Compounds for targeting the degradation of Bruton's tyrosine kinase - Patent Application 20070229633

Abstract

The present disclosure relates to a compound of formula (A), BTK-L-DSM(A), or a pharma- ceutically acceptable salt thereof, wherein DSM is a degradation signaling moiety covalently attached to a linker L, L is a linker that covalently attaches BTK to the DSM, and BTK is a Btk binding moiety represented by formula (I) or formula (II) covalently attached to the linker L, where all of the variables are as defined in the present application. The compounds described herein, or a pharma- ceutically acceptable salt thereof, can activate selective ubiquitination of the Btk protein via the ubiquitin-proteasome pathway (UPP), resulting in degradation of the Btk protein. The present disclosure also provides a method of treating a disorder responsive to modulation of Btk activity and / or degradation of Btk with at least one compound described herein. TIFF2024519496000642.tif112138

Description

[Technical field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 63 / 184,439, filed May 5, 2021, the entire contents of which are incorporated herein by reference.

[0002] Specific agents that target the degradation of Bruton's tyrosine kinase (Btk), as well as methods for making and using such agents, are provided. [Background technology]

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

[0004] Covalent attachment of multiple ubiquitin molecules by E3 ubiquitin ligases to terminal lysine residues marks the protein for proteasomal degradation, where the protein 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 ubiquitination of different proteins in vivo, which can be divided into four families: HECT domain E3s, U-box E3s, monomeric ring E3s, and multisubunit E3s.

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

[0006] Protein kinases are a large multigene family of over 500 proteins that play important roles in the development and treatment of many human diseases in oncology, neurology, and immunology. Tec kinases are non-receptor tyrosine kinases consisting of five members (Tec (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducible T cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk), and Bmx (myeloid tyrosine kinase gene on chromosome X; also known as Etk)), which are mainly expressed in hematopoietic cells, although expression of Bmx and Tec has been detected in endothelial and hepatic cells. Tec kinases (Itk, Rlk, and Tec) are expressed in T cells and are all activated downstream of T cells involved in regulating B cell activation, proliferation, and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-triphosphate (PIP3). Binding of PIP3 induces Btk to phosphorylate phospholipase C (PLCy), which hydrolyzes PIP2 to generate two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate the protein kinase PKC, which in turn induces further B cell signaling. Mutations that impair Btk enzymatic activity result in the primary immunodeficiency disorder XLA syndrome (X-linked agammaglobulinemia). Because Tec kinase plays a key role in both B and T cell signaling, it is an attractive target for autoimmune diseases.

[0007] Given that Btk plays an important role in B cell signaling, there is a great need to develop chimeric compounds that can activate the ubiquitination and degradation of Btk protein. The object of the present disclosure is to provide new compounds, methods, compositions, and methods of manufacture that are useful for the selective degradation of Btk protein in vivo via the ubiquitin proteasome pathway (UPP). Summary of the Invention

[0008] A first aspect of the present disclosure is a compound of formula (A): BTK-L-DSM (A) or a pharma- ceutically acceptable salt thereof, DSM is a degradation signaling moiety covalently attached to linker L; L is a linker that covalently attaches BTK to the DSM; a Btk binding moiety represented by Formula (I) or Formula (II), wherein BTK is covalently attached to a linker, L; [ka] or a pharma- ceutically acceptable salt thereof, A is CR 7 and N, B 1 But, CR 8 , N, and NR 8 is selected from B 2 is C or N, B 3 But, CR 8 , N, N.R. 8 , and S; Q 1 and Q 2 One of them is N and the other is C, or Q 1 and Q 2 Both are C, X is O and NR 2 is selected from R 1 But -N(R 1a ) 2 , C 1-10 R is selected from alkyl, 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic carbocyclyl, and 7- to 10-membered bicyclic heterocyclyl; 1 C represented by 1-10Alkyl, 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic carbocyclyl, and 7- to 10-membered bicyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 10 optionally replaced by R 1a But in each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl; R 1a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is selected from one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 10 or optionally replaced by Or alternatively, two R 1a together with their intervening atoms form a 3- to 7-membered monocyclic heterocyclyl which is heterocyclic with one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 10 optionally replaced by R 10 is, in each occurrence, independently, H, halogen, -OR 10a , -S(O) 2 R 10a , -CN,C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 10 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 15 or optionally replaced by Or alternatively, two R 10together with their intervening atoms form a ring A selected from 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic carbocyclyl, and 7- to 10-membered bicyclic heterocyclyl, said ring A containing one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 15 optionally replaced by R 10a but, independently in each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 15 but, independently for each occurrence, C 1-6 Alkyl, halogen, -CN, 3-7 membered monocyclic carbocyclyl, and -OR 15a Selected from R 15 C represented by 1-6 Alkyl and 3- to 7-membered monocyclic carbocyclyl are each independently selected from one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 15a or two R 15 together with the intervening atoms form a 3- to 7-membered monocyclic carbocyclyl or a 4- to 6-membered monocyclic heterocyclyl; R 15a is H, halogen, and C optionally substituted with at least one halogen 1-6 alkyl, R 2 But, H, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, R 3 But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)N(R 3a ) 2 , -C(O)OR 3a , and -C(O)R 3a Selected from R 3The C represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is selected from one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 30 optionally replaced by R 3a But in each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl; R 3a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is selected from one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 30 optionally replaced by R 30 may, in each occurrence, independently be a halogen, -OR 30a , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 30a But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; Or alternatively, R 1 and R 2 together with their intervening atoms form a ring B selected from 3- to 7-membered monocyclic heterocyclyl and 7- to 14-membered bicyclic heterocyclyl, said ring B containing one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 200 or optionally replaced by Or alternatively, R 2 and R 3together with their intervening atoms form a ring C selected from 3- to 7-membered monocyclic heterocyclyl and 7- to 10-membered bicyclic heterocyclyl, said ring C containing one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 200 optionally replaced by R 200 but, independently for each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halogen, -CN, -C(O)R 200a , -C(O) 2 R 200a , -C(O)N(R 200a ) 2 , -N(R 200a ) 2 , -N(R 200a )C(O)R 200a , -N(R 200a )C(O) 2 R 200a , -N(R 200a )C(O)N(R 200a ) 2 , -N(R 200a )S(O) 2 R 200a , -OR 200a , -OC(O)R 200a , -OC(O)N(R 200a ) 2 , -SR 200a , -S(O)R 200a , -S(O) 2 R 200a , -S(O)N(R 200a ) 2 , -S(O) 2 N(R 200a ) 2 Selected from R 200 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 250or two R 200 together with their intervening atoms form a 4- to 6-membered monocyclic heterocyclyl or a 3- to 7-membered monocyclic carbocyclyl, each of which contains one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 250 optionally replaced by R 200a but, independently in each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 200a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 250 optionally replaced by R 250 but, independently for each occurrence, C 1-6 Alkyl, halogen, and -OR 250a is selected from R 250a But H or C 1-6 is alkyl, R 4 But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halogen, -NO 2 , -CN, -OR 4a , -SR 4a , -N(R 4a ) 2 , -C(O)R 4a , -C(O)OR 4a , -S(O)R 4a , -S(O) 2 R 4a , -C(O)N(R 4a ) 2 , -SO 2 N(R4a ) 2 , -OC(O)R 4a , -N(R)C(O)R 4a , -N(R)C(O)OR 4a , -N(R)SO 2 R 4a , and -OC(O)N(R 4a ) 2 wherein R 4 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 40 optionally replaced by R 4a But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 4a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 40 optionally replaced by R 40 may, in each occurrence, independently be a halogen, -OR 40a , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 40 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R45 optionally replaced by R 40a But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 45 optionally replaced by R 45 but, independently for each occurrence, C 1-6 Alkyl, halogen, and -OR 45a is selected from R 45a But H or C 1-6 Is it an alkyl group? Or alternatively, R 3 and R 4 together with their intervening atoms form a ring D selected from a 5-7 membered monocyclic carbocyclyl and a 5-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, N, and S, said ring D containing one or more (e.g., 1-6, 1-3, or 1, 2, 3, 4, 5, or 6) R 300 optionally replaced by R 300 but, independently for each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-7 membered monocyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, halogen, -C(O)R 300a , -OR 300a , and -S(O) 2 R 300a Selected from R 300 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 350 optionally replaced by R 300a But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 300a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 350 optionally replaced by R 350 but, independently for each occurrence, C 1-6 Alkyl, halogen, -CN, -C(O)R 350a , -C(O)N(R 350a ) 2 , -C(R 350a ) 2 N(R 350a ) 2 , and -OR 350a is selected from R 350a is, in each occurrence, independently, H or C optionally substituted with 1 to 3 halogens 1-6 Alkyl or two R 350a together with the N atom to which they are attached form a 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms selected from N and O; R 5 But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, and -OR 5a Selected from R 5 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, and C2-6 each alkynyl is optionally substituted with one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) halogen; R 5a But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 5a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3-6 membered monocyclic carbocyclyl are each optionally substituted with one or more (e.g., 1-6, 1-3, or 1, 2, 3, 4, 5, or 6) halogen; R 6 But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, -OR 6a Selected from R 6 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 each alkynyl is optionally substituted with one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) halogen; R 6a But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 6a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) halogen; R 7 But, H, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, -CN, -OR 7a , -C(O)N(R 7a ) 2 , -C(O)OR 7a , and -C(O)R 7a Selected from R 7 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl is selected from one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 70 optionally replaced by R 7a but, independently in each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 7a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 70 optionally replaced by R 70 may, in each occurrence, independently be a halogen, -OR 70a , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 70 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 75 optionally replaced by R 70a But, H, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 70a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 75 optionally replaced by R 75 but, independently for each occurrence, C 1-6 Alkyl, halogen, and -OR 75a is selected from R 75a But H or C 1-6 is alkyl, R 8 may, in each occurrence, independently be H, a halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -C(O)R 8a , -C(O) 2 R 8a , -C(O)N(R 8a ) 2 , -N(R 8a ) 2 , -N(R 8a )C(O)R 8a , -N(R 8a )C(O) 2 R 8a , -N(R 8a )C(O)N(R 8a ) 2 , -N(R 8a )S(O) 2 R 8a , -OR 8a , -OC(O)R 8a , -OC(O)N(R 8a ) 2 , -SR 8a , -S(O)R 8a , -S(O) 2 R 8a , -S(O)N(R 8a )2 , -S(O) 2 N(R 8a ) 2 , 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl; R 8 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 80 optionally replaced by R 8a but, independently in each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 8a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 80 or two R 8a together with their intervening atoms, one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 80 forming a 4-6 membered monocyclic heterocyclyl optionally substituted by R 80 may, in each occurrence, independently represent a halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -C(O)R 80a , -C(O) 2 R 80a , -C(O)N(R 80a ) 2 , -N(R 80a ) 2, -N(R 80a )C(O)R 80a , -N(R 80a )C(O) 2 R 80a , -N(R 80a )C(O)N(R 80a ) 2 , -N(R 80a )S(O) 2 R 80a , -OR 80a , -OC(O)R 80a , -OC(O)N(R 80a ) 2 , -SR 80a , -S(O)R 80a , -S(O) 2 R 80a , -S(O)N(R 80a ) 2 , -S(O) 2 N(R 80a ) 2 , 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 80 The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 85 or two R 80 together with the carbon atom to which they are attached form an oxo group (-C=O)-) R 80a but, independently in each occurrence, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 80a The C represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 85 optionally replaced by R 85 but, independently for each occurrence, C 1-6 Alkyl, halogen, and -OR 85a and R 85a But H or C 1-6 is alkyl, [ka] represents a bond to the linker L, or a pharma- ceutically acceptable salt thereof.

[0009] In another aspect, the disclosure provides a method of treating a disorder responsive to modulation of Btk activity and / or degradation of Btk in a subject, comprising administering to the subject an effective amount of at least one compound described herein. The 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 the treatment of a disorder responsive to modulation of Btk activity and / or degradation of Btk. Also provided are compounds described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disorder responsive to modulation of Btk activity and / or degradation of Btk. Methods of making the compounds described herein and any synthetic intermediates are also included in the disclosure.

[0010] Other features or advantages will be apparent from the following detailed description of several embodiments, and from the appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The compounds described herein or pharmaceutically acceptable salts thereof can activate selective ubiquitination of Btk protein through the ubiquitin-proteasome pathway (UPP), leading to degradation of Btk protein. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof can modulate Btk activity.

[0012] 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 art to which this invention belongs.

[0013] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The recitation of ranges of values ​​is merely intended to serve as a shorthand method of referring individually to each separate value within the range, unless otherwise indicated 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 indicated herein or clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely to better illustrate the invention, and does not impose limitations on the scope of the invention, unless otherwise stated in the claims.

[0014] 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.

[0015] "Alkenyl" refers to an unsaturated hydrocarbon group, which may be straight chain or branched, having at least one carbon-carbon double bond. In some embodiments, an alkenyl group has 2-20 carbon atoms, 2-10 carbon atoms, or 2-6 carbon atoms. An alkenyl group may contain one, two, or three carbon-carbon double bonds, or more. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, and the like.

[0016] "Alkynyl" refers to an unsaturated hydrocarbon group, which may be straight-chained or branched, having at least one carbon-carbon triple bond. In some embodiments, an alkynyl group has 2 to 20 carbon atoms, with 2 to 10 carbon atoms, or 2 to 6 carbon atoms being preferred. An alkynyl group may contain one, two, or three carbon-carbon triple bonds, or more. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl, and the like.

[0017] In some embodiments, the number of carbon atoms in a group is indicated herein by the prefix "C x-xx " where x and xx are integers. For example, "C 1-4 "Alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0018] As used herein, the term "carbocyclyl", "carbocycle" or "carbocyclic ring" refers to a saturated or unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10, 3 to 8, 3 to 7, 3 to 5, 3 to 6, 4 to 6, 5 to 7, or 7 to 10 carbon atoms. The term "carbocyclyl" encompasses cycloalkyl groups and aromatic groups (i.e., aryl). The term "cycloalkyl" refers to a fully saturated monocyclic or bicyclic or spiro-type hydrocarbon group of 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 monocyclic cycloalkyl. Exemplary bicyclic carbocyclyl groups include 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.

[0019] In one embodiment, the carbocyclyl is a 7-10 membered bicyclic carbocyclyl. Exemplary 7-10 membered bicyclic carbocyclyls 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, decalinyl, naphthyl, and indanyl. In one embodiment, the carbocyclyl is a 3-7 membered monocyclic carbocyclyl. Exemplary 3- to 7-membered monocyclic carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl, and cycloheptatrienyl. In one embodiment, the carbocyclyl is a 5- to 7-membered monocyclic carbocyclyl, such as, but not limited to, cyclopentyl, cyclohexyl, cycloheptyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl, or cycloheptatrienyl. In another embodiment, the carbocyclyl is a 4-6 membered monocyclic carbocyclyl, such as, but not limited to, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, or phenyl. In another embodiment, the carbocyclyl is a 3-6 membered carbocyclyl, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, or phenyl.In another embodiment, the carbocyclyl is a 3-6 membered monocyclic cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In yet another embodiment, the carbocyclyl is phenyl. In yet another embodiment, the carbocyclyl is cyclopropyl.

[0020] "Halogen" or "halo" can be fluoro, chloro, bromo or iodo.

[0021] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated, monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system (e.g., fused, bridged or spiro ring system) having 3 to 14 ring members, or in particular 3 to 8 ring members, 3 to 7 ring members, 3 to 6 ring members, or 5 to 7 ring members, 4 to 7 ring members, or 4 to 6 ring members, of which at least one is a heteroatom and up to four (e.g., 1, 2, 3, or 4) may be heteroatoms, the heteroatoms being independently selected from O, S and N, where C may be oxidized (e.g., C(O)), N may be oxidized (e.g., N(O)) or quaternized, and S may be optionally oxidized to sulfoxide and sulfone. Unsaturated heterocycles include heteroaryl rings. Heterocyclyl groups may be attached to the remainder of the compound of the invention at a heteroatom or a carbon atom. The term azacyclic refers to a non-aromatic heterocyclyl having at least one nitrogen ring atom. Examples of azacyclics include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and morpholine.

[0022] In one embodiment, the heterocyclyl is a 3-7 membered monocyclic heterocyclyl (saturated or partially unsaturated (ie, non-aromatic)) having 1-2 heteroatoms selected from O, S and N. Examples of 3-7 membered monocyclic heterocyclyl include, but are not limited to, aziridinyl, oxiranyl, thirulanyl, oxaziridinyl, oxazepanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl. In one embodiment, the heterocyclyl is a 5-7 membered monocyclic heterocyclyl (saturated or partially unsaturated). Examples include pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, oxazepanyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl.

[0023] In another embodiment, the heterocyclyl is a 4-7 membered monocyclic heterocyclyl (saturated or partially unsaturated) having 1-2 heteroatoms selected from O, S, and N. Examples of 4-7 membered monocyclic heterocycles include, but are not limited to, azetidinyl, diazetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, oxazepanyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl.

[0024] In one embodiment, the heterocyclyl is a 4-6 membered monocyclic heterocyclyl (saturated or partially unsaturated) having 1-2 heteroatoms selected from O, S, and N. Examples of 4-6 membered monocyclic heterocycles include azetidinyl, diazetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, dihydrofuranyl, imidazolinyl, dihydropyranyl. , pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, and tetrazinyl.

[0025] In another embodiment, the heterocyclyl is a saturated 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms selected from O, S, and N. Examples of saturated 4-6 membered monocyclic heterocyclic ring systems include, but are not limited to, azetidinyl, diazetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithiinyl. In one embodiment, the saturated 4-6 membered monocyclic heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxinyl. In another embodiment, the saturated 4-6 membered monocyclic heterocyclyl is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0026] In one embodiment, the heterocyclyl is a 4-6 membered monocyclic heterocyclyl selected from: [ka]

[0027] In one embodiment, the heterocyclyl is a 4-6 membered monocyclic heterocyclyl selected from: [ka]

[0028] In one embodiment, the heterocyclyl is a 7-membered monocyclic heterocyclyl (saturated or partially unsaturated), such as a 7-membered monocyclic heterocyclyl having one heteroatom selected from O and N. Examples of 7-membered monocyclic heterocyclyls include, but are not limited to, azepanyl, azepinyl, oxepanyl, oxepinyl, thiepanyl, thiepinyl, diazepanyl, diazepinyl, and thiazepinyl.

[0029] In another embodiment, the heterocyclyl is a 7-11 membered or 7-10 membered bicyclic heterocyclyl. In yet another embodiment, the heterocyclyl is a 9-10 membered non-aromatic saturated or unsaturated bicyclic heterocyclyl. In another embodiment, the heterocyclyl is a 9-10 membered fused non-aromatic saturated or unsaturated bicyclic heterocyclyl. In another embodiment, the heterocyclyl is a 1,2,3,4-tetrahydroisoquinoline, 3,4-dihydro-1H-2λ 2 -isoquinolinyl, hexahydro-2H-thieno[2,3-c]pyrrolyl, hexahydro-2H-thieno[2,3-c]pyrrole-1,1-dioxido-yl, 2,3-dihydrobenzo[b][1,4]dioxinyl, azaspiro[4.4]nonanyl, azabicyclo[3.2.1]octanyl, azaspiro[2.5]octanyl, azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, azaspiro[3.4]octanyl, 6-oxa-2-azaspiro[3.4]octanyl, 2-azaspiro[3.3]heptanyl, azaspiro[5.5]undecanyl, indolinyl, and isoindolinyl. A heterocyclyl group may be attached to the remainder of a compound of the invention at a heteroatom or a carbon atom.

[0030] In one embodiment, the heterocyclyl is an 8-11 membered bicyclic heterocyclyl selected from: [ka]

[0031] In one embodiment, the heterocyclyl is a 9-10 membered non-aromatic unsaturated fused bicyclic heterocyclyl selected from: [ka]

[0032] In one embodiment, heterocyclyl is [ka] is a 9- to 11-membered fused non-aromatic bicyclic heterocyclyl selected from:

[0033] In one embodiment, heterocyclyl is [ka] and the like.

[0034] 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.

[0035] 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. Examples of 5-6 membered monocyclic heteroaryls 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, and the like. In one embodiment, the heteroaryl is a 5 membered heteroaryl. Examples of 5-membered heteroaryls include, but are not limited to, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-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 heteroaryls 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-isoindolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, thienopyridinyl, and thieno[3,2-b]pyridinyl. 2-isoindolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, thienopyridinyl, and thieno[3,2-b]pyridinyl.

[0036] In another embodiment, heteroaryl is [ka] is an 8-9 membered bicyclic heteroaryl selected from

[0037] In one embodiment, the 5-membered heteroaryl is selected from: [ka]

[0038] In one embodiment, the 5-membered heteroaryl is selected from: [ka]

[0039] In one embodiment, the 6-membered heteroaryl is selected from: [ka]

[0040] As used herein, the term "fused ring system" refers to a ring system having two rings, each of which is independently selected from carbocyclyl or heterocyclyl, where the two ring structures share two adjacent ring atoms. In one embodiment, the fused ring system has 8 to 12 ring members.

[0041] The term "bridged ring system", as used herein, is a ring system having a carbocyclyl or heterocyclyl ring in which two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably 1-3) atoms selected from C, N, O, and S. In one embodiment, the bridged ring system has 6-8 ring members.

[0042] As used herein, the term "spiro ring system" refers to a ring system having two rings, each of which is independently selected from carbocyclyl or heterocyclyl, where the two ring structures share one ring atom. In one embodiment, the spiro ring system has 5 to 8 ring members.

[0043] The term "oxo" as used herein refers to the double-bonded oxygen radical (=O) of a carbonyl group (C=O).

[0044] When the compounds provided herein are sufficiently basic or acidic to form stable non-toxic acid salts or base salts, it may be appropriate to prepare and administer the compounds as pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, or α-glycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate.

[0045] Pharmaceutically acceptable salts may be obtained, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid that provides a physiologically acceptable anion, using standard procedures well known in the art. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be formed.

[0046] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases can include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, or magnesium salts. Salts derived from organic bases include primary amines, secondary amines, or tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted cycloalkenylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, di ... Examples of amines that may be used include, but are not limited to, salts of arylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed amines of diamines and triamines, where at least two of the substituents on the amine may be different and may be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl, etc. Also included are amines where two or three of the substituents taken together with the amino nitrogen form a heterocycloalkyl or heteroaryl group.Non-limiting examples of amines may include isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine, etc. Other carboxylic acid derivatives may be useful, such as carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, etc.

[0047] The compounds described herein or their pharma- ceutically acceptable salts may contain one or more asymmetric centers in the molecule. According to the present disclosure, any structure that does not specify stereochemistry is to be understood as including all of the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, by chiral synthesis, or chromatographic separation using chiral stationary phases) are well known in the art.

[0048] When a particular stereoisomer of a compound is designated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. "Stereochemical purity" means the percent by weight of the desired stereoisomer based on the combined weight of all stereoisomers.

[0049] Where the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further to be understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. Stereoisomeric purity is the percent by weight of the desired stereoisomer encompassed by the name or structure relative to the combined weight of all stereoisomers.

[0050] Where a disclosed compound has been named or depicted by structure without indicating stereochemistry, and the compound has one chiral center, it is to be understood that the name or structure encompasses one enantiomer of the compound in pure or substantially pure form, and mixtures thereof, including racemic mixtures of the compounds, and mixtures in which one enantiomer is enriched relative to its corresponding optical isomer.

[0051] Where a disclosed compound has been named or depicted by structure without indicating stereochemistry, and for example, where the compound has at least two chiral centers, it is to be understood that the name or structure encompasses one stereoisomer in pure or substantially pure form, as well as mixtures thereof, including mixtures of stereoisomers and stereoisomeric mixtures in which one or more stereoisomers are enriched relative to the other(s).

[0052] Compounds of the present disclosure may also exist in tautomeric forms, and mixtures and separated individual tautomers are contemplated. Additionally, some compounds may exhibit polymorphism.

[0053] In one embodiment, the present invention provides a compound disclosed herein that is deuterated, where any or more positions occupied by hydrogen can contain enrichment with deuterium above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3500 times (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 times (60% deuterium incorporation), at least 4500 times (67.5% deuterium incorporation), at least 5000 times (75% deuterium), at least 5500 times (82.5% deuterium incorporation), at least 6000 times (90% deuterium incorporation), at least 6333.3 times (95% deuterium incorporation), at least 6466.7 times (97% deuterium incorporation), at least 6600 times (99% deuterium incorporation), or at least 6633.3 times (99.5% deuterium incorporation) greater. In one embodiment, hydrogen is present at its natural abundance at all positions. The compounds described herein, or pharma- ceutically acceptable salts thereof, may also exist in tautomeric forms, and mixtures and isolated individual tautomers are contemplated.

[0054] 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), a Btk binding or targeting moiety, and optionally a linker that covalently attaches the DSM to the Btk binding or targeting moiety.

[0055] In a first embodiment, the compound of the present disclosure has the formula Compound (A): BTK-L-DSM (A), or a pharma- ceutically acceptable salt thereof, wherein the BTK, L, and DSM moieties in Formula (A) are described in the first embodiment above. In some embodiments, the DSM, BTK, and linker moieties in Formula (A) are as described below.

[0056] A. BTK-Binding or Targeting Moieties In a second embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety (represented by BTK in formula (A)) is represented by formula (I) or formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: (i) A is N and Q 1 is C and Q 2 is N, or (ii) A is CH and Q 1 is C and Q 2 is C or (iii) A is CH and Q 1 is N and Q 2 is C, or (iv) A is CH and Q 1 is C and Q 2 is N, and the definitions of the other variables are as defined in the first embodiment.

[0057] In a third embodiment of the present disclosure, for a compound of formula (A) or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety, BTK, is represented by formula (I) or formula (II), 1 is CH and B 2 is C and B 3 is CH or (ii) B 1 is CH and B 2 is C and B 3 is S, or (iii) B 1 is N and B 2 is C and B 3 is CH or (iv) B 1 is CH and B 2 is C and B 3 is NR 8 or (v) B 1 is N and B 2 is N and B 3 is CH, or (vi) B 1 is CH and B 2 is N and B 3is N, and the definitions of the other variables are as defined in the first or second embodiment.

[0058] In a fourth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety, BTK, is represented by formula (I) or formula (II), wherein X is NR 2 and the definitions of the other variables are as defined in the first, second, or third embodiment.

[0059] In a fifth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the BTK of formula (A) is a Btk binding or targeting moiety represented by one of the following formulas: [ka] [ka] The definitions of the other variables are as defined in the first embodiment.

[0060] In a sixth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the BTK of formula (A) is a Btk-binding moiety represented by formula (IA) or (IC), and the definitions of the other variables are as defined in the first embodiment.

[0061] In a seventh embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), and R 1 is C 1-6 is selected from alkyl, 3-6 membered monocyclic or bicyclic carbocyclyl, 4-6 membered saturated monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl, and 9-10 membered bicyclic heteroaryl; 1-6 Alkyl, phenyl, monocyclic or bicyclic C 3-7Cycloalkyl, 4-6 membered saturated heterocyclyl, 5-6 membered monocyclic heteroaryl, and R 1 Each 9-10 membered bicyclic heteroaryl represented by the formula 10 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment.

[0062] In an eighth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 1 1 to 3 R 10 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0063] In a ninth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 1 is selected from methyl, butyl, pentyl, phenyl, bicyclo[1.1.1]pentanyl, azetidinyl, isoxazolyl, 1,2,4-oxadiazolyl, oxazolyl, pyrazolyl, triazolyl, piperidinyl, piperazinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyridazinyl, 1,2,4-thiadiazolyl, thiophenyl, and benzothiophenyl, each of which may be selected from one to three R 10 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0064] In a tenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 1 is selected from methyl, butyl, pentyl, phenyl, bicyclo[1.1.1]pentanyl, azetidinyl, isoxazolyl, 1,2,4-oxadiazolyl, oxazolyl, pyrazolyl, piperidinyl, piperazinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyridazinyl, 1,2,4-thiadiazolyl, thiophenyl, benzothiophenyl, each of which may be selected from one or three R 10 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0065] In an eleventh embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 1 is the following formula: [ka] wherein n represents an integer ranging from 0 to 3, and the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0066] In a twelfth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 1 is the following formula: [ka] wherein n represents an integer ranging from 0 to 3, with the proviso that R 1 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment, provided that the maximum valence of x is not exceeded.

[0067] In a thirteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein, at each occurrence, R 10 are independently halogen, -OR 10a , -S(O) 2 R 10a , C 1-6 alkyl, and 3- to 7-membered monocyclic carbocyclyl; R 10 C represented by 1-6 Alkyl and 3- to 7-membered monocyclic carbocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 15 or alternatively, two R 10 may, together with their intervening atoms, be one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 15 forming a 5- to 7-membered monocyclic carbocyclyl optionally substituted by R 10a is H or C in each occurrence. 1-6 is alkyl, R 15 may, in each occurrence, independently represent C 1-6 Alkyl, halogen, -OR 15a and 3- to 7-membered monocyclic carbocyclyl; R 15 C represented by 1-6 Alkyl and 3- to 7-membered monocyclic carbocyclyl have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 15a Optionally replaced by R 15ais H, halogen, and C optionally substituted with at least one (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) halogen. 1-6 alkyl, 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.

[0068] In a fourteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 10 represents, independently at each occurrence, a halogen, -OR 10a , -S(O) 2 R 10a , C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is one to three R 15 or alternatively two R 10 together with their intervening atoms, form one or three R 15 forming a 5- to 7-membered monocyclic carbocyclyl optionally substituted by R 10a is H or C in each occurrence. 1-6 is alkyl, R 15 may, in each occurrence, independently represent C 1-6 Alkyl, halogen, -OR 15a , and C 3-6 cycloalkyl; R 15 C represented by 1-6 Alkyl and C 3-6 Cycloalkyl is one to three R 15a Optionally replaced by R 15a is H, halogen, and C optionally substituted with 1 to 3 halogens 1-3alkyl, 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.

[0069] In a fifteenth embodiment of the present disclosure, for a compound of formula (A) or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety BTK of formula (A) is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), and R 10 is, for each occurrence, independently, Cl, F, -CH 3 , -CF 3 , -CH 2 -CH 3 , -CH(CH 3 ) 2 , -CHF 2 , -C(CH 3 )F 2 , -CH 2 -CF 3 , -CH 2 -C(CH 3 ) 3 , -OCH 3 , -C(CH 3 ) 3 , -O-CH(CH 3 ) 2 , -OC(CH 3 ) 3 , -O-CH 2 -C(CH 3 ) 3 , -C(CH 3 ) 2 OH, -cyclopropyl-CF 3 , -CH 2 -Cyclopropyl-CF 3 , [ka] and -S(O) 2 -CH 3 or alternatively, two R 10taken together with their intervening atoms form cyclohexane, 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.

[0070] In a sixteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 10 is, for each occurrence, independently, Cl, F, -CH 3 , -CF 3 , -CH 2 -CH 3 , -CH(CH 3 ) 2 , -CHF 2 , -C(CH 3 )F 2 , -CH 2 -CF 3 , -CH 2 -C(CH 3 ) 3 , -OCH 3 , -C(CH 3 ) 3 , -O-CH(CH 3 ) 2 , -OC(CH 3 ) 3 , -O-CH 2 -C(CH 3 ) 3 , -C(CH 3 ) 2 OH, -cyclopropyl-CF 3 , -CH 2 -Cyclopropyl-CF 3 , [ka] -S(O) 2 -CH 3 or alternatively, two R 10taken together with their intervening atoms form cyclohexane, 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.

