WO2022268052A1 - (r) -glutarimide crbn ligands and methods of use - Google Patents

(r) -glutarimide crbn ligands and methods of use Download PDF

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Publication number
WO2022268052A1
WO2022268052A1 PCT/CN2022/100017 CN2022100017W WO2022268052A1 WO 2022268052 A1 WO2022268052 A1 WO 2022268052A1 CN 2022100017 W CN2022100017 W CN 2022100017W WO 2022268052 A1 WO2022268052 A1 WO 2022268052A1
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Prior art keywords
aryl
heterocyclyl
alkyl
heteroaryl
cycloalkyl
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PCT/CN2022/100017
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French (fr)
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WO2022268052A9 (en
Inventor
Bailin LEI
Huaqing Liu
Songzhe HAN
Changxin HUO
Zhiwei Wang
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BeOne Medicines Ltd
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Beigene Ltd
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Priority to CN202410607844.6A priority Critical patent/CN118791426A/en
Priority to MX2024000082A priority patent/MX2024000082A/en
Priority to KR1020237044030A priority patent/KR20240025529A/en
Priority to AU2022300033A priority patent/AU2022300033A1/en
Priority to EP22827545.9A priority patent/EP4359403A4/en
Priority to CA3224739A priority patent/CA3224739A1/en
Priority to IL309528A priority patent/IL309528A/en
Priority to CN202280044443.3A priority patent/CN117616021A/en
Application filed by Beigene Ltd filed Critical Beigene Ltd
Priority to JP2023577943A priority patent/JP2024525181A/en
Publication of WO2022268052A1 publication Critical patent/WO2022268052A1/en
Publication of WO2022268052A9 publication Critical patent/WO2022268052A9/en
Priority to CONC2023/0017812A priority patent/CO2023017812A2/en
Priority to US18/391,154 priority patent/US20240207267A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • CRBN cereblon
  • 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. The present compounds are thus useful for the treatment or prophylaxis tumors and cancer.
  • Proteolysis targeting chimera consists of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to the protein of interest (POI) a target meant for degradation (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98: 8554–9.; Sakamoto K.M. et al., Methods Enzymol. 2005; 399: 833 ⁇ 847. ) . Rather than inhibiting the target protein's enzymatic activity, recruitment of the E3 ligase to the specific unwanted proteins results in ubiquitination and subsequent degradation of the target protein by the proteasome.
  • ubiquitin-proteasome pathway The whole 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 G.L. et al., Cell Rep. 2015, 12, 545-553; Swatek K.N. et al., Cell Res. 2016, 26, 399-422) .
  • Proteasomes are protein complexes which degrade unneeded, misfolded or abnormal proteins into small peptides to maintain the health and productivity of the cells.
  • Ubiquitin ligases also called an E3 ubiquitin ligase, directly catalyze the transfer of ubiquitin from the E2 to the target protein for degradation.
  • E3 ubiquitin ligases also called an E3 ubiquitin ligase, directly catalyze the transfer of ubiquitin from the E2 to the target protein for degradation.
  • 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: cereblon (CRBN) , Von Hippel-Lindau (VHL) , mouse double minute 2 homologue (MDM2) cellular inhibitor of apoptosis protein (cIAP) (Philipp O. et al., Chem. Biol.
  • RDF114 Human Ring Finger Protein 114
  • DCAF16 DDB1 And CUL4 Associated Factor 16
  • Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cullin-4A (CUL4A) to ubiquitinate a number of other proteins followed by the degradation via proteasomes.
  • Immunomodulatory drugs including thalidomide, lenalidomide, and pomalidomide, function as monovalent promoters of PPIs by binding to the cereblon (CRBN) subunit of the CRL4A CRBN E3 ligase complex and recruiting neosubstrate proteins.
  • CRBN cereblon subunit of the CRL4A CRBN E3 ligase complex and recruiting neosubstrate proteins.
  • One objective of the present invention is to provide compounds and derivatives formed by conjugating target protein moieties with E3 ligase Ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
  • Warhead is a targeting moiety that binds to a target protein; wherein the target protein is a mediator of a disease in a subject;
  • Linker is a divalent chemical group that connects the Warhead moiety and the 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 N at the same time;
  • R z at each occurrence, is independently selected from hydrogen, halogen, -C 1-8 alkyl, -NR Za R Zb , -OR Za , -SR Za , C 3 -C 8 cycloalkyl, 3-to 8-membered heterocyclyl or CN; each of -C 1-8 alkyl, C 3 -C 8 cycloalkyl, 3-to 8-membered heterocyclyl is optionally substituted with at least one R Zc ;
  • the moiety is linked to the moiety via any one of Z 1 , Z 2 or Z 3 which is CR z and R z is hydrogen;
  • R Za and R Zb are each independently selected from hydrogen, -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 of said -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 is optionally substituted with at least one substituent R Zd ;
  • R Zc and R Zd are each independently halogen, hydroxy, -C 1-8 alkoxy, 3-to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5-to 12-membered heteroaryl;
  • R 1 and R 2 are each independently selected from 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 ; each of -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C 3 -C 8 cyclo
  • 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.
  • Aspect 2 The compound of aspect 1, wherein at most one of Z 1 , Z 2 and Z 3 is N.
  • Aspect 3 The compound of any one of aspects 1-2, wherein Z 1 , Z 2 and Z 3 are each independently CR z .
  • Aspect 4 The compound of any one of aspects 1-3, wherein R Z , at each occurrence, is 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 methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo
  • R Za and R Zb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -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, each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycl
  • 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.
  • Aspect 5 The compound of any one of aspects 1-4, wherein R z is selected from 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 .
  • Aspect 6 The compound of any one of aspects 1-5, wherein R 1 and R 2 are each 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, -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 1
  • 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.
  • Aspect 7 The compound of any one of aspects 1-6, wherein R 1 and R 2 are each 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, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCH 2 CF 3 , -OCF 3, -SCF 3 , or phenyl.
  • Aspect 8 The compound of any one of aspects 1-7, wherein the compound is Formula (II)
  • Warhead and Linker are defined as aspect 1.
  • Aspect 9 The compound of any one of aspects 1-8, wherein Linker is wherein *refers to the position attached to the moiety, and **refers to the position attached to the moiety;
  • L 1 is selected from 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-** L1 , * L1 -NR L1a C (O) -** L1 , * L1 -C (O) NR L1a , * L1
  • R L1a and R L1b are each independently selected from 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, 5-to 12-membered heteroaryl, each of said -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 is optionally substituted with at least one substituent R L1d ;
  • each of said R L1c and R L1d are independently 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
  • L 2 is selected from 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-** L2 , * L2 -C 1-8 alkylene-NR L2a -** L2 , * L2 -NR L2a C (O) -** L2 , *
  • R L2a and R L2b are each independently selected from 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, each of said -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 is optionally substituted with at least one substituent R L2d ;
  • each of said R L2c and R L2d are independently 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
  • L 3 is selected from 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-** L3 , * L3 -NR L3a C (O) -** L3 , * L3 -C (O) NR L3a -** L3 , * L3
  • R L3a and R L3b are each independently selected from 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, each of said -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 is optionally substituted with at least one substituent R L3d ;
  • each of said R L3c and R L3d are independently 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
  • R 12 is independently selected from 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, or -CN; each of -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 optionally substituted with at least one substituent R 12c ; or
  • R 12 two R 12 together with the carbon atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R 12c ;
  • R 12a and R 12b are each independently selected from 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, each of said -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 is 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;
  • X 1 , X 2 , X 3 and X 4 are each independently selected from -CR a , or N;
  • X 5 , X 6 and X 7 are each independently selected from -NR a -, -O-, -S-and -CR a R b -;
  • X 12 and X 13 are each independently selected from -C (O) -, -NR a -and -O-;
  • Q 1 , Q 2 , Q 3 and Q 4 are each independently selected from CR a or N;
  • Q 5 is each independently selected from -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 -SO 2 -;
  • R a and R b are each independently selected from 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, 3-to 8-membered heterocyclyl, -C 6 -C 12 aryl or 5-to 12-membered heteroaryl, each of said -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 is optionally substituted with at least one substituent halogen, hydroxy, halogen, -C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkeny
  • R a and R b together with the carbon atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is 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;
  • n 1 is 0 or 1
  • n 2 and m3 is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 4 and m 5 are each independently 0, 1, 2 or 3;
  • n, n 1 , n 2, n 3 , n 4 and n 5 are each independently 0, 1, 2 or 3.
  • Aspect 10 The compound of aspect 9, wherein L 1 is selected from a single bond, -C 1-8 alkylene- (preferably -CH 2 -, -C 2 H 4 -, -C 3 H 6 -) , -CO-, -O-, -N (CH 3 ) -, -NH-,
  • Aspect 11 The compound of any one of aspects 9-10, wherein X 1 and X 2 are each independently selected from -CR a or N;
  • R a is selected from hydrogen, -F, -Cl, -Br, -I, CN, methyl, ethyl, methoxy, ethoxy, or cyclopropyl, wherein each of said methyl, ethyl, methoxy, ethoxy, and 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) ;
  • R 12 is hydrogen, oxo, methoxymethyl, hydroxymethyl, -CN or -CH 3 .
