H or C 1-3 is alkyl, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment.

[0109] In a twenty-eighth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a compound of formula (D): [ka] is a degradation signaling moiety of [ka] represents a bond to the linker L, and Y represents a CR D1 or N and Z 1 is a bond, -NR D2 -, -O-, and -CH 2 - selected from, 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 6-10 membered aryl, 5-10 membered heteroaryl, and partially saturated 4-11 membered heterocycles represented by the formula D3 and optionally substituted with G 2 Het 1 , *-NR D4 -Het1 -**, *-NR D4 -Het 1 -C 1-4 Alkyl-**, *-C 1-4 Alkyl-C(R D1 )=Het 1 -**, *-C(O)-C 1-4 Alkyl-Het 1 -**, *-Het 1 -C 1-6 Alkyl-**, *-Het 1 -O-**, *-C(O)-C 1-4 Alkyl-Het 1 -C(O)-**, *-C(O)-Het 1 -C(O)-**, *-C(O)-phenyl-C 1-4 alkyl-NHC(O)-**, where *- represents a bond to the linker L and **- represents a bond to G 1 represents a bond to Het 1 is a 4-7 membered monocyclic heterocycle or a 7-11 membered bicyclic heterocycle, each of which contains one or more (e.g., 1-6, 1-3, or 1, 2, 3, 4, 5, or 6) R D5 and optionally substituted with R D1 , H, C 1-6 alkyl, or halogen; R D2 is H or C 1-3 is alkyl, R D3 For each occurrence, H, halogen, C 1-4 Alkyl, and C 1-4 haloalkyl; R D4 is H or C 1-3 is alkyl, 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, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment.

[0110] In a twenty-ninth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), wherein Het 1 is a 4- to 7-membered monocyclic saturated heterocycle containing one or two nitrogen atoms, or a 7- to 8-membered spiro bicyclic saturated heterocycle containing one or two nitrogen atoms, each of which is D5 and the definitions of the other variables are as defined in the twenty-seventh or twenty-eighth embodiment.

[0111] In a thirtieth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), wherein Het 1 is piperidine, piperazine, 1,4-diazepane, morpholine, 2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5]nonane, or 2,6-diazaspiro[3.3]heptane, each of which contains one or two R D5 and the definitions of the other variables are as defined in the twenty-seventh or twenty-eighth embodiment.

[0112] In a thirty-first embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), wherein Het 1 is piperidine, piperazine, 2-azaspiro[3.3]heptane, or 2,6-diazaspiro[3.3]heptane, each of which contains one or two R D5 and the definitions of the other variables are as defined in the twenty-seventh or twenty-eighth embodiment.

[0113] In a thirty-second embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), wherein Het 1is expressed by the following formula: [ka] wherein n is 0, 1, or 2; [ka] represents a direct or indirect bond to the linker L, -* represents a bond to G 1 and the other variables are as defined in the 30th embodiment.

[0114] In a thirty-third embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is of formula (DI), (D-II), (D-III), (D-IV), or (DV): [ka] is a degradation signaling moiety of [ka] represents a bond to the linker L, Z 1 is 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 heterocycle; G 1 Each of the 6-10 membered aryl, 5-10 membered heteroaryl, and partially saturated 4-11 membered heterocycles represented by the formula D3 and optionally substituted with R D2 is C 1-3 is alkyl, R D3 For each occurrence, H, halogen, and C 1-4 alkyl; R D4 is C 1-3 is alkyl, R D5is halogen; n is 0, 1, or 2; 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, thirtieth, thirty-first, or thirty-second embodiment.

[0115] In a thirty-fourth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is of formula (DI), (D-II), (D-III), or (D-IV): [ka] is a degradation signaling moiety of [ka] represents a bond to the linker L, Z 1 is 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 heterocycle; G 1 Each of the 6-10 membered aryl, 5-10 membered heteroaryl, and partially saturated 4-11 membered heterocycles represented by the formula D3 and optionally substituted with R D2 is C 1-3 is alkyl, R D3 For each occurrence, H, halogen, and C 1-4 alkyl; R D4 is C 1-3 is alkyl, R D5is halogen; n is 0, 1, or 2; 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, thirtieth, thirty-first, or thirty-second embodiment.

[0116] In a thirty-fifth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI), (D-II), (D-III), (D-IV), or (DV), wherein: 1 is selected from phenyl, pyrazolyl, pyridinyl, pyrimidinyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, benzo[d]oxazol-2(3H)-one, 7,9-dihydro-8H-purin-8-one, 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, pyrazinyl, indazolyl, and indolyl, each of which may be selected from one or two R D3 and the definitions of the other variables are as defined in the twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment.

[0117] In a thirty-sixth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI), (D-II), (D-III), (D-IV), or (DV), wherein: 1 is selected from phenyl, pyrazolyl, pyridinyl and pyrimidinyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, indazolyl, and indolyl, each of which is selected from one or two R D3 and the definitions of the other variables are as defined in the twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment.

[0118] In a thirty-seventh embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI), (D-II), (D-III), (D-IV), or (DV), wherein: 1 is expressed by the following formula: [ka] wherein o is 0, 1, or 2; [ka] is G 2 represents a bond to Z 1 and the other variables are as defined in the twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment.

[0119] In a thirty-eighth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI), (D-II), (D-III), (D-IV), or (DV), wherein: 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 the definitions of the other variables are as defined in the twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment.

[0120] In a thirty-ninth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI), (D-II), (D-III), (D-IV), or (DV), wherein: 1 is expressed by the following formula: [ka] wherein o is 0, 1, or 2; [ka] is G 2 represents a bond to Z 1 and the other variables are as defined in the twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment.

[0121] In a fortieth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI), (D-II), (D-III), (D-IV), or (DV), wherein R D1 -H, -CH 3 , or F, 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, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment.

[0122] In a forty-first embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI), (D-II), (D-III), (D-IV), or (DV), wherein R D2 is H, 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, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, or fortieth embodiment.

[0123] In a forty-second embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI), (D-II), (D-III), (D-IV), or (DV), wherein R D3 For each occurrence, H, Cl, F, and -CH 3 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, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or fortieth embodiment.

[0124] In a forty-third embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI), (D-II), (D-III), (D-IV), (DV), wherein R D4 -CH 3 and the other variable definitions 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, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, fortieth, fortieth, or fortieth embodiment.

[0125] In a forty-fourth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a degradation signaling moiety of formula (D), (DI), (D-II), (D-III), (D-IV), (DV), wherein R D5is, for each occurrence, independently, F or OH, 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-two, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, forty-first, forty-second, or forty-third embodiment. In a forty-fifth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the DSM is a [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and the other variable definitions 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, or twenty-sixth embodiment.

[0126] C. Linker In a forty-sixth embodiment of the present disclosure, for compounds of formula (A), or a pharma- ceutically acceptable salt thereof, L is a bond, C 1-8 alkyl or of 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 (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) halogens; 1-4 Alkyl, Het 2 is one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R L1 is a 4- to 7-membered heterocycle optionally substituted by 3 is C 3-7 cycloalkyl or a 4- to 7-membered heterocycle; G 3 C represented by 3-7 The cycloalkyl and 4- to 7-membered heterocycle each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R L3 and optionally substituted with Z 3 is C 1-4 Alkyl, -C(O)-, or **-C 1-4 Alkyl-C(O)-*, **- is G 3 represents the bond connected to DSM, -* represents the bond connected to DSM, and C 1-4Alkyl is optionally substituted with one or more halogens; Z 4 is R L4 C optionally replaced by 1-4 is alkyl, R L1 For each occurrence, H, halogen, C 1-4 Alkyl, and C 1-4 haloalkyl; R L2 is H or C 1-4 is alkyl, 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, 4-7 membered monocyclic saturated heterocycle, or 5-6 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 independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy; R L5 , H, C 1-4 Alkyl, or C 1-4 is haloalkyl, [ka] represents binding to the IRAK binding site, -* represents binding to the degradation signaling site 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, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, forty-first, forty-second, forty-third, forty-fifth, or forty-fifth embodiment.

[0127] In a forty-seventh embodiment of the present disclosure, for compounds of formula (A), or a pharma- ceutically acceptable salt thereof, L is a bond, C 1-8 alkyl or of 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 (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) halogens; 1-4 Alkyl, Het 2 is one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R L1 is a 4- to 7-membered heterocycle optionally substituted by 3 is C 3-7 cycloalkyl or a 4- to 7-membered heterocycle; G 3 C represented by 3-7 The cycloalkyl and 4- to 7-membered heterocycle each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R L3 and optionally substituted with Z 3 is C 1-4 Alkyl or **-C 1-4 Alkyl-C(O)-*, **- is G 3 represents the bond connected to DSM, -* represents the bond connected to DSM, and C 1-4Alkyl is optionally substituted with one or more halogens; Z 4 is R L4 C optionally replaced by 1-4 is alkyl, R L1 For each occurrence, H, halogen, C 1-4 Alkyl, and C 1-4 haloalkyl; R L2 is H or C 1-4 is alkyl, 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, 4-7 membered monocyclic saturated heterocycle, or 5-6 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 independently selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy; R L5 , H, C 1-4 Alkyl, or C 1-4 is haloalkyl, [ka] represents binding to the IRAK binding site, -* represents binding to the degradation signaling site 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, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, forty-first, forty-second, forty-third, forty-fifth, or forty-fifth embodiment.

[0128] In a forty-eighth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, L is a bond or is represented by formula (L-1), (L-2) or (L-3), wherein Z 2 is a bond or -CH 2 -Het 2 is selected from azetidinyl, piperidinyl, and pyrrolidinyl; Het 2 Each of the azetidinyl, piperidinyl, and pyrrolidinyl groups represented by the formula: L1 and optionally substituted by G 3 is cyclohexyl or piperidinyl, G 3 Each of the cyclohexyl and piperidinyl represented by the formula: L3 and optionally substituted with Z 3 -CH 2 -or**-CH 2 -C(O)-* and Z 4 is R L4 -CH optionally substituted 2 - and the definitions of the other variables are as defined in the forty-sixth or forty-seventh embodiment.

[0129] In a forty-ninth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, L is a bond or 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 L4 is benzyl, and the definitions of the other variables are as defined in the 46th, 47th, or 48th embodiment.

[0130] In a fiftieth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, L is represented by formula (L-1), and Het 2 is expressed 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 46th, 47th, or 48th embodiment.

[0131] In a fifty-first embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, L is represented by formula (L-2), 3 is expressed by the following formula: [ka] wherein: [ka] indicates binding to the IRAK binding site, and -* indicates Z 3 and the other variables are as defined in the 46th, 47th, or 48th embodiment.

[0132] In a fifty-second embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, L is represented by formula (L-1), and Het 2 teeth, [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 46th, 47th, or 48th embodiment.

[0133] In a fifty-third embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, L is represented by formula (L-2), 3 teeth, [ka] wherein: [ka] indicates binding to the IRAK binding site, and -* indicates Z 3 and the other variables are as defined in the 46th, 47th, or 48th embodiment.

[0134] In a fifty-fourth embodiment of the present disclosure, for compounds of formula (A), or a pharma- ceutically acceptable salt thereof, L is of the formula: [ka] wherein: [ka] represents binding to the IRAK binding site, -* represents binding to the degradation signaling site 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, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, forty-first, forty-second, forty-third, forty-fifth, or forty-fifth embodiment.

[0135] In a fifty-fifth embodiment, for the compound of formula (A), the compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof, wherein Z 1 is a bond or -O-, and G 1 is phenyl, a 6-membered heteroaryl, or a 9-membered partially saturated bicyclic heterocycle, each of which is selected from the group consisting of halo and C 1-2 and optionally substituted with 1 or 2 substituents independently selected from alkyl, G 2 Het 1 , *-NR D4 -Het 1 -** or *-C(O)-C 1-2 Alkyl-Het 1 -**, where *- represents a bond to the linker L and **- represents a bond to G 1 represents a bond to Het 1 is piperidine optionally substituted with one or two halo or OH, R 5 is C optionally substituted with 1 halo 3-4 cycloalkyl, R D4 is H or C 1-2 alkyl, and the remainder of the variables are as described in the first embodiment.

[0136] In a fifty-sixth embodiment, for a compound of formula (A), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IVA), or (VA), or a pharma- ceutically acceptable salt thereof, G 1 is phenyl, pyridinyl, indazolyl, or 1,3-dihydro-2H-benzo[d]imidazol-2-one, each of which is selected from the group consisting of halo and C 1-2 and optionally substituted with 1 or 2 substituents independently selected from alkyl, G 2 Het 1 , *-NH-Het 1 -** or *-C(O)-CH 2 -Het 1 -**, where *- represents a bond to the linker L and **- represents a bond to G 1 represents a bond to Het 1 is piperidine optionally substituted with 1 or 2 halo or OH, and the remainder of the variables are as described in the 55th embodiment.

[0137] In a fifty-seventh embodiment, for a compound of formula (A), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IVA), or (VA), or a pharma- ceutically acceptable salt thereof, G 1 teeth, [ka] where: [ka] is G 2 represents a bond to Z 1 represents a bond to Het 1 teeth, [ka] where #- is a bond to the linker, -NH-, or -C(O)-CH 2 -, ##- stands for G 1 represents a bond to R 5is cyclopropyl or [ka] and the remaining variables are as described in the 56th embodiment.

[0138] In a fifty-eighth embodiment of the present disclosure, the compound of formula (A), or a pharma- ceutically acceptable salt thereof, is any one of the compounds of Examples 1 to 199, or a pharma- ceutically acceptable salt thereof.

[0139] In one embodiment of the disclosure, the compound of formula (A) has the following formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0140] III. Pharmaceutical Compositions and Methods of Use Another aspect of the present invention is a pharmaceutical composition comprising at least one compound described herein (e.g., a compound described in any of the embodiments above, or a pharma- ceutically acceptable salt thereof) and at least one pharma- ceutically acceptable carrier.

[0141] The compounds of the present disclosure are typically used as pharmaceutical compositions (e.g., the compounds of the present disclosure and at least one pharma- ceutically acceptable carrier). As used herein, the term "pharma-ceutically 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). Except in the event that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. For the 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).

[0142] Compounds of the present disclosure have been found to modulate IRAK4 activity and may be beneficial for the treatment of neurological diseases, neurodegenerative diseases, and other additional diseases.

[0143] In some embodiments, a compound described herein (e.g., a compound described in any of the embodiments above, or a pharma- ceutically 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 embodiments above, or a pharma- ceutically acceptable salt thereof) can be used to modulate (e.g., reduce) the level of IRAK4 protein. In some embodiments, a compound described herein, or a pharma- ceutically acceptable salt thereof (e.g., a compound described in any of the embodiments above, or a pharma- ceutically acceptable salt thereof) can be used to modulate (e.g., reduce) the activity of IRAK4 or to otherwise affect the properties and / or behavior of IRAK4, such as stability, phosphorylation, kinase activity, interactions with other proteins, etc.

[0144] In some embodiments, the present disclosure provides methods of 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 pharma- ceutically acceptable salt thereof).

[0145] 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 pharma- ceutical acceptable salt thereof), or a pharmaceutical composition described herein.

[0146] 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, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, thereby treating the autoimmune diseases, cancer, cardiovascular diseases, diseases of the central nervous system, skin diseases, eye diseases and conditions, and bone diseases in the subject.

[0147] 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.

[0148] In one embodiment, the 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 pharma- ceutical salt thereof), or a pharmaceutical composition described herein.

[0149] 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, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, cutaneous lupus erythematosus (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.

[0150] In one embodiment, the autoimmune disease is selected from rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes mellitus, systemic sclerosis, and Sjogren's syndrome, hi one embodiment, the autoimmune disease is type 1 diabetes.

[0151] 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 disclosure provides methods of treating rheumatoid arthritis or lupus. In some embodiments, the disclosure provides methods of treating multiple sclerosis. In some embodiments, the disclosure provides methods of treating systemic lupus erythematosus or atopic dermatitis.

[0152] One embodiment of the present disclosure includes a method of treating an inflammatory disease in a subject, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, thereby treating the inflammatory disease in the subject.

[0153] In one embodiment, the inflammatory disease is a pulmonary or airway disease, hi one embodiment, the pulmonary 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.

[0154] 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.

[0155] One embodiment of the present disclosure includes a method of treating an ischemic fibrotic disease, comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharma- ceutically 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.

[0156] One embodiment of the present disclosure includes a method of treating post-organ transplant fibrosis, comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, thereby treating post-organ transplant fibrosis in the subject.

[0157] One embodiment of the present disclosure includes a method of treating hypertensive or diabetic end-organ disease, comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, thereby treating the hypertensive or diabetic end-organ disease in the subject.

[0158] One embodiment of the present disclosure includes a method of treating hypertensive renal disease, comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, thereby treating the hypertensive renal disease in the subject.

[0159] 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 pharma- ceutically acceptable salt thereof, thereby treating IPF in the subject.

[0160] One embodiment of the present disclosure includes a method of treating scleroderma or systemic sclerosis, comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, thereby treating scleroderma or systemic sclerosis in the subject.

[0161] 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 pharma- ceutically acceptable salt thereof, thereby treating cirrhosis in the subject.

[0162] One embodiment of the present disclosure includes a method of treating a fibrotic disease 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 pharma- ceutically acceptable salt thereof, thereby treating a fibrotic disease in which tissue injury and / or inflammation is present in the subject. Fibrotic diseases include, for example, pancreatitis, peritonitis, burns, glomerulonephritis, complications of drug toxicity, and post-infectious scarring.

[0163] Scarring of internal organs is a major global health problem, a result of subclinical organ injury over a period of time, or a sequela of acute severe injury or inflammation. All organs can be affected by scarring, and currently there are few therapies that specifically target scarring development. Increasing evidence indicates that scarring itself leads to further decline in organ function, inflammation, and tissue ischemia. This may be directly due to deposition of fibrous matrix that impairs functions such as contractility and relaxation of the heart and vasculature, or poor lung expansion and contraction, or increased space between the microvasculature and vital cells of nutrient-starved organs, distorting normal tissue architecture. However, recent studies have shown that myofibroblasts are themselves inflammatory cells, generating cytokines, chemokines, and radicals that promote injury, and that myofibroblasts emerge as a result of migration from cells known as pericytes, which normally preserve and maintain the microvasculature. The result of this phenotypic transition is an unstable microvasculature that leads to abnormal vascularization or rarefaction.

[0164] 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 kidneys, heart, lungs, stomach, liver, pancreas, hypothalamus, stomach, uterus, bladder, diaphragm, pancreas, intestines, colon, etc.

[0165] It is contemplated that the present 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 present disclosure, methods and compositions described herein can be used to treat, prevent, and / or reduce the severity and damage from fibrosis.

[0166] The compounds of the present disclosure (e.g., a compound described in any of the above embodiments, or a pharma- ceutically acceptable salt thereof) may be useful in the treatment of cancer, e.g., a cancer selected from solid tumor cancers and hematopoietic cancers.

[0167] 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 tumors, 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 colon carcinoma). In some embodiments, the present disclosure provides a method of treating leukemia or lymphoma.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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 gammopathy. In one embodiment, the cancer is chronic lymphocytic leukemia (CLL). In another embodiment, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0172] 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.

[0173] 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 diseases, disorders or conditions listed above. The effective dose of a compound provided herein, or a pharma- ceutically acceptable salt thereof, administered to a subject may be 10 μg to 500 mg.

[0174] 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 drug dosage and to provide the patient with an elegant and easily handled product.

[0175] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, the article for distribution includes 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 may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, a label is disposed on the container that describes the contents of the container. The label may also include appropriate warnings.

[0176] Pharmaceutical compositions containing the compounds of the present disclosure will generally be formulated for parenteral or oral administration or for use as suppositories.

[0177] 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 processes, such as sterilization, and / or may contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, and the like.

[0178] Typically, the pharmaceutical composition is a tablet or gelatin capsule, which comprises the 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 or calcium salt and / or polyethylene glycol; in the case of tablets, furthermore 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, flavorant and sweetener. Tablets may be film-coated or enteric-coated according to the method known in the art.

[0179] 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 pharma-ceutical refined and palatable preparations.

[0180] Tablets may contain the active ingredient in a mixture with non-toxic, pharma- ceutically 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 may be uncoated or coated by known techniques to provide a sustained action over a longer period by delaying disintegration and absorption in the gastrointestinal tract.For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be utilized. 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.

[0181] 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, stabilizing agents, wetting agents or emulsifying agents, dissolution promoters, salts for controlling osmotic pressure, and / or buffers. In addition, they may contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating, or coating methods, respectively, and contain about 0.1-75% or about 1-50% of the active ingredient.

[0182] 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 above-listed diseases, disorders, or conditions.

[0183] Administering the compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes any suitable delivery method. Administering the compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes administering the compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal topically, enterally, parenterally, transdermally, transmucosally, by inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally. Administering the compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal also includes administering the compound that is metabolized to the compound described herein in or on the mammal's body, or a pharmaceutically acceptable salt thereof, to a mammal topically, enterally, parenterally, transdermally, transmucosally, by inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.

[0184] The compound of the present disclosure or its pharma- ceutically acceptable salt used in a subject (e.g., human) is 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. In general, the therapeutically effective dosage of the compound, pharmaceutical composition, or combination thereof depends on the species, 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 a disorder or disease.

