(R)-Glutarimide CRBN Ligands and Methods of Use

Abstract

Disclosed herein are compounds for binding to and modulating the activity of cereblon (CRBN) and methods of use thereof. The present invention also provides compounds that can be used as synthetic intermediates in the preparation of bifunctional compounds for use in targeted protein degradation. Thus, the compounds of the present invention are useful for the treatment or prevention of tumors and cancers.

Description

[Technical field]

[0001] Disclosed herein are compounds for binding to and modulating the activity of cereblon (CRBN) and methods of use thereof. The present invention also provides compounds that can be used as synthetic intermediates in the preparation of bifunctional compounds for use in targeted protein degradation. Thus, the compounds of the present invention are useful for the treatment or prevention of tumors and cancers. [Background technology]

[0002] Protein degradation targeting chimeras (PROTACs) consist of two covalently linked protein-binding molecules, one of which can engage E3 ubiquitin ligase and the other of which binds to a protein of interest (POI), the intended target for degradation (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98:8554-9.; Sakamoto KMet al., Methods Enzymol. 2005; 399:833-847.). Rather than inhibiting the enzymatic activity of the target protein, the E3 ligase is recruited to a specific unwanted protein, resulting in its ubiquitination and subsequent degradation of the target protein by the proteasome. The entire process of ubiquitination and proteasomal degradation is known as the ubiquitin-proteasome pathway (UPP) (Ardley H.et al.,Essays Biochem.2005,41,15-30; Komander D.et al.,Biochem.2012,81,203-229;Grice GL et al.,Cell Rep.2015,12,545-553;Swatek KNet al.,Cell Res.2016,26,399-422). The proteasome is a protein complex that degrades unnecessary, misfolded, or abnormal proteins into small peptides to maintain cellular health and productivity. Ubiquitin ligases, also called E3 ubiquitin ligases, directly catalyze the transfer of ubiquitin from E2s to target proteins for degradation.Although the human genome encodes over 600 putative E3 ligases, only a limited number of E3 ubiquitin ligases have been widely applied by small molecule PROTAC technology, such as cereblon (CRBN), von Hippel-Lindau (VHL), mouse double minute 2 homolog (MDM2) cellular inhibitor of apoptosis protein (cIAP) (Philipp O. et al, Chem. Biol. 2017, 12, 2570-2578), recombinant human ring finger protein 114 (RNF114) (Spradlin, JNet al. Nat. Chem. Biol. 2019, 15, 747-755), and DDB1 and CUL4 associated factor 16 (DCAF16) (Zhang, X. et al. Nat. Chem. Biol. 2019, 15, 737-746). Cereblon (CRBN) forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and cullin-4A (CUL4A) to ubiquitinate many other proteins for subsequent degradation via the proteasome (Yi-An Chen, et al., Scientific Reports 2015,5,1-13). Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, inhibit CRL4A. CRBN It functions as a monovalent promoter of PPIs by binding to the cereblon (CRBN) subunit of the E3 ligase complex and recruiting neosubstrate proteins (Matyskiela, ME et al., Nat Chem Biol 2018, 14, 981-987.). As a result, the ability of thalidomide and its derivatives to recruit CRBN has been widely applied in proteolysis-targeting chimeras (PROTAC)-related studies (Christopher T. et al. ACS Chem. Biol. 2019, 14, 342-347.; Honorine L. et al., ACS Cent. Sci. 2016, 2, 927-934). These new findings on the role of CRBN in IMiD action have stimulated intensive research into downstream factors of CRBN involved in maintaining normal function and its use as a substrate receptor where proteins recognized by CRBN can be ubiquitinated and degraded by the proteasome.

[0003] There is a need for novel compounds, compositions, and their uses that bind to the E3 ligase protein cereblon for the treatment of serious diseases. There is also a need for novel compounds that can be present in the preparation of bifunctional molecules used in the degradation of proteins. Summary of the Invention [Means for solving the problem]

[0004] One object of the present invention is to provide compounds and derivatives that are formed by conjugating a target protein moiety with an E3 ligase ligand moiety and function to recruit a target protein to an E3 ubiquitin ligase for degradation, as well as methods for their preparation and use.

[0005] Aspect 1. A compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof, or a deuterated analog thereof, or a prodrug thereof, wherein: Warhead is a targeting moiety that binds to a target protein, said target protein being a mediator of disease in a subject; A linker connects the warhead portion to the [ka] is a divalent chemical group attached to the moiety, s1 is 0 or 1, s2 is 0 or 1; Z 1 , Z 2 , and Z 3 each independently represents N or CR z where Z 1 , Z 2 , and Z 3 but not N at the same time, R zis, in each occurrence, independently, hydrogen, halogen, -C 1~8 Alkyl, -NR Za R Zb , -OR Za , -SR Za , C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or CN; 1~8 Each of alkyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclyl may optionally be selected from the group consisting of at least one R Zc is replaced by The above [ka] The part is CR z And R z Z is hydrogen 1 , Z 2 , or Z 3 via any one of the [ka] Binding to the part, R Za and R Zb each independently represents hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 alkynyl, the C3-C8 cycloalkyl, the 3-8 membered heterocyclyl, the C6-C 12 aryl, or each of said 5- to 12-membered heteroaryls may optionally contain at least one substituent R Zd is replaced by R Zc and R Zd each independently represents halogen, hydroxy, -C 1~8 Alkoxy, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; R 1 and R 2 each independently represents a halogen, -C1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C 1~8 Alkoxy, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Aryl, 5-12 membered heteroaryl, -CN, -SO2R 1a , -SO2NR 1a R 1b , -COR 1a , -CO2R 1a , -CONR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CO2R 1b , or -NR 1a SO2R 1b -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C 1~8 Alkoxy, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Each of the aryl, aryl, or 5- to 12-membered heteroaryl is optionally selected from halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 1c , -SO2R 1c , -SO2NR 1c R 1d , -COR 1c , -CO2R 1c , -CONR 1c R 1d , -NR 1c R 1d , -NR 1c COR 1d , -NR 1c CO2R 1d , or -NR 1c SO2R 1d is replaced by R1a , R 1b , R 1c , and R 1d each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 The compound is aryl, or 5- to 12-membered heteroaryl.

[0006] Aspect 2.Z 1 , Z 2 , and Z 3 The compound according to embodiment 1, wherein at most one of is N.

[0007] Aspect 3.Z 1 , Z 2 , and Z 3 However, each independently, CR z The compound according to any one of aspects 1 to 2,

[0008] Aspect 4.R Z is, in each occurrence, independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR Za R Zb , -OR Za , -SR Za , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN, each of which is optionally selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl. Zc is replaced by R Za and R Zb each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8Alkenyl, -C 2~8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and wherein the hydrogen, the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, or the 5- to 12-membered heteroaryl optionally has at least one substituent R Zd is replaced by R Zc and R Zd each independently represents -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 The compound according to any one of embodiments 1 to 3, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0009] Aspect 5.R z is selected from H, -CH3, -C2H5, F, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -C3H7, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, -CF3, or -CH(OH)CH3.

[0010] Aspect 6.R 1 and R 2each independently represents F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutylcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, 3-8 membered heterocyclyl, -C6-C 12 Aryl, 5-12 membered heteroaryl, -CN, -SO2R 1a , -SO2NR 1a R 1b , -COR 1a , -CO2R 1a , -CONR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CO2R 1b , or -NR 1a SO2R 1b and methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, 3-8 membered heterocyclyl, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl is optionally selected from F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, 3-8 membered heterocyclyl, -C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 1c, -SO2R 1c , -SO2NR 1c R 1d , -COR 1c , -CO2R 1c , -CONR 1c R 1d , -NR 1c R 1d , -NR 1c COR 1d , -NR 1c CO2R 1d , or -NR 1c SO2R 1d is replaced by R 1a , R 1b , R 1c , and R 1d each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, 3-8 membered heterocyclyl, -C6-C 12 The compound according to any one of the preceding aspects, wherein the aryl is aryl, or 5-12 membered heteroaryl.

[0011] Aspect 7.R 1 and R 2 is independently selected from F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, or phenyl.

[0012] Aspect 8. The compound is a compound of formula (II): [ka] A compound according to any one of aspects 1 to 7, wherein the warhead and linker are defined as in aspect 1.

[0013] Aspect 9. The linker is [ka] In the formula, * is [ka] indicates the position where the molecule is bonded to the moiety, and ** indicates the position where the molecule is bonded to the moiety. [ka] refers to the position at which the molecule is attached to the L 1 is a single bond, -O-, -SO2-, -C(O)-, -NR L1a -, -C3~C8 cycloalkylene-, * L1 -OC 1~8 Alkylene-** L1 , * L1 -C 1~8 Alkylene-O-** L1 , * L1 -SO2-C 1~8 Alkylene-** L1 , * L1 -C 1~8 Alkylene-SO2-** L1 , * L1 -CO-C 1~8 Alkylene-** L1 , * L1 -C 1~8 Alkylene-CO-** L1 , * L1 -NR L1a -C 1~8 Alkylene-** L1 , * L1 -C 1~8 Alkylene-NR L1a -** L1 , * L1 -NR L1a C(O)-** L1 , * L1 -C(O)NR L1a -** L1 , -C1~8 Alkylene-, -C 2~8 Alkenylene-, -C 2~8 Alkynylene-, -[O(CR L1a R L1b ) m4 ] m5 -, [ka] is selected from The -C3 to C8 cycloalkylene-, L1 -OC 1~8 Alkylene-** L1 , the above * L1 -C 1~8 Alkylene-O-** L1 , the above * L1 -SO2-C 1~8 Alkylene-** L1 , the above * L1 -C 1~8 Alkylene-SO2-** L1 , the above * L1 -CO-C 1~8 Alkylene-** L1 , the above * L1 -C 1~8 Alkylene-CO-** L1 , the above * L1 -NR L1a -C 1~8 Alkylene-** L1 , the above * L1 -C 1~8 Alkylene-NR L1a -** L1 , said -C 1~8 Alkylene-, the -C 2~8 Alkenylene-, the above-C 2~8 Alkynylene-, [ka] Each of optionally comprises at least one R L1c is replaced by In the formula, * L1 However, [ka] ** indicates the position of attachment to the moiety L1 However, [ka] refers to the position at which the molecule is attached to the R L1a and R L1b each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, and 5- to 12-membered heteroaryl; 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 alkynyl, the C3-C8 cycloalkyl, the 3-8 membered heterocyclyl, the C6-C 12 aryl, or each of said 5- to 12-membered heteroaryls may optionally contain at least one substituent R L1d is replaced by R L1c and the above R L1d each independently represents oxo, halogen, hydroxy, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; or The Two R's L1c together with the atoms to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally containing at least one substituent halogen, hydroxy, or -C 1~8 is substituted with alkyl, L 2 is a single bond, -O-, -SO2-, -CO-, -NR L2a -, -C3~C8 cycloalkylene-, * L2 -OC 1~8 Alkylene-** L2, * L2 -C 1~8 Alkylene-O-** L2 , * L2 -SO2-C 1~8 Alkylene-** L2 , * L2 -C 1~8 Alkylene-SO2-** L2 , * L2 -CO-C 1~8 Alkylene-** L2 , * L2 -C 1~8 Alkylene-CO-** L2 , * L2 -NR L2a -C 1~8 Alkylene-** L2 , * L2 -C 1~8 Alkylene-NR L2a -** L2 , * L2 -NR L2a C(O)-** L2 , * L2 -C(O)NR L2a -** L2 , -C 1~8 Alkylene-, -C 2~8 Alkenylene-, -C 2~8 Alkynylene-, -[O(CR L2a R L2b ) m4 ] m5 -, [ka] is selected from The -C3 to C8 cycloalkylene-, L2 -OC 1~8 Alkylene-** L2 , the above * L2 -C 1~8 Alkylene-O-** L2 , the above * L2 -SO2-C 1~8 Alkylene-** L2 , the above * L2 -C 1~8 Alkylene-SO2-** L2 , the above * L2 -CO-C 1~8Alkylene-** L2 , the above * L2 -C 1~8 Alkylene-CO-** L2 , the above * L2 -NR L2a -C 1~8 Alkylene-** L2 , the above * L2 -C 1~8 Alkylene-NR L2a -** L2 , said -C 1~8 Alkylene-, the -C 2~8 Alkenylene-, the above-C 2~8 Alkynylene-, [ka] each of which optionally contains at least one substituent R L2c is replaced by In the formula, * L2 However, [ka] ** indicates the position of attachment to the moiety L2 However, [ka] refers to the position at which the molecule is attached to the R L2a and R L2b each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 alkynyl, the C3-C8 cycloalkyl, the 3-8 membered heterocyclyl, the C6-C 12 aryl, or each of said 5- to 12-membered heteroaryls may optionally contain at least one substituent R L2d is replaced by RL2c and the above R L2d each independently represents oxo, halogen, hydroxy, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; or The Two R's L2c together with the atoms to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally containing at least one substituent halogen, hydroxy, -C 1~8 is substituted with alkyl, L 3 is a single bond, -O-, -SO2-, -CO-, -NR L3a -, -C3~C8 cycloalkylene-, * L3 -OC 1~8 Alkylene-** L3 , * L3 -C 1~8 Alkylene-O-** L3 , * L3 -SO2-C 1~8 Alkylene-** L3 , * L3 -C 1~8 Alkylene-SO2-** L3 , * L3 -CO-C 1~8 Alkylene-** L3 , * L3 -C 1~8 Alkylene-CO-** L3 , * L3 -NR L3a -C 1~8 Alkylene-** L3 , * L3 -C 1~8 Alkylene-NR L3a -** L3 , * L3 -NR L3a C(O)-** L3 , * L3 -C(O)NR L3a -**L3 , -C 1~8 Alkylene-, -C 2~8 Alkenylene-, -C 2~8 Alkynylene-, -[O(CR L3a R L3b ) m4 ] m5 -, [ka] is selected from The -C3 to C8 cycloalkylene-, L3 -OC 1~8 Alkylene-** L3 , the above * L3 -C 1~8 Alkylene-O-** L3 , the above * L3 -SO2-C 1~8 Alkylene-** L3 , the above * L3 -C 1~8 Alkylene-SO2-** L3 , the above * L3 -CO-C 1~8 Alkylene-** L3 , the above * L3 -C 1~8 Alkylene-CO-** L3 , the above * L3 -NR L3a -C 1~8 Alkylene-** L3 , the above * L3 -C 1~8 Alkylene-NR L3a -** L3 , said -C 1~8 Alkylene-, the -C 2~8 Alkenylene-, the above-C 2~8 Alkynylene-, [ka] each of which optionally contains at least one substituent R L3c is replaced by In the formula, * L3 However, [ka] ** indicates the position of attachment to the moiety L3 However, [ka] refers to the position at which the molecule is attached to the R L3a and R L3b each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 alkynyl, the C3-C8 cycloalkyl, the 3-8 membered heterocyclyl, the C6-C 12 aryl, or each of said 5- to 12-membered heteroaryls may optionally contain at least one substituent R L3d is replaced by R L3c and the above R L3d each independently represents oxo, halogen, hydroxy, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; or The Two R's L3c together with the atoms to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally containing at least one substituent halogen, hydroxy, or -C 1~8 is substituted with alkyl, R 12 are independently hydrogen, halogen, -C 1~8 Alkyl, -NR 12a R 12b , -OR 12a, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo, or -CN; 1~8 Alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl has at least one substituent R 12c is replaced by, or The Two R's 12 together with the carbon atom to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally containing at least one substituent R 12c is replaced by R 12a and R 12b each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5- to 12-membered heteroaryl; 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 alkynyl, the C3-C8 cycloalkyl, the 3-8 membered heterocyclyl, the C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups may optionally contain at least one substituent R 12d is replaced by, or R 12c and R 12d each independently represents halogen, hydroxy, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl or 5- to 12-membered heteroaryl; X 1 , X 2 , X 3 , and X4 Each independently, -CR a or N, X 5 , X 6 , and X 7 each independently represents -NR a -, -O-, -S-, and -CR a R b - selected from X 12 and X 13 each independently represents -C(O)-, -NR a -, and -O-; Q 1 , Q 2 , Q 3 , and Q 4 However, each independently, CR a or N, Q 5 each independently represents -O-, -NR a -, -CR a R b -, -S-, or -C(O)-; P 1 is a single bond, -O-, -NR a -, -CR a R b -, -S-, -SO-, or -SO2-; At each occurrence, R a and R b each independently represents hydrogen, hydroxy, halogen, CN, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5- to 12-membered heteroaryl; 1~8 Alkyl, said -C 1~8 Alkoxy, the above-C 2~8 alkenyl, said -C 2~8 alkynyl, the -C3-C8 cycloalkyl, the 3- to 8-membered heterocyclyl, the -C6- 12The aryl or each of the 5- to 12-membered heteroaryl may optionally have at least one substituent hydrogen, halogen, hydroxy, halogen, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 substituted with aryl, or 5-12 membered heteroaryl, or R a and R b together with the carbon atom to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally containing at least one substituent halogen, hydroxy, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 substituted with aryl or 5-12 membered heteroaryl; m1 is 0 or 1; m2 and m3 are 0, 1, 2, 3, 4, 5, 6, 7, or 8; m4 and m5 are each independently 0, 1, 2, or 3; The compound of any one of aspects 1-8, wherein n, n1, n2, n3, n4, and n5 are each independently 0, 1, 2, or 3.

[0014] Aspect 10.L 1 is a single bond, -C 1~8 Alkylene- (preferably -CH2-, -C2H4-, -C3H6-), -CO-, -O-, -N(CH3)-, -NH-, [ka] 10. The compound according to embodiment 9, selected from:

[0015] Aspect 11.X 1 and X 2 Each independently, -CR a or N, R a is selected from hydrogen, -F, -Cl, -Br, -I, CN, methyl, ethyl, methoxy, ethoxy, or cyclopropyl, each of said methyl, said ethyl, said methoxy, said ethoxy, and said cyclopropyl being optionally substituted with at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl (preferably, X 1 and X 2 are each independently selected from CH, C(F), C(CH3), or N; m1=1 or 0, R 12 The compound according to any one of aspects 9-10, wherein is hydrogen, oxo, methoxymethyl, hydroxymethyl, -CN, or -CH3.

[0016] In the embodiment 12, m1 is 1, preferably [ka] The part is, [ka] and * X However, [ka] ** indicates the position of attachment to the moiety X However, [ka] 12. The compound according to any one of embodiments 9 to 11, wherein the moiety is designated as the position at which the compound is attached.

[0017] Aspect 13. m1 is 1, [ka] The part is, [ka] 13. The compound according to any one of aspects 9 to 12, wherein

[0018] Aspect 14.L 2 is a single bond, -C 1~8 Alkylene- (preferably -CH2-, -C2H4-, -C3H6-), -CO-, -O-, -N(CH3)-, -NH-, [ka] 14. The compound according to any one of aspects 9 to 13, selected from:

[0019] Aspect 15.L 3 is a single bond, -C 1~8 Alkylene- (preferably -CH2-, -C2H4-, -C3H6-), -CO-, -O-, -N(CH3)-, -NH-, [ka] 15. The compound according to any one of aspects 9 to 14, selected from:

[0020] Aspect 16.L 2 is a single bond, or L 3 is a single bond, or L 2 is a single bond, and L 3 A compound according to any one of aspects 9 to 15, wherein is a single bond.

[0021] Aspect 17. The above [ka] but, [ka] [ka] [ka] 17. The compound according to any one of aspects 9 to 16, selected from:

[0022] Aspect 18. The warhead is a moiety that binds to a target protein, said target protein being a structural protein, a receptor, an enzyme, a cell surface protein, a protein associated with the integrity of a cell (including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, protein degradation, biosynthesis), kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction activity, structural molecule activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell surface protein, ... cell surface protein, protein associated with the integrity of a cell (including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, protein degradation, cell surface protein, protein associated with the integrity of a cell (including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, protein associated with the integrity of a cell (including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, cell surface protein, protein associated with the integrity of a cell (including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, cell surface protein, protein associated with the integrity of a cell (including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, cell 18. The compound according to any one of aspects 1 to 17, wherein the compound is selected from the group consisting of proteins having cell motility, membrane fusion, cell-cell signaling, regulation of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenicity, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biosynthesis activity, and translation regulator activity).

[0023] Aspect 19. A warhead is a moiety that binds to a target protein, said target protein being selected from the group consisting of ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptors, dopamine receptors, G proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosoma, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinases (including Bruton's tyrosine kinase), CD23, CD124, tyrosine kinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neuroxinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7), farnesyltransferase, geranylgeranyltransferase, TrkA (NGF receptor), beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytoplasmic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20 monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylsuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor associated kinase-3 (IRAK-3 or IRAK-M), or enolpyruvylshikimate-phosphate synthase.

[0024] Aspect 20. Warhead [ka] where: R 13 But -P(O)R 13a R 13b , -SO2R 13a , -SO2-NR 13a R 13b , or -N(R 13a )-SO2R 13b is selected from R 13a and R 13b are each independently selected from hydrogen, -C1-C8 alkyl, or -C3-C8 cycloalkyl, wherein said -C1-C8 alkyl or -C3-C8 cycloalkyl is optionally substituted with at least one halogen; R 14 and R 15 each independently represents hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, -CN, -OR 14a , -SO2R 14a , -SO2NR 14a R 14b , -COR 14a , -CO2R 14a , -CONR 14a R 14b , -NR 14a R 14b , -NR 14a COR 14b , -NR 14a CO2R 14b , or -NR 14a SO2R 14b -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl optionally contains at least one substituent R 14d is replaced by, or R 14 and R 15 together with the carbon atom to which they are attached form a 5- or 6-membered unsaturated or saturated ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally containing at least one substituent R 14e is replaced by R 14e is, in each occurrence, independently selected from hydrogen, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo (=O), -OR14a , thioxo(=S), -SR 14a , -CN, -SO2R 14a , -SO2NR 14a R 14b , -COR 14a , -CO2R 14a , -CONR 14a R 14b , -NR 14a R 14b , -NR 14a COR 14b , -NR 14a CO2R 14b , or -NR 14a SO2R 14b and -C1-C8 alkyl, -C1-C8 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, aryl, or 5- to 12-membered heteroaryl may optionally contain at least one substituent R 14d is replaced by R 14a and R 14b are each independently hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; R 14d is, in each occurrence, independently selected from halogen, -OH, -CN, oxo, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5- to 12-membered heteroaryl; R 4 is hydrogen, halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Aryl, 5-12 membered heteroaryl, -CN, -SO2R 4a , -SO2NR 4a R 4b , -COR4a , -CO2R 4a , -CONR 4a R 4b , -NR 4a R 4b , -NR 4a COR 4b , -NR 4a CO2R 4b , or -NR 4a SO2R 4b and selected from -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl is optionally selected from halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 4c , -SO2R 4c , -SO2NR 4c R 4d , -COR 4c , -CO2R 4c , -CONR 4c R 4d , -NR 4c R 4d , -NR 4c COR 4d , -NR 4c CO2R 4d , or -NR 4c SO2R 4d is replaced by R 4a , R 4b , R 4c , and R 4d each independently represents hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; R 9 , R 10 , and R 11 each independently represents hydrogen, halogen, -C1-C8 alkyl, -NR9a R 9b , -OR 9a , -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, 5-12 membered heteroaryl, oxo, or -CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, aryl, or 5- to 12-membered heteroaryl may optionally contain at least one substituent R 9c is replaced by R 9a and R 9b each independently represents hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; and wherein said -C1-C8 alkyl, said -C2-C8 alkenyl, said -C2-C8 alkynyl, said C3-C8 cycloalkyl, said 3-8 membered heterocyclyl, said C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl optionally contains at least one substituent R 9d is replaced by, or R 9c and R 9d each independently represents halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl or 5- to 12-membered heteroaryl; Z 4 , Z 5 , Z 6 , and Z 7 Each independently, -CR Z4 or N, R Z4 is, in each occurrence, independently selected from hydrogen, halogen, -C1-C8 alkyl, -NR Z4a R Z4b , -OR Z4a , -SR Z4a , C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C12 aryl, 5-12 membered heteroaryl, or CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, aryl, or 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one R Z4c is replaced by R Z4a and R Z4b each independently represents hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; and 12 aryl, or each of said 5- to 12-membered heteroaryls may optionally contain at least one substituent R Z4d is replaced by R Z4c and R Z4d each independently represents halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 20. The compound according to any one of the preceding embodiments, wherein R is aryl, or 5-12 membered heteroaryl.

[0025] Aspect 21.R 13 But -P(O)R 13a R 13b or -N(R 13a )-SO2R 13b Selected from R 13a and R 13b are each independently hydrogen, -C1 to -C8 alkyl (preferably -CH3, -C2H5, -C3H7, -C4H9, or -C5H 11, more preferably selected from -CH3, -CH2CH3, -CH2CH2CH3, -iso-C3H7, -CH2CH2CH2CH3, -iso-C4H9, -sec-C4H9, or -tert-C4H9), or C3-C8 cycloalkyl (preferably cyclopropyl, cyclobutyl, or cyclopentyl).

[0026] Aspect 22.R 13 is selected from -P(O)(CH3)2, -NH-SO2CH3, or -N(CH3)-SO2CH3.