[0071] In a seventeenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 2 is H or C 1-3 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, fifteenth, or sixteenth embodiment.

[0072] In an eighteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 2 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, or sixteenth embodiment.

[0073] In a nineteenth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 1 and R 2 together with their intervening atoms form a ring B selected from 3- to 7-membered monocyclic heterocyclyl and 9- to 10-membered bicyclic heterocyclyl, and ring B is selected from 1 to 3 R 200and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment.

[0074] In a twentieth embodiment of the present disclosure, for the compound according to the sixteenth embodiment, or a pharma- ceutically acceptable salt thereof, ring B is represented by the following formula: [ka] wherein m is 0, 1, 2, or 3, and the definitions of the other variables are as defined in the nineteenth embodiment.

[0075] In a twenty-first embodiment of the present disclosure, for the compound according to the sixteenth or seventeenth embodiment, or a pharma- ceutically acceptable salt thereof, R 200 is halo or C optionally substituted with 1 to 3 halogens 1-6 alkyl, and the definitions of the other variables are as defined in the nineteenth or twentieth embodiment.

[0076] In a twenty-second embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety, BTK, of formula (A) is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein X is O, and the other variables are as defined in the first, second, or third embodiment.

[0077] In a twenty-third embodiment of the present disclosure, for the compound according to the nineteenth embodiment, or a pharma- ceutically acceptable salt thereof, R 1 1 to 3 R 10 and wherein the definitions of the other variables are as defined in the twenty-second embodiment.

[0078] In a twenty-fourth embodiment of the present disclosure, for the compound according to the nineteenth embodiment, or a pharma- ceutically acceptable salt thereof, R 1is pyrrolidinyl, piperidinyl, or piperazinyl, each of which may be one or three R 10 and the definitions of the other variables are as defined in the twenty-second embodiment.

[0079] In a twenty-fifth embodiment of the present disclosure, for a compound according to the nineteenth, twentieth, or twenty-first embodiment, or a pharma- ceutically acceptable salt thereof, R 10 For each occurrence, independently, -OR 10a or C optionally substituted with 1 to 3 halogens 1-6 is alkyl, R 10a is C 1-6 alkyl, and the other variables are as defined in the twenty-second, twenty-third, or twenty-fourth embodiment.

[0080] In a twenty-sixth embodiment of the present disclosure, for a compound according to the nineteenth, twentieth, or twenty-first embodiment, or a pharma- ceutically acceptable salt thereof, R 10 -CH 2 -C(CH 3 ) 3 , -CH 2 -CF 3 , and -OC(CH 3 ) 3 and the definitions of the other variables are as defined in the twenty-second, twenty-third, or twenty-fourth embodiment.

[0081] In a twenty-seventh embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 3 is H or C 1-4 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, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment.

[0082] In a twenty-eighth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 3 is H, 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.

[0083] In a twenty-ninth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 4 , H, C 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, and -OR 4a Selected from R 4a , H, C 1-6 Alkyl, or C 1-6 and 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, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment.

[0084] In a thirtieth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 4 , H, C 1-4 Alkyl, halogen, and -OR 4a Selected from R4a is C 1-4 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, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment.

[0085] In a thirty-first embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 4 is H, F, Cl, -CH 3 , CH(CH 3 ) 2 , and -OCH 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, or thirtieth embodiment.

[0086] In a thirty-second embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 3 and R 4 together with their intervening atoms form ring D, which is a 7-membered monocyclic heterocyclyl having one heteroatom selected from N and O, and ring D is R 300 and optionally substituted with the other variable definitions 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.

[0087] In a thirty-third embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein ring D is an oxepane or azepane, each of which is selected from the group consisting of R 300 Optionally substituted with R 300 is C 1-6 alkyl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 6-membered monocyclic heterocyclyl, 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.

[0088] In a thirty-fourth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 5 , H, C 1-4 alkyl, or halogen, 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, or thirty-third embodiment.

[0089] In a thirty-fifth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 5is H, 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, thirtieth, thirty-first, thirty-second, or thirty-third embodiment.

[0090] In a thirty-sixth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 6 , H, C 1-4 alkyl, or halogen, 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, or thirty-fifth embodiment.

[0091] In a thirty-seventh embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (I), (II), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or (IIA), wherein R 6 -H, -CH 3 , or F, 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, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment.

[0092] In a thirty-eighth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (III) or formula (IV), [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is phenyl, 4- to 6-membered saturated monocyclic heterocyclyl, or 5- or 6-membered heteroaryl, each of which is selected from 1 to 3 R 10 Optionally substituted with R 10 represents, independently at each occurrence, a halogen, -OR 10a , -S(O) 2 R 10a , C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is one to three R 15 or alternatively two R 10 Together with their intervening atoms, they form one to three R 15 forming a 5- to 7-membered monocyclic carbocyclyl optionally substituted by R 10a is H or C in each occurrence. 1-6 is alkyl, R 15 may, in each occurrence, independently represent C 1-6 Alkyl, halogen, -OR 15a , and C 3-6 cycloalkyl; R 15 C represented by 1-6 Alkyl and C 3-6 Cycloalkyl is one to three R 15a Optionally replaced by R 15a is H, halogen, and C optionally substituted with 1 to 3 halogens 1-3 alkyl, and the definitions of the other variables are as defined in the first embodiment.

[0093] In a thirty-ninth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (III) or formula (IV), wherein R 1 is phenyl, isoxazolyl, 1,2,4-oxadiazolyl, pyrazolyl, triazolyl, or azetidinyl, each of which is selected from one to three R 10 and the definitions of the other variables are as defined in the thirty-eighth embodiment.

[0094] In a fortieth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (III) or formula (IV), wherein R 1 is phenyl, 1,2,4-oxadiazolyl, pyrazolyl, or azetidinyl, each of which is selected from one to three R 10 and the definitions of the other variables are as defined in the thirty-eighth embodiment.

[0095] In a forty-first embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (III) or formula (IV), wherein R 1 is the following formula: [ka] is represented by R 10 is C optionally substituted with 1 to 3 halogens 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-6 cycloalkyl, n is 0 or 1, and the definitions of the other variables are as defined in the thirty-eighth embodiment.

[0096] In a forty-second embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (III) or formula (IV), wherein R 1 is the following formula: [ka] is represented by R 10 is C optionally substituted with 1 to 3 halogens 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-6 cycloalkyl, and the definitions of the other variables are as defined in the thirty-eighth embodiment.

[0097] In a forty-third embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (III) or formula (IV), wherein R 10 is -C(CH 3 ) 3 or [ka] and the other variable definitions are as defined in the thirty-eighth, thirty-ninth, fortieth, forty-first, or forty-second embodiment.

[0098] In a forty-fourth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (III) or formula (IV), wherein R 4 is C 1-3 alkyl or halogen, and the definitions of the other variables are as defined in the thirty-eighth, thirty-ninth, fortieth ... alkyl, or halogen, and the definitions of the other variables are as defined in the thirty-eighth, thirty-ninth, thirty-ninth, fortieth, fortieth, fortieth, fortieth,

[0099] In a forty-fifth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, the Btk binding or targeting moiety of formula (A), BTK, is represented by formula (III) or formula (IV), wherein R 4 -CH 3 or F, and the definitions of the other variables are as defined in the thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, or forty-fourth embodiment.

[0100] B. Degradation Signaling Moiety (DSM) The degradation signaling moiety (DSM) in the compound of formula (A) or a pharma- ceutically acceptable salt thereof may be any suitable moiety that binds to an E3 ubiquitin ligase (e.g., a cereblon protein), such as those described in WO2020 / 210630 entitled "Tricyclic Degraders of Ikaros and Aiolos"; WO2020 / 181232 entitled "Heterocyclic Compounds for Medical Treatment"; WO2020 / 132561 entitled "Targeted Protein Degradation"; WO2019 / 204354 entitled "Spirocyclic Compounds"; WO2019 / 099868 entitled "Degraders and Degrons for Targeted Protein Degradation"; WO2018 / 237026 entitled "N / O-Linked Degrons and Degronimers for Protein Degradation"; WO2018 / 237026 entitled "Amine-Linked C3-Glutarimide The degronimer may be a degron or an E3 ubiquitin ligase binding or targeting moiety described in WO2017 / 197051 entitled "Degronimers for Target Protein Degradation"; WO2017 / 197055 entitled "Heterocyclic Degronimers for Target Protein Degradation"; WO2017 / 197036 entitled "Spirocyclic Degronimers for Target Protein Degradation"; WO2017 / 197046 entitled "C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation"; and WO2017 / 197056 entitled "Bromodomain Targeting Degronimers for Target Protein Degradation."Other degradation signaling moieties or E3 ubiquitin ligase binding or targeting moieties that can be used include those described in WO2015 / 160845, WO2016 / 105518, WO2016 / 118666, WO2016 / 149668, WO2016 / 197032, WO2016 / 197114, WO2017 / 007612, WO2017 / 011371, WO2017 / 011590, WO2017 / 030814, WO2017 / 046036, WO2017 / 176708, WO2017 / 176957, WO2017 / 1804 17, WO2018 / 053354, WO2018 / 071606, WO2018 / 102067, WO2018 / 102725, WO2018 / 118598, WO2018 / 119357, WO2018 / 119441, WO2018 / 119448, WO2018 / 140809, WO2018 / 144649, WO2018 / 119448, WO2018 / 226542, WO2019 / 023553, WO2019 / 195201, WO2019 / 199816, and WO2019 / 099926. The entire teachings of the above-referenced PCT publications are hereby incorporated by reference.

[0101] In a forty-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): [ka] During the ceremony, [ka] represents the bond to the linker L, [ka] represents an optional double bond, and Y represents CR D1 or N and Z 1 is a bond, -NR D6 -, -O-, -CH 2 -, [ka] is selected from [ka] But, G 1 represents a bond to [ka] represents a bond to Y, and G 1 is selected from a bond, a 3- to 7-membered monocyclic carbocyclyl, a 5- to 6-membered monocyclic heterocyclyl, and a 9- to 14-membered bicyclic or tricyclic heterocyclyl; G 1 The 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heterocyclyl, and 9- to 14-membered bicyclic or tricyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R D4 Optionally replaced by G 2 But, binding, [ka] 3-7 membered monocyclic carbocyclyl, Het, [ka] is selected from [ka] represents the bond to the linker L, [ka] But, G 1 represents a bond to G 2 and Het each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R D5 Het is 4-7 membered monocyclic heterocyclyl or 9-11 membered bicyclic heterocyclyl; R D1 , R D2 , and R D3 each independently represents H or C1-6 alkyl or alternatively, R D1 and R D3 When any double bond is absent, together with the intervening atoms, R D4 is, for each occurrence, independently, H, halogen, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 or alternatively, two R D4 together with the intervening atoms form a 4- to 6-membered monocyclic heterocyclyl; R D5 may, in each occurrence, independently be H, a halogen, OH, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 or alternatively, two R D5 together with the intervening atoms form a 3- to 6-membered monocyclic carbocyclyl or a 4- to 6-membered monocyclic heterocyclyl; R D6 But H or C 1-3 Alkyl, except that Z 1 , G 1 and G 2 is not a bond, 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-two, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, fortieth, fortieth, fortieth,

[0102] In a forty-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), wherein Y is CR D1 or N and Z 1 But, binding, [ka] is selected from the group consisting of [ka] But, G 1 represents a bond to [ka] represents a bond to Y, and G 1 is selected from a bond, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heterocyclyl, and 9- to 11-membered bicyclic heterocyclyl; G 1 The 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heterocyclyl, and 9- to 11-membered bicyclic heterocyclyl each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R D4 Optionally replaced by G 2 But, binding, [ka] 3-7 membered monocyclic carbocyclyl, Het, [ka] is selected from the group consisting of [ka] represents the bond to the linker L, [ka] But, G 1 represents a bond to G 2 and Het each have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R D5 Het is 4-7 membered monocyclic heterocyclyl or 9-11 membered bicyclic heterocyclyl; R D1 , R D2 , and R D3 each independently represents H or C 1-6alkyl or alternatively, R D1 and R D3 When any double bond is absent, together with the intervening atoms, R D4 is, for each occurrence, independently, H, halogen, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 or alternatively, two R D4 together with the intervening atoms form a 4- to 6-membered monocyclic heterocyclyl; R D5 may, in each occurrence, independently be H, a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 1-4 or alternatively, two R D5 together with the intervening atoms form a 3- to 6-membered monocyclic carbocyclyl or a 4- to 6-membered monocyclic heterocyclyl; R D6 But H or C 1-3 Alkyl, except that Z 1 , G 1 and G 2 is not a bond, 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-two, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, fortieth, fortieth, fortieth, fortieth,

[0103] In a forty-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 (DI), (D-II), (D-III), or (D-IV), [ka] In the formula, Het 1is the expression: [ka] is represented by [ka] is the Ar of formula (DI) 1 Or C of formula (D-IV) 1-4 indicates the point of attachment to the alkyl group, p is 1 or 2, q is 1, 2, or 3, Z 2 is CH or N, and Z 2a is CH 2 or O and R D5a and R D5b is, in each occurrence, independently: H, C 1-4 Alkyl, halogen, OH, or C 1-4 Alkoxy or R D5a and R D5b together with the carbon atom to which they are attached, C 3-6 Form a cycloalkyl, R D5c and R D5d is, in each occurrence, independently: H, C 1-4 Alkyl, halogen, OH, or C 1-4 Alkoxy or R D5a and R D5c Together, -(CH 2 ) t -, t is 1, 2 or 3, Ar 1 is phenyl, phenyl fused with a 5- to 7-membered heterocyclyl, naphthalenyl fused with a 5- to 7-membered heterocyclyl, a 5- to 6-membered monocyclic heteroaryl, or a 9- to 10-membered bicyclic heteroaryl, and each of the phenyl, phenyl fused with a 5- to 7-membered heterocyclyl, the 5- to 6-membered monocyclic heteroaryl, and the 9- to 10-membered bicyclic heteroaryl may each be selected from the group consisting of 1 to 3 R D4 , optionally replaced by Z 1 is a bond, NR D6 , or O and R D6 is H or C 1-4alkyl, and the definitions of the other variables are as defined in the 46th embodiment.

[0104] In a forty-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 (DI), (D-II), (D-III), or (D-IV), and Het 1 is expressed by the following formula: [ka] [ka] Ar 1 p is 1 or 2, q is 1, 2, or 3, and Z 2 is CH or N, and Z 2a is CH 2 or O and R D5a and R D5b is, in each occurrence, independently: H, C 1-4 alkyl, or halogen, or R D5a and R D5b together with the carbon atom to which they are attached, C 3-6 Form a cycloalkyl, R D5c and R D5d is, in each occurrence, independently: H, C 1-4 alkyl, or halogen, or R D5a and R D5c Together, -(CH 2 ) t -, t is 1, 2 or 3, Ar 1 is phenyl, phenyl fused with a 5- to 7-membered heterocyclyl, 5- to 6-membered monocyclic heteroaryl, or 9- to 10-membered bicyclic heteroaryl, and each of the phenyl, phenyl fused with a 5- to 7-membered heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 9- to 10-membered bicyclic heteroaryl is selected from the group consisting of 1 to 3 R D4 , optionally replaced by Z 1 is a bond, NR D6 , or O and RD6 is H or C 1-4 alkyl, and the definitions of the other variables are as defined in the 46th embodiment.

[0105] In a fiftieth 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 (DI), (D-II), (D-III), or (D-IV), and Ar 1 is phenyl, pyrazole, pyrazolo-pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, benz[cd]indol-2(1H)-onyl, imidazo-pyridinyl or indazolyl, each of which is selected from one to three R D4 and the definitions of the other variables are as defined in the forty-eighth or forty-ninth embodiment.

[0106] In a fifty-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 (DI), (D-II), (D-III), or (D-IV), and Ar 1 is phenyl, pyrazole, pyridinyl, pyrimidinyl, pyridazinyl, or indazolyl, each of which is selected from 1 to 3 R D4 and the definitions of the other variables are as defined in the forty-eighth or forty-ninth embodiment.

[0107] In a fifty-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 (DI), (D-II), (D-III), or (D-IV), and Ar 1 is the expression: [ka] During the ceremony, [ka] Het 1 represents a bond to [ka] is Z 1 represents a bond to R D4 may, in each occurrence, independently represent C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and C 1-4 alkoxy, r is 0, 1, or 2, and the other variables are as defined in the forty-eighth embodiment. In a fifty-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 (DI), (D-II), (D-III), or (D-IV), and Ar 1 is the expression: [ka] is represented by During the ceremony, [ka] Het 1 represents a bond to [ka] is Z 1 represents a bond to R D4 For each occurrence, independently, C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, and C 1-4 alkoxy, r is 0, 1, or 2, and the definitions of the other variables are as defined in the forty-eighth or forty-ninth embodiment.

[0108] In a fifty-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 (DI), (D-II), (D-III), or (D-IV), and R D4 is, for each occurrence independently, -CH 3 , F, Cl, CF 3 , and -OCH 3and the definitions of the other variables are as defined in the 52nd or 53rd embodiment.

[0109] In a 55th 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 (DI), (D-II), (D-III), or (D-IV), where (i) p is 1 and q is 1, (ii) p is 2 and q is 2, or (iii) p is 1 and q is 3, and the definitions of the other variables are as defined in the 48th, 49th, 50th, 51st, 52nd, 53rd, or 54th embodiment.

[0110] In a fifty-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 (DI), (D-II), (D-III), or (D-IV), wherein Het 1 is azetidine, piperidine, piperazine, pyrrolidine, azabicyclo[3.2.1]octane, or azaspiro[2.5]octane, each of which is C 1-3 Alkyl, halogen, OH, and C 1-3 Optionally substituted with 1 to 3 substituents independently selected from alkoxy, or two of the substituents together with the carbon atom to which they are attached are C 3-6 and forming a cycloalkyl, and the definitions of the other variables are as defined in the 48th, 49th, 50th, 51st, 52nd, 53rd, or 54th embodiment.

[0111] In a fifty-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 (DI), (D-II), (D-III), or (D-IV), wherein Het 1 is azetidine, piperidine, piperazine, pyrrolidine, azabicyclo[3.2.1]octane, or azaspiro[2.5]octane, each of which is C 1-3Optionally substituted with 1 to 3 substituents independently selected from alkyl and halogen, or two of the substituents together with the carbon atom to which they are attached are C 3-6 and forming a cycloalkyl, and the definitions of the other variables are as defined in the 48th, 49th, 50th, 51st, 52nd, 53rd, or 54th embodiment.

[0112] In a fifty-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 (DI), (D-II), (D-III), or (D-IV), and the substituents are independently -CH 3 , F, Cl, OH, and -OCH 3 and the definitions of the other variables are as defined in the 56th or 57th embodiment.

[0113] In a fifty-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 (DI), (D-II), (D-III), or (D-IV), and the substituents are independently -CH 3 , F, and Cl, and the definitions of the other variables are as defined in the 56th or 57th embodiment.

[0114] In a sixtieth 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 (DI), (D-II), (D-III), or (D-IV), and Het 1 is the following formula: [ka] and the definitions of the other variables are as defined in the forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third, or fifty-fourth embodiment.

[0115] In a sixty-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 (DI), (D-II), (D-III), or (D-IV), and Het 1 is the following formula: [ka] and the definitions of the other variables are as defined in the forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third, or fifty-fourth embodiment.

[0116] In a sixty-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), or (D-IV), and R D1 , R D2 , R D3 are each independently H or -CH 3 and the other variable definitions are as defined in the 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, or 61st embodiment.

[0117] In a sixty-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), or (D-IV), and R D1 , R D2 , R D3 is independently at each occurrence H, and the definitions of the other variables are as defined in the 62nd embodiment.

[0118] In a sixty-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), or (D-IV), and R D6 is H or -CH 3and the other variable definitions are as defined in the 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, or 63rd embodiment.

[0119] In a sixty-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), or (D-IV), and R D6 is H, and the definitions of the other variables are as defined in the 64th embodiment.

[0120] In a sixty-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 represented by formula (D-IA1-1), (D-IA3), (D-IIA), (D-IIIA), or (D-IVA), [ka] In the formula, Ar 1 is phenyl, pyrazole, pyrazolo-pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, benz[cd]indol-2(1H)-onyl, imidazo-pyridinyl, or indazolyl, each of which is selected from the group consisting of halogen and C 13 optionally substituted with 1 or 2 substituents independently selected from alkyl; Z 1 is a bond, NH, or O, and R D5a and R D5b are each independently H, OH, F, or -OCH 3 and R D6 is H or CH 3 And Het 1 is piperidine, piperazine, or pyrrolidine, and Y is CH, C(CH 3 ), or -N-, and the definitions of the other variables are as defined in the 46th embodiment.

[0121] In a sixty-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 represented by formula (D-IA1), (D-IA2), (D-IIA), (D-IIIA), or (D-IVA), [ka] In the formula, Ar 1 is phenyl, pyrazole, pyridinyl, pyrimidinyl, pyridazinyl, or indazolyl, each of which is optionally substituted with one or two halogens; Z 1 is a bond, NH, or O, and R D6 is H or CH 3 And Het 1 is piperidine, piperazine, or pyrrolidine, and Y is CH, C(CH 3 ), or -N-, and the definitions of the other variables are as defined in the 47th embodiment.

[0122] In a sixty-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 represented by formula (D-IA1), (D-IA1-1), (D-IA2), (D-IA3), (D-IIA), (D-IIIA), or (D-IVA), and Ar 1 is phenyl, pyrazolo-pyridinyl, pyridinyl, benzisoxazolyl, benz[cd]indol-2(1H)-onyl, imidazo-pyridinyl, or indazolyl, each of which is selected from the group consisting of halogen and C 1-3 Optionally substituted with 1 or 2 substituents independently selected from alkyl, and the definitions of the other variables are as defined in the 66th or 67th embodiment.

[0123] In a sixty-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 represented by formula (D-IA1), (D-IA1-1), (D-IA2), (D-IA3), (D-IIA), (D-IIIA), or (D-IVA), and Ar1 is phenyl or indazolyl, and the definitions of the other variables are as defined in the 66th or 67th embodiment.

[0124] In a seventieth 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 represented by formula (D-IA1), (D-IA1-1), (D-IA2), (D-IA3), (D-IIA), (D-IIIA), or (D-IVA), and Ar 1 is the following formula: [ka] is represented by [ka] is Z 1 and the definitions of the other variables are as defined in the 67th or 68th embodiment.

[0125] In a seventy-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 represented by formula (D-IA1), (D-IA1-1), (D-IA2), (D-IA3), (D-IIA), (D-IIIA), or (D-IVA), and Ar 1 is the following formula: [ka] is represented by [ka] is Z 1 and the definitions of the other variables are as defined in the 67th or 68th embodiment.

[0126] In a seventy-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 represented by formula (D-IA1), (D-IA1-1), (D-IA2), (D-IA3), (D-IIA), (D-IIIA), or (D-IVA); 1 is the following formula: [ka] and the definitions of the other variables are as defined in the 66th, 67th, 68th, 69th, 70th, or 71st embodiment.

[0127] In a seventy-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 represented by formula (D-IA1), (D-IA1-1), (D-IA2), (D-IA3), (D-IIA), (D-IIIA), or (D-IVA); 1 is the following formula: [ka] and the definitions of the other variables are as defined in the 66th, 67th, 68th, 69th, 70th, or 71st embodiment.

[0128] In a seventy-fourth embodiment of the present disclosure, for compounds of formula (A), or a pharma- ceutically acceptable salt thereof, DSM is represented by any one of the following attached to L: [ka] wherein Y is CH or N, 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, fortieth, fortieth, fortieth, fortieth, fortieth,

[0129] In a seventy-fifth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, DSM is a degradation signaling moiety represented by one of the following attached to L: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, 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 ...

[0130] In a seventy-sixth embodiment of the present disclosure, the compound of formula (A), or a pharma- ceutically acceptable salt thereof, is represented by one of the following formulas (A-Ia-1), (A-Ib), (A-Ic), (A-II), (A-III), or (A-IV): [ka] [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is phenyl, 1,2,4-oxadiazolyl, pyrazolyl, triazolyl, or azetidinyl, each of which is selected from one to three R 10 Optionally replaced by R 10 is C optionally substituted with 1 to 3 halogens 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-6 cycloalkyl, R 4 , H, C 1-4 Alkyl, halogen, or -OR 4a Selected from R 4a is C 1-4 Alkyl, Ar 1is phenyl, pyrazole, pyrazolo-pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, benz[cd]indol-2(1H)-onyl, imidazo-pyridinyl, or indazolyl, each or each of which is optionally substituted with one or two halogens; Z 1 is a bond, CH 2 , NH, or O; R D5a and R D5b are each independently H, OH, F, or -OCH 3 and R D6 is H or CH 3 And Het 1 is piperidine or piperazine, and Y is CH, C(CH 3 ), or -N-, and the definitions of the other variables are as defined in the first embodiment.

[0131] In a seventy-seventh embodiment of the present disclosure, the compound of formula (A), or a pharma- ceutically acceptable salt thereof, is represented by one of the following formulas (A-Ia), (A-Ib), (A-II), (A-III), or (A-IV): [ka] [ka] In the formula, R 1 is phenyl, 1,2,4-oxadiazolyl, pyrazolyl, or azetidinyl, each of which is selected from 1 to 3 R 10 Optionally replaced by R 10 is C optionally substituted with 1 to 3 halogens 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-6 cycloalkyl, R 4 , H, C 1-4 Alkyl, halogen, or -OR 4a Selected from R 4a is C 1-4 Alkyl, Ar 1is phenyl, pyrazole, pyridinyl, pyrimidinyl, pyridazinyl, or indazolyl, each or each of which is optionally substituted with one or two halogens; Z 1 is a bond, NH, or O, and R D6 is H or CH 3 And Het 1 is piperidine or piperazine, and Y is CH, C(CH 3 ), or -N-, and the definitions of the other variables are as defined in the first embodiment.

[0132] In a seventy-eighth embodiment of the present disclosure, the compound of formula (A), or a pharma- ceutically acceptable salt thereof, is represented by one of the following formulas (A-Ia-1), (A-Ib), (A-Ic), (A-II), (A-III), or (A-IV), wherein R 1 is expressed by the following formula: [ka] Ar 1 teeth, [ka] where: [ka] is Z 1 represents a bond to Het 1 teeth, [ka] where: [ka] is C 1-4 represents a bond to an alkyl, and the other variables are as defined in the 76th or 77th embodiment.

[0133] In a seventy-ninth embodiment of the present disclosure, the compound of formula (A), or a pharma- ceutically acceptable salt thereof, is represented by one of the following formulas (A-Ia), (A-Ia-1), (A-Ib), (A-Ic), (A-II), (A-III), or (A-IV), wherein R 1 is the expression: [ka] is represented by Ar 1 teeth, [ka] where: [ka] is Z 1 represents a bond to Het 1 teeth, [ka] and R 10 is C optionally substituted with 1 to 3 halogens 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-6 cycloalkyl, and the definitions of the other variables are as defined in the 76th or 77th embodiment.

[0134] In an eightieth embodiment of the present disclosure, the compound of formula (A), or a pharma- ceutically acceptable salt thereof, is represented by one of formulas (A-Ia), (A-Ia-1), (A-Ib), (A-Ic), (A-II), (A-III), or (A-IV), wherein R 10 is -C(CH 3 ) 3 or [ka] and R 4 is F or -CH 3and Y is CH or N, and the definitions of the other variables are as defined in the 76th, 77th, 78th, or 79th embodiment.

[0135] C. Linker In an eighty-first embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, L is represented by the following formula (L-1), (L-2), (L-3), (L-4), or (L-5): [ka] During the ceremony, Ar 2 is phenyl, naphthyl, phenyl fused to a 5- or 6-membered heterocycle, 5- or 6-membered monocyclic heteroaryl, or 9-10-membered bicyclic heteroaryl, each of which is selected from 1 to 3 R L1 optionally replaced by G 3 But, bond, C 1-6 Alkyl, -O-, or -OC 1-6 alkyl-O-; Z 3 is a bond, -NR L2 -, -O-, -C(=O)-, C 4-6 cycloalkyl, phenyl, 4- to 6-membered saturated monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, each of which is selected from the group consisting of 1 to 3 R L1 optionally replaced by G 4 But bond or C 1-8 is alkyl, R L1 may, in each occurrence, independently be H, a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is an alkoxy; R L2 But H or C 1-3 Alkyl, Alk 1 But, bond, C 1-4 Alkyl, C 2-4Alkynyl, or C 3-6 is cycloalkyl, 1-4 Alkyl, C 2-4 Alkynyl, and C 3-6 each cycloalkyl is optionally substituted with 1 to 3 halogens; Z 4 is a bond, -O-, -NR L2 or a 4-10 membered saturated monocyclic or bicyclic heterocyclyl; Alk 2 is a bond or C optionally substituted with 1 to 3 halogens 1-8 is alkyl, G 5 is a bond, phenyl, naphthyl, 5- or 6-membered heteroaryl, 4- to 10-membered monocyclic or bicyclic saturated heterocyclyl, 3- to 10-membered monocyclic or bicyclic saturated carbocyclyl, or -(O-CH 2 -CH 2 ) t -, wherein the phenyl, naphthyl, 5- or 6-membered heteroaryl, 4- to 10-membered monocyclic or bicyclic saturated heterocyclyl, and 3- to 10-membered monocyclic and bicyclic saturated carbocyclyl are each independently selected from 1 to 3 R L1 and t is an integer from 2 to 8; Alk 3 is a bond or C optionally substituted with 1 to 3 halogens 1-6 Alkyl or C 3-6 cycloalkyl, Alk 4 is a bond or C optionally substituted with 1 to 3 halogens 1-6 is alkyl, G 6 But, bond, C 1-6 Alkyl, or [ka] where: [ka] But, Het 2 represents a bond to Het 2is a 4-10 membered saturated monocyclic or bicyclic heterocyclyl; G 7 But, C 3-7 is cycloalkyl, [ka] represents the connection to the DSM, [ka] represents binding to BTK, while However, for formula (L-2), Alk 1 and Alk 2 In the formula (L-3), one of the groups is not a bond, and Alk 3 , G 5 , and Alk 4 is not a bond, and the definitions of the other variables are as follows: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, As defined in the 40th, 41st, 42nd, 43rd, 44th, 45th, 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, 64th, 65th, 66th, 67th, 68th, 69th, 70th, 71st, 72nd, 73rd, 74th, 75th, 76th, 77th, 78th, 79th, or 80th embodiment.