[0185] Thus, the compounds described herein or pharma- ceutically acceptable salts thereof may be administered systemically, e.g., orally, in combination with a pharma- ceutically 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 directly combined with the food of the patient's diet. For therapeutic oral administration, the compounds described herein or pharma- ceutically 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, or wafers, and 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.

[0186] The 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.

[0187] In certain embodiments, the disclosure relates to the aforementioned method of administering the compound 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 non-toxic surfactant. In certain embodiments, the disclosure relates to the aforementioned method of administering the compound parenterally. In certain embodiments, the disclosure relates to the aforementioned method of administering the compound systemically.

[0188] 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 a sterile injectable or infusible solution or dispersion. In either case, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

[0189] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent with various other ingredients as mentioned above, as required, and then sterilizing by filtration. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation method can be vacuum drying and freeze-drying techniques, which can produce a powder of the active ingredient and any additional desired ingredient present in the previously sterile-filtered solution.

[0190] 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 pharma- ceutically acceptable salts thereof can be dissolved or dispersed at effective levels, optionally with the aid of nontoxic surfactants.

[0191] Useful dosages of the compounds described herein or their pharma- ceutically 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 in the art; see, for example, U.S. Patent No. 4,938,949, which is incorporated by reference in its entirety.

[0192] The amount of the compound described herein or its pharma- ceutically acceptable salt required for use in treatment will vary not only with the particular salt selected, but also with 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.

[0193] The compounds described herein, or pharma- ceutically 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.

[0194] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

[0195] The disclosed method may include a kit that includes a compound described herein or a pharma- ceutically acceptable salt thereof, and instructional materials that can explain administering a compound described herein or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof, to a cell or a subject. This should be construed to include other embodiments of kits known to those skilled in the art, such as a kit that includes a solvent (e.g., sterile) for dissolving or suspending a compound described herein or a pharma- ceutically acceptable salt thereof, or a composition, before administering the compound described herein or a pharma- ceutically acceptable salt thereof, or a composition, to a cell or a subject. In some embodiments, the subject may be a human. EXAMPLES

[0196] IV. Working Examples A. Abbreviations and acronyms used herein include the following: ACN: Acetonitrile (CH 3 CN) AcOH: means acetic acid; t-Amyl-OH: 2-methylbutan-2-ol Aq.: means aqueous solution; Ar: means argon; br: means wide area; tBuXPhos Pd G3 means [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate ℃: means degrees Celsius; CAN is cerium ammonium nitrate [(NH 4 ) 2 Ce(NO 3 ) 6 ] CDCl 3 : means deuterochloroform; CDI: 1,1′-carbonyldiimidazole; CH 2 Cl 2 : means methylene chloride CaCl 2 : means calcium chloride; Cs 2 CO 3 : means cesium carbonate; d: means double line; dd: means double double line; δ: means chemical shift; D 2 O: means heavy water; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM: dichloromethane; DDQ means 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEA: Diethylamine Dess-Martin periodinane is a 3-oxo-1λ 5 ,2-Benzoiodoxol-1,1,1(3H)-triyl triacetate DIPEA: diisopropylethylamine; DMF: Dimethylformamide DMSO: means dimethyl sulfoxide; DMSO-d 6 : means hexadeuterodimethylsulfoxide; ESI: electrospray ionization Et: means ethyl; Et 3 N stands for 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; HCO 2 H: means formic acid; HCl: means hydrochloric acid; HPLC: means high pressure liquid chromatography; 1 1 H NMR: proton nuclear magnetic resonance; H 2 O: means water; IPA: stands for isopropyl alcohol; K 2 CO 3 : means potassium carbonate; KOH: Potassium hydroxide; L: stands for liter; LC: liquid chromatography; LC-MS: 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; MeOH-d 4 : means deuteromethanol; MHz: stands for Megahertz; Min(s): Minute(s) MS m / z: means mass spectrum peak; MTBE: tert-butyl methyl ether; M / V: means mass-volume ratio; N2 or N 2 : means nitrogen; NH 3 : means ammonia; NH 4 Cl means ammonium chloride Na: means sodium; NaH: means sodium hydride; NaHCO 3 : means sodium bicarbonate; NaOH: means sodium hydroxide; NaOCN means sodium cyanate Na 2 SO 4 : means sodium sulfate; NH 4 Cl: ammonium chloride; NH 4 OAc means ammonium acetate NH 4 HCO 3 : means ammonium bicarbonate; NH 4 OH: ammonium hydroxide; Pd 2 (dba) 3 : means tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl 2 : [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-Bu 3 P) 2 means bis(tri-tert-butylphosphine)palladium(0) PE or Pet Ether: means petroleum ether; Psi: means pounds per square inch; PTSA means p-toluenesulfonic acid monohydrate q: means quartet; R f means the retention factor RT: means room temperature; RuPhos means 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl s: means single line; sat.: means saturated; soln.: means solution; SFC: stands for supercritical fluid chromatography; t: means triple line; TEA: means triethylamine; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; TLC: thin layer chromatography; μmol: means micromolar; UPLC stands for ultra-performance liquid chromatography V: Capacity XPhos: means 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0197] B. General method The compounds of the examples were analyzed or purified according to one of the purification methods mentioned below unless otherwise stated.

[0198] 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 using 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 using pressurized nitrogen (about 10-15 psi) to pass the solvent through the column ("flash chromatography").

[0199] Reactions were carried out under a nitrogen atmosphere unless otherwise noted. Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum.

[0200] C. Analysis method NMR Equipment Specifications: Bruker AVANCE III 400 Bruker AVANCE III HD 400 Bruker AVANCE NEO 400

[0201] 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 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 DAD and an Agilent LC\MS G1956A,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

[0202] 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 equipped with a PDA detector

[0203] 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

[0204] SFC Equipment Specifications: Waters 150 / 200 Purification System Waters Investigator Waters UPC2 Sepiatec Screening System

[0205] Typically, compounds of formula (A) can be prepared according to the scheme provided below. The following examples serve to illustrate the present disclosure without limiting the scope of the disclosure. Methods for preparing such compounds will now be described.

[0206] The present disclosure further includes any variation of the subject process in which the reactants are used in the form of their salts or optically pure materials. The compounds and intermediates of the present disclosure can also be converted into each other according to methods well known to those skilled in the art.

[0207] 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 min) Run Time: 4.8 minutes Column: Acquity UPLC BEH / X-Bridge BEH C18, 1.7μm / 2.5μm, 2.1×50mm Flow rate: 0.5mL / 0.6mL / min Temperature: 40℃

[0208] Method 2 10mM ammonium acetate solution (aqueous phase) 100% acetonitrile (organic phase) Mode: Gradient %B (5 to 95 in 3.7 min) Run Time: 4.8 minutes Column: Acquity UPLC BEH / X-Bridge BEH C18, 1.7μm / 2.5μm, 2.1×50mm Flow rate: 0.5mL / 0.6mL / min Temperature: 40℃

[0209] Method 3 0.1% TFA aqueous solution (aqueous phase) 100% acetonitrile (organic phase) Mode: Gradient %B (5 to 95 in 3.7 min) Run Time: 4.8 minutes Column: Acquity UPLC BEH / X-Bridge BEH C18, 1.7μm / 2.5μm, 2.1×50mm Flow rate: 0.5mL / 0.6mL / min Temperature: 40℃

[0210] Method 4 10mM ammonium bicarbonate solution (aqueous phase) 100% acetonitrile (organic phase) Mode: Gradient %B (5 to 95 in 3.7 min) Run Time: 4.8 minutes Column: Acquity UPLC BEH / X-Bridge BEH C18, 1.7μm / 2.5μm, 2.1×50mm Flow rate: 0.5mL / 0.6mL / min Temperature: 40℃

[0211] Method 5 Mobile phase: A:0.0375% TFA / H 2 O(v / v) B: 0.01875% TFA / ACN (v / v) Column: Kinetex EVO C18 30*2.1mm, 5μm Flow rate: 1.5mL / min Temperature: 50℃ Gradient: 5-95% B, 0-60% B, 30-90% B, or 50-100% B in 1.55 min.

[0212] Method 6 Mobile phase: A: 0.025% NH 3 H 2 O / H 2 O(v / v) B:ACN Column: Kinetex EVO C18 30*2.1mm, 5μm Flow rate: 1.5mL / min Temperature: 50℃ Gradient: 5-95% B, 0-60% B, 30-90% B, or 50-100% B in 1.55 min.

[0213] E. Synthesis of Degradation Signaling Moieties [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.

[0214] Synthesis of 3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione [ka]

[0215] 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) in a round bottom flask was purged with argon gas for 10 minutes, after which granular potassium carbonate (11.31 g, 81.82 mmol) was added. The solution was purged with argon gas for an additional 20 minutes, after which palladium; triphenylphosphane (1.58 g, 1.36 mmol) was added and the reaction was stirred at 90° C. for 16 hours. The progress of the reaction 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 / z267.15 [M-tBu+H] + .

[0216] 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) was added palladium (10% on carbon, type 487, dry) (3 g, 28.19 mmol) at room temperature. The reaction mixture was stirred at this temperature for 6 h under hydrogen atmosphere 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 / z239.30 [M-tBu+H] + .

[0217] 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, then 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 / 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 / z404.3 [MH] - .

[0218] 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) and NaHCO 3 The pH was adjusted to 7 with hexanes and filtered. The filtrate was concentrated in vacuum 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] + .

[0219] Synthesis of 3-[3-(4-piperidyl)anilino]piperidine-2,6-dione [ka]

[0220] 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) was added sodium carbonate (7.87 g, 74.26 mmol) and palladium acetate (555.70 mg, 2.48 mmol). The mixture was stirred at 90° C. for 12 h. After LC-MS showed consumption of 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) and concentrated to 100 mL with NaCl. 2 SO 4The mixture was dried at 40° C., 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] + .

[0221] 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) was added 10 wt% Pd / C (400 mg). The mixture was heated at 25° C. for 5 h under H 2 The reaction was monitored by TLC while stirring under atmosphere (15 psi). Upon completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated in vacuum. Compound tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate (3.5 g, 12.66 mmol, 96.35% yield) was obtained as a white solid. 1 HNMR (400MHz, DMSO-d 6 ) 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 (brd, J =12.6 Hz, 2H),1.40 (s,10H).

[0222] Step 3: 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 with NaHCO 3(2.28 g, 27.14 mmol) was added 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 layer was washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., 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] + .

[0223] Step 4: To a stirred 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 4M HCl / dioxane (4M, 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] + .

[0224] Synthesis of 3-((6-(piperidin-4-yl)pyridin-3-yl)amino)piperidine-2,6-dione [ka]

[0225] 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) was added 10 wt% palladium on carbon (type 487, dry) (3.49 g, 32.75 mmol) and the reaction was stirred under hydrogen atmosphere for 16 h. 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 / 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] - .

[0226] 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) in a sealed tube was added sodium bicarbonate (19.69 g, 234.35 mmol). The reaction mixture was stirred at 85° C. for 16 h. 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 cold 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 / 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 light green solid. LC-MS (ES) - ):m / z 387.28[MH] - .

[0227] 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 progress of the reaction 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] + .

[0228] Synthesis of 3-[4-(3,3-difluoro-4-piperidyl)anilino]piperidine-2,6-dione [ka]

[0229] Step 1: To a stirred solution of 1-bromo-4-nitro-benzene (5 g, 24.75 mmol, 2.56 mL) in DMF (40 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.91 g, 27.23 mmol) and potassium acetate (6.07 g, 61.88 mmol). The resulting mixture was purged with argon gas for 30 minutes, after which palladium acetate (166.71 mg, 742.55 μmol) was added and the reaction was refluxed at 60° C. for 6 hours. After completion of the reaction as indicated by TLC, the mixture was poured into cold water (100 mL) and the resulting solid was filtered and dried under high vacuum to give 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (3.5 g, 9.84 mmol, 39.74% yield) as a brown to black solid. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J= 8.8 Hz, 2H), 7.96(d, J=8.8 Hz, 2H), 1.37(s, 12H).

[0230] Step 2: In a sealed tube, to a solution of tert-butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)-2,6-dihydropyridine-1-carboxylate (8.0 g, 21.78 mmol) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (7.05 g, 28.32 mmol) in 1,4-dioxane (80 mL) was added sodium carbonate (4.62 g, 43.56 mmol) and cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (1.59 g, 2.18 mmol) under argon atmosphere. The resulting mixture was stirred at 55 C for 3 hours and the progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, it was washed with water and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 230-400 mesh, EtOAc / pet ether) to give tert-butyl 3,3-difluoro-4-(4-nitrophenyl)-2,6-dihydropyridine-1-carboxylate (4.4 g, 11.64 mmol, 53.42% yield) as a gummy solid; H NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.8Hz,2H), 7.74(d, J=8.8Hz,2H), 6.83(bs, 1H),4.22 (bs,2H), 3.97(t, J=6.8Hz,2H).

[0231] Step 3: To a stirred solution of tert-butyl 3,3-difluoro-4-(4-nitrophenyl)-2,6-dihydropyridine-1-carboxylate (9.0 g, 26.45 mmol) in ethyl acetate (100 mL) was added platinum(IV) oxide (6.01 g, 26.45 mmol). The reaction flask was evacuated and backfilled with hydrogen gas using a hydrogen bladder, and the reaction was stirred under hydrogen atmosphere at room temperature for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through a celite bed, and the filtrate was concentrated and purified by column chromatography (silica gel, ethyl acetate / pet ether) to give tert-butyl 4-(4-aminophenyl)-3,3-difluoro-piperidine-1-carboxylate (5.4 g, 14.63 mmol, 55.31% yield) as a white solid. LC-MS (ES + ): m / z 257.2 [M-tBu+H] + .

[0232] Step 4: To a stirred solution of tert-butyl 4-(4-aminophenyl)-3,3-difluoro-piperidine-1-carboxylate (5.0 g, 16.01 mmol) and 3-bromopiperidine-2,6-dione (9.22 g, 48.02 mmol) in DMF (50 mL) was added sodium bicarbonate (8.07 g, 96.04 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 16 h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The crude compound was purified by column chromatography (silica gel 100-200 mesh, 15% EtOAc / pet ether) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3,3-difluoro-piperidine-1-carboxylate (5.17 g, 11.77 mmol, 73.54% yield). LC-MS (ES - ): m / z 422.24[MH] - .

[0233] Step 5: To a stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3,3-difluoro-piperidine-1-carboxylate (0.5 g, 1.18 mmol) in dioxane (2 mL) was added HCl (4 M, 5 mL) under nitrogen atmosphere. The reaction was stirred at 0-28 °C for 2 h and monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was concentrated to dryness and washed with diethyl ether (10 mL x 2) to give 3-[4-(3,3-difluoro-4-piperidyl)anilino]piperidine-2,6-dione HCl salt (0.4 g, 1.06 mmol, 89.45% yield) as a solid. LC-MS (ES + ): m / z 324.09[M+H] + .

[0234] Synthesis of 1-(4-(piperidin-4-yl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The intermediate 1-(4-(piperidin-4-yl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione was prepared according to the method described on page 353 of WO2020132561A1.

[0235] Synthesis of 3-[4-(4-piperidyl)phenoxy]piperidine-2,6-dione [ka]

[0236] 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 / 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] + .

[0237] Step 2: 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., sodium hydride (93.78 mg, 3.61 mmol) was added slowly. After the addition, the reaction mixture was heated at 70° C. for 30 min. After it was cooled again 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 h. 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 / 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] + .

[0238] 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 h. 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] + .

[0239] Synthesis of 3-[4-(2,5-diazaspiro[3.4]octan-5-ylmethyl)phenoxy]piperidine-2,6-dione [ka]

[0240] Step 1: To a stirred solution of tert-butyl 3-oxoazetidine-1-carboxylate (200 g, 1.17 mol) in ethanol (2000 mL) was added hydroxylamine hydrochloride (162.37 g, 2.34 mol, 97.23 mL) and anhydrous sodium acetate (383.33 g, 4.67 mol). The reaction mixture was stirred at 75-80° C. for 2 hours. After completion of the reaction as indicated by TLC, the reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo and the crude product was extracted with ethyl acetate, washed with brine solution and concentrated with NaCl. 2 SO 4Drying at 400 rpm and evaporation gave tert-butyl 3-(hydroxyimino)azetidine-1-carboxylate (198 g, 1.02 mol, 87.38% yield) as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 4.50 (d,J=10.8Hz, 4H), 1.40 (s,9H).

[0241] Step 2: To a stirred solution of tert-butyl 3-hydroxyiminoazetidine-1-carboxylate (135 g, 725.00 mmol) in acetonitrile (1800 mL) was added urea peroxide (409.20 g, 4.35 mol) and disodium hydrogen phosphate (617.52 g, 4.35 mol). (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (456.82 g, 2.17 mol, 306.59 mL) was then added slowly (an exotherm was observed) and the reaction mixture was heated to reflux at 60-70 °C for 3-4 h. After the reaction was complete as indicated by TLC, the reaction was quenched with ice-cold water and the mixture was extracted with ethyl acetate, washed with brine solution, and diluted with NaCl. 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by column chromatography (15-20% ethyl acetate / pet ether) to give tert-butyl 3-nitroazetidine-1-carboxylate (60 g, 280.89 mmol, 38.88% yield). 1H NMR (400 MHz, CDCl3) δ 5.20-5.10 (m, 1H), 4.43-4.30 (m, 4H), 1.45(s, 9H).

[0242] Step 3: A stirred solution of tert-butyl 3-nitroazetidine-1-carboxylate (5 g, 24.73 mmol) in methanol (50 mL) was cooled to 0° C. Potassium carbonate (5.13 g, 37.09 mmol) was added to the reaction mixture at 0° C., followed by methyl acrylate (2.55 g, 29.67 mmol, 2.67 mL), and the reaction mixture was stirred at this temperature for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 15-20% ethyl acetate / pet ether) to give tert-butyl 3-(3-methoxy-3-oxo-propyl)-3-nitro-azetidine-1-carboxylate (4 g, 13.18 mmol, 53.31% yield) as a brown gummy solid. LC-MS (ES + ):m / z [M+H] + .1H NMR(400 MHz,CDCl3) δ 4.46 (d, J=10Hz,2H), 4.04(d, J=10Hz,2H), 3.70(s, 3H),2.56-2.52 (m,2H), 2.38-2.34(m, 2H),1.44 (s,9H).

[0243] Step 4: A solution of tert-butyl 3-(3-methoxy-3-oxo-propyl)-3-nitro-azetidine-1-carboxylate (40 g, 138.75 mmol) in methanol (400 mL) was cooled to -10°C and sodium borohydride (15.75 g, 416.24 mmol) was added. Nickel(II) chloride hexahydrate, 98% (23.67 g, 83.25 mmol) was then added in portions over 1 h (the color of the solution changed from green to black). The reaction mixture was stirred at -10°C for 1 h. After the reaction was complete as shown by TLC, the reaction was quenched with potassium carbonate solution (76.6 g in 80 mL water) at 0°C. The reaction mixture was stirred at room temperature for 2 h, filtered through celite and washed with ethyl acetate. The filtrate was extracted with ethyl acetate, washed with brine solution and dried over sodium sulfate. The organic layer was concentrated in vacuo to give a brown gummy liquid. The crude product was triturated with pentane and evaporated to give the product tert-butyl 2,5-diazaspiro[3.4]octane-2-carboxylate (25 g, 104.96 mmol, 75.65% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 3.86 (s,4H), 2.23-2.15(m, 4H), 1.37 (s,9H).

[0244] Step 5: To a stirred solution of 4-hydroxybenzaldehyde (20 g, 163.77 mmol, 17.70 mL) in ACN (300 mL) was added dicesium carbonate (160.08 g, 491.32 mmol) and the reaction was stirred for 30 min at 70° C. Then 3-bromopiperidine-2,6-dione (73.11 g, 380.77 mmol) was added to the reaction mixture, which was stirred for an additional 18 h at 70° C. The progress of the reaction was monitored by TLC / LC-MS. After completion of the reaction, the solvent was removed under reduced pressure and the crude product was diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with anhydrous Na 2 SO 4The mixture was dried at 40° C. and concentrated in vacuo. The crude compound was purified by column chromatography (Davisil silica, 40% ethyl acetate / pet ether) to give 4-[(2,6-dioxo-3-piperidyl)oxy]benzaldehyde (10.26 g, 43.70 mmol, 26.68% yield) as an off-white solid. LC-MS (ES + ): m / z 234.35[M+H] + .

[0245] Step 6: In a sealed tube, a solution of 4-[(2,6-dioxo-3-piperidyl)oxy]benzaldehyde (0.250 g, 1.07 mmol), tert-butyl 2,5-diazaspiro[3.4]octane-2-carboxylate (227.56 mg, 1.07 mmol), acetic acid (0.250 g, 4.16 mmol, 238.10 μL) in methanol (3 mL) was stirred at 60° C. for 3 h. The reaction was then warmed to room temperature and sodium cyanoborohydride (134.72 mg, 2.14 mmol) was added and stirred at this temperature for 16 h. The progress of the reaction was monitored by LC-MS. After completion of the reaction, it was quenched with water. The reaction mixture was then concentrated under reduced pressure to give the crude product, which was purified by reverse-phase preparative HPLC to give tert-butyl 5-[[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]methyl]-2,5-diazaspiro[3.4]octane-2-carboxylate (0.150 g, 345.74 μmol, 32.25% yield) as an off-white solid. LC-MS (ES + ): m / z 430.42[M+H] + .