[0027] Aspect 23.R 13 is -P(O)(CH3)2.

[0028] Aspect 24.R 14 and R 15 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, -CN, -OR 14a , -SO2R 14a , -SO2NR 14a R 14b , -COR 14a , -CO2R 14a , -CONR 14a R 14b , -NR 14a R 14b , -NR 14a COR 14b , -NR 14a CO2R 14b , or -NR 14a SO2R 14b methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, C6-C 12Each of the aryl or 5- to 12-membered heteroaryl has at least one substituent R 14d Optionally replaced by, or R 14 and R 15 together with the carbon atom to which they are attached form a 5- or 6-membered unsaturated or saturated ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally containing at least one substituent R 14e is replaced by R 14e are each independently selected from the group consisting of -H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, 3-8 membered heterocyclyl, 5-12 membered heteroaryl, oxo, -CN, CF3, CHF2, CH2F, thioxo, -SCF3, -SCHF2, -SCH2F, -SCH2CF3, -SCF2CH3, -SCF2CF3, -SO2R 14a , -SO2NR 14a R 14b , -COR 14a , -CO2R 14a , -CONR 14a R 14b , -NR 14a R 14b , -NR 14a COR 14b , -NR 14a CO2R 14b , or -NR 14a SO2R 14b wherein each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, 3- to 8-membered heterocyclyl, and 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one substituent R 14dis replaced by R 14a and R 14b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C1-C8 alkoxy-C1-C8 alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; R 14d is, at each occurrence, independently, halogen, --OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0029] Aspect 25.R 14 and R 15 together with the carbon atom to which they are attached form a 5- or 6-membered unsaturated (preferably aromatic) or saturated ring, said ring containing 1 or 2 nitrogen heteroatoms, said ring optionally containing at least one substituent -H, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or iso-), butyl, pentyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CH2OH, -SCH3, -SC2H5, oxo, thioxo, -CF3, -CHF2, -CH2F, -SCF3, -OMe, -OC2H5, -CN, -C(O)CH3, [ka] 21. The compound according to embodiment 20, wherein said compound is substituted with

[0030] Aspect 26.R 14 and R 15are taken together with the carbon atom to which they are attached to form a 6-membered unsaturated (preferably aromatic) ring, said ring containing 1 or 2 nitrogen heteroatoms, said ring being optionally substituted with one substituent -H, -F, -Cl, -Br, -I, methyl, ethyl, or cyclopropyl.

[0031] Aspect 27.R 4 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C2-C8 alkenyl, -C2-C8 alkynyl, or -C1-C8 alkoxy, each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C2-C8 alkenyl, or -C2-C8 alkynyl is optionally substituted with -F, -Cl, -Br, -I, oxo, or -CN.

[0032] Aspect 28.R 4 is hydrogen, -F, -Cl, -Br, -I, -CH3, -CF3, -CH2F, or -CHF2.

[0033] Aspect 29.R 4 is hydrogen, -F, -Cl, -Br, or -I.

[0034] Aspect 30.R 9 , R 10 , and R 11 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR 9a R 9b , -OR 9a, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo, or -CN, each of which may optionally be selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, optionally selected from at least one substituent R 9c is replaced by R 9a and R 9b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may optionally be selected from at least one substituent R 9d is replaced by R 9c and R 9d is independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0035] Aspect 31.R 9 , R 10 , and R 11is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, -NH2, -NHCH3, -OH, -OCH3, -OC2H5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2OH, -CH2OMe, oxo, or -CN.

[0036] Aspect 32.R 9 , R 10 , and R 11 is independently selected from hydrogen, -CH3, -F, -Cl, -Br, or -I.

[0037] Aspect 33.Z 4 , Z 5 , Z 6 , and Z 7 Each independently, -CR 4z and R 4Z is, in each occurrence, independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl octyl, -NR 4Za R 4Zb , -OR 4Za , -SR 4Za , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN, each of which is optionally selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl. 4Zc is replaced by R 4Za and R 4Zbare each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of the hydrogen, the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, -C2-C8 alkenyl, the -C2-C8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, or the 5- to 12-membered heteroaryl is optionally selected from at least one substituent R 4Zd is replaced by R 4Zc and R 4Zd are each independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0038] Aspect 34.R 4z is H, -CH3, -C2H5, F, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -C3H7, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, -CF3, -CH(OH)CH3, [ka] 21. The compound according to embodiment 20, selected from:

[0039] 35. A warhead, [ka] where: [ka] is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , and R 107 are each independently hydrogen, halogen, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 10a , -SO2R 10a , -COR 10a , -CO2R 10a , -CONR 10a R 10b , -C(=NR 10a )NR 10b R 10c , -NR 10a R 10b , -NR 10a COR 10b , -NR 10a CONR 10b R 10c , -NR 10a CO2R 10b , -NR 10a SONR 10b R 10c , -NR 10a SO2NR 10b R 10c , or -NR 10a SO2R 10b and said -C 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 109 is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the aromatic ring is optionally 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C 1~8 Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 10a , -SO2R 10a , -COR 10a , -CO2R 10a , -CONR 10a R 10b , -C(=NR 10a )NR 10b R 10c , -NR 10a R 10b , -NR 10a COR 10b , -NR 10a CONR 10b R 10c , -NR 10a CO2R 10b , -NR 10a SONR 10b R 10c , -NR 10a SO2NR 10b R 10c , or -NR 10a SO2R 10b and -C 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p1, p2, and p3 are each independently 0, 1, 2, 3, or 4; R 10a , R 10b , and R10c each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 The compound according to any one of the embodiments 1-19, which is alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0040] Aspect 36. The above [ka] but, [ka] and In the formula, Z 8 , Z 9 , Z 10 , and Z 11 are each independently selected from CH or N, [ka] **cy1 indicates the position where the molecule is bonded to the L 1 The compound according to embodiment 35, wherein the compound is a compound having a structure as described above.

[0041] Aspect 37. The above [ka] but, [ka] 36. The compound according to embodiment 35, selected from:

[0042] p3 is 0, 1, or 2, and each R 107 are independently halogen, -C 1~8 Alkyl, or -C 1~8 The compound according to embodiment 35, wherein the alkoxy is preferably selected from F, Cl, Br, I, CH3, or -OCH3.

[0043] Aspect 39.R10a and R 10b is independently selected from hydrogen or CH3; and n1 is 1 or 2.

[0044] Aspect 40.R 101 is methyl, -CH2OH, -OCH3, -CH2OCH3, or halogen, p1 is 0 or 1, R 102

[0046] 36. The compound according to embodiment 35, wherein is halogen.

[0045] Aspect 41.R 103 and R 105 is hydrogen and R 104 is selected from hydrogen or methyl.

[0046] Aspect 42.R 109 but [ka] and Y 101 , Y 102 , Y 103 , and Y 104 is selected from CH, O, S, or N; R 111 But hydrogen, halogen, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 10a , -SO2R 10a , -COR 10a , -CO2R 10a , -CONR 10a R 10b , -C(=NR 10a )NR 10b R 10c , -NR 10a R 10b , -NR 10a COR 10b , -NR 10a CONR 10b R 10c , -NR 10a CO2R 10b, -NR 10a SONR 10b R 10c , -NR 10a SO2NR 10b R 10c , or -NR 10a SO2R 10b -C is selected from 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 10a , R 10b , and R 10c each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 The compound according to embodiment 35, wherein p6 is 0, 1, 2, 3, or 4;

[0047] Aspect 43.Y 101 is CH, S, N, or O, and Y 102 is CH, O, or N, and Y 103 is O, S, or N, and Y 104 is S, CH, or N.

[0048] 44. A warhead, [ka] and ring A 201 and B. 201 are each independently an aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, sulfur, and oxygen as ring members (multiple ring members are possible); Z 201 , Z 203 , and Z 204 each independently represents N or CR20z and L 201 But independently, bond, -C 1~8 Alkylene-, -N(R 204 )-, -O-, -S-, *L201 -C 1~8 Alkylene-O- **L201 , *L201 -OC 1~8 Alkylene- **L201 , *L201 -N(R 204 )CO- **L201 , *L201 -CON(R 204 )- **L201 , *L201 -N(R 204 )CO-C 1~8 Alkylene- **L201 , *L201 -CON(R 204 )-C 1~8 Alkylene- **L201 , *L201 -N(R 204 )-C 1~8 Alkylene- **L201 , *L201 -C 1~8 Alkylene-N(R 204 )- **L201 , -heterocyclene-, or -heteroarylene-, 1~8 Alkylene-, *L201 -C 1~8 Alkylene-O- **L201 , the above *L201 -OC 1~8 Alkylene- **L201 , the above *L201 -N(R 204 )CO-C 1~8 Alkylene- **L201 , the above *L201 -CON(R 204 )-C 1~8 Alkylene- **L201 , the above *L201 -N(R 204 )-C 1~8 Alkylene- **L201 , the above *L201 -C 1~8 Alkylene-N(R 204 )- **L201Each of the -heterocyclene- and -heteroarylene- may optionally contain at least one substituent R 20L is replaced by In the formula, * L201 indicates the position of attachment to ring A, and ** L201 indicates the position of attachment to ring B, m201, n201, and q201 are each independently 0, 1, 2, 3, or 4; t201 is 0, 1, or 2; R 201 , R 202 , and R 204 each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from halogen, hydroxy, -C 1~8 substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 20L , R 203 , R 205 , and R 206 are each independently hydrogen, halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 20a , -SO2R 20a , -COR 20a , -CO2R 20a , -CONR 20a R 20b , -C(=NR 20a )NR 20b R 20c , -NR 20a R 20b , -NR 20a COR 20b , -NR20a CONR 20b R 20c , -NR 20a CO2R 20b , -NR 20a SONR 20b R 20c , -NR 20a SO2NR 20b R 20c , or -NR 20a SO2R 20b and said -C 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, the or the heteroaryl may optionally be selected from at least one of halogen, hydroxy, -C 1~8 Alkyl, -C 1~8 substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 20z But hydrogen, halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 20a , -SO2R 20a , -COR 20a , -CO2R 20a , -CONR 20a R 20b , -C(=NR 20a )NR 20b R 20c , -NR 20a R 20b , -NR 20a COR 20b , -NR 20a CONR 20b R 20c , -NR 20a CO2R 20b , -NR 20a SONR 20b R 20c , -NR 20a SO2NR 20b R 20c , or -NR 20a SO2R 20b-C is selected from 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may optionally be selected from at least one of halogen, hydroxy, -C 1~8 Alkyl, -C 1~8 substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 20a , R 20b , and R 20c each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Or two R's 20L together with the atom(s) to which they are attached form a 3-12 membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring members(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 203f , -SO2R 203f , -SO2NR 203f R 203g , -COR 203f , -CO2R 203f , -CONR 203f R 203g , -C(=NR 203f )NR 203g R 203h , -NR 203f R 203g , -NR 203f COR 203g , -NR 203f CONR 203g R 203h , -NR 203f CO2R 203f , -NR 203fSONR 203f R 203g , -NR 203f SO2NR 203g R 203h , or -NR 203f SO2R 203g and wherein the -C 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from halogen, -C 1~8 Alkyl, -OR 203i , -NR 203i R 203j , cycloalkyl, heterocyclyl, aryl, or heteroaryl; Or two R's 203 together with the atoms to which they are attached form a 3-12 membered ring, said ring containing at least 0, 1, or 2 additional heteroatoms as ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 203f , -SO2R 203f , -SO2NR 203f R 203g , -COR 203f , -CO2R 203f , -CONR 203f R 203g , -C(=NR 203f )NR 203g R 203h , -NR 203f R 203g , -NR 203f COR 203g , -NR 203f CONR 203g R 203h , -NR 203f CO2R 203f , -NR 203fSONR 203f R 203g , -NR 203f SO2NR 203g R 203h , or -NR 203f SO2R 203g and wherein the -C 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from halogen, -C 1~8 Alkyl, -OR 203i , -NR 203i R 203j , cycloalkyl, heterocyclyl, aryl, or heteroaryl; Or R 4 and R 3 together with the atom to which they are attached form a 3-12 membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 203f , -SO2R 203f , -SO2NR 203f R 203g , -COR 203f , -CO2R 203f , -CONR 203f R 203g , -C(=NR 203f )NR 203g R 203h , -NR 203f R 203g , -NR 203f COR 203g , -NR 203f CONR 203g R 203h , -NR 203f CO2R 203f , -NR203f SONR 203f R 203g , -NR 203f SO2NR 203g R 203h , or -NR 203f SO2R 203g and wherein the -C 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from halogen, -C 1~8 Alkyl, -OR 203i , -NR 203i R 203j , cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 203f , R 203g , R 203h , R 203i , and R 203j each independently represents hydrogen, -C 1~8 Alkyl, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 The compound according to any one of the embodiments 1-19, which is alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0049] Aspect 45.L 201 The bonds are -CH2-, -C2H4-, -C3H6-, -C4H8-, and -C5H 10 -, -O-, -NH-, *L201 -NHCH2- **L201 , *L201 -NHC2H4- **L201 , *L201 -NHC3H6- **L201 , *L201 -NHC4H8- **L201 , *L201 -NHC5H 10 - **L201 , *L201 -OCH2- **L201 ,*L201 -OC2H4- **L201 , *L201 -OC3H6- **L201 , *L201 -OC4H8- **L201 , *L201 -OC5H 10 - **L201 , *L201 -CH2O- **L201 , *L201 -C2H4O- **L201 , *L201 -C3H6O- **L201 , *L201 -C4H8O- **L201 , *L201 -C5H 10 O- **L201 , *L201 -CONH- **L201 , *L201 -NHCO- **L201 , *L201 -CONHCH2- **L201 , *L201 -CONHC2H4- **L201 , *L201 -CONHC3H6- **L201 , *L201 -CONHC4H8- **L201 , *L201 -CONHC5H 10 - **L201 , 3- to 8-membered heterocyclene-, or 5- to 6-membered heteroarylene-, and 10 -, said -O-, said -NH-, said *L201 -NHCH2- **L201 , the above *L201 -NHC2H4- **L201 , the above *L201 -NHC3H6- **L201 , the above *L201 -NHC4H8- **L201 , the above *L201 -NHC5H 10 - **L201 , the above *L201 -OCH2- **L201 , the above *L201 -OC2H4- **L201 , *L201 -OC3H6- **L201 , the above*L201 -OC4H8- **L201 , the above *L201 -OC5H 10 - **L201 , *L201 -CH2O- **L201 , the above *L201 -C2H4O- **L201 , the above *L201 -C3H6O- **L201 , the above *L201 -C4H8O- **L201 , the above *L201 -C5H 10 O- **L201 , the above *L201 -CONH- **L201 , the above *L201 -NHCO- **L201 , the above *L201 -CONHCH2- **L201 , the above *L201 -CONHC2H4- **L201 , the above *L201 -CONHC3H6- **L201 , the above *L201 -CONHC4H8- **L201 , the above *L201 -CONHC5H 10 - **L201 Each of the 3- to 8-membered heterocyclene- and the 5- to 6-membered heteroarylene- may optionally be represented by at least one substituent R 20L is replaced by R 20L 45. The compound according to embodiment 44, wherein

[0050] Aspect 46.L 201 is a bond, -O-, *L201 -OCH2- **L201 , *L201 -CH2O- **L201 , -NH-, *L201 -CONH- **L201 , *L201 -NHCO- **L201 , *L201 -CONHCH2- **L201 , *L201 -CONHCH2CH2- **L201 , *L201 -CONHCH2CH2CH2- **L201 , *L201-CONHCH(CH3)- **L201 , *L201 -CONHCH(C2H5)- **L201 , *L201 -NHCH2- **L201 , *L201 -NHCH2CH2- **L201 , *L201 -NHCH2CH2CH2- **L201 , *L201 -NHCH(CH3)- **L201 ,or *L -NHCH(C2H5)- **L 45. The compound according to embodiment 44, wherein

[0051] Aspect 47.L 201 but, *L201 -N(R 204 )CO- **L201 and R 203 and R 204 together with the atoms to which they are attached form a 5-, 6-, or 7-membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally being selected from -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 45. The compound according to embodiment 44, wherein the compound is substituted with at least one substituent independently selected from , cycloalkyl, heterocyclyl, aryl, heteroaryl, or oxo.

[0052] Aspect 48. The above [ka] The part is, [ka] In the formula, Z 205 , Z 206 , Z 207 , Z 208 , Z 209 , Z 206 ', Z 207 ', Z 208 ', and Z209 ' are each independently N or C(H), and Z 210 is N(H), O, or S.

[0053] Embodiment 49. A compound according to embodiment 44, wherein ring A201 is a 5-6 membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, sulfur, and oxygen as ring member(s).

[0054] Embodiment 50. A compound according to embodiment 44, wherein ring A201 is phenyl, naphthalenyl, quinoxalinyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, thiazolyl, oxazolyl, oxadiazole, pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, furanyl, pyrimidinyl, pyrazinyl, pyrrolopyridinyl, or dihydropyrrolopyrazinyl.

[0055] Aspect 51. The above [ka] The part is, [ka] 45. The compound according to embodiment 44, wherein

[0056] Aspect 52.R 203 is hydrogen, oxo, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 , cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyrrolyl, or phenyl; 11 , the -OCH3, the -OC2H5, the -OC3H7, the -OC4H9, the -OC5H 11, the cyclopropyl, the cyclobutyl, the cyclopentyl, the tetrahydropyrrolyl, or the phenyl may each optionally be selected from the group consisting of at least one of -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 45. The compound according to embodiment 44, wherein the compound is substituted with -OH, cyclopropyl, cyclobutyl, or cyclopentyl.

[0057] Aspect 53.R 203 is hydrogen, oxo, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl, fluoromethyl, -OMe, -OEt, -OPr, -OBu, cyclopropyl, cyclobutyl, tetrahydropyrrolyl, or phenyl.

[0058] Aspect 54. Two R 203 together with the atoms to which they are attached form a 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally being selected from -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 ,-OCH3,-OC2H5,-OC3H7,-OC4H9,-OC5H 11 , -OH, -CN, cyclopropyl, cyclobutyl, or cyclopentyl.

[0059] Aspect 55. The above [ka] The part is, [ka] 45. The compound according to embodiment 44, wherein

[0060] Aspect 56. The above [ka] The part is, [ka] In the formula, Z 205 , Z 206 , Z 207 , and Z 208 45. The compound according to embodiment 44, wherein

[0061] Aspect 57. The above [ka] The part is, [ka] 45. The compound according to embodiment 44, wherein

[0062] Embodiment 58. Ring B201 is phenyl, pyridinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyrimidinyl, or pyrazinyl, each of which is optionally selected from (R 206 ) q201 45. The compound according to embodiment 44, wherein said compound is substituted with

[0063] Aspect 59.R 206 is hydrogen, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CN, -OCH3, -OC2H5, -OC3H7, -OC4H9, or -OC5H 11 wherein the -CH3, -C2H5, -C3H7, -C4H9, -C5H 11, the -OCH3, the -OC2H5, the -OC3H7, the -OC4H9, or the -OC5H 11 each of which is optionally selected from -F, -Cl, -Br, -I, hydroxy, -C 1~8 The compound according to embodiment 44, which is substituted with an alkyloxy, a cycloalkyl, a heterocyclyl, an aryl, or a heteroaryl.

[0064] Aspect 60. The above [ka] The part is, [ka] 45. The compound according to embodiment 44, wherein

[0065] Aspect 61.R 201 and R 202 each independently represents hydrogen, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -C 2~8 Alkenyl, -C 2~8 The compound according to embodiment 44, wherein the compound is alkynyl or aryl.

[0066] Aspect 62.R 201 and R 202 are both H.

[0067] Aspect 63.R 205 are independently hydrogen, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -C 2~8 Alkenyl, -C 2~8 The compound according to embodiment 44, wherein the compound is alkynyl or aryl.

[0068] Aspect 64.R 20z is hydrogen, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, or -C5H 11 45. The compound according to embodiment 44, wherein

[0069] Aspect 65. The above [ka] The part is, [ka] [ka] [ka] [ka] The compound according to any one of aspects 44 to 64, wherein

[0070] 66. A warhead, [ka] where: Cy302 is a 5- or 6-membered saturated or unsaturated ring (preferably an aromatic ring) containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring members (or ring members); At each occurrence, R 301 , R 302 , R 303 , R 304 , and R 308 are each independently hydrogen, halogen, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR 30c , -SO2R 30c , -COR 30c , -CO2R 30c , -CONR 30c R 30d , -C(=NR 30c )NR 30d R 30e , -NR 30c R 30d, -NR 30c COR 30d , -NR 30c CONR 30d R 30e , -NR 30c CO2R 30d , -NR 30c SONR 30d R 30e , -NR 30c SO2NR 30d R 30e , or -NR 30c SO2R 30d and said -C 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 306 and R 307 each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 305 is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring member(s), and the aromatic ring is optionally selected from halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C 1~8Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 30c , -SO2R 30c , -COR 30c , -CO2R 30c , -CONR 30c R 30d , -C(=NR 30c )NR 30d R 30e , -NR 30c R 30d , -NR 30c COR 30d , -NR 30c CONR 30d R 30e , -NR 30c CO2R 30d , -NR 30c SONR 30d R 30e , -NR 30c SO2NR 30d R 30e , or -NR 30c SO2R 30d and -C 1~8 Alkyl, said -C 2~8 alkenyl, said -C 2~8 Each of alkynyl, said cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl is optionally selected from the group consisting of -C 1~8 Alkyl, halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p301 and p302 are each independently 0, 1, 2, 3, or 4; R 30c , R 30d , and R 30e each independently represents hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R 30c and R 30d ) or (R 30dand R 30e ), together with the atoms to which they are attached, form a 3-12 membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 The compound according to any one of aspects 1-19, substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0071] Aspect 67.R 301 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 30c , -SO2R 30c , -COR 30c , -CO2R 30c , -CONR 30c R 30d , -C(=NR 30c )NR 30d R 30e , -NR 30c R 30d , -NR 30c COR 30d , -NR 30c CONR 30d R 30e , -NR 30c CO2R 30d , -NR 30c SONR 30d R 30e , -NR 30c SO2NR 30d R 30e , or -NR 30c SO2R 30dand the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 alkenyl, said -C 2~8 Each of alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from F, Cl, Br, I, hydroxy, -haloC 1~8 substituted with alkyl, -methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R 30c , R 30d and R 30e each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R 30c and R 30d ) or (R 30d and R 30e ), together with the atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8The compound according to embodiment 66, substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0072] Aspect 68.R 301 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxypentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 A compound according to any one of aspects 66 to 67, wherein R1 is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, or -NO2, preferably, R1 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl.

[0073] Aspect 69.R 302 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 30c , -SO2R 30c , -COR 30c , -CO2R 30c , -CONR 30c R 30d , -C(=NR 30c )NR 30d R 30e , -NR 30c R 30d , -NR 30c COR 30d , -NR 30c CONR 30d R 30e , -NR30c CO2R 30d , -NR 30c SONR 30d R 30e , -NR 30c SO2NR 30d R 30e , or -NR 30c SO2R 30d and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 alkenyl, said -C 2~8 Each of alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from F, Cl, Br, I, hydroxy, -haloC 1~8 substituted with alkyl, -methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R 30c , R 30d and R 30e each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R 30c and R 30d ) or (R 30d and R 30e), together with the atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 The compound according to any one of embodiments 66-68, substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0074] Aspect 70.R 302 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, or -NO2, preferably 302 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN, or -NO2.

[0075] Aspect 71.R 303 and R 304 each independently represents hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR30c , -SO2R 30c , -COR 30c , -CO2R 30c , -CONR 30c R 30d , -C(=NR 30c )NR 30d R 30e , -NR 30c R 30d , -NR 30c COR 30d , -NR 30c CONR 30d R 30e , -NR 30c CO2R 30d , -NR 30c SONR 30d R 30e , -NR 30c SO2NR 30d R 30e , or -NR 30c SO2R 30d and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 alkenyl, said -C 2~8 Each of alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from F, Cl, Br, I, hydroxy, -haloC 1~8 substituted with alkyl, -methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R 30c , R 30d and R 30e each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R 30c and R 30d ) or (R 30d and R 30e ), together with the atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 The compound according to any one of embodiments 66-70, substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0076] Aspect 72.R 303 and R 304 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, or -CN, preferably R 303 and R 304 is independently hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0077] Aspect 73. The above [ka] The part is, [ka] and *303 is the above [ka] **303 indicates the position where the [ka] 73. The compound of any of embodiments 66-72, wherein the moiety is designated as the position of attachment.

[0078] Aspect 74.R 306 and R 307 each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; 2~8 alkenyl, said -C 2~8 Each of alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from F, Cl, Br, I, hydroxy, -haloC 1~8 substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl, preferably R 306 and R 307 is independently H, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0079] Aspect 75.R 305 but [ka] and Y 301 , Y 302 , Y 303 , and Y 304 are each independently selected from CH, O, S, or N; R 315 are each independently hydrogen, halogen, -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 30c , -SO2R 30c , -COR 30c , -CO2R 30c , -CONR 30c R 30d , -C(=NR 30c )NR 30d R 30e , -NR 30c R 30d , -NR 30c COR 30d , -NR 30c CONR 30d R 30e , -NR 30c CO2R 30d , -NR 30c SONR 30d R 30e , -NR 30c SO2NR 30d R 30e , or -NR 30c SO2R 30d -C is selected from 1~8 Alkyl, said -C 1~8 Alkoxy, the above-C 2~8 alkenyl, said -C 2~8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 30c , R 30d , and R 30eand p307 is 0, 1, 2, 3, or 4.