[0136] In an eighty-second embodiment of the present disclosure, for compounds of formula (A), or a pharma- ceutically acceptable salt thereof, L is represented by the following formula (L-1), (L-2), (L-3), or (L-4), wherein: Ar 2 is phenyl, naphthyl, phenyl fused to a 5- or 6-membered heterocycle, 5- or 6-membered monocyclic heteroaryl, or 9-10-membered bicyclic heteroaryl, each of which is selected from 1 to 3 R L1Optionally replaced by G 3 But, bond, C 1-6 Alkyl, -O-, or -OC 1-6 alkyl-O-; Z 3 is a bond, -NR L2 -, -O-, -C(=O)-, C 4-6 cycloalkyl, phenyl, 4- to 6-membered saturated monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, each of which is selected from the group consisting of 1 to 3 R L1 Optionally replaced by G 4 But bond or C 1-8 is alkyl, R L1 is, for each occurrence independently, H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 Alkoxy, R L2 But H or C 1-3 Alkyl, Alk 1 But, bond, C 1-4 Alkyl, C 2-4 Alkynyl, or C 3-6 is cycloalkyl, 1-4 Alkyl, C 2-4 Alkynyl, and C 3-6 each cycloalkyl is optionally substituted with 1 to 3 halogens; Z 4 is a bond, -O-, -NR L2 or 4-10 membered saturated monocyclic or bicyclic heterocyclyl; 2 is a bond or C optionally substituted with 1 to 3 halogens 1-8 is alkyl, G 5 is a bond, phenyl, naphthyl, 5- or 6-membered heteroaryl, 4- to 10-membered monocyclic or bicyclic saturated heterocyclyl, 3- to 10-membered monocyclic or bicyclic saturated carbocyclyl, or -(O-CH 2 -CH 2 ) t-, and the phenyl, naphthyl, 5- or 6-membered heteroaryl, 4- to 10-membered monocyclic or bicyclic saturated heterocyclyl, and 3- to 10-membered monocyclic and bicyclic saturated carbocyclyl are each selected from 1 to 3 R L1 and t is an integer from 2 to 8; 3 is a bond or C optionally substituted with 1 to 3 halogens 1-6 Alkyl or C 3-6 cycloalkyl, Alk 4 is a bond or C optionally substituted with 1 to 3 halogens 1-6 is alkyl, G 6 But, bond, C 1-6 Alkyl, or [ka] where: [ka] But, Het 2 represents a bond to Het 2 is a 4-10 membered saturated monocyclic or bicyclic heterocyclyl; [ka] represents the connection to the DSM, [ka] represents a bond to BTK, with the proviso that for formula (L-2), Alk 1 and Alk 2 In the formula (L-3), one of the groups is not a bond, and Alk 3 , G 5 , and Alk 4is not a bond, and the definitions of the other variables are as follows: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, As defined in the 40th, 41st, 42nd, 43rd, 44th, 45th, 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, 64th, 65th, 66th, 67th, 68th, 69th, 70th, 71st, 72nd, 73rd, 74th, 75th, 76th, 77th, 78th, 79th, or 80th embodiment.

[0137] In an eighty-third embodiment of the present disclosure, for compounds of formula (A), or pharma- ceutically acceptable salts thereof, L is represented by the following formula (L-1), (L-2), (L-3), (L-4), or (L-5), wherein Ar 2 Phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, thiophenyl, imidazolyl, oxazolyl, imidazole thiazolyl, imidazopyridinyl, indazolyl, thienopyridinyl, 2λ 2 -isoindolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or 3,4-dihydro-1H-2λ 2 -isoquinolinyl, each of which is selected from the group consisting of one or two R L1 , optionally replaced by Z 3 is a bond, -NR L2 -, -O-, -C(=O)-, cyclobutyl, piperazinyl, or pyrazolyl; G 5 is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl, azetidinyl, oxazolyl, pyrazolyl, or pyridinyl, each of which is selected from one or two R L1 , optionally replaced by Z 4 is a bond, -O-, -NR L2, azaspiro[3.3]heptanyl, or piperazinyl; Het 2 is azaspiro[5.5]undecanyl, azaspiro[2.4]heptanyl, azaspiro[4.4]nonanyl, azaspiro[3.4]octanyl, 6-oxa-azaspiro[3.4]octanyl, hexahydro-2H-thieno[2,3-c]pyrrolyl 1,1-dioxide, pyrrolidinyl, morpholinyl, piperidinyl, or azepanyl, and the other variables are as defined in the 81st or 82nd embodiment.

[0138] In an eighty-fourth embodiment of the present disclosure, for compounds of formula (A), or pharma- ceutically acceptable salts thereof, L is represented by the following formula (L-1), (L-2), (L-3), (L-4), or (L-5), wherein Ar 2 However, phenyl, naphthyl, pyridinyl, pyrimidinyl, thiazolyl, thiophenyl, imidazolyl, oxazolyl, imidazole thiazolyl, imidazopyridinyl, indazolyl, thienopyridinyl, 2λ 2 -isoindolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or 3,4-dihydro-1H-2λ 2 -isoquinolinyl, each of which is selected from the group consisting of one or two R L1 , optionally replaced by Z 3 is a bond, -NR L2 -, -O-, -C(=O)-, cyclobutyl, piperazinyl, or pyrazolyl; G 5 is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl, azetidinyl, oxazolyl, pyrazolyl, or pyridinyl, each of which is selected from one or two R L1 , optionally replaced by Z 4 is a bond, -O-, -NR L2 , azaspiro[3.3]heptanyl, or piperazinyl; Het 2is azaspiro[5.5]undecanyl, azaspiro[2.4]heptanyl, azaspiro[4.4]nonanyl, azaspiro[3.4]octanyl, 6-oxa-azaspiro[3.4]octanyl, hexahydro-2H-thieno[2,3-c]pyrrolyl 1,1-dioxide, pyrrolidinyl, morpholinyl, piperidinyl, or azepanyl, and the other variables are as defined in the 81st or 82nd embodiment.

[0139] In an eighty-fifth embodiment of the present disclosure, for compounds of formula (A), or pharma- ceutically acceptable salts thereof, L is represented by the following formula (L-1), (L-2), (L-3), (L-4), or (L-5), wherein R L1 is, in each occurrence, independently, F, Cl, CH 3 , or OCH 3 and R L2 is H or CH 3 and the definitions of the other variables are as defined in the 81st, 82nd, 83rd, or 84th embodiment.

[0140] In an eighty-sixth embodiment of the present disclosure, for compounds of formula (A), or a pharma- ceutically acceptable salt thereof, L is represented by the following formula: [ka] In the formula, Ar 2 is phenyl fused to a 5-membered heterocycle, a 6-membered saturated monocyclic heterocyclyl, or a 6-membered heteroaryl, each of which is optionally substituted with one or two halogens; s1 is 0 or an integer from 1 to 4; s2 is 0 or an integer from 1 to 4; s3 is an integer from 1 to 3; and s4 and s5 are each independently 0 or an integer from 1 to 3, with the proviso that at least one of s4 and s5 is not 0; and the other variables are as defined in the 81 embodiment.

[0141] In an eighty-seventh embodiment of the present disclosure, for compounds of formula (A), or a pharma- ceutically acceptable salt thereof, L is represented by the following formula: [ka] In the formula, Ar 2 is phenyl fused to phenyl, a 5-membered heterocycle, a 6-membered saturated monocyclic heterocyclyl, or a 6-membered heteroaryl, each of which is optionally substituted with one or two halogens; s1 is 0 or an integer from 1 to 4; s2 is 0 or an integer from 1 to 4; and the other variables are as defined in the 81st embodiment.

[0142] In an eighty-eighth embodiment of the present disclosure, for compounds of formula (A), or a pharma- ceutically acceptable salt thereof, L is represented by formula (L-1A), (L-1B), (L-1C), or (L-2A), and Ar 2 is piperazinyl, phenyl, pyridine, pyrimidine, or 2λ 2 -isoindoline, each of which is optionally substituted with one or two F, and the definitions of the other variables are as defined in the 86th or 87th embodiment.

[0143] In an eighty-ninth embodiment of the present disclosure, for a compound of formula (A), or a pharma- ceutically acceptable salt thereof, wherein L is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] wherein: [ka] represents the bond to the DSM, [ka] represents binding to BTK, and other variable definitions are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , as defined in the 42nd, 43rd, 44th, 45th, 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, 64th, 65th, 66th, 67th, 68th, 69th, 70th, 71st, 72nd, 73rd, 74th, 75th, 76th, 77th, 78th, 79th, or 80th embodiment.

[0144] In a 90th embodiment, the compound has the formula: [ka] or or a pharma- ceutically acceptable salt thereof, wherein R 1 is 1,2,4-oxadiazolyl or triazolyl, each of which is R 10 is replaced by R 10 But, C 1-4 alkyl, Y is N or CH, Ar 1is indozolyl or benzisoxazolyl, each of which is halo and C 1-2 Optionally substituted with 1 or 2 substituents independently selected from alkyl.

[0145] In a 91st embodiment, the compound is represented by formula (AV) or a pharma- ceutically acceptable salt thereof, wherein R 1 but, [ka] and Ar 1 but, [ka] where: [ka] represents a bond to Y, and the definitions of the other variables are as defined in the 90th embodiment.

[0146] In a 92nd embodiment, the compound is represented by formula (AV) or a pharma- ceutically acceptable salt thereof, wherein R 10 is -C(CH 3 ) 3 and the definitions of the other variables are as defined in the 90th or 91st embodiment.

[0147] In a 93rd 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 300, or a pharma- ceutically acceptable salt thereof.

[0148] III. Pharmaceutical Compositions and Methods of Use Another aspect of the disclosure is a pharmaceutical composition comprising at least one compound described herein (e.g., a compound described in any one of the first to sixth embodiments above, or a pharma- ceutically acceptable salt thereof) and at least one pharma- ceutically acceptable carrier.

[0149] In some embodiments, a compound described herein (e.g., a compound described in any one of the first through sixth embodiments above, or a pharma- ceutically acceptable salt thereof) can be used to cause degradation of Btk protein. In some embodiments, a compound described herein (e.g., a compound described in any one of the first through sixth embodiments above, or a pharma- ceutically acceptable salt thereof) can be used to modulate (e.g., reduce) the level of Btk protein. In some embodiments, a compound described herein, or a pharma- ceutically acceptable salt thereof (e.g., a compound described in any one of the first through sixth embodiments above, or a pharma- ceutically acceptable salt thereof) can be used to modulate (e.g., decrease) the activity of Btk or otherwise affect the properties and / or behavior of Btk, such as stability, phosphorylation, kinase activity, interactions with other proteins, etc.

[0150] In some embodiments, the disclosure provides methods of reducing Btk protein levels and / or Btk enzyme 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 one of the first through sixth embodiments above, or a pharma- ceutically acceptable salt thereof).

[0151] One aspect of the disclosure includes a method of treating a disorder responsive to degradation of Btk and / or inhibition of Btk 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 one of the first to sixth embodiments above, or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition described herein.

[0152] In one embodiment, the present invention provides a method of treating autoimmune diseases, inflammatory diseases, and cancer in a subject in need of such treatment, comprising administering to the subject an effective amount of at least one compound described herein (e.g., a compound described in any one of the first to sixth embodiments above, or a pharma- ceutical composition described herein).

[0153] The term "autoimmune disorder" includes diseases or disorders involving an inappropriate immune response to natural antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, type 1 diabetes mellitus, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, 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. 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 invention provides methods of treating rheumatoid arthritis or lupus. In some embodiments, the invention provides methods of treating multiple sclerosis. In some embodiments, the invention provides methods of treating systemic lupus erythematosus or atopic dermatitis.

[0154] The compounds of the present disclosure (e.g., a compound described in any one of the first to sixth embodiments above, 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.

[0155] The term "cancer" includes diseases or disorders involving abnormal growth and / or proliferation of cells, such as, for example, glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability high colon carcinoma). In some embodiments, the present disclosure provides a method of treating leukemia or lymphoma.

[0156] 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, colorectal 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.

[0157] 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 and dendritic neoplasms.

[0158] Examples of B-cell neoplasms include chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL), Waldenstrom's macroglobulinemia, 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 cell B-cell lymphoma, intravascular large cell B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, and acute lymphocytic leukemia.

[0159] 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 macroglobulinemia.

[0160] In one embodiment, the cancer is chronic lymphocytic leukemia (CLL). In another embodiment, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0161] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0162] As used herein, the term "treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely reducing the extent of a disease, disorder or syndrome; ameliorating or improving clinical symptoms or indicators associated with a disorder; or delaying, inhibiting or reducing the likelihood of progression of a disease, disorder or syndrome.

[0163] The effective dose of a compound provided herein, or a pharma- ceutically acceptable salt thereof, administered to a subject can be from 10 μg to 500 mg.

[0164] 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, via 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 a compound that metabolizes to the compound described herein or a pharmaceutically acceptable salt thereof in or on the surface of the mammal's body topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally to a mammal.

[0165] 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. 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, be varied 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.

[0166] Tablets, troches, pills, capsules and the like 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.

[0167] The active compound may be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.

[0168] Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

[0169] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent containing various other ingredients as listed above, as required, followed by filtration sterilization. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation method can be vacuum drying and freeze-drying technology, which can obtain a powder of the active ingredient and any additional desired ingredients present in a previously sterile-filtered solution.

[0170] 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 non-toxic surfactants.

[0171] Useful doses of the compounds described herein or their pharma- ceutically acceptable salts can be determined by comparing their in vitro and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; see, for example, U.S. Patent No. 4,938,949, which is incorporated by reference in its entirety.

[0172] The amount of the compound described herein or a pharma- ceutically acceptable salt thereof required for therapeutic use 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 may ultimately be left to the discretion of the attending physician or clinician. In general, however, the dosage may range from about 0.1 to about 10 mg / kg body weight per day.

[0173] 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.

[0174] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

[0175] 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

[0176] Abbreviations and acronyms used herein include the following: AcOH = acetic acid; Aq. = aqueous; Bn = benzyl; Boc = tert-butoxycarbonyl; br=wide range; ℃=Celsius temperature; CDCl3 = deutero-chloroform; CO 2 = carbon dioxide; Cs 2 CO 3 = Cesium carbonate; δ = chemical shift; d=doublet; dd=double doublet; DCE = 1,2-dichloroethane DCM = dichloromethane; DIPEA = N-ethyldiisopropylamine or N,N-diisopropylethylamine; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; DMSO-d6 = hexadeuterodimethylsulfoxide; Et = ethyl; Et2 O = ether; EtOH = ethanol; EtOAc = ethyl acetate; Equiv. = equal amount; g = grams; HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBr = hydrogen bromide; HCl = hydrochloric acid; 1 H NMR = proton nuclear magnetic resonance; H 2 O=water; HPLC = high pressure liquid chromatography; h=time; K 2 CO 3 = Potassium carbonate; KHSO 4 = potassium hydrogen sulfate; KOAc = potassium acetate; K 3 PO 4 = potassium phosphate tribasic; L = liters; LCMS = liquid chromatography mass spectrometry; m=multiplet; M = moles; Me = methyl; MeCN = acetonitrile; MeOH = methanol; mg = milligrams; MHz = Megahertz; mins=minutes; mL = milliliters; mmol = millimolar; MS m / z = mass spectrum peak; N 2 = nitrogen; Na 2 CO 3 = sodium carbonate; NaHCO 3 = sodium bicarbonate; NaOH = sodium hydroxide; Na 2 SO 4 = sodium sulfate; NH 3 = ammonia; NH 4 Cl = ammonium chloride; Pd(amphoteric)Cl 2 = Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd / C = palladium on carbon; Pd(dppf)Cl 2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); POCl 3 = Phosphoryl chloride PyBOP = benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate q=quartet; RT=room temperature; s=singlet; sat.=saturated; SFC = supercritical fluid chromatography; Si-CBH = Silica-bound cyanoborohydride SiO 2 = silicon dioxide; SOR=Specific optical rotation soln. or sol. = solution; t=triplet; TBAI = Tetra-n-butylammonium iodide TBAF = tetrabutylammonium fluoride; TEA = triethylamine; TFA = trifluoroacetic acid; Tf 2 O = trifluoromethanesulfonic anhydride; THF = tetrahydrofuran; TLC = thin layer chromatography; μL = microliter; μmol = micromolar.

[0177] I. Analysis method NMR Equipment Specifications: Bruker AVANCE DRX 500 Varian UNITYplus 400 LC / MS Equipment Specifications: Agilent 1200 series LC / MSD system equipped with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6130A, G6120B mass spectrometers. Agilent Technologies 1260 Infinity LC / MSD system equipped with a DAD\ELSD Alltech 3300 and an Agilent LC\MSD G6120B mass spectrometer. Agilent Technologies 1260 Infinity II LC / MSD system equipped with a DAD\ELSD G7102A 1290 Infinity II and an Agilent LC\MSD G6120B mass spectrometer. Agilent 1260 series LC / MSD system equipped with a DAD\ELSD and an Agilent LC\MSD (G6120B) mass spectrometer. UHPLC Agilent 1290 series LC / MSD system equipped with a DAD\ELSD and an Agilent LC\MSD (G6125B) mass spectrometer. LC Method 2 min: Injection volume: 0.5μl Column temperature: 60℃ UV scan: 207-223nM 246~262nM 272~288nM Agilent Poroshell 120 SB-C18 4.6×30mm 2.7μm UHPLC Guard Infinity Lab Poroshell 120 with SB-C18 4.6×5mm 2.7μm Mobile phase A: 0.1% FA in water Mobile phase B: 0.1% FA in acetonitrile [Table 1] LC Method 6 min: Injection volume: 0.5μl Column temperature: 60℃ UV scan: 207-223nM 246~262nM 272~288nM Agilent Poroshell 120 SB-C18 4.6×30mm 2.7μm UHPLC Guard Infinity Lab Poroshell 120 with SB-C18 4.6×5mm 2.7μm Mobile phase A: 0.1% FA in water Mobile phase B: 0.1% FA in acetonitrile [Table 2]

[0178] II. Synthesis of BTK-Linker Precursor Synthesis of N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] Step 1: To a stirred solution of 6-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (20 g, 93.45 mmol) in toluene (75 mL), POCl 3 (659.12 g, 4.30 mol) was added at room temperature. The reaction mixture was warmed to 100° C. and stirred for 12 h. The reaction mixture was then concentrated in vacuo and NaHCO 3 The reaction mixture was quenched with a saturated solution of water and ethyl acetate. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine and added Na 2 SO 4The mixture was dried at 40° C. and concentrated to give the crude product. The crude product was purified by flash column chromatography (silica gel 60-120 mesh, 0-5% ethyl acetate in pet ether) to give the product 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (18 g, 76.66 mmol, 82.03% yield) as an off-white solid. LC-MS (ES + ): m / z 232.25[M+H] + .

[0179] Step 2: To a stirred solution of tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (80 g, 230.38 mmol) in dioxane (350 mL) was added 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (69.62 g, 299.49 mmol) at room temperature, followed by potassium carbonate (95.52 g, 691.13 mmol) in water (90 mL) under an argon atmosphere. The reaction mixture was repeatedly degassed with argon gas and Pd(dppf)Cl was added. 2· CH 2 Cl 2 (8.43 g, 11.52 mmol) was added in one portion to the reaction mixture. The reaction mixture was again degassed with argon gas and then heated at 50 °C for 16 h. The crude product was purified by flash column chromatography (0-100% ethyl acetate in pet ether) to give tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (76 g, 173.02 mmol, 75.10% yield) as a yellow solid. LC-MS (ES + ): m / z 417.0.3[M+H] + .

[0180] Step 3: To a stirred solution of tert-butyl N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (15 g, 35.95 mmol) in DCM (200 mL) was added 4M HCl in dioxane (120 mL) dropwise at 0° C. The reaction was stirred at 27° C. for 3 h. The reaction was concentrated under reduced pressure, basified with saturated bicarbonate solution, and extracted with ethyl acetate (100 mL×4). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel 230-400 mesh, 0-20% MeOH in DCM) to give [4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methanamine (11 g, 33.64 mmol, 93.57% yield). LC-MS (ES) + ): m / z 316.95[M+H] + .

[0181] Step 4: To a stirred solution of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine HCl salt (10 g, 28.28 mmol) in toluene (100 mL) was added ethyl 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (6.73 g, 33.93 mmol) and the reaction mixture was cooled to 0° C. Trimethylaluminum (2.04 g, 28.28 mmol, 2.72 mL) was added and the reaction was heated at 90° C. for 12 h. Upon completion, the reaction was cooled, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under high vacuum to give the crude product. The resulting crude product was purified by column chromatography (silica gel) to give N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (8.6 g, 17.41 mmol, 61.56% yield) as a yellow solid. LC-MS (ES) + ): m / z 469.21[M+H] + .

[0182] Synthesis of 5-(tert-butyl)-N-(2-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] A mixture of N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (100 mg, 213.07 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (216.42 mg, 852.27 μmol), potassium acetate (41.82 mg, 426.14 μmol, 26.64 μL) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (20.31 mg, 42.61 μmol) in dioxane (2 mL) was degassed and cooled to 10° C. with N 2 The mixture was then purged three times with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (SiO 2 , PE:EA=1:1). 5-(tert-butyl)-N-(2-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (92 mg, 113.66 μmol, 53.35% yield) was obtained as a yellow solid. LC-MS (ES + ): m / z 517.5[M+H] + .

[0183] Synthesis of 5-(tert-butyl)-N-(4-(6-(5-formylpyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(tert-butyl)-N-(2-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (92 mg, 178.16 μmol), 6-bromonicotinaldehyde (66.28 mg, 356.31 μmol), Pd(dppf)Cl in dioxane (1.6 mL). 2 ·CH 2 Cl 2 (14.55 mg, 17.82 μmol) and K 2 CO 3 The mixture (73.87 mg, 534.47 μmol, 32.26 μL) was degassed and filled with N 2 The mixture was then purged three times with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 3 hours. The reaction mixture was placed under reduced pressure to give a residue. The residue was analyzed by preparative TLC (SiO 2 , PE:EA=2:3). 5-(tert-butyl)-N-(4-(6-(5-formylpyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (40 mg, 66.92 μmol, 37.56% yield) was obtained as a yellow solid. LC-MS (ES + ): m / z 496.5[M+H] + .

[0184] Synthesis of 5-tert-butyl-N-[[4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide [ka] To a stirred solution of N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide (3.0 g, 6.39 mmol) in argon-purged dioxane (40 mL) and water (10 mL), potassium carbonate (2.65 g, 19.18 mmol) and (4-formylphenyl)boronic acid (1.73 g, 11.51 mmol) were added at room temperature and the reaction mixture was stirred at this temperature for 10 minutes. Pd(dppf)Cl 2 ·CH 2 Cl 2 (467.71 mg, 639.20 μmol) was added and the reaction was heated at 85° C. for 16 h and the progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine solution (50 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, 0-100% ethyl acetate in pet ether) to give 5-tert-butyl-N-[[4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (2.57 g, 4.57 mmol, 71.54% yield). LC-MS(ES+): m / z 495.30[M+H] + .

[0185] Synthesis of 5-(tert-butyl)-N-(4-(6-(3-chloro-4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] H 2To a solution of N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (100 mg, 213.07 μmol), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (85.18 mg, 319.60 μmol) and sodium carbonate (22.58 mg, 213.07 μmol) in O (0.2 mL) and dioxane (0.8 mL) was added cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (15.59 mg, 21.31 μmol) and the mixture was cooled to 5° C. for 1 h. 2 The reaction mixture was concentrated under reduced pressure to remove dioxane and washed with saturated NH 4 Poured into aqueous Cl (3 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 5-(tert-butyl)-N-(4-(6-(3-chloro-4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (80 mg, 127.34 μmol, 59.76% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ=10.50(s,1H),8.60(s,1H),8.32(s,1H),8.01(d,J=1.6Hz,2H),7.97(brd,J=11.2Hz,1H),7.79(d,J=1.6Hz, 1H),7.71(d,J=8.4Hz,1H),7.59(brd,J=7.9Hz,1H),7.43(s,1H),4.84-4.75(m,2H),2.55(s,3H),1.49(s,9H). LC-MS(ES+):m / z,529.3[M+H] + .

[0186] Synthesis of 5-(tert-butyl)-N-(4-(6-(4-formyl-3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] H 2 To a solution of N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (100 mg, 213.07 μmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (83.77 mg, 319.60 μmol), and sodium carbonate (22.58 mg, 213.07 μmol) in 2H2O (0.2 mL) and dioxane (0.8 mL), Pd(dppf)Cl 2· CH 2 Cl 2 (15.59 mg, 21.31 μmol) was added. The mixture was then cooled to 5° C. 2 The reaction was stirred at 100° C. under atmospheric pressure for 12 h and the progress of the reaction was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure to remove dioxane and saturated NH 4 Poured into aqueous Cl solution (3 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). The compound 5-(tert-butyl)-N-(4-(6-(4-formyl-3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (100 mg, 168.52 μmol, 79.09% yield) was obtained as a yellow oil. 1 HNMR (400MHz, CDCl 3)δ=10.44(s,1H),8.52(d,J=1.2Hz,1H),8.22(d,J=1.6Hz,1H),7.93(brs,2H),7.87(dd,J=1.2,8.0Hz,1H),7.52(d,J=8.4Hz,1H), 7.33(d,J=8.0Hz,1H),7.29(d,J=1.6Hz,1H),7.23(s,1H),4.76(d,J=6.0Hz,2H),4.02(s,3H),2.50(s,3H),1.47(d,J=0.8Hz,9H). LC-MS(ES + ): m / z 525.3 [M+H] + .

[0187] Synthesis of 5-tert-butyl-N-[[4-[6-(3-fluoro-4-formyl-phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide (100 mg, 213.07 μmol) and (3-fluoro-4-formyl-phenyl)boronic acid (39.36 mg, 234.37 μmol) in dioxane (1 mL) and water (0.2 mL), Pd(dppf)Cl 2· CH 2 Cl 2(7.80 mg, 10.65 μmol) and sodium carbonate (67.75 mg, 639.20 μmol) were added. The mixture was stirred at 100° C. for 12 hours. The progress of the reaction was monitored by LC-MS. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate=3 / 1). The compound 5-tert-butyl-N-[[4-[6-(3-fluoro-4-formyl-phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (60 mg, 117.07 μmol, yield 54.94%) was obtained as a yellow solid. 1 HNMR (400MHz, CDCl 3 ) δ = 10.30 (s, 1H), 8.48 (s, 1H), 8.16 (d, J = 1.3 Hz, 1H), 7.91 - 7.83 (m, 3H), 7.55- 7.38 (m, 3H), 7.24 (d, J = 1.3 Hz, 1H), 4.71 (br s, 2H), 2.46 (s, 3H), 1.41 (s, 9H). LC-MS(ES + ): m / z 513.4 [M+H] + .

[0188] Synthesis of 5-tert-butyl-N-[[4-[6-(4-formyl-2-methoxy-phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide (200 mg, 426.14 μmol) and (4-formyl-2-methoxy-phenyl)boronic acid (84.36 mg, 468.75 μmol) in dioxane (2 mL) and water (0.4 mL), Pd(dppf)Cl 2· CH2 Cl 2 (15.59 mg, 21.31 μmol) and sodium carbonate (135.50 mg, 1.28 mmol) were added. The mixture was stirred at 100° C. for 12 h. The progress of the reaction was monitored by LC-MS. The reaction mixture was diluted with H 2 The mixture was quenched by adding 200 mL of 2-chloro-3,4-dichloro-1,1-diphenyl-2,2-diphenyl-1,2-diol (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether / ethyl acetate = 3 / 1). The compound 5-tert-butyl-N-[[4-[6-(4-formyl-2-methoxy-phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (120 mg, 228.76 μmol, 53.68% yield) was obtained as a yellow solid. LC-MS (ES + ): m / z 525.4[M+H] + .

[0189] Synthesis of 5-(tert-butyl)-N-(4-(6-(4-formyl-2-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (100 mg, 213.07 μmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (83.90 mg, 340.91 μmol), Pd(dppf)Cl in dioxane (1 mL) and water (81 μL). 2· CH 2 Cl 2A mixture of (15.59 mg, 21.31 μmol) and sodium carbonate (50 mg, 471.75 μmol) was degassed and diluted with N 2 The mixture was purged with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 12 hours. The progress of the reaction was monitored by LC-MS. After completion, the reaction mixture was concentrated under reduced pressure to remove water and dioxane, and the residue was purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate=6 / 1 to 5 / 1). The compound 5-(tert-butyl)-N-(4-(6-(4-formyl-2-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (81 mg, 130.41 μmol, 61.21% yield) was obtained as a yellow solid. 1 HNMR (400MHz, DMSO-d 6 )δppm1.44(s,9H)2.47(s,3H)2.58(s,3H)4.56(d,J=6.0Hz,2H)7.44-7.50(m,2H)7.81(s,2H)7. 87(s,1H)8.00-8.09(m,2H)8.55(d,J=1.2Hz,1H)8.67(s,1H)9.53(t,J=6.0Hz,1H)10.02(s,1H). LC-MS(ES + ): m / z 509.3 [M+H] + .

[0190] Synthesis of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluorobenzyl)carbamate [ka] Step 1: To a stirred solution of 4-bromo-2-fluorobenzonitrile (65 g, 324.99 mmol) in dry THF (500 mL) was added borane; tetrahydrofuran (1 M solution) (83.79 g, 974.97 mmol, 95.43 mL) in N 2Dropwise addition at 0° C. under ambient conditions. The reaction mixture was allowed to slowly warm to room temperature over 1 h and heated at 80° C. for 12 h. After completion of the reaction, the reaction mixture was cooled to 0° C. and carefully quenched with methanol (750 ml) over 1 h at 0° C. with stirring (Note: Exothermicity and evolution of gas was carefully controlled by slow addition and external cooling). The quenched reaction mixture was concentrated to give a residual mass, which was then dissolved in ethyl acetate (500 ml) and HCl (g) in 1,4-dioxane (4 M solution) (59.25 g, 1.62 mol, 74.06 mL) was added dropwise at 0° C. The reaction mixture was stirred for 30 min and the solidified mass was filtered, washed with diethyl ether (500 ml) and dried to give (4-bromo-2-fluorophenyl)methanamine HCl salt (62 g, 244.91 mmol, 75.36% yield) as a colorless solid. LC-MS (ES + ): m / z 187.32 [M+H-NH 3 ] + .

[0191] Step 2: To a stirred solution of (4-bromo-2-fluorophenyl)methanamine HCl salt (70 g, 291.06 mmol) in dry DCM (2000 mL) was added triethylamine (73.63 g, 727.65 mmol, 101.42 mL) with N 2Dropwise addition at 20° C. under ambient atmosphere. The reaction mixture was stirred at the same temperature for 30 min and tert-butoxycarbonyl tert-butyl carbonate (69.88 g, 320.17 mmol, 73.48 mL) in DCM (500 ml) was added dropwise over 1 h. The reaction mixture was allowed to warm to room temperature over 1 h and stirred at ambient temperature for 12 h and the progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was quenched with ice-cold water (500 ml) and the organic layer was partitioned. The organic layer was further washed with water (3×500 ml), brine (1×200 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. The crude product was purified by flash column chromatography (silica gel 100 / 200 mesh, 2-5% ethyl acetate in hexanes) to give tert-butyl N-[(4-bromo-2-fluoro-phenyl)methyl]carbamate (64 g, 199.90 mmol, 68.68% yield) as a colorless solid. LC-MS (ES + ): m / z 247.88[M-56+H] + .

[0192] Step 3: To a stirred solution of tert-butyl N-[(4-bromo-2-fluoro-phenyl)methyl]carbamate (64 g, 210.42 mmol) in dry 1,4-dioxane (640 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (69.46 g, 273.54 mmol), followed by potassium acetate (51.63 g, 526.05 mmol) at room temperature under an argon atmosphere. The reaction mixture was degassed with argon gas for 10 min and Pd(dppf)Cl 2(1.54 g, 2.10 mmol) was added in one portion. The reaction mixture was degassed again with argon gas for another 15 min and then heated to 90 °C for 12 h. The reaction mixture was filtered through a bed of celite and washed with ethyl acetate (100 ml). The filtrate was concentrated to a residue mass, dissolved in ethyl acetate (500 ml), washed with water (2 x 300 ml), brine (1 x 100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound. The crude product was purified by flash column chromatography (silica gel 100 / 200 mesh, 5-25% ethyl acetate in hexane) to give tert-butyl N-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (70 g, 179.37 mmol, 85.25% yield) as a white solid. LC-MS (ES + ): m / z 296.36 [M-56+H] + .