[0246] Step 7: To a solution of tert-butyl 5-[[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]methyl]-2,5-diazaspiro[3.4]octane-2-carboxylate (0.150 g, 349.24 μmol) in DCM (2 mL), TFA (398.20 mg, 3.49 mmol, 269.05 μL) was added at 0° C. and the reaction mixture was stirred at room temperature for 4 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-(2,5-diazaspiro[3.4]octan-5-ylmethyl)phenoxy]piperidine-2,6-dione TFA salt (0.150 g, 312.30 μmol, 89.42% yield) as a brown semi-solid. LC-MS (ES + ): m / z 330.08[M+H] +.

[0247] Synthesis of 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione [ka]

[0248] Step 1: In a 500 mL round bottom flask was added tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (10 g, 29.39 mmol) in 1,4 dioxane (100 mL), 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), followed by potassium acetate (8.65 g, 88.17 mmol) at room temperature under argon atmosphere. After degassing the reaction mixture with argon for 20 minutes, cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (2.40 g, 2.94 mmol) were added and the reaction was heated at 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 / 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] + .

[0249] 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 potassium phosphate tribasic (16.44 g, 77.46 mmol) at room temperature under argon atmosphere. The reaction mixture was degassed with argon for 20 minutes, after which cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (1.89 g, 2.58 mmol) were added and the reaction was heated at 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 / pet ether) to give the desired product as a yellow thick 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] + .

[0250] Step 3: To 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 10 wt% palladium on charcoal (14 g, 25.42 mmol) and the reaction was stirred at room temperature under hydrogen pressure (70 psi) for 16 h. The progress of the reaction 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 in 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] - .

[0251] 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 h 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] - .

[0252] Synthesis of 3-(3-fluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione [ka] The procedure was essentially similar to that of 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione, except that the synthesis started from tert-butyl 4-(4-bromo-2-fluoro-phenyl)piperidine-1-carboxylate instead of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate and palladium hydroxide was used instead of palladium in step 3. LC-MS (ES + ): m / z 291.37[M+H] + .

[0253] Synthesis of 3-(2,5-difluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione [ka]

[0254] Step 1: A mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g, 32.34 mmol), 1,4-dibromo-2,5-difluoro-benzene (9.67 g, 35.57 mmol), cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (2.37 g, 3.23 mmol), and cesium carbonate (42.15 g, 129.36 mmol) in dioxane (100 mL) and water (20 mL) was degassed and purified with N. 2 The mixture was purged with N for 16 h at 80 °C. 2 Stir under atmosphere.

[0255] After completion of the reaction as confirmed by LC-MS, the suspension was filtered through a celite pad. The filtrate was diluted with water (200 mL x 2) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (silica gel, pet ether / ethyl acetate = 10 / 1 to 5 / 1). The compound tert-butyl 4-(4-bromo-2,5-difluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (5.16 g, 11.31 mmol, 34.96% yield) was obtained as a white solid. LC-MS (ES + ): m / z 317.9 [M-tBu+H] + .

[0256] Step 2: To a solution (10 mL) of tert-butyl 4-(4-bromo-2,5-difluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (4.7 g, 12.56 mmol) in water and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.24 g, 12.56 mmol) was added cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (918.98 mg, 1.26 mmol) and potassium carbonate (5.21 g, 37.68 mmol). The mixture was stirred at 80° C. for 16 hours under nitrogen atmosphere. After complete consumption of the reactants as confirmed by LC-MS, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, pet ether / ethyl acetate = 100 / 1 to 10 / 1). Compound tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,5-difluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (6.4 g, 10.95 mmol, 87.16% yield) was obtained as a light yellow solid. LC-MS (ES +): m / z 585.3[M+H] + .

[0257] Step 3: A solution of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,5-difluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (6.4 g, 10.95 mmol) in THF (60 mL) was added to Pd / C (1.75 g, 1.64 mmol, 0.1 purity) in N 2 The suspension was degassed and diluted with H 2 The mixture was purged three times with H 2 (15 Psi) at 25° C. for 5 h. After complete consumption of the reactants as indicated by LC-MS, the reaction mixture was filtered and the filtrate was concentrated to give a solid. This crude product was used in the next step without further purification. Compound tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-2,5-difluorophenyl)piperidine-1-carboxylate (4 g, 6.29 mmol, 57.49% yield) was obtained as an off-white solid. LC-MS (ES + ): m / z 353.1 [M-tBu+H] + .

[0258] Step 4: A solution of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)-2,5-difluoro-phenyl]piperidine-1-carboxylate (4 g, 9.79 mmol) and HCl (16.00 g, 438.83 mmol, 20 mL) was stirred at 25° C. for 2 hours. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was used in the next step without further purification. Compound 3-(2,5-difluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione HCl salt (3.4 g, 9.76 mmol, 99.69% yield) was obtained as an off-white solid. LC-MS (ES + ): m / z 309.2[M+H] + .

[0259] Synthesis of 3-[4-(3,3-difluoro-4-piperidyl)phenyl]piperidine-2,6-dione [ka]

[0260] Step 1: To a stirred solution of 3,3-difluoropiperidin-4-one (0.5 g, 3.70 mmol) in DCM (10 mL) was added triethylamine (561.70 mg, 5.55 mmol, 773.69 μL) and the reaction mixture was stirred for 10 min. Tert-butoxycarbonyl tert-butyl carbonate (969.18 mg, 4.44 mmol, 1.02 mL) was then added and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LC-MS. Upon completion, the reaction was quenched by the addition of water (10 mL) and stirred for 5 min. The mixture was then extracted with DCM (2×10 mL) and the organic layer was washed with 10 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product as a brown gum (700 mg, 48.25% yield). 1 HNMR (400MHz, DMSO-d 6 ) δ 6.38 (s, 2H), 3.60 (t,J = 11.6Hz, 2H), 3.37 (bs,2H), 1.68(bs, 2H), 1.39 (s,9H). This compound is in the hydrate form.

[0261] Step 2: To a stirred solution of tert-butyl 3,3-difluoro-4-oxo-piperidine-1-carboxylate (5 g, 21.26 mmol) in DCM (50 mL) was added triethylamine (6.45 g, 63.77 mmol, 8.89 mL) and the reaction was stirred for 1 h at −30° C. Then trifluoromethylsulfonyl trifluoromethanesulfonate (9.00 g, 31.88 mmol, 5.36 mL) was added and the reaction was stirred at −30° C. for 16 h and monitored by LC-MS and TLC. Upon completion, the reaction was quenched with water (3×50 ml) and extracted with DCM (3×50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (Devisil-silica, 7% ethyl acetate / petroleum ether) to give the compound tert-butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)-2,6-dihydropyridine-1-carboxylate (1.8 g, 4.42 mmol, 20.80% yield) as a yellow gummy liquid. LC-MS (ES + ): m / z 268.16[M-100+H] + .

[0262] Step 3: To a stirred solution of tert-butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)-2,6-dihydropyridine-1-carboxylate (3.5 g, 9.53 mmol) and 2,6-dibenzyloxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine (5.64 g, 11.44 mmol) in dioxane (40 mL) and water (10 mL) was added sodium carbonate (2.52 g, 23.82 mmol). The mixture was immersed in N 2The mixture was degassed at 40° C. and cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (697.26 mg, 952.93 μmol) was added at room temperature. The reaction was stirred at 60° C. for 12 hours and the progress was monitored by TLC and LC-MS. After the reaction was completed, it was diluted with water (50 mL) and extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (20-30% ethyl acetate / pet ether) to give tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,3-difluoro-2,6-dihydropyridine-1-carboxylate (2.0 g, 2.84 mmol, 29.80% yield) as a brown solid. LC-MS (ES + ): m / z 585.44[M+H] + .

[0263] Step 4: To a stirred solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,3-difluoro-2,6-dihydropyridine-1-carboxylate (2 g, 3.42 mmol) in THF (40 mL) was added ethyl acetate (10 mL), 10 wt% palladium on carbon (wet) (1.82 g, 17.10 mmol), and dioxoplatinum (932.15 mg, 4.11 mmol). The reaction was stirred at room temperature under a hydrogen atmosphere for 12 hours and the progress of the reaction was monitored by TLC and LC-MS. Upon completion, the reaction mixture was filtered through Celite with the aid of ethyl acetate and the filtrate was concentrated under reduced pressure to give the crude product, which was triturated with diethyl ether. The diethyl ether layer was decanted and the desired product was dried under reduced pressure to give tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]-3,3-difluoro-piperidine-1-carboxylate (995 mg, 2.22 mmol, 64.92% yield). LC-MS (ES - ): m / z 407.12[MH] - .

[0264] Step 5: To a stirred solution of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)phenyl]-3,3-difluoro-piperidine-1-carboxylate (0.1 g, 244.84 μmol) in DCM (2 mL) was added TFA (4.44 g, 38.94 mmol, 3 mL) under nitrogen and the reaction was stirred at 0-28 °C for 2 h. The reaction progress was monitored by TLC and LC-MS. Upon completion, the reaction was evaporated to dryness and washed with diethyl ether (10 mL x 2) to give 3-[4-(3,3-difluoro-4-piperidyl)phenyl]piperidine-2,6-dione TFA salt (85 mg, 100.63 μmol, 41.10% yield) as a solid. LC-MS (ES + ): m / z 309.00 [M+H] + .

[0265] Synthesis of 3-[4-(3,3-difluoro-4-piperidyl)-2,5-difluoro-phenyl]piperidine-2,6-dione [ka]

[0266] Step 1: To a solution of 4-bromo-2,5-difluoro-aniline (5.2 g, 25.00 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (12.70 g, 50.00 mmol) in dioxane (3 mL) was added potassium acetate (7.36 g, 75.00 mmol) at room temperature. The reaction mixture was degassed with argon for 10 minutes and cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (1.02 g, 1.25 mmol) were added. The reaction mixture was degassed with argon for another 5 minutes and stirred at 100° C. for 12 hours. The reaction mixture was then concentrated in vacuo to give the crude product, which was purified by column chromatography (davisil silica, 12% ethyl acetate / pet ether) to give 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7 g, 11.36 mmol, 45.46% yield) as a pale yellow solid. LC-MS (ES + ): m / z 255.46[M+H] + .

[0267] Step 2: To a stirred solution of 2,6-dibenzyloxypyridine (6 g, 20.59 mmol) in acetonitrile (200 mL) was slowly added 1-iodopyrrolidine-2,5-dione (4.63 g, 20.59 mmol) at 0° C. The reaction was then warmed and stirred at 80° C. for 2 h while being monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was concentrated in vacuo and extracted with cold water (100 ml) and ethyl acetate (200 ml). The combined organic layers were washed with water, brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude compound was washed with pentane to give the product 2,6-dibenzyloxy-3-iodo-pyridine (6 g, 9.06 mmol, 43.99% yield) as a pale yellow solid. LC-MS (ES + ): m / z 418.28[M+H] + .

[0268] Step 3: In a sealed tube, to a solution of 2,6-dibenzyloxy-3-iodo-pyridine (10 g, 23.97 mmol) and 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.34 g, 28.76 mmol) in dioxane (30 mL) and water (0.3 mL) was added anhydrous potassium carbonate, 99% (9.94 g, 71.90 mmol) at room temperature. The reaction mixture was degassed with argon for 10 minutes, and then cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (1.75 g, 2.40 mmol) were added. The reaction mixture was degassed with argon for another 5 minutes and stirred at 110° C. for 16 hours. The reaction mixture was then concentrated in vacuo to give the crude product, which was purified by column chromatography (silica gel 200-400 mesh, 10% ethyl acetate / pet ether) to give 4-(2,6-dibenzyloxy-3-pyridyl)-2,5-difluoro-aniline (6 g, 12.90 mmol, 53.83% yield) as a pale yellow solid. LC-MS (ES + ): m / z 419.22[M+H] + .

[0269] Step 4: A solution of copper(I) bromide (2.06 g, 14.34 mmol, 436.72 μL), tert-butylnitrile (2.96 g, 28.68 mmol, 3.41 mL) in acetonitrile (50 mL) was cooled to 0° C. Then, 4-(2,6-dibenzyloxy-3-pyridyl)-2,5-difluoro-aniline (6 g, 14.34 mmol) in acetonitrile (20 mL) was added to the reaction mixture at the same temperature. The reaction was slowly warmed to 25° C. and stirred for 16 h and monitored by TLC. After completion of the reaction, water (100 mL) was added to the reaction mixture, extracted with ethyl acetate (100 mL x 2), and the organic layer was concentrated in vacuo to give 2,6-dibenzyloxy-3-(4-bromo-2,5-difluoro-phenyl)pyridine (4.4 g, 7.27 mmol, 50.70% yield) as a pale yellow oil. LC-MS (ES + ): m / z 482.28[M+H] + .

[0270] Step 5: In a sealed tube, potassium acetate (2.69 g, 27.37 mmol) was added to a solution of 2,6-dibenzyloxy-3-(4-bromo-2,5-difluoro-phenyl)pyridine (4.4 g, 9.12 mmol) and (4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.63 g, 18.25 mmol) in dioxane (50 mL) at room temperature. The reaction mixture was degassed with argon for 10 min and then cooled to room temperature. The reaction mixture was cooled to room temperature and cooled to room temperature. The reaction mixture was then ... .75 mg, 456.13 μmol) was added. The reaction mixture was degassed with argon for an additional 5 min and then stirred at 110° C. for 16 h. The reaction mixture was then concentrated in vacuo to give the crude product, which was purified by column chromatography (Davisil silica, 10% ethyl acetate / pet ether) to give 2,6-dibenzyloxy-3-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine (5.6 g, 4.97 mmol, 54.52% yield) as a light brown oil. LC-MS (ES + ): m / z 530.46[M+H] + .

[0271] Step 6: In a sealed tube, anhydrous sodium acetate (2.01 g, 24.50 mmol) was added to a solution of tert-butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)-2,6-dihydropyridine-1-carboxylate (3.0 g, 8.17 mmol) and 2,6-dibenzyloxy-3-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine (5.19 g, 9.80 mmol) in dioxane (120 mL) at room temperature. The reaction mixture was degassed with argon for 10 minutes, and then cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (298.83 mg, 408.40 μmol) were added. The reaction mixture was degassed with argon for another 5 minutes and stirred at 110° C. for 16 hours. The reaction mixture was then concentrated in vacuo to give the crude product, which was purified by column chromatography (silica gel 200-400 mesh, 12% ethyl acetate / pet ether) to give tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)-2,5-difluoro-phenyl]-3,3-difluoro-2,6-dihydropyridine-1-carboxylate (2.6 g, 3.25 mmol, 39.79% yield) as a light brown solid. LC-MS (ES) + ): m / z 621.43[M+H] + .

[0272] Step 7: To a stirred solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)-2,5-difluoro-phenyl]-3,3-difluoro-2,6-dihydropyridine-1-carboxylate (2.6 g, 4.19 mmol) in THF (20 mL) and ethyl acetate (80 mL) was added palladium (10% on carbon, Type 487, dry) (445.82 mg, 4.19 mmol), platinum(IV) oxide hydrate (1.03 g, 4.19 mmol), and the mixture was diluted with H 2The reaction was stirred under a balloon for 16 hours and monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)-2,5-difluoro-phenyl]-3,3-difluoro-piperidine-1-carboxylate (1.46 g, 1.95 mmol, 46.58% yield) as a light brown sticky mass. LC-MS (ES - ): m / z 443.41[MH] - .

[0273] Step 8: To a stirred solution of tert-butyl 4-[4-(2,6-dioxo-3-piperidyl)-2,5-difluoro-phenyl]-3,3-difluoro-piperidine-1-carboxylate (1.46 g, 3.29 mmol) in DCM (50 mL), trifluoroacetic acid (1.87 g, 16.43 mmol, 1.27 mL) was added to the reaction mixture and stirred at 25° C. for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated in vacuo and the crude product was washed with 50% ethyl acetate / pet ether (70 mL) to give 3-[4-(3,3-difluoro-4-piperidyl)-2,5-difluoro-phenyl]piperidine-2,6-dione TFA salt (0.6475 g, 1.26 mmol, 38.34% yield). LC-MS (ES + ): m / z 345.15[M+H] + .

[0274] Synthesis of 3-methyl-3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione [ka]

[0275] Step 1: To a solution of 2-(4-bromophenyl)acetonitrile (2 g, 10.20 mmol, 1.34 mL) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (1 M, 12.24 mL) under argon atmosphere at -78°C. The mixture was stirred at -78°C for 0.5 h, then iodomethane (1.59 g, 11.22 mmol, 698.61 μL) was added and the mixture was stirred at -78°C for 2 h. The reaction mixture was quenched by the addition of ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic layers were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10 g silica, 0-10% ethyl acetate / petroleum ether gradient at 70 mL / min) to give 2-(4-bromophenyl)propanenitrile (1.41 g, 6.64 mmol, 65.13% yield) as a yellow oil. 1 HNMR (400MHz, CDCl 3 )δ 7.54-7.52(m, 2H),7.27-7.24 (m,2H), 3.88(q, J =7.2 Hz,1H), 1.65-1.63(d, J =7.2 Hz,3H).

[0276] Step 2: To a solution of 2-(4-bromophenyl)propanenitrile (1 g, 4.76 mmol) in dioxane (10 mL) was added 40% w / w benzyltrimethylammonium hydroxide (796.15 mg, 1.90 mmol) in methanol and 2-(4-bromophenyl)propanenitrile (1 g, 4.76 mmol) at 0° C., and the mixture was stirred at 25° C. for 4 h. The reaction mixture was quenched by the addition of ammonium chloride (20 mL) at 0° C. and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 4-(4-bromophenyl)-4-cyano-pentanoate (1.05 g, 3.51 mmol, 73.73% yield) as a yellow oil. 1 HNMR (400MHz, CDCl3 )δ 7.47-7.45(m, 2H),7.26-7.24 (m,2H), 3.56(s, 3H),2.42-2.14 (m,4H), 1.66(s, 3H).

[0277] Step 3: A mixture of methyl 4-(4-bromophenyl)-4-cyano-pentanoate (1.05 g, 3.55 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.32 g, 4.25 mmol), cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (129.71 mg, 177.27 μmol) and cesium fluoride (1.62 g, 10.64 mmol, 392.15 μL) in water (2 mL) and dioxane (10 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 90° C. for 12 hours under nitrogen atmosphere. The reaction mixture was quenched by the addition of water (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with NaCl (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10 g silica, 0-20% ethyl acetate / petroleum ether gradient at 60 mL / min) to give tert-butyl 4-[4-(1-cyano-4-methoxy-1-methyl-4-oxo-butyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.3 g, 3.23 mmol, 91.09% yield) as a yellow oil. LC-MS (ES + ): m / z 299.1 [M+H-Boc] + .

[0278] Step 4: To a solution of tert-butyl 4-[4-(1-cyano-4-methoxy-1-methyl-4-oxo-butyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.3 g, 3.26 mmol) in ethyl acetate (20 mL) was added 5% palladium on activated charcoal paste (347.17 mg, 3.26 mmol) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen at 25° C. for 4 h. The reaction mixture was filtered and concentrated under reduced pressure. The product tert-butyl 4-[4-(1-cyano-4-methoxy-1-methyl-4-oxo-butyl)phenyl]piperidine-1-carboxylate (1.3 g, 3.25 mmol, 99.50% yield) was used in the next step without further purification. LC-MS (ES) + ): m / z 423.3 [M+Na] + .

[0279] Step 5: To a solution of tert-butyl 4-[4-(1-cyano-4-methoxy-1-methyl-4-oxo-butyl)phenyl]piperidine-1-carboxylate (11.7 g, 29.21 mmol) in water (10 mL) and methanol (100 mL) was added pearls of sodium hydroxide (2.34 g, 58.43 mmol, 1.10 mL) and the mixture was stirred for 12 h at 25° C. The reaction mixture was concentrated under reduced pressure to remove MeOH, diluted with HO (50 mL) and extracted with ethyl acetate (100 mL×2). The pH of the aqueous layer was adjusted to 5 with 1M HCl, extracted with DCM (100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-[4-(1-tert-butoxycarbonyl-4-piperidyl)phenyl]-4-cyano-pentanoic acid (9.5 g, 23.35 mmol, 79.94% yield) as a white solid, which was used in the next step without further purification. 1 HNMR (400MHz, DMSO-d 6) δ =12.57 - 12.04 (m, 1H),7.46 - 7.38 (m, 2H),7.32 (d,J = 8.4Hz, 2H),4.15 - 4.00 (m, 2H),2.94 - 2.65 (m, 3H),2.33 - 2.13 (m, 3H),2.11 - 1.97 (m, 1H),1.75 (brd, J =12.5 Hz,2H), 1.67(s, 3H),1.55 - 1.44 (m, 2H),1.42 (s,9H).