[0080] Aspect 76.Y 301 is CH, S, N, or O, and Y 302 is CH, S, O, or N, and Y 303 is CH, O, S, or N, and Y 304 is CH, O, S, or N.

[0081] Aspect 77. The above [ka] but, [ka] 76. The compound according to embodiment 75, selected from:

[0082] Aspect 78.R 315 is -H, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH(OH)CH2CH3, -CH2CH(OH)CH3, -CH2OCH3, -CFH2, -CF2H, -CF3, -CH2CF3, -CH2CH2CF3, wherein said -CH3, said -C2H5, said -C3H7, said -C4H9, said -C5H 11 , wherein -CH 13 , the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the -C 2~8 alkenyl, said -C2~8 Each alkynyl optionally has at least one of F, Cl, Br, I, hydroxy, -haloC 1~8 Alkyl, -C 1~8 The compound according to embodiment 75, which is substituted with an alkyloxy, a cycloalkyl, a heterocyclyl, an aryl, or a heteroaryl.

[0083] Aspect 79.R 315 but, [ka] 76. The compound according to embodiment 75, selected from:

[0084] Aspect 80. The above [ka] The part is, [ka] 80. The compound according to any one of aspects 66 to 79, wherein

[0085] Embodiment 81. A compound according to any one of embodiments 66 to 80, wherein Cy302 is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring member(s).

[0086] Aspect 82. The above [ka] but, [ka] and Y 301 , Y 302 , Y 303 , and Y 304 are each independently defined as in embodiment 66; In the formula, *Cy302 is [ka] -N(R 307 )-, and **Cy302 is [ka] 82. The compound of any one of embodiments 66-81, wherein the moiety is designated as the position of attachment.

[0087] Aspect 83. The above [ka] but, [ka] [ka] 83. The compound according to any one of embodiments 66 to 82, wherein

[0088] Aspect 84.R 308 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 30c , -SO2R 30c , -COR 30c , -CO2R 30c , -CONR 30c R 30d , -C(=NR 30c )NR 30d R 30e , -NR 30c R 30d , -NR 30c COR 30d , -NR 30c CONR 30d R 30e , -NR 30c CO2R 30d , -NR30c SONR 30d R 30e , -NR 30c SO2NR 30d R 30e , or -NR 30c SO2R 30d and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 alkenyl, said -C 2~8 Each of alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the aryl, or the heteroaryl is optionally selected from F, Cl, Br, I, hydroxy, -haloC 1~8 substituted with alkyl, -methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R 30c , R 30d and R 30e each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R 30c and R 30d ) or (R 30d and R 30e ), together with the atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally containing halogen, -C1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 The compound according to any one of embodiments 66-83, substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0089] Aspect 85.R 308 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2~8 Alkenyl, -C 2~8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, or -NO2, preferably 308 The compound according to any one of aspects 66-84, wherein is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN, or -NO2.

[0090] Aspect 86. The above [ka] but, [ka] 86. The compound according to any one of embodiments 66 to 85,

[0091] Aspect 87. The above [ka] The part is, [ka] 86. The compound according to any one of embodiments 66 to 85, selected from:

[0092] Embodiment 88. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 87, or a pharma- ceutically acceptable salt, tautomer, or prodrug thereof, and a pharma- ceutically acceptable excipient.

[0093] Embodiment 89. A method of treating a disease that can be treated by degrading said target protein to which said warheads can bind, by using a compound according to any one of embodiments 1 to 87.

[0094] Aspect 90. The target protein is a structural protein, a receptor, an enzyme, a cell surface protein, a protein associated with the integral function of a cell (including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, protein degradation, biosynthesis), kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction substance activity, structural molecule activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion. 90. The method of claim 89, wherein the protein is selected from the group consisting of proteins having an activity of intercellular signaling, regulation of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, virulence, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biosynthesis activity, and translation regulator activity).

[0095] Aspect 91. A warhead is a moiety that binds to a target protein, said target protein being selected from the group consisting of ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptors, dopamine receptors, G proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosoma, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinases (including Bruton's tyrosine kinase), CD23, CD124, tyrosine kinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neuroxinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7), farnesyltransferase, geranylgeranyltransferase, TrkA (NGF receptor), beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytoplasmic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20 monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylsuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor-associated kinase-3 (IRAK-3 or IRAK-M), or enolpyruvylshikimate-phosphate synthase.

[0096] Aspect 92. The method of aspect 89, wherein the disease is cancer.

[0097] Embodiment 93. A compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof, or a deuterated analog thereof, or a prodrug thereof, wherein: Warhead, Linker, s2, Z 1 , Z 2 , Z3 , R 1 , and R 2 is defined as in any of the preceding aspects, The compound, wherein s1 is 0.

[0098] Aspect 94. A method of binding to and altering the specificity of the cereblon complex to induce degradation of complex-associated proteins by using a compound according to claim 93, said proteins being ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein i.e. Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosoma, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinases (including Bruton's tyrosine kinase), CD23, CD124, tyrosine kinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neuroxinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7), farnesyltransferase, geranylgeranyltransferase, TrkA (NGF receptor), beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytoplasmic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20 monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylsuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor associated kinase-3 (IRAK-3 or IRAK-M), enolpyruvylshikimate-phosphate synthase, or neosubstrate (e.g., IKZF1, IKZF3, and CK1a).

[0099] Aspect 95. A method of treating a CRBN-mediated disorder, disease, or condition in a patient, comprising administering to said patient a pharmaceutical composition according to claim 93, preferably wherein said disorder, disease, or condition is selected from a proliferative disorder, a neurological disorder, and a transplant-related disorder.

[0100] In one of the further embodiments, the compound is selected from the following: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0101] The following terms have the meanings indicated throughout this specification.

[0102] Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0103] The following terms have the meanings indicated throughout this specification.

[0104] As used in this specification, including the accompanying embodiments, singular forms of words (e.g., "a," "an," and "the") include the corresponding plural references unless the context clearly dictates otherwise.

[0105] The term "or" is used interchangeably with the term "and / or," unless context clearly dictates otherwise.

[0106] As used herein, the term "subject" refers to mammals and humans, preferably humans.

[0107] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18 (for example, 1 to 12, as a further example, 1 to 10, and as yet further examples, 1 to 8, or 1 to 6, or 1 to 4) carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1~6Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl ... Examples of such alkyl groups include aryl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0108] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0109] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu").

[0110] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.

[0111] The term "hexyl" includes 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0112] The term "alkylene" refers to a divalent alkyl group formed by removing two hydrogens from an alkane. Alkylenes include, but are not limited to, methylene, ethylene, propylene, and the like.

[0113] The term "halogen" includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0114] The term "alkenyl" includes hydrocarbon groups selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 (for example, 2 to 8, and further example, 2 to 6) carbon atoms. Alkenyl groups, such as C 2~6 Examples of alkenyl include, but are not limited to, ethenyl or vinyl groups, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups.

[0115] The term "alkenylene" refers to a divalent alkenyl group formed by removing two hydrogens from an alkene. Alkenylene includes, but is not limited to, vinylidene, butenylene, and the like.

[0116] The term "alkynyl" includes hydrocarbon groups selected from linear and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 (for example, 2 to 8, and further example, 2 to 6) carbon atoms. Alkynyl groups, such as C 2~6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0117] The term "alkynylene" refers to a divalent alkynyl group formed by removing two hydrogens from an alkyne. Alkenylene includes, but is not limited to, ethynylene.

[0118] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0119] For example, the cycloalkyl group can contain 3 to 12 (for example, 3 to 10, as a further example, 3 to 8, as a further example, 3 to 6, 3 to 5, or 3 to 4) carbon atoms. As yet a further example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12 (for example, 3 to 10, as a further example, 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups, such as C 3~8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In preferred embodiments, cycloalkyl is a monocyclic ring (C 3~6Examples of bicyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include groups having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include groups arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0120] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings that share one atom.

[0121] The term "fused cycloalkyl" includes bicyclic cycloalkyl groups, as defined herein, that are saturated and are formed by two or more rings sharing two adjacent atoms.

[0122] The term "bridged cycloalkyl" includes a cyclic structure formed by two rings containing carbon atoms and sharing two non-adjacent atoms. The term "7-10 membered bridged cycloalkyl" includes a cyclic structure formed by two rings containing 7-12 carbon atoms and sharing two non-adjacent atoms.

[0123] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo 3-8 membered cycloalkyl, benzo C 4~6Examples include cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused rings, which refers to cyclic structures containing 8-9 ring atoms in the above examples.

[0124] The term "aryl", used alone or in combination with other terms, includes groups selected from the following:

[0125] 5- and 6-membered carbocyclic aromatic rings, for example, phenyl; Bicyclic ring systems in which at least one ring is carbocyclic and aromatic (e.g., 7-12 membered bicyclic ring systems), such as naphthyl and indanyl; and Tricyclic ring systems in which at least one ring is carbocyclic and aromatic (eg, 10-15 membered tricyclic ring systems), such as fluorenyl.

[0126] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5~10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0127] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0128] The term "heteroaryl" includes groups selected from:

[0129] a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom (e.g., 1-4, in some embodiments 1-3, and in some embodiments 1-2 heteroatoms) selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring atoms being carbon; a 7-12 membered bicyclic ring containing at least one heteroatom (e.g., 1-4, in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon atoms, and at least one ring being aromatic, with at least one heteroatom being within the aromatic ring; and An 11-14 membered tricyclic ring containing at least one heteroatom (e.g., 1-4, in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms) selected from N, O, and S, the remaining ring atoms being carbon, and at least one ring is aromatic, with at least one heteroatom being in the aromatic ring.

[0130] When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is 1 or less. When a heteroaryl group contains one or more heteroatom ring members, the heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form an N-oxide.

[0131] Specifically, the term "bicyclic fused heteroaryl" includes 7-12 membered, preferably 7-10 membered, more preferably 9 or 10 membered fused bicyclic heteroaryl rings as defined herein. Typically, a bicyclic fused heteroaryl is a 5 / 5 membered, 5 / 6 membered, 6 / 6 membered, or 6 / 7 membered bicyclic. The group can be attached to the remainder of the molecule via either ring.

[0132] "Heterocyclyl", "heterocycle", or "heterocyclic" are interchangeable and include non-aromatic heterocyclyl groups that contain one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro rings, i.e., monocyclic heterocyclyl groups, bridged heterocyclyl groups, spiro heterocyclyl groups, and fused heterocyclyl groups.

[0133] The term H or hydrogen as disclosed herein includes hydrogen and the non-radioactive isotope deuterium.

[0134] The term "at least one substituent" disclosed herein includes, for example, 1 to 4 (for example, 1 to 3, and further example, 1 or 2) substituents, provided that valence theory is satisfied. For example, "at least one substituent F" disclosed herein includes 1 to 4 (for example, 1 to 3, and further example, 1 or 2) substituents F.

[0135] The term "divalent" refers to a linking group capable of forming a covalent bond with two other moieties. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkane to form a linking group. The terms "divalent aryl group," "divalent heterocyclyl group," or "divalent heteroaryl group" are intended to be understood in a similar manner.

[0136] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they can further exist as diastereomers. Enantiomers and diastereomers are included in the broader classification of stereoisomers. All possible stereoisomers are intended to be included, such as substantially pure separated enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharma- ceutically acceptable salts are intended to be included. Unless otherwise specifically stated, a reference to an isomer applies to any possible isomer. In any case where the isomeric composition is not specified, all possible isomers are included.

[0137] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bonds are intended to include both E and Z geometric isomers.

[0138] When the compounds disclosed herein contain disubstituted cyclic ring systems, the substituents found in such ring systems can be in cis and trans form.Cis form means that both substituents are found on the top side of the arrangement of the two substituents on carbon, while trans form means that they are on the opposite sides.For example, disubstituted cyclic ring systems can be cyclohexyl or cyclobutyl rings.

[0139] It may be advantageous to separate reaction products from each other and / or from starting materials. The desired products at each step or sequence of steps are separated and / or purified (hereinafter, separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any method, including, for example, reversed and normal phase, size exclusion, ion exchange, high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus, small-scale analytical, simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. It is believed that one skilled in the art can select and apply the technique most likely to achieve the desired separation.

[0140] "Diastereomers" refer to stereoisomers of a compound that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by using a chiral HPLC column.

[0141] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolving the racemic mixture using methods such as diastereomer formation using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3)(1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers under direct chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0142] Some of the compounds disclosed herein may exist with different points of attachment of hydrogen, which are called tautomers. For example, compounds containing a carbonyl -CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Both the keto and enol forms, individually and mixtures thereof, are intended to be included where applicable.

[0143] "Prodrug" refers to a derivative of an active agent that requires a transformation within the body to release the active agent. In some embodiments, the transformation is enzymatic. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the active agent.

[0144] "Deuterated Analog" refers to a derivative of an active agent in which any hydrogen has been replaced with deuterium. In some embodiments, the deuterated moiety is on the warhead moiety. In some embodiments, the deuterated moiety is on the link moiety. In some embodiments, the deuterated moiety is on the Degron moiety.

[0145] "Pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans or lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or may be prepared separately by reacting free base functions with a suitable organic acid, or acidic groups with a suitable base. The term also includes salts of stereoisomers (e.g., enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the invention.

[0146] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an acid addition salt, for example a pharma- ceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharma-ceutically acceptable addition salts without undue experimentation.

[0147] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to contacting an exogenous pharmaceutical, therapeutic, diagnostic, or composition with an animal, human, experimental subject, cell, tissue, organ, or biological fluid. Treatment of a cell includes contacting a reagent with the cell and, in cases where the fluid is in contact with the cell, contacting a reagent with a biological fluid. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell with a reagent, diagnostic, binding compound, or another cell. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0148] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient (e.g., a compound) that, when administered to a subject to treat a disease or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. The term "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case may be apparent to one of ordinary skill in the art or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug thereof, and / or at least one pharma- ceutically acceptable salt thereof, effective to "treat" a disease or disorder in a subject, as defined herein. In the case of a combination therapy, the term "therapeutically effective amount" refers to the total amount of the combination objects to effectively treat a disease, disorder, or condition.

[0149] The term "disease" refers to any disease, ailment, illness, symptom, or indication, and may be interchangeable with the terms "disorder" or "condition."

[0150] Throughout this specification and the embodiments which follow, unless the context requires otherwise, the term "comprise" and variations thereof (e.g., "comprises" and "comprising") are intended to specify the presence of the feature which follows it but do not exclude the presence or addition of one or more other features. As used herein, "comprising" can be substituted with "containing," "including," or, in some cases, "having."

[0151] Throughout this specification and the following embodiments, "C n~m " or "C n ~C m " denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbon atoms. Examples include 1~8 , C 1~6 , C1 to C8, C1 to C6, etc.

[0152] Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. EXAMPLES

[0153] The following examples are intended to be purely illustrative and should not be considered limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Temperature units are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, TCI, and used without further purification unless otherwise indicated. Unless otherwise indicated, reactions shown below were carried out under a positive pressure of nitrogen or argon, or in anhydrous solvents with drying tubes. Reaction flasks were fitted with rubber septa, substrates and reagents were introduced via syringe, and glassware was oven-dried and / or heat-dried.

[0154] 1 1 H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. 1 HNMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone, or (CD3)2CO as solvents with tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; DO: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05) as reference standards. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sexlet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). When coupling constants are given, they are reported in Hertz (Hz).

[0155] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190-400 nm), Mass detector: 6120 SQ, Mobile phase A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, Column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm, Gradient method: Flow rate: 1.8 mL / min, Time (min), A (%), B (%) [Table 2] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190-400 nm), Mass detector: G6125C SQ, Mobile phase A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, Column: Poroshell 120 EC-C18, 4.6×50 mm, 2.7 pm, Gradient method: Flow rate: 1.8 mL / min, Time (min), A (%), B (%) [Table 3] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II) Detector: MWD (190-400 nm), Mass detector: G6125C SQ, Mobile phase A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, Column: Poroshell 120 EC-C18, 4.6×50 mm, 2.7 pm, Gradient method: Flow rate: 1.2 mL / min, Time (min), A (%), B (%) [Table 4] Preparative HPLC was performed on a column (150×21.2 mm ID, 5 pm, Gemini NXC 18) with a flow rate of 20 ml / min, injection volume of 2 ml, room temperature, and UV detection at 214 nm and 254 nm.

[0156] In the examples below, the following abbreviations are used: [Table 5-1] [Table 5-2] [Table 5-3]

[0157] Examples 2 and 13: (S,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione (2) and (R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione (13) Step 1: Ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate [ka] To a solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (10 g, 43.1 mmol) in THF (150 mL) was added LDA (2M, 24 mL, 48 mmol) dropwise at -65°C in 20 min, the reaction solution was stirred at this temperature for 1 h, and then ethyl 3-bromopropanoate (9.4 g, 51.7 mmol) in THF (30 mL) was added dropwise over 10 min. The resulting solution was stirred at -65°C for 30 min, and then the temperature was allowed to rise to room temperature. The reaction was quenched by adding saturated aqueous NH4Cl (50 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL x 3), the organic layers were combined, washed with brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (13.8 g, 96.5%). [M+H] + = 332.0.

[0158] Step 2: 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoic acid [ka] To a solution of ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate (13.5 g, 40.7 mmol) in THF / H2O (90 mL / 30 mL) was added LiOH (2.9 g, 0.122 mol). The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with water and the layers were separated. The pH value of the aqueous layer was adjusted to 4-5 with 1 M HCl and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (10.2 g, 82.5%). [M+H] + = 304.2.

[0159] Step 3: 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a stirred solution of 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoic acid (10.2 g, 33.5 mmol) in toluene (100 mL) was added concentrated H2SO4 (2 mL, 36.9 mmol). The resulting solution was stirred at 100 °C for 3 h. The reaction mixture was concentrated under vacuum and then the mixture was poured into water. The pH value was adjusted to 7-8 with saturated aqueous NaHCO3 and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the product (8.2 g, 80.4%). [M+H] + = 304.3.

[0160] Step 4: (S,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione and (R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a stirred solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (8.2 g, 27.0 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.4 g, 32.4 mmol) in DMF / H2O (100 mL / 20 mL) was added Pd(dtbpf)Cl2 (883 mg, 1.35 mmol) and CsF (8.2 g, 54.0 mmol). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. The reaction solution was diluted with water (400 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SFC (IH (3*25 cm, 5 um), 13% EtOH / 87% CO2, 100 bar, 100 ml / min) to give (S,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione (corresponding to peak B (2.049 min / 254 nm)) (3.1 g, 39.0%) and (R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione (corresponding to peak A (1.679 min / 254 nm)) (2.9 g, 36.5%). (S,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione and (R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione 1 The HNMR and LCMS data were the same. 1 H NMR (500 MHz, DMSO) δ 10.92 (s, 1H), 7.41 (d, J = 12.9 Hz, 1H), 7.06 (d, J = 10.7 Hz, 2H), 5.82 (d, J = 12.9 Hz, 1H), 4.17-4.13 (m, 1H), 3.92- 3.88 (m, 2H), 3.45-3.39 (m, 1H), 2.82 - 2.76 (m, 1H), 2.12-2.07 (m, 1H), 2.00-1.96 (m, 1H), 1.26 (t, J = 7.0 Hz, 3H).[M+H] + =295.9.

[0161] Examples 5 and 6: (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (5) and (R)-1-(4-((S)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (6) Step 1: Methyl (R)-1-(4-bromo-3,5-difluorophenyl)pyrrolidine-3-carboxylate [ka] To a solution of 2-bromo-1,3-difluoro-5-iodobenzene (15 g, 47 mmol), methyl (R)-pyrrolidine-3-carboxylate hydrochloride (8.56 g, 51.7 mmol), and K3PO4 (20 g, 94 mmol) in 250 mL DMSO, CuI (893 mg, 4.7 mmol) and L-proline (1 g, 9.4 mmol) were added. The mixture was stirred at 80 °C for 16 h. After LCMS showed the reaction was complete, the mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layer was washed with brine and separated. The organic phase was concentrated and purified by silica column chromatography (PE:EA = 50:1 to 30:1) to give the product (4.9 g, 32.5%). [M+H] + = 320.1.

[0162] Step 2: Methyl (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylate [ka] To a solution of methyl (R)-1-(4-bromo-3,5-difluorophenyl)pyrrolidine-3-carboxylate (4.9 g, 15.3 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.7 g, 16 mmol), and CsF (4.6 g, 30.6 mmol) in 150 mL of DMF and 15 mL of water, Pd(dtbpf)Cl2 (498 mg, 0.8 mmol) was added. The mixture was stirred at 80 °C for 4 h. After LCMS showed the reaction was complete, the mixture was washed with water and extracted with EtOAc. The organic layer was washed with brine and separated. The organic phase was concentrated in vacuum and purified by CombiFlash (EA:PE=1:10) to give the product (7.9 g, 97.4%). [M+H] + = 531.3.

[0163] Step 3: (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid [ka] To a solution of methyl (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylate (7.9 g, 14.9 mmol) in 100 mL THF and 20 mL water, LiOH (394 mg, 16.4 mmol) in 10 mL water was added dropwise at room temperature. The mixture was stirred at room temperature for 15 minutes. After TLC showed the reaction was complete, the mixture was concentrated in vacuum at room temperature. The residue was diluted with water and adjusted to pH<5 with 1N HCl aqueous solution. The liquid was extracted with EtOAc and separated. The organic phase was dried over Na2SO4 and concentrated in vacuum to give the product (7.4 g, 96.0%). [M+H] + = 517.2.

[0164] Step 4: (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (5) and (R)-1-(4-((S)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (6) [ka] To a solution of (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (7.4 g, 14.3 mmol) in 50 mL DCM and 250 mL iPrOH was added Pd / C (7.4 g, 10%). The mixture was stirred under hydrogen atmosphere (balloon) at 40° C. for 16 hours. After LCMS showed the reaction was complete, the mixture was cooled to room temperature and filtered directly through Celite. The filtrate was concentrated in vacuum to give the crude product, which was purified by SFC (IH (3*25 cm, 5 um), 13% EtOH / 87% CO2, 100 bar, 100 ml / min). The product, (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid, corresponded to peak A (0.655 min / 254 nm) (1.6 g, 34%). 1 H NMR (500 MHz, DMSO) δ 12.52 (s, 1H), 10.84 (s, 1H), 6.23 (d, J = 12.1 Hz, 2H), 4.02 (dd, J = 12.6, 5.0 Hz, 1H), 3.47 - 3.36 (m, 2H), 3.32 - 3.22 (m, 2H), 3.21 - 3.14 (m, 1H), 2.83 - 2.72 (m, 1H), 2.49 (m, 1H), 2.26 - 2.03 (m, 3H), 1.94 (m, 1H).[M+H] + = 338.9. Also, (R)-1-(4-((S)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid corresponded to peak B (1.811 min / 254 nm) (1.5 g, 32%). 1H NMR (500 MHz, DMSO) δ 12.53 (s, 1H), 10.84 (s, 1H), 6.23 (d, J = 12.1 Hz, 2H), 4.02 (dd, J = 12.6, 5.0 Hz, 1H), 3.49 - 3.36 (m, 2H), 3.32 - 3.21 (m, 2H), 3.21 - 3.14 (m, 1H), 2.77 (m, 1H), 2.49 (m, 1H), 2.25 - 2.03 (m, 3H), 1.99 - 1.88 (m, 1H).[M+H] + = 339.0.

[0165] Example 7: (R)-3-(2,6-difluoro-4-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 9. (R)-3-(2,6-difluoro-4-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione was purified by SFC ((IH(3*25cm, 5um), 13% EtOH / 87% CO2, 100 bar, 100mL / min) corresponding to peak A (2.028min / 254nm) (230mg, 31%). 1 H NMR (500 MHz, DMSO) δ 10.83 (s, 1H), 6.17 (d, J = 12.2 Hz, 2H), 4.71 (t, J = 5.2 Hz, 1H), 4.01 (dd, J = 12.6, 5.0 Hz, 1H), 3.46 - 3.35 (m, 2H), 3.31 - 3.16 (m, 3H), 2.99 (dd, J = 9.7, 6.3 Hz, 1H), 2.83 - 2.72 (m, 1H), 2.48 (m, 1H), 2.46 - 2.37 (m, 1H), 2.14 - 1.90 (m, 3H), 1.74 (ddd, J = 14.9, 7.4 Hz, 1H).[M+H] + = 325.0.

[0166] Example 9: 3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)piperidine-2,6-dione Step 1: (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methanol [ka] To a stirred mixture of methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate (1.7 g, 3.29 mmol) in THF (20 mL) was added LiAlH4 (1 M in THF, 4.27 mL, 4.27 mmol) dropwise at 0 °C. The mixture was then stirred for 2 h and the reaction was quenched with water (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (1.4 g, 87%). [M+H] + = 489.2.