  • Aspect 12 The compound of any one of aspects 9-11, wherein m 1 is 1; preferably, moiety is wherein * X refers to the position attached to moiety, and ** X refers to the position attached to the moiety.
  • Aspect 13 The compound of any one of aspects 9-12, wherein m 1 is 1, moiety is
  • Aspect 14 The compound of any one of aspects 9-13, wherein L 2 is selected from a single bond, -C 1- 8 alkylene- (preferably -CH 2 -, -C 2 H 4 -, -C 3 H 6 -) , -CO-, -O-, -N (CH 3 ) -, -NH-,
  • Aspect 15 The compound of any one of aspects 9-14, wherein L 3 is selected from single bond, -C 1- 8 alkylene- (preferably -CH 2 -, -C 2 H 4 -, -C 3 H 6 -) , -CO-, -O-, -N (CH 3 ) -, -NH-,
  • Aspect 16 The compound of any one of aspects 9-15, wherein L 2 is a single bond; or L 3 is a single bond; or L 2 is a single bond and L 3 is a single bond.
  • Aspect 17 The compound of any one of aspects 9-16, wherein is selected from
  • Warhead is a moiety which binds to a target protein
  • said target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism) , antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate) , receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity,
  • Warhead is a moiety which binds to a target protein
  • said target protein is selected from the group consisting of ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apotosis 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 (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthe
  • Aspect 20 The compound of any one of aspects 1-19, wherein Warhead is wherein R 13 is selected from -P (O) R 13a R 13b , -SO 2 R 13a , -SO 2 -NR 13a R 13b or -N (R 13a ) -SO 2 R 13b ;
  • R 13a and R 13b are each independently selected from hydrogen, -C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl, said -C 1 -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 selected from 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 ; 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 14d
  • R 14 and R 15 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated or saturated ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R 14e ;
  • R 14a and R 14b are each independently selected from hydrogen, -C 1 -C 8 alkyl, -C 1 -C 8 haloalkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, C 1 -C 8 alkoxy-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;
  • R 14d is 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;
  • R 4 is selected from hydrogen, halogen, -C 1 -C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, -C 1 -C 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 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 ; each of -C 1 -C 8 alkyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, -C 1
  • 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;
  • R 9 , R 10 and R 11 are each independently selected from 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; 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 selected from 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; each of said -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 is 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;
  • Z 4 , Z 5 , Z 6 and Z 7 are each independently selected from -CR Z4 , or N;
  • R Z4 is independently selected from hydrogen, halogen, -C 1 -C 8 alkyl, -NR Z4a R Z4b , -OR Z4a , -SR Z4a , C 3 -C 8 cycloalkyl, 3-to 8-membered heterocyclyl, C 6 -C 12 aryl, 5-to 12-membered heteroaryl, or CN; 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 R Z4c ;
  • R Z4a and R Z4b are each independently selected from 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, each of said -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 is optionally substituted with at least one substituent R Z4d ;
  • R Z4c and R Z4d 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.
  • R 13 is selected from -P (O) R 13a R 13b or -N (R 13a ) -SO 2 R 13b , wherein R 13a and R 13b are each independently selected from hydrogen, -C 1 -C 8 alkyl (preferably -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 or -C 5 H 11 ; more preferably -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -iso-C 3 H 7 , -CH 2 CH 2 CH 2 CH 3 , -iso-C 4 H 9 , -sec-C 4 H 9 or -tert-C 4 H 9 ) or C 3 -C 8 cycloalkyl (preferably cyclopropyl, cyclobutyl or cyclopentyl) .
  • R 13a and R 13b are each independently selected from hydrogen, -C 1 -C 8 alkyl (preferably -CH 3
  • Aspect 22 The compound of aspect 20, wherein R 13 is selected from -P (O) (CH 3 ) 2 , -NH-SO 2 CH 3 or -N (CH 3 ) -SO 2 CH 3 .
  • Aspect 23 The compound of aspect 20, wherein R 13 is -P (O) (CH 3 ) 2 .
  • R 14 and R 15 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 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
  • R 14 and R 15 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated or saturated ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R 14e ;
  • R 14e is independently -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-to 8-membered heterocyclyl, 5-to 12-membered heteroaryl, oxo, -CN, CF 3 , CHF 2 , CH 2 F, thioxo, -SCF 3 , -SCHF 2 , -SCH 2 F, -SCH 2 CF 3 , -SCF 2 CH 3 ,
  • 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, C 1 -C 8 alkoxy-C 1 -C 8 alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl;
  • R 14d is independently halogen, -OH, 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.
  • Aspect 25 The compound of aspect 20, wherein R 14 and R 15 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated (preferred aromatic) or saturated ring, said ring comprising 1 or 2 nitrogen heteroatoms; said ring is optionally substituted with 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, -CH 2 OH, -SCH 3 , -SC 2 H 5 , oxo, thioxo, -CF 3 , -CHF 2 , -CH 2 F, -SCF 3 ,
  • Aspect 26 The compound of aspect 20, wherein R 14 and R 15 together with the carbon atoms to which they are attached, form a 6-membered unsaturated (preferred aromatic) , said ring comprising 1 or 2 nitrogen heteroatoms; said ring is optionally substituted with one substituent -H, -F, -Cl, -Br, -I, methyl, ethyl or cyclopropyl.
  • Aspect 27 The compound of aspect 20, wherein R 4 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl or -C 1 -C 8 alkoxy; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2 -
  • Aspect 28 The compound of aspect 20, wherein R 4 is hydrogen, -F, -Cl, -Br, -I, -CH 3 , -CF 3 , -CH 2 F, or -CHF 2 .
  • Aspect 29 The compound of aspect 20, wherein R 4 is hydrogen, -F, -Cl, -Br or -I.
  • R 9 , R 10 and R 11 are each independently selected from 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 -methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohe
  • 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, each of said 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 is optionally substituted with at least one substitu
  • R 9c and R 9d are each 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-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl.
  • Aspect 31 The compound of aspect 20, wherein R 9 , R 10 and R 11 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, -NH 2 , -NHCH 3 , -OH, -OCH 3 , -OC 2 H 5 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 OH, -CH 2 OMe, oxo, or -CN.
  • Aspect 32 The compound of aspect 20, wherein R 9 , R 10 and R 11 are each independently selected from hydrogen, -CH 3, -F, -Cl, -Br or -I.
  • Aspect 33 The compound of aspect 20, wherein Z 4 , Z 5 , Z 6 and Z 7 are each independently -CR 4z ;
  • R 4Z is 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 methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloo
  • R 4Za and R 4Zb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl, each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo
  • R 4Zc and R 4Zd are each independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1 -C 8 alkoxy, -C 2 -C 8 alkenyl, -C 2 -C 8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl, or 5-to 12-membered heteroaryl.
  • Aspect 34 The compound of aspect 20, wherein R 4z is selected from 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 , -CH (OH) CH 3 ,
  • Aspect 35 The compound of any one of aspects 1-19, wherein Warhead is
  • 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.
  • Z 8 , Z 9 , Z 10 and Z 11 are each independently selected from CH or N; wherein *cy1 refers to the position attached to the moiety, and **cy1 refers to the position attached to L 1 .
  • Aspect 37 The compound of aspect 35, wherein is selected from
  • Aspect 38 The compound of aspect 35, wherein p3 is 0, 1, or 2, and each R 107 is independently selected from halogen, -C 1-8 alkyl, or -C 1-8 alkoxy, preferably F, Cl, Br, I, CH 3 , or -OCH 3 .
  • Aspect 39 The compound of aspect 35, wherein R 10a and R 10b are independently selected from hydrogen or CH 3 ; and n1 is 1 or 2.
  • Aspect 40 The compound of aspect 35, wherein R 101 is methyl, -CH 2 OH, -OCH 3 , -CH 2 OCH 3 or halogen; p1 is 0 or 1, and R 102 is halogen.
  • Aspect 41 The compound of aspect 35, wherein R 103 and R 105 are hydrogen; and R 104 is selected from hydrogen or methyl.
  • R 109 is Y 101 , Y 102 , Y 103 and Y 104 are selected from CH, O, S or N;
  • Aspect 43 The compound of aspect 35, wherein Y 101 is CH, S, N or O; Y 102 is CH, O or N; Y 103 is O, S or N; and Y 104 is S, CH or N.
  • Aspect 44 The compound of any one of aspects 1-19, wherein Warhead is
  • ring A 201 and B 201 are each independently an aromatic ring comprising 0-3 heteroatoms selected from nitrogen, sulfur and oxygen as ring member (s) ;
  • Z 201 , Z 203 and Z 204 are each independently N or CR 20z ;
  • 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-, wherein each of said -C 1-8 alkylene
  • 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, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -C 1-8 alkyoxy, 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;
  • 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.