[0280] Step 6: A mixture of 4-[4-(1-tert-butoxycarbonyl-4-piperidyl)phenyl]-4-cyano-pentanoic acid (6.5 g, 16.82 mmol), acetic acid (52.50 g, 874.27 mmol, 50 mL), and sulfuric acid (1.65 g, 16.82 mmol, 10 mL) was stirred at 100 °C for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse-phase flash chromatography (flow rate: 100 mL / min; gradient: 100-50% water / acetonitrile (with HCl modifier) ​​in 15 min; column: 330 g Flash Column Welch Ultimate XB_C18 20-40 μm; 120A) to give 3-methyl-3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione hydrochloride (4.40 g, 13.07 mmol, 77.73% yield) as a yellow solid. 1 HNMR (400MHz, DMSO-d 6 ) δ =10.94 (s,1H), 9.10- 8.74(m, 2H),7.28 - 7.21 (m, 4H),3.36 (brs, 2H),2.98 (brt, J =10.3 Hz,2H), 2.88- 2.78(m, 1H),2.49 - 2.41 (m, 1H),2.40 - 2.32 (m, 1H),2.14 - 2.02 (m, 2H),1.93 - 1.82 (m, 4H),1.42 (s,3H).

[0281] Synthesis of 3-fluoro-3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione [ka]

[0282] 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 / 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] - .

[0283] 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 lithium 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 min. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was cooled to room temperature and eluted with NH4 It was quenched with Cl 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] - .

[0284] 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 h. 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] + .

[0285] Synthesis of 1-[4-(4-piperidyl)phenyl]hexahydropyrimidine-2,4-dione [ka]

[0286] Step 1: A solution of tert-butyl 4-(4-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (15.0 g, 49.29 mmol) in methanol (300 mL) was degassed with argon gas for 10 min. To this reaction mixture, 10 wt% palladium on carbon (10.49 g, 98.57 mmol) was added at room temperature and hydrogenation was carried out using a Parr apparatus at 70 psi for 16 h. The reaction progress was monitored by LC-MS. Upon completion, the reaction was filtered through a celite bed and washed with methanol (4×20 mL). The organic layer was concentrated under reduced pressure at 45° C. to give the desired product tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (11.8 g, 34.14 mmol, 69.26% yield) as an off-white solid, which was carried on to the next step without further purification. LC-MS (ES + ): m / z 177.17[M-100+H] + .

[0287] Step 2: A mixture of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (16 g, 57.89 mmol), DBU lactate (ionic liquid) (10.28 g, 34.74 mmol), and ethyl acrylate (7.53 g, 75.26 mmol, 8.02 mL) was stirred at 90° C. for 3 h. The reaction progress was monitored by TLC and LC-MS. Upon completion, the reaction was cooled to room temperature and diluted with ethyl acetate. The aqueous layer was separated and the organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by CombiFlash® using 5-10% ethyl acetate in hexane as eluent to give tert-butyl 4-[4-[(3-ethoxy-3-oxo-propyl)amino]phenyl]piperidine-1-carboxylate (12.5 g, 31.54 mmol, 54.48% yield) as a gummy yellow liquid. LC-MS (ES + ): m / z 321.2 [M-tBu+H] + .

[0288] Step 3: To a stirred solution of tert-butyl 4-[4-[(3-ethoxy-3-oxo-propyl)amino]phenyl]piperidine-1-carboxylate (15 g, 39.84 mmol) in benzene (100 mL) was added carbononitridic bromide (6.75 g, 63.75 mmol, 3.34 mL) and sodium bicarbonate (5.36 g, 63.75 mmol) simultaneously and the reaction was stirred at room temperature for 24 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with ethyl acetate (20 ml). The organic phase was washed with water, separated, dried over sodium sulfate, and concentrated in vacuo to give a crude residue which was purified by column chromatography to give tert-butyl 4-[4-[cyano-(3-ethoxy-3-oxo-propyl)amino]phenyl]piperidine-1-carboxylate (12.5 g, 29.58 mmol, 74.24% yield) as a semi-solid. LC-MS (ES + ): m / z 402.2[M+H] + .

[0289] Step 4: A stirred solution of tert-butyl 4-[4-[cyano-(3-ethoxy-3-oxo-propyl)amino]phenyl]piperidine-1-carboxylate (12.5 g, 31.13 mmol), trichloroindigane (2.07 g, 9.34 mmol) and (1Z)-acetaldehyde oxime (5.52 g, 93.40 mmol) in toluene (100 mL) was refluxed for 1 h. After complete consumption of the starting material as monitored by TLC, the reaction mixture was concentrated in vacuo and washed with pentane to give tert-butyl 4-[4-[carbamoyl-(3-ethoxy-3-oxo-propyl)amino]phenyl]piperidine-1-carboxylate (12 g, 26.03 mmol, 83.61% yield) as a gummy liquid, which was used in the next step without further purification. LC-MS (ES) + ): m / z 364.4 [M-tBu+H] + .

[0290] Step 5: A solution of tert-butyl 4-[4-[carbamoyl-(3-ethoxy-3-oxo-propyl)amino]phenyl]piperidine-1-carboxylate (12 g, 28.60 mmol) in acetonitrile (120 mL) was heated at 60° C. with stirring. Triton B (40% in methanol) (17.94 g, 42.91 mmol, 19.50 mL) was added to the mixture and the reaction was stirred at the same temperature for 10 min. After complete consumption of the starting material (confirmed by TLC and LC-MS), the reaction mixture was concentrated in vacuo and the crude residue was purified by column chromatography to give tert-butyl 4-[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]piperidine-1-carboxylate (8 g, 21.21 mmol, 74.14% yield) as a white solid. LC-MS (ES + ): m / z 318.1 [M-tBu+H] + .

[0291] Step 6: To a stirred suspension of tert-butyl 4-[4-(2,4-dioxohexahydropyrimidin-1-yl)phenyl]piperidine-1-carboxylate (13.50 g, 36.15 mmol) in dioxane (40 mL) was added 4M HCl / dioxane (50 mL) at 0° C. and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction as evidenced by LC-MS, the volatiles were removed under vacuum to give 1-[4-(4-piperidyl)phenyl]hexahydropyrimidine-2,4-dione HCl salt (11.1 g, 34.77 mmol, 96.18% yield) as a white solid. LC-MS (ES + ): m / z 274.4[M+H] + .

[0292] Synthesis of 3-[4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl]piperidine-2,6-dione [ka]

[0293] Step 1: In a 50 mL Schlenk tube, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (8.0 g, 40.35 mmol) and 1-bromo-4-iodo-benzene (11.42 g, 40.35 mmol) in toluene (80 mL) were degassed with nitrogen for 15 min. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (3.30 g, 4.04 mmol) and sodium tert-butoxide (19.39 g, 201.75 mmol) were added and the mixture was degassed for an additional 5 min. The reaction mixture was sealed and heated at 65° C. for 60 h and monitored by TLC and UPLC. After complete consumption of the starting material, the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 0-20% ethyl acetate / pet ether) to give tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (8.5 g, 22.85 mmol, 56.64% yield) as an off-white solid. LC-MS (ES + ): m / z 354.9[M+H] + .

[0294] Step 2: To a stirred solution of tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (5 g, 14.15 mmol) in dioxane (60 mL) in a sealed tube, bis(pinacolato)diboron (5.03 g, 19.82 mmol) was added followed by potassium acetate (4.17 g, 42.46 mmol). The reaction mixture was degassed with nitrogen for 10 min and then diluted with Pd(dppf)Cl. 2(1.16 g, 1.42 mmol) was added and the mixture was degassed with nitrogen for 10 min and then heated at 90 °C for 16 h. The progress of the reaction was monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was cooled to room temperature and the mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the crude compound, which was purified by column chromatography (silica gel 100-200 mesh) to give tert-butyl 6-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (5.1 g, 12.35 mmol, 87.24% yield) as a white solid. LC-MS (ES + ): m / z 401.2[M+H] + .

[0295] Step 3: To a stirred solution of 2,6-dibenzyloxy-3-bromo-pyridine (0.5 g, 1.35 mmol) and tert-butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (648.75 mg, 1.62 mmol) in dioxane (4.00 mL) and water (2 mL) was added sodium tert-butoxide (389.36 mg, 4.05 mmol) and the reaction mixture was degassed for 15 minutes before adding cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (197.63 mg, 270.10 μmol). The reaction mixture was stirred at 100° C. for 16 hours. After completion of the reaction as confirmed by LC-MS, the reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure at 50° C. The crude compound was purified by flash column chromatography (silica gel 100-200 mesh, 0-50% ethyl acetate / pet ether) to give tert-butyl 6-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.35 g, 596.33 μmol, 44.16% yield). LC-MS (ES) + ): m / z 564.45[M+H]+ .

[0296] Step 4: To a stirred solution of tert-butyl 6-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.3 g, 532.21 μmol) in ethanol (20 mL) and THF (20 mL) was added 10% palladium on carbon (wet) (0.3 g, 2.82 mmol) under nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 16 hours under a hydrogen balloon. After completion of the reaction as confirmed by LC-MS, the reaction mixture was filtered through a Celite pad and concentrated under reduced pressure at 45° C. The crude compound was purified by flash column chromatography (silica gel 100-200 mesh, 0-30% ethyl acetate / pet ether) to give tert-butyl 6-[4-(2,6-dioxo-3-piperidyl)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.15 g, 350.35 μmol, 65.83% yield). LC-MS (ES) + ): m / z 386.36[M+H] + .

[0297] Step 5: To a stirred solution of tert-butyl 6-[4-(2,6-dioxo-3-piperidyl)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.1 g, 259.43 μmol) in DCM (10 mL) was added trifluoroacetic acid (147.90 mg, 1.30 mmol, 99.93 μL) at 0° C. The reaction mixture was stirred at room temperature for 6 h. After completion of the reaction as confirmed by LC-MS, the reaction mixture was concentrated under reduced pressure at 40° C. to give 3-[4-(2,6-diazaspiro[3.3]heptane-2-yl)phenyl]piperidine-2,6-dione TFA salt (0.1 g, 239.18 μmol, 92.19% yield). LC-MS (ES + ): m / z 286.32[M+H] + .

[0298] Synthesis of 1-[1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2,4-dione [ka]

[0299] Step 1: To a stirred solution of 4-bromo-2-fluorobenzonitrile (25 g, 125.00 mmol) in ethanol (500 mL) was added methylhydrazine (85% aqueous solution) (51.83 g, 1.12 mol) at room temperature. The reaction mixture was heated at 125° C. in an autoclave (1000 ml) for 7 h. The reaction mixture was cooled to room temperature, poured into ice-cold water (2000 ml) and stirred well for 30 min. The coagulated mass was filtered off, washed with water and dried well to give 6-bromo-1-methyl-1H-indazol-3-amine (25 g, 105.05 mmol, 84.05% yield) as an off-white solid. LC-MS (ES + ): m / z 291.37[M+H] + .

[0300] Step 2: To a stirred solution of 6-bromo-1-methyl-indazol-3-amine (50 g, 221.17 mmol) in HCl (2 M aqueous) (500.00 mL) was added tetrabutylammonium bromide (7.13 g, 22.12 mmol) at room temperature. The reaction mixture was heated to 55° C. (internal temperature) and acrylic acid (23.91 g, 331.75 mmol, 22.77 mL) was added dropwise at this temperature. The reaction was then heated to 100° C. (external) for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with ice-cold water (1000 ml). This was stirred with vigorously stirring until 2M NaHCO 3 The mixture was neutralized to pH 6.5-7 with 1000 ml of ethyl acetate. The solid precipitate was filtered off, washed with excess ice-cold water, and thoroughly dried to give 3-[(6-bromo-1-methyl-indazol-3-yl)amino]propanoic acid (54 g, 163.30 mmol, 73.84% yield) as an off-white solid. LC-MS (ES + ): m / z 298.28[M+H]+ .

[0301] Step 3: To a stirred solution of 3-[(6-bromo-1-methyl-indazol-3-yl)amino]propanoic acid (160 g, 536.67 mmol) in acetic acid (1.07 kg, 17.76 mol, 1.02 L) was added sodium cyanate, 95% (46.67 g, 717.88 mmol). The reaction mixture was heated at 100° C. for 12 h and its progress was monitored by TLC. Upon completion, the reaction was cooled to room temperature, filtered through a Buchner funnel and washed with water (2×500 mL). The product was thoroughly dried to give 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (175 g, 527.69 mmol, 98.33% yield) as an off-white solid. LC-MS (ES + ): m / z 323.27[M+H] + .

[0302] Step 4: To a solution of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (15 g, 46.42 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (18.66 g, 60.34 mmol) in 1,4-dioxane (150 mL) and water (30 mL) was added anhydrous sodium acetate (11.42 g, 139.26 mmol) at room temperature. The reaction mixture was degassed with argon gas for 10 minutes and 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (3.40 g, 4.64 mmol) was added. The reaction mixture was degassed with argon for an additional 5 minutes and then stirred at 90° C. for 16 hours. The reaction mixture was then concentrated in vacuo to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh, 70% ethyl acetate / pet ether) to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (18 g, 34.69 mmol, 74.73% yield) as a brown solid. LC-MS (ES) + ): m / z 426.44[M+H] + .

[0303] Step 5: A solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (3.6 g, 8.46 mmol) in ethanol (30 ml) and DCM (10 ml) and catalytic amount of glacial acetic acid (508.09 mg, 8.46 mmol, 3 ml) was added to a Parr Shaker hydrogenator. 10 wt% palladium on carbon (3.08 g, 25.38 mmol) was added to the mixture under an inert atmosphere and the resulting reaction was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LC-MS. Upon completion, the reaction was filtered through a celite bed and washed with 10% MeOH / DCM. The filtrate was concentrated under reduced pressure to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperidine-1-carboxylate (3.6 g, 8.17 mmol, 96.55% yield). LC-MS (ES + ): m / z 428.45[M+H] + .

[0304] Step 6: To a stirred solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperidine-1-carboxylate (2.7 g, 6.32 mmol) in DCM (20 mL) was added TFA (22.20 g, 194.70 mmol, 15 mL) at 0° C. The reaction was stirred for 3 h and the reaction progress was monitored by TLC and LC-MS. Upon completion, the reaction mixture was evaporated to give the crude product, which was triturated with diethyl ether and concentrated in vacuo to give 1-[1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2,4-dione TFA salt (2.5 g, 4.92 mmol, 77.93% yield) as a brown solid. LC-MS (ES + ): m / z 328.48[M+H] + .

[0305] Synthesis of 1-[6-(3,3-difluoro-4-piperidyl)-5-fluoro-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione [ka]

[0306] Step 1: Acetonitrile (200 mL) was added to a solution of 4-amino-2,5-difluoro-benzonitrile (50 g, 324.43 mmol) in ice water (150 mL) and sulfuric acid (150 mL) at 0° C. in a 5000 mL four-neck round bottom flask. Aqueous solution (120 mL) of sodium nitrite (40.29 g, 583.97 mmol, 18.57 mL) was added at 0° C. over 1 h, and the resulting mixture was further stirred at this temperature for 1 h. Then, aqueous solution (120 mL) of potassium iodide (107.71 g, 648.86 mmol) was added at 0° C. and stirred for 80 min. The reaction mixture was quenched with sodium thiosulfate at 0° C., stirred for 30 min, filtered, washed with water (1000 mL), and dried under reduced pressure. The crude compound was purified by flash column chromatography (silica gel 230-400 mesh. 0-10% ethyl acetate / petroleum ether) to give 2,5-difluoro-4-iodo-benzonitrile (45 g, 152.83 mmol, 47.11% yield) as an off-white solid, which was carried on directly to the next step. 1 H NMR (400 MHz, DMSO-d 6 ): δ8.21-8.17 (m,2H), 8.02-7.99(m, 2H).

[0307] Step 2: To a suspension of 2,5-difluoro-4-iodo-benzonitrile (70 g, 264.15 mmol) in ethanol (700 mL) in a 1000 mL three-neck round bottom flask was added 85% aqueous methylhydrazine (57.27 g, 1.06 mol, 65.83 mL) at ambient temperature. The resulting mixture was stirred at 80° C. for 16 h. The reaction mixture was cooled to 0° C. and diluted with water (1800 mL). After a solid was formed, it was stirred for another 30 min, filtered, washed with water (1200 mL), petroleum ether (1200 mL), and dried under reduced pressure to give 5-fluoro-6-iodo-1-methyl-indazol-3-amine (45 g, 147.52 mmol, 55.85% yield) as a pale yellow solid. LC-MS (ES + ): m / z 292.0 [M+H] + .

[0308] Step 3: In a 1000 mL three-neck round bottom flask, to a suspension of 1,8-diazabicyclo[5.4.0]undec-7-ene (36.98 g, 242.92 mmol, 36.26 mL) was added lactic acid 85% aqueous solution (aq.soln.) (21.88 g, 242.92 mmol, 18.24 mL) at 0° C. The resulting mixture was stirred at ambient temperature for 16 hours. To the above reaction mixture, 5-fluoro-6-iodo-1-methyl-indazol-3-amine (57 g, 186.86 mmol) and ethyl but-3-enoate (149.30 g, 1.31 mol, 158.83 mL) were added at ambient temperature. The resulting mixture was stirred at 80° C. for 48 hours. The reaction mixture was cooled to 0° C., quenched with water (500 mL), extracted with ethyl acetate (3×400 mL), washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica gel 230-400 mesh, 20-30% ethyl acetate / petroleum ether) to give ethyl 3-[(5-fluoro-6-iodo-1-methyl-indazol-3-yl)amino]propanoate (55 g, 125.74 mmol, 67.29% yield) as a pale yellow semi-solid. LC-MS (ES) +): m / z 392.0 [M+H] + .

[0309] Step 4: To a 1000 mL three-necked round bottom flask containing a well-stirred suspension of ethyl 3-[(5-fluoro-6-iodo-1-methyl-indazol-3-yl)amino]propanoate (55 g, 125.74 mmol) in acetic acid (550 mL) was added sodium cyanate (16.35 g, 251.48 mmol) at ambient temperature. The resulting mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure, cooled to 0° C., quenched with 10% sodium bicarbonate (1300 mL), and extracted with dichloromethane (600 mL). The organic layer was washed with 10% sodium bicarbonate (500 mL), brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica gel 230-400 mesh, 90-100% ethyl acetate / petroleum ether) to give ethyl 3-[carbamoyl-(5-fluoro-6-iodo-1-methyl-indazol-3-yl)amino]propanoate (40 g, 89.56 mmol, 71.23% yield) as an off-white solid. LC-MS (ES + ): m / z 435.0 [M+H] + .

[0310] Step 5: To a 1000 mL one-neck round-bottom flask containing a well-stirred solution of ethyl 3-[carbamoyl-(5-fluoro-6-iodo-1-methyl-indazol-3-yl)amino]propanoate (67.4 g, 150.91 mmol) in acetonitrile (330 mL) was added 40% benzyltrimethylammonium hydroxide (18.93 g, 45.27 mmol, 20.58 mL) in methanol at ambient temperature. The resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with petroleum ether (330 mL) and the resulting solid was filtered, washed with petroleum ether (500 mL) and dried under reduced pressure to give 1-(5-fluoro-6-iodo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (50.67 g, 128.25 mmol, 84.98% yield) as an off-white solid. LC-MS (ES) + ): m / z 389.0 [M+H] + .

[0311] Step 6: To a stirred 250 mL sealed tube containing 1-(5-fluoro-6-iodo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (2.5 g, 6.44 mmol) in dioxane (20 mL) was added bis(pinacolato)diboron (7.07 g, 27.85 mmol) and potassium acetate (5.47 g, 55.70 mmol). The reaction mixture was degassed with nitrogen for 10 min, followed by addition of Pd(dppf)Cl. 2 CH 2 Cl 2(1.52 g, 1.86 mmol) was added to the reaction mixture and the reaction mixture was degassed with nitrogen for another 10 min. The reaction mixture was heated at 100° C. for 16 h while the progress of the reaction was monitored by TLC and UPLC. The reaction mixture was cooled to room temperature, diluted with water and then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The organic layers were concentrated under reduced pressure to give the crude product, which was purified by column chromatography (Biotage® Isolera, the desired product was eluted with 60% to 65% ethyl acetate in petroleum ether). The compound 1-[5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]hexahydropyrimidine-2,4-dione (2 g, 3.13 mmol, 48.65% yield) was obtained as an off-white solid. LC-MS (ES + ): m / z 389.3 [M+H] + .

[0312] Step 7: To a well-stirred 250 mL sealed tube containing a solution of 1-[5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-yl]hexahydropyrimidine-2,4-dione (1.0 g, 2.58 mmol) and tert-butyl 3,3-difluoro-4-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-2,6-dihydropyridine-1-carboxylate (1.47 g, 2.83 mmol) in 1'4-dioxane (16 mL) and water (4 mL) was added sodium carbonate (819.09 mg, 7.73 mmol). The mixture was purged with nitrogen gas for 10 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (210.20 mg, 257.60 μmol) was added and the reaction mixture was purged with nitrogen for another 2 min. The resulting mixture was stirred at 60° C. for 2 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the mixture was cooled to room temperature and the reaction mass was diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (silica gel 100-200 mesh, 50-80% ethyl acetate / petroleum ether) to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-3,3-difluoro-2,6-dihydropyridine-1-carboxylate (1.0 g, 1.84 mmol, 71.25% yield) as a light brown solid. LC-MS (ES+): m / z 480.5 [M+H] + .