[0193] Step 4: To a stirred solution of 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (25 g, 107.54 mmol) and tert-butyl(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (30.22 g, 86.03 mmol) in dry dioxane (500 mL) was added potassium carbonate (29.73 g, 215.09 mmol), followed by water (125 mL) at room temperature under an argon atmosphere. The reaction mixture was degassed with argon gas for 10 min and Pd(dppf)Cl 2(786.90 mg, 1.08 mmol) was added in one portion. The reaction mixture was degassed again with argon gas for an additional 15 min and then heated at 60 °C for 5 h. The reaction mixture was filtered through a bed of celite and washed with ethyl acetate (100 ml). The filtrate was concentrated to a residue mass, dissolved in ethyl acetate (500 ml), washed with water (2 x 100 ml), brine (1 x 100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound. The crude product was purified by flash column chromatography (silica gel 100-200 mesh, 20-30% ethyl acetate in hexanes) to give tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluorobenzyl)carbamate (26 g, 60.78 mmol, 56.52% yield) as a yellow solid. LC-MS (ES + ): m / z 422.48[M+H] + .

[0194] Synthesis of N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluoro-phenyl]methyl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide [ka] Step 1: To a solution of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluorobenzyl)carbamate (10 g, 23.74 mmol) in DCM (100 mL) was added 4 M hydrogen chloride in 1,4-dioxane (50 mL) at 0° C. 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 neutralized with saturated sodium bicarbonate solution and extracted with 10% MeOH / DCM. The organic layer was concentrated to give [4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluoro-phenyl]methanamine (7.5 g, 23.31 mmol, 98.19% yield). LC-MS (ES + ): m / z 321.28[M+H] + .

[0195] Step 2: To a stirred solution of [4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluoro-phenyl]methanamine (7.5 g, 23.35 mmol) in toluene (150 mL) was added ethyl 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (9.26 g, 46.71 mmol) at 0° C. Then trimethylaluminum 2M in toluene (4.21 g, 58.38 mmol) was added and the reaction was allowed to equilibrate to room temperature for 5 minutes. The reaction was heated at 80° C. for 3 hours and the progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated in vacuo to give the crude product, which was purified by flash column chromatography (silica gel 230-400 mesh, 80% ethyl acetate / petroleum ether) to give N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluoro-phenyl]methyl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide (4.5 g, 7.67 mmol, 32.84% yield). LC-MS (ES) + ): m / z 473.27[M+H] + .

[0196] Synthesis of 5-tert-butyl-N-[[2-fluoro-4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide [ka] To a stirred solution of N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluoro-phenyl]methyl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide (1 g, 2.11 mmol) in argon-purged dioxane (16 mL) and water (4 mL) was added potassium carbonate (876.02 mg, 6.34 mmol) and (4-formylphenyl)boronic acid (506.88 mg, 3.38 mmol) and the reaction mixture was stirred at room temperature for 10 min. Pd(dppf)Cl 2· CH 2 Cl 2 After addition of (154.60 mg, 211.28 μmol), the reaction mixture was heated at 90° C. for 16 h. The progress of the reaction was monitored by TLC and LC-MS. Upon completion, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel 100-200 mesh, 0-100% ethyl acetate in pet ether) to give 5-tert-butyl-N-[[2-fluoro-4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (0.9 g, 1.75 mmol, 82.68% yield). LC-MS (ES + ): m / z 499.43 [M+H] + .

[0197] Synthesis of 5-tert-butyl-N-[[2-fluoro-4-[6-(3-fluoro-4-formyl-phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide [ka] To a stirred solution of N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluoro-phenyl]methyl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide (1.5 g, 3.17 mmol) and (3-fluoro-4-formyl-phenyl)boronic acid (798.32 mg, 4.75 mmol) in dioxane (16 mL) and water (4 mL) was added potassium carbonate (1.31 g, 9.51 mmol) at room temperature. The reaction mixture was degassed with argon for 10 min, followed by addition of Pd(ampho)Cl. 2 (224.41 mg, 316.93 μmol) was added. The reaction mixture was degassed with argon for another 5 min and it was stirred at 90 °C for 16 h. The reaction mixture was then concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh, 20% ethyl acetate in pet ether) to give 5-tert-butyl-N-[[2-fluoro-4-[6-(3-fluoro-4-formyl-phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (1.9 g, 3.08 mmol, 97.30% yield) as a yellow solid. LC-MS (ES + ): m / z 517.62[M+H] + .

[0198] Synthesis of 5-tert-butyl-N-[[2-fluoro-4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-N-methyl-1,2,4-oxadiazole-3-carboxamide [ka] Step 1: To a stirred solution of N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluoro-phenyl]methyl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide (0.5 g, 1.06 mmol) in THF (10 mL) was added sodium hydride (41.22 mg, 1.58 mmol) followed by iodomethane (149.95 mg, 1.06 mmol, 65.77 μL). The reaction mixture was stirred at 0° C. for 4 h. After completion of the reaction, the reaction mixture was diluted with ice water and extracted with ethyl acetate (30 ml×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh, 20% ethyl acetate in pet ether) to give N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluoro-phenyl]methyl]-5-tert-butyl-N-methyl-1,2,4-oxadiazole-3-carboxamide (0.3 g, 548.57 μmol, 51.93% yield). LC-MS (ES) + ): m / z 487.44[M+H] + .

[0199] Step 2: To a stirred solution of N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluoro-phenyl]methyl]-5-tert-butyl-N-methyl-1,2,4-oxadiazole-3-carboxamide (0.3 g, 615.61 μmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (214.31 mg, 923.41 μmol) in dioxane (8 mL) and water (2 mL), potassium carbonate (255.24 mg, 1.85 mmol) was added at room temperature. The reaction mixture was degassed with argon for 10 minutes, and then Pd(ampho)Cl2 (43.59 mg, 61.56 μmol) was added. The reaction mixture was then degassed with argon for an additional 5 min and stirred at 90° C. for 16 h. The reaction mixture was then concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh, 20% ethyl acetate in pet ether) to give 5-tert-butyl-N-[[2-fluoro-4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-N-methyl-1,2,4-oxadiazole-3-carboxamide (0.350 g, 390.68 μmol, 63.46% yield) as a yellow solid.

[0200] Synthesis of 5-(tert-butyl)-N-(2-chloro-4-(6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The procedure used is essentially the same as that for 5-tert-butyl-N-[[2-fluoro-4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide, except that 4-bromo-2-chloro-benzonitrile was used instead of 4-bromo-2-fluorobenzonitrile.

[0201] 5-(tert-butyl)-N-(2-chloro-4-(6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide. LC-MS (ES + ): m / z 515.17[M+H] + .

[0202] Synthesis of 5-(tert-butyl)-N-(4-(6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methoxybenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The procedure used is essentially identical to that of 5-tert-butyl-N-[[2-fluoro-4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide, except that the synthesis was initiated with (4-bromo-2-methoxy-phenyl)methanamine instead of (4-bromo-2-fluorophenyl)methanamine.

[0203] 5-tert-Butyl-N-[[4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methoxy-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide. LC-MS (ES + ): m / z 511.30[M+H] + .

[0204] Synthesis of 5-(tert-butyl)-N-(2-chloro-5-fluoro-4-(6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] Step 1: A solution of (4-bromo-2-chloro-5-fluoro-phenyl)methanol (94.0 g, 392.53 mmol) and isoindoline-1,3-dione (86.63 g, 588.80 mmol, 71.60 mL) in THF (1000 mL) was cooled to 0° C., followed by the addition of triphenylphosphine (154.44 g, 588.80 mmol). This was followed by the dropwise addition of isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (119.06 g, 588.80 mmol, 115.59 mL) at 0° C., and the reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC. After completion, the volatiles were removed under reduced pressure and DCM (100 mL) was added to the residue. The precipitate was filtered and washed with diethyl ether (100 mL). The filtrate was then concentrated and the crude product was purified by column chromatography (silica gel 230-400 mesh, 0-50% ethyl acetate in pet ether) to give 2-[(4-bromo-2-chloro-5-fluoro-phenyl)methyl]-3a,7a-dihydroisoindole-1,3-dione (190.0 g, 314.53 mmol, 80.13% yield) as an off-white solid. LC-MS (ES) + ): m / z 368.07[M+H] + .

[0205] Step 2: To a stirred solution of 2-[(4-bromo-2-chloro-5-fluoro-phenyl)methyl]isoindoline-1,3-dione (190.0 g, 515.49 mmol) in methanol (4000 mL) was added hydrazine hydrate (129.03 g, 2.58 mol, 125.27 mL). The reaction mixture was stirred at 70° C. for 2 h. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water (200 mL) and most of the methanol or volatiles were removed under reduced pressure. The aqueous suspension was acidified with 1N HCl solution (1000 mL) and filtered. The filtrate (aqueous layer) was washed with DCM (200 mL×3), basified with 1N NaOH until pH was 12, and extracted with DCM (200 mL×3) and 9:1 DCM / MeOH (200 mL×3). The combined organic layers were washed with brine solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh, 0-10% ethyl acetate in pet ether) to give (4-bromo-2-chloro-5-fluoro-phenyl)methanamine (65.0 g, 239.55 mmol, 46.47% yield) as a light grey liquid. LC-MS (ES) + ): m / z 238.22[M+H] + .

[0206] Steps 3 to 8 have the same procedure as that of 5-tert-butyl-N-[[2-fluoro-4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide. Step 3: tert-Butyl N-[(4-bromo-2-chloro-5-fluoro-phenyl)methyl]carbamate. LC-MS(ES + ): m / z 238.22 [M-tBu+H] + . Step 4: tert-Butyl-N-[[2-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate. LC-MS (ES + ): m / z 330.41 [M-tBu+H] + . Step 5: tert-Butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-chloro-5-fluorobenzyl)carbamate. LC-MS(ES + ): m / z 455.31[M+H] + . Step 6: (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-chloro-5-fluorophenyl)methanamine. LC-MS(ES + ): m / z 355.32[M+H] + . Step 7: N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-chloro-5-fluorobenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide. LC-MS (ES + ): m / z 507.43[M+H] + . Step 8: 5-(tert-butyl)-N-(2-chloro-5-fluoro-4-(6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide. LC-MS (ES + ): m / z 533.18[M+H] + .

[0207] Synthesis of tert-butyl N-[[4-[6-(4-hydroxybut-1-ynyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]carbamate [ka] A solution of tert-butyl N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (5 g, 11.98 mmol), but-3-yn-1-ol (4.20 g, 59.90 mmol, 4.53 mL) and triethylamine (12.12 g, 119.80 mmol, 16.70 mL) in 1,4-dioxane (50 mL) was purged with argon gas for 15 minutes. Copper iodide (760.38 mg, 2.40 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.68 g, 2.40 mmol) were then added to the reaction mixture, which was stirred at 110° C. for 16 hours. The reaction mixture was filtered through a bed of celite and washed with ethyl acetate (100 mL×2). 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 flash column chromatography (silica gel 230-400 mesh, 0-100% ethyl acetate in pet ether) to give tert-butyl N-[[4-[6-(4-hydroxybut-1-ynyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]carbamate (4 g, 9.54 mmol, 79.64% yield). LC-MS (ES) + ): m / z 407.46[M+H] + .

[0208] Synthesis of tert-butyl N-[[2-methyl-4-[6-(4-oxobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate [ka] Step 1: To a solution of tert-butyl N-[[4-[6-(4-hydroxybut-1-ynyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylphenyl]methyl]carbamate (0.5 g, 1.23 mmol) in DCM (9.40 mL) was added triethylamine (622.36 mg, 6.15 mmol, 857.25 μL), DMAP (15.03 mg, 123.01 μmol) and acetic anhydride (251.15 mg, 2.46 mmol, 232.12 μL) at 0° C. Then the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with DCM. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product 4-[4-[4-[(tert-butoxycarbonylamino)methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]but-3-ynyl acetate (0.5 g, 1.05 mmol, 85.00% yield). LC-MS (ES) + ): m / z 449.45[M+H] + .

[0209] Step 2: Palladium on carbon (10 wt%) (9.08 g, 85.28 mmol) was added to a solution of 4-[4-[4-[(tert-butoxycarbonylamino)methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]but-3-ynyl acetate (9 g, 20.07 mmol) in ethyl acetate (100 mL) under hydrogen atmosphere at 27° C. The reaction mixture was stirred at 27° C. for 6 hours. Upon completion of the reaction, the reaction mixture was filtered through Celite and washed with ethyl acetate (100 mL×2). The organic layer was concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (silica gel 230-400 mesh, 0-100% ethyl acetate in pet ether) to give 4-[4-[4-[(tert-butoxycarbonylamino)methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]butyl acetate (7.5 g, 14.58 mmol, 72.68% yield) as a yellow viscous liquid. LC-MS (ES) +): m / z 453.90[M+H] + .

[0210] Step 3: To a solution of 4-[4-[4-[(tert-butoxycarbonylamino)methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]butyl acetate (7.5 g, 16.57 mmol) in THF (80 mL) and water (20 mL) was added lithium hydroxide monohydrate 98% (6.95 g, 165.73 mmol) at 0° C. The reaction mixture was stirred at 60° C. for 10 h and the progress of the reaction was monitored by TLC and LC-MS. After consumption of the starting material, the reaction was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh, 0-10% ethyl acetate in pet ether) to give tert-butyl N-[[4-[6-(4-hydroxybutyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]carbamate (5 g, 11.21 mmol, 67.61% yield). LC-MS (ES) + ): m / z 411.48[M+H] + .

[0211] Step 4: To a solution of tert-butyl N-[[4-[6-(4-hydroxybutyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]carbamate (1.01 g, 2.46 mmol) was added Dess-Martin periodinane (1.57 g, 3.69 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and monitored by TLC and LC-MS. After consumption of the starting material, the reaction was diluted with DCM and filtered through a celite pad. The reaction mixture was then washed with saturated sodium bicarbonate solution (100 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh, 0-100% ethyl acetate in pet ether) to give tert-butyl N-[[2-methyl-4-[6-(4-oxobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (0.7 g, 1.37 mmol, 55.73% yield). LC-MS (ES) + ): m / z 409.46[M+H] + .

[0212] Synthesis of 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)but-3-yn-1-yl methanesulfonate [ka] Step 1: To a stirred solution of [4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methanamine (2.8 g, 8.83 mmol) in toluene (60 mL) was added triethylamine (2.68 g, 26.48 mmol, 3.69 mL) at 0° C. and stirred for 10 minutes. Trimethylarmane (1.27 g, 17.66 mmol, 1.57 mL) was added dropwise and the reaction mass was stirred at 27° C. for 30 minutes followed by the addition of a solution of ethyl 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (1.75 g, 8.83 mmol) in toluene (2 mL). Finally, the reaction mass was allowed to stir at 120° C. for 2 hours in a sealed tube. The reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (100-200 mesh silica 0-50% EA:Pet ether solvent gradient) to give N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (2.9 g, 6.13 mmol, 69.46% yield) as a yellow solid. LC-MS (ES) + ): m / z 470.55[M+H] + .

[0213] Step 2: To a stirred solution of N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (500 mg, 1.07 mmol) in THF (5 mL) was added but-3-yn-1-ol (89.60 mg, 1.28 mmol, 96.66 μL), copper(I) iodide (24.35 mg, 127.84 μmol, 4.33 μL) and triethylamine (215.60 mg, 2.13 mmol, 296.97 μL). The reaction mixture was purged with argon for 10 min and Pd(PPh 3 )Cl 2(17.95 mg, 25.57 μmol) was added and heated at 90° C. for 16 h. The reaction mixture was cooled to ambient temperature, diluted with water (10 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting crude was purified by reverse phase (0-100% gradient of 0.1% FA in water:ACN) to give 5-tert-butyl-N-[[4-[6-(4-hydroxybut-1-ynyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (220 mg, 0.372 mmol, 34.93% yield) as a yellow sticky solid. LC-MS (ES + ): m / z 459.78[M+H] + .

[0214] Step 3: To a suspension of 5-tert-butyl-N-[[4-[6-(4-hydroxybut-1-ynyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (220 mg, 479.81 μmol) in DCM (3 mL) was added methanesulfonyl chloride (54.96 mg, 479.81 μmol, 37.14 μL) at 0° C. and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate and extracted with ethyl acetate. The combined organic layers were concentrated under vacuum and the resulting crude was purified by column chromatography (100-200 mesh silica; 0-30% EA:PE solvent gradient) to give 4-[4-[4-[[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]but-3-ynyl methanesulfonate (200 mg, 324.08 μmol, 67.54% yield). LC-MS (ES) + ): m / z 537.19[M+H] + .

[0215] tert-Butyl N-[[2-fluoro-4-[6-(4-oxobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate was prepared following the synthesis of tert-butyl N-[[2-methyl-4-[6-(4-oxobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate. [ka] LC-MS(ES + ): m / z 413.46[M+H] + .

[0216] Synthesis of 5-tert-butyl-N-[[2-fluoro-4-[6-(2-oxoethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide [ka] Step 1: To a stirred solution of tert-butyl N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-fluoro-phenyl]methyl]carbamate (4.3 g, 10.21 mmol) in THF (20 mL) was added tributyl(vinyl)stannane (12.95 g, 40.83 mmol, 11.88 mL) and degassed for 15 min. After cooling the solution to 0° C., XPhos Pd G2 (1.20 g, 1.53 mmol) was added and the reaction mixture was then stirred at 90° C. After completion of the reaction, the reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was distilled under reduced pressure and purified by column chromatography (10% ethyl acetate in pet ether) to give tert-butyl N-[[2-fluoro-4-(6-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl]methyl]carbamate (3.6 g, 9.09 mmol, 89.03% yield). LC-MS (ES + ): m / z 369.41[M+H] + .

[0217] Step 2: To a stirred solution of tert-butyl N-[[2-fluoro-4-(6-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl]methyl]carbamate (2 g, 5.43 mmol) in dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (20 mL) at 0° C. under inert atmosphere. The reaction mixture was then stirred at room temperature for 2 h and monitored by TLC and LC-MS. After completion, the crude material was concentrated under reduced pressure, triturated with diethyl ether (2*100 mL) and then dried to give [2-fluoro-4-(6-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl]methanamine hydrochloride (1.7 g, 5.39 mmol, 99.36% yield) as a pale yellow solid. LC-MS (ES + ): m / z 269.36[M+H] + .

[0218] Step 3: To a stirred solution of (5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)oxylithium (2.02 g, 11.48 mmol) in DMF (10 mL) was added DIPEA (4.45 g, 34.45 mmol, 6.00 mL) and stirred for 5 min, followed by (5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)oxylithium (2.02 g, 11.48 mmol). Finally, PyBOP (4.48 g, 8.61 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. After completion, the reaction mixture was quenched with ice flakes to give a solid. The solid was filtered and purified by normal phase column chromatography (silica gel, 25% ethyl acetate in pet ether) to give 5-tert-butyl-N-[[2-fluoro-4-(6-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (1 g, 2.11 mmol, 36.81% yield) as a pale yellow solid. LC-MS (ES + ): m / z 421.95[M+H] + .

[0219] Step 4: To a stirred solution of 5-tert-butyl-N-[[2-fluoro-4-(6-vinylpyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (1 g, 2.38 mmol) in DCM (5 mL) was added trifluoroacetic acid (13.56 g, 118.92 mmol, 9.16 mL) at 0° C., followed by lead(IV) tetraacetate (1.05 g, 2.38 mmol) at the same temperature and stirred at room temperature for 3 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-tert-butyl-N-[[2-fluoro-4-[6-(2-oxoethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (0.9 g, 1.44 mmol, 60.69% yield), which was used without further purification. LC-MS (ES - ): m / z 435.21[MH] - .

[0220] Synthesis of tert-butyl N-[[4-(6-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate [ka] Step 1: To a solution of tert-butyl N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (5 g, 11.98 mmol) and zinc dicyanide (2.81 g, 23.96 mmol) in DMF (50 mL), tetrakis(triphenylphosphine)-palladium(0) (1.38 g, 1.20 mmol) was added at room temperature and the reaction mixture was stirred at 120° C. for 40 min. Saturated sodium bicarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate (50 mL×3). The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel 230-400 mesh, 0-30% ethyl acetate in pet ether) to give tert-butyl N-[[4-(6-cyanopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (3.8 g, 10.20 mmol, 85.13% yield). LC-MS (ES) + ): m / z 364.42[M+H] + .

[0221] Step 2: To a stirred solution of tert-butyl N-[[4-(6-cyanopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (3.4 g, 9.36 mmol) in water (8 mL), pyridine (16 mL), and AcOH (8 mL) was added sodium hypophosphite monohydrate (8.27 g, 79.52 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 30 min. Raney nickel (3.4 g, 57.93 mmol) was added in portions, and the reaction mixture was stirred at 65° C. for 2 h. The reaction mixture was then filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was quenched with water (60 mL), and extraction was performed with ethyl acetate (50 mL×3). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh, 0-10% ethyl acetate in pet ether) to give tert-butyl N-[[4-(6-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (1.2 g, 3.05 mmol, 32.56% yield). LC-MS (ES) + ): m / z 367.24[M+H] + .

[0222] Synthesis of tert-butyl N-[[4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-2-methyl-phenyl]methyl]carbamate [ka] Step 1: To a stirred solution of 2-acetylpyrrole (95 g, 870.56 mmol) in THF (10 mL), Amberlyst (0.09 g, 870.56 mmol), 1-bromopyrrolidine-2,5-dione (154.95 g, 870.56 mmol, 73.78 mL) was added under nitrogen atmosphere at -25°C. The reaction was monitored by TLC and LC-MS. After completion of the reaction, the residual mass was dissolved in ethyl acetate (500 mL), washed with water (1 x 100 mL), brine (1 x 100 mL) and washed with anhydrous Na 2 SO 4 The crude product was further purified by column chromatography on silica gel (100 / 200 mesh) and the product was eluted with 30-50% EtOAc / Hexanes to give the product 1-(4-bromo-1H-pyrrol-2-yl)ethan-1-one (154 g, 655.24 mmol, 75.27% yield) as a white solid. 1 HNMR (400MHz, DMSO-d 6 )δ=12.12(s,1H),7.20(s,1H),7.08(s,1H),2.34(s,3H).

[0223] Step 2: Toluene (150 mL) was added to a stirred solution of 1-(4-bromo-1H-pyrrol-2-yl)ethan-1-one (30 g, 159.56 mmol) and then heated at 80° C. for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (100 mL). The organic layer was fractionated from the filtrate and concentrated. The resulting crude product was purified by column chromatography using 10% methanol / DCM as an elution gradient to give (E)-1-(4-bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one (24.5 g, 65.51 mmol, 41.06% yield) as a yellow solid. LC-MS (ES + ): m / z 242.9[M+H] + .

[0224] Step 3: To a stirred solution of potassium tert-butoxide (83.08 g, 740.44 mmol) in NMP (1 L), (E)-1-(4-bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one (120.0 g, 493.62 mmol) was added and the reaction mixture was stirred at room temperature for 1-2 h. The reaction mixture was then cooled to -5 °C. Amino 4-nitrobenzoate (143.85 g, 789.80 mmol) was added and stirred at 0-5 °C for 16 h. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the pH was maintained at 2-3 and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and the crude material was purified by column chromatography (30% ethyl acetate in pet ether) to give 6-bromopyrrolo[1,2-b]pyridazin-4-ol (40.0 g, 184.84 mmol, 37.44% yield) as a yellow solid. LC-MS (ES - ): m / z 211.1[MH] - .

[0225] Step 4: A stirred solution of 6-bromopyrrolo[1,2-b]pyridazin-4-ol (7.0 g, 32.86 mmol) in DCM (500 mL) and the reaction mixture was cooled at 0° C. Triethylamine (9.98 g, 98.58 mmol, 13.74 mL), 4-dimethylaminopyridine (401.44 mg, 3.29 mmol), and trifluoromethyl N-phenyl-N-(trifluoromethoxysulfonyl)sulfamate (19.19 g, 49.29 mmol) were added sequentially and the reaction was monitored by LC-MS. Upon completion of the reaction, the mixture was quenched with citric acid and extracted with DCM. The organic layer was separated, washed with brine, and diluted with NaCl. 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product. The crude mixture was purified by column chromatography to give (6-bromopyrrolo[1,2-b]pyridazin-4-yl)trifluoromethanesulfonate (4.0 g, 11.51 mmol, 35.02% yield) as a colorless liquid. LC-MS (ES - ): m / z 343.1[MH]- .

[0226] Step 5: To a stirred solution of (6-bromopyrrolo[1,2-b]pyridazin-4-yl)trifluoromethanesulfonate (6.0 g, 17.39 mmol) and tert-butyl N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (4.83 g, 13.91 mmol) in dioxane (80 mL) / water (20 mL) under an argon atmosphere was added potassium carbonate (7.21 g, 52.16 mmol), Pd(dppf)Cl 2 (1.27 g, 1.74 mmol) was added. The reaction mixture was stirred at 50° C. for 16 h and the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was washed with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuum under reduced pressure. The crude was purified by column chromatography (230-400 mesh silica gel) using ethyl acetate in pet ether as eluent to give tert-butyl N-[[4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-2-methyl-phenyl]methyl]carbamate (5.5 g, 13.15 mmol, 75.61% yield) as a green sticky solid. LC-MS (ES + ): m / z 416.3[M+H] + .

[0227] Synthesis of tert-butyl N-[[4-(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-2-fluoro-phenyl]methyl]carbamate [ka] Step 1: To a solution of 2-bromo-7-chloro-pyrazolo[1,5-a]pyrimidine (2 g, 8.60 mmol) and tert-butyl N-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (2.42 g, 6.88 mmol) in dioxane (40 mL) was added granular potassium carbonate (2.38 g, 17.21 mmol) in water (8 mL) and the mixture was cooled to 37° C. for 1 hour. 2 The mixture was then purged with Pd(dppf)Cl for 15 minutes. 2 (314.76 mg, 430.17 μmol) was added and purged with nitrogen gas for 5 minutes. The reaction mixture was then heated to 60° C. for 2 hours and monitored by TLC and LC-MS. Upon completion, the mixture was filtered through a bed of Celite and the filtrate was concentrated to give the crude. The crude was purified by normal phase column chromatography (Devisil silica, 20% ethyl acetate / petroleum ether) using a Biotage® to give tert-butyl N-[[4-(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-2-fluoro-phenyl]methyl]carbamate (1.6 g, 3.29 mmol, 38.26% yield). LC-MS (ES + ): m / z 421.5[M+H] + .

[0228] Synthesis of 5-(tert-butyl)-N-(2-methyl-4-(6-(piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide: [ka] Step 1: 1,4-Dioxane (450 mL) and H 2 tert-Butyl N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (41.3 g, 118.93 mmol), 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (27.65 g, 118.93 mmol), K 2CO 3 (49.31 g, 356.80 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 A solution of (4.86 g, 5.95 mmol) was stirred at 80° C. for 18 h under an inert atmosphere. After cooling to room temperature, the mixture was diluted in water (400 mL) and extracted with ethyl acetate (250 mL×3). The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (Companion Combiflash; 720 g SiO 2 ; petroleum ether / EtOAc) to give tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (30.1 g, 68.52 mmol, 58% yield). 1 HNMR (500MHz, CDCl 3 )δ=8.49(s,1H),7.85(m,3H),7.42(brd,J=8.2Hz,1H),7.07(s,1H),4.92(brs,1H),4.40(brs,2H),2.43(s,3H),1.49(s,9H).

[0229] Step 2: tert-Butyl N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl]methyl]carbamate (29 g, 69.49 mmol), benzyl piperazine-1-carboxylate (45.92 g, 208.48 mmol, 40.21 mL), Cs 2 CO 3 (67.93 g, 208.48 mmol) was dissolved in 1,4-dioxane (350 mL). The solution was degassed under reduced pressure followed by the addition of RuPhos Pd G4 (3.54 g, 4.17 mmol). The reaction mixture was heated at 80° C. overnight under an argon atmosphere. After cooling to room temperature, the mixture was 2 The mixture was diluted with 2,5-dichloromethane (300 mL) and extracted with ethyl acetate (250 mL × 3). The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by column chromatography (Companion Combiflash; 720 g SiO 2; petroleum ether / EtOAc) to give benzyl 4-(4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)piperazine-1-carboxylate (22.1 g, 38.83 mmol, 56% yield) as a yellow oil. LC-MS (ES + ):m / z=557.4[M+H] + .

[0230] Step 3: To a solution of benzyl 4-[4-[4-[(2,2-dimethylpropanoylamino)methyl]-3-methylphenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]piperazine-1-carboxylate (10.6 g, 19.61 mmol) in 1,4-dioxane (40 mL) was added 24.51 mL of HCl in dioxane (4 M in dioxane, 24.51 mL) at room temperature and stirred for 7 h. The reaction mixture was evaporated in vacuum, triturated with MTBE (50 ml) and filtered to give benzyl 4-[4-[4-(aminomethyl)-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]piperazine-1-carboxylate (8.95 g, 16.52 mmol, 84% yield, hydrochloride salt) as a red solid. LC-MS (ES) + ):m / z=457.0[M+H] + .

[0231] Step 4: To a solution of benzyl 4-[4-[4-(aminomethyl)-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]piperazine-1-carboxylate (19.05 g, 38.64 mmol) in DCM (500 mL) and DMF (50 mL) was added 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (10.21 g, 57.96 mmol), HATU (22.10 g, 57.96 mmol), and DIPEA (14.98 g, 115.92 mmol, 20.19 mL). The mixture was stirred at 20° C. overnight. The mixture was poured into water (250 mL) and extracted with DCM (100 mL×3). The combined organic layers were washed with brine (2×150 mL), dried, and concentrated. The residue was purified by column chromatography (Companion CombiFlash; 240 g SiO 2 petroleum ether / MTBE (with 0-100% MTBE, flow rate = 80 mL / min. Rv = 50-130) to give benzyl 4-[4-[4-[[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]piperazine-1-carboxylate (7.2 g, 11.24 mmol, 29% yield) as a yellow solid. LC-MS (ES + ):m / z=609.2[M+H]+.

[0232] Step 5: A solution of benzyl 4-[4-[4-[[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]methyl]-3-methylphenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]piperazine-1-carboxylate (2.05 g, 3.37 mmol) and 10 wt% palladium on carbon (358.41 mg, 336.79 μmol) in methanol (120 mL) and HCl in water (1 M, 16.84 mL) was stirred under hydrogen atmosphere (1 atm) at room temperature for 14 h. The solution was filtered and concentrated in vacuo. For neutralization, 1 M potassium carbonate (1 M in water) was added and the solution was extracted with DCM (25 mL x 3) and evaporated. The crude material was purified by chromatography (Companion CombiFlash; 40 g SiO 2 Purification by elution with chloroform / methanol+TEA (2%), methanol+TEA (2%), 5-8% (flow rate = 40 mL / min, Rv = 5-12 CV) gave 5-tert-butyl-N-[[2-methyl-4-(6-piperazin-1-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (0.75 g, 1.45 mmol, 43% yield) as a yellow solid. LC-MS (ES) + ):m / z=475.2[M+H]+.