  • Aspect 45 The compound according to any one of Aspects 44, wherein L 201 is a bond, -CH 2 -, -C 2 H 4 -, -C 3 H 6 -, -C 4 H 8 -, -C 5 H 10 -, -O-, -NH-, *L201 -NHCH 2 - **L201 , *L201 -NHC 2 H 4 - **L201 , *L201 -NHC 3 H 6 - **L201 , *L201 -NHC 4 H 8 - **L201 , *L201 -NHC 5 H 10 - **L201 , *L201 -OCH 2 - **L201 , *L201 -OC 2 H 4 - **L201 , *L201 -OC 3 H 6 - **L201 , *L201 -OC 4 H 8 - **L201 , *L201 -OC 5 H 10 - **L201 , *L201 -CH 2 O- **L201 ,
  • Aspect 46 The compound according to Aspect 44, wherein L 201 is a bond, -O-, *L201 -OCH 2 - **L201 , *L201 -CH 2 O- **L201 , -NH-, *L201 -CONH- **L201 , *L201 -NHCO- **L201 , *L201 -CONHCH 2 - **L201 , *L201 -CONHCH 2 CH 2 - **L201 , *L201 -CONHCH 2 CH 2 CH 2 - **L201 , *L201 -CONHCH (CH 3 ) - **L201 , *L201 -CONHCH (C 2 H 5 ) - **L201 , *L201 -NHCH 2 - **L201 , *L201 -NHCH 2 CH 2 - **L201 , *L201 -NHCH 2 CH 2 CH 2 - **L201 , *L201 -NHCH (CH 3 ) - **L201 or *L
  • Aspect 47 The compound according to Aspect 44, wherein L 201 is *L201 -N (R 204 ) CO- **L201 , R 203 and R 204 , together with the atoms to which they are attached, form a 5-, 6-or 7-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from -F, -Cl, -Br, -I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , cycloalkyl, heterocyclyl, aryl, heteroaryl, or oxo.
  • Aspect 48 The compound according to Aspect 44, wherein moiety is wherein Z 205 , Z 206 , Z 207 , Z 208 , Z 209 , Z 206 ’, Z 207 ’, Z 208 ’ and Z 209 ’ are each independently N or C (H) ; Z 210 is N (H) , O or S.
  • Aspect 49 The compound according to Aspect 44, wherein ring A201 is a 5-to 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, sulfur and oxygen as ring member (s) .
  • Aspect 50 The compound according to Aspect 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.
  • Aspect 51 The compound according to Aspect 44, wherein the moiety is
  • Aspect 52 The compound according to Aspect 44, wherein R 203 is hydrogen, oxo, -F, -Cl, -Br, -I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OC 4 H 9 , -OC 5 H 11 , cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyrrolyl or phenyl, wherein each of said -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OC 4 H 9 , -OC 5 H 11 , cyclopropyl, cyclobutyl, cycl
  • Aspect 53 The compound according to Aspect 44, wherein 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.
  • Aspect 54 The compound according to Aspect 44, wherein two R 203 , together with the atoms to which they are attached, form a 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from -F, -Cl, -Br, -I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OC 4 H 9 , -OC 5 H 11 , -OH, -CN, cyclopropyl, cyclobutyl or cyclopentyl.
  • Aspect 55 The compound according to Aspect 44, wherein the moiety is
  • Aspect 56 The compound according to Aspect 44, wherein the moiety is wherein Z 205 , Z 206 , Z 207 and Z 208 are defined as above.
  • Aspect 58 The compound according to Aspect 44, wherein 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 substituted with (R 206 ) q201 .
  • Aspect 59 The compound according to Aspect 44, wherein R 206 is hydrogen, -F, -Cl, -Br, -I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -CN, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OC 4 H 9 or -OC 5 H 11 , wherein each of said -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OC 4 H 9 or -OC 5 H 11 is optionally substituted with -F, -Cl, -Br, -I, hydroxy, -C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • Aspect 60 The compound according to Aspect 44, wherein the moiety is
  • Aspect 61 The compound according to Aspect 44, wherein R 201 and R 202 are each independently hydrogen, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -C 2-8 alkenyl, -C 2-8 alkynyl or aryl.
  • Aspect 62 The compound according to Aspect 44, wherein R 201 and R 202 are both H.
  • Aspect 63 The compound according to Aspect 44, wherein R 205 is independently hydrogen, -F, -Cl, -Br, -I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -C 2-8 alkenyl, -C 2-8 alkynyl or aryl.
  • Aspect 64 The compound according to Aspect 44, wherein R 20z is hydrogen, -F, -Cl, -Br, -I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 or -C 5 H 11 .
  • Aspect 65 The compound according to any one of Aspects 44 to 64, wherein the moiety is
  • Aspect 66 The compound of any one of aspects 1-19, wherein Warhead is
  • Cy302 is a 5-or 6-membered saturated ring or unsaturated ring (preferably aromatic ring) comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member (s) ;
  • R 306 and R 307 are each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8 alkyl, -C 1-8 alkyoxy, 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 atom (s) to which they are attached, form a 3-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is 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 or -NO 2 .
  • Aspect 67 The compound of Aspect 66, wherein
  • R 30c , R 30d and R 30e are each independently 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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is 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 or -NO 2 .
  • Aspect 68 The compound of any aspect of Aspects 66-67, wherein 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 or -NO 2 ; preferably R1 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl.
  • Aspect 69 The compound of any aspect of Aspects 66-68, wherein
  • R 30c , R 30d and R 30e are each independently 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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is 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 or -NO 2 .
  • Aspect 70 The compound of any aspect of Aspects 66-69, wherein 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 -NO 2 ; preferably R 302 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl,
  • Aspect 71 The compound of any aspect of Aspects 66-70, wherein
  • R 30c , R 30d and R 30e are each independently 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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is 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 or -NO 2 .
  • Aspect 72 The compound of any aspect of Aspects 66-71, wherein 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 are each independently hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl or cyclopentyl.
  • Aspect 73 The compound of any aspect of Aspects 66-72, wherein the moiety is wherein *303 refers to the position attached to the moiety, and **303 refers to the position attached to moiety.
  • Aspect 74 The compound of any aspect of Aspects 66-73, wherein R 306 and R 307 are each independently 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, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
  • Aspect 76 The compound of Aspect 75, wherein Y 301 is CH, S, N or O; Y 302 is CH, S, O or N; Y 303 is CH, O, S or N; and Y 304 is CH, O, S or N.
  • Aspect 77 The compound of Aspect 75, wherein is selected from
  • Aspect 78 The compound according to Aspect 75, wherein, R 315 is selected from -H, -F, -Cl, -Br, -I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -C 6 H 13 , methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -CH 2 OH, -CH 2 CH 2 OH, -CH (OH) CH 3 , -CH 2 CH 2 CH 2 OH, -CH (OH) CH 2 CH 3 , -CH 2 CH (OH) CH 3 , -CH 2 OCH 3 , -CFH 2 , -CF 2 H, -CF 3 , -
  • Aspect 80 The compound of any aspect of Aspects 66-79, wherein the moiety is
  • Aspect 81 The compound of any aspect of Aspects 66-80, wherein Cy302 is a 5-or 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member (s) .
  • Aspect 82 The compound of any aspect of Aspects 66-81, wherein is
  • Y 301 , Y 302 , Y 303 and Y 304 are each independently defined as in aspect 66;
  • Aspect 83 The compound of any aspect of Aspects 66-82, wherein is
  • Aspect 84 The compound of any aspect of Aspects 66-83, wherein
  • R 30c , R 30d and R 30e are each independently 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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is 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 or -NO 2 .
  • Aspect 85 The compound of any aspect of Aspects 66-84, wherein 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 -NO 2 ; preferably R 308 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl,
  • Aspect 86 The compound of any aspect of Aspects 66-85, wherein is
  • Aspect 87 The compound of any aspect of Aspects 66-85, wherein the moiety is selected from
  • a pharmaceutical composition comprising a compound of any one of Aspects 1-87 or a pharmaceutically acceptable salt, tautomer or prodrug thereof, together with a pharmaceutically acceptable excipient.
  • Aspect 89 A method of treating a disease that can be treated by degrading the target protein that the Warhead can combine by using a compound of any one of Aspects 1-87 .
  • Aspect 90 The method of aspect 89, wherein said target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism) , antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate) , receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, 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
  • Warhead is a moiety which binds to a target protein, wherein said target protein is selected from the group consisting of ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apotosis 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 (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate syntha
  • G Proteins i.e., Gq
  • Aspect 92 The method of Aspect 89, wherein the disease is a cancer.
  • Warhead, Linker, s2, Z 1 , Z 2 , Z 3 , R 1 and R 2 are defined as in any preceding aspects;
  • Aspect 94 A method of binding and altering the specificity of cereblon complex to induce the degradation of a complex-associated protein by using the compound of Claim 93, wherein the protein is selected from ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apotosis 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 (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymid
  • a method of treating an CRBN-mediated disorder, disease, or condition in a patient comprising administering to said patient the pharmaceutical composition of claim 93, preferably, the disorder disease, or condition is selected from proliferative disorders, neurological disorders and disorder associated with transplantation.