[0313] Step 8: To a 25 mL flask containing a well-stirred solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-3,3-difluoro-2,6-dihydropyridine-1-carboxylate (1.4 g, 2.92 mmol) in anhydrous methanol (5 mL), palladium hydroxide on carbon, 20 wt%, 50% water (820.14 mg, 5.84 mmol) was added at room temperature. The contents were stirred at room temperature under hydrogen gas for 16 hours. The progress of the reaction was monitored by UPLC and TLC. After complete conversion of the starting material, the reaction mixture was filtered through a celite pad under nitrogen atmosphere and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (Biotage® Isolera, the desired product was eluted with 10% to 15% methanol in DCM) to give tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-3,3-difluoro-piperidine-1-carboxylate (0.6 g, 1.06 mmol, 36.15% yield) as an off-white solid. LC-MS (ES + ): m / z 426.2 [M-tBu+H] + .

[0314] Step 9: To a 50 mL one-neck round bottom flask containing tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-3,3-difluoro-piperidine-1-carboxylate (70 mg, 145.39 μmol) in DCM (10 mL) was added 4M, 99% hydrogen chloride in 1,4-dioxane (800.00 mg, 21.94 mmol, 1 mL) at 0° C. and the resulting reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC and UPLC. After completion of the reaction, the reaction mixture was concentrated under vacuum and washed with diethyl ether to give the product 1-[6-(3,3-difluoro-4-piperidyl)-5-fluoro-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione HCl salt (60 mg, 119.77 μmol, 82.38% yield) as an off-white solid. LC-MS (ES + ): m / z 382.2 [M+H] + .

[0315] Synthesis of 1-(1-methyl-6-piperazin-1-yl-indazol-3-yl)hexahydropyrimidine-2,4-dione [ka]

[0316] 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 min and then Pd(t-Bu 3 P) 2(79.07 mg, 154.73 μmol) was added and then degassed again for 5 min. It was stirred at 110° C. for 16 h while the progress of the reaction was monitored by LC-MS. The reaction mixture was evaporated to give 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) and anhydrous Na 2 SO 4 Drying at 40° C. and evaporation gave 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] + .

[0317] Step 2: To a stirred solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperazine-1-carboxylate (0.3 g, 700.14 μmol) 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] + .

[0318] Synthesis of 1-(5-fluoro-1-methyl-6-piperazin-1-yl-indazol-3-yl)hexahydropyrimidine-2,4-dione [ka]

[0319] Step 1: A solution of 4-bromo-2,5-difluoro-benzonitrile (10 g, 45.87 mmol) in EtOH (30 mL) was added to methylhydrazine sulfate (19.84 g, 137.62 mmol) and Et 3 N (18.57 g, 183.49 mmol, 25.61 mL) was added. The mixture was stirred at 80° C. for 12 h. LC-MS showed complete consumption of starting material and one main 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) and 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, 95% purity) as a yellow solid. 1 H-NMR (400 MHz, DMSO-d 6 ) 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] + .

[0320] 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 with the desired mass detected. The entire reaction mixture was diluted with NaHCO until pH=8. 3The mixture was basified with a saturated solution of 1,2-dichloro-1,3-difluoro-2,4-dichloro-1,5-difluoro-2,6-dichloro-1,7-difluoro-2,8-dichloro-1,5-difluoro-1,6-dichloro-1,7-difluoro-1,8-dichloro-1,5-difluoro ... + ): m / z 318.2[M+H] + .

[0321] 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 h. To the mixture was added HCl (260 mL). The mixture was stirred at 60° C. for an additional 3 h. LCMS showed complete consumption of the starting material and one major peak with the desired mass was detected. The reaction mixture was cooled to room temperature, stirred for 1 h, 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, 90.26% purity) as a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) 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).

[0322] Step 4: 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 with Pd-PEPPSI-IHeptCl (427.40 mg, 439.71 μmol) and Cs 2 CO 3 (14.33 g, 43.97 mmol) at 25 °C 2 The reaction mixture was heated at 100° C. under N 2 The mixture was stirred at room temperature for 16 h. LC-MS showed 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 washed with Na 2 SO 4 It was dried at 40° C., filtered, and concentrated to give a residue which 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-d 6 ) δ= 10.53(s, 1H),7.38 (d,J = 12.8Hz, 1H),7.16 (d,J = 6.8Hz, 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).

[0323] 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 4M HCl / dioxane (30 mL) was stirred at 25° C. for 2 h. TLC showed that the reactant was consumed and a new spot had formed. The reaction mixture was concentrated to give 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 grey solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ= 10.54(s, 1H),9.22 (brs, 2H),7.41 (d,J = 12.4Hz, 1H),7.23 (d,J = 7.2Hz, 1H),3.97 (s,3H), 3.91- 3.88(m, 2H),3.31 (brs, 8H),2.76 - 2.72 (m, 2H).

[0324] Synthesis of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione [ka]

[0325] Step 1: To sodium hydride (dispersion in oil) (53.51 g, 2.33 mol), 60% dispersion in mineral oil, 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, an exotherm was observed. This temperature was maintained for 30 min. To this solution was added 98% 4-bromo-1-fluoro-2-nitrobenzene (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 this temperature was maintained 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, an exotherm was observed. Saturated NaCl solution (10V) was added below 15°C and warmed to room temperature. The layers were separated and the organic layer was concentrated under vacuum. The aqueous layer was taken and extracted with DCM (15V) and kept aside. The organic layer was combined with the crude, washed with water (5V) and concentrated completely under vacuum at 45°C. The crude was poured into DCM (2.5V) at 45°C and kept for 15 minutes until dissolved, then pet ether (10V) was added at 45°C and kept at 45°C for 1 hour. Cooled to room temperature and kept for 30 minutes. Filtration and washing with pet ether (2*3V) gave 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (400g, 686mmol, 91% yield). LC-MS (ES + ): m / z 506.32[M+H] + .

[0326] Step 2: A solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)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 in small portions 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 diluted with 10% NH 4 Quenched with Cl solution (5V), water (5V) followed by DCM (10V) was added and then stirred 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 concentrated completely under vacuum at 40°C. The residue was removed 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 min, cooled to room temperature and maintained for 30 min. The pure product was filtered and washed with Pet ether (3V). LC-MS (ES + ): m / z 476.33[M+H] + .

[0327] 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. The CDI was charged as a single lot. An initial temperature of 25°C was monitored and a final temperature of 35°C was noted over 15 min. The reaction was stirred at room temperature for 14 h. TLC indicated consumption of starting material. The reaction was charged to water (420 mL) at room temperature. A precipitate formed (note: a minimum of 1 h was required for slow addition on bulk scale) and the mixture was stirred for 3 h. The solid was filtered and washed with water and pet ether (2 x 35 ml). The product was dried under vacuum for 7 hours at 50° C. 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] + .

[0328] 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, after which methyl iodide (stored over copper) (31.16 g, 214.99 mmol, 13.37 mL) was added dropwise over 30 min. The progress of the reaction 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 vacuum. The solid was extracted with ethyl acetate, then 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, 99.91% purity) as a light brown solid. LC-MS (ES + ): m / z 516.14 [M+H] + .

[0329] 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 and 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 bed of celite 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 anhydrous Na 2 SO 4 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 / 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 / z619.41 [M+H] + .

[0330] 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 palladium (10% 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 hours. The reaction mass was cooled to room temperature and then filtered and washed with DCM and MeOH. The filtrate was taken and distilled completely under vacuum at 45 °C. To this crude residue was added IPA (3 V) and heated to 60 °C for 15 minutes. Pet ether (3V) was added and the mixture was cooled to room temperature and stirred at this temperature for 1 h. 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] - .

[0331] 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 added trifluoroacetic acid (55.87 g, 490.03 mmol, 37.75 mL) slowly at 0-5 °C and this temperature was maintained for 15 min. The reaction was allowed to warm to room temperature and maintained for 3 h. LCMS was in accordance with the formation of the product. DCM and TFA were removed under vacuum at 40 °C and the crude was stripped with toluene (2 x 5 V) and diethyl ether was added and the formation of a solid was observed. The reaction was decanted after the addition of diethyl ether (3 x 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, washed with MeOH, and 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] - .

[0332] Synthesis of 3-[5-(3,3-difluoro-4-piperidyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione [ka]

[0333] Step 1: In a 100 mL sealed tube, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.11 g, 4.36 mmol) and potassium acetate (855.25 mg, 8.71 mmol) were added to a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (1.5 g, 2.90 mmol) in 1,4 dioxane (1 mL) at room temperature under argon gas. The reaction mixture was degassed with argon for 20 minutes, after which cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (118.61 mg, 145.24 μmol) were added and the reaction was heated at 100° C. for 6 hours while monitoring by TLC and LC-MS. After completion of the reaction, the solvent was removed under reduced pressure and extracted using EtOAc (50 mL×3) and water (50 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (100-200 mesh silica gel, 0-30% EtOAc / pet ether) to give 1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-2-one (1.3 g, 2.17 mmol, 74.66% yield) as a pale yellow solid. LC-MS (ES) + ): m / z 264.36 [M+H] + .

[0334] Step 2: In a sealed tube, tert-butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)-2,6-dihydropyridine-1-carboxylate (938.67 mg, 2.56 mmol) and sodium acetate (524.13 mg, 6.39 mmol) were added to a solution of 1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-2-one (1.2 g, 2.13 mmol) in dioxane (12 mL) and water (4 mL) at room temperature under argon gas. The reaction mixture was degassed with argon for 20 minutes. After degassing, cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (155.83 mg, 212.97 μmol) were added and the reaction was heated at 100° C. for 16 h with TLC and LC-MS monitoring. The catalyst was filtered off through Celite and washed with ethyl acetate (20 mL×3). The filtrate was washed with water (20 mL) and brine solution (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (230-400 mesh silica gel, 0-60% EtOAc / pet ether) to give tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,3-difluoro-2,6-dihydropyridine-1-carboxylate (1.3 g, 1.97 mmol, 92.30% yield) as a colorless thick liquid. LC-MS (ES) + ): m / z 655.34 [M+H] + .

[0335] Step 3: To a stirred solution of tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,3-difluoro-2,6-dihydropyridine-1-carboxylate (1.3 g, 1.99 mmol) in ethyl acetate (20 mL) and ethanol (5 mL) was added palladium (10% on carbon, type 487, dry) (975.00 mg, 9.16 mmol) and dioxoplatinum (433.33 mg, 1.91 mmol). The reaction was stirred at room temperature under a hydrogen atmosphere for 6 hours. The progress of the reaction was monitored by TLC and LC-MS. The reaction mixture was filtered through Celite with the aid of ethyl acetate (50 mL) and the filtrate was concentrated under reduced pressure. The crude product was triturated with diethyl ether (30 mL), then decanted and dried under reduced pressure to give the product 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 white solid. LC-MS (ES + ): m / z 479.35 [M+H] + .

[0336] Step 4: TFA (3.33 g, 29.20 mmol, 2.25 mL) was added over 5 min to a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,3-difluoro-piperidine-1-carboxylate (0.45 g, 940.46 μmol.) in DCM (10 mL) stirred at 0° C. The reaction mixture was stirred at 25° C. for 4 h while the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated and co-distilled with toluene (10 ml) and diethyl ether (2 x 50 ml) to give the product 3-[5-(3,3-difluoro-4-piperidyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (0.3 g, 536.15 μmol, 57.01% yield) as a yellow solid. LC-MS (ES +): m / z 379.53 [M+H] + .

[0337] Synthesis of 3-[3-methyl-2-oxo-4-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione [ka]

[0338] 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 and then stirred at -78°C for 1 h. 1-Fluoro-3-iodo-2-nitro-benzene (43.58 g, 163.21 mmol) was added dropwise as a THF solution (500 mL) at -78°C and then stirred at -78°C for 1 h. After the reaction was complete as confirmed by TLC, the reaction 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 well for 15 min until a brown solid was formed, which was filtered through a Buchner funnel and washed with pet ether (2 x 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). LC-MS (ES + ): m / z 554.20 [M+H] + .

[0339] Step 2: To a solution of 2,6-dibenzyloxy-N-(3-iodo-2-nitro-phenyl)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 h. The reaction mixture was stirred at room temperature for 30 min. Upon completion of the reaction by TLC, the reaction was filtered through Celite and washed with ethyl acetate. The organic layer was separated and washed with brine solution and anhydrous Na 2 SO 4 The organic layer was evaporated to give a black gummy solid. To this crude residue, PET ether was added and stirred until a brown solid was obtained. The solid was filtered through a Buchner funnel, then 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] + .

[0340] 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 min. 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 h while being monitored by TLC. Upon completion, saturated NaHCO was added slowly at 0° C. 3 The reaction was quenched with a solution and effervescence was observed. The reaction mass was extracted with DCM and then washed with brine solution and anhydrous Na 2 SO 4The organic layer was evaporated to give a light brown solid. Diethyl ether was added to the crude solid, which was stirred well and then 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] + .

[0341] 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 cooled to 0° C. Sodium hydride (60% dispersion in mineral oil) (5.60 g, 243.75 mmol) was added in small portions 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 was slowly decanted into ice-cold water. An off-white solid precipitated and was filtered through a Buchner funnel, then 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 min, after which 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] + .

[0342] 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 before adding palladium triphenylphosphane (5.13 g, 4.44 mmol). 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 / 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] + .

[0343] 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) was added dihydroxypalladium (5.72 g, 40.73 mmol). The reaction mixture was stirred at 60-65 °C under 150 psi hydrogen gas for 12 h. TLC and LC-MS were checked to confirm 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] + .

[0344] 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. The reaction was complete by TLC (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 (10.71 g, 22.39 mmol, 99.06% yield, 95.40% purity, TFA salt) as an off-white solid. LC-MS (ES + ): m / z 343.33 [M+H] + .

[0345] Synthesis of 3-[3-methyl-4-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione [ka]

[0346] 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)azanilide (1.09 g, 6.53 mmol, 6.5 mL) dropwise over 15 min at -78°C. The reaction was maintained at -78°C for 1 h, after which 1-bromo-3-fluoro-2-nitro-benzene (1.44 g, 6.53 mmol) was added dropwise. The reaction mixture was stirred for an additional 2 h. 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] + .

[0347] 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 under vacuum and extracted with EtOAc (250 ml). The organic layer was separated and washed with anhydrous Na 2 SO 4 The mixture was dried at rt and then evaporated under vacuum. The crude material was purified by column chromatography on Devisil silica (eluent 0-70% EtOAc / 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] + .

[0348] 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 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] - .

[0349] 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), 60% dispersion in mineral oil, at 0°C. The reaction mixture was allowed to warm to room temperature and maintained for 1 hour. The reaction was again cooled 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 allowed to naturally warm to room temperature and maintained for 1 hour. The progress of the reaction was followed and confirmed by TLC (20% ethyl acetate:pet ether, Rf value: 0.3).

[0350] Upon completion, the reaction was quenched into ice-cold water to precipitate an off-white solid, which was isolated by vacuum filtration and Buchner funnel, and washed 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] + .

[0351] Step 5: In a sealed tube, sodium 2-methylpropan-2-olate (279.16 mg, 2.90 mmol) was added to 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). The reaction was degassed with argon for 15 min, then tBuXPhos PdG3 (76.88 mg, 96.83 μmol) was added to the reaction mixture and degassed for an additional 5 min. The reaction mixture was then heated at 90° C. for 5 h. 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 / 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) + ): m / z 672.41 [M+Na] + .

[0352] Step 6: Tert-Butyl N-[1-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]-N-methyl-carbamate (0.415 g, 638.68 μmol) was solvated in ethanol (3 mL) and methanol (3 mL) and purged with nitrogen for 10 min. To this solution was added palladium (10% on carbon, type 487, dry) (67.97 mg, 638.68 μmol) and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (rubber bladder) for 5 h. The progress of the reaction was monitored by TLC (10% methanol 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] + .

[0353] 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) at 0° C., TFA (72.54 mg, 636.20 μmol, 49.01 μL) was added 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] + .

[0354] Synthesis of 3-[3-methyl-5-(4-piperidyl)indol-1-yl]piperidine-2,6-dione [ka]

[0355] Step 1: To a solution of 5-bromo-3-methyl-indoline (5.5 g, 25.93 mmol) in DMF (70 mL) in a sealed tube was added 3-bromopiperidine-2,6-dione (7.47 g, 38.90 mmol) and sodium bicarbonate (6.54 g, 77.80 mmol, 3.03 mL). The reaction mixture was stirred with heating at 70° C. for 48 h. The reaction was monitored by TLC and LC-MS, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and sodium bicarbonate was added. 2 SO 4 The crude was purified by column chromatography using 30% ethyl acetate in hexane as eluent to give 3-(5-bromo-3-methyl-indolin-1-yl)piperidine-2,6-dione (2.5 g, 7.43 mmol, 28.64% yield, 96% purity). LC-MS (ES + ): m / z 323.26 [M+H] + .

[0356] Step 2: To a stirred solution of compound 3-(5-bromo-3-methyl-indolin-1-yl)piperidine-2,6-dione (2.5 g, 7.74 mmol) in DCM (80 mL) was added DDQ (2.11 g, 9.28 mmol) slowly at 0° C. After addition, stirring was continued for 1 h at room temperature. The reaction was monitored by LC-MS and TLC. After the formation of the product was confirmed by LC-MS, the reaction mixture was extracted with DCM and the organic layer was washed with 1M NaOH. The organic layer was then washed with Na 2 SO 4The crude was purified by column chromatography (silica gel, 40% ethyl acetate in hexanes) to give 3-(5-bromo-3-methyl-indol-1-yl)piperidine-2,6-dione (911.38 mg, 2.83 mmol, 36.58% yield). LC-MS (ES + ): m / z321.11 [M+H] + .

[0357] Step 3: 3-(5-Bromo-3-methyl-indol-1-yl)piperidine-2,6-dione (0.05 g, 155.68 μmol) was placed in a 250 mL round-bottom flask and solvated in 1,4-dioxane (2 mL) and water (0.2 mL). Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (62.58 mg, 202.39 μmol) and anhydrous sodium acetate (38.31 mg, 467.04 μmol) were added at room temperature under argon gas. The reaction mixture was degassed with argon for 20 minutes. After degassing, cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (11.39 mg, 15.57 μmol) were added and the reaction was heated at 80° C. for 6 h with monitoring by TLC and LC-MS. The catalyst was filtered through Celite and washed with ethyl acetate (10 mL×3). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh, 0-50% ethyl acetate / pet ether) to give tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-indol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (0.04 g, 49.11 μmol, 31.55% yield) as a grey solid. LC-MS (ES - ): m / z 422.51 [MH] - .

[0358] Step 4: Tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-indol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (0.1 g, 236.13 μmol) was charged to a round-bottom flask and solvated in ethyl acetate (2 mL). Palladium (10% on carbon, type 487, dry) (25.13 mg, 236.13 μmol) was added to the stirring solution, followed by H 2 Pressure was applied from the bladder and the reaction was stirred continuously at room temperature for 16 hours. The progress of the reaction was checked by LC-MS, then the reaction mixture was filtered through a celite bed and washed with ethyl acetate (10 mL) and methanol (10 mL). The filtrate was concentrated under reduced pressure to give the crude product, which was triturated with n-pentane (5 mL) and concentrated under reduced pressure to give the desired product tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-indol-5-yl]piperidine-1-carboxylate (0.08 g, 131.60 μmol, 55.73% yield) as a grey solid. LC-MS (ES - ): m / z 424.34 [MH] - .

[0359] Step 5: To a stirred solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-indol-5-yl]piperidine-1-carboxylate (0.03 g, 70.50 μmol) in DCM (5 mL) was added TFA (40.19 mg, 352.51 μmol, 27.16 μL) at 0° C. The reaction was stirred at room temperature for 16 h. The progress of the reaction was monitored by LC-MS. After completion of the reaction, the solvent was evaporated under vacuum to give the crude product, which was triturated with diethyl ether (10 mL) and then filtered to give 3-[3-methyl-5-(4-piperidyl)indol-1-yl]piperidine-2,6-dione TFA salt (0.015 g, 29.36 μmol, 41.64% yield) as a grey solid. LC-MS (ES + ): m / z 326.35 [M+H] + .

[0360] Synthesis of 3-[3-methyl-5-[4-(methylamino)-1-piperidyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione [ka]

[0361] Step 1: In a sealed tube, sodium 2-methylpropan-2-olate (558.30 mg, 5.81 mmol) was added to 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). The reaction was degassed with argon for 15 min, then tBuXPhos PdG3 (153.76 mg, 193.65 μmol) was added to the reaction mixture, which was degassed again for 5 min. The reaction mixture was then heated at 90° C. for 16 h and the progress of the reaction 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 / 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] + .

[0362] 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 palladium (10% 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 at room temperature under hydrogen atmosphere (1 atm pressure) for 5 h. 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] + .

[0363] 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) at 0° C., TFA (77.38 mg, 678.62 μmol, 52.28 μL) was added 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, 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] + .

[0364] Synthesis of 3-[3-methyl-5-[[4-(methylamino)-1-piperidyl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione [ka]

[0365] Step 1: To a stirred solution of 4-bromo-2-fluoro-1-nitro-benzene (10 g, 4.55 mmol) in THF (100 mL) cooled to 0° C., methanamine (141.17 g, 4.55 mmol, 157.03 μL) was added dropwise. The reaction was heated to 60° C. for 16 h and the reaction progress was monitored by LC-MS and TLC (10% EtOAc in pet ether; R f =0.7). The reaction was concentrated to give a crude solid, which was washed twice with pentane and dried to give 5-bromo-N-methyl-2-nitro-aniline (600 mg, 2.49 mmol, 54.85% yield). LC-MS (ES + ): m / z 231.24 [M+H] + .