[0167] Step 2: 3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)piperidine-2,6-dione [ka] To a solution of (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methanol (1.40 g, 2.87 mmol) in iPrOH (20 mL) and DCM (20 mL) was added Pd / C (1.0 g, 10 wt%), which was stirred at room temperature under hydrogen atmosphere for 48 h. The resulting mixture was filtered and the solid was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to give the product (450 mg, 51%). 1H NMR (500 MHz, DMSO) δ 10.85 (s, 1H), 6.08 (d, J = 11.2 Hz, 2H), 4.77 (t, J = 5.2 Hz, 1H), 4.02 (dd, J = 12.6, 4.9 Hz, 1H), 3.84 (t, J = 7.7 Hz, 2H), 3.56 (t, J = 5.8 Hz, 4H), 2.77 (ddd, J = 18.2, 13.0, 5.3 Hz, 2H), 2.50 (m, 1H), 2.14 - 2.01 (m, 1H), 1.98 - 1.88 (m, 1H).[M+H] + = 311.0.

[0168] Example 12: (3R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyrrolidine-3-carboxylic acid Step 1: 2,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine [ka] To a stirred mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (this intermediate can be prepared according to the method described in WO2017197046) (8.3 g, 20 mmol) and 4-bromoiodobenzene (5.6 g, 20 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL) was added K2CO3 (5.5 g, 40 mmol) and Pd(dppf)Cl2 (1.4 g, 2 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE=1:10) to give the product (4.5 g, 50%). [M+H] + = 446.2.

[0169] Step 2: Methyl (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pyrrolidine-3-carboxylate [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (4.5 g, 10 mmol), methyl (R)-pyrrolidine-3-carboxylate hydrochloride (2.5 g, 15 mmol), and Cs2CO3 (15 g, 45 mmol) in 50 mL 1,4-dioxane, Pd2(dba)3 (915 mg, 1 mmol) and Xantphos (1.16 g, 2 mmol) were added. The mixture was stirred at 80° C. under nitrogen atmosphere for 16 h. After LCMS showed the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica column chromatography (EA:PE=1:10) to give the product (2.1 g, 42.5%). [M+H] + = 494.9.

[0170] Step 3: (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pyrrolidine-3-carboxylic acid [ka] To a solution of methyl (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pyrrolidine-3-carboxylate (2.1 g, 4.25 mmol) in 30 mL of THF and 10 mL of water, LiOH-H2O (178 mg, 4.25 mmol) in 2 mL of water was added dropwise at room temperature. The mixture was stirred at room temperature for 15 min. Upon completion of the reaction as determined by TLC, the mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH<5 with 1N aqueous HCl. The liquid was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (60 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the product (2 g, 98%). [M+H] + = 481.6.

[0171] Step 4: (3R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyrrolidine-3-carboxylic acid [ka] To a solution of (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pyrrolidine-3-carboxylic acid (2 g, 4.17 mmol) in 5 mL DCM and 100 mL iPrOH was added Pd / C (2 g, 10%). The mixture was stirred under hydrogen atmosphere (balloon) at 45° C. for 16 h. Upon completion of the reaction as determined by LCMS, the mixture was cooled to room temperature and filtered directly through Celite. The solid was partitioned between DCM (5 mL) and MeOH (50 mL) which was sonicated for 5 min. The mixture was filtered through Celite and the combined filtrate was concentrated in vacuo to give the product (1.2 g, 95%). 1 H NMR (500 MHz, DMSO) δ 12.49 (s, 1H), 10.74 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.51 (d, J = 8.5 Hz, 2H), 3.68 (dd, J = 10.7, 4.9 Hz, 1H), 3.40 (m, 2H), 3.31 - 3.20 (m, 2H), 3.19 - 3.12 (m, 1H), 2.61 (ddd, J = 16.6, 10.9, 5.3 Hz, 1H), 2.44 (m, 1H), 2.25 - 2.06 (m, 3H), 2.04 - 1.93 (m, 1H).[M+H] + = 303.1.

[0172] Example 14: (S)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylic acid [ka] The title compound was prepared in a similar manner to Example 12. (S)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylic acid was purified by SFC (IH (3*25cm, 5um), 13% EtOH / 87% CO2, 100 bar, 100ml / min) corresponding to peak A (1.165min / 254nm) (670mg, 26%). 1 H NMR (500 MHz, DMSO) δ 12.47 (s, 1H), 10.84 (s, 1H), 6.17 (d, J = 12.1 Hz, 2H), 4.01 (m, 1H), 3.48 (m, 2H), 3.16 (d, J = 9.5 Hz, 1H), 3.08 (d, J = 9.4 Hz, 1H), 2.89 (t, J = 8.0 Hz, 1H), 2.83 - 2.72 (m, 1H), 2.54 (s, 1H), 2.08 (m, 1H), 1.98 - 1.86 (m, 1H), 1.23 (s, 3H), 1.00 (s, 3H).[M+H] + = 367.1.

[0173] Example 15: 3-(4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione Step 1: 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol [ka] 2-(4-Bromophenyl)ethan-1-ol (20 g, 100 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (38.1 g, 150 mmol), Pd(dppf)Cl2 (7.3 g, 10 mmol), KOAc (19.6 g, 200 mmol) were placed in 1,4-dioxane (400 mL). The resulting mixture was then heated to 100° C. and stirred for 2 h. The mixture was cooled to room temperature. After filtration, the filtrate was concentrated in vacuo to give the crude product (28 g, crude), which was used directly without further purification. [M+H]+ =249.2.

[0174] Step 2: 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)ethan-1-ol [ka] A mixture of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol (28 g, crude), Pd(dppf)Cl2 (7.3 g, 10 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (36.9 g, 100 mmol), and Cs2CO3 (65.2 g, 200 mmol) in 1,4-dioxane (300 mL) and water (30 mL) was stirred at 100 °C under nitrogen atmosphere overnight. The reaction was cooled to room temperature, the solids were filtered off, and the filtrate was concentrated and purified on a silica gel column (eluted with EtOAc / hexanes = 1:2) to give the crude product, which was used directly in the next step. [M+H] + =412.2.

[0175] Step 3: 3-(4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione [ka] 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)ethan-1-ol (crude from previous step) was dissolved in MeOH (500 mL) and Pd / C (10%, w / w, 5 g) was added to the solution in one portion. The resulting mixture was stirred under hydrogen atmosphere (1 atm) overnight. The solids were filtered off and the filtrate was concentrated in vacuo to give the crude product. The crude was triturated with MTBE (50 mL) to give the desired product (13.5 g, 57.9% yield for three steps). 1H NMR (500 MHz, DMSO) δ 10.81 (s, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 4.63 (t, J = 5.2 Hz, 1H), 3.80 (dd, J = 11.4, 4.9 Hz, 1H), 3.59 (dd, J = 12.3, 7.0 Hz, 2H), 2.76 - 2.58 (m, 3H), 2.49 - 2.44 (m, 1H), 2.23 - 2.09 (m, 1H), 2.02 (dt, J = 8.3, 4.8 Hz, 1H).[M+H] + =234.1. Example 16: (R)-3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione

[0176] Step 1: tert-Butyl 4-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] A mixture of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (4 g, 16 mmol), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (6.4 g, 24 mmol), K2CO3 (4.4 g, 32 mmol) in DMF (50 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was allowed to cool to room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (1:1) to give the product (7 g, 90%). [M+H] + = 499.0.

[0177] Step 2: tert-Butyl 4-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (7 g, 14 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.3 g, 28 mmol), Pd(dppf)Cl2 (1.1 g, 1.4 mmol), and K3PO4 (8.9 g, 42 mmol) in DMF (160 mL) and water (20 mL) was stirred in a flask at 90 °C under nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3 x 1000 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (1:1)) to give the product (5 g, 80%). [M+H] + = 447.0.

[0178] Step 3: tert-Butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate (5 g, 11.2 mmol) in MeOH (100 mL) and DCM (20 mL) under nitrogen atmosphere was added Pd / C (wet, 10%) (1 g). The resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. The resulting mixture was filtered and the solid was washed with DCM / CH3OH (10:1, 200 mL). The filtrate was concentrated under reduced pressure to give the product (4.0 g, 85.3%). [M+H] += 419.1.

[0179] Step 4: (6-aminoquinoxalin-5-yl)dimethylphosphine oxide [ka] A mixture of 5-bromoquinoxalin-6-amine (10 g, 44.8 mmol), dimethylphosphine oxide (10.5 g, 134.5 mmol), Pd(OAc)2 (1.0 g, 4.5 mmol), Xanphos (5.2 g, 9 mmol), and K3PO4 (28 g, 134 mmol) in DMF (250 mL) and water (50 mL) was stirred in a flask at 130 °C under nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature. The resulting mixture was extracted with DCM (3 x 1000 mL). The combined organic layers were washed with brine (1000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give the product (6 g, 60%). [M+H] + = 222.0.

[0180] Step 5: (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka] A mixture of (6-aminoquinoxalin-5-yl)dimethylphosphine oxide (6 g, 27.3 mmol), 5-bromo-2,4-dichloropyrimidine (12.3 g, 54.6 mmol) in THF (200 mL) was stirred in a flask at 0° C. under nitrogen atmosphere, followed by the addition of 54 mL KHMDS (1M in THF). The reaction mixture was allowed to warm to room temperature for 2 h. The reaction was quenched with water, and the mixture was extracted with DCM, washed three times with saturated brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give the product (4 g, 35%). [M+H] + = 412.0.

[0181] Step 6: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide [ka] A mixture of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (2 g, 4.8 mmol), tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (2.6 g, 6.3 mmol), and MsOH (184 mg, 1.92 mmol) in t-BuOH (20 mL) was stirred in a flask at 90° C. under nitrogen atmosphere overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the product (2 g, 60%). [M+H] + = 694.0.

[0182] Step 7: (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde [ka] (R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione (3.1 g, 10.4 mmol) was dissolved in FA (50 mL). The resulting solution was stirred at room temperature for 2 h. The reaction solution was evaporated to dryness to give the product (2.6 g, 91.8%). [M+H] + = 268.1.

[0183] Step 8: (R)-3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound (34 mg, 25%) was prepared in a similar manner to step 9 of example 21 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde. 1 H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.96 (s, 1H), 8.86 (dt, J = 22.8, 11.4 Hz, 3H), 8.28 (d, J = 9.1 Hz, 2H), 7.90 (d, J = 8.9 Hz, 1H), 7.37 (s, 1H), 7.03 (d, J = 10.0 Hz, 2H), 6.81 (s, 1H), 4.20 (dd, J = 12.8, 5.0 Hz, 1H), 3.77 (s, 3H), 3.01 (d, J = 11.5 Hz, 2H), 2.76 (m, 6H), 2.54 (d, J = 1.8 Hz, 6H), 2.48 (s, 5H), 2.36 (s, 2H), 2.13 (d, J = 9.6 Hz, 1H), 2.02 (d, J = 14.4 Hz, 7H), 1.87 (d, J = 11.4 Hz, 2H), 1.58 (d, J = 8.8 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H);[M+H] + = 945.6.

[0184] Example 17: (S)-3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was synthesized in a similar manner to Example 16. 1 H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.96 (s, 1H), 8.86 (dt, J = 22.8, 11.4 Hz, 3H), 8.28 (d, J = 9.1 Hz, 2H), 7.90 (d, J = 8.9 Hz, 1H), 7.37 (s, 1H), 7.03 (d, J = 10.0 Hz, 2H), 6.81 (s, 1H), 4.20 (dd, J = 12.8, 5.0 Hz, 1H), 3.77 (s, 3H), 3.01 (d, J = 11.5 Hz, 2H), 2.76 (m, 6H), 2.54 (d, J = 1.8 Hz, 6H), 2.48 (s, 5H), 2.36 (s, 2H), 2.13 (d, J = 9.6 Hz, 1H), 2.02 (d, J = 14.4 Hz, 7H), 1.87 (d, J = 11.4 Hz, 2H), 1.58 (d, J = 8.8 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H);[M+H] + = 945.6.

[0185] Example 18: 3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was synthesized in a similar manner to Example 16. 1 H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.96 (s, 1H), 8.86 (dt, J = 22.8, 11.4 Hz, 3H), 8.28 (d, J = 9.1 Hz, 2H), 7.90 (d, J = 8.9 Hz, 1H), 7.37 (s, 1H), 7.03 (d, J = 10.0 Hz, 2H), 6.81 (s, 1H), 4.20 (dd, J = 12.8, 5.0 Hz, 1H), 3.77 (s, 3H), 3.01 (d, J = 11.5 Hz, 2H), 2.76 (m, 6H), 2.54 (d, J = 1.8 Hz, 6H), 2.48 (s, 5H), 2.36 (s, 2H), 2.13 (d, J = 9.6 Hz, 1H), 2.02 (d, J = 14.4 Hz, 7H), 1.87 (d, J = 11.4 Hz, 2H), 1.58 (d, J = 8.8 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H);[M+H] + = 945.6. Example 19: 3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidine-2,6-dione [ka] The title compound was synthesized in a similar manner to Example 16. 1H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 10.83 (s, 1H), 8.87 (d, J = 4.2 Hz, 3H), 8.28 (d, J = 8.8 Hz, 2H), 7.92 (s, 2H), 7.16 (d, J = 19.2 Hz, 4H), 6.81 (s, 1H), 3.77 (s, 4H), 3.00-3.02 (m, 4H), 2.71-2.75 (m, 6H), 2.26-2.40 (m, 12H), 2.02 (m, 7H), 1.85-1.87 (m, 2H), 1.58 (d, J = 11.1 Hz, 2H), 0.93 (s, 3H);[M+H] + =909.3.

[0186] Example 20: (S)-3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (500 mg, 0.694 mmol) and (S)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (222.49 mg, 0.832 mmol; this compound was obtained in a similar manner to "(R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde") in dichloromethane (8 mL) was stirred in a flask at room temperature for 2 hours. To the mixture was added sodium triacetoxyborohydride (146.34 mg, 0.694 mmol) and the reaction was stirred at room temperature for an additional 2 h. The resulting mixture was diluted with H2O (60 mL) and the layers were separated. The aqueous layer was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product (600 mg), which was purified by HPLC chromatography (gradient elution of 0.1% FA in water:acetonitrile = 90:10 to 50:50) to give the product (475 mg, 70%). 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 10.88 (s, 1H), 8.49 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J = 12.4 Hz, 1H), 7.94 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 7.26 (s, 1H), 6.96 (d, J = 10.0 Hz, 2H), 6.68 (s, 1H), 4.13 (dd, J = 12.6, 5.0 Hz, 1H), 3.69 (s, 3H), 2.86 (dd, J = 15.2, 7.6 Hz, 4H), 2.79 - 2.65 (m, 4H), 2.59 (t, J = 11.3 Hz, 3H), 2.47 (s, 4H), 2.41 - 2.31 (m, 4H), 2.22 (d, J = 4.7 Hz, 3H), 2.05 (s, 2H), 1.92 (d, J = 13.3 Hz, 7H), 1.77 (d, J = 10.2 Hz, 2H), 1.47 (d, J = 8.8 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H), 0.70 (s, 3H).[M+H] + = 972.7

[0187] Example 21: (R)-3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: 6-Nitroquinolin-2-ol [ka] To a solution of quinolin-2-ol (6 g, 41.3 mmol) in concentrated H2SO4 (98%) (50 mL) was added a solution of concentrated HNO3 (63%) (3.12 g, 49.6 mmol) dropwise with stirring at 0° C. The mixture was then stirred at room temperature for 1 h. The mixture was then diluted with water (200 mL) at 0° C., the reaction mixture was filtered, the solid was washed with H2O (500 mL) and dried in vacuum to give 6-nitroquinolin-2-ol (5.5 g, 69.9%). [M+H] + = 191.1.

[0188] Step 2: 2-Chloro-6-nitroquinoline [ka] A solution of 6-nitroquinolin-2-ol (5.5 g, 28.78 mmol) in POCl3 (50 mL) was stirred at 100° C. for 2 h. The mixture was then cooled to room temperature and then concentrated in vacuo. The residue was purified by Combiflash (silica column, 40 g, DCM:MeOH=15:1) to give 2-chloro-6-nitroquinoline (5 g, 82.9%). [M+H] + = 209.1.

[0189] Step 3: 6-Nitro-2-vinylquinoline [ka] To a suspension of 2-chloro-6-nitroquinoline (5 g, 23.9 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.37 g, 47.84 mmol) in dioxane (40 mL) and water (10 mL) was added K2CO3 (9.91 g, 71.77 mmol) and Pd(dppf)Cl2 (1.74 g, 2.39 mmol) under N2. The mixture was warmed to 100 °C and stirred for 16 h. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by Combiflash (silica column, 40 g, DCM:MeOH=15:1) to give 6-nitro-2-vinylquinoline (4.5 g, 93.9%). [M+H] + = 201.1.

[0190] Step 4: 2-Ethylquinolin-6-amine [ka] To a suspension of 6-nitro-2-vinylquinoline (4.5 g, 22.38 mmol) in MeOH (20 mL) was added Pd / C (1.5 g). The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The mixture was then filtered and the solid was washed with MeOH. The filtrate was concentrated in vacuo to give 2-ethylquinolin-6-amine (3.84 g, 99.2%). [M+H] + = 173.1.

[0191] Step 5: 2-Ethyl-5-iodoquinolin-6-amine [ka] The title compound (4.5 g, 75.3%) was prepared from 2-ethylquinolin-6-amine and ICl in a similar manner to step 1 of example 22. [M+H] + = 299.1.

[0192] Step 6: (6-amino-2-ethylquinolin-5-yl)dimethylphosphine oxide [ka] The title compound (3.5 g, 93.5%) was prepared from 2-ethyl-5-iodoquinolin-6-amine and dimethylphosphine oxide in a similar manner to step 2 of example 22. [M+H] + = 249.1.

[0193] Step 7: (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide [ka] The title compound (2.5 g, 40.38%) was prepared from (6-amino-2-ethylquinolin-5-yl)dimethylphosphine oxide and 5-bromo-2,4-dichloropyrimidine in a similar manner to step 3 of example 22. [M+H] + = 439.6.

[0194] Step 8: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide [ka] The title compound (2.0 g, 48.78%) was prepared from (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and tert-butyl 4-(1-(4-amino-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate in a similar manner to step 4 of example 22. [M+H] + = 721.5.

[0195] Step 9: (R)-3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (500 mg, 0.694 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (222.49 mg, 0.832 mmol) in dichloromethane (8 mL) was stirred at room temperature in a flask for 2 h. To the mixture was added sodium triacetoxyborohydride (146.34 mg, 0.694 mmol) and the reaction was stirred at room temperature for an additional 2 h. The resulting mixture was diluted with HO (60 mL) and the layers were separated. The aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC chromatography (gradient elution, 0.1% FA in water:acetonitrile=90:10 to 50:50) to give the product (480 mg, 71.2%). 1H NMR (500 MHz, DMSO) δ 11.73 (s, 1H), 10.88 (s, 1H), 8.49 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J = 12.4 Hz, 1H), 7.94 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 7.26 (s, 1H), 6.96 (d, J = 10.0 Hz, 2H), 6.68 (s, 1H), 4.13 (dd, J = 12.6, 5.0 Hz, 1H), 3.69 (s, 3H), 2.86 (dd, J = 15.2, 7.6 Hz, 4H), 2.79 - 2.65 (m, 4H), 2.59 (t, J = 11.3 Hz, 3H), 2.47 (s, 4H), 2.41 - 2.31 (m, 4H), 2.22 (d, J = 4.7 Hz, 3H), 2.05 (s, 2H), 1.92 (d, J = 13.3 Hz, 7H), 1.77 (d, J = 10.2 Hz, 2H), 1.47 (d, J = 8.8 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H), 0.70 (s, 3H).[M+H] + = 972.7

[0196] Example 22: (R)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: 5-Iodo-2-methylquinolin-6-amine [ka] To a solution of 2-methylquinolin-6-amine (5 g, 31.62 mmol) in AcOH (50 mL) was added dropwise a solution of ICl (8.85 g, 37.95 mmol) in AcOH (10 mL). The mixture was stirred at 5°C-10°C. The mixture was then stirred at room temperature for 1 h. The reaction solution was concentrated to dryness, and the mixture was diluted with water (200 mL) and neutralized with solid K2CO3. The mixture was extracted with DCM (3 x 150 mL). The combined organic phase was washed with brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH=20:1) to give the product (7.1 g, 79.06%). [M+H] + = 285.2.

[0197] Step 2: (6-amino-2-methylquinolin-5-yl)dimethylphosphine oxide [ka] To a solution of 5-iodo-2-methylquinolin-6-amine (7.1 g, 24.99 mmol) and dimethylphosphine oxide (2.93 g, 37.49 mmol) in dioxane (100 mL) was added Pd(OAc)2 (0.55 g, 2.45 mmol), Xantphos (2.89 g, 4.99 mmol), and K3PO4 (10.61 g, 49.98 mmol) under nitrogen atmosphere. The mixture was degassed under vacuum and purged with nitrogen several times. The mixture was stirred at 100 °C under a nitrogen balloon for 6 h. The reaction mixture was extracted with DCM (3 x 50 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH = 15:1) to give the product (4.5 g, 76.9%). [M+H] + = 235.2.

[0198] Step 3: (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide [ka] A solution of (6-amino-2-methylquinolin-5-yl)dimethylphosphine oxide (4.5 g, 19.21 mmol), 5-bromo-2,4-dichloropyrimidine (13.13 g, 57.64 mmol), and DIEA (7.45 g, 57.64 mmol) in n-BuOH (100 mL) was stirred at 120° C. for 12 h. The reaction solution was concentrated to dryness, and then the crude product was purified by recrystallization from EA:PE=5:1 (50 mL). The mixture was filtered, and the filter cake was washed with DCM (3×50 mL). The combined organic phase was washed with brine (2×100 mL), dried over Na2SO4, and concentrated in vacuo to give the product (5.5 g, 67.3%). [M+H] + = 425.2.

[0199] Step 4: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide [ka] A solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (5.5 g, 12.91 mmol), TsOH (6.67 g, 38.73 mmol), and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate (5.67 g, 13.56 mmol) in n-BuOH (80 mL) was stirred at 100° C. for 12 h. The reaction mixture was adjusted to pH=8 with 1M NaOH and extracted with DCM (3×80 mL). The combined organic phase was washed with brine (2×100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH=8:1) to give the product (5.2 g, 57.01%). [M+H] + = 707.3.

[0200] Step 5: (R)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.07 mmol), (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (24 mg, 0.07 mmol), and DIEA (26 mg, 0.2 mmol) in 10 mL DCM was added a solution of 50% wtT3P in EtOAc (64 mg, 0.1 mmol). The mixture was stirred at 25° C. for 16 h. After LCMS showed the reaction was complete, the mixture was quenched with 10 mL of water. The organic phase was concentrated in vacuo and purified by preparative HPLC equipped with C-18 column chromatography (gradient elution of 0.1% FA in water:acetonitrile=90:10 to 60:40) to give the desired product (21.69 mg, 30.1% yield). 1H NMR (500 MHz, DMSO) δ 11.76 (s, 1H), 10.84 (s, 1H), 8.56 (d, J = 8.9 Hz, 1H), 8.30 (d, J = 7.1 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.46 - 7.33 (m, 2H), 6.74 (s, 1H), 6.23 (d, J = 12.1 Hz, 2H), 4.02 (dd, J = 12.6, 5.1 Hz, 1H), 3.76 (s, 3H), 3.59 - 3.42 (m, 6H), 3.36 - 3.22 (m, 4H), 2.95 (d, J = 10.7 Hz, 2H), 2.83 - 2.73 (m, 1H), 2.70 - 2.62 (m, 5H), 2.56 (d, J = 15.8 Hz, 2H), 2.45 - 2.35 (m, 3H), 2.30 (d, J = 7.1 Hz, 2H), 2.21 - 2.03 (m, 3H), 2.03 - 1.91 (m, 7H), 1.84 (d, J = 10.2 Hz, 2H), 1.65 - 1.50 (m, 2H), 0.92 - 0.63 (m, 3H).[M+H] + = 1027.6.

[0201] Example 24: (R)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (1.15 g, 1.60 mmol), (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (595 mg, 1.76 mmol), DIEA (411 mg, 3.19 mmol), and T3P (763 mg, 2.4 mmol) in dichloromethane (8 mL) was stirred in a flask at room temperature for 0.5 h. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC chromatography (gradient elution, 0.1% FA in water:acetonitrile=90:10 to 50:50) to give the product (800 mg, 48.3%). 1 H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 10.84 (s, 1H), 8.56 (d, J = 8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.34 (s, 1H), 6.75 (s, 1H), 6.23 (d, J = 12.2 Hz, 2H), 4.02 (dd, J = 12.3, 4.7 Hz, 1H), 3.76 (s, 3H), 3.65-3.41 (m, 7H), 3.31-3.23 (m, 4H), 3.01-2.88 (m, 4H), 2.84-2.74 (m, 1H), 2.68 (t, J = 11.1 Hz, 2H), 2.57 (m, 3H), 2.38 (m, 1H), 2.30 (m, 2H), 2.19-2.06 (m, 3H), 1.98 (d, J = 13.3 Hz, 6H), 1.96-1.91 (m, 1H), 1.84 (d, J = 10.1 Hz, 2H), 1.57 (d, J = 9.9 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H), 0.77 (s, 3H).[M+H] + =1041.7.