[0233] 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)benzoic acid: [ka] N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide (4.01 g, 8.54 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.33 g, 9.40 mmol), Pd(dppf)Cl in 1,4-dioxane (40 mL) and water (10 mL).2 ·CH 2 Cl 2 (697.74 mg, 854.40 μmol), and K 2 CO 3 A solution of (3.54 g, 25.63 mmol) was stirred at 90° C. for 12 h under an inert atmosphere. After cooling to room temperature, the mixture was concentrated, then diluted in water (250 ml) and filtered. The filtrate was dissolved in 1M NaHSO 4 The solid was then acidified with water (pH 3-4) and filtered. The solid was dried and purified by CH 3 The mixture was refluxed in CN (40 ml) and filtered. The cake was poured into CH 3 Washing with CN (20 ml) and drying gave 4-[4-[4-[[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]benzoic acid (3.7 g, 6.59 mmol, 77% yield) as a yellow solid. LC-MS (ES) + ):m / z=511.2[M+H]+.

[0234] 5-(tert-butyl)-N-(4-(6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide: [ka] 1,4-Dioxane (75 mL) and H 2 To a solution of tert-butyl N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (3.65 g, 8.75 mmol) in 2H2O (7.5 mL) was added (4-formylphenyl)boronic acid (1.44 g, 9.62 mmol), KCl under inert atmosphere. 2 CO 3 (3.63 g, 26.24 mmol) and Pd(dppf)Cl 2 CH 2 Cl 2(357.15 mg, 437.34 μmol) was added. The mixture was stirred at 80° C. for 18 h. After cooling to room temperature, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with brine, dried, filtered and concentrated. The residue was purified by column chromatography (Companion Combiflash; 120 g SiO 2 ; petroleum ether / EtOAc flow rate = 75 ml / min, Rv = 40-80 cv) to give tert-butyl N-[[4-[6-(4-formylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]carbamate (1.72 g, 3.69 mmol, 42% yield) as a yellow solid. LC-MS (ES + ):m / z=495.1[M+H]+.

[0235] 5-(tert-butyl)-N-(2-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] Step 1: A solution of tert-butyl N-[[4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl]methyl]carbamate (10 g, 21.81 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.65 g, 26.17 mmol), and KOAc (6.42 g, 65.42 mmol) in 1,4-dioxane (150 mL) was degassed and then heated at 80° C. overnight under an argon atmosphere. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (200 ml), filtered, and washed with brine (200 ml×2). The organic layer was extracted with Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Companion; 120 g SiO 2 ; purification by petroleum ether / MtBE (with 0-50% MtBE), flow rate = 85 ml / min, Rv = 8-9 cv) to give tert-butyl N-[[2-methyl-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (5 g, 9.69 mmol, 44% yield) as a yellow solid. 1 HNMR (500MHz, CDCl 3 )δ=8.55-8.42(m,1H),8.14(m,1H),8.02-7.83(m,2H),7.50-7.33(m,2H ), 4.82 (brs, 1H), 4.40 (brs, 2H), 2.54-2.33 (m, 3H), 1.48-1.27 (m, 21H).

[0236] Step 2: To a stirred solution of tert-butyl N-[[2-methyl-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (0.5 g, 1.08 mmol) in DCM (10 mL) was added TFA (5 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was triturated with diethyl ether (50 mL) to give [2-methyl-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methanamine (0.4 g, 355.53 μmol, 33.02% yield, TFA salt) as a yellow solid.

[0237] Step 3: To a solution of tert-butyl N-[[2-methyl-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (5 g, 10.77 mmol) in DCM (50 mL) was added TFA (33.09 g, 290.20 mmol, 22.22 mL) at room temperature. The solution was stirred for 48 h and then concentrated to give [2-methyl-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methanamine (5 g, 8.90 mmol, 83% yield trifluoroacetate) as a dark yellow oil, which was used in the next step without purification. A solution of [2-methyl-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methanamine (2.4 g, 5.03 mmol, trifluoroacetate), (5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)oxylithium (1.33 g, 7.26 mmol, lithium), HATU (2.88 g, 7.54 mmol), and DIPEA (1.95 g, 15.09 mmol, 2.63 mL) in DCM (50 ml) was stirred at room temperature overnight. The solution was washed with water, brine (50 ml x 2) and Na 2 SO 4 The mixture was dried over 1000 cc, filtered and concentrated. The residue was crystallized from i-PrOH\ether (2:1) to give 5-tert-butyl-N-[[2-methyl-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (0.91 g, 1.59 mmol, 31.54% yield). LC-MS (ES) + ):m / z=517.2[M+H] + .

[0238] Synthesis of 2-(4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate [ka] Step 1: Stir a solution of tert-butyl N-[[2-methyl-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (2.0 g, 4.31 mmol) and 2-(4-bromopyrazol-1-yl)ethyl acetate (1.00 g, 4.31 mmol) in 1,4-dioxane (24 mL) / water (6 mL) under an argon atmosphere, followed by K 2 CO 3 (1.79 g, 12.92 mmol) and PdCl 2 (dtbpf) (280.71 mg, 430.70 μmol) was added. The resulting mixture was stirred at 80° C. for 2 h and the progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was washed with water and extracted with ethyl acetate (3×100 mL), the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude. The crude was purified by column on (230-400 silica) EtOAc in PE as eluent to obtain ethyl 2-[4-[4-[4-[(tert-butoxycarbonylamino)methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrazol-1-yl]acetate (1.4 g, 2.68 mmol, 62.21% yield) as a yellow solid. LC-MS (ES + ): m / z 491.66[M+H] + .

[0239] Step 2: To a stirred solution of 2-[4-[4-[4-[(tert-butoxycarbonylamino)methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrazol-1-yl]ethyl acetate (1.4 g, 2.85 mmol) in DCM (30.0 mL) under inert atmosphere was added a 4.0 M solution of hydrogen chloride in dioxane (7.13 mL) at 0° C. The reaction mixture was then stirred at room temperature for 2 h and monitored by TLC and LCMS. After completion, the crude was concentrated under reduced pressure, triturated with diethyl ether (2×50 mL), and then dried again to give 2-[4-[4-[4-(aminomethyl)-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrazol-1-yl]ethyl acetate (1.4 g, 3.28 mmol) as a pale yellow solid. LC-MS (ES + ): m / z 391.35[M+H] + .

[0240] Step 3: To a stirred solution of 2-[4-[4-[4-(aminomethyl)-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrazol-1-yl]ethyl acetate (1.4 g, 3.28 mmol) and (5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)oxylithium (866.26 mg, 4.92 mmol) in DMF (15 mL) was added DIPEA (2.12 g, 16.40 mmol, 2.86 mL) and PyBOP (3.41 g, 6.56 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude material. The crude was washed with water and extracted with ethyl acetate (3×50 mL) and the combined organic layers were concentrated under reduced pressure to give the crude, which was purified by column chromatography using 230-400 mesh silica and ethyl acetate / pet ether as eluent to give 2-[4-[4-[4-[[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrazol-1-yl]ethyl acetate (0.8 g, 1.29 mmol, 39.26% yield) as a yellow solid. LC-MS (ES) + ): m / z 543.50[M+H] + .

[0241] Step 4: To a stirred solution of 2-[4-[4-[4-[[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrazol-1-yl]ethyl acetate (0.8 g, 1.47 mmol) in tetrahydrofuran (8 mL) / water (2 mL) was added lithium hydroxide monohydrate (92.80 mg, 2.21 mmol) at room temperature and stirred for 2 h. The solvent was reduced under pressure and the crude product was washed with 1N HCl solution to give 5-tert-butyl-N-[[4-[6-[1-(2-hydroxyethyl)pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (0.5 g, 864.25 μmol, 58.62% yield) as a yellow solid. LC-MS (ES) + ): m / z 501.57[M+H] + .

[0242] Step 5: To a solution of 5-tert-butyl-N-[[4-[6-[1-(2-hydroxyethyl)pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide (0.55 g, 1.10 mmol) in DCM (5 mL) was added methanesulfonyl chloride (188.80 mg, 1.65 mmol, 127.83 μL) at room temperature and the reaction mixture was cooled to 0° C. Triethylamine (222.37 mg, 2.20 mmol, 306.30 μL) was added dropwise and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (20 mL) and saturated NaHCO 3The organic layer was dried over sodium sulfate and concentrated in vacuo to give 2-[4-[4-[4-[[(5-tert-butyl-1,2,4-oxadiazole-3-carbonyl)amino]methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]pyrazol-1-yl]ethyl methanesulfonate (0.5 g, 713.22 μmol, 64.91% yield), which was used in the next step without purification. LC-MS (ES) + ): m / z 579.61[M+H] + .

[0243] Synthesis of 3-((4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)propyl methanesulfonate [ka] Step 1: To a stirred solution of tert-butyl N-[[2-methyl-4-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (1 g, 2.15 mmol) in THF (15 mL) was slowly added sodium hydroxide (1.72 g, 43.07 mmol) in water. The reaction mixture was then stirred for 10 min and 35% aqueous hydrogen peroxide (1.47 g, 43.07 mmol, 1.33 mL) was added dropwise (while the addition reaction mixture turned dark red and fluorescence was observed), stirred at room temperature for 16 h and monitored by TLC and LC-MS. After completion, it was neutralized with 1.5 N HCl solution and extracted with ethyl acetate. The resulting organic layer was washed with brine solution and Na 2 SO 4The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 0-60% EA in PE to give tert-butyl N-[[4-(6-hydroxypyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (0.6 g, 1.46 mmol, 67.61% yield) as a deep pink liquid. LC-MS (ES + ): m / z 355.45[M+H] + .

[0244] Step 2: To a solution of tert-butyl N-[[4-(6-hydroxypyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (1.5 g, 4.23 mmol) and 3-bromopropoxy-tert-butyl-dimethyl-silane (2.14 g, 8.46 mmol) in DMF (20 mL) was added potassium carbonate (1.75 g, 12.69 mmol) and stirred at 80° C. for 5 h. The reaction mixture was quenched with ice-cold water (100 mL) and extracted with ethyl acetate (50 mL×3). The organics were washed with water (100 mL) and brine solution (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl N-[[4-[6-[3-[tert-butyl(dimethyl)silyl]oxypropoxy]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]carbamate (2 g, 2.24 mmol, 52.88% yield). LC-MS (ES) + ): m / z 527.58[M+H] + .

[0245] Step 3: Argon gas was purged through a solution of tert-butyl N-[[4-[6-[3-[tertbutyl(dimethyl)silyl]oxypropoxy]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]carbamate (2 g, 3.80 mmol) in THF (40 mL) for 5 min, followed by addition of tetrabutylammonium fluoride (1 M, 5.70 mL) to the reaction mixture at 0° C. The resulting mixture was stirred at 27° C. for 2 h. The reaction was monitored by TLC and LCMS. After the starting material was consumed. The reaction was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude was purified by column chromatography on silica gel (230-400 mesh) (using 0-10% EtOAc in pet ether as eluent) to give tert-butyl N-[[4-[6-(3-hydroxypropoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]carbamate (0.9 g, 1.75 mmol, 45.97% yield). LC-MS (ES) + ): m / z 413.62[M+H] + .

[0246] Step 4: To a solution of tert-butyl N-[[4-[6-(3-hydroxypropoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]carbamate (0.9 g, 2.18 mmol) in DCM (10 mL) was added triethylamine (1.10 g, 10.90 mmol, 1.52 mL) and stirred for 5 min, after which MsCl (374.58 mg, 3.27 mmol, 253.61 μL) was added to the reaction mixture at 0° C. The resulting mixture was stirred at 27° C. for 3 h. The reaction mixture was quenched with saturated bicarbonate solution (50 mL) and extracted with DCM (50 mL×3). The DCM layer was washed with water (50 mL) and brine solution (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-[4-[4-[(tert-butoxycarbonylamino)methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]oxypropyl methanesulfonate (0.9 g, 1.36 mmol, 62.28% yield). LC-MS (ES + ): m / z 491.73[M+H] + .

[0247] Synthesis of (R)-3-((4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)oxy)-2-fluoropropyl trifluoromethanesulfonate [ka] Step 1: To a stirred solution of tert-butyl N-[[4-(6-hydroxypyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (10 g, 28.22 mmol) in ethanol (100 mL) was added potassium carbonate (11.70 g, 84.65 mmol, 5.11 mL) followed by (2S)-2-(trityloxymethyl)oxirane (8.93 g, 28.22 mmol) and the reaction mixture was heated at 70° C. for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The obtained crude was diluted with water (200 mL) and extracted with ethyl acetate (200×3 mL). The combined organic layers were washed with brine solution (100×3 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The resulting crude product was purified by silica gel (100-200 mesh, 25% ethyl acetate in PET ether as mobile phase) to give tert-butyl N-[[2-methyl-4-[6-[(2S)-2-hydroxy-3-trityloxy-propoxy]pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (6 g, 7.78 mmol, 27.58% yield) as a yellow solid. LC-MS (ES) + ): m / z 671.51[M+H] + .

[0248] Step 2: To a stirred solution of tert-butyl N-[[2-methyl-4-[6-[rac-(2S)-2-hydroxy-3-trityloxy-propoxy]pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (6.00 g, 8.94 mmol) in DCM (60 mL) was added (diethylamino)sulfur trifluoride (3.60 g, 22.36 mmol, 2.95 mL) at -78°C and stirred at the same temperature for 20 min and then warmed to room temperature for 10 min. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The resulting crude was purified by silica gel (100-200 mesh, 25% ethyl acetate in pet ether as mobile phase) to give tert-butyl N-[[2-methyl-4-[6-[(2R)-2-fluoro-3-trityloxy-propoxy]pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (2.5 g, 2.86 mmol, 31.99% yield) as a yellow solid. LC-MS (ES) + ): m / z 673.73[M+H] + .

[0249] Step 3: To a stirred solution of tert-butyl N-[[2-methyl-4-[6-[(2R)-2-fluoro-3-trityloxy-propoxy]pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (4.00 g, 5.95 mmol) in DCM, trifluoroacetic acid was added at −78° C. and stirred at the same temperature for 1 h. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The resulting crude was purified by silica gel (100-200 mesh, 40% ethyl acetate in PET ether as mobile phase) to give tert-butyl N-[[2-methyl-4-[6-[rac-(2S)-2-fluoro-3-hydroxy-propoxy]pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (2 g, 4.46 mmol, 75.02% yield) as a yellow solid. LC-MS (ES) + ): m / z 431.23[M+H] + .

[0250] Step 4: To a stirred solution of tert-butyl N-[[2-methyl-4-[6-[rac-(2S)-2-fluoro-3-hydroxy-propoxy]pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (1 g, 2.32 mmol) in DCM (10 mL) was added 2,6-lutidine (622.30 mg, 5.81 mmol, 674.21 μL) followed by trifluoromethanesulfonic anhydride (1.18 g, 4.18 mmol, 703.49 μL) at −10° C. and the reaction mixture was stirred at the same temperature for 30 min. After completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under high vacuum to give the crude product. The resulting crude was purified by silica gel (230-400 mesh, 10% ethyl acetate in pet ether as mobile phase) to give [(2R)-3-[4-[4-[(tert-butoxycarbonylamino)methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]oxy-2-fluoro-propyl]trifluoromethanesulfonate (0.7 g, 1.02 mmol, 43.92% yield) as a yellow oil. LC-MS (ES) + ): m / z 563.57[M+H] + .

[0251] Synthesis of tert-butyl (2-methyl-4-(6-(2-oxoethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] Step 1: To a stirred solution of tert-butyl N-[[4-(6-hydroxypyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (0.6 g, 1.69 mmol) in acetone (15 mL), potassium carbonate (anhydrous) 99% (701.95 mg, 5.08 mmol) was added and stirred at room temperature for 30 minutes. Then, 3-bromoprop-1-ene (307.22 mg, 2.54 mmol, 219.44 μL) was added and allowed to stir at room temperature for 16 hours. After completion, the reaction mass was concentrated under reduced pressure and the crude was purified by normal phase column chromatography using Biotage (Davisil silica, 10% ethyl acetate / PE as eluent) to give tert-butyl N-[[4-(6-allyloxypyro[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (0.45 g, 1.04 mmol, 61.47% yield). LC-MS (ES) + ): m / z 395.48[M+H] + .

[0252] Step 2: To a stirred solution of tert-butyl N-[[4-(6-allyloxypyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methyl-phenyl]methyl]carbamate (0.42 g, 1.06 mmol) in THF (2 mL) was added potassium osmate(VI) dihydrate (19.62 mg, 53.24 μmol), followed by sodium periodate (1.14 g, 5.32 mmol) in water (2 mL), stirred for 1 h and monitored by TLC. After completion, it was quenched with water, extracted with ethyl acetate, concentrated, and the resulting residue was taken up in THF (2 mL), sodium periodate (1.14 g, 5.32 mmol) in water (2 mL) was added, stirred for 1 h and monitored by TLC and LCMS analysis. Again, it was quenched with water and extracted with ethyl acetate. The organic layer was concentrated to 100 mL with 10% NaCl. 2 SO 4The mixture was dried at 40° C. and concentrated under reduced pressure to give tert-butyl N-[[2-methyl-4-[6-(2-oxoethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]carbamate (0.2 g, 200.03 μmol, 18.79% yield) as a pale yellow compound. LC-MS (ES + ): m / z 397.41[M+H] + .

[0253] Synthesis of tert-butyl (4-(6-(3-formylcyclobutoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] Step 1: To a stirred solution of tert-butyl N-[[4-(6-hydroxypyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl]methyl]carbamate (1.5 g, 4.23 mmol) in DMF (25 mL) was added methyl 3-((methylsulfonyl)oxy)cyclobutane-1-carboxylate (1.32 g, 6.35 mmol) at room temperature followed by potassium carbonate (1.75 g, 12.70 mmol) at 80° C. for 18 h. The progress of the reaction was monitored by LC-MS and TLC. Upon completion, the reaction was diluted with water (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with brine solution (50 mL) and then the organic layer was washed with anhydrous NaCl. 2 SO 4 The crude was purified by column chromatography using silica gel 230-400 mesh (20-25% EA / PE) to give methyl 3-[4-[4-[(tert-butoxycarbonylamino)methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]oxycyclobutanecarboxylate (1 g, 1.71 mmol, 40.52% yield) as a yellow liquid. LC-MS (ES + ): m / z 467.38[M+H] + .

[0254] Step 2: To a stirred solution of methyl 3-[4-[4-[(tert-butoxycarbonylamino)methyl]-3-methyl-phenyl]pyrrolo[2,1-f][1,2,4]triazin-6-yl]oxycyclobutanecarboxylate (1 g, 2.14 mmol) in THF (40 mL) was added LAH in THF (2.4 M, 1.79 mL) slowly at −78° C. and stirred for about 1 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with cold water (50 mL) and the aqueous layer was extracted with EtOAc (3×40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product tert-butyl N-[[4-[6-[3-(hydroxymethyl)cyclobutoxy]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylphenyl]methyl]carbamate (0.8 g, 1.53 mmol, 71.49% yield) as a yellow liquid. LC-MS (ES) + ): m / z 439.35[M+H] + .

[0255] Step 3: To a stirred solution of tert-butyl N-[[4-[6-[3-(hydroxymethyl)cyclobutoxy]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methylphenyl]methyl]carbamate (1 g, 2.28 mmol) in DCM (50 mL) was added Dess-Martin periodinane (1.45 g, 3.42 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 2 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with DCM (100 mL) and washed with saturated NaHCO 3 The combined organic layers were dried over sodium sulfate and concentrated under high vacuum to give the crude product tert-butyl N-[[4-[6-(3-formylcyclobutoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methyl]carbamate (900 mg, 742.26 μmol, 32.55% yield) as a yellow oil. The crude product was used in the next step without further purification. LC-MS (ES+ ): m / z 437.69[M+H] + .

[0256] Synthesis of tert-butyl (8-(6-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)carbamate [ka] Step 1: To a stirred solution of 3-bromophenol (20 g, 115.60 mmol) and methyl 4-bromobutanoate (25.20 g, 139.21 mmol) in DMF (100 mL) was added K 2 CO 3 (31.95 g, 231.20 mmol) was added at room temperature and stirred for 30 min. The reaction mixture was then stirred at 95° C. for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×400 mL). The organic layer was washed with brine (200 mL) and then Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure to give the crude product, methyl 4-(3-bromophenoxy)butanoate (23.8 g, 80.16 mmol, 69.34% yield) as a brown liquid. LC-MS (ES + ): m / z 272.10[M+H] + .

[0257] Step 2: To a stirred solution of methyl 4-(3-bromophenoxy)butanoate (18 g, 65.90 mmol) in methanol (100 mL) was added 3N aqueous NaOH solution (70 mL) at room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, MeOH was removed by concentration and diluted with water (100 mL). The reaction mass was acidified to pH=2 with concentrated HCl (20 mL) and extracted with ethyl acetate (2×500 mL). The organic layer was washed with Na 2 SO 4The mixture was dried at 40° C. and concentrated under reduced pressure to give 4-(3-bromophenoxy)butanoic acid (15 g, 54.53 mmol, 82.74% yield) as a brown semi-solid. LC-MS (ES + ): m / z 257.25[M+H] + .

[0258] Step 3: To a stirred solution of polyphosphoric acid (20 g) and Celite (15 g) in toluene (50 mL) was added 4-(3-bromophenoxy)butanoic acid (5 g, 19.30 mmol) at room temperature. The reaction mixture was then stirred at 110° C. for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a Celite bed and the bed was washed with ethyl acetate (300 mL). The organic layer was washed with water (200 mL) and then with Na 2 SO 4 The crude was purified by column chromatography using 230-400 silica eluted with 0-10% ethyl acetate in pet ether to give the product 8-bromo-3,4-dihydro-2H-1-benzoxepin-5-one (2.5 g, 9.20 mmol, 47.66% yield) as a pale yellow liquid. LC-MS (ES + ): m / z 241.08[M+H] + .

[0259] Step 4: To a stirred solution of 8-bromo-3,4-dihydro-2H-1-benzoxepin-5-one (3.9 g, 16.18 mmol) in methanol (65 mL) was added acetic acid (1.13 g, 18.87 mmol, 1.08 mL), 7M ammonia in MeOH (16.18 mmol, 67 mL), and sodium cyanoborohydride (2.21 g, 35.17 mmol). The reaction mixture was heated in a steel bomb at 75° C. for 12 h. Upon completion, the reaction mixture was concentrated in vacuo and the product was extracted with DCM (2×50 mL), washed with water (1×25 mL) and brine solution (1×25 mL), then diluted with NaCl. 2 SO 4The organic layer was concentrated under vacuum to give a residue which was purified by column chromatography using 80-100% EtOAc / PE as eluent to give 8-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5-amine (1.8 g, 6.69 mmol, 41.36% yield) as a brown sticky solid. 1 HNMR (400MHz, DMSO-d 6 )δ7.45(d,1H,J=8.4Hz),7.27(dd,J=8.4,8.4Hz,1H),7.14-7.096(m,2H),4.67(t,J=18,1 H),4.23(d,J=12Hz,1H),3.61(t,J=9.6Hz,1H),1.94-1.84(m,3H),1.62(t,J=9.6Hz,2H).

[0260] Step 5: To a stirred solution of 8-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5-amine (2.7 g, 11.15 mmol) in dry DCM (33.19 mL) was added triethylamine (2.26 g, 22.30 mmol, 3.11 mL) with N 2 The reaction mixture was stirred at the same temperature for 30 minutes, and (Boc) 2 O (2.68 g, 12.27 mmol, 2.82 mL) was added dropwise over 1 h. The reaction mixture was allowed to warm to room temperature and stirred at ambient temperature for 12 h. The reaction mixture was quenched with ice-cold water (50 ml) and the organic layer was separated. The organic layer was further washed with water (3×50 ml), brine (1×50 ml) and added Na 2 SO 4 The mixture was dried at rt, filtered and concentrated in vacuo to give the crude compound which was purified by column chromatography using silica gel (100 / 200 mesh) and 40-50% ethyl acetate in hexanes to give tert-butyl N-(8-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5-yl)carbamate (1.65 g, 4.34 mmol, 38.91% yield) as a colorless solid. 1 HNMR (400MHz, DMSO-d 6)δ7.45(d,1H,J=8.4Hz),7.27(dd,J=8.4,8.4Hz,1H),7.14-7.096(m,2H),4.67(t,J=18,1H),4.23( d,J=12Hz,1H),3.61(t,J=9.6Hz,1H),1.94-1.84(m,3H),1.62(t,J=9.6Hz,2H),1.46-1.37(m,12H).

[0261] Step 6: To a stirred solution of tert-butyl N-(8-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5-yl)carbamate (2 g, 5.84 mmol) in 1,4-dioxane (30 mL), 2 pin 2 (1.56 g, 7.01 mmol) and potassium acetate (1.43 g, 14.61 mmol, 913.30 μL) were added, and the entire reaction mixture was degassed for 10 min, after which PdCl 2 (dppf) (42.76 mg, 58.44 μmol) was added and the reaction mixture was stirred at 90-95 °C for 16 h. After completion of the reaction, the reaction mixture was filtered through Celite and concentrated under high vacuum. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were concentrated and purified by column chromatography to give tert-butyl N-[8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1-benzoxepin-5-yl]carbamate (1.7 g, 4.15 mmol, 70.99% yield). 1 HNMR (400MHz, DMSO-d 6 )δ7.42(d,1H,J=8.4Hz),7.36(d,J=7.6Hz,1H),7.20(t,J=6.4Hz,2H),4.73(t,J=9.2Hz,1H),4.21(t,J=11.6Hz,1H),3 .55(t,J=10.0Hz,1H),1.988-1.844(m,4H),1.60(d,J=10.0Hz,1H),1.41(d,J=16.0Hz,9H),1.27(s,14H),1.16(s,3H).

[0262] Step 7: To a stirred solution of 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (1.48 g, 6.37 mmol) and tert-butyl N-[8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1-benzoxepin-5-yl]carbamate (1.98 g, 5.09 mmol) in water (15 mL) and 1,4-dioxane (60 mL), was added K 2 CO 3 (2.20 g, 15.92 mmol) was added at room temperature under argon. The reaction mixture was degassed with argon for 10 min and PdCl 2 (dppf) (0.117 g, 159.16 μmol) was added in one portion. The reaction mixture was again degassed with argon for an additional 15 min, then the reaction was heated to 60 °C for 12 h. The reaction mixture was filtered through a bed of celite and washed with ethyl acetate (100 mL). The filtrate was concentrated to give the crude compound, which was purified by column chromatography on silica gel (100 / 200 mesh). The product was eluted with 20-30% ethyl acetate in hexane to give tert-butyl N-[8-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,3,4,5-tetrahydro-1-benzoxepin-5-yl]carbamate (2 g, 2.98 mmol, 46.76% yield) as a yellow solid. LC-MS (ES) + ): m / z 459.54[M+H] + .

[0263] Step 8: To a solution of tert-butyl (8-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)carbamate (500 mg, 1.09 mmol) in 1,4-dioxane (15.21 mL), triethylamine (330.44 mg, 3.27 mmol, 455.16 μL), but-3-yn-1-ol (76.29 mg, 1.09 mmol, 82.30 μL) and CuI (20.73 mg, 108.85 μmol) were added at room temperature under purging. The reaction mixture was purged with argon gas for 10 minutes followed by addition of Pd(dppf)Cl. 2 (38.20 mg, 54.43 μmol) was added. The reaction mixture was purged with argon for another 5 min and it was stirred at 90° C. for 4 h. Upon completion of the reaction, the reaction mixture was filtered through Celite and concentrated in vacuo to give the crude product, which was purified by flash chromatography using 230-400 mesh silica and 60-70% ethyl acetate in petroleum ether as eluent to give tert-butyl (8-(6-(4-hydroxybut-1-yn-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)carbamate (350 mg, 758.82 μmol, 69.71% yield) (2.5 g, 4.25 mmol, 45.39% yield) as a yellow gum. LC-MS (ES + ): m / z 449.66[M+H] + .

[0264] Step 9: To a stirred solution of tert-butyl (8-(6-(4-hydroxybut-1-yn-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)carbamate (800 mg, 1.78 mmol) in ethyl acetate (15 mL) and ethanol (5 mL) was added 10% Pd / C on a 50% wet basis (800 mg, 1.78 mmol). The resulting reaction mixture was cooled to 5° C. for 2 hours at 37° C. for 1 hour and then cooled to 5° C. for 2 hours. 2The mixture was stirred at room temperature under reduced pressure for 4 hours. Upon completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated to give crude tert-butyl (8-(6-(4-hydroxybutyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)carbamate (400 mg, 617.31 μmol, 34.61% yield). LC-MS (ES + ): m / z 453.61[M+H] + .

[0265] Step 10: To a stirred solution of tert-butyl (8-(6-(4-hydroxybutyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)carbamate (300 mg, 662.92 μmol) in DCM (15 mL) was added TEA (67.08 mg, 662.92 μmol, 92.40 μL) followed by MsCl (75.94 mg, 662.92 μmol, 51.41 μL) at 0° C. The resulting reaction mixture was stirred at room temperature under an inert atmosphere. Upon completion, the reaction was quenched in water (100 mL), extracted with DCM (2×30 mL) and then washed with brine (1×30 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo to give 4-(4-(5-((tert-butoxycarbonyl)amino)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)butyl methanesulfonate (300 mg, 529.12 μmol, 79.82% yield). LC-MS (ES + ): m / z 531.65[M+H] + .

[0266] Step 11: To a stirred solution of 4-(4-(5-((tert-butoxycarbonyl)amino)-2,3,4,5-tetrahydrobenzo[b]oxepin-8-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)butyl methanesulfonate (300 mg, 565.36 μmol) in acetone (10 mL) was added LiBr (49.10 mg, 565.36 μmol, 14.19 μL). The resulting reaction mixture was stirred at 80° C. under inert atmosphere. Completion of the reaction was confirmed by LCMS. After completion, the reaction mass was concentrated to give the crude product which was quenched in water (15 mL), extracted with DCM (2×10 mL) and washed with brine (1×15 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo to give tert-butyl (8-(6-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)carbamate (200 mg, 299.74 μmol, 53.02% yield). LC-MS (ES + ): m / z 515.56[M+H] + .

[0267] III. Synthesis of DSM Precursors 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. [ka]

[0268] The intermediate 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione was prepared according to the method described on page 268 of WO2018237026A1. [ka]

[0269] 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. [ka]

[0270] The intermediate 3-(2-oxo-6-(piperidin-4-yl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione was prepared according to the method described on page 203 of WO2021127586 A1. [ka]

[0271] The intermediate 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione was prepared according to the method described on page 197 of WO2021127586 A1. [ka]

[0272] Synthesis of 3-[4-(2,2-dimethyl-4-piperidyl)anilino]piperidine-2,6-dione [ka] Step 1: A solution of tert-butyl 6,6-dimethyl-4-(4-nitrophenyl)-2,5-dihydropyridine-1-carboxylate (2.3 g, 6.92 mmol) and 10 wt% palladium on carbon (736.43 mg, 6.92 mmol) in ethanol (15 mL) and ethyl acetate (15 mL) was stirred at room temperature under hydrogen pressure for 16 h. The reaction was filtered through a bed of celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel 230-400 mesh, 0-100% ethyl acetate in pet ether) to give tert-butyl 4-(4-aminophenyl)-2,2-dimethyl-piperidine-1-carboxylate (1.5 g, 4.68 mmol, 67.64% yield) as a white solid. LC-MS (ES) + ): m / z 305.43[M+H] + .