  • the compound is selected from:
  • subject refers to mammal and human, preferably human.
  • alkyl includes a hydrocarbon group selected from linear and branched, saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms.
  • alkyl groups comprising from 1 to 6 carbon atoms include, but 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, 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-penty
  • propyl includes 1-propyl or n-propyl ( “n-Pr” ) , 2-propyl or isopropyl ( “i-Pr” ) .
  • butyl includes 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” ) .
  • pentyl includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.
  • 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.
  • alkylene refers to a divalent alkyl group by removing two hydrogen from alkane.
  • Alkylene includes but not limited to methylene, ethylene, propylene, and so on.
  • halogen includes fluoro (F) , chloro (Cl) , bromo (Br) and iodo (I) .
  • alkenyl group e.g., C 2-6 alkenyl
  • examples of the alkenyl group, e.g., C 2-6 alkenyl include, but not limited to ethenyl or vinyl, 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 hexa-1, 3-dienyl groups.
  • alkenylene refers to a divalent alkenyl group by removing two hydrogen from alkene.
  • Alkenylene includes but not limited to, vinylidene, butenylene, and so on.
  • alkynyl includes a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C ⁇ C triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms.
  • alkynyl group e.g., C 2-6 alkynyl
  • alkynylene refers to a divalent alkynyl group by removing two hydrogen from alkyne.
  • Alkenylene includes but not limited to ethynylene and so on.
  • cycloalkyl includes a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl.
  • the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms.
  • the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms.
  • Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.
  • examples of the saturated monocyclic cycloalkyl group include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C 3-6 cycloalkyl) , including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • bicyclic cycloalkyl groups include those having from 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.
  • bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5, 6] and [6, 6] ring systems.
  • spiro cycloalkyl includes a cyclic structure which contains carbon atoms and is formed by at least two rings sharing one atom.
  • fused cycloalkyl includes a bicyclic cycloalkyl group as defined herein which is saturated and is formed by two or more rings sharing two adjacent atoms.
  • bridged cycloalkyl includes a cyclic structure which contains carbon atoms and is formed by two rings sharing two atoms which are not adjacent to each other.
  • 7 to 10 membered bridged cycloalkyl includes a cyclic structure which contains 7 to 12 carbon atoms and is formed by two rings sharing two atoms which are not adjacent to each other.
  • 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, as well as benzo 3 to 8 membered cycloalkyl, benzo C 4- 6 cycloalkenyl, 2, 3-dihydro-1H-indenyl, 1H-indenyl, 1, 2, 3, 4-tetralyl, 1, 4-dihydronaphthyl, etc.
  • Preferred embodiments are 8 to 9 membered fused rings, which refer to cyclic structures containing 8 to 9 ring atoms within the above examples.
  • aryl used alone or in combination with other terms includes a group selected from:
  • bicyclic ring systems such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and,
  • tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, e.g., fluorenyl.
  • a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl) .
  • Examples of a monocyclic or bicyclic aromatic hydrocarbon ring includes, but not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like.
  • the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring.
  • the aromatic hydrocarbon ring is a phenyl ring.
  • bicyclic fused aryl includes a bicyclic aryl ring as defined herein.
  • the typical bicyclic fused aryl is naphthalene.
  • heteroaryl includes a group selected from:
  • 5-, 6-or 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N) , sulfur (S) and oxygen (O) , with the remaining ring atoms being carbon;
  • 7-to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and
  • 11-to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring (s) of the heteroaryl group can be oxidized to form N-oxides.
  • bicyclic fused heteroaryl includes a 7-to 12-membered, preferably 7-to 10-membered, more preferably 9-or 10-membered fused bicyclic heteroaryl ring as defined herein.
  • a bicyclic fused heteroaryl is 5-membered/5-membered, 5-membered/6-membered, 6-membered/6-membered, or 6-membered/7-membered bicyclic. The group can be attached to the remainder of the molecule through either ring.
  • Heterocyclyl , “heterocycle” or “heterocyclic” are interchangeable and include a non-aromatic heterocyclyl group comprising 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 ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.
  • H or hydrogen disclosed herein includes Hydrogen and the non-radioisotope deuterium.
  • At least one substituent includes, for example, from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents, provided that the theory of valence is met.
  • at least one substituent F disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents F.
  • divalent refers to a linking group capable of forming covalent bonds with two other moieties.
  • a divalent cycloalkyl group refers to a cycloalkyl group obtained by removing two hydrogen from the corresponding cycloalkane to form a linking group.
  • divalent aryl group refers to a cycloalkyl group obtained by removing two hydrogen from the corresponding cycloalkane to form a linking group.
  • divalent heterocyclyl group or “divalent heteroaryl group” should be understood in a similar manner.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.
  • substituents found on such ring system may adopt cis and trans formations.
  • Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides.
  • the di-substituted cyclic ring system may be cyclohexyl or cyclobutyl ring.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium 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 techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • Diastereomers refer to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • a single stereoisomer e.g., a substantially pure enantiomer
  • Racemic mixtures of chiral compounds of the 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 reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
  • keto and enol forms are also intended to be included where applicable.
  • 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 an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
  • deuterated analog refers to a derivative of an active agent that an arbitrary hydrogen is substituted with deuterium.
  • the deuterated site is on the Warhead moiety.
  • the deuterated site is on the Linker moiety.
  • the deuterated site is on the Degron moiety.
  • “Pharmaceutically acceptable salts” refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.
  • the term also includes salts of the stereoisomers (such as enantiomers and/or diastereomers) , tautomers and prodrugs of the compound of the invention.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • administration when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administration and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.
  • subject herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.
  • an effective amount refers to an amount of the active ingredient, such as compound that, when administered to a subject for treating 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 symptom.
  • therapeutically effective amount can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, 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. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
  • “therapeutically effective amount” is an amount of at least one compound and/or at least one stereoisomer, tautomer or prodrug thereof, and/or at least one pharmaceutically acceptable salt thereof disclosed herein effective to “treat” as defined herein, a disease or disorder in a subject.
  • the term “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
  • disease refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition” .
  • C n-m or “C n -C m ” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 , C 1 -C 8 , C 1 -C 6 , and the like.
  • reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven dried and/or heat dried.
  • LCMS-1 LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190-400 nm) , Mass detector: 6120 SQ Mobile phase: A: water with 0.1%Formic acid, B: acetonitrile with 0.1%Formic acid Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7pm Gradient method: Flow: 1.8 mL/min Time (min) A (%) B (%)
  • LCMS, LCMS-3 LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190-400 nm) , Mass detector: G6125C SQ Mobile phase: A: water with 0.1%Formic acid, B: acetonitrile with 0.1%Formic acid Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7pm Gradient method: Flow: 1.8 mL/min Time (min) A (%) B (%)
  • LCMS-2 LC-MS spectrometer (Agilent 1290 Infinity II) Detector: MWD (190-400 nm) , Mass detector: G6125C SQ Mobile phase: A: water with 0.1%Formic acid, B: acetonitrile with 0.1%Formic acid Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7pm Gradient method: Flow: 1.2 mL/min Time (min) A (%) B (%)
  • Preparative HPLC was conducted on a column (150 x 21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml/min, injection volume 2 ml, at room temperature and UV Detection at 214 nm and 254 nm.
  • Step 1 ethyl 4- (4-bromo-2, 6-difluorophenyl) -4-cyanobutanoate
  • Step 2 4- (4-bromo-2, 6-difluorophenyl) -4-cyanobutanoic acid
  • 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
  • reaction solution was diluted with water (400 mL) , and extracted with EtOAc (100 mL x 2) .
  • EtOAc 100 mL x 2
  • the combined organic layers were washed with water (100 mL) and brine (100 mL) , dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 1 methyl (R) -1- (4-bromo-3, 5-difluorophenyl) pyrrolidine-3-carboxylate
  • Step 2 methyl (R) -1- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) -3, 5-difluorophenyl) pyrrolidine-3-carboxylate
  • Step 3 (R) -1- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) -3, 5-difluorophenyl) pyrrolidine-3-carboxylic acid
  • 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)
  • Step 1 (1- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) -3, 5-difluorophenyl) azetidin-3-yl) methanol
  • Step 2 3- (2, 6-difluoro-4- (3- (hydroxymethyl) azetidin-1-yl) phenyl) piperidine-2, 6-dione
  • Step 1 2, 6-bis (benzyloxy) -3- (4-bromophenyl) pyridine
  • Step 2 methyl (R) -1- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) phenyl) pyrrolidine-3-carboxylate
  • Step 3 (R) -1- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) phenyl) pyrrolidine-3-carboxylic acid
  • Step 4 (3R) -1- (4- (2, 6-dioxopiperidin-3-yl) phenyl) pyrrolidine-3-carboxylic acid
  • Step 1 2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethan-1-ol
  • Step 2 2- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) phenyl) ethan-1-ol
  • Step 3 3- (4- (2-hydroxyethyl) phenyl) piperidine-2, 6-dione
  • Step 1 tert-butyl 4- (1- (2-bromo-5-methoxy-4-nitrophenyl) piperidin-4-yl) piperazine-1-carboxylate
  • Step 2 tert-butyl 4- (1- (5-methoxy-4-nitro-2-vinylphenyl) piperidin-4-yl) piperazine-1-carboxylate
  • Step 3 tert-butyl 4- (1- (4-amino-2-ethyl-5-methoxyphenyl) piperidin-4-yl) piperazine-1-carboxylate
  • Step 5 (6- ( (5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide
  • 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
  • Step 7 (R) -2- (4- (2, 6-dioxopiperidin-3-yl) -3, 5-difluorophenyl) acetaldehyde
  • 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
  • Example 21 step 9 The title compound (34 mg, 25%) was prepared in a manner similar to that in Example 21 step 9 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.