[0202] Example 25: (S)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO) δ 11.80 (s, 1H), 10.84 (s, 1H), 8.56 (d, J = 8.9 Hz, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.34 (s, 1H), 6.75 (s, 1H), 6.23 (d, J = 12.2 Hz, 2H), 4.02 (dd, J = 12.3, 4.7 Hz, 1H), 3.76 (s, 3H), 3.65-3.41 (m, 7H), 3.31-3.23 (m, 4H), 3.01-2.88 (m, 4H), 2.84-2.74 (m, 1H), 2.68 (t, J = 11.1 Hz, 2H), 2.57 (m, 3H), 2.38 (m, 1H), 2.30 (m, 2H), 2.19-2.06 (m, 3H), 1.98 (d, J = 13.3 Hz, 6H), 1.96-1.91 (m, 1H), 1.84 (d, J = 10.1 Hz, 2H), 1.57 (d, J = 9.9 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H), 0.77 (s, 3H).[M+H] + =1041.7.

[0203] Example 26: (R)-3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropoxy-2-ethylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: 1-Bromo-2-chloro-4-cyclopropoxy-5-nitrobenzene [ka] To a solution of 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (4 g, 15.7 mmol) in DMSO (50 mL) was added cyclopropanol (912 mg, 15.7 mmol) and K2CO3 (4.34 g, 31.4 mmol) at 20° C. The mixture was then warmed to 70° C. and stirred for 16 h. The mixture was then diluted with EA (200 mL) and washed with water (100 mL×2) and brine (100 mL×2). The organic layers were then combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Combiflash (silica column, 80 g, PE:EA=10:1) to give the product (3.5 g, 76.2%).

[0204] Step 2: tert-Butyl 4-(1-(2-bromo-5-cyclopropoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] To a solution of 1-bromo-2-chloro-4-cyclopropoxy-5-nitrobenzene (3.5 g, 12.0 mmol) in MeCN (50 mL) was added tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (3.56 g, 13.2 mmol) and K2CO3 (3.31 g, 24.0 mmol) at 25°C. The mixture was then stirred at 80°C for 16 h. The mixture was then cooled to room temperature and filtered. The solid was washed with EA. The filtrate was then concentrated in vacuo. The residue was purified by Combiflash (silica column, 80 g, DCM:MeOH=30:1) to give tert-butyl 4-(1-(2-bromo-5-cyclopropoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (4 g, 63.3%). [M+H] + = 525.3.

[0205] Step 3: tert-Butyl 4-(1-(5-cyclopropoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] To a suspension of tert-butyl 4-(1-(2-bromo-5-cyclopropoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (2 g, 3.8 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (879 mg, 5.7 mmol) in dioxane (16 mL) and water (4 mL) was added K2CO3 (1.57 g, 11.4 mmol) and Pd(dppf)Cl2 (139 mg, 0.19 mmol) under nitrogen atmosphere. The mixture was warmed to 100 °C and stirred for 16 h. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by Combiflash (silica column, 40 g, DCM:MeOH=15:1) to give tert-butyl 4-(1-(5-cyclopropoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate (1.4 g, 77.9%). [M+H] + = 473.3.

[0206] Step 4: tert-Butyl 4-(1-(4-amino-5-cyclopropoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] To a suspension of tert-butyl 4-(1-(5-cyclopropoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate (1.4 g, 3.0 mmol) in MeOH (20 mL) was added Pd / C (1 g). The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The mixture was then filtered and the solid was washed with MeOH. The filtrate was concentrated in vacuo to give tert-butyl 4-(1-(4-amino-5-cyclopropoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate (1.2 g, 90.0%). [M+H] + = 445.3.

[0207] Step 5: (6-((5-bromo-2-((2-cyclopropoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide [ka] To a solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (553 mg, 1.3 mmol) in n-BuOH (10 mL) was added tert-butyl 4-(1-(4-amino-5-cyclopropoxy-2-ethylphenyl)piperidin-4-yl)piperazine-1-carboxylate (600 mg, 1.3 mmol) at 20° C. 4-Methylbenzenesulfonic acid (783 mg, 4.6 mmol) was added to the reaction mixture at 20° C. Then the mixture was stirred at 100° C. for 13 h. The mixture was diluted with water (100 mL), adjusted to pH=8 with 5N NaOH solution, and extracted with DCM (150 mL×3). The combined organic layer was washed with brine (150 mL×3), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM / MeOH (0.5% NH4OH) = 10 / 1 to 5 / 1). (6-((5-bromo-2-((2-cyclopropoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (500 mg, 52%) was obtained. [M+H] + = 733.2.

[0208] Step 6: (R)-3-(4-(2-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropoxy-2-ethylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound (32 mg, 48%) was prepared in a similar manner to step 9 of example 21 from (6-((5-bromo-2-((2-cyclopropoxy-5-ethyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde. 1 H NMR (500 MHz, DMSO) δ 11.74 (s, 1H), 10.95 (s, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 7.5 Hz, 1H), 8.21 (s, 1H), 7.85-7.84 (m, 2H), 7.43 (d, J = 8.5 Hz, 1H), 7.39 (s, 1H), 7.04 (d, J = 10.0 Hz, 2H), 6.98 (s, 1H), 4.20 (dd, J = 12.5, 5.0 Hz, 1H), 3.81 (dq, J = 9.0, 3.0 Hz, 1H), 2.98 (d, J = 10.5 Hz, 2H), 2.85 - 2.76 (m, 4H), 2.75 - 2.51 (m, 14H), 2.17 (m, 5H), 1.96 (m, 9H), 1.69-1.53 ​​(m, 2H), 0.75 (t, J = 7.5, 3H), 0.70 (m, 2H), 0.61 - 0.56 (m, 2H).[M+H] + = 984.3.

[0209] Examples 28 and 29: (R)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (28) and (S)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (29). [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-methylquinolin-5-yl)dimethylphosphine oxide (140 mg, 0.2 mmol), (3R)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyrrolidine-3-carboxylic acid (60 mg, 0.2 mmol), and DIEA (51 mg, 0.4 mmol) in 5 mL of anhydrous DCM was added T3P (190 mg, 0.3 mmol, 50% wt EtOAc solution). The mixture was stirred at room temperature for 30 min. Upon completion of the reaction as determined by LCMS, the mixture was diluted with 10 mL of water. The mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by preparative TLC (DCM:MeOH = 15:1) gave a mixture of two diastereomers, which could be separated by chiral HPLC (IF (2 * 25 cm, 5 um), 60% MtBE / 40% MeOH:DCM = 1:1 / 0.1% DEA, 80 bar, 20 ml / min). The product, (R)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (28), corresponded to peak A (1.192 min / 254 nm) (2.7 mg, 1%). 1H NMR (500 MHz, DMSO) δ 11.78 (s, 1H), 10.75 (s, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.39 (s, 1H), 7.00 (d, J = 8.3 Hz, 2H), 6.74 (s, 1H), 6.51 (d, J = 8.4 Hz, 2H), 3.76 (s, 3H), 3.69 (dd, J = 10.6, 4.8 Hz, 1H), 3.59 - 3.42 (m, 6H), 3.32 - 3.21 (m, 3H), 2.95 (d, J = 10.2 Hz, 2H), 2.70 - 2.60 (m, 5H), 2.60 - 2.53 (m, 3H), 2.49 - 2.41 (m, 3H), 2.37 (m, 1H), 2.30 (d, J = 6.5 Hz, 2H), 2.20 - 2.06 (m, 3H), 2.00 (m, 7H), 1.83 (d, J = 10.6 Hz, 2H), 1.57 (m, 2H), 0.77 (s, 3H).[M+H] + = 991.7. (S)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (29) corresponded to peak B (2.190 min / 254 nm) (2.8 mg, 1%). 1H NMR (500 MHz, DMSO) δ 11.78 (s, 1H), 10.75 (s, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.39 (s, 1H), 7.00 (d, J = 8.3 Hz, 2H), 6.74 (s, 1H), 6.51 (d, J = 8.4 Hz, 2H), 3.76 (s, 3H), 3.69 (dd, J = 10.6, 4.8 Hz, 1H), 3.57 - 3.40 (m, 6H), 3.30 - 3.19 (m, 3H), 2.95 (d, J = 10.2 Hz, 2H), 2.72 - 2.63 (m, 5H), 2.60 - 2.53 (m, 3H), 2.49 - 2.41 (m, 3H), 2.37 (m, 1H), 2.30 (d, J = 6.4 Hz, 2H), 2.15 - 2.06 (m, 3H), 2.00 (m, 7H), 1.83 (d, J = 10.6 Hz, 2H), 1.57 (m, 2H), 0.77 (s, 3H).[M+H] + = 991.7.

[0210] Example 31: 3-(tert-butyl)-N-(4-(5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: (2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine [ka] A solution of tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (1.05 g, 3.0 mmol) in HCl / dioxane (10 mL) was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure to give the desired product (850 mg, 99%). [M+H] + = 248.1.

[0211] Step 2: 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (850 mg, 3.0 mmol), sodium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (860 mg, 4.5 mmol), and DIEA (1.2 g, 9.0 mmol) in DMF (10 mL) was added PyBOP (2.1 g, 4.5 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (PE:EtOAc=10:1 to 2:1 gradient elution) to give the product (1.0 g, 73%). [M+H]+ = 400.2.

[0212] Step 3: tert-Butyl 5-bromo-3-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate [ka] A mixture of tert-butyl 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (550 mg, 1.3 mmol), 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (522 mg, 1.3 mmol), Pd(dppf)Cl2 (95 mg, 0.13 mmol), and Cs2CO3 (638 mg, 1.95 mmol) in dioxane (15 mL) / HO (3 mL) was stirred in a round-bottom flask at 80 °C under nitrogen atmosphere for 1 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EtOAc=10:1 to 4:1 gradient elution) to give the product (390 mg, 53%). [M+H] + = 569.1.

[0213] Step 4: tert-Butyl 5-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-3-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate [ka] A mixture of tert-butyl 5-bromo-3-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (390 mg, 0.68 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (265 mg, 0.68 mmol), Pd(dppf)Cl2 (50 mg, 0.068 mmol), and Cs2CO3 (335 mg, 1.03 mmol) in dioxane (15 mL) / HO (3 mL) was stirred in a round-bottom flask at 90 °C under N2 for 3 h. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH=100:1 to 10:1 gradient elution) to give the product (270 mg, 53%). [M+H] + = 750.5.

[0214] Step 5: 5-(tert-butyl)-N-(2-methyl-4-(5-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] A solution of tert-butyl 5-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-3-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (270 mg, 0.36 mmol) in HCl / dioxane (10 mL) was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure to give the desired product (220 mg, 99%). [M+H] + = 550.3.

[0215] Step 6: 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)acetaldehyde [ka] A mixture of 3-(4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (235 mg, 1 mmol) and IBX (420 mg, 1.5 mmol) in DMSO (10 mL) was stirred in a flask at 25° C. for 2 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo to give the product (200 mg, 86%). [M+H]+ = 232.1.

[0216] Step 7: 3-(tert-butyl)-N-(4-(5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound (12 mg, 25%) was prepared in a similar manner to step 9 of example 21 from 3-(tert-butyl)-N-(2-methyl-4-(5-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide and 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)acetaldehyde. 1H NMR (500 MHz, DMSO) δ 13.84 (s, 1H), 10.82 (s, 1H), 9.85 (t, J = 6.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 1.9 Hz, 1H), 7.97 - 7.87 (m, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.41 (m, 3H), 7.21 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 4.53 (d, J = 5.9 Hz, 2H), 3.82 (dd, J = 11.4, 4.9 Hz, 1H), 3.10 (d, J = 11.2 Hz, 2H), 2.81 - 2.72 (m, 2H), 2.70 - 2.55 (m, 3H), 2.46 (m, 4H), 2.16 (m, 3H), 2.07 - 1.98 (m, 1H), 1.81 (m, 2H), 1.77 - 1.66 (m, 2H), 1.37 (s, 9H).[M+H] + =766.3.

[0217] Example 32: (R)-3-(tert-butyl)-N-(4-(5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was prepared using a procedure similar to that of Example 31. 1H NMR (500 MHz, DMSO) δ 13.84 (s, 1H), 10.95 (s, 1H), 9.85 (t, J = 6.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 7.95 - 7.84 (m, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.41 (dd, J = 14.9, 8.1 Hz, 3H), 7.05 (d, J = 10.0 Hz, 2H), 4.53 (d, J = 5.9 Hz, 2H), 4.21 (dd, J = 12.8, 5.0Hz, 1H), 3.08 (d, J = 10.1 Hz, 2H), 2.87 - 2.76 (m, 3H), 2.59 (m, 3H), 2.45 (s, 3H), 2.13 (m, 3H), 2.05 - 1.96 (m, 1H), 1.80 (m, 2H), 1.75 - 1.64 (m, 2H), 1.37 (s, 9H).[M+H] + =802.2.

[0218] Example B33: 7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2-fluoro-5-methyl-4-((6-methylpyridin-2-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide Step 1: 5-Amino-3-bromo-1-(2,5-dibromophenethyl)-1H-pyrazole-4-carbonitrile [ka] A mixture of 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (20.0 g, 107 mmol), 2,5-dibromophenethyl 4-methylbenzenesulfonate (60.1 g, 139.2 mmol), and K2CO3 (29.6 g, 214 mmol) in DMF (300.0 mL) was stirred at 80 °C overnight. The mixture was treated with water (500 mL), extracted with dichloromethane (3 × 30 mL), and washed with brine (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 93:7 gradient elution) to give the product (8.0 g, 16.8%). [M+H] + = 448.0.

[0219] Step 2: 2,7-Dibromo-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carbonitrile [ka] A mixture of 5-amino-3-bromo-1-(2,5-dibromophenethyl)-1H-pyrazole-4-carbonitrile (8.0 g, 18 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (383.4 mg, 2.7 mmol), copper(I) iodide (513 mg, 2.7 mmol), potassium carbonate (7.45 g, 54 mmol) in DMF (100 mL) was stirred at 95 °C under nitrogen overnight. The mixture was treated with water (300 mL) and filtered to give the crude product, which was purified by silica gel column chromatography (PE:EA = 80:20 to 50:50 gradient elution) to give the product (2.2 g, 33.3%). 1 H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 7.44 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.33 (s, 2H), 3.13 (s, 2H);[M+H] + = 367.0.

[0220] Step 3: Benzyl 4-(2-bromo-3-cyano-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepin-7-yl)piperazine-1-carboxylate [ka] A mixture of 2,7-dibromo-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carbonitrile (1.6 g, 4.37 mmol), tert-butyl piperazine-1-carboxylate (1.44 g, 6.56 mmol), BrettPhos Pd G4 (349 mg, 0.437 mmol), BrettPhos (235 mg, 0.437 mmol), and LiHMDS (11 mL, 22 mmol, 2.0 M) in THF (10.0 mL) was stirred in a sealed tube at 75 °C for 6 h. The mixture was then evaporated in vacuum to give the crude product, which was purified by silica gel column chromatography (PE:EA = 80:20 to 50:50 gradient elution) to give the product (350 mg, 15.9%). 1 H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 7.35 (d, J = 15.9 Hz, 5H), 7.15 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 13.2 Hz, 2H), 5.11 (s, 2H), 4.28 (s, 2H), 3.53 (s, 4H), 3.06 (s, 6H);[M+H] + = 507.0.

[0221] Step 4: 4-Bromo-5-fluoro-2-methyl-N-(6-methylpyridin-2-yl)benzamide [ka] A mixture of methyl 4-bromo-5-fluoro-2-methylbenzoate (1 g, 0.00406 mol) and 6-methylpyridin-2-amine (0.44 g, 0.00406 mol) in THF (30 mL) was stirred at 0°C-5°C for 5 min, and LiHMDS (6.2 mL, 0.00812 mol, 1.3 M) was added dropwise. The mixture was stirred at room temperature overnight. The mixture was then quenched with NH4Cl solution, extracted with EA (3 x 50 mL) and washed with brine (100 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the product (1.67 g, crude). [M+H] + = 323.0.

[0222] Step 5: 5-Fluoro-2-methyl-N-(6-methylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] A mixture of 4-bromo-5-fluoro-2-methyl-N-(6-methylpyridin-2-yl)benzamide (1.5 g, 0.00467 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.78 g, 0.00700 mol), Pd(dppf)Cl2 (170 mg, 0.000233 mol), and KOAc (915 mg, 0.00934 mol) in dioxane (30.0 mL) was stirred at 93 °C under N2 overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 100%:0% to 50%:50%) to give the product (530 mg, 31%). [M+H] + = 371.0.

[0223] Step 6: Benzyl 4-(3-cyano-2-(2-fluoro-5-methyl-4-((6-methylpyridin-2-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepin-7-yl)piperazine-1-carboxylate [ka] A mixture of benzyl 4-(2-bromo-3-cyano-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepin-7-yl)piperazine-1-carboxylate (725 mg, 1.43 mmol), 5-fluoro-2-methyl-N-(6-methylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (530 mg, 1.43 mmol), Na2CO3 (303 mg, 1.86 mmol), and Pd(PPh3)4 (165 mg, 0.143 mmol) in dioxane / water (20 mL / 4 mL) was stirred at 95° C. under N2 overnight. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=100%:0% to 0%:100%) to give the desired product (347 mg, 36%). [M+H] + = 671.0.

[0224] Step 7: 2-(2-fluoro-5-methyl-4-((6-methylpyridin-2-yl)carbamoyl)phenyl)-7-(piperazin-1-yl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide [ka] A mixture of benzyl 4-(3-cyano-2-(2-fluoro-5-methyl-4-((6-methylpyridin-2-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepin-7-yl)piperazine-1-carboxylate (347 mg, 0.517 mmol) in methanesulfonic acid (10.0 mL) was stirred at 100° C. for 30 min. The mixture was then cooled, basified with aqueous sodium hydroxide to pH 12, extracted with dichloromethane (3×30 mL), and washed with water (3×30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product (225 mg, crude).

[0225] Step 8: 7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2-fluoro-5-methyl-4-((6-methylpyridin-2-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide [ka] A mixture of 2-(2-fluoro-5-methyl-4-((6-methylpyridin-2-yl)carbamoyl)phenyl)-7-(piperazin-1-yl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide (100 mg, crude), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (70 mg, 0.234 mmol) in dichloromethane (5 mL) and MeOH (5 mL) was stirred at room temperature for 5 min. Then HOAc (0.06 mL) was added. The mixture was stirred at room temperature overnight. Then NaBH(OAc)3 (191 mg, 0.90 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (DCM:MeOH=100%:0% to 90%:10% gradient elution) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (9.28 mg, 6%). 1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 10.27 (s, 1H), 9.70 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.41 (dd, J = 20.0, 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.90-6.86 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 4.40-4.32 (m, 2H), 3.73-3.64 (m, 4H), 3.20-3.13 (m, 2H), 3.09 (s, 4H), 2.71-2.62 (m, 4H), 2.53-2.51 (m, 6H), 2.42 (s, 3H), 2.37 (s, 3H), 2.22 (d, J = 8.0 Hz, 2H), 1.81 (d, J = 12.0 Hz, 2H), 1.72 (s, 1H), 1.28-1.16 (m, 2H);[M+H] + = 840.5.

[0226] Example B34: 7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2-fluoro-3-methyl-4-((6-methylpyridin-2-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide Step 1: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine-4-carbaldehyde [ka] To a mixture of 1-(4-(4-(hydroxymethyl)piperidin-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (95.1 mg, 0.30 mmol) in DMSO (5 mL) was added IBX (109 mg, 0.39 mmol). The reaction was stirred at room temperature for 16 h. The mixture was then washed with water and extracted with dichloromethane (3×60 mL). The organic phases were combined and washed with brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (gradient elution of PE:EA=80:20 to 30:70) to give the product (40 mg, 42%). [M+H] + = 315.2.

[0227] Step 2: 7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2-fluoro-3-methyl-4-((6-methylpyridin-2-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide [ka] A mixture of 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine-4-carbaldehyde (40 mg, 0.13 mmol) and 2-(2-fluoro-3-methyl-4-((6-methylpyridin-2-yl)carbamoyl)phenyl)-7-(piperazin-1-yl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide (this compound was synthesized by a method similar to that of the intermediate of B33) (70 mg, 0.13 mmol) in MeOH (2.0 mL), DCM (6.0 mL), and acetic acid (0.1 mL) was stirred at room temperature for 16 h, then NaBH(OAc)3 (110 mg, 0.52 mmol) was added and stirred at room temperature for 1 h. The mixture was treated with water (30 mL), extracted with dichloromethane (3 × 30 mL), and washed with brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 90:10 gradient elution) to give the product (14 mg, 16%). 1 H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 10.30 (s, 1H), 9.72 (s, 1H), 8.02 (d, J = 8.5 Hz,1H), 7.75 (t, J = 7.9 Hz, 1H), 7.36 (q, J = 7.9 Hz, 2H), 7.12-7.00 (m, 4H), 6.91-6.80 (m, 3H), 4.41-4.33 (m, 2H), 3.71 (t, J = 6.7 Hz, 2H), 3.20-3.00 (m, 9H), 2.64 (dt, J = 23.7, 9.2 Hz, 6H), 2.42 (s, 3H), 2.33-2.20 (m, 8H), 1.88-1.79 (m, 2H), 1.77-1.63 (m, 1H), 1.36-1.19 (m, 4H);[M+H] + = 854.7.

[0228] Example B35: (R)-7-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)-2-(2-fluoro-3-methyl-4-((6-methylpyridin-2-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide [ka] The title compound was synthesized in the same manner as in Example B34. 1 H NMR (500 MHz, DMSO) δ 10.98 (s, 1H), 10.82 (s, 1H), 9.79 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.40-7.32 (m, 2H), 7.14 (d, J = 9.8 Hz, 2H), 7.05 (d, J = 7.5 Hz, 1H), 6.98-6.91 (m, 3H), 4.41-4.36 (m, 2H), 4.24 (dd, J = 12.6, 5.0 Hz, 1H), 3.84-3.77 (m, 2H), 3.69-3.62 (m, 2H), 3.57-2.48 (m, 2H), 3.25-3.15 (m, 4H), 3.11-3.06 (m, 2H), 3.02-2.94 (m, 2H), 2.88-2.77 (m, 1H), 2.58-2.52 (m, 1H), 2.43 (s, 3H), 2.31 (d, J = 1.7 Hz, 3H), 2.18-2.10 (m, 1H), 2.04-1.97 (m, 1H);[M+H] + = 806.6.

[0229] Example B36: 7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2-fluoro-3-methyl-4-((1-methyl-1H-imidazol-4-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide Step 1: 4-Bromo-2-fluoro-3-methylaniline [ka] To a solution of 2-fluoro-3-methylaniline (11.5 g, 92 mmol) dissolved in ACN (170 mL) was added NBS (19.7 g, 110.4 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. The mixture was washed with water and extracted with DCM. The organic layers were combined, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=9:1) to give the product (14.6 g, 78%). [M+H] + = 204.1.

[0230] Step 2: Methyl 4-amino-3-fluoro-2-methylbenzoate [ka] Et3N (10.1 g, 100 mmol) was added dropwise to a solution of 4-bromo-2-fluoro-3-methylaniline (10.2 g, 50 mmol), Pd(dppf)Cl2 (1.83 g, 2.50 mmol) in MeOH (140 mL). The mixture was stirred at 90 °C under CO atmosphere for 16 h. The mixture was concentrated in vacuum. The mixture was washed with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1) to give the product (2.53 g, 28%). [M+H] + = 184.1.

[0231] Step 3: Methyl 3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ka] To a solution of 4-amino-3-fluoro-2-methylbenzoate (2.53 g, 13.8 mmol), tert-butylnitrile (2.84 g, 27.6 mmol), and BPO (334 mg, 1.38 mmol) in ACN (70 mL) was added (Bpin)2 (3.86 g, 15.2 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The mixture was washed with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EtOAc=12:1) to give the product (1.83 g, 45%). 1 H NMR (500 MHz, CDCl3) δ 7.67-7.53 (m, 2H), 3.90 (s, 3H), 2.47 (d, J = 2.1 Hz, 3H), 1.37 (s, 12H).

[0232] Step 4: Benzyl 4-(3-cyano-2-(2-fluoro-4-(methoxycarbonyl)-3-methylphenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepin-7-yl)piperazine-1-carboxylate [ka] A mixture of benzyl 4-(2-bromo-3-cyano-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepin-7-yl)piperazine-1-carboxylate (0.84 g, 1.66 mmol), methyl 3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.636 g, 2.16 mmol), Pd(dppf)Cl2 (0.124 g, 0.17 mmol), and Na2CO3 (0.352 g, 3.32 mmol) in dioxane (25 mL) and H2O (3 mL) was stirred at 95° C. under N2 for 16 h. The mixture was then washed with water and extracted with dichloromethane (3×60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE:EA=80:20 to 50:50 gradient elution) to give the product (345 mg, 35%). [M+H] + = 595.3.