[0366] Step 2: To a stirred solution of 5-bromo-N-methyl-2-nitro-aniline (5 g, 10.82 mmol) in ethanol (50 mL) and water (50 mL) was added iron (3.02 g, 54.10 mmol) and ammonium chloride, 98+% (2.89 g, 54.10 mmol). The reaction was heated to about 90° C. for 16 hours and the progress of the reaction was monitored by LC-MS and TLC (30% EtOAc in pet ether, R f=0.5). The reaction was filtered through Celite, concentrated, diluted with water and extracted with EtOAc. The organic layer was washed with brine solution, dried over sodium sulfate and the solvent was evaporated. The crude was washed with diethyl ether and pentane to give 4-bromo-N2-methyl-benzene-1,2-diamine (4 g, 954.92 mmol, 88.24% yield) as a dark red liquid. LC-MS (ES + ): m / z 203.27 [M+2H] + .

[0367] Step 3: To a stirred solution of 4-bromo-N2-methyl-benzene-1,2-diamine (5 g, 24.87 mmol) in acetonitrile (40 mL) was added di(imidazol-1-yl)methanone (24.19 g, 149.21 mmol) and pyridine (5.90 g, 74.60 mmol, 6.03 mL). The reaction mixture was heated to 85° C. for 16 h and the progress of the reaction was monitored by LC-MS and TLC (50% EtOAc in pet ether). The reaction mixture was poured into cold water and the precipitated crude product was filtered and then washed with excess cold water to remove pyridine. The resulting crude compound was washed with diethyl ether and pentane to give 5-bromo-3-methyl-1H-benzimidazol-2-one (5 g, 21.58 mmol, 86.78% yield) as an off-white solid. LC-MS (ES + ): m / z 227.17[M+H] + .

[0368] Step 4: To a stirred solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (2.5 g, 11.01 mmol) in dioxane (25 mL) was added potassium trifluoro(vinyl)borane (1.47 g, 11.01 mmol) and cesium carbonate (3.59 g, 11.01 mmol). The reaction was purged with argon for 15 minutes, after which cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron (899.15 mg, 1.10 mmol) were added. The reaction was heated to 90° C. for 4 hours and the progress of the reaction was monitored by LC-MS and TLC (50% ethyl acetate in pet ether, R f =0.6). The reaction mixture was quenched with cold water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate, and the solvent was concentrated to give the crude product, which was purified by reverse phase column chromatography (1% ammonium acetate / acetonitrile) to give 3-methyl-5-vinyl-1H-benzimidazol-2-one (1.5 g, 7.75 mmol, 70.39% yield) as an off-white solid. LC-MS (ES + ): m / z 175.38 [M+H] + .

[0369] Step 5: A stirred solution of 3-methyl-5-vinyl-1H-benzimidazol-2-one (1.5 g, 8.61 mmol) in 1,4-dioxane (15 mL) and water (15 mL) was cooled to 0° C. and 2,6-dimethylpyridine (1.85 g, 17.22 mmol, 2.00 mL) was added. Sodium periodate (3.68 g, 17.22 mmol) and tetraoxoosmium (218.91 mg, 861.09 μmol) were then added. The reaction mass was stirred at 28° C. for 2 hours and the progress of the reaction was monitored by LC-MS and TLC (50% EtOAc in Pet ether, R f=0.5). The reaction mixture was quenched with EtOAc, filtered, and concentrated to give the crude product, which was purified by reverse-phase column chromatography (1% ammonium acetate / acetonitrile) to give 3-methyl-2-oxo-1H-benzimidazole-5-carbaldehyde (1 g, 5.62 mmol, 65.26% yield) as a brown solid. LC-MS (ES + ): m / z 177.39 [M+H] + .

[0370] Step 6: To a stirred solution of 3-methyl-2-oxo-1H-benzimidazole-5-carbaldehyde (2.0 g, 11.35 mmol) in methanol (20 mL) cooled to 0° C. was added acetic acid (681.72 mg, 11.35 mmol, 649.26 μL) and tert-butyl N-methyl-N-(4-piperidyl)carbamate (2.43 g, 11.35 mmol), along with molecular sieves. The reaction was heated to 65° C. for 4 h and then cooled to 0° C. Sodium cyanoborohydride (713.39 mg, 11.35 mmol) was added in portions over 15 min. The reaction was stirred at 28° C. for 16 h. The progress of the reaction was monitored by LC-MS and TLC (50% ethyl acetate in pet ether, R f =0.5). The reaction mixture was quenched with water (5 ml) and concentrated to give the crude product, which was purified by reverse phase column chromatography (1% ammonium acetate / acetonitrile) to give the partially purified compound tert-butyl N-methyl-N-[1-[(3-methyl-2-oxo-1H-benzimidazol-5-yl)methyl]-4-piperidyl]carbamate (2.0 g, 3.63 mmol, 31.99% yield), which was carried on to the next step without further purification. LC-MS (ES + ): m / z 375.35 [M+H] + .

[0371] Step 7: A stirred solution of tert-butyl N-methyl-N-[1-[(3-methyl-2-oxo-1H-benzimidazol-5-yl)methyl]-4-piperidyl]carbamate (2.5 g, 6.68 mmol) in THF (25 mL) was cooled to 0° C. and NaH (767.41 mg, 33.38 mmol) was added in small portions followed by 18-crown-6 (882.28 mg, 3.34 mmol, 747.70 μL). The reaction mass was stirred at 28° C. for 2 h, cooled to 0° C. and 3-bromopiperidine-2,6-dione (1.28 g, 6.68 mmol) was added. The progress of the reaction was monitored by LC-MS and TLC (50% EtOAc in pet ether, R f =0.5) and the reaction was stirred at 65° C. for 6 h. The reaction mixture was quenched with cold water and extracted with ethyl acetate. The organic layer was separated, washed with brine solution and dried over sodium sulfate. The solvent was evaporated to give the crude compound, which was purified using preparative HPLC to give tert-butyl N-[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-4-piperidyl]-N-methyl-carbamate (600 mg, 1.09 mmol, 16.29% yield) as an off-white solid. LC-MS (ES + ): m / z 486.95 [M+H] + .

[0372] Step 8: A stirred solution of tert-butyl N-[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]-4-piperidyl]-N-methyl-carbamate (50 mg, 102.97 μmol) in DCM (2 mL) was cooled to 0° C. and TFA (117.41 mg, 1.03 mmol, 79.33 μL) was added. The reaction mixture was stirred at 28° C. for 2 h and the progress of the reaction was monitored by LC-MS and TLC (10% MeOH in DCM, R f=0.4). The reaction mixture was concentrated to remove DCM and excess TFA. The crude product was isolated, cooled to 0° C., washed with cold diethyl ether (5 ml×3) and pentane, then lyophilized to give 3-[3-methyl-5-[[4-(methylamino)-1-piperidyl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione TFA salt (18 mg, 31.11 μmol, 30.21% yield) as an off-white solid. LC-MS (ES + ): m / z 386.32 [M+H] + .

[0373] Synthesis of 3-[4-[4-(methylamino)-1-piperidyl]anilino]piperidine-2,6-dione [ka]

[0374] 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 distillation (Eq.: 0.4 in 10% ethyl acetate / pet ether) and LC-MS. Upon completion, the reaction was concentrated under vacuum 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] + .

[0375] 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 palladium (10% on carbon, type 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 (pH 7.0:0.4 in 50% ethyl acetate / pet ether) and LCMS. 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] + .

[0376] 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 h. The progress of the reaction was monitored by TLC (R f 0.4) in 50% ethyl acetate / pet ether, which indicated consumption of the starting material. The reaction mixture was then quenched with water, extracted with ethyl acetate, the organic layer was washed with brine, and then washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. 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] + .

[0377] 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 4M HCl / 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 distillation (0.4 in 50% ethyl acetate / pet ether) and LCMS. 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] + .

[0378] Synthesis of 3-[4-[[4-(methylamino)-1-piperidyl]methyl]anilino]piperidine-2,6-dione [ka]

[0379] Step 1: To a stirred solution of 4-bromobenzaldehyde (1 g, 5.40 mmol), tert-butyl N-methyl-N-(4-piperidyl)carbamate (1.16 g, 5.40 mmol) in methanol (30 mL) was added acetic acid (324.57 mg, 5.40 mmol, 309.12 μL). The reaction mixture was then heated at room temperature for 10 min with N 2The mixture was stirred under atmospheric pressure. Sodium cyanoborohydride (679.29 mg, 10.81 mmol) was then added slowly. The reaction mixture was then stirred at room temperature for 16 hours. The completion of the reaction was checked by TLC and LC-MS. After completion of the reaction, the reaction mixture was concentrated under vacuum. Then, work-up was carried out by using EtOAc and water. The combined organic layer was concentrated under reduced pressure. The crude was further purified using silica gel flash column chromatography to give tert-butyl N-[1-[(4-bromophenyl)methyl]-4-piperidyl]-N-methyl-carbamate (1.06, 2.77 mmol, 51.16% yield). 1 H NMR (400 MHz, CDCl 3 ) δ: 7.49 (dd, J = 8.4 & 8.2 Hz 2H), 7.23 (dd, J= 8.4 & 3.2 Hz 2H), 4.65 (s, 2H), 3.42 (s, 2H), 2.90 (m, 2H), 2.72 (s, 3H), 2.04 (m, 2H), 1.99(m, 1H), 1.72 (m, 2H), 1.57 (s, 9H).

[0380] Step 2: To a stirred solution of tert-butyl N-[1-[(4-bromophenyl)methyl]-4-piperidyl]-N-methyl-carbamate (1 g, 2.61 mmol) in 1,4 dioxane (10 mL) was added sodium tert-butoxide (626.78 mg, 6.52 mmol) and ammonia gas was added by purging at 0° C. for 15 min. Then tBuXPhos Pd G3 (310.82 mg, 391.32 μmol) was added and the reaction was stirred at 90° C. for 16 h. The progress of the reaction was monitored by TLC (40% EtOAc:PE, R fValue: 0.3) and monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered through a celite bed and the filtrate was concentrated to give the crude product, which was purified by flash column chromatography (neutral alumina, 40% ethyl acetate / pet ether) to give tert-butyl N-[1-[(4-aminophenyl)methyl]-4-piperidyl]-N-methyl-carbamate (0.750 g, 1.80 mmol, 69.12% yield). LC-MS (ES + ): m / z 320.44 [M+H] + .

[0381] Step 3: Tert-butyl N-[1-[(4-aminophenyl)methyl]-4-piperidyl]-N-methyl-carbamate (1 g, 3.13 mmol) was dissolved in DMF (40 mL) and 3-bromopiperidine-2,6-dione (1.80 g, 9.39 mmol) and sodium bicarbonate (788.97 mg, 9.39 mmol) were added. The reaction mixture was heated to 100° C. for 16 h. The progress of the reaction was monitored by TLC, which indicated consumption of starting material. The reaction mixture was then quenched with water, extracted with ethyl acetate, and the organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 The crude compound was purified by reverse phase preparative HPLC to give tert-butyl N-[1-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]-4-piperidyl]-N-methyl-carbamate (0.45 g, 877.97 μmol, 28.05% yield). LC-MS (ES + ): m / z431.32 [M+H] + .

[0382] Step 4: To a stirred solution of tert-butyl N-[1-[[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]methyl]-4-piperidyl]-N-methyl-carbamate (0.15 g, 348.40 μmol) in DCM (5 mL) at 0° C., TFA (1.48 g, 12.98 mmol, 1 mL) was added over 5 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 crude compound, which was purified by preparative HPLC to give 3-[4-[[4-(methylamino)-1-piperidyl]methyl]anilino]piperidine-2,6-dione (0.022 g, 62.48 μmol, 17.93% yield) as an off-white solid. LC-MS (ES + ): m / z 330.95 [M+H] + .

[0383] Synthesis of 3-[3-[[4-(methylamino)-1-piperidyl]methyl]anilino]piperidine-2,6-dione [ka]

[0384] 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-butyl methyl(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 h. After 3 h, 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 h. After complete consumption of 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 by 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] + .

[0385] 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 dissolved in NaO tBu (2.26 g, 23.54 mmol) was added. It was purged with ammonia gas for 20 min, 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 h. 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] + .

[0386] Step 3: To a stirred solution of tert-butyl N-[1-[(3-aminophenyl)methyl]-4-piperidyl]-N-methyl-carbamate (2.0 g, 6.28 mmol) in DMF (20 mL) was added NaHCO 3 (1.58 g, 18.84 mmol) was added and the solution was purged with argon gas for 15 min. Then, 3-bromopiperidine-2,6-dione (3.62 g, 18.84 mmol) was added and the resulting reaction mixture was heated at 90° C. with stirring for 16 h. 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] + .

[0387] 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 progress of the reaction 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 light red solid. LC-MS (ES + ): m / z 331.51 [M+H] + .

[0388] Synthesis of 3-[3-[4-(methylamino)-1-piperidyl]anilino]piperidine-2,6-dione [ka]

[0389] 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)dipalladium(0) (1.13 g, 1.12 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (286.44 mg, 495.04 μmol). The reaction was stirred for 15 min before adding 1-bromo-3-nitro-benzene (5.0 g, 24.75 mmol, 52.52 μL). The reaction mixture was stirred at 100° C. 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 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] + .

[0390] 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 / 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] + .

[0391] Step 3: To a stirred solution of tert-butyl N-[1-(3-aminophenyl)-4-piperidyl]-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 stirred at 80° C. for 16 h 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 / 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] + .

[0392] 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 h 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] + .

[0393] Synthesis of 3-[3-[4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione [ka]

[0394] Step 1: (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)phosphane; 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) were 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 diluted with cold water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give the compound 2,6-dibenzyloxy-3-(3-bromophenyl)pyridine (1.500 g, 1.41 mmol, 28.35% yield). LCMS (ES + ): m / z 446.2 [M + H] + .

[0395] 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 at 100° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with cold water, and extracted with ethyl acetate. The combined organic layer was washed with water, brine, and anhydrous Na 2 SO 4The mixture was dried at 40° C. for 1 hour, 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). LCMS (ES + ): m / z 580.3 [M + H] + .

[0396] Step 3: To a stirred solution of tert-butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)phenyl]-4-piperidyl]-N-methyl-carbamate (1.8 g, 3.10 mmol) in a 1:5:4 mixture of ethyl acetate:ethanol:THF (30 mL) was added 10% palladium on carbon (type 487, 1.8 g). The reaction mixture was then heated to 37° C. for 1 hour at 4° C. for 2 hours. 2 The mixture was stirred under (1 atm pressure) for 16 hours. The reaction mixture was passed through a celite bed, then washed with methanol and concentrated under reduced pressure to obtain the desired crude compound. The crude material was purified by reverse phase column chromatography (column / dimensions: X-SELECT C18 (19×250×5 um) Mobile phase A: 0.1% FA in water (aq) Mobile phase B: ACN(org) 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 obtain 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). LCMS (ES - ): m / z 400.3 [M - H] + .

[0397] Step 4: 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) were stirred for 4 h at 0° C. 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). LCMS (ES + ): m / z 302.3 [M + H] + .

[0398] Synthesis of 3-[4-[4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione [ka]

[0399] Step 1: To 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) in a sealed tube was added potassium carbonate (8.25 g, 59.75 mmol). The reaction mixture was purged with argon for 20 min, and then Pd(dppf)Cl 2(1.46 g, 1.99 mmol) was added and the reaction was stirred at 90° C. for 16 h and 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 / 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. LCMS (ES + ): m / z 446.1 [M + H] + .

[0400] 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), (CH 3 ) 3 CONa (861.24 mg) was added. 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 progress of the reaction 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). LCMS (ES + ): m / z 581.00 [M + H] + .

[0401] 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) was added Pd / C (3.14 g, 25.87 mmol) under hydrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by LC-MS. After the starting material was consumed, the resulting crude 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 aqueous solution (aq), mobile phase B: ACN (org)) 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). LCMS (ES + ): m / z 402.5 [M + H] + .

[0402] 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. LCMS (ES + ): m / z 302.5 [M + H] + .

[0403] Synthesis of 3-[4-[3,3-difluoro-4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione [ka]

[0404] Step 1: To a stirred solution of 2,6-dibenzyloxy-3-(4-bromophenyl)pyridine (1 g, 2.24 mmol) in toluene (10 mL) in a sealed tube, sodium tert-butoxide (645.93 mg, 6.72 mmol) was added. After 10 min, N-benzyl-3,3-difluoro-N-methyl-piperidin-4-amine (646.04 mg, 2.69 mmol) was added and the resulting reaction mixture was stirred at 100° C. for 16 h. The progress of the reaction was monitored by LC-MS. The reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography using 80% acetonitrile (200 mL) and water (300 mL) to give N-benzyl-1-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,3-difluoro-N-methyl-piperidin-4-amine (0.4 g, 614.15 μmol, 27.41% yield). LCMS (ES + ): m / z 606.5[M + H] + .

[0405] Step 2: A stirred solution of N-benzyl-1-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]-3,3-difluoro-N-methyl-piperidin-4-amine (1 g, 1.65 mmol) in EtOH (7 mL) and ethyl acetate (7 mL) was degassed with argon for 10 min. Palladium on carbon (1.00 g, 8.25 mmol) was added to the reaction mixture, which was then stirred at room temperature for 16 h in H 2Stirring was performed under a balloon. Upon completion of the reaction, it was filtered through a bed of Celite and washed with EtOH and EtOAc. The filtrate was evaporated under reduced pressure to give 3-[4-[3,3-difluoro-4-(methylamino)-1-piperidyl]phenyl]piperidine-2,6-dione TFA salt (0.45 g, 968.22 μmol, 58.65% yield) as a dark green solid. LCMS (ES + ): m / z 338.5[M + H] + .

[0406] Synthesis of 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetic acid [ka]

[0407] Step 1: To a 500 mL multi-necked round bottom flask containing a well-stirred solution of tert-butyl acetate (2.64 g, 22.70 mmol, 3.06 mL) in anhydrous THF (75 mL) was added (diisopropylamino)lithium (2 M, 22.70 mL) at −78° C. under inert atmosphere. The resulting contents were then stirred at −78° C. for 30 minutes. Thereafter, hydroxy-oxo-[4-(4-oxo-1-piperidyl)phenyl]ammonium (5.02 g, 22.70 mmol) in THF (50 mL) was added to the reaction mixture at −78° C. and the reaction was allowed to warm to −20° C. and stirred at the same temperature for 3 hours. After consumption of starting material as indicated by TLC, the reaction was quenched with saturated ammonium chloride (100 mL). The reaction mixture was partitioned between ethyl acetate (250 mL) and water (200 mL). The organic layer was separated, washed with brine solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (silica gel 60-120 mesh, 0-50% EtOAc / n-hexane) to give [4-[4-(2-tert-butoxy-2-oxo-ethyl)-4-hydroxy-1-piperidyl]phenyl]-hydroxy-oxo-ammonium (3 g, 6.68 mmol, 29.41% yield) as a yellow solid. LC-MS (ES) + ): m / z 337.4 [M + H] + .

[0408] Step 2: To a 100 mL one-neck round bottom flask containing a well-stirred solution of [4-[4-(2-tert-butoxy-2-oxo-ethyl)-4-hydroxy-1-piperidyl]phenyl]-hydroxy-oxo-ammonium (3 g, 8.89 mmol) in ethyl acetate (30 mL) was added 10% palladium on activated carbon (50% wet) (946.26 mg, 8.89 mmol) under inert atmosphere at room temperature. The reaction was then stirred under hydrogen atmosphere for 16 hours at room temperature. After consumption of starting material by TLC, the reaction mixture was filtered through a Celite pad and the Celite pad was washed with ethyl acetate (300 mL). The filtrate was concentrated under reduced pressure to give crude tert-butyl 2-[1-(4-aminophenyl)-4-hydroxy-4-piperidyl]acetate (2.5 g, 8.04 mmol, 90.42% yield) as an off-white solid. LCMS (ES + ): m / z 307.2 [M + H] + .

[0409] Step 3: To a 100 mL sealed tube containing well-stirred 3-bromopiperidine-2,6-dione (1.57 g, 8.16 mmol) and tert-butyl 2-[1-(4-aminophenyl)-4-hydroxy-4-piperidyl]acetate (2.5 g, 8.16 mmol) in DMF (30 mL) was added sodium bicarbonate (2.06 g, 24.48 mmol) at ambient temperature under nitrogen atmosphere. The reaction was then heated to 70° C. for 16 hours. After consumption of starting material as indicated by LCMS, the reaction mixture was poured into cold water (150 mL). The reaction mixture was partitioned between ethyl acetate (350 mL) and water (100 mL). The organic layer was separated, washed with brine solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude material, which was purified by flash column chromatography (silica gel 60-120 mesh, 0-100% EtOAc / n-hexane) to give tert-butyl 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetate (2 g, 4.75 mmol, 58.24% yield) as a blue solid. LC-MS (ES+ ): m / z 418.4 [M+H] + .