  • 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
  • Step 7 (6- ( (5-bromo-2-chloropyrimidin-4-yl) amino) -2-ethylquinolin-5-yl) dimethylphosphine oxide
  • 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
  • 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
  • Step 3 (6- ( (5-bromo-2-chloropyrimidin-4-yl) amino) -2-methylquinolin-5-yl) dimethylphosphine oxide
  • 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
  • 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
  • Step 2 tert-butyl 4- (1- (2-bromo-5-cyclopropoxy-4-nitrophenyl) piperidin-4-yl) piperazine-1- carboxylate
  • Step 3 tert-butyl 4- (1- (5-cyclopropoxy-4-nitro-2-vinylphenyl) piperidin-4-yl) piperazine-1- carboxylate
  • Step 4 tert-butyl 4- (1- (4-amino-5-cyclopropoxy-2-ethylphenyl) piperidin-4-yl) piperazine-1- carboxylate
  • 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
  • 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
  • Example 21 step 9 The title compound (32 mg, 48%) was prepared in a manner similar to that in Example 21 step 9 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.
  • Step 1 (2-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanamine
  • 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
  • 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
  • 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
  • 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
  • Step 6 2- (4- (2, 6-dioxopiperidin-3-yl) phenyl) acetaldehyde
  • 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
  • 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
  • Step 2 2, 7-dibromo-9, 10-dihydro-4H-benzo [d] pyrazolo [1, 5-a] [1, 3] diazepine-3-carbonitrile
  • 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
  • Step 4 4-bromo-5-fluoro-2-methyl-N- (6-methylpyridin-2-yl) benzamide
  • Step 5 5-fluoro-2-methyl-N- (6-methylpyridin-2-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl) benzamide
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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 3 methyl 3-fluoro-2-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Step 2 tert-butyl 4- (3- ( (6-chloropyrimidin-4-yl) amino) phenyl) piperazine-1-carboxylate
  • 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
  • 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
  • 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
  • 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
  • Step 2 tert-butyl 4- (6- ( (diphenylmethylene) amino) pyridazin-3-yl) piperazine-1-carboxylate
  • Step 3 tert-butyl 4- (6-aminopyridazin-3-yl) piperazine-1-carboxylate
  • 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
  • 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
  • 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
  • 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
  • Example 42 3- ( (4- (4- (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
  • Step 2 ethyl 2- (4-amino-3, 5-difluorophenyl) acetate
  • Step 3 ethyl 2- (3, 5-difluoro-4-iodophenyl) acetate
  • Step 4 ethyl 2- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) -3, 5-difluorophenyl) acetate
  • Step 5 2- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) -3, 5-difluorophenyl) ethanol
  • Step 6 3- (2, 6-difluoro-4- (2-hydroxyethyl) phenyl) piperidine-2, 6-dione
  • Step 7 4- (2, 6-dioxopiperidin-3-yl) -3, 5-difluorophenethyl methanesulfonate
  • Step 8 3- ( (4- (4- (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
  • H1975-clone#28 (Del19/T790M/C797S) was stably expressed in H1975 cell lines (from ATCC) by lentivirus-mediated over-expression.
  • the EGFR over-expressed cells then underwent gene knockout, in which the EGFR targeting sgRNA was designed to only target the endogenous EGFR copies and preserve the exogenous EGFR copies.
  • the edited H1975 cells were seeded in 96 well plates at the concentration of 1 cell/cell, cultured for about 2 weeks to allow single clones formation. The formed clones were screened by DNA sequencing and whole exon sequencing analysis for the desired edition.
  • H1975-clone#28 was finally confirmed as homozygous Del19/T790M/C797S EGFR clone
  • 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#11835-030) , 10%heat-inactive FBS, 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3799) .
  • H1975-clone#28 (Del19/T790M/C797S) 10000 cells/well correspondingly in cell culture medium [RPMI1640 (Gibco, Cat#72400-047) , 10%heat-inactive FBS, 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3599) .
  • 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 incubate for 16h, 37°C, 5%CO 2
  • H1975-#28 cells are treated with compounds diluted in 0.2%DMSO cell culture medium on day 2, incubate for 16h, 37°C, 5%CO 2 .
  • the final concentriation of compounds in all assay is start with 10uM, 5-fold dilution, total 8 doses were included.
  • TMD-8 cells are seeded at 20000 cells/well at a volume of 15 ⁇ l/well in cell culture medium [RPMI1640 (Gibco, phenol red free, Cat#11835-030) , 10%heat-inactive FBS, 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3799) .
  • TMD-8 cells are treated with compounds diluted in 0.2%DMSO, dilution is done according to the following protocol: (1) make 500 ⁇ stock solution in DMSO from 1mM by 6-fold dilution, total 8 doses were included; (2) make 2 ⁇ solution in cell culture medium by transferring 0.5 ⁇ l 500 ⁇ stock solution into 125 ⁇ l medium; (3) 15 ⁇ l of 2 ⁇ solution is added to cells and incubate for 6h.
  • HTRF lysis buffer After 16h treatment, add HTRF lysis buffer to each well ; seal the plate and incubate 1 hour at room temperature on a plate shaker; Once the cells are lysed, 16 ⁇ L of cell lysate are transferred to a PE 384-well HTRF detection plate; 4 ⁇ L of pre-mixed HTRF antibodies are added to each well ; Cover the plate with a plate sealer, spin 1000 rpm for 1 min, Incubate overnight at room temperature; Read on BMG PheraStar with HTRF protocol (337nm-665nm-620nm) .
  • High control Cell group with added DMSO and without compound, indicating microplate readings without EGFR degradation
  • Dmax is the maximum percentage of inhibition (degradation) .
  • High control Cell group with added DMSO and without compound, indicating microplate readings without BTK degradation
  • Dmax is the maximum percentage of inhibition (degradation) .
  • the IC 50 (DC 50 ) value of a compound can be obtained by fitting the following equation
  • X and Y are known values, and IC 50 , Hillslope, Top and Bottom are the parameters obtained by fitting with software.
  • Y is the inhibition percentage (calculated from the equation)
  • X is the concentration of the compound
  • IC 50 is the concentration of the compound when the 50%inhibition is reached. The smaller the IC 50 value is, the stronger the inhibitory ability of the compound is. Vice versa, the higher the IC 50 value is, the weaker the ability the inhibitory ability of the compound is
  • Hillslope represents the slope of the fitted curve, generally around 1 *
  • Bottom represents the minimum value of the curve obtained by data fitting, which is generally 0% ⁇ 20%
  • Top represents the maximum value of the curve obtained by data fitting, which is generally 100% ⁇ 20%.
  • the experimental data were fitted by calculating and analyzing with Dotmatics data analysis software.
  • Biochemical potency of compound was determined by using CRBN&DDB1 protein (His Tag) .
  • CRBN&DDB1 protein CRBN, aa 40-442, DDB1, 1-1140, Viva Biotech
  • TR-FRET time-resolved fluorescence-resonance energy transfer
  • the protein was preincubated with compound for 60 minutes at room temperature and biotin labeled thalidomide was added to plate. After further incubation at room temperature for 60 minutes detection reagents Mab Anti-6His Eu cryptate Gold (Cisbio, Cat#61HI2KLB) and Streptavidin-XL665 (Cisbio, Cat#610SAXLG) were added to plate. Plates were sealed and incubated at room temperature for 1 hour, and the TR-FRET signals (ex337nm, em665nm/620nm) were recorded on a PHERAstar FSX plate reader (BMG Labtech) .
  • the inhibition percentage of CRBN&DDB1 protein interaction with biotin labeled thalidomide in presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 665 nm to that at 620 nm.
  • IC 50 was derived from fitting the dose-response %inhibition data to the four-parameter logistic model by Dotmatics.
  • TMD-8 cells were seeded at 20000 cells/well at a volume of 15 ⁇ l/well in cell culture medium [RPMI1640 (Gibco, phenol red free, Cat#11835-030) , 10%heat-inactive FBS, 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3799) .
  • TMD-8 cells were treated with compounds diluted in 0.2%DMSO, dilution was done according to the following protocol: (1) making 500 ⁇ stock solution in DMSO from 1mM by 6-fold dilution, total 8 doses were included; (2) making 2 ⁇ solution in cell culture medium by transferring 0.5 ⁇ l 500 ⁇ stock solution into 125 ⁇ l medium; (3) adding 15 ⁇ l of 2 ⁇ solution to cells for incubation of 6h.