[0273] Step 2: A solution of tert-butyl 4-(4-aminophenyl)-2,2-dimethyl-piperidine-1-carboxylate (0.2 g, 656.97 μmol), 3-bromopiperidine-2,6-dione (378.44 mg, 1.97 mmol) and sodium bicarbonate (551.90 mg, 6.57 mmol) in DMF (3 mL) was purged with argon for 15 minutes. The resulting mixture was stirred at 70° C. for 16 hours. The reaction mixture was quenched with water and washed with ethyl acetate (50 mL×2). The filtrate was washed with water (50 mL) and brine solution (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel 230-400 mesh, 0-100% ethyl acetate in pet ether) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-2,2-dimethyl-piperidine-1-carboxylate (0.18 g, 412.74 μmol, 62.82% yield). LC-MS (ES) + ): m / z 416.36[M+H] + .

[0274] Step 3: To a stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-2,2-dimethyl-piperidine-1-carboxylate (1 g, 2.41 mmol) in DCM (15 mL) was added dropwise trifluoroacetic acid 99% (7.40 g, 64.90 mmol, 5 mL) at 0° C. The reaction was stirred at 27° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product which was triturated with diethyl ether to give the final product 3-[4-(2,2-dimethyl-4-piperidyl)anilino]piperidine-2,6-dione TFA salt (1 g, 2.22 mmol, 92.21% yield) as a grey solid. LC-MS (ES + ): m / z 316.39[M+H] + .

[0275] The intermediate 3-[4-(8-azabicyclo[3.2.1]octan-3-yl)anilino]piperidine-2,6-dione was prepared following the synthesis of 3-[4-(2,2-dimethyl-4-piperidyl)anilino]piperidine-2,6-dione. [ka] LC-MS(ES + ): m / z 314.36[M+H] + .

[0276] The intermediate 3-((4-(piperidin-3-yl)phenyl)amino)piperidine-2,6-dione was prepared following the synthesis of 3-[4-(2,2-dimethyl-4-piperidyl)anilino]piperidine-2,6-dione. [ka] LC-MS(ES + ): m / z 288.36[M+H] + .

[0277] The intermediate 3-((4-(piperidin-4-yl)-3-(trifluoromethyl)phenyl)amino)piperidine-2,6-dione was prepared following the synthesis of 3-[4-(2,2-dimethyl-4-piperidyl)anilino]piperidine-2,6-dione. [ka] LC-MS(ES + ): m / z 245.10[M+H] + .

[0278] Synthesis of 3-[4-(3,3-difluoro-4-piperidyl)anilino]piperidine-2,6-dione [ka] 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 the reaction was complete 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, 40% yield) as a brown-black solid. 1 HNMR (400MHz, CDCl 3 )δ8.19(d,J=8.8Hz,2H),7.96(d,J=8.8Hz,2H),1.37(s,12H).

[0279] Step 2: In a sealed tube, 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 to sodium carbonate (4.62 g, 43.56 mmol) and Pd(dppf)Cl under an argon atmosphere. 2 (1.59 g, 2.18 mmol) was added. The resulting mixture was stirred at 55° C. for 3 h 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 (3×250 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 in pet ether) to give tert-butyl 3,3-difluoro-4-(4-nitrophenyl)-2,6-dihydropyridine-1-carboxylate (4.4 g, 11.64 mmol, 53% yield) as a sticky solid. 1 HNMR (400MHz, CDCl 3 )δ8.27(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),1.44(s,9H).

[0280] 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 back-filled 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 shown by TLC, the reaction mixture was filtered through a bed of celite. 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% yield) as a white solid. LC-MS (ES + ): m / z 257.2 [M-tBu+H] + .

[0281] 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 in 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, 74% yield). LC-MS (ES - ): m / z 422.24[MH] - .

[0282] 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 hydrochloride (0.4 g, 1.06 mmol, 89% yield) as a solid. LC-MS (ES + ): m / z 324.09[M+H] + .

[0283] Synthesis of (3S)-3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione and (3R)-3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione [ka] Step 1: A solution of 1-bromo-2-fluoro-4-nitro-benzene (6 g, 27.27 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (8.43 g, 27.27 mmol) in dioxane (60 mL) and water (15 mL) in a round bottom flask was purged with argon gas for 10 minutes, followed by the addition of granular potassium carbonate (11.31 g, 81.82 mmol). The solution was purged with argon gas for an additional 20 minutes, after which Pd(PPh 3 ) 4(1.58 g, 1.36 mmol) was added and the reaction was stirred at 90° C. for 16 h. The progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was filtered through a bed of celite 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 (2×150 ml). The combined organic layers were concentrated in vacuo and purified by normal phase column chromatography (Devisil silica, 5% ethyl acetate in pet ether) to give tert-butyl 4-(2-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.95 g, 18.27 mmol, 67.01% yield) as a pale yellow solid. LC-MS (ES + ): m / z 267.15[M-tBu+H] + .

[0284] 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 10% palladium on carbon, 487 type, dry (3 g, 28.19 mmol) at room temperature. The reaction mixture was stirred at this temperature under hydrogen atmosphere for 6 hours and the progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the compound tert-butyl 4-(4-amino-2-fluoro-phenyl)piperidine-1-carboxylate (2.5 g, 5.95 mmol, 63.88% yield) as a purple solid, which was carried on to the next step without purification. LC-MS (ES + ): m / z 239.30 [M-tBu+H] + .

[0285] 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 minutes, after which sodium bicarbonate (3.57 g, 42.46 mmol) was added and the reaction was heated at 60° C. for 16 hours. The progress of the reaction was monitored by LC-MS and TLC. After completion of the reaction, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by column chromatography (Devisil silica, 0-30% ethyl acetate in pet ether) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (1.8 g, 3.64 mmol, 42.86% yield) as a brown solid. LC-MS (ES) - ): m / z 404.3[MH] - .

[0286] Step 4: Racemic tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperidine-1-carboxylate (800 mg, 1.97 mmol) was separated by chiral SFC column to give peak 1 (380 mg, 927.83 μmol, 47.02% yield) as an off-white solid and peak 2 (360 mg, 879.00 μmol, 44.55% yield) as an off-white solid. SFC conditions YMC Cellulose SC [250 x 30 mm, 5 microns] Mobile phase: 40% IPA-CO2 Flow rate: 120mL / min Cycle time: 7.6 minutes Back pressure: 100 bar UV: 210nm

[0287] [ka] Peak 1: tert-Butyl 4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]piperidine-1-carboxylate. >99.99% ee. LC-MS (ES - ): m / z 404.2[MH] - .

[0288] [ka] Peak-2: tert-Butyl 4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]piperidine-1-carboxylate. >99.99% ee. LC-MS (ES + ): m / z 406.1 [M+H] + .

[0289] Step 5: To a stirred solution of tert-butyl 4-[4-[[(3S)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]piperidine-1-carboxylate (0.1 g, 246.63 μmol) in DCM (15 mL) was added trifluoroacetic acid (740.00 mg, 6.49 mmol, 0.5 mL) dropwise at 0° C. The reaction was stirred at 27° C. for 3 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product, which was triturated with diethyl ether to give (3S)-3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione TFA salt (0.100 g, 223.91 μmol, 90.79% yield) as a light blue solid. LC-MS (ES + ): m / z 306.35[M+H] + .

[0290] Step 6: In a 50 mL one-neck round bottom flask, a solution of tert-butyl 4-[4-[[(3R)-2,6-dioxo-3-piperidyl]amino]-2-fluoro-phenyl]piperidine-1-carboxylate (1.8 g, 4.44 mmol) in dry DCM (8 mL) was added at 0° C. with 4 M hydrogen chloride solution in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 2 h and monitored by UPLC. After consumption of the starting material, the reaction mixture was concentrated under reduced pressure, triturated with diethyl ether (20 ml) and dried under reduced pressure to give (3R)-3-[3-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione HCl salt (1.5 g, 4.32 mmol, 97.26% yield) as an off-white solid. LC-MS (ES+): m / z 306.2 [M+H] + .

[0291] Synthesis of 3-[4-[3-(methylamino)propyl]anilino]piperidine-2,6-dione [ka] Step 1: To a stirred solution of tert-butyl N-methyl-N-[3-(4-nitrophenyl)prop-2-ynyl]carbamate (9.2 g, 31.69 mmol) in THF (40 mL), methanol (40 mL), and water (20 mL) at 0° C., zinc (41.44 g, 633.80 mmol) and ammonia hydrochloride (33.90 g, 633.80 mmol) were added and the mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LC-MS. The reaction was filtered through a bed of Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to a residue. Saturated NaHCO 3The solution was added to the residue and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel 100-200 mesh, 15% ethyl acetate in pet ether) to give tert-butyl N-[3-(4-aminophenyl)prop-2-ynyl]-N-methyl-carbamate (8.50 g, 29.39 mmol, 92.73% yield). LC-MS (ES) + ): m / z 261.40[M+H] + .

[0292] Step 2: To a stirred solution of tert-butyl N-[3-(4-aminophenyl)prop-2-ynyl]-N-methyl-carbamate (8 g, 30.73 mmol) in ethyl acetate (100 mL) and ethanol (100 mL) at room temperature was added 10 wt% palladium on carbon (10 g, 93.97 mmol) and the reaction was stirred at this temperature under a hydrogen atmosphere. Upon completion, the reaction was filtered through a bed of celite, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh, 0-10% ethyl acetate in pet ether) to give tert-butyl N-[3-(4-aminophenyl)propyl]-N-methyl-carbamate (5.9 g, 20.68 mmol, 67.29% yield). LC-MS (ES) + ): m / z 265.32[M+H] + .

[0293] Step 3: An oven-dried sealed tube (50 mL) was charged with tert-butyl N-[3-(4-aminophenyl)propyl]-N-methyl-carbamate (600 mg, 2.27 mmol) and 3-bromopiperidine-2,6-dione (522.95 mg, 2.72 mmol) in DMF (5 mL). Sodium bicarbonate (571.99 mg, 6.81 mmol) was added at room temperature and the mixture was stirred at 85° C. for 16 h. The reaction mixture was cooled to room temperature, poured onto ice (200 g), extracted with ethyl acetate (2×150 mL), and the combined organics were then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography (100 g snap, 230 × 400 mesh silica, 80-90% ethyl acetate in petroleum ether) to give tert-butyl N-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl]-N-methyl-carbamate (500 mg, 972.14 μmol, 42.83% yield) as a pale yellow liquid. LC-MS (ES) - ): m / z 374.2[MH] - .

[0294] Step 4: To a stirred solution of tert-butyl N-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl]-N-methyl-carbamate (0.5 g, 1.33 mmol) in DCM (10 mL) under argon atmosphere, 2,2,2-trifluoroacetic acid (5.92 g, 51.92 mmol, 4 mL) was added at 0° C. and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude compound. The crude product was washed with ether to give 3-[4-[3-(methylamino)propyl]anilino]piperidine-2,6-dione TFA salt (0.4 g, 886.36 μmol, 66.56% yield). LC-MS (ES + ): m / z 276.41[M+H] + .

[0295] Synthesis of 3-[4-(3-piperazin-1-ylpropyl)anilino]piperidine-2,6-dione [ka] Step 1: To a stirred solution of 3-(4-nitrophenyl)propanoic acid (10 g, 51.24 mmol) in THF (100 mL) was added borane in tetrahydrofuran solution (1 M, 10 mL) at 0° C. under nitrogen and the reaction was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give 3-(4-nitrophenyl)propan-1-ol (9 g, 47.19 mmol, 92.10% yield) as a crude product, which was used in the next step without purification. LC-MS (ES + ): m / z 182.1 [M+H] + .

[0296] Step 2: Argon gas was purged through a solution of 3-(4-nitrophenyl)propan-1-ol (3 g, 16.56 mmol) and triphenylphosphine (17.37 g, 66.24 mmol) in DCM (50 mL) for 15 min, followed by the addition of carbon tetrabromide (21.97 g, 66.24 mmol, 6.42 mL) to the reaction mixture at 0 °C. The resulting mixture was stirred at 27 °C for 3 h. The crude mixture was purified by column chromatography (silica gel 230-400 mesh, 0-50% ethyl acetate in pet ether) to give 1-(3-bromopropyl)-4-nitro-benzene (3.5 g, 13.62 mmol, 82.26% yield). 1 HNMR (400MHz, DMSO-d 6 )δ7.21(d,J=8.6Hz,2H),6.57(d,J=8.6Hz,2H),3.53(t,J=6.8Hz,2H),2.57(t,J=6.8Hz,2H),1.90(t,J=7.6Hz,2H).

[0297] Step 3: To a solution of tert-butyl piperazine-1-carboxylate (915.67 mg, 4.92 mmol) in acetonitrile (15 mL) in a 100 mL round bottom flask was added N-ethyl-N-isopropyl-propan-2-amine (1.59 g, 12.29 mmol, 2.14 mL) and 1-(3-bromopropyl)-4-nitro-benzene (1 g, 4.10 mmol). The reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed with water. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography (silica gel 100-230 mesh, 20-30% ethyl acetate in petroleum ether) to give tert-butyl 4-[3-(4-nitrophenyl)propyl]piperazine-1-carboxylate (1.14 g, 3.01 mmol, 73.56% yield) as a solid. LC-MS (ES) + ): m / z 350.3 [M+H] + .

[0298] Step 4: To a solution of tert-butyl 4-[3-(4-nitrophenyl)propyl]piperazine-1-carboxylate (1.00 g, 2.86 mmol) in methanol (15 mL) in a 100 mL round bottom flask was added Pd / C (143.21 mg, 2.86 mmol). The reaction mixture was stirred under hydrogen bladder atmosphere at 25° C. for 16 h. The progress of the reaction was monitored by LC-MS and TLC. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate. The collected filtrate was concentrated under reduced pressure to give the crude compound tert-butyl 4-[3-(4-aminophenyl)propyl]piperazine-1-carboxylate (0.9 g, 2.75 mmol, 96.03% yield), which was used in the next step without further purification. LC-MS (ES + ): m / z 320.3[M+H] + .

[0299] Step 5: To a solution of tert-butyl 4-[3-(4-aminophenyl)propyl]piperazine-1-carboxylate (0.9 g, 2.82 mmol) in DMF (15 mL) in a 50 mL round bottom flask was added sodium bicarbonate (591.71 mg, 7.04 mmol) and 3-bromopiperidine-2,6-dione (703.27 mg, 3.66 mmol). The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with water. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography (silica gel 100-230 mesh, 40-50% ethyl acetate in petroleum ether) to give tert-butyl 4-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl]piperazine-1-carboxylate (0.5 g, 865.78 μmol, 30.73% yield). LC-MS (ES) + ): m / z 431.7[M+H] + .

[0300] Step 6: To a solution of tert-butyl 4-[3-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]propyl]piperazine-1-carboxylate (80 mg, 185.81 μmol) in dioxane (1 mL) was added HCl (4 M in dioxane, 2 mL) under nitrogen at 0° C. and stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated and triturated with diethyl ether (50 ml) to give 3-[4-(3-piperazin-1-ylpropyl)anilino]piperidine-2,6-dione HCl salt (0.05 g, 88.58 μmol, 47.67% yield). LC-MS (ES) + ): m / z 331.5[M+H] + .

[0301] Synthesis of 3-((4-((3S,4R)-3-hydroxypiperidin-4-yl)phenyl)amino)piperidine-2,6-dione [ka] Step 1: To a stirred solution of tert-butyl (3R,4S)-4-(4-aminophenyl)-3-hydroxy-piperidine-1-carboxylate (1.00 g, 3.42 mmol) in dry DMF (7 mL), 3-bromopiperidine-2,6-dione (1.97 g, 10.26 mmol) was added, followed by sodium bicarbonate (2.87 g, 34.20 mmol). The reaction mixture was heated at 85° C. for 12 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (1×20 mL) and anhydrous Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated to give the crude product. The crude was purified by column chromatography on 230-400mess silica gel (0-70% ethyl acetate in pet ether as eluent) to give the product tert-butyl (3R,4S)-4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3-hydroxy-piperidine-1-carboxylate (1.0 g, 2.13 mmol, 62.32% yield). LC-MS (ES - ): m / z 402.44[MH] - .

[0302] Step 2: To a stirred solution of tert-butyl (3R,4S)-4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-3-hydroxy-piperidine-1-carboxylate (0.300 g, 743.55 μmol) in DCM (20 mL) was added 2,2,2-trifluoroacetic acid (38.94 mmol, 3.00 mL). The reaction mixture was then stirred at room temperature for 1 h and monitored by TLC and LCMS. After completion, the crude was concentrated under reduced pressure, triturated with diethyl ether (2×20 mL), and then dried again to give 3-[4-[(3R,4S)-3-hydroxy-4-piperidyl]anilino]piperidine-2,6-dione (0.280 g, 637.31 μmol, 85.71% yield) as an off-white solid. LC-MS (ES + ): m / z 304.15[M+H] + .

[0303] Synthesis of 3-[[1-[2-(methylamino)ethyl]pyrazol-3-yl]amino]piperidine-2,6-dione [ka] Step 1: To a solution of 3-nitro-1H-pyrazole (10 g, 88.44 mmol) in THF (100 mL) was added 2-bromoethanol (16.58 g, 132.66 mmol, 9.42 mL) and potassium carbonate (anhydrous) 99% (30.56 g, 221.09 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 70° C. and stirred for 12 h. The reaction mixture was then concentrated to give a residual mass, which was dissolved in ethyl acetate (250 mL), washed with water (1×100 mL), brine (1×100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product 2-(3-nitropyrazol-1-yl)ethanol (9 g, 51.55 mmol, 58.29% yield), which was used in the next step without further purification. LC-MS (ES + ): m / z 158.4[M+H] + .

[0304] Step 2: To a solution of 2-(3-nitropyrazol-1-yl)ethanol (10 g, 63.64 mmol) in DCM (100 mL) was added N-ethyl-N-isopropyl-propan-2-amine (12.34 g, 95.46 mmol, 16.63 mL) at room temperature and the reaction mixture was cooled to 0° C. Then, methanesulfonyl chloride (10.94 g, 95.46 mmol, 7.39 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with DCM (700 mL), washed with saturated sodium bicarbonate solution (500 mL) and washed with aqueous brine solution (300 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude product 2-(3-nitropyrazol-1-yl)ethyl methanesulfonate (14 g, 47.62 mmol, 74.82% yield) as a brown solid, which was used in the next step without purification. LC-MS (ES + ): m / z 236.3[M+H] + .

[0305] Step 3: In a sealed tube, a 33 wt% solution of methylamine in absolute ethanol (29.76 mmol, 35 mL) was added to a stirred solution of 2-(3-nitropyrazol-1-yl)ethyl methanesulfonate (7 g, 29.76 mmol) in THF (10 mL) at 0° C. The reaction was heated at 70° C. for 16 h. After completion, the reaction mixture was concentrated in vacuo to give the crude compound N-methyl-2-(3-nitropyrazol-1-yl)ethanamine (4.5 g, 10.31 mmol, 34.66% yield) as a brown viscous material, which was used in the next step without purification. LC-MS (ES) + ): m / z 171.3[M+H] + .

[0306] Step 4: To a solution of N-methyl-2-(3-nitropyrazol-1-yl)ethanamine (7 g, 41.14 mmol) in dry DCM (70 mL) was added N,N-dimethylpyridin-4-amine (5.03 g, 41.14 mmol). 2The mixture was stirred at the same temperature for 5 min and tert-butoxycarbonyl tert-butyl carbonate (13.47 g, 61.70 mmol, 14.16 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h as monitored by TLC. The reaction mixture was then quenched with ice-cold water (200 ml) and the organic layer was fractionated. The organic layer was washed with water (3×100 mL), brine (1×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give the crude compound. The crude was purified by column chromatography (silica gel 100-200 mesh) to give tert-butyl N-methyl-N-[2-(3-nitropyrazol-1-yl)ethyl]carbamate (6 g, 18.65 mmol, 45.33% yield) as a colorless liquid. LC-MS (ES + ): m / z 293.4 [M+Na] + .

[0307] Step 5: To a solution of tert-butyl N-methyl-N-[2-(3-nitropyrazol-1-yl)ethyl]carbamate (6 g, 22.20 mmol) in ethyl acetate (60 mL) was added 10% palladium on carbon, type 487, dry (2.36 g, 22.20 mmol) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at balloon pressure for 32 h. It was then filtered through a bed of celite and washed with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure to give tert-butyl N-[2-(3-aminopyrazol-1-yl)ethyl]-N-methyl-carbamate (5 g, 19.35 mmol, 87.17% yield) as a colorless gel, which was used in the next step without further purification. LC-MS (ES) + ): m / z 241.2[M+H] + .

[0308] Step 6: To a solution of tert-butyl N-[2-(3-aminopyrazol-1-yl)ethyl]-N-methyl-carbamate (1.6 g, 6.66 mmol) and 3-bromopiperidine-2,6-dione (3.84 g, 19.97 mmol) in DMF (16 mL) was added sodium bicarbonate (3.36 g, 39.95 mmol, 1.55 mL) in a sealed tube. The reaction mixture was stirred at 70° C. for 16 h. Upon completion of the reaction, the reaction mixture was poured into ice-cold water. The product was extracted using EtOAc and the organic layer was washed with cold brine solution to obtain the crude product. Purification by column chromatography (silica gel 230-400 mesh, 0-100% ethyl acetate in petroleum ether) afforded tert-butyl N-[2-[3-[(2,6-dioxo-3-piperidyl)amino]pyrazol-1-yl]ethyl]-N-methyl-carbamate (1.8 g, 4.00 mmol, 60.01% yield) as a green viscous material. LC-MS (ES - ): m / z 350.3[MH] - .

[0309] Step 7: To a solution of tert-butyl N-[2-[3-[(2,6-dioxo-3-piperidyl)amino]pyrazol-1-yl]ethyl]-N-methyl-carbamate (0.25 g, 711.44 μmol) in DCM (5 mL) was added 4 M hydrogen chloride solution in dioxane (2.5 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated in vacuo to give the crude product, which was triturated with diethyl ether (50 mL) to give 3-[[1-[2-(methylamino)ethyl]pyrazol-3-yl]amino]piperidine-2,6-dione (0.15 g, 459.64 μmol, 64.61% yield) as a light blue solid. LC-MS (ES + ): m / z 252.4[M+H] + .

[0310] Synthesis of 3-[[1-(4-piperidyl)pyrazol-3-yl]amino]piperidine-2,6-dione [ka] Step 1: To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (30 g, 149.06 mmol) in DCM (300 mL) was added triethylamine (150.83 g, 1.49 mol, 207.76 mL) and stirred for 5 min. Mesyl chloride (25.61 g, 223.59 mmol, 17.31 mL) was added to the reaction mixture at 0° C. and the resulting mixture was stirred at 27° C. for 16 h. The reaction mixture was quenched with water and extracted with DCM (100 mL×3). The organic layer 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, 0-100% ethyl acetate in pet ether) to give tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (40 g, 136.03 mmol, 91.26% yield). 1 HNMR (400MHz, DMSO-d 6 )δ7.21(d,J=8.6Hz,2H),6.57(d,J=8.6Hz,2H),3.53(t,J=6.8Hz,2H),2.57(t,J=6.8Hz,2H),1.90(t,J=7.6Hz,2H).

[0311] Step 2: To a solution of 3-nitro-1H-pyrazole (10 g, 88.44 mmol) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (37.06 g, 132.66 mmol) in DMF (200 mL) was added cesium carbonate (86.44 g, 265.31 mmol) and the reaction was stirred at 65 °C for 16 h. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the crude mixture was purified by column chromatography (30% to 40% ethyl acetate in pet ether) to give tert-butyl 4-(3-nitropyrazol-1-yl)piperidine-1-carboxylate (4 g, 11.88 mmol, 13.43% yield) as a white semi-liquid. LC-MS (ES +):m / z 241.2[[MC(CH 3 ) 3 ]+H]+H] + .

[0312] Step 3: A solution of tert-butyl 4-(3-nitropyrazol-1-yl)piperidine-1-carboxylate (4 g, 13.50 mmol) in THF (20 mL) and methanol (20 mL) was diluted with NH 4 Cl (14.44 g, 269.98 mmol) was added, followed by a suspension of zinc (8.83 g, 134.99 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction, the mixture was filtered through a bed of celite and the filtrate was diluted with water (50 ml) and extracted with ethyl acetate (250 ml). The organic layer was separated and washed with anhydrous Na 2 SO 4 The organic layer was evaporated under vacuum to give the crude compound, which was purified by column chromatography (Devisil silica, 0-100% ethyl acetate in hexanes) to give tert-butyl 4-(3-aminopyrazol-1-yl)piperidine-1-carboxylate (2.5 g, 6.57 mmol, 48.68% yield) as a brown solid. LC-MS (ES + ):m / z 211.2[[MC(CH 3 ) 3 ]+H]+H] + .

[0313] Step 4: To a solution of tert-butyl 4-(3-aminopyrazol-1-yl)piperidine-1-carboxylate (2.0 g, 7.51 mmol) and 3-bromopiperidine-2,6-dione (4.33 g, 22.53 mmol) in DMF (10 mL) was added sodium bicarbonate (6.31 g, 75.09 mmol) in a sealed tube. The reaction mixture was stirred at 75° C. for 16 h. Upon completion of the reaction, the mixture was poured into ice-cold water and extracted using ethyl acetate. The organic layer was washed with cold brine solution to give the crude product. Purification by reverse phase chromatography on Celite using 10% formic acid in water gave tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)amino]pyrazol-1-yl]piperidine-1-carboxylate (1.1 g, 2.84 mmol, 37.83% yield) as a light grey solid. LC-MS (ES + ): m / z 378.3[M+H] + .

[0314] Step 5: To a solution of tert-butyl 4-[3-[(2,6-dioxo-3-piperidyl)amino]pyrazol-1-yl]piperidine-1-carboxylate (0.900 g, 2.38 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (271.89 mg, 2.38 mmol, 183.71 μL) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and triturated with diethyl ether (100 mL) to give 3-[[1-(4-piperidyl)pyrazol-3-yl]amino]piperidine-2,6-dione (0.900 g, 1.61 mmol, 67.51% yield) as a black solid. LC-MS (ES) + ): m / z 278.5[M+H] + .

[0315] Synthesis of 3-((5-(piperidin-4-yl)pyridin-2-yl)amino)piperidine-2,6-dione [ka] Step 1: A solution of 5-bromo-2-nitro-pyridine (15 g, 73.89 mmol) in dioxane (150 mL) was added to tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (25.13 g, 81.28 mmol), potassium carbonate (anhydrous) 99% (30.64 g, 221.68 mmol) in water (30 mL). The mixture was purged with nitrogen gas for 20 minutes, after which Pd(dppf)Cl was added. 2 (2.70 g, 3.69 mmol) was added and the reaction was refluxed at 80 °C for 4 h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction was diluted with cold water and extracted with ethyl acetate. The organic layer was washed with brine solution and concentrated to dryness. The resulting crude product was purified by column chromatography (silica gel 100-200 mesh, 0-20% ethyl acetate in pet ether) to give tert-butyl 4-(6-nitro-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (18 g, 57.18 mmol, 77.39% yield) as an off-white solid. LC-MS (ES + ): m / z 306.42[M+H] + .

[0316] Step 2: To a stirred solution of tert-butyl 4-(6-nitro-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (5 g, 16.38 mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon, type 487, dry (4.36 g, 40.94 mmol). The reaction was stirred under hydrogen gas for 16 h. The progress of the reaction was monitored by TLC and LC-MS. Upon completion, the reaction was filtered through a bed of celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to give tert-butyl 4-(6-amino-3-pyridyl)piperidine-1-carboxylate (4.4 g, 15.45 mmol, 94.35% yield) as a solid. LC-MS (ES + ): m / z 278.46[M+H] + .

[0317] Step 3: To a stirred solution of tert-butyl 4-(6-amino-3-pyridyl)piperidine-1-carboxylate (2 g, 7.21 mmol) in DMF (20 mL) in a sealed tube under argon atmosphere, sodium bicarbonate (6.06 g, 72.11 mmol) was added followed by 3-bromopiperidine-2,6-dione (13.85 g, 72.11 mmol). The reaction mixture was stirred at 80° C. for 16 hours and the progress of the reaction was monitored by TLC. The reaction mixture was poured into ice-cold water and stirred for 30 minutes. The solid product was separated by filtration and washed with water and pet ether. The product in the filtrate was extracted with ethyl acetate. The solid product was then dissolved in dichloromethane / methanol (5 / 1) and combined with the extracted product in ethyl acetate. It was dried over sodium sulfate and evaporated to dryness to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh, 0-100% ethyl acetate in pet ether) to give tert-butyl 4-[6-[(2,6-dioxo-3-piperidyl)amino]-3-pyridyl]piperidine-1-carboxylate (2.8 g, 4.61 mmol, 63.97% yield) as a pale yellow solid. LC-MS (ES) + ): m / z 389.25[M+H] + .

[0318] Step 4: To a solution of tert-butyl 4-[6-[(2,6-dioxo-3-piperidyl)amino]-3-pyridyl]piperidine-1-carboxylate (1.1 g, 2.83 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (322.88 mg, 2.83 mmol, 218.16 μL) at 0° C. and the reaction 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 (50 mL) to give 3-[[5-(4-piperidyl)-2-pyridyl]amino]piperidine-2,6-dione TFA salt (1.1 g, 2.05 mmol, 72.41% yield) as an off-white solid. LC-MS (ES) + ): m / z 289.47[M+H]+ .

[0319] Synthesis of 3-((6-(piperidin-4-yl)pyridin-3-yl)amino)piperidine-2,6-dione [ka] Step 1: To a stirred solution of tert-butyl 4-(5-nitro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (10 g, 32.75 mmol) in ethyl acetate (100 mL) 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 progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated to dryness. The resulting crude product was purified by column chromatography (silica gel 60-120 mesh, 0-30% ethyl acetate in pet ether) to give tert-butyl 4-(5-amino-2-pyridyl)piperidine-1-carboxylate (7 g, 23.47 mmol, 71.66% yield). LC-MS (ES - ): m / z 276.24[MH] - .

[0320] Step 2: To a stirred solution of tert-butyl 4-(5-amino-2-pyridyl)piperidine-1-carboxylate (6.5 g, 23.44 mmol) and 3-bromopiperidine-2,6-dione (13.50 g, 70.31 mmol) in DMF (40 mL) was added sodium bicarbonate (19.69 g, 234.35 mmol) in a sealed tube. The reaction mixture was stirred at 85° C. for 16 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 chilled brine solution, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh, 0-100% ethyl acetate in pet ether) to give tert-butyl 4-[5-[(2,6-dioxo-3-piperidyl)amino]-2-pyridyl]piperidine-1-carboxylate (2.84 g, 6.40 mmol, 27.32% yield) as a pale green solid. LC-MS (ES) - ):m / z 387.28[MH] - .

[0321] 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] + .