[0410] Step 4: To a one-necked round bottom flask containing a well-stirred solution of tert-butyl 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetate (1 g, 2.40 mmol) in DCM (5 mL) was added hydrogen chloride in dioxane (4 M, 10 mL) at room temperature under nitrogen atmosphere and the resulting contents were stirred at the same temperature for 2 h. After consumption of starting material as indicated by TLC, the reaction mixture was concentrated under reduced pressure to give a crude product which was azeotroped with toluene (2×15 mL) and triturated with MTBE (2×20 mL) to give 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetic acid HCl salt (900 mg, 2.05 mmol, 85.62% yield) as a brown solid. LC-MS (ES) + ): m / z 361.2 [M+H] + .

[0411] Synthesis of 2-[1-[2-chloro-4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-6-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetic acid [ka]

[0412] Step 1: To a solution of tert-butyl 2-(4-hydroxy-4-piperidyl)acetate (8 g, 37.16 mmol) and 1-chloro-2,3-difluoro-5-nitro-benzene (6.54 g, 33.78 mmol) in DMSO (80 mL) was added potassium carbonate (14.01 g, 101.34 mmol). The mixture was stirred at 110° C. for 1 h. The reaction mixture was cooled to 20° C. and filtered. The filtrate was quenched with water (200 ml). The resulting mixture was filtered under vacuum and the filter cake was dried under vacuum to give the product tert-butyl 2-[1-(2-chloro-6-fluoro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate (13 g, 33.43 mmol, 98.97% yield) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )δ = 8.07 - 8.06(m, 1H),7.85-7.81 (dd,1H), 3.85(s, 1H),3.65-3.52 (t,2H), 3.24-3.12(d, 2H),2.46 (s,2H), 1.78-1.71(m, 4H),1.49 (s,9H).

[0413] Step 2: To a mixture of tert-butyl 2-[1-(2-chloro-6-fluoro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate (13 g, 33.43 mmol) in water (40 mL), ethanol (200 mL) was added ammonium chloride (8.94 g, 167.17 mmol, 5.84 mL) and iron powder (11.20 g, 200.61 mmol, 1.43 mL). The mixture was stirred at 90° C. for 1 hour. The reaction mixture was cooled to 25° C. and filtered through diatomaceous earth. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with water (300 mL) and extracted with ethyl acetate (300 mL×2). The combined organic layers were washed with brine (200 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Tert-butyl 2-[1-(4-amino-2-chloro-6-fluoro-phenyl)-4-hydroxy-4-piperidyl]acetate (11 g, 30.65 mmol, 91.69% yield) was obtained as an orange oil.1 HNMR (400MHz, CDCl 3 )δ = 6.50-6.49 (m, 1H),6.29-6.25 (dd,1H), 3.72-3.61(m, 3H),3.43-3.32 (m,2H), 3.89-3.78(m, 2H),2.45 (s,2H), 1.75-1.72(m, 4H),1.48 (s,9H).

[0414] Step 3: A stirred solution of tert-butyl 2-[1-(4-amino-2-chloro-6-fluoro-phenyl)-4-hydroxy-4-piperidyl]acetate (4.2 g, 11.70 mmol) and 2,6-dibenzyloxy-3-bromo-pyridine (6.50 g, 17.56 mmol) in dioxane (45 mL) was degassed with nitrogen for 15 min and then cesium carbonate (11.44 g, 35.11 mmol), XPhos (557.97 mg, 1.17 mmol) and Pd 2 (dba) 3 (1.07 g, 1.17 mmol) was added at 25 °C. The mixture was degassed with nitrogen for another 5 min and then heated to 100 °C under nitrogen atmosphere for 16 h. The mixture was cooled to 25 °C, diluted with water (300 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 0 / 1 to 5 / 1) to give tert-butyl 2-[1-[2-chloro-4-[(2,6-dibenzyloxy-3-pyridyl)amino]-6-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (5.7 g, 8.79 mmol, 75.13% yield) as a yellow oil. LC-MS (ES + ): m / z 648.2[M+H] + .

[0415] Step 4-1: A mixture of tert-butyl 2-[1-[2-chloro-4-[(2,6-dibenzyloxy-3-pyridyl)amino]-6-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (5.6 g, 8.64 mmol) in ethyl acetate (57 mL) was added to Pd / C (570 mg) and lithium chloride (732.55 mg, 17.28 mmol) under N 2 The mixture was heated at 25° C. for 16 h under H 2 (35 Psi). The mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give a residue, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=5 / 1 to 2 / 1) to give tert-butyl 2-[1-[2-chloro-4-[(2,6-dioxo-3-piperidyl)amino]-6-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (1.9 g, 4.04 mmol, 46.80% yield) as a blue solid. 1 HNMR (400MHz, DMSO-d 6 ) δ =10.79 (s,1H),6.57 (s,1H), 6.46-6.41(dd, 1H),6.21 (d,1H), 4.43(s,1H), 4.35-4.30(m, 1H),3.31 - 3.16 (m, 2H),2.78 - 2.63 (m, LC-MS(ES) + ): m / z 470.1 [M+H] + .

[0416] Step 4-2: Tert-Butyl 2-[1-[2-chloro-4-[(2,6-dioxo-3-piperidyl)amino]-6-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (2.2 g, 4.68 mmol) was purified by preparative SFC using the following conditions: Sample preparation: IPA and CH 2 Cl 2Add 100ml to the sample Equipment:Waters 80Q Mobile phase: supercritical CO 2 50% IPA (Neu) Flow rate: 70g / min Cycle time: 4.4 minutes, total time: 550 minutes Single injection volume: 1.5ml Back pressure: CO 2 In order to keep the temperature in supercritical flow, 100 bar is required.

[0417] The compound tert-butyl 2-[1-[2-chloro-4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-6-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (900 mg, 1.84 mmol, 39.27% ​​yield) was obtained as a blue solid, which was confirmed by HPLC and SFC.

[0418] The compound tert-butyl 2-[1-[2-chloro-4-[[(3R)-2,6-dioxo-3-piperidyl]amino]-6-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (1 g, 2.13 mmol, 45.45% yield) was obtained as a blue solid.

[0419] Step 5: To a solution of tert-butyl 2-[1-[2-chloro-4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-6-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (0.25 g, 531.99 μmol) in DCM (3 mL) was added 4M hydrochloric acid in 1,4 dioxane (3 mL). The mixture was stirred at 20° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was triturated with diethyl ether and filtered to give the product 2-[1-[2-chloro-4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-6-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetic acid HCl salt (240 mg, 522.33 μmol, 98.18% yield) as a blue solid. LC-MS (ES + ): m / z 414.1 [M+H] + .

[0420] Synthesis of 2-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetic acid [ka]

[0421] Step 1: In a sealed tube, tert-butyl 2-(4-hydroxy-4-piperidyl)acetate (602.34 mg, 2.80 mmol) and cesium carbonate (2.73 g, 8.39 mmol) were added to a solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.4 g, 2.80 mmol) in 1,4-dioxane (10.0 mL) at room temperature under nitrogen atmosphere with stirring. The reaction mixture was degassed with nitrogen for 15 min, and then RuPhos (130.56 mg, 279.78 μmol) and RuPhosPdG3 (234.00 mg, 279.78 μmol) were added to the reaction mixture. The mixture was again degassed with nitrogen for 5 min and heated to 100° C. for 2.5 h. After completion of the reaction by TLC, the reaction mixture was diluted with ethyl acetate (50.0 mL) and washed with water (20.0 ml) and brine solution (30.0 mL). 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 (silica gel 100-200 mesh, 50% ethyl acetate / pet ether) to give tert-butyl 2-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetate (1.1 g, 1.64 mmol, 58.64% yield) as an off-white solid. LC-MS (ES) + ): m / z 635.2 [M+H] + .

[0422] Step 2: To a stirred, nitrogen purged solution of tert-butyl 2-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetate (2.0 g, 3.15 mmol) in 1,4-dioxane (30 mL), palladium hydroxide on carbon, 20 wt% dry basis (442.48 mg, 3.15 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered through a celite bed, washed with ethyl acetate (200 mL) and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, 75% ethyl acetate / pet ether) to give tert-butyl 2-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetate (1.2 g, 2.59 mmol, 82.34% yield) as an off-white solid. LC-MS (ES + ): m / z 457.2 [M+H] + .

[0423] Step 3: To a stirred solution of tert-butyl 2-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetate (1.2 g, 2.59 mmol) in 1,4-dioxane (15 mL) cooled to 0° C., 4.0 M hydrogen chloride in dioxane (648.58 mmol) was added dropwise and the reaction was stirred at room temperature for 50 hours. After completion of the reaction, the reaction mixture was concentrated, washed with hexane (100 mL) and dried to give the product 2-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetic acid HCl salt (1.15 g, 2.16 mmol, 83.40% yield) as an off-white solid. LC-MS (ES + ): m / z 401.2 [M+H] + .

[0424] Synthesis of 2-(1-(4-(2,6-dioxopiperidin-3-yl)-2,5-difluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid [ka]

[0425] Step 1: A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (20 g, 139.68 mmol, 17.86 mL), 1,4-dibromo-2,5-difluoro-benzene (113.93 g, 419.04 mmol), copper iodide (6.65 g, 34.92 mmol, 1.18 mL), potassium carbonate (57.92 g, 419.04 mmol) and (2S)-pyrrolidine-2-carboxamide (7.97 g, 69.84 mmol) in DMSO (120 mL) was degassed and purified with N 2 The mixture was then purged with N for 6 h at 60 °C. 2 The mixture was stirred under atmospheric pressure. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0-10% ethyl acetate / petroleum ether at 50 mL / min). Compound 8-(4-bromo-2,5-difluoro-phenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.8 g, 4.31 mmol, 3.09% yield) was obtained as a white solid. LC-MS (ES + ): m / z 334.0 [M+H] + .

[0426] Step 2: 8-(4-bromo-2,5-difluoro-phenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.8 g, 5.39 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.37 g, 8.08 mmol), cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (394.15 mg, 538.67 μmol), K 2 CO 3 A mixture of (2.23 g, 16.16 mmol) in DMF (20 mL) and water (4 mL) was degassed and purified with N 2 The mixture was purged with N for 0.5 h at 25 °C. 2 The mixture was then stirred under N 2 at 80° C. for 16 h. 2 After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with CaCl 2 The mixture was washed with hexane (20 mL) and brine (20 mL). It was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, 0-50% ethyl acetate / petroleum ether at 60 mL / min). The compound 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,5-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.8 g, 2.46 mmol, 45.61% yield) was obtained as a white solid. LC-MS (ES + ): m / z 545.2[M+H] + .

[0427] Step 3: To a solution of 8-[4-(2,6-dibenzyloxy-3-pyridyl)-2,5-difluoro-phenyl]-1,4-dioxa-8-azaspiro[4.5]decane (1.0 g, 1.36 mmol) in acetone (90 mL) and water (21 mL) was added PTSA (935.97 mg, 5.44 mmol). The mixture was stirred at 50° C. for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to remove acetone and the residue was extracted with NaHCO 3 The mixture was diluted with ethyl acetate (30 mL×3) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 1-[4-(2,6-dibenzyloxy-3-pyridyl)-2,5-difluoro-phenyl]piperidin-4-one (1.03 g, 1.03 mmol, 75.72% yield) was obtained as a white solid. LC-MS (ES + ): m / z 501.2 [M+ H] + .

[0428] Step 4: To a solution of LDA (1M, 3.02 mL) in THF (45 mL) was added tert-butyl acetate (336.27 mg, 2.89 mmol, 389.65 μL) dropwise at −70° C. After the addition, the mixture was stirred at −78° C. for 1 h, and then a solution of 1-[4-(2,6-dibenzyloxy-3-pyridyl)-2,5-difluoro-phenyl]piperidin-4-one (1.8 g, 2.52 mmol) in THF (45 mL) was added dropwise via a funnel. After 30 min at −70° C., the mixture was stirred at 20° C. for 1 h. After the reaction was complete, the reaction mixture was diluted with NH 4The reaction was quenched by the addition of Cl solution (10 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (15 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0-40% ethyl acetate / petroleum ether at 50 mL / min). Tert-butyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,5-difluorophenyl)-4-hydroxypiperidin-4-yl)acetate (600 mg, 846.45 μmol, 33.63% yield) was obtained as a yellow solid. LC-MS (ES + ): m / z 617.3[M+H] + .

[0429] Step 5: To a solution of tert-butyl 2-[1-[4-(2,6-dibenzyloxy-3-pyridyl)-2,5-difluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (0.6 g, 972.93 μmol) in methanol (5 mL) was added 10% Pd / C (590.83 mg, 486.47 μmol). The mixture was stirred at 25° C. for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove methanol. The crude product tert-butyl 2-(1-(4-(2,6-dioxopiperidin-3-yl)-2,5-difluorophenyl)-4-hydroxypiperidin-4-yl)acetate (0.4 g, 912.28 μmol, 93.77% yield) was used in the next step without further purification. LC-MS (ES) + ): m / z 437.1[MH] + .

[0430] Step 6: To a solution of tert-butyl 2-(1-(4-(2,6-dioxopiperidin-3-yl)-2,5-difluorophenyl)-4-hydroxypiperidin-4-yl)acetate (0.4 g, 912.28 μmol) in DCM (2 mL) was added HCl (12 M, 760.23 μL). The mixture was stirred at 25° C. for 5 h. The residue was purified by preparative HPLC (ACSWH-GX-U / Phenomenex Luna C18 150×40 mm×15 um; water (0.1% TFA) / ACN; 10-40% gradient; time (min): 11). The compound 2-(1-(4-(2,6-dioxopiperidin-3-yl)-2,5-difluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid (0.1 g, 238.77 μmol, 26.17% yield) was obtained as a white solid. 1 HNMR (400MHz, DMSO-d 6 ) δ =12.53 (s,1H), 10.85(s, 1H),7.10 (dd,J = 7.2,13.2 Hz,1H), 6.85(dd, J =7.2, 12.0Hz, 1H),4.43 - 4.12 (m, 1H),4.09 - 3.87 (m, 2H),3.15 - 2.95 (m, 3H),2.78 - 2.65 (m, 1H),2.53 (brd, J =3.6 Hz,1H), 2.40(s, 2H),2.19 (dq,J = 3.6,13.0 Hz,1H), 2.00- 1.91(m, 1H),1.85 - 1.75 (m, 2H),1.72 - 1.64 (m, 2H).

[0431] Synthesis of 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2,5-difluoro-phenyl]-4-hydroxy-4-piperidyl]acetic acid [ka]

[0432] Step 1: To a solution of 1,2,4-trifluoro-5-nitro-benzene (4 g, 22.59 mmol, 2.60 mL) and tert-butyl 2-(4-hydroxy-4-piperidyl)acetate (4.86 g, 22.59 mmol) in acetonitrile (50 mL), TEA (85.72 mg, 847.07 μmol, 118.06 μL) was added, and then the mixture was stirred at 20° C. for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0 to 1 / 1) to give tert-butyl 2-[1-(2,5-difluoro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate (5 g, 13.32 mmol, 58.97% yield) as a yellow solid. LC-MS (ES + ): m / z 373.2[M+H] + .

[0433] Step 2: To a solution of tert-butyl 2-[1-(2,5-difluoro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate (2 g, 5.37 mmol) in ethanol (20 mL) and water (4 mL) was added iron (1.20 g, 21.48 mmol) and ammonium chloride (2.30 g, 42.97 mmol), and the mixture was then stirred at 20° C. for 3 h. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to give tert-butyl 2-[1-(4-amino-2,5-difluoro-phenyl)-4-hydroxy-4-piperidyl]acetate (1.5 g, 4.24 mmol, 78.95% yield) as a brown solid. LC-MS (ES) + ): m / z 343.2[M+H] + .

[0434] Step 3: To a solution of 2,6-dibenzyloxy-3-bromo-pyridine (1.47 g, 3.98 mmol) and tert-butyl 2-[1-(4-amino-2,5-difluoro-phenyl)-4-hydroxy-4-piperidyl]acetate (1.5 g, 4.38 mmol) in dioxane (15 mL) was added cesium carbonate (3.89 g, 11.95 mmol) and tBuXPhos Pd G3 (316.79 mg, 398.28 μmol). The mixture was then heated at 90° C. for 16 h under N 2 The mixture was stirred under atmospheric pressure. Upon completion, the reaction was quenched with water (30 mL) and then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0 to 1 / 1) to give tert-butyl 2-[1-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2,5-difluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (1.3 g, 1.95 mmol, 49.05% yield) as a brown oil. LC-MS (ES + ): m / z 632.5[M+H] + .

[0435] Step 4: To a solution of tert-butyl 2-[1-[4-[(2,6-dibenzyloxy-3-pyridyl)amino]-2,5-difluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (1.3 g, 2.06 mmol) in ethyl acetate (15 mL) was added 10% Pd (219.00 mg, 205.79 μmol) and the mixture was heated at 20 °C for 16 h under H 2 (15 psi). After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2,5-difluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (0.8 g, 1.76 mmol, 85.72% yield) as a brown oil. LC-MS (ES + ): m / z 454.3[M+H] +.

[0436] Step 5: To a solution of tert-butyl 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2,5-difluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (0.8 g, 1.76 mmol) in DCM (8 mL) was added hydrochloric acid (12 M, 1.47 mL) at 0° C., and the mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with acetonitrile (5 mL) and stirred at 25° C. for 15 min. It was then filtered, and the filter cake was dried under vacuum to give 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2,5-difluoro-phenyl]-4-hydroxy-4-piperidyl]acetic acid HCl salt (600 mg, 1.38 mmol, 78.40% yield) as a purple solid. LC-MS(ES+): m / z398.1 [M+H] + .

[0437] Synthesis of 1-[2,5-dichloro-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetic acid [ka]

[0438] Step 1: To a solution of 1,4-dichloro-2-fluoro-5-nitro-benzene (2 g, 9.52 mmol, 1.30 mL) and tert-butyl 2-(4-hydroxy-4-piperidyl)acetate (2.26 g, 10.48 mmol) in acetonitrile (20 mL) was added TEA (1.45 g, 14.29 mmol, 1.99 mL). The mixture was stirred at 25° C. for 2 h. Upon completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (5 mL×3) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The product was carried on to the next step without purification. The compound tert-butyl 2-[1-(2,5-dichloro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate (3.5 g, 8.48 mmol, 89.02% yield) was obtained as a yellow solid. LC-MS (ES + ): m / z 405.1 [M+H] + .

[0439] Step 2: To a solution of tert-butyl 2-[1-(2,5-dichloro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate (3.5 g, 8.64 mmol) in ethanol (30 mL) and water (6 mL) was added iron (1.93 g, 34.54 mmol, 245.46 μL). The mixture was stirred at 25° C. for 5 h. The reaction mixture was filtered, concentrated under reduced pressure, and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (5 mL×3) and diluted with Na 2 SO 4 The mixture was dried at 40° C. for 1 hour, filtered, and concentrated under reduced pressure to give tert-butyl 2-[1-(4-amino-2,5-dichloro-phenyl)-4-hydroxy-4-piperidyl]acetate (3 g, 7.89 mmol, 91.32% yield) as a yellow solid. LC-MS (ES + ): m / z 375.1 [M+H] + .

[0440] Step 3: To a solution of tert-butyl 2-[1-(4-amino-2,5-dichloro-phenyl)-4-hydroxy-4-piperidyl]acetate (1 g, 2.66 mmol) and 2,6-dibenzyloxy-3-bromo-pyridine (1.18 g, 3.20 mmol) in t-amyl-OH (10 mL) was added cesium carbonate (2.60 g, 7.99 mmol) and X-Phos-Pd G4 (229.28 mg, 266.46 μmol). The mixture was stirred at 90° C. for 16 hours. The reaction mixture was filtered, concentrated under reduced pressure, and then extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (5 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give tert-butyl 2-[1-[2,5-dichloro-4-[(2,6-dibenzyloxy-3-pyridyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetate (550 mg, 723.94 μmol, 27.17% yield) as a yellow oil. LC-MS (ES + ): m / z 664.1 [M+H] + .

[0441] Step 4: To a solution of tert-butyl 2-[1-[2,5-dichloro-4-[(2,6-dibenzyloxy-3-pyridyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetate (550 mg, 827.55 μmol) in ethyl acetate (6 mL) was added 10% Pd / C (50 mg) and the mixture was heated at 25 °C for 6 h under H 2 (15 psi). The reaction mixture was filtered and concentrated under reduced pressure. This material was carried forward crude. The compound tert-butyl 2-[1-[2,5-dichloro-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetate (150 mg, 245.36 μmol, 29.65% yield) was obtained as a black solid. LC-MS (ES + ): m / z 486.2[M+H] + .

[0442] Step 5: To a solution of tert-butyl 2-[1-[2,5-dichloro-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetate (150 mg, 308.40 μmol) in DCM (2 mL) was added hydrochloric acid (12 M, 257.00 μL) at 0° C., and the mixture was then stirred at 25° C. for 1 h. After completion, the reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (TFA conditions) to give 1-[2,5-dichloro-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetic acid (90 mg, 180.51 μmol, 58.53% yield) as a black solid. LC-MS (ES + ): m / z 429.9[M+H] + .