[0233] Step 5: Benzyl 4-(3-cyano-2-(2-fluoro-3-methyl-4-((1-methyl-1H-imidazol-4-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepin-7-yl)piperazine-1-carboxylate [ka] To a mixture of benzyl 4-(3-cyano-2-(2-fluoro-4-(methoxycarbonyl)-3-methylphenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepin-7-yl)piperazine-1-carboxylate (0.345 g, 0.581 mmol) and 1-methyl-1H-imidazol-4-amine hydrochloride (0.077 g, 0.581 mmol) in THF (8.0 mL) was added LiHMDS (1.74 mL, 1 M) dropwise. The reaction was stirred at 60° C. for 2 h and then cooled. The mixture was washed with water and extracted with dichloromethane (3×30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the product (365 mg, 95%). [M+H] + =660.2.

[0234] Step 6: 2-(2-fluoro-3-methyl-4-((1-methyl-1H-imidazol-4-yl)carbamoyl)phenyl)-7-(piperazin-1-yl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide [ka] A mixture of benzyl 4-(3-cyano-2-(2-fluoro-3-methyl-4-((1-methyl-1H-imidazol-4-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepin-7-yl)piperazine-1-carboxylate (0.36 g, 0.55 mmol) in methanesulfonic acid (10.0 mL) was stirred at 100° C. for 1 h. The mixture was then cooled, basified with aqueous sodium hydroxide to pH 12, and extracted with dichloromethane (3×30 mL) and water (3×30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product (290 mg, 97%). [M+H] + = 544.1.

[0235] Step 7: 7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2-fluoro-3-methyl-4-((1-methyl-1H-imidazol-4-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide [ka] A mixture of 2-(2-fluoro-3-methyl-4-((1-methyl-1H-imidazol-4-yl)carbamoyl)phenyl)-7-(piperazin-1-yl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide (140 mg, 0.26 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (78 mg, 0.26 mmol) in MeOH (2.0 mL), DCM (6.0 mL), and acetic acid (0.1 mL) was stirred at room temperature for 16 h, then NaBH(OAc)3 (220 mg, 1.04 mmol) was added and stirred at room temperature for 1 h. The mixture was treated with water (30 mL), extracted with dichloromethane (3 × 30 mL), and washed with brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 85:15 gradient elution) to give the product (120 mg, 56%). 1H NMR (500 MHz, DMSO) δ 10.76 (s, 1H), 10.25 (s, 1H), 9.69 (s, 1H), 7.43 (s, 1H), 7.38 (s, 1H), 7.33 (s, 2H), 7.13 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 4.39-4.33 (m, 2H), 3.75-3.61 (m, 8H), 3.33 (d, J = 1.5 Hz, 3H), 3.19-3.14 (m, 2H), 3.11-3.03 (m, 4H), 2.69-2.62 (m, 5H), 2.28 (d, J = 1.6 Hz, 3H), 2.25-2.19 (m, 2H), 1.84-1.78 (m, 2H), 1.76-1.66 (m, 1H), 1.30-1.16 (m, 3H);[M+H] + = 829.6.

[0236] Example B37: (R)-7-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)-2-(2-fluoro-3-methyl-4-((1-methyl-1H-imidazol-4-yl)carbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide [ka] The title compound was synthesized in the same manner as in Example B36. 1H NMR (500 MHz, DMSO) δ 10.95 (s, 1H), 10.75 (s, 1H), 9.69 (s, 1H), 7.43 (s, 1H), 7.38 (d, J = 1.1 Hz, 1H), 7.35-7.31 (m, 2H), 7.06 (d, J = 10.0 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.86-6.82 (m, 1H), 4.40-4.32 (m, 2H), 4.20 (dd, J = 12.5, 4.9 Hz, 1H), 3.66 (s, 3H), 3.19-3.14 (m, 2H), [M+H] + = 795.5.

[0237] Example B38: (R)-7-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)-2-(2-fluoro-3-methyl-4-(thiazol-4-ylcarbamoyl)phenyl)-9,10-dihydro-4H-benzo[d]pyrazolo[1,5-a][1,3]diazepine-3-carboxamide [ka] The title compound was synthesized in the same manner as in Example B36. 1H NMR (500 MHz, DMSO) δ 11.52 (s, 1H), 10.98 (s, 1H), 9.76 (s, 1H), 9.03 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.44-7.35 (m, 2H), 7.13 (d, J = 9.8 Hz, 2H), 6.99-6.90 (m, 3H), 4.43-4.35 (m, 2H), 4.24 (dd, J = 12.7, 5.0 Hz, 1H), 3.85-3.75 (m, 2H), 3.69-3.61 (m, 2H), 3.51-3.44 (m, 2H), 3.26-3.14 (m, 4H), 3.09-3.06 (m, 2H), 3.04-2.94 (m, 2H), 2.87-2.77 (m, 1H), 2.58-2.52 (m, 1H), 2.32 (d, J = 1.7 Hz, 3H), 2.18-2.10 (m, 1H), 2.04-1.97 (m, 1H);[M+H] + = 797.8.

[0238] Example C39: (R)-3-(tert-butyl)-N-(1-(4-(6-((3-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (R)-1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-amine hydrochloride (2 g, 6.3 mmol), ethyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (2.5 g, 12.6 mmol), and K2CO3 (2.6 g, 18.9 mmol) in EtOH (50 mL) was stirred at 80° C. for 16 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (1:1) to give the product (660 mg, 24%). [M+H] + = 432.3.

[0239] Step 2: tert-Butyl 4-(3-((6-chloropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate [ka] To a stirred mixture of tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (1.5 g, 5.41 mmol) and 4,6-dichloropyrimidine (0.926 g, 5.95 mmol) in ethanol (30 mL) was added DIEA (2.1 g, 16.23 mmol) at room temperature. The resulting mixture was stirred at 78 °C under nitrogen atmosphere for 6 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 5% to 50% EtOAc in petroleum ether to give the product (1.4 g, 65%). [M+H] + = 390.1.

[0240] Step 3: tert-Butyl (R)-4-(3-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-2-fluoro-5-methylphenyl)pyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate [ka] To a stirred mixture of tert-butyl 4-(3-((6-chloropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (296 mg, 0.759 mmol) and (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (360 mg, 0.835 mmol) in dioxane (12 mL) and HO (3 mL) was added KCO (210 mg, 1.52 mmol) and Pd(dppf)Cl (31 mg, 0.038 mmol) under nitrogen atmosphere at room temperature. The resulting mixture was stirred at 89 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10% to 90% EtOAc in petroleum ether to give the product (290 mg, 58%). [M+H] + = 659.3.

[0241] Step 4: (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(6-((3-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a stirred solution of tert-butyl (R)-4-(3-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-2-fluoro-5-methylphenyl)pyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (290 mg, 0.44 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature. The resulting solution was stirred at room temperature for 2 h and concentrated in vacuo. The residue (234 mg, crude) was used directly in the next step without further purification. [M+H] + = 559.3.

[0242] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((3-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(6-((3-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.234 g, 0.418 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.189 g, 0.628 mmol) in 1,2-dichloroethane (8 mL) and HOAc (25 mg) was stirred at room temperature in a round-bottom flask for 0.5 h. To the mixture was added NaBH(OAc)3 (0.222 g, 1.04 mmol) and stirred at room temperature for 12 h. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (0.097 g, 27%). 1H NMR (500 MHz, DMSO) δ 10.25 (s, 1H), 9.85 (d, J = 7.9 Hz, 1H), 9.62 (s, 1H), 8.70 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 13.1 Hz, 1H), 7.25 (d, J = 11.5 Hz, 2H), 7.19-7.08 (m, 4H), 6.93 (d, J = 9.1 Hz, 2H), 6.65 (d, J = 7.1 Hz, 1H), 5.30 (t, J = 7.1 Hz, 1H), 3.69 (t, J = 6.7 Hz, 4H), 3.19-3.10 (m, 4H), 2.69-2.65 (m, 4H), 2.39 (s, 4H), 2.22 (d, J = 7.1 Hz, 2H), 1.87-1.65 (m, 4H), 1.50 (d, J = 7.0 Hz, 3H), 1.37 (s, 9H), 1.29-1.15 (m, 4H), 0.87-0.71 (m, 1H);[M+H] + = 844.6.

[0243] Example C40: (R)-3-(tert-butyl)-N-(1-(4-(2-((6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-Butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate [ka] To a stirred solution of 3,6-dichloropyridazine (5 g, 33.56 mmol) and tert-butyl piperazine-1-carboxylate (9.4 g, 50.35 mmol) in DMF (100 mL) was added TEA (10.2 g, 100.69 mmol) dropwise at room temperature. The resulting mixture was stirred at 80° C. for 16 h and diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (8.1 g, 81%). [M+H] + = 299.1.

[0244] Step 2: tert-Butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate [ka] To a stirred mixture of tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate (2 g, 6.69 mmol) and diphenylmethanimine (1.8 g, 10.04 mmol) in toluene (40.00 mL), Pd2(dba)3 (0.31 g, 0.34 mmol), BINAP (0.42 g, 0.67 mmol), and Cs2CO3 (4.36 g, 13.39 mmol) were added in portions at room temperature. The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 16 h and concentrated in vacuum. The residue was purified by silica gel column chromatography to give the title product (1.4 g, 47%). [M+H] + = 444.2.

[0245] Step 3: tert-Butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate [ka] To a stirred mixture of tert-butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate (1.35 g, 3.04 mmol) and citric acid (13.5 mL, 70.27 mmol) in THF (20 mL) was added H2O (13.5 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title product (710 mg, 83%). [M+H] + = 280.2.

[0246] Step 4: tert-Butyl (R)-4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridazin-3-yl)piperazine-1-carboxylate [ka] To a stirred mixture of tert-butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate (500 mg, 1.79 mmol) and (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (obtained in a similar manner to Example C39) (858.90 mg, 2.15 mmol) in dioxane (10 mL) was added XPhos (170.66 mg, 0.36 mmol), XPhos Pd G3 (151.51 mg, 0.18 mmol), and Cs2CO3 (1.17 g, 3.58 mmol) in portions at room temperature. The resulting mixture was stirred at 100° C. for 16 hours under a nitrogen atmosphere and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title product (314 mg, 27%). [M+H] + = 643.2.

[0247] Step 5: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((6-(piperazin-1-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A solution of tert-butyl (R)-4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridazin-3-yl)piperazine-1-carboxylate (314 mg, 0.49 mmol) and HCl in 1,4-dioxane (6 mL) in DCM (6 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was triturated with Et2O to give the title product (254 mg, 89%). [M+H] + = 543.3.

[0248] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(2-((6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((6-(piperazin-1-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.17 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.2 mmol), NaBH(OAc)3 (106 mg, 0.5 mmol), and NaOAc (82 mg, 1.0 mmol) in DCE was stirred at room temperature for 16 h. The mixture was concentrated and purified by silica gel column chromatography to give the title product (50 mg, 36%). 1 H NMR (500 MHz, DMSO) δ 10.24 (d, J = 5.3 Hz, 2H), 9.89 (d, J = 7.8 Hz, 1H), 8.72 (s, 1H), 8.05-7.79 (m, 4H), 7.62 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 9.9 Hz, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 5.39-5.29 (m, 1H), 3.74-3.64 (m, 4H), 3.52 (s, 4H), 2.71-2.61 (m, 4H), 2.51-2.44 (m, 7H), 2.23 (d, J = 7.1 Hz, 2H), 1.82 (d, J = 11.7 Hz, 2H), 1.78-1.68 (m, 1H), 1.51 (d, J = 6.9 Hz, 3H), 1.36 (s, 9H), 1.30-1.26 (m, 2H);[M+H] + = 828.6.

[0249] Example C41: 3-(tert-butyl)-N-((R)-1-(4-(6-((5-(4-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized in a similar manner to Example C40. 1 H NMR (500 MHz, DMSO) δ 10.95 (s, 1H), 9.99 (s, 1H), 9.89 (d, J = 5.0 Hz, 1H), 8.70 (s, 1H), 8.05-8.03 (m, 2H), 7.84-7.83 (m, 2H), 7.69-7.60 (m, 2H), 7.46 (dd, J = 10.0 Hz, 5.0 Hz, 1H), 7.06 (d, J = 10.0 Hz, 2H), 5.35-5.31 (m, 1H), 4.22-4.18 (m, 1H), 3.14 (s, 4H), 2.83-2.77 (m, 3H), 2.62-2.60 (m, 5H), 2.47 (s, 3H), 2.15-2.11 (m, 1H), 2.01-1.99 (m, 1H), 1.51 (d, J = 5.0 Hz, 3H), 1.38-1.34 (m, 9H), 1.23-1.18 (m, 2H);[M+H] + = 793.7.

[0250] Example 42: 3-((4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)piperidin-1-yl)-3-methoxyphenyl)amino)-6-ethyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide Step 1: Ethyl 2-(3,5-difluoro-4-nitrophenyl)acetate [ka] A solution of 1,3-difluoro-2-nitrobenzene (50.0 g, 314.4 mmol) in NMP (300 mL) was cooled to -20 °C under N2 atmosphere. Then a mixture of ethyl 2-chloroacetate (65.5 g, 534.7 mmol) and t-BuOK (121.0 g, 1.08 mol) in NMP (50 mL) was added slowly over 2 h at -10 °C to -20 °C. After stirring for 2 h, the reaction was quenched by pouring into 1 M HCl (200 mL) and ice water. The mixture was extracted with EA (300 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4. The solution was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EA = 200 / 1 to 100 / 1) to give the product (13.7 g, 18%). 1 H NMR (400 MHz, CDCl3) δ H 7.06 (d, J = 8.4 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.65 (s, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0251] Step 2: Ethyl 2-(4-amino-3,5-difluorophenyl)acetate [ka] To a solution of ethyl 2-(3,5-difluoro-4-nitrophenyl)acetate (13.7 g, 56 mmol) in MeOH (150 mL) was added 10% Pd / C (1.5 g) at room temperature. The mixture was stirred at room temperature under H2 atmosphere for 5 h. Filtered in vacuum to remove Pd / C and concentrated in vacuum to give the product (12.2 g), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO_d6) δ H 6.82 (d, J = 8.0 Hz, 2H), 5.69 (s, 2H), 4.06 (q, J = 7.2 Hz, 2H), 3.52 (s, 2H), 1.17 (t, J = 7.2 Hz, 3H).[M+H] + = 216.4.

[0252] Step 3: Ethyl 2-(3,5-difluoro-4-iodophenyl)acetate [ka] A solution of ethyl 2-(4-amino-3,5-difluorophenyl)acetate (12.2 g, 56 mmol) in MeCN (150 mL) was cooled to 0° C. under N2 atmosphere and CuI (21.2 g, 112 mmol) was added. After stirring for 10 min, tert-butyl nitrite (11.5 g, 112 mmol) was added dropwise over 30 min. The mixture was then stirred at room temperature overnight. The reaction was quenched by pouring into water and extracted with EA (300 mL×3). All organic layers were combined, washed with brine and dried over Na2SO4. The solution was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EA=500 / 1-100 / 1) to give the product (8.8 g, 48%). [M+H] + = 326.5.

[0253] Step 4: Ethyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)acetate [ka] To a solution of ethyl 2-(3,5-difluoro-4-iodophenyl)acetate (8.8 g, 27.0 mmol) in a mixed solvent of 1,4-dioxane / H2O (100 mL / 20 mL), K2CO3 (9.3 g, 67.4 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (14.6 g, 35.0 mol), and Pd(dppf)Cl2 (2.9 g, 4.0 mmol) were added under N2 atmosphere. The resulting solution was stirred at 100 °C for 6 h. The mixture was diluted with water (300 mL) and extracted with EA (300 mL × 3). All organic layers were combined, washed with brine (300 mL), and dried over Na2SO4. The solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE / EA=200 / 1) to give the product (8.2 g, 62%).1 H NMR (400 MHz, CDCl3) δ H 7.49 (d, J = 8.0 Hz, 1H), 7.40-7.24 (m, 10H), 6.90 (d, J = 8.0 Hz, 2H), 6.47 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H), 5.33 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.61 (s, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0254] Step 5: 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)ethanol [ka] A solution of ethyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)acetate (8.2 g, 16.7 mol) in THF (100 mL) was cooled to 0° C. under N2 atmosphere and 1.5 M DIBAL-H in THF (45 mL, 67.5 mol) was added dropwise over 30 min. The mixture was then stirred at room temperature for 2 h. The reaction was quenched by pouring into water and extracted with EA (300 mL×3). All organic layers were combined, washed with brine and dried over Na2SO4. The solution was concentrated in vacuo and the residue was purified by column chromatography (PE / EA=10 / 1-3 / 1) to give the product (6.6 g, 88%). 1 H NMR (400 MHz, CDCl3) δ H 7.49 (d, J = 8.0 Hz, 1H), 7.42-7.25 (m, 9H), 6.84 (d, J = 8.0 Hz, 2H), 6.47 (d, J = 8.0 Hz, 1H), 5.38 (s, 2H), 5.33 (s, 2H), 3.90 (m, 2H), 2.87 (t, J = 6.4 Hz, 2H).[M+H] + = 448.3.

[0255] Step 6: 3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione [ka] To a solution of 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)ethanol (6.6 g, 14.7 mmol) in DCM (150 mL) was added TFA (50 mL). After stirring overnight, the mixture was concentrated in vacuo. The residue was dissolved in MeOH (200 mL) and 10% Pd / C (1.0 g) was added. The resulting mixture was stirred at room temperature under H2 atmosphere for 2 days. The mixture was filtered and the filtrate was concentrated to give a residue which was purified by reverse phase flash C18 chromatography (ACN / water=0%-30%) to give the title compound (2.1 g, 53%). [M+H] + = 270.1.

[0256] Step 7: 4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate [ka] To a solution of 3-(2,6-difluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (1 g, 3.71 mmol) and TEA (1.13 g, 11.14 mmol) in 20 mL DCM was added MsCl (510 mg, 4.46 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 4 h. The mixture was quenched with aqueous NaHCO3 and extracted with DCM. The organic layer was separated and concentrated. The residue was purified by silica column chromatography (MeOH:DCM=0-6%) to give the product (1.1 g, 85.3% yield). [M+H] + =348.1.

[0257] Step 8: 3-((4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)piperidin-1-yl)-3-methoxyphenyl)amino)-6-ethyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide [ka] To a solution of 6-ethyl-3-((3-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide (50 mg, 0.09 mmol) and 4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl methanesulfonate (48 mg, 0.14 mmol) in 3 mL ACN and 0.5 mL DMSO was added KI (46 mg, 0.28 mmol) and DIEA (60 mg, 0.46 mmol). The mixture was stirred at 85° C. for 16 hours. After LCMS showed the reaction was complete, the mixture was concentrated in vacuo. The residue was washed with water and extracted with DCM. The organic layer was separated and concentrated. The residue was purified by preparative TLC (DCM / MeOH=10:1) to give the crude product, which was purified by preparative HPLC to give the product (8.1 mg, 11% yield). 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.97 (s, 1H), 7.54 (d, J = 2.7 Hz, 1H), 7.28 - 7.22 (m, 2H), 7.03 (d, J = 10.2 Hz, 3H), 6.81 (t, J = 8.6 Hz, 2H), 4.20 (dd, J = 12.7, 5.0 Hz, 1H), 4.16 - 4.06 (m, 1H), 3.92 (d, J = 6.5 Hz, 2H), 3.81 (s, 3H), 3.41 - 3.31 (m, 9H), 2.86 - 2.71 (m, 3H), 2.62 - 2.52 (m, 8H), 2.47 (s, 2H), 2.26 (t, J = 11.1 Hz, 1H), 2.12 (dt, J = 13.0, 9.2 Hz, 1H), 2.03 - 1.96 (m, 1H), 1.89 - 1.78 (m, 4H), 1.70 - 1.48 (m, 4H), 1.19 (t, J = 7.4 Hz, 3H);[M+H] + = 790.7.

[0258] Test Example 1 cell degradation Cell line generation H1975 clone #28 (Del19 / T790M / C797S) was stably expressed in H1975 cell line (from ATCC) by lentivirus-mediated overexpression. EGFR-overexpressing cells were then subjected to gene knockout, in which EGFR-targeting sgRNA was designed to target only the endogenous EGFR copy and spare the exogenous EGFR copy. Following gene knockout, edited H1975 cells were seeded in 96-well plates at a concentration of 1 cell / cell and cultured for approximately 2 weeks to form single clones. The formed clones were screened for the desired editing by DNA sequencing and whole exon sequencing analysis. H1975 clone #28 was finally confirmed to be a homozygous Del19 / T790M / C797S EGFR clone.

[0259] Cell treatment 1a) BaF3 WT, BaF3-LTC(L858R / T790M / C797S), BaF3-DTC(Del19 / T790M / C797S) cells are seeded at 20000 cells / well (LTC & DTC) in cell culture medium [RPMI1640 (Gibco; phenol red free; Cat. No. 11835-030), 10% heat inactivated FBS, 1% PS (Gibco; Cat. No. 10378)] in Corning 96-well plates (Cat. No. 3799).

[0260] 1b) On day 1, 10,000 cells / well of H1975 clone #28 (Del19 / T790M / C797S) are plated in a Corning 96-well plate (cat. no. 3599) in cell culture medium [RPMI1640 (Gibco; cat. no. 72400-047), 10% heat-inactivated FBS, 1% PS (Gibco; cat. no. 10378)] as described above.

[0261] BaF3-LTC(L858R / T790M / C797S) and BaF3-DTC(Del19 / T790M / C797S) cells are treated with compounds diluted in 0.2% DMSO cell culture medium and incubated at 37°C, 5% CO2 for 16 hours, and H1975-#28 cells treated with compounds diluted in 0.2% DMSO cell culture medium are incubated at 37°C, 5% CO2 for 16 hours on day 2. The final concentration of compound in all assays is 10 uM, starting with 5-fold dilutions, including a total of 8 doses.

[0262] 1c) TMD-8 cells are seeded at 20000 cells / well in a volume of 15 μl / well in cell culture medium [RPMI1640 (Gibco; phenol red free; Cat. No. 11835-030), 10% heat inactivated FBS, 1% PS (Gibco; Cat. No. 10378)] in Corning 96-well plates (Cat. No. 3799). TMD-8 cells are treated with compounds diluted in 0.2% DMSO, dilutions are made according to the following protocol: (1) A 500× stock solution in DMSO is made from 1 mM by 6-fold dilution to include a total of 8 doses. (2) A 2× solution in cell culture medium is made by transferring 0.5 μl of the 500× stock solution to 125 μl of medium. (3) 15 μl of the 2× solution is added to the cells and incubated for 6 hours.

[0263] HTRF assay (EGFR degradation) After 16 hours of treatment, add HTRF lysis buffer to each well, seal the plate and incubate for 1 hour at room temperature on a plate shaker. Once cells are lysed, transfer 16μL of cell lysate to a PE 384-well HTRF detection plate. Add 4μL of premixed HTRF antibody to each well. Cover plate with plate sealer and spin at 1000rpm for 1 minute. Incubate overnight at room temperature. Read on a BMG PheraStar with HTRF protocol (337nm-665nm-620nm).

[0264] The percentage of inhibition (degradation) of the compound was calculated according to the following formula: Percentage Inhibition of Compound=100−100×(Signal−Low Control) / (High Control−Low Control), where: Signal = each test compound group Low control = lysis buffer only without cells (indicating complete degradation of EGFR) High control = cells with DMSO and no compound (showing microplate readings with no EGFR degradation) Dmax is the maximum inhibition (degradation) percentage.

[0265] HTRF assay (BTK degradation) After 6 hours of treatment, add 10 μl of 4x lysis buffer to each well, seal the plate and incubate 30 minutes at room temperature on a plate shaker. Once cells are lysed, transfer 16 μL of cell lysate to a PE 384-well HTRF detection plate. Add 4 μL of premixed HTRF antibody to each well. Cover plate with plate sealer and spin at 1000 rpm for 1 minute. Incubate overnight at room temperature. Read on a BMG PheraStar with HTRF protocol (337nm-665nm-620nm).

[0266] The percentage of inhibition (degradation) of the compound was calculated according to the following formula: Percentage inhibition of compound = 100 - 100 x (signal - low control) / (high control - low control) During the ceremony, Signal = each test compound group Low control = lysis buffer only without cells (indicating that BTK is completely degraded) High control = cells with DMSO and no compound (showing microplate readings with no BTK degradation) Dmax is the maximum inhibition (degradation) percentage.