[0322] Synthesis of 3-((5-fluoro-6-(piperidin-4-yl)pyridin-3-yl)amino)piperidine-2,6-dione [ka] Step 1: To a solution of benzyl 2-chloro-3-fluoro-5-nitro-pyridine (10 g, 56.65 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (26.27 g, 84.97 mmol) in 1,4-dioxane (100 mL) and water (25 mL) was added potassium carbonate (anhydrous) 99% (23.49 g, 169.94 mmol) at room temperature. The reaction mixture was degassed with argon for 10 min and Pd(dppf)Cl 2 (2.07 g, 2.83 mmol) was added. The reaction mixture was degassed with argon for another 5 min and it was stirred at 80 °C for 16 h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography using 230-400 mesh silica gel and 0-10% ethyl acetate in pet ether as eluent to give tert-butyl 4-(3-fluoro-5-nitro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (18 g, 48.99 mmol, 86.49% yield) as an off-white solid. LC-MS (ES - ): m / z 322.40[MH] - Step 2: A stirred solution of tert-butyl 4-(3-fluoro-5-nitro-2-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (5 g, 15.46 mmol) in ethanol (25 mL) and ethyl acetate (25 mL) was degassed with argon for 10 min. 10% palladium on carbon, type 487, dry (5 g) was added at room temperature and H 2The mixture was stirred at room temperature under balloon pressure for 16 hours. 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 the crude product, which was purified by silica gel column chromatography using 0-100% EA-PE as the eluent to give tert-butyl 4-(5-amino-3-fluoro-2-pyridyl)piperidine-1-carboxylate (4 g, 12.60 mmol, 81.45% yield). LC-MS (ES) + ): m / z 296.56[M+H] + Step 3: To a solution of 2,6-dibenzyloxy-3-bromo-pyridine (13 g, 35.11 mmol) and tert-butyl 4-(5-amino-3-fluoro-2-pyridyl)piperidine-1-carboxylate (8.30 g, 28.09 mmol) in Toulene (130 mL) was added cesium carbonate (14.87 g, 45.65 mmol) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and Pd(dba) 2 (1.61 g, 1.76 mmol), BrettPhos (942.36 mg, 1.76 mmol) were added. The reaction mixture was degassed with nitrogen gas for an additional 5 min and stirred at 110 °C for 16 h. The reaction mixture was filtered through a bed of celite and washed with ethyl acetate (150 mL). The organic layer was washed with water (100 mL) and brine solution (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified using Davisil silica gel column chromatography (0-40% EA-PE as eluent) to give tert-butyl 4-[5-[(2,6-dibenzyloxy-3-pyridyl)amino]-3-fluoro-2-pyridyl]piperidine-1-carboxylate (9 g, 13.39 mmol, 38.14% yield) as a brown gum. LC-MS (ES + ): m / z 586.62[M+H] + Step 4: A stirred solution of tert-butyl 4-[5-[(2,6-dibenzyloxy-3-pyridyl)amino]-3-fluoro-2-pyridyl]piperidine-1-carboxylate (9 g, 15.39 mmol) in EtOAc (100 mL) was degassed with argon for 10 min. 10% palladium on carbon, 60% wet basis (9 g) was added at room temperature and H 2 The mixture was stirred at 25° C. for 16 h under −60 Psi pressure (Parr Shaker). Upon completion of the reaction, it was filtered through a bed of Celite and washed with EtOAc. The filtrate was evaporated under reduced pressure to give the crude product, which was purified using silica gel (100-200 mesh) column chromatography and 0-100% EA-PE as the eluent to give tert-butyl 4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperidine-1-carboxylate (5.5 g, 13.29 mmol, 86.33% yield) as a pale green solid. LC-MS (ES) + ): m / z 407.09[M+H] + Step 5: Trifluoroacetic acid (1 mL) was added dropwise to a stirred solution of tert-butyl 4-[5-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-2-pyridyl]piperidine-1-carboxylate (240 mg, 590.48 μmol) in DCM (5 mL) cooled to 0° C. under an inert atmosphere. The reaction mixture was then stirred at room temperature for 2 h. Upon completion of the reaction, the mixture was concentrated under reduced pressure and the crude product was triturated with diethyl ether (3×5 mL) to give the TFA salt of 3-[[5-fluoro-6-(4-piperidyl)-3-pyridyl]amino]piperidine-2,6-dione (220 mg, 492.07 μmol, 83.33% yield) as a green solid. LC-MS (ES + ): m / z 307.11[M+H] +

[0323] The intermediate 3-((6-(piperidin-4-yl)pyridazin-3-yl)amino)piperidine-2,6-dione was prepared essentially following the synthesis of 3-[[6-(4-piperidyl)-3-pyridyl]amino]piperidine-2,6-dione. [ka] LC-MS(ES + ): m / z 290.2[M+H] + .

[0324] Synthesis of 3-[(6-piperazin-1-yl-3-pyridyl)amino]piperidine-2,6-dione [ka] Step 1: To a stirred solution of 2-bromo-5-nitropyridine (12 g, 59.12 mmol) in DMF (120 mL) was added tert-butyl piperazine-1-carboxylate (14.31 g, 76.85 mmol) followed by potassium carbonate (8.17 g, 59.12 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated at 80° C. for 3 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (500 mL) and filtered. The resulting residue was washed with pentane (100 mL) and dried under vacuum to obtain the compound tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (15 g, 46.22 mmol, 78.18% yield) as a yellow solid. LC-MS (ES) + ): m / z 209.40 [M-Boc+H] + .

[0325] The procedure from step 2 to step 4 was the same as that for the synthesis of intermediate 3-((6-(piperidin-4-yl)pyridin-3-yl)amino)piperidine-2,6-dione, and the product 3-[(6-piperazin-1-yl-3-pyridyl)amino]piperidine-2,6-dione was confirmed by LC-MS. LC-MS (ES + ): m / z 290.45[M+H] + .

[0326] Synthesis of 3-((5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione [ka] Step 1: To a stirred solution of tert-butyl piperazine-1-carboxylate (26.38 g, 141.62 mmol) in MeCN (41.45 mL) under nitrogen was added potassium carbonate (19.57 g, 141.62 mmol, 8.55 mL) and 2-chloro-3-fluoro-5-nitro-pyridine (25 g, 141.62 mmol) at room temperature. The resulting mixture was heated at 70° C. for 6 h. Upon completion of the reaction, the reaction was cooled to room temperature, diluted with ice-cold water and dried under vacuum to give the crude product, which was purified by silica gel column chromatography (60 / 120 mesh) using 0-30% EA-PE as eluent to give tert-butyl 4-(3-fluoro-5-nitro-2-pyridyl)piperazine-1-carboxylate (42 g, 115.84 mmol, 81.80% yield) as a yellow solid.

[0327] Step 2: To a stirred solution of tert-butyl 4-(3-fluoro-5-nitro-2-pyridyl)piperazine-1-carboxylate (20 g, 61.29 mmol) in methanol (100 mL) and THF (100 mL) was added ammonium chloride (32.78 g, 612.89 mmol, 21.43 mL) followed by a mixture of Zn (40.08 g, 612.89 mmol) in water (50 mL) under an argon atmosphere at 0° C. The reaction mixture was stirred at room temperature for 3 h. It was then filtered through a bed of Celite and washed with MeOH (100 mL) and THF (100 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude was purified by silica gel column chromatography (100 / 200 mesh and 0-50% EA-PE as eluent) to give tert-butyl 4-(5-amino-3-fluoro-2-pyridyl)piperazine-1-carboxylate (15 g, 40.49 mmol, 66.07% yield) as a brown solid. LC-MS (ES + ): m / z 297.61[M+H] + .

[0328] The procedure from step 3 to step 4 was the same as that for the synthesis of intermediate 3-((6-(piperidin-4-yl)pyridin-3-yl)amino)piperidine-2,6-dione, and the product 3-((5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione was confirmed by LC-MS. LC-MS (ES + ): m / z 308.30[M+H] + .

[0329] Synthesis of 3-((5-(piperidin-4-yl)pyrazin-2-yl)amino)piperidine-2,6-dione [ka] Step 1: 5-Bromopyrazin-2-amine (3 g, 17.24 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5.86 g, 18.97 mmol), Pd(dppf)Cl in dioxane (60 mL) and water (15 mL). 2 A mixture of (1.41 g, 1.72 mmol) and sodium carbonate (5.48 g, 51.72 mmol) was degassed and subjected to N 2 The mixture was purged with N 2 The mixture was stirred at 100° C. under atmosphere for 12 h. After LC-MS showed complete consumption of 5-bromopyrazin-2-amine, the reaction mixture was concentrated under reduced pressure to give the crude product tert-butyl 4-(5-aminopyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.6 g, 7.99 mmol, 46.34% yield) as a yellow solid. LC-MS (ES + ): m / z 277.4[M+H] + The product was used directly in the next step without further purification.

[0330] Step 2: A mixture of tert-butyl 4-(5-aminopyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (500 mg, 1.81 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (669.91 mg, 1.81 mmol), cesium carbonate (1.47 g, 4.52 mmol), dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane (97.12 mg, 180.94 μmol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (82.85 mg, 90.47 μmol) in toluene (1 mL) was degassed and cooled with N 2 The mixture was then purged with N 2 The mixture was stirred at 110° C. under atmospheric pressure for 12 hours. After the reaction was completed as shown by LC-MS, the reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=50 / 1 to 3 / 1) to give the compound tert-butyl 4-(5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 1.70 mmol, yield 94.04%) as a yellow solid. LC-MS (ES + ): m / z 566.2[M+H] + .

[0331] Step 3: To a solution of tert-butyl 4-(5-((2,6-bis(benzyloxy)pyridin-3-yl)amino)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1 g, 1.77 mmol) in DMF (50 mL) under a nitrogen atmosphere was added palladium (10% carbon, wet, 500 mg). The suspension was degassed and diluted with H 2The mixture was stirred under hydrogen atmosphere (15 Psi) at 25° C. for 12 h. The reaction was monitored by LC-MS. After completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (silica gel, DCM:MeOH=10:1) to give the compound tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)pyrazin-2-yl)piperidine-1-carboxylate (134 mg, 320.34 μmol, 18.12% yield) as a yellow solid. LC-MS (ES + ): m / z 334.2 [M-tBu+H] + .

[0332] Step 4: A solution of tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)amino)pyrazin-2-yl)piperidine-1-carboxylate (130 mg, 333.81 μmol) in dioxane (2 mL) was added with 4M hydrogen chloride solution in dioxane (2.55 mL). The mixture was stirred at 25° C. for 0.5 h. The reaction was monitored by LC-MS. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly in the next step without further purification. Compound 3-((5-(piperidin-4-yl)pyrazin-2-yl)amino)piperidine-2,6-dione HCl salt (96 mg, 265.20 μmol, 79.45% yield) was obtained as a blue solid. LC-MS (ES + ): m / z 290.4[M+H] + .

[0333] The intermediate 3-[[5-(4-piperidyl)pyrimidin-2-yl]amino]piperidine-2,6-dione was prepared essentially following the synthesis of 3-((5-(piperidin-4-yl)pyrazin-2-yl)amino)piperidine-2,6-dione. [ka] LC-MS(ES + ): m / z 290.4[M+H] + .

[0334] Synthesis of 3-[[2-(4-piperidyl)pyrimidin-5-yl]amino]piperidine-2,6-dione [ka] Step 1: To a stirred solution of 2-chloro-5-nitro-pyrimidine (3.4 g, 21.31 mmol) in ethanol (29 mL) and water (7 mL) was added iron powder (5.95 g, 106.56 mmol) and ammonium chloride (2.28 g, 42.63 mmol). The reaction mixture was stirred at 70° C. for 6 h. The progress of the reaction was monitored by TLC and LC-MS. After the reaction was completed, the mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The resulting solid was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (30% ethyl acetate in pet ether) to give 2-chloropyrimidin-5-amine (1.5 g, 10.71 mmol, 50.24% yield) as a light brown sticky compound. LC-MS (ES + ): m / z 130.1 [M+H] + .

[0335] Step 2: To a mixture of 2-chloropyrimidin-5-amine (3 g, 23.16 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (8.59 g, 27.79 mmol) in dioxane (30 mL) and water (3 mL), Pd(dppf)Cl 2(1.89 g, 2.32 mmol) and cesium carbonate (15.09 g, 46.32 mmol) were added. The reaction was stirred at 100° C. for 12 hours. After the reaction was completed as shown by LC-MS, the reaction mixture was concentrated to give a residue which was purified by flash column chromatography (petroleum ether / ethyl acetate=1 / 1). The desired product tert-butyl 4-(5-aminopyrimidin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.42 g, 12.51 mmol, 54.04% yield) was obtained as a yellow solid. LC-MS (ES + ): m / z 276.9[M+H] + .

[0336] Step 3: To a solution of tert-butyl 4-(5-aminopyrimidin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.42 g, 19.61 mmol) in ethanol (30 mL) was added 5% palladium on activated charcoal paste (1.67 g, 15.69 mmol) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi) at 25° C. for 4 h. After completion of the reaction was confirmed by LC-MS, the reaction mixture was filtered and concentrated to give a residue, which was purified by preparative TLC (petroleum ether / ethyl acetate=1 / 1). The desired product tert-butyl 4-(5-aminopyrimidin-2-yl)piperidine-1-carboxylate (4.23 g, 11.96 mmol, 60.98% yield) was obtained as a yellow solid. LC-MS (ES + ): m / z 279.4[M+H] + .

[0337] Step 4: To a mixture of tert-butyl 4-(5-aminopyrimidin-2-yl)piperidine-1-carboxylate (3.5 g, 12.57 mmol) and 2,6-dibenzyloxy-3-bromo-pyridine (6.05 g, 16.35 mmol) in dioxane (20 mL), Pd 2 (dba) 3(1.15 g, 1.26 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (1.46 g, 2.51 mmol) and cesium carbonate (8.19 g, 25.15 mmol) were added. The reaction was stirred at 100° C. for 12 hours until LC-MS confirmed the reaction was complete. The reaction mixture was then concentrated and purified by preparative TLC (petroleum ether / ethyl acetate=2 / 1). The desired product tert-butyl 4-[5-[(2,6-dibenzyloxy-3-pyridyl)amino]pyrimidin-2-yl]piperidine-1-carboxylate (5.16 g, 3.35 mmol, 26.67% yield) was obtained as a yellow solid. LC-MS (ES + ): m / z 568.6[M+H] + .

[0338] Step 5: To a solution of tert-butyl 4-[5-[(2,6-dibenzyloxy-3-pyridyl)amino]pyrimidin-2-yl]piperidine-1-carboxylate (50 mg, 88.08 μmol) in ethyl acetate (1.5 mL) was added 20 wt% palladium hydroxide on carbon (24.74 mg, 176.16 μmol). The mixture was purged with hydrogen three times and stirred under hydrogen atmosphere (15 psi) at 15° C. for 1 h. After the reaction was complete as shown by LC-MS, the desired product tert-butyl 4-[5-[(2,6-dioxo-3-piperidyl)amino]pyrimidin-2-yl]piperidine-1-carboxylate (28 mg, 71.18 μmol, 80.81% yield) was obtained as a yellow solid, which was purified by preparative TLC (ethyl acetate). LC-MS (ES + ): m / z 334[M-55] + .

[0339] Step 6: A 4M solution of hydrogen chloride in dioxane (2 mL) was added to tert-butyl 4-[5-[(2,6-dioxo-3-piperidyl)amino]pyrimidin-2-yl]piperidine-1-carboxylate (150 mg, 385.16 μmol) at 10° C. The resulting mixture was allowed to warm to room temperature and stirred for 16 h. After completion of the reaction (as indicated by TLC and LC-MS), the reaction mixture was concentrated under reduced pressure, triturated with ether, and lyophilized to give 3-[[2-(4-piperidyl)pyrimidin-5-yl]amino]piperidine-2,6-dione HCl salt (90 mg, 256.28 μmol, 66.54% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ) 10.87 (s,1H),9.03(bs,1H),8.78(bs,1H),8.27(s,2H),4.50-4.46(m,1H),3.31-3.29(m ,2H),3.05-2.97(m,3H),2.72-2.68(m,1H),2.62-2.58(m,1H),2.07-1.88(m,6H). LC-MS(ES + ): m / z 290.1 ​​[M+H] + .

[0340] Synthesis of 3-[2-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione [ka] Step 1: To a stirred solution of tert-butyl 4-(3-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.00 g, 15.51 mmol) in ethyl acetate (25 mL) and dioxane (25 mL) was added 20 wt% palladium hydroxide on carbon (2.18 g, 15.51 mmol). Hydrogen gas was bubbled through the reaction for 10 min to saturate the solution and hydrogenation (1 atm) was carried out at room temperature for 16 h. The progress of the reaction was monitored by TLC and LC-MS. Upon completion, the reaction mixture was purged with nitrogen and the catalyst was removed by filtration through a celite pad. The filtrate was concentrated under reduced pressure to give crude tert-butyl 4-(4-amino-3-fluoro-phenyl)piperidine-1-carboxylate (4.2 g, 14.05 mmol, 90.60% yield) as a light brown liquid. LC-MS (ES + ): m / z 195.2[M+H-100] + .

[0341] Step 2: To a solution of tert-butyl 4-(4-amino-3-fluoro-phenyl)piperidine-1-carboxylate (1 g, 3.40 mmol) in DMF (10 mL) in a sealed tube, sodium bicarbonate (998.84 mg, 11.89 mmol) was added followed by 3-bromopiperidine-2,6-dione (1.63 g, 8.49 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 70° C. for 12 h and the reaction progress was monitored by TLC / LC-MS. After completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was washed with brine solution (30 mL) and dried over sodium sulfate. The solution was then concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel, 60% ethyl acetate in pet ether) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-phenyl]piperidine-1-carboxylate (0.6 g, 1.30 mmol, 38.31% yield). LC-MS (ES + ): m / z 306.2[M+H-100] + .

[0342] Step 3: To a stirred solution of tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)amino]-3-fluoro-phenyl]piperidine-1-carboxylate (0.6 g, 1.48 mmol) in dioxane (4 mL) was added 4 M hydrogen chloride solution (369.95 μL) under nitrogen atmosphere at 5° C. The reaction mixture was stirred at room temperature for 6 h and the progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 3-[2-fluoro-4-(4-piperidyl)anilino]piperidine-2,6-dione HCl salt (0.5 g, 1.45 mmol, 97.86% yield) as an off-white solid. LC-MS (ES + ): m / z 306.2[M+H] + .

[0343] Synthesis of 3-[3-chloro-4-(4-piperidyl)anilino]piperidine-2,6-dione [ka] Step 1: To a solution of tert-butyl 4-(4-amino-2-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (1 g, 3.24 mmol) in ethyl acetate (30 mL), PtO 2 (303.70 mg, 1.34 mmol) was added and the system was then filled with N 2 The mixture was stirred at 20° C. for 12 hours and the progress of the reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuum. Compound tert-butyl 4-(4-amino-2-chlorophenyl)piperidine-1-carboxylate (0.44 g, 1.38 mmol, 42.56% yield) was obtained as a black solid and used in the next step without purification. LC-MS (ES + ): m / z 255.1 [M-tBu+H] + .

[0344] Step 2: To a solution of tert-butyl 4-(4-amino-2-chloro-phenyl)piperidine-1-carboxylate (2.1 g, 6.76 mmol) and 3-bromopiperidine-2,6-dione (1.95 g, 10.13 mmol) in acetonitrile (4 mL) was added tetrabutylammonium iodide (249.56 mg, 675.64 μmol) and sodium bicarbonate (1.70 g, 20.27 mmol). The mixture was stirred at 90° C. for 12 hours and the progress of the reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=100 / 1-3 / 1) to obtain the compound tert-butyl 4-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (0.8 g, 1.65 mmol, yield 34.18%) as a blue solid. LC-MS (ES + ): m / z 366.0 [M-tBu+H] + .

[0345] Step 3: To a stirred solution of tert-butyl 4-[2-chloro-4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperidine-1-carboxylate (0.1 g, 237.01 μmol) in DCM (10 mL) was added 4M HCl in dioxane (0.5 mL) dropwise at 0° C. The reaction was stirred at 27° C. for 3 h. The reaction was concentrated under reduced pressure to give the crude. The crude was triturated with ether to give 3-[3-chloro-4-(4-piperidyl)anilino]piperidine-2,6-dione HCl salt (0.084 g, 231.70 μmol, 97.76% yield) as an off-white solid. LC-MS (ES) + ): m / z 322.16[M+H] + .

[0346] Synthesis of 3-[4-(4-piperidyl)phenoxy]piperidine-2,6-dione [ka] Step 1: A solution of 4-(4-piperidyl)phenol HBr salt (2.00 g, 7.75 mmol) in DCM (20 mL) was added to a 100 mL round-bottom flask. tert-Butoxycarbonyl tert-butyl carbonate (2.03 g, 9.30 mmol, 2.13 mL) and triethylamine (3.92 g, 38.74 mmol, 5.40 mL) were added and the resulting mixture was stirred at room temperature for 2 h. After completion of the reaction (confirmed by TLC), the reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by flash column chromatography (silica gel 230-400 mesh, 0-80% ethyl acetate in pet ether) to give tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (1.8 g, 6.45 mmol, 83.22% yield) as a white solid. LC-MS (ES + ): m / z 178.2 [M-Boc+H] + .

[0347] Step 2: Sodium hydride (93.78 mg, 3.61 mmol) was added slowly to a stirred solution of tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (1.0 g, 3.61 mmol) in THF (10 mL) at 0° C. After the addition, the reaction mixture was heated at 70° C. for 30 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 in pet ether) to give tert-butyl 4-[4-[(2,6-dioxo-3-piperidyl)oxy]phenyl]piperidine-1-carboxylate (0.5 g, 1.05 mmol, 29.17% yield). LC-MS (ES + ): m / z 411.41 [M+Na] + .

[0348] 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 under vacuum 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] + .

[0349] Synthesis of 3-(3-fluoro-4-(piperidin-4-yl)phenoxy)piperidine-2,6-dione [ka] Step 1: A solution of 4-bromo-3-fluoro-phenol (500 mg, 2.62 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (971.34 mg, 3.14 mmol) and potassium phosphate tribasic anhydrous (1.39 g, 6.54 mmol) in 1,4-dioxane (10 mL) was purged with nitrogen for 5 min and diluted with Pd(dppf)Cl 2 ·CH 2 Cl 2 (213.78 mg, 261.78 μmol) was added. The resulting mixture was stirred at 100 °C for 3 h. It was then cooled to ambient temperature, diluted with ethyl acetate, filtered through celite and washed with ethyl acetate. The solvent was completely evaporated under reduced pressure and the crude product was purified by column chromatography (silica) using 0-20% ethyl acetate in pet ether as eluent to give tert-butyl 4-(2-fluoro-4-hydroxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (690 mg, 2.28 mmol, 87.16% yield) as an off-white solid. LC-MS (ES + ): m / z 194.0 [M-Boc+H] + .

[0350] Step 2: To a stirred solution of tert-butyl 4-(2-fluoro-4-hydroxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (690 mg, 2.35 mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon, type 487, dry (100 mg, 939.67 μmol) under nitrogen pressure. The resulting mixture was stirred at 25° C. for 2 h. The resulting mixture was filtered through Celite and washed with ethyl acetate (100 mL). The solvent was completely evaporated under reduced pressure to give tert-butyl 4-(2-fluoro-4-hydroxy-phenyl)piperidine-1-carboxylate (650 mg, 2.15 mmol, 91.50% yield) as an off-white solid. LC-MS (ES) + ): m / z 196.2 [M-Boc+H] + .

[0351] The procedure from step 3 to step 4 was the same as that for the synthesis of intermediate 3-[4-(4-piperidyl)phenoxy]piperidine-2,6-dione, and the product 3-(3-fluoro-4-(piperidin-4-yl)phenoxy)piperidine-2,6-dione was confirmed by LC-MS. LC-MS (ES + ): m / z 307.11[M+H] + .

[0352] Synthesis of 3-((6-(piperidin-4-yl)pyridin-3-yl)oxy)piperidine-2,6-dione [ka] The procedure from step 1 to step 4 was the same as that for the synthesis of intermediate 3-[4-(4-piperidyl)phenoxy]piperidine-2,6-dione, and the product 3-((6-(piperidin-4-yl)pyridin-3-yl)oxy)piperidine-2,6-dione was confirmed by LC-MS. LC-MS (ES + ): m / z 290.55[M+H] + .

[0353] Synthesis of 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione [ka] Step 1: To a 500 mL round bottom flask was added a solution of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (10 g, 29.39 mmol) in 1,4-dioxane (100 mL), followed by 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 an argon atmosphere. The reaction mixture was degassed with argon for 20 min and then diluted with Pd(dppf)Cl. 2 (2.40 g, 2.94 mmol) was added and the reaction was heated at 100 °C for 6 h and monitored 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 x 3) and water (200 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh, 0-30% EtOAc in pet ether) to give tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-1-carboxylate (10 g, 24.27 mmol, 82.58% yield) as a pale yellow solid. LC-MS (ES + ): m / z 332.41 [M-56+H] + .

[0354] Step 2: To a 500 mL round bottom flask was added 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), 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 an argon atmosphere. The reaction mixture was degassed with argon for 20 minutes and then Pd(dppf)Cl was added. 2 (1.89 g, 2.58 mmol) was added and the reaction was heated at 110 °C for 16 h and monitored using TLC and LC-MS. Upon completion of the reaction, the catalyst was filtered through a celite bed and washed with ethyl acetate (100 mL x 3). The filtrate was washed with water (100 mL) and brine solution (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 230-400 mesh, 0-40% ethyl acetate in PET ether) to give the desired product as a deep yellow liquid which was triturated with PET ether to give pure tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]piperidine-1-carboxylate (7 g, 11.57 mmol, 44.80% yield) as a white solid. LC-MS (ES + ): m / z 551.43[M+H] + .

[0355] Step 3: A solution of tert-butyl 4-[4-(2,6-dibenzyloxy-3-pyridyl)phenyl]piperidine-1-carboxylate (14 g, 25.42 mmol) in ethyl acetate (420 mL) was added to 10 wt% palladium on 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 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] - .

[0356] 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] - .

[0357] Synthesis of 3-(3-fluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione [ka] These procedures were essentially identical to those for 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione, except that for step 3, the synthesis of 3-(3-fluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione was started with 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. LC-MS (ES) + ): m / z 291.37[M+H] +

[0358] Synthesis of 3-(3,5-difluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione [ka] These steps are repeated for step 2: 2 The procedure is essentially identical to that for 3-[4-(4-piperidyl)phenyl]piperidine-2,6-dione, except that XPhos Pd G2 was used as the catalyst instead of trifluoroacetic acid, and for step 4, 4 M HCl in dioxane was used for deprotection instead of trifluoroacetic acid.

[0359] 3-(3,5-Difluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione. LC-MS (ES + ): m / z 309.1 [M+H] + .

[0360] Synthesis of 3-[4-(3,3-difluoro-4-piperidyl)phenyl]piperidine-2,6-dione [ka] Step 1: To a stirred solution of 3,3-difluoropiperidin-4-one (0.5 g, 3.70 mmol) in DCM (10 mL), triethylamine (561.70 mg, 5.55 mmol, 773.69 μL) was added and the reaction mixture was stirred for 10 min. Then, tert-butoxycarbonyl tert-butyl carbonate (969.18 mg, 4.44 mmol, 1.02 mL) was 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 adding water (10 mL) and stirred for 5 min. The mixture was then extracted with DCM (2×10 mL). 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 sticky solid. (700 mg, 48.25% yield). 1 HNMR (400MHz, DMSO-d 6 ) δ 6.38 (s, 2H), 3.60 (t, J = 11.6 Hz, 2H), 3.37 (bs, 2H), 1.68 (bs, 2H), 1.39 (s, 9H). This compound is in the form of a hydrate.

[0361] 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 at −30° C. for 1 h. Following this, 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 viscous liquid. LC-MS (ES + ): m / z 268.16 [M-Boc+H] + .

[0362] 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 2 Degass with Pd(dppf)Cl 2(697.26 mg, 952.93 μmol) was added at room temperature. The reaction was stirred at 60° C. for 12 h and its 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 in 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] + .

[0363] 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) and ethyl acetate (10 mL) was added 10 wt % palladium on carbon, wet (1.82 g, 17.10 mmol) and PtO 2 (932.15 mg, 4.11 mmol) was added. The reaction was stirred under hydrogen atmosphere at room temperature 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, ethyl acetate was used 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] - .

[0364] 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] + .

[0365] Synthesis of 1-[4-(4-piperidyl)phenyl]hexahydropyrimidine-2,4-dione [ka] 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. Palladium on carbon 10% by weight (10.49 g, 98.57 mmol) was added to the reaction mixture at room temperature and hydrogenation was carried out at 70 psi for 16 h using a Parr apparatus. The progress of the reaction was monitored by LC-MS. Upon completion, the reaction was filtered through a bed of celite 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] + .

[0366] 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 progress of the reaction 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 viscous yellow liquid. LC-MS (ES + ): m / z 321.2 [M-tBu+H] + .

[0367] 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 cyanogen bromide (6.75 g, 63.75 mmol, 3.34 mL) and sodium bicarbonate (5.36 g, 63.75 mmol) simultaneously. The reaction was stirred at room temperature for 24 h. After complete consumption of the 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 under vacuum to give a crude residue which was purified by column chromatography to give tert-butyl 4-[4-[cyano-(3-ethoxy-3-oxopropyl)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] + .

[0368] Step 4: A stirred solution of tert-butyl 4-[4-[cyano-(3-ethoxy-3-oxopropyl)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-oxopropyl)amino]phenyl]piperidine-1-carboxylate (12 g, 26.03 mmol, 83.61% yield) as a viscous liquid, which was used in the next step without further purification. LC-MS (ES) + ): m / z 364.4 [M-tBu+H] + .

[0369] 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] + .

[0370] 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 in dioxane (50 mL) at 0° C. and the reaction mixture was stirred at room temperature for 3 h. After the reaction was complete 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] + .

[0371] Synthesis of 3-[4-[2-(methylamino)ethyl]phenyl]piperidine-2,6-dione [ka] Step 1: To a stirred solution of 2,6-dibenzyloxy-3-bromo-pyridine (25 g, 67.52 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (25.72 g, 101.29 mmol) in 1,4-dioxane (250 mL) was added potassium acetate (13.25 g, 135.05 mmol, 8.44 mL) at room temperature. The reaction mixture was then degassed with argon gas for 10 minutes and then diluted with Pd(dppf)Cl. 2(2.76 g, 3.38 mmol) was added. The reaction mixture was again degassed with argon gas for 2 min and the reaction mixture was stirred at 100 °C for 16 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (200 mL). The organic layer was washed with water (2 x 100 mL), dried over anhydrous so...