[0443] Synthesis of 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetic acid [ka]

[0444] Step 1: To a stirred solution of piperidin-4-one HCl salt (20 g, 147.50 mmol) and 1,2-difluoro-4-nitro-benzene (26.99 g, 169.63 mmol, 18.74 mL) in DMSO (200 mL) was added N,N-diisopropylethylamine (19.06 g, 147.50 mmol, 25.69 mL). The reaction was stirred at 80° C. overnight and monitored by TLC. After 16 h, when complete consumption of the reactants was observed by TLC, ice-cold water was added to the reaction mixture and the solid was filtered through a Buchner funnel. The solid was thoroughly dried to give 1-(2-fluoro-4-nitro-phenyl)piperidin-4-one (28 g, 115.66 mmol, 78.41% yield). LC-MS (ES - ): m / z 237.1[MH] - .

[0445] Step 2: To a stirred solution of tert-butyl acetate (7.31 g, 62.97 mmol, 8.47 mL) in THF was added lithium diisopropylamide (13.49 g, 125.94 mmol) at -78°C. The mixture was allowed to stir for 1 hour, after which 1-(2-fluoro-4-nitro-phenyl)piperidin-4-one (15 g, 62.97 mmol) was added. The reaction was continued for 2 hours under nitrogen atmosphere. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution and the product was extracted with ethyl acetate (2 x 200 mL) and concentrated to give the crude product. The crude product was purified using flash column chromatography (silica gel, 40% ethyl acetate / pet ether) to give tert-butyl 2-[1-(2-fluoro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate (17.6 g, 43.71 mmol, 69.41% yield) as a gummy brown liquid. LC-MS (ES + ): m / z 355.2[M+H] + .

[0446] Step 3: To a stirred solution of tert-butyl 2-[1-(2-fluoro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate (17.6 g, 49.67 mmol) in ethanol (200 mL) was added palladium (10% on carbon, type 487, dry) (15 g, 140.95 mmol). The reaction was carried out at room temperature under hydrogen atmosphere for 5 hours. The reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was concentrated and the crude product was purified using flash column chromatography (silica gel, 45% ethyl acetate / pet ether) to obtain the compound tert-butyl 2-[1-(4-amino-2-fluoro-phenyl)-4-hydroxy-4-piperidyl]acetate (13 g, 38.99 mmol, 78.51% yield). LC-MS (ES + ): m / z 325.2[M+H] + .

[0447] Step 4: To a stirred solution of tert-butyl 2-[1-(4-amino-2-fluoro-phenyl)-4-hydroxy-4-piperidyl]acetate (13 g, 40.08 mmol) and 3-bromopiperidine-2,6-dione (15.39 g, 80.15 mmol) in DMF (100 mL) was added sodium bicarbonate (6.73 g, 80.15 mmol). The reaction was carried out at 65° C. overnight and monitored by TLC. After completion of the reaction, the product was extracted by workup with ethyl acetate and water. The extracted organic layer was dried over anhydrous sodium sulfate and concentrated under high vacuum to give the crude product, which was purified using flash column chromatography (silica gel, 45% ethyl acetate / pet ether) to give tert-butyl 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (11.5 g, 65.41% yield). LC-MS (ES + ): m / z 436.2 [M+H] + .

[0448] Step 5: To a stirred solution of tert-butyl 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetate (411 mg, 943.77 μmol) in DCM (10 mL) was added dropwise 99% hydrogen chloride in 1,4-dioxane (4 M, 4.72 mL) at 0° C. The reaction mixture was stirred at room temperature for 24 h and monitored by UPLC. After the reaction was complete, the reaction mixture was evaporated to dryness under reduced pressure. The product was redissolved in DCM and MTBE was added to give a precipitate. The solid was decanted by centrifugation. The solvent was removed. The solid was dried under high vacuum to give 2-[1-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]-4-hydroxy-4-piperidyl]acetic acid HCl salt (365 mg, 789.96 μmol, 83.70% yield) as a grey solid. LC-MS (ES + ): m / z 380.3 [M+H] + .

[0449] Synthesis of 2-[1-[2-chloro-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetic acid [ka]

[0450] Step 1: To a solution of 1,2-dichloro-4-nitro-benzene (5 g, 26.04 mmol) and 1,2-dichloro-4-nitro-benzene (5 g, 26.04 mmol) in DMSO (50 mL) was added potassium carbonate (10.80 g, 78.13 mmol). The mixture was stirred at 110° C. for 1 h. The reaction was cooled to 20° C., poured into water (500 mL), and the mixture was extracted with EtOAc (200 mL×3). The combined organic phase was washed with brine (200×2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 2-[1-(2-chloro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate (9.4 g, 22.8 mmol, 87.6% yield). 1 HNMR (400MHz, DMSO-d 6 ) δ =8.20 (d,J =2.8 Hz,1H), 8.12(dd, J = 2.8, 8.8 Hz,1H), 7.28(d, J = 8.8 Hz, 1H),4.65 (s,1H), 3.29(br d, J = 12.0 Hz, 2H),3.19 - 3.08 (m, 2H),2.39 (s,2H), 1.88- 1.78(m, 2H),1.76 - 1.67 (m, 2H),1.41 (s,9H).

[0451] Step 2: To a mixture of tert-butyl 2-[1-(2-chloro-4-nitro-phenyl)-4-hydroxy-4-piperidyl]acetate (9.4 g, 25.35 mmol) in ethanol (190 mL) and water (38 mL) was added ammonium chloride (4.07 g, 76.05 mmol) and iron powder (4.25 g, 76.05 mmol). The reaction mixture was stirred at 90° C. for 16 h. After the reaction was complete, the reaction mixture was filtered to remove the iron powder and concentrated to remove the solvent. It was then poured into water (400 mL) and the mixture was extracted with EtOAc (200 mL×3). The combined organic phase was washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2-[1-(4-amino-2-chloro-phenyl)-4-hydroxy-4-piperidyl]acetate (8.64 g, 22.94 mmol, 90% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ= 6.88(d, J = 8.4 Hz, 1H),6.61 (d,J =2.4 Hz,1H), 6.47(dd, J = 2.4, 8.4 Hz,1H), 4.96(br s, 2H), 4.43 (s,1H), 2.89- 2.80(m, 2H),2.79 - 2.72 (m, 2H),2.34 (s,2H), 1.82- 1.72(m, 2H),1.68 - 1.60 (m, 2H),1.41 (s,9H).

[0452] Step 3: To a stirred solution of tert-butyl 2-[1-(4-amino-2-chloro-phenyl)-4-hydroxy-4-piperidyl]acetate (6.4 g, 18.78 mmol) in acetonitrile (100 mL) was added TBAI (13 g, 9.39 mmol), NaHCO 3(4.41 g, 56.33 mmol) was added. After stirring for 5 min, 3-bromopiperidine-2,6-dione (3.61 g, 18.78 mmol) was added at room temperature. After 10 min, the temperature of the reaction was raised to 90° C. and the reaction was continued for about 72 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (400 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1:1) to give tert-butyl 2-[1-[2-chloro-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-4-hydroxy-4-piperidyl]acetate carbamate (4.0 g, 8.41 mmol, 44.8% yield) as a blue solid. 1 HNMR (400MHz, DMSO-d 6 ) δ =10.78 (s,1H), 6.95(d, J = 8.8 Hz, 1H),6.74 (d,J =2.4 Hz,1H), 6.59(dd, J = 2.4, 8.8 Hz,1H), 5.83(d, J = 8.0 Hz, 1H),4.47 (s,1H), 4.32- 4.25(m, 1H),2.91 ...

Claims

1. Formula (A): IRAK-L-DSM(A) compound, or a pharmaceutically acceptable salt thereof [wherein, DSM is a degradation signaling site covalently bonded to linker L, L is a linker that covalently bonds IRAK to DSM, IRAK is a IRAK4 binding site covalently bonded to linker L, represented by formula (I); 【Chemical 1】 wherein, selected from A １ is selected from N, CH, and CR ３ and A ２ is selected from N, CH, and CR ４ 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 R ５ and which is optionally substituted 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, and having 1 to 3 Rs ５ wherein said heterocyclic ring may optionally be substituted by iv. 1 to 3 R's ５ wherein the partial or fully saturated C ３－６ cycloalkyl may optionally be substituted 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 by 1 to 3 Rs ５ wherein said carbocyclic ring system is optionally substituted represents the bond to the linker L]. R ２ is hydrogen, C １－４ alkyl, or halogen, and R ３ and R ４ each is independently selected from halogen, C １－４ alkyl, nitrile, and -OR ６ wherein said C １－４ alkyl is optionally substituted with C １－４ alkoxy or at least one halogen, R ５ For each entity, 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 (wherein the C １－４ alkyl is optionally substituted with one or more substituents independently selected from CN, halo, C １－４ alkoxy, and hydroxyl, and the C ３－６ cycloalkyl and the 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 an intervening atom, may 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 (wherein the phenyl, the C ４－６ carbocycle, and the 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 a 4- to 7-membered partially or fully saturated heterocyclic ring containing one or two heteroatoms selected from hydrogen, C １－５ alkyl, C ３－６ cycloalkyl, 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 R ６ The C １－５ alkyl represented by is independently selected from halogen, hydroxyl, C １－５ alkyl, C １－４ alkoxy, C １－４ haloalkoxy, C ３－６ cycloalkyl, 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 is optionally substituted with 1 to 3 substituents R ６ａ , and R ６ The C ３－６ cycloalkyl represented by is optionally substituted with 1 to 3 substituents R １－４ alkyl, C １－４ haloalkyl, and C １－４ alkoxy, and R ６ｂ , and R ６ 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 are optionally substituted with 1 to 3 substituents R １－４ alkyl and oxo, and R ６ｃ , and R ６ａ The C ３－６ cycloalkyl, the phenyl, and the 4- to 7-membered partially or fully saturated heterocyclic ring are optionally substituted with 1 to 3 R ７ , Each R ７ is independently selected from oxo, halogen, C １－４ haloalkyl, and C １－４ alkyl, R ８ and R ９ each is independently selected from 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 each independently represents hydrogen or C １－４ alkyl, 【Chemical 2】

2. IRAK is a IRAK4 binding site represented by formula (IA), (IB), or (IC): The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a IRAK4 binding site represented by the formula. 【Chemical Formula 3】 (ii) R1 is 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, selected from

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 , a 5- or 6-membered partially or fully saturated heterocyclic ring having 1 to 2 heteroatoms independently selected from oxygen and nitrogen, said heterocyclic ring optionally substituted by 1 to 3 R ５ , and 9- to 10-membered bicyclic heteroaryl having 1, 2 or 3 nitrogen atoms, said ring system optionally substituted by 1 to 3 R ５ , selected from the group consisting of: (iii) R1 is represented by one of the following formulas: wherein m is 0, 1, or 2, [Chemical Formula 4] (iv) R1 is represented by one of the following formulas: or, 【Chemical Formula 5】 (v) R1 is represented by one of the following formulas: The compound according to claim 1, or a pharmaceutically acceptable salt thereof. ​

4.

5. IRAK is a IRAK4 binding site represented by one of the following formulas: R ２ is hydrogen, the compound according to claim 1, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a IRAK4 binding site represented by the formula. (ii) R3 is -CF3 or -O-CH(CH3)2, [Chemical Formula 7] The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

6. (i) R ３ is C １－４ alkyl or -OR ６ wherein said C １－４ alkyl is optionally substituted with at least one halogen, and R ６ is C １－５ alkyl, or (ii) For each occurrence, R5 is independently selected from -CH3, -CHF2, -CF3, F, cyclopropyl, and The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. (i) R ５ is, for each entity, C １－４ alkyl, halogen, C １－４ haloalkyl, and C ３－４ cycloalkyl, independently selected, said C ３－４ cycloalkyl is optionally substituted with one halo, or,

8. [Chemical 8] IRAK is represented by the following formula:

9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein the compound is as described.

10. 【Chemical Formula 9-1】 【Chemical Formula 9-2】 an IRAK binding site represented by one of them, wherein R ５ is C １－３ alkyl C １－３ haloalkyl, or C ３－４ cycloalkyl, and the C ３－４ cycloalkyl is optionally substituted with one halo, the compound according to claim 1, or a pharmaceutically acceptable salt thereof. DSM is a degradation signaling site represented by formula (D): R ５ is CH ３ , CHF ２ , CF ３ , cyclopropyl, or 【Chemical 10】 wherein, represents the bond to the linker L,

11. 【Chemical 11】 ​ 【Chemical Formula 12】 ​ Y is CR Ｄ１ or N, and Z １ is selected from 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 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 and optionally substituted in some cases, G ２ is Het １ *, -NR Ｄ４ -C ４－６ cycloalkyl-**, *, -NR Ｄ４ -Het １ -**, *, -NR Ｄ４ -Het １ -C １－４ alkyl-**, *, -C １－４ alkyl-C(R Ｄ１ )=Het １ -**, *, -C(O)-C １－４ alkyl-Het １ -**, *, -Het １ -C １－６ alkyl-**, *, -Het １ -O-**, *, -C(O)-C １－４ alkyl-Het １ -C(O)-**, *, -C(O)-Het １ -C(O)-**, *, -C(O)-phenyl-C １－４ alkyl-NHC(O)-**, *, -C(O)-C １－６ alkyl-NR Ｄ４ -**, *, -NR Ｄ４ -cycloalkyl-**, *, -O-Het １ -**, or *, -NR Ｄ４ -C １－４ alkyl-Het １ selected from, *- represents a bond to the linker L, **- represents a bond to G １ and, Het １ is a 4- to 7-membered monocyclic heterocycle or a 7- to 11-membered bicyclic heterocycle, 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, R Ｄ２ is H or C １－３ and is alkyl, R Ｄ３ is independently selected for each entity 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 is independently selected from H, halogen, hydroxyl, C １－４ alkyl, C １－４ haloalkyl, and C １－４ alkoxy for each occurrence, the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. ​ (i) Het １ is a 4- to 7-membered monocyclic saturated heterocycle containing one or two nitrogen atoms, or a 7- to 8-membered saturated spirobicyclic heterocycle containing one or two nitrogen atoms, each of which is optionally substituted with one or two R Ｄ５ groups (ii) Het1 is piperidine, piperazine, 1,4-diazepane, morpholine, 2-azaspiro[3.3]heptane, 2,5-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5]nonane, or 2,6-diazaspiro[3.3]heptane, each of which is optionally substituted with one or two RD5, or, (iii) Het1 is of the formula: 【Chemical 13】 represented by any one of the following, wherein n is 0, 1, or 2, 【Chemical 14】 represents a direct or indirect bond to the linker L, and ―* represents a direct or indirect bond to G1, The compound according to claim 10, or a pharmaceutically acceptable salt thereof. **Claim 12** DSM is a degradation signal transduction site of formula (D-I), (D-II), (D-III), (D-IV) or (D-V): 【Chemical Formula 15】 wherein, 【Chemical 16】 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 C １－３ alkyl, and R Ｄ３ is independently selected for each entity from H, halogen, and C １－４ alkyl R Ｄ４ is H or C １－３ and is alkyl, R Ｄ５ is a halogen, and n is 0, 1, or 2, The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

13. (i) G １ is selected from phenyl, pyrazolyl, pyridinyl, pyrimidinyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, benzo[d]oxazol-2(3H)-one, 7,9-dihydro-8H-purin-8-one, 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, pyrazinyl, indazolyl, and indolyl, each of which is optionally substituted with one or two R Ｄ３ groups, (ii) G1 is of the formula: 【Chemical 17】 represented by any one of the following, wherein o is 0, 1, or 2, 【Chemical Formula 18】 represents a bond to G2, and ―* represents a bond to Z1, (iii) 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, or, (iv) G1 is of the formula: 【Chemical Formula 19】 represented by any one of the following, wherein o is 0, 1, or 2, 【Chemical 20】 represents a bond to G2, and ―* represents a bond to Z1, The compound according to claim 10, or a pharmaceutically acceptable salt thereof.

14. (i) R Ｄ１ is H, -CH ３ or F, (ii) RD2 is H, (iii) RD3 is independently selected from H, Cl, F, and -CH3 for each occurrence, (iv) RD4 is -CH3, and / or, (v) RD5 is independently F or OH for each occurrence, The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. **Claim 15** DSM is bonded to L, 【Chemical Formula 21-1】 【Chemical Formula 21-2】 [Chemical Formula 21-3] 【Chemical 21-4】 [Chemical 21-5] 【Chemical Formula 21-6】 [Chemical 21-7] 【Chemical 21-8】 【Chemical Formula 21-9】 【Chemical Formula 21-10】 [[Chemical 21-11]] 【Chemical Formula 21-12】 ​ 【Chemical 21-14】 representing any one of the following, The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. **Claim 16** L is a bond, C １－８ is alkyl or has the formula (L-1), (L-2) or (L-3): 【Chemical 22】 represented by, wherein, Z ２ is C, optionally substituted by a bond or one or more halogens １－４ alkyl, and Het ２ is a 4- to 7-membered heterocyclic ring optionally substituted by one or more R Ｌ１ and is optionally substituted by one or more R G ３ is a 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, -C(O)-, or **-C １－４ alkyl-C(O)-*, where **- represents a bond connected to G ３ -* 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 optionally substituted by R １－４ alkyl, R Ｌ１ is independently selected for each entity from H, halogen, C １－４ alkyl, and C １－４ haloalkyl; R Ｌ２ is H or C １－４ and is alkyl, R Ｌ３ is independently selected for each entity from H, halogen, C １－４ alkyl, and C １－４ haloalkyl; R Ｌ４ is halo, -OR Ｌ５ or halogen, C ３－７ cycloalkyl, phenyl, a 4- to 7-membered monocyclic saturated heterocycle, or a 5- to 6-membered heteroaryl, optionally substituted by C １－４ alkyl, wherein said C ３－７ cycloalkyl, said phenyl, said 4- to 7-membered monocyclic saturated heterocycle, and said 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 23】 represents binding to the IRAK binding site, -* represents binding to the degradation signal transduction site DSM, a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. **Claim 17** Z ２ is a bond or -CH ２ -. 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 cyclohexyl or piperidinyl, and the cyclohexyl and piperidinyl represented by G ３ are each optionally substituted with one or more R Ｌ３ groups. Z ３ is -CH ２ - or **-CH ２ -C(O)-*, and Z ４ is optionally substituted by R Ｌ４ -CH ２ - as defined in claim 16, or a pharmaceutically acceptable salt thereof. **Claim 18** R Ｌ１ is H, R Ｌ２ is H, R Ｌ３ is H, R Ｌ４ The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R is benzyl.

19. (i) L is represented by formula (L-1), and Het ２ is the following formula: 【Chemical 24】 is represented by one of, wherein 【Chemical 25】 represents the bond to Z ２ and represents the bond to -* represents binding to the degradation signal transduction site DSM, (ii) L is represented by formula (L-2), and G3 is the following formula: 【Chemical 26】 is represented by one of, wherein 【Chemical 27】 represents binding to the IRAK binding site, -* represents binding to Z3, (iii) L is represented by formula (L-1), and Het2 is 【Chemical 28】 wherein 【Chemical Formula 29】 represents binding to Z2, -* represents binding to the degradation signal transduction site DSM, (iv) L is represented by formula (L-2), and G3 is 【Chemical Formula 30】 represented by, wherein 【Chemical 31】 represents binding to the IRAK binding site, -* represents binding to Z3, or (v) L is the following formula: 【Chemical 32】 is represented by any one of, wherein 【Chemical 33】 represents binding to the IRAK binding site, -* represents binding to the degradation signal transduction site DSM, a compound according to claim 16, or a pharmaceutically acceptable salt thereof. **Claim 20** The compound is the following formula: 【Chemical 34】 represented by, or a pharmaceutically acceptable salt thereof, wherein Z １ is a bond or -O-, G １ is phenyl, 6-membered heteroaryl, or 9-membered partially saturated bicyclic heterocycle, each of which is optionally substituted with one or two substituents independently selected from halo and C １－２ alkyl, G ２ is Het １ , *-NR Ｄ４ -Het １ -**, or *-C(O)-C １－２ alkyl-Het １ -**, where *- represents a bond to the linker L, and **- represents a bond to G １ and Het １ is piperidine optionally substituted with one or two halo or OH, R ５ is C optionally substituted with one halo ３－４ cycloalkyl, and R Ｄ４ is H or C １－２ alkyl, and the compound according to claim 1.

21. (i) G １ is phenyl, pyridinyl, indazolyl, or 1,3-dihydro-2H-benzo[d]imidazol-2-one, each of which is optionally substituted with one or two substituents independently selected from halo and C １－２ alkyl, G ２ is Het １ , *-NH-Het １ -**, or *-C(O)-CH ２ -Het １ -**, where *- represents the bond to the linker L and **- represents the bond to G １ and, Het １ is piperidine optionally substituted with one or two halo or OH, or (ii) G1 is 【Chemical 35】 where 【Chemical 36】 represents binding to G2, -* represents binding to Z1, Het1 is 【Chemical 37】 where #- represents binding to the linker, -NH-, or -C(O)-CH2-, ##- represents binding to G1, R5 is cyclopropyl or 【Chemical 38】 where, a compound according to claim 20, or a pharmaceutically acceptable salt thereof. **Claim 22** A compound according to claim 1 selected from the compounds of any one of Examples 1 to 199, or a pharmaceutically acceptable salt thereof. **Claim 23** A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. **Claim 24** A pharmaceutical composition for treating an IRAK4-mediated disease, comprising an effective amount of a compound according to any one of claims 1 to 5 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, hyperglobulinemia D, 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, deficiency of IL-1 receptor antagonist, 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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