[0267] Compound IC 50 (DC 50 ) values ​​can be obtained by fitting the following formula: Y=Bottom+(TOP-Bottom) / (1+((IC 50 / X)^hillslope)) where X and Y are known values ​​and IC 50 , Hillslope, Top, and Bottom are parameters obtained by fitting with the software. Y is the inhibition percentage (calculated from the formula), X is the compound concentration, and IC 50 is the concentration of compound at which 50% inhibition is reached. IC 50 The smaller the IC value, the stronger the inhibitory potential of the compound. 50The higher the value, the weaker the inhibitory ability of the compound. Hillslope corresponds to the slope of the fitted curve, which is generally around 1*. Bottom corresponds to the minimum value of the curve obtained by data fitting, which is generally 0%±20%. Top corresponds to the maximum value of the curve obtained by data fitting, which is generally 100%±20%. The experimental data was fitted by calculation and analysis using Dotmatics data analysis software. [Table 6] [Table 7] [Table 8]

[0268] Test Example 2 HTRF (Homogeneous Time-Resolved Fluorescence) Assay CRBN&DDB1 protein (His tag) was used to quantify the biochemical potency of compounds. Compounds were tested for blocking the binding of CRBN&DDB1 protein (CRBN, aa 40-442, DDB1, 1-1140; Viva Biotech) to biotin-labeled thalidomide in a time-resolved fluorescence resonance energy transfer (TR-FRET) based assay. The assay was performed in a 384-well low volume black plate in a reaction mixture of CRBN&DDB1 protein, 30 nM biotin-labeled thalidomide, and 0-10 μM compound in a buffer containing 50 mM HEPES pH 7.5, 50 mM NaCl, 0.01% BSA, 1 mM DTT, and 0.015% Brij-35. Proteins were preincubated with compounds for 60 min at room temperature and biotin-labeled thalidomide was added to the plate. After further incubation at room temperature for 60 min, detection reagents Mab Anti-6His Eu cryptate Gold (Cisbio; Cat. No. 61HI2KLB) and Streptavidin-XL665 (Cisbio; Cat. No. 610SAXLG) were added to the plate. The plate was sealed and incubated at room temperature for 1 h, and the TR-FRET signal (ex 337 nm, em 665 nm / 620 nm) was recorded on a PHERAstar FSX plate reader (BMG Labtech). The percentage inhibition of the interaction of CRBN&DDB1 protein with biotin-labeled thalidomide in the presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 665 nm to fluorescence at 620 nm. The IC was calculated by fitting the dose-response % inhibition data to a four-parameter logistic model by Dotmatics. 50 This led to the conclusion.

[0269] 4-parameter logistic equation: Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)). X is the logarithm of the concentration of the compound. Y is the % inhibition in X, Bottom is the bottom of the curve effect. Top is the top of the curve effect. HillSlope is the Hill slope coefficient. [Table 9]

[0270] Test Example 3 cell degradation Cell treatment TMD-8 cells were seeded at 20000 cells / well in a volume of 15 μl / well in cell culture medium [RPMI1640 (Gibco; phenol red free; Cat. No. 11835-030), 10% heat inactivated FBS, 1% PS (Gibco; Cat. No. 10378)] in Corning 96-well plates (Cat. No. 3799). TMD-8 cells were treated with compounds diluted in 0.2% DMSO, and dilutions were made according to the following protocol: (1) 500× stock solutions in DMSO were made from 1 mM by 6-fold dilution, including a total of 8 doses. (2) 2× solution in cell culture medium was made by transferring 0.5 μl of 500× stock solution to 125 μl medium. (3) 15 μl of 2× solution was added to the cells and incubated for 6 hours.

[0271] HTRF assay After 6 hours of treatment, 10 μl of 4× lysis buffer was added to each well. The plate was sealed and incubated at room temperature for 30 minutes on a plate shaker. Once the cells were lysed, 16 μL of cell lysate was transferred to a PE 384-well HTRF detection plate. 4 μL of premixed HTRF antibody was added to each well. The plate was covered with a plate sealer and then spun at 1000 rpm for 1 minute, then incubated at room temperature overnight. Results were read on a BMG PheraStar with HTRF protocol (337 nm-665 nm-620 nm).

[0272] The percentage of inhibition (degradation) of the compound was calculated according to the following formula: Percentage Inhibition of Compound=100−100×(Signal−Low Control) / (High Control−Low Control), where: Signal = each test compound group Low control = lysis buffer only without cells (indicating that BTK is completely degraded) High control = cells with DMSO and no compound (showing microplate readings with no BTK degradation) Dmax is the maximum inhibition (degradation) percentage.

[0273] Compound IC 50 (DC 50 ) values ​​can be obtained by fitting the following formula: Y=Bottom+(TOP-Bottom) / (1+((IC 50 / X)^hillslope)) where X and Y are known values ​​and IC 50 , Hillslope, Top, and Bottom are parameters obtained by fitting with the software. Y is the inhibition percentage (calculated from the formula), X is the compound concentration, and IC 50 is the concentration of compound at which 50% inhibition is reached. IC 50 The smaller the IC value, the stronger the inhibitory potential of the compound. 50 The higher the value, the weaker the inhibitory ability of the compound. Hillslope corresponds to the slope of the fitted curve, which is generally around 1*. Bottom corresponds to the minimum value of the curve obtained by data fitting, which is generally 0%±20%. Top corresponds to the maximum value of the curve obtained by data fitting, which is generally 100%±20%. The experimental data was fitted by calculation and analysis using Dotmatics data analysis software.

[0274] HEK-293 cell treatment HEK-293 cells were seeded at 2000 cells / well in a volume of 50ul / well in cell culture medium [DMEM (Gibco; Catalog No. 11965-092), 10% heat inactivated FBS (Gibco; Catalog No. 10099), 1% PS (Gibco; Catalog No. 10378)] in Corning 96-well plates (Cat. No. 3903) and then cultured overnight. HEK-293 cells were treated with compounds diluted in 0.2% DMSO, and dilutions were made according to the following protocol: (1) A 500x stock solution in DMSO was made from 5mM by 4-fold dilution, including a total of 8 doses. (2) A 2x solution in cell culture medium was made by transferring 0.5ul of the 500x stock solution to 125ul of medium. (3) 50ul of the 2x solution was added to the cells and incubated for 72 hours.

[0275] Cytotoxicity detection 25 μl of CellTiter-Glo® Reagent [(Promega); Cat. No. G7572] was added to each well of a 96-well plate. The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. The plate was then incubated at room temperature for 10 minutes to stabilize the luminescence signal. Luminescence was recorded using the luminescence protocol on a BMG PheraStar.

[0276] Calculation of IC50 The percentage of inhibition of the compound was calculated by the following formula: Percentage of inhibition of compound = 100 - 100 x (signal - low control) / (high control - low control). During the ceremony, Signal = each test compound group Low control = medium only (no cells) (indicating complete inhibition of cell proliferation) High control = cells with DMSO and no compound (demonstrating no inhibition of cell proliferation) Imax is the maximum percentage inhibition.

[0277] The IC50 value of a compound can be obtained by fitting the following formula: Y=Bottom+(TOP-Bottom) / (1+((IC50 / X)^hillslope)) In the formula, X and Y are known values, and IC50, Hillslope, Top, and Bottom are parameters obtained by fitting with software. Y is the inhibition percentage (calculated from the formula), X is the concentration of the compound, and IC50 is the concentration of the compound when 50% inhibition is reached. The smaller the IC50 value, the stronger the inhibitory ability of the compound. Vice versa, the higher the IC50 value, the weaker the inhibitory ability of the compound. Hillslope corresponds to the slope of the fitted curve, which is generally around 1*. Bottom corresponds to the minimum value of the curve obtained by data fitting, which is generally 0%±20%. Top corresponds to the maximum value of the curve obtained by data fitting, which is generally 100%±20%. The experimental data was fitted by calculation and analysis using Dotmatics data analysis software. [Table 10]

[0278] Test Example 4 Cell treatment THP-1 cells are seeded at 100000 cells / well in a volume of 15 μl / well in cell culture medium [RPMI1640 (Gibco; phenol red-free; catalog number 11835-030), 10% heat-inactivated FBS, 1% PS (Gibco; catalog number 10378)] in Corning 96-well plates (catalog number 3799). THP-1 cells are treated with compounds diluted in 0.2% DMSO, dilutions are made according to the following protocol: (1) A 500× stock solution in DMSO is made from 5 mM by 5-fold dilution to include a total of 8 doses. (2) A 2× solution in cell culture medium is made by transferring 0.5 μl of the 500× stock solution to 125 μl of medium. (3) 15 μl of the 2× solution is added to the cells and incubated for 6 hours.

[0279] HTRF assay After 6 hours of treatment, add 10 μl of 4x lysis buffer to each well, seal the plate and incubate for 1 hour at room temperature on a plate shaker. Once cells are lysed, transfer 16 μL of cell lysate to a PE 384-well HTRF detection plate (for triple mutant cells, lysate was diluted with a qual volume of 1x lysis buffer before transfer). Add 4 μL of premixed HTRF antibody to each well. Cover plate with plate sealer and spin at 1000 rpm for 1 minute. Incubate overnight at room temperature. Read on BMG PheraStar with HTRF protocol (337nm-665nm-620nm).

[0280] The percentage of inhibition (degradation) of the compound was calculated according to the following formula: Percentage inhibition of compound = 100 - 100 x (signal - low control) / (high control - low control) During the ceremony, Signal = each test compound group Low control = lysis buffer only without cells (indicating complete degradation of IRAKM) High control = cells with DMSO and no compound (showing microplate readings with no IRAKM degradation) Dmax is the maximum inhibition (degradation) percentage.

[0281] Compound IC 50 (DC 50 ) values ​​can be obtained by fitting the following formula: Y=Bottom+(TOP-Bottom) / (1+((IC 50 / X)^hillslope)) where X and Y are known values ​​and IC 50 , Hillslope, Top, and Bottom are parameters obtained by fitting with the software. Y is the inhibition percentage (calculated from the formula), X is the compound concentration, and IC 50 is the concentration of compound at which 50% inhibition is reached. IC 50The smaller the IC value, the stronger the inhibitory potential of the compound. 50 The higher the value, the weaker the inhibitory ability of the compound. Hillslope corresponds to the slope of the fitted curve, which is generally around 1*. Bottom corresponds to the minimum value of the curve obtained by data fitting, which is generally 0%±20%. Top corresponds to the maximum value of the curve obtained by data fitting, which is generally 100%±20%. The experimental data was fitted by calculation and analysis using Dotmatics data analysis software. [Table 11]

[0282] The foregoing examples and descriptions of certain specific embodiments should be considered as illustrative, rather than limiting, of the invention defined by the claims. As will be readily understood, numerous variations and combinations of the features described above can be utilized without departing from the invention as set forth in the claims. All such variations are intended to be within the scope of the present invention. All cited documents are incorporated herein by reference in their entirety.

[0283] Where any prior art publication is referred to herein, it is to be understood that such reference is not an admission that the publication constitutes part of the general knowledge in the art in any country.

Claims

1. A compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, or a deuterated analog thereof, or a prodrug thereof, wherein the Warhead is a targeting moiety that binds to a target protein, and the target protein is a mediator of a disease in a subject, the linker is a divalent chemical group that connects the Warhead moiety to the 【Chemical Formula 2】 moiety, s1 is 0 or 1, s2 is 0 or 1, Z 1 , Z 2 , and Z 3 are each independently N or CR z , provided that Z 1 , Z 2 , and Z 3 are not simultaneously N R z is, in each occurrence, independently, hydrogen, halogen, -C 1～8 alkyl, -NR Za R Zb , -OR Za , -SR Za , C 3 to C 8 cycloalkyl, 3- to 8-membered heterocyclyl, or CN, and -C 1～8 alkyl, C 3 to C 8 cycloalkyl, 3- to 8-membered heterocyclyl are each optionally substituted with at least one R Zc ; the 【Chemical Formula 3】 The part is CR z where R z is hydrogen, Z 1 Z 2 or Z 3 through any one of the above-mentioned [Chemical Formula 4] binds to the moiety, R Za and R Zb are each independently hydrogen, -C 1 to -C 8 alkyl, C 3 to -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 to -C 12 aryl, or 5- to 12-membered heteroaryl, and each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said C 3 to -C 8 cycloalkyl, said 3- to 8-membered heterocyclyl, said C 6 to -C 12 aryl, or said 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Zd . R Zc and R Zd are each independently halogen, hydroxy, -C 1 to C 8 alkyl, C 3 to C 8 cycloalkyl, -C 1～8 alkoxy, 3- to 8-membered heterocyclyl, C 6 to C 12 aryl, or 5- to 12-membered heteroaryl, and R 1 and R 2 are each independently halogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, -C 1～8 alkoxy, -C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 aryl, 5- to 12-membered heteroaryl, -CN, -SO 2 R 1a , -SO 2 NR 1a R 1b , -COR 1a , -CO 2 R 1a , -CONR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CO 2 R 1b , or -NR 1a SO 2 R 1b and -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, -C 1～8 alkoxy, -C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 aryl, or 5- to 12-membered heteroaryl each is optionally halogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, -C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 ~C 12 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 1c , -SO 2 R 1c , -SO 2 NR 1c R 1d 、 -COR 1c 、 -CO 2 R 1c 、 -CONR 1c R 1d 、 -NR 1c R 1d 、 -NR 1c COR 1d 、 -NR 1c CO 2 R 1d 、 or -NR 1c SO 2 R 1d is replaced by R 1a , R 1b , R 1c , and R 1d are each independently hydrogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5- to 12-membered heteroaryl, said compound.

2. (i) Among Z 1 , Z 2 , and Z 3 , at most one of them is N, or (ii) Z1, Z2, and Z3 are each independently CRz, the compound according to Claim 1.

3. (i) R Z is, in each occurrence, independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR Za R Zb , -OR Za , -SR Za , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, or CN, and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a 3- to 8-membered heterocyclyl is optionally substituted with at least one R Zc ; R Za and R Zb are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, and each of the hydrogen, the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, or the 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Zd and is substituted with R Zc and R Zd are each independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1～8 alkoxy, -C 2～8 alkenyl, -C 2～8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, or (ii) R z is H, -CH 3 , -C 2 H 5 , F, -CH 2 F, -CHF 2 , -CF 3 , -OCH 3 , -OC 2 H 5 , -C 3 H 7 , -OCH 2 F, -OCHF 2 , -OCH 2 CF 3 , -OCF 3 , -SCF 3 , -CF 3 , or -CH(OH)CH 3 is, The compound according to claim 1.

4. (i) R 1 and R 2 are each independently F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2～8 alkenyl, -C 2～8 alkynyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 aryl, 5- to 12-membered heteroaryl, -CN, -SO 2 R 1a , -SO 2 NR 1a R 1b , -COR 1a , -CO 2 R 1a , -CONR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CO 2 R 1b , or -NR 1a SO 2 R 1b and are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2～8 alkenyl, -C 2～8 alkynyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 Each of aryl and 5- to 12-membered heteroaryl is optionally F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2～8 alkenyl, -C 2～8 alkynyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 1c , -SO 2 R 1c , -SO 2 NR 1c R 1d , -COR 1c , -CO 2 R 1c , -CONR 1c R 1d , -NR 1c R 1d , -NR 1c COR 1d , -NR 1c CO 2 R 1d , or -NR 1c SO 2 R 1d and is substituted by R 1a 、 R 1b 、 R 1c 、 and R 1d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2～8 alkenyl, -C 2～8 alkynyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 aryl, or 5- to 12-membered heteroaryl, or (ii) R 1 and R 2 are each independently F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCH 2 CF 3 , -OCF 3 or phenyl. The compound according to claim 1.

5. The compound according to claim 1, wherein the compound is a compound of formula (II): 【Chemical Formula 5】

6. The linker is wherein * indicates the position of binding to the 【Chemical Formula 6】 moiety, and ** indicates the position of binding to the 【Chemical Formula 7】 moiety, 【Chemical Formula 8】 is L 1 is a single bond, -O-, -SO 2 -, -C(O)-, -NR L1a -, -C 3 ~C 8 cycloalkylene-*, L1 -O-C 1～8 alkylene-** L1 , * L1 -C 1～8 alkylene-O-** L1 , * L1 -SO 2 -C 1～8 alkylene-** L1 , * L1 -C 1～8 alkylene-SO 2 -** L1 , * L1 -CO-C 1～8 alkylene-** L1 , * L1 -C 1～8 alkylene-CO-** L1 , * L1 -NR L1a -C 1～8 alkylene-** L1 , * L1 -C 1～8 alkylene-NR L1a -** L1 , * L1 -NR L1a C(O)-** L1 , * L1 -C(O)NR L1a -** L1 , -C 1～8 alkylene-, -C 2～8 alkenylene-, -C 2～8 alkynylene-, -[O(CR L1a R L1b ) m4 m5 , 【Chemical Formula 9】 indicating the position of binding to the moiety, the aforesaid -C 3 ~C 8 cycloalkylene-, the aforesaid * L1 -O-C 1～8 alkylene-** L1 the aforesaid * L1 -C 1～8 alkylene-O-** L1 the aforesaid * L1 -SO 2 -C 1～8 alkylene-** L1 the aforesaid * L1 -C 1～8 alkylene-SO 2 -** L1 the aforesaid * L1 -CO-C 1～8 alkylene-** L1 the aforesaid * L1 -C 1～8 alkylene-CO-** L1 the aforesaid * L1 -NR L1a -C 1～8 alkylene-** L1 the aforesaid * L1 -C 1～8 alkylene-NR L1a -** L1 the aforesaid -C 1～8 alkylene-, the aforesaid -C 2～8 alkenylene-, the aforesaid -C 2～8 alkynylene-, 【Chemical Formula 10】 each of which is optionally substituted with at least one R L1c and is substituted with In the formula, * L1 is the above-mentioned 【Chemical Formula 11】 Refers to the position to be coupled to the part, ** L1 is the said 【Chemical Formula 12】 is R L1a and R L1b are each independently hydrogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5- to 12-membered heteroaryl, wherein each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said C 3 -C 8 cycloalkyl, said 3- to 8-membered heterocyclyl, said C 6 -C 12 aryl, or said 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R L1d and said R L1c and said R L1d each independently is oxo, halogen, hydroxy, -C 1～8 alkyl, -C 1～8 alkoxy, -C 2～8 alkenyl, -C 2～8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5- to 12-membered heteroaryl, or Two Rs L1c together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring optionally being substituted with at least one substituent halogen, hydroxy, or -C 1～8 alkyl, L 2 is a single bond, -O-, -SO 2 -, -CO-, -NR L2a -, -C 3 ~C 8 cycloalkylene-, * L2 -O-C 1～8 alkylene- ** L2 , * L2 -C 1～8 alkylene-O- ** L2 , * L2 -SO 2 -C 1～8 alkylene- ** L2 , * L2 -C 1～8 alkylene-SO 2 - ** L2 , * L2 -CO-C 1～8 alkylene- ** L2 , * L2 -C 1～8 alkylene-CO- ** L2 , * L2 -NR L2a -C 1～8 alkylene- ** L2 , * L2 -C 1～8 alkylene-NR L2a - ** L2 , * L2 -NR L2a C(O)- ** L2 , * L2 -C(O)NR L2a - ** L2 , -C 1～8 alkylene-, -C 2～8 alkenylene-, -C 2～8 alkynylene-, -[O(CR L2a R L2b ) m4 m5 , 【Chemical 13】 indicating the position of binding to the moiety, the aforesaid -C 3 ~C 8 cycloalkylene-, the aforesaid * L2 -O-C 1～8 alkylene-** L2 the aforesaid * L2 -C 1～8 alkylene-O-** L2 the aforesaid * L2 -SO 2 -C 1～8 alkylene-** L2 the aforesaid * L2 -C 1～8 alkylene-SO 2 -** L2 the aforesaid * L2 -CO-C 1～8 alkylene-** L2 the aforesaid * L2 -C 1～8 alkylene-CO-** L2 the aforesaid * L2 -NR L2a -C 1～8 alkylene-** L2 the aforesaid * L2 -C 1～8 alkylene-NR L2a -** L2 the aforesaid -C 1～8 alkylene-, the aforesaid -C 2～8 alkenylene-, the aforesaid -C 2～8 alkynylene-, 【Chemical Formula 14】 each of which is optionally substituted with at least one substituent R L2c and is substituted with In the formula, * L2 is the 【Chemical Formula 15】 Refers to the position of joining to the part, ** L2 is the said 【Chemical 16】 is R L2a and R L2b are each independently hydrogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5- to 12-membered heteroaryl, and each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said C 3 -C 8 cycloalkyl, said 3- to 8-membered heterocyclyl, said C 6 -C 12 aryl, or said 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R L2d . said R L2c and said R L2d each independently is oxo, halogen, hydroxy, -C 1～8 alkyl, -C 1～8 alkoxy, -C 2～8 alkenyl, -C 2～8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5- to 12-membered heteroaryl, or Two Rs L2c together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring optionally being substituted with at least one substituent halogen, hydroxy, -C 1～8 substituted with alkyl, L 3 is a single bond, -O-, -SO 2 -, -CO-, -NR L3a -, -C 3 ~C 8 cycloalkylene-*, L3 -O-C 1～8 alkylene-** L3 , * L3 -C 1～8 alkylene-O-** L3 , * L3 -SO 2 -C 1～8 alkylene-** L3 , * L3 -C 1～8 alkylene-SO 2 -** L3 , * L3 -CO-C 1～8 alkylene-** L3 , * L3 -C 1～8 alkylene-CO-** L3 , * L3 -NR L3a -C 1～8 alkylene-** L3 , * L3 -C 1～8 alkylene-NR L3a -** L3 , * L3 -NR L3a C(O)-** L3 , * L3 -C(O)NR L3a -** L3 , -C 1～8 alkylene-, -C 2～8 alkenylene-, -C 2～8 alkynylene-, -[O(CR L3a R L3b ) m4 m5 , 【Chemical 17】 indicating the position of binding to the moiety, the aforesaid -C 3 ~C 8 cycloalkylene-, the aforesaid * L3 -O-C 1～8 alkylene-** L3 the aforesaid * L3 -C 1～8 alkylene-O-** L3 the aforesaid * L3 -SO 2 -C 1～8 alkylene-** L3 the aforesaid * L3 -C 1～8 alkylene-SO 2 -** L3 the aforesaid * L3 -CO-C 1～8 alkylene-** L3 the aforesaid * L3 -C 1～8 alkylene-CO-** L3 the aforesaid * L3 -NR L3a -C 1～8 alkylene-** L3 the aforesaid * L3 -C 1～8 alkylene-NR L3a -** L3 the aforesaid -C 1～8 alkylene-, the aforesaid -C 2～8 alkenylene- 【Chemical 18】 each of which is optionally substituted with at least one substituent R L3c and is substituted with In the formula, * L3 is the aforesaid 【Chemical Formula 19】 Refers to the position of connection to the part, ** L3 is the said 【Chemical 20】 selected from and / or R L3a and R L3b are each independently hydrogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5- to 12-membered heteroaryl, wherein each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said C 3 -C 8 cycloalkyl, said 3- to 8-membered heterocyclyl, said C 6 -C 12 aryl, or said 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R L3d . said R L3c and said R L3d each independently is oxo, halogen, hydroxy, -C 1～8 alkyl, -C 1～8 alkoxy, -C 2～8 alkenyl, -C 2～8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5- to 12-membered heteroaryl, or Two Rs L3c together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring optionally being substituted with at least one substituent halogen, hydroxy, or -C 1～8 substituted with alkyl, R 12 is independently hydrogen, halogen, -C 1～8 alkyl, -NR 12a R 12b , -OR 12a , -C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 aryl, 5- to 12-membered heteroaryl, oxo, -CN, and -C 1～8 alkyl, C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 ~C 12 aryl, or 5- to 12-membered heteroaryl is each substituted with at least one substituent R 12c or Two Rs 12 together with the carbon atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring optionally being substituted with at least one substituent R 12c and being substituted with R 12a and R 12b are each independently hydrogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, -C 3 -C 8 -cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 -C 12 -aryl, or 5- to 12-membered heteroaryl, wherein said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said C 3 -C 8 -cycloalkyl, said 3- to 8-membered heterocyclyl, said C 6 -C 12 -aryl, or said 5- to 12-membered heteroaryl is each optionally substituted with at least one substituent R 12d or R 12c and R 12d are each independently halogen, hydroxy, -C 1～8 alkyl, -C 1～8 alkoxy, -C 2～8 alkenyl, -C 2～8 alkynyl, -C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 -C 12 aryl, or 5- to 12-membered heteroaryl, and X 1 , X 2 , X 3 , and X 4 are each independently -CR a or N, and X 5 , X 6 , and X 7 are each independently, -NR a -, -O-, -S-, and -CR a R b - selected from, X 12 and X 13 each independently is selected from -C(O)-, -NR a -, and -O-, Q 1 , Q 2 , Q 3 , and Q 4 are each independently CR a or N, Q 5 is, independently of each other, -O-, -NR a -, -CR a R b -, -S-, or -C(O)-, and P 1 is a single bond, -O-, -NR a -, -CR a R b -, -S-, -SO-, or -SO 2 -, and In each occurrence, R a and R b are each independently hydrogen, hydroxy, halogen, CN, -C 1～8 alkyl, -C 1～8 alkoxy, -C 2～8 alkenyl, -C 2～8 alkynyl, -C 3 -C 8 cycloalkyl, a 3- to 8-membered heterocyclyl, -C 6 -C 12 aryl, or a 5- to 12-membered heteroaryl, and the -C 1～8 alkyl, the -C 1～8 alkoxy, the -C 2～8 alkenyl, the -C 2～8 alkynyl, the -C 3 -C 8 cycloalkyl, the 3- to 8-membered heterocyclyl, the -C 6 -C 12 aryl, or the 5- to 12-membered heteroaryl may each optionally be substituted with at least one substituent hydrogen, halogen, hydroxy, halogen, -C 1～8 alkyl, -C 1～8 alkoxy, -C 2～8 alkenyl, -C 2～8 alkynyl, -C 3 -C 8 cycloalkyl, a 3- to 8-membered heterocyclyl, -C 6 -C 12 aryl, or a 5- to 12-membered heteroaryl, or R a and R b together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being optionally substituted with at least one substituent halogen, hydroxy, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, -C 1～8 alkoxy, -C 2～8 alkenyl, -C 2～8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5- to 12-membered heteroaryl, m 1 is 0 or 1, and m 2 and m3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8, and m 4 and m 5 are each independently 0, 1, 2, or 3, n, n 1 , n 2 , n 3 , n 4 , and n 5 The compound according to claim 1, wherein n, n, n, n, n, and n are each independently 0, 1, 2, or 3.