Claims

1. A compound of formula (A), BTK-L-DSM (A) or a pharma- ceutically acceptable salt thereof, DSM is a degradation signaling moiety covalently attached to a linker L; L is a linker that covalently attaches BTK to the DSM; a Btk binding moiety represented by formula (I) or formula (II), wherein BTK is covalently attached to a linker, L; 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, A is CR ７ and N; B １ But, CR ８ , N, and N ８ is selected from B ２ is C or N, B ３ But, CR ８ , N.R. ８ , and S; Q １ and Q. ２ One of is N and the other is C, or Q １ and Q. ２ are both C, X is O and NR ２ is selected from R １ But -N(R １ａ ) ２ , C １－１０ is selected from alkyl, 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic carbocyclyl, and 7- to 10-membered bicyclic heterocyclyl; R １ The C represented by １－１０ Alkyl, 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic carbocyclyl, and 7- to 10-membered bicyclic heterocyclyl each may be represented by one or more R １０ optionally replaced by R １ａ may each occur independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl; R １ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Each alkynyl is selected from one or more R １０ or alternatively, two R １ａ together with their intervening atoms, one or more R １０ forming a 3- to 7-membered monocyclic heterocyclyl optionally substituted by R １０ is, in each occurrence, independently H, halogen, -OR １０ａ , -S(O) ２ R １０ａ , -C.N., C. １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R １０ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R １５ or optionally replaced by Or alternatively, two R １０ together with their intervening atoms form a ring A selected from 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic carbocyclyl, and 7- to 10-membered bicyclic heterocyclyl, said ring A being selected from one or more R １５ optionally replaced by R １０ａ may each occur independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ selected from alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R １５ may, in each occurrence, independently: C １－６ Alkyl, halogen, -CN, 3- to 7-membered monocyclic carbocyclyl, and -OR １５ａ is selected from R １５ The C represented by １－６ Alkyl and 3- to 7-membered monocyclic carbocyclyl are each independently selected from the group consisting of one or more R １５ａ or two R １５ together with their intervening atoms form a 3- to 7-membered monocyclic carbocyclyl or a 4- to 6-membered monocyclic heterocyclyl; R １５ａ is H, halogen, and C optionally substituted with at least one halogen; １－６ alkyl, R ２ But, H, C １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ alkynyl, R ３ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -C(O)N(R ３ａ ) ２ , -C(O)OR ３ａ and -C(O)R ３ａ is selected from R ３ The C represented by １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Each alkynyl is selected from one or more R ３０ optionally replaced by R ３ａ may each occur independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl; R ３ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Each alkynyl is selected from one or more R ３０ optionally replaced by R ３０ is, in each occurrence, independently, a halogen, -OR ３０ａ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ selected from alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ３０ａ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; Or alternatively, R １ and R ２ together with their intervening atoms form a ring B selected from 3- to 7-membered monocyclic heterocyclyl and 7- to 14-membered bicyclic heterocyclyl, said ring B being selected from one or more R ２００ or optionally replaced by Or alternatively, R ２ and R ３ together with their intervening atoms form a ring C selected from 3- to 7-membered monocyclic heterocyclyl and 7- to 10-membered bicyclic heterocyclyl, said ring C being selected from one or more R ２００ optionally replaced by R ２００ may, in each occurrence, independently: C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, -CN, -C(O)R ２００ａ , -C(O) ２ R ２００ａ , -C(O)N(R ２００ａ ) ２ , -N(R ２００ａ ) ２ , -N(R ２００ａ ) C(O)R ２００ａ , -N(R ２００ａ ) C(O) ２ R ２００ａ , -N(R ２００ａ ) C(O)N(R ２００ａ ) ２ , -N(R ２００ａ ) S (O) ２ R ２００ａ , -OR ２００ａ , -OC(O)R ２００ａ , -OC(O)N(R ２００ａ ) ２ , -SR ２００ａ , -S(O)R ２００ａ , -S(O) ２ R ２００ａ , -S(O)N(R ２００ａ ) ２ , -S(O) ２ N (R ２００ａ ) ２ is selected from R ２００ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be one or more R ２５０ or two R ２００ together with their intervening atoms form a 4- to 6-membered monocyclic heterocyclyl or a 3- to 7-membered monocyclic carbocyclyl, each of which is represented by one or more R ２５０ optionally replaced by R ２００ａ may each occur independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ２００ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ２５０ optionally replaced by R ２５０ may, in each occurrence, independently: C １－６ Alkyl, halogen, and -OR ２５０ａ is selected from R ２５０ａ is H or C １－６ is alkyl, R ４ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, -NO ２ , -CN, -OR ４ａ , -SR ４ａ , -N(R ４ａ ) ２ , -C(O)R ４ａ , -C(O)OR ４ａ , -S(O)R ４ａ , -S(O) ２ R ４ａ , -C(O)N(R ４ａ ) ２ , -SO ２ N (R ４ａ ) ２ , -OC(O)R ４ａ , -N(R)C(O)R ４ａ , -N(R)C(O)OR ４ａ , -N(R)SO ２ R ４ａ and -OC(O)N(R ４ａ ) ２ wherein R ４ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ４０ optionally replaced by R ４ａ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ４ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ４０ optionally replaced by R ４０ is, in each occurrence, independently, a halogen, -OR ４０ａ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ４０ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ４５ optionally replaced by R ４０ａ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ４５ optionally replaced by R ４５ may, in each occurrence, independently: C １－６ Alkyl, halogen, and -OR ４５ａ is selected from R ４５ａ is H or C １－６ Is it an alkyl group? Or alternatively, R ３ and R ４ together with their intervening atoms form a ring D selected from a 5- to 7-membered monocyclic carbocyclyl and a 5- to 7-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from O, N, and S, said ring D being selected from one or more R ３００ optionally replaced by R ３００ may, in each occurrence, independently: C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, -C(O)R ３００ａ , -OR ３００ａ , and -S(O) ２ R ３００ａ is selected from R ３００ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ３５０ optionally replaced by R ３００ａ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ３００ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ３５０ optionally replaced by R ３５０ may, in each occurrence, independently: C １－６ Alkyl, halogen, -CN, -C(O)R ３５０ａ , -C(O)N(R ３５０ａ ) ２ , -C(R ３５０ａ ) ２ N (R ３５０ａ ) ２ , and -OR ３５０ａ is selected from R ３５０ａ is, in each occurrence, independently, H or C optionally substituted with 1 to 3 halogens; １－６ alkyl or two R ３５０ａ together with the N atom to which they are attached form a 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms selected from N and O; R ５ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, and -OR ５ａ is selected from R ５ The C represented by １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ alkynyl is optionally substituted with one or more halogens; R ５ａ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ５ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 6-membered monocyclic carbocyclyl, each optionally substituted with one or more halogens; R ６ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, -OR ６ａ is selected from R ６ The C represented by １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ each alkynyl is optionally substituted with one or more halogen; R ６ａ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ６ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with one or more halogens; R ７ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -CN, -OR ７ａ , -C(O)N(R ７ａ ) ２ , -C(O)OR ７ａ and -C(O)R ７ａ is selected from R ７ The C represented by １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Each alkynyl is selected from one or more R ７０ optionally replaced by R ７ａ may each occur independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ７ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ７０ optionally replaced by R ７０ is, in each occurrence, independently, a halogen, -OR ７０ａ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ７０ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each independently selected from the group consisting of one or more R ７５ optionally replaced by R ７０ａ But, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ７０ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ７５ optionally replaced by R ７５ may, in each occurrence, independently: C １－６ Alkyl, halogen, and -OR ７５ａ is selected from R ７５ａ is H or C １－６ is alkyl, R ８ is, in each occurrence, independently, H, halogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -CN, -C(O)R ８ａ , -C(O) ２ R ８ａ , -C(O)N(R ８ａ ) ２ , -N(R ８ａ ) ２ , -N(R ８ａ ) C(O)R ８ａ , -N(R ８ａ ) C(O) ２ R ８ａ , -N(R ８ａ ) C(O)N(R ８ａ ) ２ , -N(R ８ａ ) S (O) ２ R ８ａ , -OR ８ａ , -OC(O)R ８ａ , -OC(O)N(R ８ａ ) ２ , -SR ８ａ , -S(O)R ８ａ , -S(O) ２ R ８ａ , -S(O)N(R ８ａ ) ２ , -S(O) ２ N (R ８ａ ) ２ , 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl; R ８ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl each may be represented by one or more R ８０ optionally replaced by R ８ａ may each occur independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ８ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ８０ or two R ８ａ together with their intervening atoms, one or more R ８０ forming a 4-6 membered monocyclic heterocyclyl optionally substituted by R ８０ is, independently in each occurrence, a halogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, -CN, -C(O)R ８０ａ , -C(O) ２ R ８０ａ , -C(O)N(R ８０ａ ) ２ , -N(R ８０ａ ) ２ , -N(R ８０ａ ) C(O)R ８０ａ , -N(R ８０ａ ) C(O) ２ R ８０ａ , -N(R ８０ａ ) C(O)N(R ８０ａ ) ２ , -N(R ８０ａ ) S (O) ２ R ８０ａ , -OR ８０ａ , -OC(O)R ８０ａ , -OC(O)N(R ８０ａ ) ２ , -SR ８０ａ , -S(O)R ８０ａ , -S(O) ２ R ８０ａ , -S(O)N(R ８０ａ ) ２ , -S(O) ２ N (R ８０ａ ) ２ , 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ８０ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ８５ or two R ８０ together with the carbon atom to which they are attached form an oxo group (-C=O)-), R ８０ａ may each occur independently: H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ８０ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each may be represented by one or more R ８５ optionally replaced by R ８５ may, in each occurrence, independently: C １－６ Alkyl, halogen, and -OR ８５ａ and R ８５ａ is H or C １－６ is alkyl, 【Chemistry 2】 represents a bond to a linker L, or a pharma- ceutically acceptable salt thereof.

2. (a) (i) A is N and Q １ is C and Q ２ is N or (ii) A is CH and Q １ is C and Q ２ is C or (iii) A is CH and Q １ is N and Q ２ is C, or (iv) A is CH and Q １ is C and Q ２ is N, and / or (b) (i) B 1 is CH, B 2 is C and B 3 is CH; or (ii) B 1 is CH, B 2 is C and B 3 is S; or (iii) B 1 is N, B 2 is C and B 3 is CH; (iv) B 1 is CH, B 2 is C and B 3 is NR 8 ; (v) B 1 is N, B 2 is N and B 3 is CH; or (vi) B 1 is CH, B 2 is N and B 3 is N; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

3. BTK in formula (A) is a Btk binding moiety represented by one of the following formulas: 【Chemistry 3】 Preferably, the BTK in formula (A) is a Btk binding moiety represented by formula (IA) or (IC), or a pharma- ceutically acceptable salt thereof:

2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

4. (i) R １ But, C １－６ is selected from alkyl, 3- to 6-membered monocyclic or bicyclic carbocyclyl, 4- to 6-membered saturated monocyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 9- to 10-membered bicyclic heteroaryl; R １ The C represented by １－６ Alkyl, phenyl, monocyclic or bicyclic C ３－７ Cycloalkyl, 4- to 6-membered saturated heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 9- to 10-membered bicyclic heteroaryl each may be represented by one or more R １０ optionally replaced by (ii) R 1 is a 5-membered monocyclic heteroaryl optionally substituted with 1 to 3 R 10 ; (iii) R 1 is selected from methyl, butyl, pentyl, phenyl, bicyclo[1.1.1]pentanyl, azetidinyl, isoxazolyl, 1,2,4-oxadiazolyl, oxazolyl, pyrazolyl, triazolyl, piperidinyl, piperazinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyridazinyl, 1,2,4-thiadiazolyl, thiophenyl, benzothiophenyl, each of which is optionally substituted with one to three R 10 ; or (iv) R 1 is a group represented by the following formula: 【Chemistry 4】 wherein n represents an integer ranging from 0 to 3; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. (i) R １０ is, in each occurrence, independently, a halogen, -OR １０ａ , -S(O) ２ R １０ａ , C １－６ alkyl, and 3- to 7-membered monocyclic carbocyclyl; R １０ The C represented by １－６ The alkyl and 3- to 7-membered monocyclic carbocyclyl each have one or more R １５ or alternatively, two R １０ together with their intervening atoms, one or more R １５ forming a 5- to 7-membered monocyclic carbocyclyl optionally substituted by R １０ａ In each occurrence, H or C １－６ is alkyl, R １５ may, in each occurrence, independently: C １－６ Alkyl, halogen, -OR １５ａ and 3- to 7-membered monocyclic carbocyclyl; R １５ The C represented by １－６ The alkyl and the 3- to 7-membered monocyclic carbocyclyl are each independently selected from the group consisting of one or more R １５ａ optionally replaced by R １５ａ is H, halogen, and C optionally substituted with at least one halogen; １－６ selected from alkyl, or (ii) R 10 in each occurrence is independently Cl, F, —CH 3 , —CF 3 , —CH 2 —CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —C(CH 3 )F 2 , —CH 2 —CF 3 , —CH 2 —C(CH 3 ) 3 , —OCH 3 , —C(CH 3 ) 3 , —O—CH(CH 3 ) 2 , —O—C(CH 3 ) 3 , —O—CH 2 —C(CH 3 ) 3 , —C(CH 3 ) 2 OH, -cyclopropyl-CF 3 , —CH 2 -cyclopropyl-CF 3 , 【Chemistry 5】 and -S(O) 2 -CH 3 , or alternatively, two R 10 together with their intervening atoms form a cyclohexane; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

6. R ２ is H or C １－３ The compound according to any one of claims 1 to 3, wherein R 2 is H, or a pharma- ceutically acceptable salt thereof.

7. (i) R １ and R ２ together with their intervening atoms form a ring B selected from 3- to 7-membered monocyclic heterocyclyl and 9- to 10-membered bicyclic heterocyclyl, said ring B being selected from 1 to 3 R ２００ and preferably, said ring B is represented by the following formula: 【Chemistry 6】 wherein m is 0, 1, 2, or 3; and (ii) R 200 is halo or C 1-6 alkyl optionally substituted with 1 to 3 halogens; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

8. 3. The compound of claim 1 or 2, wherein X is O, or a pharma- ceutically acceptable salt thereof.

9. (i) R １ But 1 to 3 R １０ or (ii) R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with one or three R 10 ; Optionally, (i) R 10 at each occurrence is independently —OR 10a or C 1-6 alkyl optionally substituted with 1 to 3 halogens, and R 10a is C 1-6 alkyl; or (ii) R 10 is selected from —CH 2 —C(CH 3 ) 3 , —CH 2 —CF 3 , and —O—C(CH 3 ) 3 ; 9. The compound of claim 8, or a pharma- ceutically acceptable salt thereof.

10. (i) R ３ is H or C １－４ alkyl, preferably R 3 is H; (ii) R 4 is (a) is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, halogen, and —OR 4a , where R 4a is H, C 1-6 alkyl, or C 1-6 haloalkyl; or (b) selected from H, F, Cl, -CH3, -CH(CH3)2, and -OCH3; and / or (iii) R 3 and R 4 together with their intervening atoms form Ring D which is a 7-membered monocyclic heterocyclyl having one heteroatom selected from N and O, Ring D is optionally substituted with R 300 , preferably Ring D is oxepane or azepane, optionally substituted with R 300 , R 300 is C 1-6 alkyl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 6-membered monocyclic heterocyclyl; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

11. (i) R ５ But, H, C １－４ alkyl or halogen, preferably R 5 is H; and / or (ii) R 6 is H, C 1-4 alkyl, or halogen, preferably R 6 is H, —CH 3 , or F; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

12. wherein BTK in formula (A) is a Btk-binding moiety represented by formula (III) or formula (IV): 【Chemistry 7】 2. The compound of claim 1, wherein: R １ is phenyl, 4-6 membered saturated monocyclic heterocyclyl, or 5- or 6-membered heteroaryl, each of which is selected from 1-3 R １０ optionally replaced by R １０ is, in each occurrence, independently, a halogen, -OR １０ａ , -S(O) ２ R １０ａ , C １－６ Alkyl, and C ３－６ cycloalkyl, wherein C １－６ Alkyl and C ３－６ Cycloalkyl is one to three R １５ or alternatively, two R １０ together with the intermediate atoms, 1 to 3 R １５ forming a 5- to 7-membered monocyclic carbocyclyl optionally substituted by R １０ａ In each occurrence, H or C １－６ is alkyl, R １５ may, in each occurrence, independently: C １－６ Alkyl, halogen, -OR １５ａ , and C ３－６ cycloalkyl; R １５ The C represented by １－６ Alkyl and the C ３－６ Cycloalkyl is one to three R １５ａ optionally replaced by R １５ａ is H, halogen, and C optionally substituted with 1 to 3 halogens; １－３ alkyl, or a pharma- ceutically acceptable salt thereof.

13. (i) R １ is phenyl, isoxazolyl, 1,2,4-oxadiazolyl, pyrazolyl, triazolyl, or azetidinyl, each of which is selected from one to three R １０ or (ii) R 1 is a group represented by the following formula: 【Chemistry 8】 wherein R 10 is C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl optionally substituted with 1 to 3 halogens; n is 0 or 1; and optionally R 10 is —C(CH 3 ) 3 or 【Chemistry 9】 , which is represented by 13. The compound of claim 12, or a pharma- ceutically acceptable salt thereof.

14. R ４ But, C １－３ alkyl or halogen, preferably R 4 is —CH 3 or F; 14. A compound according to claim 12 or 13, or a pharma- ceutically acceptable salt thereof. (i) the DSM is a degradation signaling moiety of formula (D): 【Chemistry 10】 During the ceremony, 【Chemistry 11】 represents a bond to the linker L, 【Chemistry 12】 represents an optional double bond, Y is CR Ｄ１ or N, Z １ But, binding, 【Chemistry 13】 is selected from 【Chemistry 14】 But, G １ represents a bond to 【Chemistry 15】 represents a bond to Y, G １ is selected from a bond, a 3- to 7-membered monocyclic carbocyclyl, a 5- to 6-membered monocyclic heterocyclyl, a 9- to 14-membered bicyclic or tricyclic heterocyclyl; G １ The 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heterocyclyl, and 9- to 14-membered bicyclic or tricyclic heterocyclyl each represented by one or more R Ｄ４ optionally replaced by G ２ But, binding, 【Chemistry 16】 3-7 membered monocyclic carbocyclyl, Het, 【Chemistry 17】 is selected from the group consisting of 【Chemistry 18】 represents a bond to the linker L, 【Chemistry 19】 But, G １ represents a bond to ２ and Het each represent one or more R Ｄ５ optionally replaced by Het is 4- to 7-membered monocyclic heterocyclyl or 9- to 11-membered bicyclic heterocyclyl; R Ｄ１ , R Ｄ２ , and R Ｄ３ each independently represents H or C １－６ Is it an alkyl group? Or alternatively, R Ｄ１ and R Ｄ３ taken together with the intervening atoms, when the optional double bond is absent, form a 4- to 6-membered carbocyclyl; R Ｄ４ is, independently at each occurrence, H, halogen, oxo, C １－４ Alkyl, C １－４ Haloalkyl and C １－４ or alternatively, two R Ｄ４ together with the intervening atoms form a 4- to 6-membered monocyclic heterocyclyl; R Ｄ５ is, in each occurrence, independently, H, halogen, OH, C １－４ Alkyl, C １－４ Haloalkyl and C １－４ or alternatively, two R Ｄ５ together with their intervening atoms form a 3- to 6-membered monocyclic carbocyclyl or a 4- to 6-membered monocyclic heterocyclyl; R Ｄ６ is H or C １－３ Although it is an alkyl However, Z １ , G １ , and G ２ is not a bond; or (ii) the DSM is a degradation signaling moiety of formula (DI), (D-II), (D-III), or (D-IV); 【Chemistry 20】 During the ceremony, Het 1 is represented by the following formula: 【Chemistry 21】 During the ceremony, 【Chemical 22】 represents the point of attachment to Ar 1 of formula (DI) or to the C 1-4 alkyl group of formula (D-IV); p is 1 or 2; q is 1, 2, or 3; Z 2 is CH or N; Z 2a is CH 2 or O; R D5a and R D5b at each occurrence are each independently H, C 1-4 alkyl, halogen, OH, or C 1-4 alkoxy, or R D5a and R D5b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; R D5c and R D5d at each occurrence are each independently H, C 1-4 alkyl, halogen, OH, or C 1-4 alkoxy; or R D5a and R D5c taken together form -(CH 2 ) t -; t is 1, 2, or 3; Ar 1 is phenyl, phenyl fused to a 5- to 7-membered heterocyclyl, naphthalenyl fused to a 5- to 7-membered heterocyclyl, a 5- to 6-membered monocyclic heteroaryl, or a 9- to 10-membered bicyclic heteroaryl, each of which is optionally substituted with 1 to 3 R D4 ; Z 1 is a bond, NR D6 , or O; R D6 is H or C 1-4 alkyl; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

16. (i) Ar １ is phenyl, pyrazole, pyrazolo-pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, benzo[cd]indol-2(1H)-onyl, imidazo-pyridinyl, or indazolyl, each of which is selected from one to three R Ｄ４ optionally replaced by, or (ii) Ar 1 is represented by the following formula: 【Chemistry 23】 During the ceremony, 【Chemistry 24】 represents a bond to Het 1 , 【Chemistry 25】 represents a bond to Z 1 ; R D4 at each occurrence is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halogen, and C 1-4 alkoxy, preferably R D4 at each occurrence is independently selected from -CH 3 , F, Cl, CF 3 , and -OCH 3 ; r is 0, 1, or 2; 16. The compound of claim 15, or a pharma- ceutically acceptable salt thereof.

17. (i) p is 1 and q is 1, or (ii) p is 2 and q is 2; or (iii) The compound of claim 15, wherein p is 1 and q is 3, or a pharma- ceutically acceptable salt thereof.

18. (i) Het １ is azetidine, piperidine, piperazine, pyrrolidine, azabicyclo[3.2.1]octane, or azaspiro[2.5]octane, each of which is １－３ Alkyl, halogen, OH, and C １－３ or two substituents, together with the carbon atom to which they are attached, are optionally substituted with 1 to 3 substituents independently selected from alkoxy; ３－６ forming a cycloalkyl; or (ii) Het 1 is represented by the following formula: 【Chemistry 26】 16. A compound according to any one of claims 15, or a pharma- ceutically acceptable salt thereof.

19. (i) R Ｄ１ , R Ｄ２ , R Ｄ３ are each independently H or -CH ３ and / or wherein R D1 , R D2 , R D3 are each H. (ii) R D6 is H or —CH 3 , preferably R D6 is H; 16. A compound according to any one of claims 15, or a pharma- ceutically acceptable salt thereof.

20. DSM is a degradation signaling moiety represented by the formula: 【Chemical 27】 During the ceremony, Ar １ is phenyl, pyrazole, pyrazolo-pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, benzo[cd]indol-2(1H)-onyl, imidazo-pyridinyl, or indazolyl, each of which is selected from the group consisting of halogen and C １３ optionally substituted with 1 or 2 substituents independently selected from alkyl; Z １ is a bond, NH, or O; R Ｄ５ａ and R Ｄ５ｂ are each independently H, OH, F, or —OCH ３ and R Ｄ６ is H or CH ３ and Het １ is piperidine, piperazine, or pyrrolidine; Y is CH, C(CH ３ 16. The compound of claim 15, wherein: -N-, -N-, or -N-, or a pharma- ceutically acceptable salt thereof.

21. (a) (i) Ar 1 is phenyl, pyrazolo-pyridinyl, pyridinyl, benzisoxazolyl, benzo[cd]indol-2(1H)-onyl, imidazo-pyridinyl, or indazolyl, each of which is selected from the group consisting of halogen and C １－３ optionally substituted with one or two substituents independently selected from alkyl, preferably Ar 1 is phenyl or indazolyl; (ii) Ar 1 is represented by the formula: 【Chemistry 28】 Ar 1 is represented by the following formula: 【Chemical 29】 During the ceremony, 【Chemistry 30】 represents a bond to Z 1 , and / or (b) Het 1 is represented by the formula: 【Chemistry 31】 21. The compound of claim 20, or a pharma- ceutically acceptable salt thereof.

22. (i) The DSM is represented by any one of the following: 【Chemistry 32】 wherein Y is CH or N; or (ii) DSM represents any one of the following attached to L: 【Chemistry 33-1】 【Chemistry 33-2】 【Chemistry 33-3】 【Chemistry 33-4】 【Chemistry 33-5】 【Chemistry 33-6】 【Chemistry 33-7】 【Chemistry 33-8】 【Chemistry 33-9】 【Chemistry 33-10】 【Chemistry 33-11】 The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

23. The compound is represented by the formula: 【Chemistry 34-1】 【Chemistry 34-2】 2. A compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R １ is phenyl, 1,2,4-oxadiazolyl, pyrazolyl, triazolyl, or azetidinyl, each of which is selected from 1 to 3 R １０ optionally replaced by R １０ C optionally substituted with 1 to 3 halogens １－４ Alkyl, C １－４ Haloalkyl, or C ３－６ is cycloalkyl, R ４ But, H, C １－４ Alkyl, halogen, and -OR ４ａ is selected from R ４ａ But, C １－４ is alkyl, Ar １ is phenyl, pyrazole, pyrazolo-pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, benzisoxazolyl, benzo[cd]indol-2(1H)-onyl, imidazo-pyridinyl, or indazolyl, each of which is optionally substituted with one or two halogens; Z １ is a bond, CH ２ , NH, or O; R Ｄ５ａ and R Ｄ５ｂ are each independently H, OH, F, or —OCH ３ and R Ｄ６ is H or CH ３ and Het １ is piperidine or piperazine, Y is CH, C(CH ３ ), or —N—, or a pharma- ceutically acceptable salt thereof.

24. (i) R １ is expressed by the following formula: 【Chemistry 35】 Ar １ but, 【Chemical 36】 and During the ceremony, 【Chemical 37】 But, Z １ represents a bond to Het １ but, 【Chemical Formula 38】 where: 【Chemical 39】 But, C １－４ represents a bond to an alkyl, or (ii) R 1 is represented by the following formula: 【Chemistry 40】 Ar 1 is 【Chemistry 41】 and During the ceremony, 【Chemistry 42】 represents a bond to Z 1 ; Het 1 is 【Chemistry 43】 where: 【Chemistry 44】 represents a bond to a C 1-4 alkyl, and optionally R 10 is —C(CH 3 ) 3 or 【Chemistry 45】 and R 4 is F or —CH 3 ; Y is CH or N; 24. The compound of claim 23, or a pharma- ceutically acceptable salt thereof.

25. L is represented by the following formula: 【Chemistry 46】 Ar ２ is phenyl, naphthyl, phenyl fused to a 5- or 6-membered heterocycle, 5- or 6-membered monocyclic heteroaryl, or 9-10-membered bicyclic heteroaryl, each of which is selected from 1-3 R Ｌ１ optionally replaced by G ３ is bond, C １－６ Alkyl, —O—, or —O—C １－６ alkyl-O-, Z ３ is a bond, -NR Ｌ２ -, -O-, -C(=O)-, C ４－６ cycloalkyl, phenyl, 4- to 6-membered saturated monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, wherein the phenyl, 4- to 6-membered saturated monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl each have 1 to 3 R Ｌ１ optionally replaced by G ４ is a bond or C １－８ is alkyl, R Ｌ１ is, in each occurrence, independently, H, halogen, C １－４ Alkyl, C １－４ Haloalkyl, or C １－４ is an alkoxy; R Ｌ２ is H or C １－３ is alkyl, Alk １ is bond, C １－４ Alkyl, C ２－４ Alkynyl, or C ３－６ cycloalkyl, １－４ Alkyl, C ２－４ Alkynyl, and C ３－６ each cycloalkyl is optionally substituted with 1 to 3 halogen; Z ４ is a bond, —O—, —NR Ｌ２ or a 4-10 membered saturated monocyclic or bicyclic heterocyclyl; Alk ２ is a bond or C optionally substituted with 1 to 3 halogens １－８ is alkyl, G ５ is a bond, phenyl, naphthyl, 5- or 6-membered heteroaryl, 4- to 10-membered monocyclic or bicyclic saturated heterocyclyl, 3- to 10-membered monocyclic or bicyclic saturated carbocyclyl, or -(O-CH ２ -CH ２ ) ｔ -, wherein said phenyl, naphthyl, 5- or 6-membered heteroaryl, 4- to 10-membered monocyclic or bicyclic saturated heterocyclyl, and 3- to 10-membered monocyclic and bicyclic saturated carbocyclyl each have 1 to 3 R Ｌ１ optionally replaced by t is an integer from 2 to 8; Alk ３ is a bond or C optionally substituted with 1 to 3 halogens １－６ Alkyl or C ３－６ is cycloalkyl, Alk ４ is a bond or C optionally substituted with 1 to 3 halogens １－６ is alkyl, G ６ is bond, C １－６ Alkyl, or 【Chemistry 47】 where: 【Chemistry 48】 But, ２ represents a bond to Het ２ is a 4-10 membered saturated monocyclic or bicyclic heterocyclyl; G ７ But, C ３－７ is cycloalkyl, 【Chemistry 49】 represents the bond to the DSM; 【Chemistry 50】 represents binding to BTK, while However, in the case of formula (L-2), Alk １ and Alk ２ When one of is not a bond and is represented by formula (L-3), Alk ３ , G ５ , and Alk ４ is not a bond, and optionally (i) Ar 2 is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, thiophenyl, imidazolyl, oxazolyl, imidazolethiazolyl, imidazopyridinyl, indazolyl, thienopyridinyl, 2λ 2 -isoindolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, or 3,4-dihydro-1H-2λ 2 -isoquinolinyl, each of which is optionally substituted by one or two R L1 ; Z 3 is a bond, —NR L2 —, —O—, —C(═O)—, cyclobutyl, piperazinyl, or pyrazolyl; G 5 is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl, azetidinyl, oxazolyl, pyrazolyl, or pyridinyl, each of which is optionally substituted with one or two R L1 ; Z 4 is a bond, —O—, —NR L2 , azaspiro[3.3]heptanyl, or piperazinyl; Het 2 is azaspiro[5.5]undecanyl, azaspiro[2.4]heptanyl, azaspiro[4.4]nonanyl, azaspiro[3.4]octanyl, 6-oxa-azaspiro[3.4]octanyl, hexahydro-2H-thieno[2,3-c]pyrrolyl 1,1-dioxide, pyrrolidinyl, morpholinyl, piperidinyl, or azepanyl; and / or (ii) R L1 in each occurrence is independently F, Cl, CH 3 , or OCH 3 ; R L2 is H or CH 3 ; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

26. (i) L is represented by the following formula: 【Chemistry 51】 During the ceremony, Ar ２ is phenyl, a 5-membered heterocycle, a 6-membered saturated monocyclic heterocyclyl, or a phenyl fused to a 6-membered heteroaryl, each of which is optionally substituted with one or two halogens, preferably Ar 2 is piperazinyl, phenyl, pyridine, pyrimidine, or 2λ 2 -isoindoline, each of which is optionally substituted with one or two F; s1 is 0 or an integer from 1 to 4; s2 is 0 or an integer from 1 to 4; s3 is an integer from 1 to 3, s4 and s5 are each independently 0 or an integer from 1 to 3, provided that at least one of s4 and s5 is not 0; or (ii) L represents any one of the following: 【Chemistry 52-1】 【Chemistry 52-2】 【Chemistry 52-3】 【Chemistry 52-4】 【Chemistry 52-5】 【Chemistry 52-6】 【Chemistry 52-7】 【Chemistry 52-8】 【Chemistry 52-9】 26. The compound of claim 25, or a pharma- ceutically acceptable salt thereof.

27. The compound is represented by the formula: 【Chemistry 53】 2. A compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R １ is 1,2,4-oxadiazolyl or triazolyl, each of which is R １０ is substituted with R １０ But, C １－４ is alkyl, Y is N or CH; Ar １ is indozolyl or benzisoxazolyl, each of which is halo and C １－２ optionally substituted with 1 or 2 substituents independently selected from alkyl, R 1 is 【Chemical Formula 54】 and Ar 1 is 【Chemistry 55】 where: 【Chemistry 56】 represents a bond to Y, preferably R 10 is —C(CH 3 ) 3 ; The compound or a pharma- ceutically acceptable salt thereof.

28. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

29. A pharmaceutical composition for treating a disorder responsive to degradation and / or inhibition of Bruton's tyrosine kinase, comprising an effective amount of a compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, optionally wherein said disorder is an autoimmune disorder, rheumatoid arthritis, systemic lupus erythematosus, atopic dermatitis, or cancer, preferably wherein said autoimmune disorder is multiple sclerosis and said cancer is leukemia or lymphoma.

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