  • the inhibition (degradation) percentage of the compound was calculated by the following equation:
  • High control Cell group with added DMSO and without compound, indicating microplate readings without BTK degradation
  • Dmax is the maximum percentage of inhibition (degradation) .
  • the IC 50 (DC 50 ) value of a compound can be obtained by fitting the following equation
  • Y Bottom + (TOP-Bottom) / (1 + ( (IC 50 /X) ⁇ hillslope) )
  • X and Y are known values
  • IC 50 , Hillslope, Top and Bottom are the parameters obtained by fitting with software.
  • Y is the inhibition percentage (calculated from the equation)
  • X is the concentration of the compound
  • IC 50 is the concentration of the compound when the 50%inhibition is reached. The smaller the IC 50 value is, the stronger the inhibitory ability of the compound is.
  • HEK-293 cells were seeded at 2000 cells/well at a volume of 50ul/well in cell culture medium [DMEM (Gibco, Cat#11965-092) , 10%heat-inactive FBS (Gibco, Cat#10099) , 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3903) , and then incubated overnight.
  • DMEM Gibco, Cat#11965-092
  • 10%heat-inactive FBS Gibco, Cat#10099
  • 1%PS Gabco, Cat#10378
  • HEK-293 cells were treated with compounds diluted in 0.2%DMSO, dilution was done according to the following protocol: (1) making 500 ⁇ stock solution in DMSO from 5mM by 4-fold dilution, total 8 doses were included; (2) making 2 ⁇ solution in cell culture medium by transferring 0.5ul 500 ⁇ stock solution into 125ul medium; (3) adding 50ul of 2 ⁇ solution to cells for incubation of 72h.
  • High control Cell group with added DMSO and without compound, indicating cells proliferation with no inhibition
  • Imax is the maximum percentage of inhibition.
  • the IC50 value of a compound can be obtained by fitting the following equation
  • X and Y are known values, and IC50, Hillslope, Top and Bottom are the parameters obtained by fitting with software.
  • Y is the inhibition percentage (calculated from the equation)
  • X is the concentration of the compound
  • IC50 is the concentration of the compound when the 50%inhibition is reached. The smaller the IC50 value is, the stronger the inhibitory ability of the compound is. Vice versa, the higher the IC50 value is, the weaker the ability the inhibitory ability of the compound is
  • Hillslope represents the slope of the fitted curve, generally around 1 *
  • Bottom represents the minimum value of the curve obtained by data fitting, which is generally 0% ⁇ 20%
  • Top represents the maximum value of the curve obtained by data fitting, which is generally 100% ⁇ 20%.
  • the experimental data were fitted by calculating and analyzing with Dotmatics data analysis software.
  • THP-1 cells are seeded at 100000 cells/well at a volume of 15 ⁇ l/well in cell culture medium [RPMI1640 (Gibco, phenol red free, Cat#11835-030) , 10%heat-inactive FBS, 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3799) .
  • THP-1 cells are treated with compounds diluted in 0.2%DMSO, dilution is done according to the following protocol: (1) make 500 ⁇ stock solution in DMSO from 5mM by 5-fold dilution, total 8 doses were included; (2) make 2 ⁇ solution in cell culture medium by transferring 0.5 ⁇ l 500 ⁇ stock solution into 125 ⁇ l medium; (3) 15 ⁇ l of 2 ⁇ solution is added to cells and incubate for 6h.
  • High control Cell group with added DMSO and without compound, indicating microplate readings without IRAKM degradation
  • Dmax is the maximum percentage of inhibition (degradation) .
  • the IC 50 (DC 50 ) value of a compound can be obtained by fitting the following equation
  • X and Y are known values, and IC 50 , Hillslope, Top and Bottom are the parameters obtained by fitting with software.
  • Y is the inhibition percentage (calculated from the equation)
  • X is the concentration of the compound
  • IC 50 is the concentration of the compound when the 50%inhibition is reached. The smaller the IC 50 value is, the stronger the inhibitory ability of the compound is. Vice versa, the higher the IC 50 value is, the weaker the ability the inhibitory ability of the compound is;
  • Hillslope represents the slope of the fitted curve, generally around 1 *;
  • the experimental data were fitted by calculating and analyzing with Dotmatics data analysis software.

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Abstract

Disclosed herein are compounds for binding and modulating the activity of cereblon (CRBN), and methods of use. 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. The present compounds are thus useful for the treatment or prophylaxis tumors and cancer.

Description

(R) -GLUTARIMIDE CRBN LIGANDS AND METHODS OF USE FIELD OF THE INVENTION
Disclosed herein are compounds for binding and modulating the activity of cereblon (CRBN) , and methods of use. 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. The present compounds are thus useful for the treatment or prophylaxis tumors and cancer.
BACKGROUND OF THE INVENTION
Proteolysis targeting chimera (PROTAC) consists of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to the protein of interest (POI) a target meant for degradation (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98: 8554–9.; Sakamoto K.M. et al., Methods Enzymol. 2005; 399: 833‐847. ) . Rather than inhibiting the target protein's enzymatic activity, recruitment of the E3 ligase to the specific unwanted proteins results in ubiquitination and subsequent degradation of the target protein by the proteasome. The whole 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 G.L. et al., Cell Rep. 2015, 12, 545-553; Swatek K.N. et al., Cell Res. 2016, 26, 399-422) . Proteasomes are protein complexes which degrade unneeded, misfolded or abnormal proteins into small peptides to maintain the health and productivity of the cells. Ubiquitin ligases, also called an E3 ubiquitin ligase, directly catalyze the transfer of ubiquitin from the E2 to the target protein 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: cereblon (CRBN) , Von Hippel-Lindau (VHL) , mouse double minute 2 homologue (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, J.N. et 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 a number of other proteins followed by the degradation via proteasomes. (Yi-An Chen, et al., Scientific Reports 2015, 5, 1–13) . Immunomodulatory drugs (IMiDs) , including thalidomide, lenalidomide, and pomalidomide, function as monovalent promoters of PPIs by binding to the cereblon (CRBN) subunit of the CRL4A CRBN E3 ligase complex and recruiting neosubstrate proteins. (Matyskiela, M.E. et al., Nat Chem Biol 2018, 14, 981-987. ) As a consequence, the ability of thalidomide, and its derivatives, to recruit CRBN has been widely applied in proteolysis-targeting chimeras (PROTACs) 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 regarding the role of CRBN in IMiD action stimulated intense investigation of CRBN’s downstream factors involved in maintaining regular function of a cell and its use as a substrate receptor in which the proteins recognized by CRBN might be ubiquitinated and degraded by proteasomes.
There is a need for new compounds, compositions and uses thereof that bind to E3 ligase protein cereblon for the treatment of serious diseases. There is also a need for new compounds that may be in the preparation of bifunctional molecules that are used in the degradation of proteins.
SUMMARY OF THE INVENTION
One objective of the present invention is to provide compounds and derivatives formed by conjugating target protein moieties with E3 ligase Ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
Aspect 1. A compound of Formula (I) :
Figure PCTCN2022100017-appb-000001
or a pharmaceutically acceptable salt thereof, or a deuterated analog thereof, or a prodrug thereof, wherein:
Warhead is a targeting moiety that binds to a target protein; wherein the target protein is a mediator of a disease in a subject;
Linker is a divalent chemical group that connects the Warhead moiety and the
Figure PCTCN2022100017-appb-000002
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 N at the same time;
R z, at each occurrence, is independently selected from hydrogen, halogen, -C 1-8alkyl, -NR ZaR Zb, -OR Za, -SR Za, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl or CN; each of -C 1-8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl is optionally substituted with at least one R Zc;
the
Figure PCTCN2022100017-appb-000003
moiety is linked to the
Figure PCTCN2022100017-appb-000004
moiety via any one of Z 1, Z 2 or Z 3 which is CR z and R z is hydrogen;
R Za and R Zb are each independently selected from hydrogen, -C 1-C 8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 2- 8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 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 1-8alkoxy, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl;
R 1 and R 2 are each independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 1- 8alkoxy, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, -CN, -SO 2R 1a, -SO 2NR 1aR 1b, -COR 1a, -CO 2R 1a, -CONR 1aR 1b, -NR 1aR 1b, -NR 1aCOR 1b, -NR 1aCO 2R 1b, or –NR 1aSO 2R 1b; each of -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 1-8alkoxy, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo, -CN, -OR 1c, -SO 2R 1c, -SO 2NR 1cR 1d, -COR 1c, -CO 2R 1c, -CONR 1cR 1d, -NR 1cR 1d, -NR 1cCOR 1d, -NR 1cCO 2R 1d, or –NR 1cSO 2R 1d;
R 1a, R 1b, R 1c and R 1d are each independently hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl.
Aspect 2. The compound of aspect 1, wherein at most one of Z 1, Z 2 and Z 3 is N.
Aspect 3. The compound of any one of aspects 1-2, wherein Z 1, Z 2 and Z 3 are each independently CR z.