7. (i) L 1 is a single bond, -C 1～8 alkylene-(preferably, -CH 2 -, -C 2 H 4 -, -C 3 H 6 -, -CO-, -O-, -N(CH 3 ), -NH-, 【Chemical Formula 21】 the moiety is (ii) X 1 and X 2 are each independently, -CR a or N, and R a is hydrogen, -F, -Cl, -Br, -I, CN, methyl, ethyl, methoxy, ethoxy, or cyclopropyl, and each of said methyl, said ethyl, said methoxy, said ethoxy, and said cyclopropyl is optionally substituted with at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl (preferably, X 1 and X 2 are each independently selected from CH, C(F), C(CH 3 ), or N), m 1 is 1 or 0, and R 12 is hydrogen, oxo, methoxymethyl, hydroxymethyl, -CN, or -CH 3 and / or (iii) (a) m 1 is 1, and the 【Chemical 22】 indicating the position of binding to the moiety, or 【Chemical 23】 and, * X is the said 【Chemical Formula 24】 Refers to the position where it is coupled to the part, ** X is the said 【Chemical Formula 25】 the moiety is (iii)(b) m 1 is 1, and the 【Chemical 26】 is 【Chemical 27】 The compound according to claim 6. is and / or

8. (i) L 2 is a single bond, -C 1～8 alkylene-(preferably, -CH 2 -, -C 2 H 4 -, -C 3 H 6 -, -CO-, -O-, -N(CH 3 ), -NH-, 【Chemical Formula 28】 is, The compound according to claim 6. (ii) L 3 is a single bond, -C 1～8 alkylene-(preferably, -CH 2 -, -C 2 H 4 -, -C 3 H 6 -, -CO-, -O-, -N(CH 3 ), -NH-, 【Chemical Formula 29-1】 [Chemical 29-2] (ii) the

9. (i) L 2 or L 3 is a single bond, or L 2 and L 3 are single bonds, is 【Chemical Formula 30】 is, The compound according to claim 6. 【Chemical Formula 31-1】 【Chemical Figure 31-2】 【Chemical Formula 31-3】 [Chemical 31-4] ​ **Claim 10**: (i) The warhead is a portion that binds to a target protein, and the target protein is a structural protein, receptor, enzyme, cell surface protein, protein related to the integrative function of cells (including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (assimilation and dissimilation), antioxidant activity, proteolysis, biosynthesis), kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signaling substance activity, structural molecule activity, binding activity (protein, lipid, carbohydrate), receptor activity, cell motility, membrane fusion, intercellular information transmission, regulation of biological processes, development, cell differentiation, protein having a response to stimuli, behavioral protein, cell adhesion protein, protein involved in cell death, and protein involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenicity, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biosynthesis activity, and translation regulator activity), or (ii) a warhead that is a portion that binds to a target protein, wherein the target protein is an ErbB receptor, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, Trypanosoma GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and analogs, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase (including Bruton's tyrosine kinase), CD23, CD124, tyrosine kinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycine amide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha-reductase inhibitor, angiotensin II, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7), farnesyltransferase, geranylgeranyltransferase, TrkA (NGF receptor), beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-2 / neu, telomerase inhibition, cytoplasmic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20 monooxygenase, GABA-activated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor-associated kinase-3 (IRAK-3 or IRAK-M), and enolpyruvylshikimate-phosphate synthase selected from the group consisting of The compound according to claim 1. **Claim 11**: (i) The warhead is 【Chemical 32】 and R 13 is -P(O)R 13a R 13b , -SO 2 R 13a , -SO 2 , -NR 13a R 13b , or -N(R 13a )-SO 2 R 13b and R 13a and R 13b are each independently hydrogen, -C 1 to C 8 alkyl, or C 3 to C 8 cycloalkyl, and said -C 1 to C 8 alkyl or C 3 -C 8 cycloalkyl is optionally substituted with at least one halogen, R 14 and R 15 are each independently hydrogen, halogen, -C 1 ~C 8 alkyl, -C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 ~C 12 aryl, 5- to 12-membered heteroaryl, -CN, -OR 14a , -SO 2 R 14a , -SO 2 NR 14a R 14b , -COR 14a , -CO 2 R 14a , -CONR 14a R 14b , -NR 14a R 14b , -NR 14a COR 14b , -NR 14a CO 2 R 14b , or -NR 14a SO 2 R 14b and -C 1 ~C 8 alkyl, C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 ~C 12 aryl, or 5- to 12-membered heteroaryl each is optionally substituted with at least one substituent R 14d or R 14 and R 15 together with the carbon atom to which they are attached form a 5- or 6-membered unsaturated or saturated ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring optionally being substituted with at least one substituent R 14e and being substituted with R 14e is, in each occurrence, independently, hydrogen, halogen, -C 1 to -C 8 alkyl, -C 1 to -C 8 alkoxy, -C 3 to -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, 5- to 12-membered heteroaryl, oxo(=O), -OR 14a , thioxo(=S), -SR 14a , -CN, -SO 2 R 14a , -SO 2 NR 14a R 14b , -COR 14a , -CO 2 R 14a , -CONR 14a R 14b , -NR 14a R 14b , -NR 14a COR 14b , -NR 14a CO 2 R 14b , or -NR 14a SO 2 R 14b and, -C 1 -C 8 alkyl, -C 1 to -C 8 alkoxy, C 3 to -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 to -C 12 aryl, or 5- to 12-membered heteroaryl each is optionally substituted with at least one substituent R 14d and, R 14a and R 14b are each independently hydrogen, -C 1 to -C 8 alkyl, -C 1 to -C 8 haloalkyl, -C 2 to -C 8 alkenyl, -C 2 to -C 8 alkynyl, C 1 to C 8 alkoxy, -C 1 to -C 8 alkyl-, C 3 to C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 to C 12 aryl, or 5- to 12-membered heteroaryl, and R 14d is, in each occurrence, independently halogen, -OH, -CN, oxo, -C 1 ~C 8 alkyl, -C 2 ~C 8 alkenyl, -C 2 ~C 8 alkynyl, -C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 aryl, or 5- to 12-membered heteroaryl, and R 4 is hydrogen, halogen, -C 1 to -C 8 alkyl, -C 2 to -C 8 alkenyl, -C 2 to -C 8 alkynyl, -C 1 to -C 8 alkoxy, -C 3 to -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 to -C 12 aryl, 5- to 12-membered heteroaryl, -CN, -SO 2 R 4a , -SO 2 NR 4a R 4b , -COR 4a , -CO 2 R 4a , -CONR 4a R 4b , -NR 4a R 4b , -NR 4a COR 4b , -NR 4a CO 2 R 4b , or -NR 4a SO 2 R 4b and each of -C 1 to -C 8 alkyl, -C 2 to -C 8 alkenyl, -C 2 to -C 8 alkynyl, -C 1 to -C 8 alkoxy, -C 3 to -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 to -C 12 aryl, or 5- to 12-membered heteroaryl is optionally halogen, -C 1 to -C 8 alkyl, -C 2 to -C 8 alkenyl, -C 2 to -C 8 alkynyl, -C 3 to -C 8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 -aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 4c -SO 2 R 4c -SO 2 NR 4c R 4d -COR 4c -CO 2 R 4c -CONR 4c R 4d -NR 4c R 4d -NR 4c COR 4d -NR 4c CO 2 R 4d or -NR 4c SO 2 R 4d and is substituted with R 4a 、 R 4b 、 R 4c 、 and R 4d are each independently hydrogen, -C 1 - C 8 alkyl, -C 2 - C 8 alkenyl, -C 2 - C 8 alkynyl, C 3 - C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 - C 12 aryl, or 5- to 12-membered heteroaryl, and R 9 、R 10 、and R 11 are each independently hydrogen, halogen, -C 1 ~C 8 alkyl, -NR 9a R 9b 、-OR 9a 、-C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 aryl, 5- to 12-membered heteroaryl, oxo, or -CN, and each of -C 1 ~C 8 alkyl, C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 ~C 12 aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R 9c . R 9a and R 9b are each independently hydrogen, -C 1 ~C 8 alkyl, -C 2 ~C 8 alkenyl, -C 2 ~C 8 alkynyl, -C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 aryl, or 5- to 12-membered heteroaryl, wherein said -C 1 -C 8 alkyl, said -C 2 -C 8 alkenyl, said -C 2 -C 8 alkynyl, said C 3 -C 8 cycloalkyl, said 3- to 8-membered heterocyclyl, said C 6 -C 12 aryl, or 5- to 12-membered heteroaryl is each optionally substituted with at least one substituent R 9d or R 9c and R 9d are each independently halogen, hydroxy, -C 1 ~C 8 alkyl, -C 1 ~C 8 alkoxy, -C 2 -C 8 alkenyl, -C 2 ~C 8 alkynyl, -C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, -C 6 ~C 12 aryl, or 5- to 12-membered heteroaryl, and Z 4 , Z 5 , Z 6 , and Z 7 are each independently, -CR Z4 or N, and R Z4 is, in each occurrence, independently, hydrogen, halogen, -C 1 to -C 8 alkyl, -NR Z4a R Z4b , -OR Z4a , -SR Z4a , C 3 to -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 to -C 12 aryl, 5- to 12-membered heteroaryl, or CN, and each of -C 1 to -C 8 alkyl, C 3 to -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 to -C 12 aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one R Z4c , R Z4a and R Z4b each independently is hydrogen, -C 1 ~C 8 alkyl, -C 2 ~C 8 alkenyl, -C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 ~C 12 aryl, or 5- to 12-membered heteroaryl, and each of the -C 1 ~C 8 alkyl, the -C 2 ~C 8 alkenyl, the -C 2 ~C 8 alkynyl, the C 3 ~C 8 cycloalkyl, the 3- to 8-membered heterocyclyl, the C 6 ~C 12 aryl, or the 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Z4d and R Z4c and R Z4d are each independently halogen, hydroxy, -C 1 to -C 8 alkyl, -C 1 to -C 8 alkoxy, -C 2 to -C 8 alkenyl, -C 2 to -C 8 alkynyl, C 3 to -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 to -C 12 aryl, or 5- to 12-membered heteroaryl, or (ii) The warhead is 【Chemical 33】 wherein 【Chemical Formula 34】 is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. R 101 、R 102 、R 103 、R 104 、R 105 、R 106 、and R 107 are each independently hydrogen, halogen, -C 1～8 alkyl, -C 1～8 alkoxy, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2 , -OR 10a , -SO 2 R 10a , -COR 10a , -CO 2 R 10a , -CONR 10a R 10b , -C(=NR 10a )NR 10b R 10c , -NR 10a R 10b , -NR 10a COR 10b , -NR 10a CONR 10b R 10c , -NR 10a CO 2 R 10b , -NR 10a SONR 10b R 10c , -NR 10a SO 2 NR 10b R 10c , or -NR 10a SO 2 R 10b and each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1～8 alkyl, -C 1～8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, R 109 is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the aromatic ring is optionally halogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, -C 1～8 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2 , -OR 10a , -SO 2 R 10a , -COR 10a , -CO 2 R 10a , -CONR 10a R 10b , -C(=NR 10a )NR 10b R 10c , -NR 10a R 10b , -NR 10a COR 10b , -NR 10a CONR 10b R 10c , -NR 10a CO 2 R 10b , -NR 10a SONR 10b R 10c , -NR 10a SO 2 NR 10b R 10c , or -NR 10a SO 2 R 10b and is substituted with, each of the -C 1～8 alkyl, the -C 2～8 alkenyl, the -C 2～8 alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1～8 alkyl, -C 1～8 alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, p1, p2, and p3 are each independently 0, 1, 2, 3, or 4. R 10a 、R 10b 、and R 10c are each independently hydrogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or (iii) The warhead is 【Chemical 35】 and ring A 201 and B 201 are each independently an aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, sulfur, and oxygen as ring members (plural possible). Z 201 , Z 203 , and Z 204 are each independently N or CR 20z and L 201 is independently a bond, -C 1～8 alkylene-, -N(R 204 ), -O-, -S-, *L201 -C 1～8 alkylene-O- **L201 , *L201 -O-C 1～8 alkylene- **L201 , *L201 -N(R 204 )CO- **L201 , *L201 -CON(R 204 )- **L201 , *L201 -N(R 204 )CO-C 1～8 alkylene- **L201 , *L201 -CON(R 204 )-C 1～8 alkylene- **L201 , *L201 -N(R 204 )-C 1～8 alkylene- **L201 , *L201 -C 1～8 alkylene-N(R 204 )- **L201 , -heterocyclene-, or -heteroarylene-, and the -C 1～8 alkylene-, the *L201 -C 1～8 alkylene-O- **L201 , the *L201 -O-C 1～8 alkylene- **L201 , the *L201 -N(R 204 )CO-C 1～8 alkylene- **L201 , the *L201 -CON(R 204 )-C 1～8 alkylene- **L201 , the *L201 -N(R 204 )-C 1～8 alkylene- **L201 , the *L201 -C 1～8 alkylene-N(R 204 )- **L201 , each of said -heterocyclene- and said -heteroarylene- is optionally substituted with at least one substituent R 20L and is substituted with In the formula, * L201 indicates the position bonded to ring A, and ** L201 indicates the position bonded to ring B. m201, n201, and q201 are each independently 0, 1, 2, 3, or 4. t201 is 0, 1, or 2. R 201 、 R 202 、 and R 204 are each independently hydrogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl is optionally substituted with halogen, hydroxy, -C 1～8 alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, R 20L 、R 203 、R 205 、and R 206 are each independently hydrogen, halogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2 、-OR 20a 、-SO 2 R 20a 、-COR 20a 、-CO 2 R 20a 、-CONR 20a R 20b 、-C(=NR 20a )NR 20b R 20c 、-NR 20a R 20b 、-NR 20a COR 20b 、-NR 20a CONR 20b R 20c 、-NR 20a CO 2 R 20b 、-NR 20a SONR 20b R 20c 、-NR 20a SO 2 NR 20b R 20c 、or -NR 20a SO 2 R 20b and wherein said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said cycloalkyl, said heterocyclyl, said aryl, said or heteroaryl are each optionally substituted with at least one halogen, hydroxy, -C 1～8 alkyl, -C 1～8 alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, R 20z is hydrogen, halogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2 , -OR 20a , -SO 2 R 20a , -COR 20a , -CO 2 R 20a , -CONR 20a R 20b , -C(=NR 20a )NR 20b R 20c , -NR 20a R 20b , -NR 20a COR 20b , -NR 20a CONR 20b R 20c , -NR 20a CO 2 R 20b , -NR 20a SONR 20b R 20c , -NR 20a SO 2 NR 20b R 20c , or -NR 20a SO 2 R 20b and wherein each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl is optionally substituted with at least one halogen, hydroxy, -C 1～8 alkyl, -C 1～8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, R 20a 、 R 20b 、 and R 20c are each independently hydrogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, Alternatively, two Rs 20L together with the atom(s) to which they are attached form a 3- to 12-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur as ring member(s), said ring optionally being substituted with at least one substituent independently selected from halogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR 203f , -SO 2 R 203f , -SO 2 NR 203f R 203g , -COR 203f , -CO 2 R 203f , -CONR 203f R 203g , -C(=NR 203f )NR 203g R 203h , -NR 203f R 203g , -NR 203f COR 203g , -NR 203f CONR 203g R 203h , -NR 203f CO 2 R 203f , -NR 203f SONR 203f R 203g , -NR 203f SO 2 NR 203g R 203h , and -NR 203f SO 2 R 203g and each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl optionally being substituted with halogen, -C 1～8 alkyl, -OR 203i , -NR 203i R 203j is substituted with at least one substituent selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, Alternatively, two Rs 203 together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing at least 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur as ring members (plural possible), said ring optionally being substituted with at least one substituent independently selected from halogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR 203f , -SO 2 R 203f , -SO 2 NR 203f R 203g , -COR 203f , -CO 2 R 203f , -CONR 203f R 203g , -C(=NR 203f )NR 203g R 203h , -NR 203f R 203g , -NR 203f COR 203g , -NR 203f CONR 203g R 203h , -NR 203f CO 2 R 203f , -NR 203f SONR 203f R 203g , -NR 203f SO 2 NR 203g R 203h , and -NR 203f SO 2 R 203g and each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl being optionally substituted with halogen, -C 1～8 alkyl, -OR 203i , -NR 203i R 203j and is substituted with at least one substituent selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; Alternatively, R 4 and R 3 One of them, together with the atoms to which they are attached, forms a 3- to 12-membered ring, and the ring contains 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur as ring members (plural), and the ring is optionally substituted with a halogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR 203f , -SO 2 R 203f , -SO 2 NR 203f R 203g , -COR 203f , -CO 2 R 203f , -CONR 203f R 203g , -C(=NR 203f )NR 203g R 203h , -NR 203f R 203g , -NR 203f COR 203g , -NR 203f CONR 203g R 203h , -NR 203f CO 2 R 203f , -NR 203f SONR 203f R 203g , -NR 203f SO 2 NR 203g R 203h , and -NR 203f SO 2 R 203g and is substituted with at least one substituent independently selected from the group consisting of, and each of the -C 1～8 alkyl, the -C 2～8 alkenyl, the -C 2～8 alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally substituted with a halogen, -C 1～8 alkyl, -OR 203i , -NR 203i R 203j , substituted with at least one substituent selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, R 203f 、 R 203g 、 R 203h 、 R 203i 、 and R 203j are each independently hydrogen, -C 1～8 alkyl, C 1～8 alkoxy, -C 1～8 alkyl-, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or (iv) The warhead is 【Chemical 36】 wherein Cy302 is a 5- or 6-membered saturated or unsaturated ring (preferably an aromatic ring) containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring members (plural possible). In each occurrence, R 301 , R 302 , R 303 , R 304 and R 308 are each independently hydrogen, halogen, -C 1～8 alkyl, -C 1～8 alkoxy, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo(=O), -CN, -NO 2 , -OR 30c , -SO 2 R 30c , -COR 30c , -CO 2 R 30c , -CONR 30c R 30d , -C(=NR 30c )NR 30d R 30e , -NR 30c R 30d , -NR 30c COR 30d , -NR 30c CONR 30d R 30e , -NR 30c CO 2 R 30d , -NR 30c SONR 30d R 30e , -NR 30c SO 2 NR 30d R 30e , or -NR 30c SO 2 R 30d ; and each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1～8 alkyl, -C 1～8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl. R 306 and R 307 each independently is hydrogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of said -C 1～8 alkyl, said -C 2～8 alkenyl, said -C 2～8 alkynyl, said cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1～8 alkyl, -C 1～8 alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, R 305 is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring members (plural possible), and the aromatic ring is optionally substituted with halogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, -C 1～8 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2 , -OR 30c , -SO 2 R 30c , -COR 30c , -CO 2 R 30c , -CONR 30c R 30d , -C(=NR 30c )NR 30d R 30e , -NR 30c R 30d , -NR 30c COR 30d , -NR 30c CONR 30d R 30e , -NR 30c CO 2 R 30d , -NR 30c SONR 30d R 30e , -NR 30c SO 2 NR 30d R 30e , or -NR 30c SO 2 R 30d and is substituted with -C 1～8 alkyl, the -C 2～8 alkenyl, the -C 2～8 alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl, each of which is optionally substituted with -C 1～8 alkyl, halogen, hydroxy, -haloC 1～8 alkyl, -C 1～8 alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, p301 and p302 are each independently 0, 1, 2, 3, or 4. R 30c 、 R 30d 、 and R 30e are each independently hydrogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or (R 30c and R 30d ) or (R 30d and R 30e ) together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur as ring members (plural possible), said ring being optionally substituted with at least one substituent independently selected from halogen, -C 1～8 alkyl, -C 2～8 alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, and -NO 2 ​ The compound according to claim 1. **Claim 12** A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, tautomer, or prodrug thereof, and a pharmaceutically acceptable excipient.

13. (i) A method for treating a disease in a subject in need thereof, wherein the method comprises degradation of a target protein, and the target protein is selected from the group consisting of a structural protein, a receptor, an enzyme, a cell surface protein, a protein related to the integrative function of a cell (including a protein involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (assimilation and dissimilation), antioxidant activity, proteolysis, biosynthesis), kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signaling substance activity, structural molecule activity, binding activity (protein, lipid, carbohydrate), receptor activity, cell motility, membrane fusion, intercellular communication, regulation of biological processes, development, cell differentiation, a protein having a response to a stimulus, an action protein, a cell adhesion protein, a protein involved in cell death, and a protein involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenicity, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biosynthesis activity, and translation regulator activity); Optionally, the warhead is the part that binds to the target protein, and the target protein is ErbB receptor, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, Trypanosoma GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and analogs, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase (including Bruton's tyrosine kinase), CD23, CD124, tyrosine kinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycine amide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitor, angiotensin II, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA (NGF receptor), beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-2 / neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20 monooxygenase, GABA-activated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor-associated kinase-3 (IRAK-3 or IRAK-M), and enolpyruvylshikimate-phosphate synthase, a method selected from the group consisting of (ii) A method for treating cancer, or (iii) A method for treating a CRBN-mediated disorder, disease, or condition in a patient, comprising administering the compound to the patient, optionally, wherein the disorder, disease, or condition is selected from a proliferative disorder, a neurological disorder, and a disorder related to transplantation Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, tautomer, or prodrug thereof in the manufacture of a medicament for use.

14. (i) A method for treating a disease in a subject in need thereof, wherein wherein the method involves degradation of a target protein, and the target protein is selected from the group consisting of a structural protein, a receptor, an enzyme, a cell surface protein, a protein related to the integrative function of a cell (including a protein involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (assimilation and dissimilation), antioxidant activity, proteolysis, biosynthesis), kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signaling molecule activity, structural molecule activity, binding activity (protein, lipid, carbohydrate), receptor activity, cell motility, membrane fusion, intercellular communication, regulation of biological processes, development, cell differentiation, a protein having a response to a stimulus, an action protein, a cell adhesion protein, a protein involved in cell death, and a protein involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenicity, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biosynthesis activity, and translation regulator activity). Optionally, the warhead is the moiety that binds to the target protein, and the target protein is an ErbB receptor, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, Trypanosoma GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and analogs, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase (including Bruton's tyrosine kinase), CD23, CD124, tyrosine kinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycine amide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7), farnesyltransferase, geranylgeranyltransferase, TrkA (NGF receptor), beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20 monooxygenase, GABA-activated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor-associated kinase-3 (IRAK-3 or IRAK-M), and enolpyruvylshikimate-phosphate synthase, a method selected from the group consisting of (ii) a method for treating cancer, or (iii) a method for treating a CRBN-mediated disorder, disease, or condition in a patient, comprising administering the pharmaceutical composition to the patient, optionally, wherein the disorder, the disease, or the condition is selected from a proliferative disorder, a neurological disorder, and a disorder related to transplantation The pharmaceutical composition according to claim 12 for use.

15. The compound according to claim 1, wherein s1 is 0.

16. Use of the compound according to claim 15 or a pharmaceutically acceptable salt, tautomer, or prodrug thereof in the manufacture of a medicament for use in a method of binding to the cereblon complex, modifying its specificity, and inducing degradation of the complex-associated protein, wherein the protein is ErbB receptor, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, Trypanosoma GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and analogs, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multi-drug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase (including Bruton's tyrosine kinase), CD23, CD124, tyrosine kinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3Use selected from the group consisting of RNA helicase, glycine amide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitor, angiotensin II, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7), farnesyl transferase, geranylgeranyl transferase, TrkA (NGF receptor), beta amyloid, tyrosine kinase Flk-II KDR, vitronectin receptor, integrin receptor, Her-2 / neu, telomerase inhibition, cytoplasmic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20 monooxygenase, GABAergic chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor-associated kinase-3 (IRAK-3 or IRAK-M), enolpyruvylshikimate-phosphate synthase, and neo-substrates (e.g., IKZF1, IKZF3, and CK1a).

17. A pharmaceutical composition containing the compound according to claim 15 or a pharmaceutically acceptable salt, tautomer, or prodrug thereof for use in a method of binding to the cereblon complex, modifying its specificity, and inducing degradation of the complex-associated protein The protein is ErbB receptor, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, Trypanosoma GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and analogs, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase (including Bruton's tyrosine kinase), CD23, CD124, tyrosine kinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3A pharmaceutical composition selected from the group consisting of RNA helicase, glycine amide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitor, angiotensin II, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and its receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA (NGF receptor), beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-2 / neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase, ecdysone 20 monooxygenase, GABA-activated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor-associated kinase-3 (IRAK-3 or IRAK-M), enolpyruvylshikimate-phosphate synthase, and neosubstrates (e.g., IKZF1, IKZF3, and CK1a).

Images