Aspect 4. The compound of any one of aspects 1-3, wherein R Z, at each occurrence, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR ZaR 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 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 is optionally substituted with at least one R Zc;
R Za and R Zb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl, each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R Zd;
R Zc and R Zd are each independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl, or 5-to 12-membered heteroaryl.
Aspect 5. The compound of any one of aspects 1-4, wherein R z is selected from H, -CH 3, -C 2H 5, F, -CH 2F, -CHF 2, -CF 3, -OCH 3, -OC 2H 5, -C 3H 7, -OCH 2F, -OCHF 2, -OCH 2CF 3, -OCF 3, -SCF 3, -CF 3 or -CH (OH) CH 3.
Aspect 6. The compound of any one of aspects 1-5, wherein R 1 and R 2 are each 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, -C 2-8alkenyl, -C 2-8alkynyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, -CN, -SO 2R 1a, -SO 2NR 1aR 1b, -COR 1a, -CO 2R 1a, -CONR 1aR 1b, -NR 1aR 1b, -NR 1aCOR 1b, -NR 1aCO 2R 1b, or –NR 1aSO 2R 1b; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8alkenyl, -C 2-8alkynyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl is optionally substituted with 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- 8alkenyl, -C 2-8alkynyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo, -CN, -OR 1c, -SO 2R 1c, -SO 2NR 1cR 1d, -COR 1c, -CO 2R 1c, -CONR 1cR 1d, -NR 1cR 1d, -NR 1cCOR 1d, -NR 1cCO 2R 1d, or –NR 1cSO 2R 1d;
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- 8alkenyl, -C 2-8alkynyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, or 5-to 12-membered heteroaryl.
Aspect 7. The compound of any one of aspects 1-6, wherein R 1 and R 2 are each 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, -CH 2F, -CHF 2, -CF 3, -OCH 2F, -OCHF 2, -OCH 2CF 3, -OCF 3, -SCF 3, or phenyl.
Aspect 8. The compound of any one of aspects 1-7, wherein the compound is Formula (II)
Figure PCTCN2022100017-appb-000005
wherein Warhead and Linker are defined as aspect 1.
Aspect 9. The compound of any one of aspects 1-8, wherein Linker is
Figure PCTCN2022100017-appb-000006
wherein *refers to the position attached to the
Figure PCTCN2022100017-appb-000007
moiety, and **refers to the position attached to the
Figure PCTCN2022100017-appb-000008
moiety;
L 1 is selected from a single bond, -O-, -SO 2-, -C (O) -, -NR L1a-, -C 3-C 8cycloalkylene-, * L1-O-C 1- 8alkylene-** L1, * L1-C 1-8alkylene-O-** L1, * L1-SO 2-C 1-8alkylene-** L1, * L1-C 1-8alkylene-SO 2-** L1, * L1-CO-C 1-8alkylene-** L1, * L1-C 1-8alkylene-CO-** L1, * L1-NR L1a-C 1-8alkylene-** L1, * L1-C 1-8alkylene-NR L1a-** L1, * L1-NR L1aC (O) -** L1, * L1-C (O) NR L1a-** L1, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2-8alkynylene-, - [O (CR L1aR L1b)  m4]  m5-, 
Figure PCTCN2022100017-appb-000009
Figure PCTCN2022100017-appb-000010
wherein each of said -C 3-C 8cycloalkylene-, * L1-O-C 1-8alkylene-** L1, * L1-C 1-8alkylene-O-** L1, * L1-SO 2-C 1-8alkylene-** L1, * L1-C 1-8alkylene-SO 2-** L1, * L1-CO-C 1-8alkylene-** L1, * L1-C 1-8alkylene-CO-** L1, * L1-NR L1a-C 1-8alkylene-** L1, * L1-C 1-8alkylene-NR L1a-** L1, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2- 8alkynylene-, 
Figure PCTCN2022100017-appb-000011
Figure PCTCN2022100017-appb-000012
Figure PCTCN2022100017-appb-000013
is optionally substituted with at least one R L1c;
wherein * L1 refers to the position attached to the
Figure PCTCN2022100017-appb-000014
moiety, and ** L1 refers to the position attached to the
Figure PCTCN2022100017-appb-000015
moiety;
R L1a and R L1b are each independently selected from hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R L1d;
each of said R L1c and R L1d are independently oxo, halogen, hydroxy, -C 1-8alkyl, -C 1-8alkoxy, -C 2- 8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl; or
two R L1c together with the atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, or -C 1-8alkyl;
L 2 is selected from a single bond, -O-, -SO 2-, -CO-, -NR L2a-, -C 3-C 8cycloalkylene-, * L2-O-C 1- 8alkylene-** L2, * L2-C 1-8alkylene-O-** L2, * L2-SO 2-C 1-8alkylene-** L2, * L2-C 1-8alkylene-SO 2-** L2, * L2-CO-C 1-8alkylene-** L2, * L2-C 1-8alkylene-CO-** L2, * L2-NR L2a-C 1-8alkylene-** L2, * L2-C 1-8alkylene-NR L2a-** L2, * L2-NR L2aC (O) -** L2, * L2-C (O) NR L2a-** L2, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2-8alkynylene-, - [O (CR L2aR L2b)  m4]  m5-, 
Figure PCTCN2022100017-appb-000016
Figure PCTCN2022100017-appb-000017
Figure PCTCN2022100017-appb-000018
wherein each of said -C 3-C 8cycloalkylene-, * L2-O-C 1-8alkylene-** L2, * L2-C 1-8alkylene-O-** L2, * L2-SO 2-C 1-8alkylene-** L2, * L2-C 1-8alkylene-SO 2-** L2, * L2-CO-C 1-8alkylene-** L2, * L2-C 1-8alkylene-CO-** L2, * L2-NR L2a-C 1-8alkylene-** L2, * L2-C 1-8alkylene-NR L2a-** L2, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2- 8alkynylene-, 
Figure PCTCN2022100017-appb-000019
Figure PCTCN2022100017-appb-000020
Figure PCTCN2022100017-appb-000021
is optionally substituted with at least one substituent R L2c;
wherein * L2 refers to the position attached to the
Figure PCTCN2022100017-appb-000022
moiety, and ** L2 refers to the position attached to the
Figure PCTCN2022100017-appb-000023
moiety;
R L2a and R L2b are each independently selected from hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R L2d;
each of said R L2c and R L2d are independently oxo, halogen, hydroxy, -C 1-8alkyl, -C 1-8alkoxy, -C 2- 8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl; or
two R L2c together with the atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, -C 1-8alkyl;
L 3 is selected from a single bond, -O-, -SO 2-, -CO-, -NR L3a-, -C 3-C 8cycloalkylene-, * L3-O-C 1- 8alkylene-** L3, * L3-C 1-8alkylene-O-** L3, * L3-SO 2-C 1-8alkylene-** L3, * L3-C 1-8alkylene-SO 2-** L3, * L3-CO-C 1-8alkylene-** L3, * L3-C 1-8alkylene-CO-** L3, * L3-NR L3a-C 1-8alkylene-** L3, * L3-C 1-8alkylene-NR L3a-** L3, * L3-NR L3aC (O) -** L3, * L3-C (O) NR L3a-** L3, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2-8alkynylene-, - [O (CR L3aR L3b)  m4]  m5-, 
Figure PCTCN2022100017-appb-000024
Figure PCTCN2022100017-appb-000025
wherein each of said -C 3-C 8cycloalkylene-, * L3-O-C 1-8alkylene-** L3, * L3-C 1-8alkylene-O-** L3, * L3-SO 2-C 1-8alkylene-** L3, * L3-C 1-8alkylene-SO 2-** L3, * L3-CO-C 1-8alkylene-** L3, * L3-C 1-8alkylene-CO-** L3, * L3-NR L3a-C 1-8alkylene-** L3, * L3-C 1-8alkylene-NR L3a-** L3, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2- 8alkynylene-, 
Figure PCTCN2022100017-appb-000026
Figure PCTCN2022100017-appb-000027
Figure PCTCN2022100017-appb-000028
is optionally substituted with at least one substituent R L3c; wherein * L3 refers to the position attached to the
Figure PCTCN2022100017-appb-000029
moiety, and ** L3 refers to the position attached to the
Figure PCTCN2022100017-appb-000030
moiety;
R L3a and R L3b are each independently selected from hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R L3d;
each of said R L3c and R L3d are independently oxo, halogen, hydroxy, -C 1-8alkyl, -C 1-8alkoxy, -C 2- 8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl; or
two R L3c together with the atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, or -C 1-8alkyl;
R 12 is independently selected from hydrogen, halogen, -C 1-8alkyl, -NR 12aR 12b, -OR 12a, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo, or -CN; each of -C 1-8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 12c; or
two R 12 together with the carbon atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R 12c;
R 12a and R 12b are each independently selected from hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 12d; or
R 12c and R 12d are each independently halogen, hydroxy, -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2- 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl;
X 1, X 2, X 3 and X 4 are each independently selected from -CR a, or N;
X 5, X 6 and X 7 are each independently selected from -NR a-, -O-, -S-and -CR aR b-;
X 12 and X 13 are each independently selected from -C (O) -, -NR a-and -O-;
Q 1, Q 2, Q 3 and Q 4 are each independently selected from CR a or N;
Q 5 is each independently selected from -O-, -NR a-, -CR aR b-, -S-or -C (O) -;
P 1 is a single bond, -O-, -NR a-, -CR aR b -, -S-, -SO-or -SO 2-;
at each occurrence, R a and R b are each independently selected from hydrogen, hydroxy, halogen, CN, -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2- 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, halogen, -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl; or
R a and R b together with the carbon atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl,  -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl;
m 1 is 0 or 1;
m 2 and m3 is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
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 are each independently 0, 1, 2 or 3.
Aspect 10. The compound of aspect 9, wherein L 1 is selected from a single bond, -C 1-8alkylene- (preferably -CH 2-, -C 2H 4-, -C 3H 6-) , -CO-, -O-, -N (CH 3) -, -NH-, 
Figure PCTCN2022100017-appb-000031
Figure PCTCN2022100017-appb-000032
Aspect 11. The compound of any one of aspects 9-10, wherein X 1 and X 2 are each independently selected from -CR a or N;
R a is selected from hydrogen, -F, -Cl, -Br, -I, CN, methyl, ethyl, methoxy, ethoxy, or cyclopropyl, wherein each of said methyl, ethyl, methoxy, ethoxy, and 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=1 or 0;
R 12 is hydrogen, oxo, methoxymethyl, hydroxymethyl, -CN or -CH 3.
Aspect 12. The compound of any one of aspects 9-11, wherein m 1 is 1; preferably, 
Figure PCTCN2022100017-appb-000033
moiety is
Figure PCTCN2022100017-appb-000034
Figure PCTCN2022100017-appb-000035
Figure PCTCN2022100017-appb-000036
wherein * X refers to the position attached to
Figure PCTCN2022100017-appb-000037
moiety, and ** X refers to the position attached to the
Figure PCTCN2022100017-appb-000038
moiety.
Aspect 13. The compound of any one of aspects 9-12, wherein m 1 is 1, 
Figure PCTCN2022100017-appb-000039
moiety is 
Figure PCTCN2022100017-appb-000040
Aspect 14. The compound of any one of aspects 9-13, wherein L 2 is selected from a single bond, -C 1- 8alkylene- (preferably -CH 2-, -C 2H 4-, -C 3H 6-) , -CO-, -O-, -N (CH 3) -, -NH-, 
Figure PCTCN2022100017-appb-000041
Figure PCTCN2022100017-appb-000042
Figure PCTCN2022100017-appb-000043
Aspect 15. The compound of any one of aspects 9-14, wherein L 3 is selected from single bond, -C 1- 8alkylene- (preferably -CH 2-, -C 2H 4-, -C 3H 6-) , -CO-, -O-, -N (CH 3) -, -NH-, 
Figure PCTCN2022100017-appb-000044
Figure PCTCN2022100017-appb-000045
Figure PCTCN2022100017-appb-000046
Aspect 16. The compound of any one of aspects 9-15, wherein L 2 is a single bond; or L 3 is a single bond; or L 2 is a single bond and L 3 is a single bond.
Aspect 17. The compound of any one of aspects 9-16, wherein
Figure PCTCN2022100017-appb-000047
is selected from
Figure PCTCN2022100017-appb-000048
Figure PCTCN2022100017-appb-000049
Figure PCTCN2022100017-appb-000050
Figure PCTCN2022100017-appb-000051
Aspect 18. The compound of any one of aspects 1-17, wherein Warhead is a moiety which binds to a target protein, wherein said target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism) , antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate) , receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, 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, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity and translation regulator activity.
Aspect 19. The compound of any one of aspects 1-18, wherein Warhead is a moiety which binds to a target protein, wherein said target protein is selected from the group consisting of ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apotosis 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 (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug 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-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) , protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7) , farnesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic  phospholipaseA2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channels, Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor associated kinase-3 (IRAK-3 or IRAK-M) or enolpyruvyl-shikimate-phosphate synthase.
Aspect 20. The compound of any one of aspects 1-19, wherein Warhead is
Figure PCTCN2022100017-appb-000052
wherein R 13 is selected from -P (O) R 13aR 13b, -SO 2R 13a, -SO 2-NR 13aR 13b or -N (R 13a) -SO 2R 13b;
R 13a and R 13b are each independently selected from hydrogen, -C 1-C 8alkyl or C 3-C 8cycloalkyl, said -C 1-C 8alkyl or C 3-C 8cycloalkyl is optionally substituted with at least one halogen;
R 14 and R 15 are each independently selected from hydrogen, halogen, -C 1-C 8alkyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, -CN, -OR 14a, -SO 2R 14a, -SO 2NR 14aR 14b, -COR 14a, -CO 2R 14a, -CONR 14aR 14b, -NR 14aR 14b, -NR 14aCOR 14b, -NR 14aCO 2R 14b, or –NR 14aSO 2R 14b; each of -C 1-C 8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 14d, or
R 14 and R 15 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated or saturated ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R 14e;
R 14e, at each occurrence, is independently hydrogen, halogen, -C 1-C 8alkyl, -C 1-C 8alkoxy, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo (=O) , -OR 14a, thioxo (=S) , -SR 14a, -CN, -SO 2R 14a, -SO 2NR 14aR 14b, -COR 14a, -CO 2R 14a, -CONR 14aR 14b, -NR 14aR 14b, -NR 14aCOR 14b, -NR 14aCO 2R 14b or -NR 14aSO 2R 14b; each of -C 1-C 8alkyl, -C 1-C 8alkoxy, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 14d;
R 14a and R 14b are each independently selected from hydrogen, -C 1-C 8alkyl, -C 1-C 8haloalkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 1-C 8alkoxy-C 1-C 8alkyl-, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl;
R 14d, at each occurrence, is independently halogen, -OH, -CN, oxo, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, or 5-to 12-membered heteroaryl;
R 4 is selected from hydrogen, halogen, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 1-C 8alkoxy, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, -CN, -SO 2R 4a, -SO 2NR 4aR 4b, -COR 4a, -CO 2R 4a, -CONR 4aR 4b, -NR 4aR 4b, -NR 4aCOR 4b, -NR 4aCO 2R 4b or -NR 4aSO 2R 4b; each of -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 1-C 8alkoxy, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with  halogen, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo, -CN, -OR 4c, -SO 2R 4c, -SO 2NR 4cR 4d, -COR 4c, -CO 2R 4c, -CONR 4cR 4d, -NR 4cR 4d, -NR 4cCOR 4d, -NR 4cCO 2R 4d or -NR 4cSO 2R 4d;
R 4a, R 4b, R 4c and R 4d are each independently hydrogen, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl;
R 9, R 10 and R 11 are each independently selected from hydrogen, halogen, -C 1-C 8alkyl, -NR 9aR 9b, -OR 9a, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo or -CN; each of -C 1-C 8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 9c;
R 9a and R 9b are each independently selected from hydrogen, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl; each of said -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 9d; or
R 9c and R 9d are each independently halogen, hydroxy, -C 1-C 8alkyl, -C 1-C 8alkoxy, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl;
Z 4, Z 5, Z 6 and Z 7 are each independently selected from -CR Z4, or N;
R Z4, at each occurrence, is independently selected from hydrogen, halogen, -C 1-C 8alkyl, -NR Z4aR Z4b, -OR Z4a, -SR Z4a, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, or CN; each of -C 1-C 8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl is optionally substituted with at least one R Z4c;
R Z4a and R Z4b are each independently selected from hydrogen, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl, each of said -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R Z4d;
R Z4c and R Z4d are each independently halogen, hydroxy, -C 1-C 8alkyl, -C 1-C 8alkoxy, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl.
Aspect 21. The compound of aspect 20, wherein R 13 is selected from -P (O) R 13aR 13b or -N (R 13a) -SO 2R 13b, wherein R 13a and R 13b are each independently selected from hydrogen, -C 1-C 8alkyl (preferably -CH 3, -C 2H 5, -C 3H 7, -C 4H 9 or -C 5H 11; more preferably -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -iso-C 3H 7, -CH 2CH 2CH 2CH 3, -iso-C 4H 9, -sec-C 4H 9 or -tert-C 4H 9) or C 3-C 8cycloalkyl (preferably cyclopropyl, cyclobutyl or cyclopentyl) .
Aspect 22. The compound of aspect 20, wherein R 13 is selected from -P (O) (CH 3)  2, -NH-SO 2CH 3 or -N (CH 3) -SO 2CH 3.
Aspect 23. The compound of aspect 20, wherein R 13 is -P (O) (CH 3)  2.
Aspect 24. The compound of aspect 20, wherein R 14 and R 15 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl,  5-to 12-membered heteroaryl, -CN, -OR 14a, -SO 2R 14a, -SO 2NR 14aR 14b, -COR 14a, -CO 2R 14a, -CONR 14aR 14b, -NR 14aR 14b, -NR 14aCOR 14b, -NR 14aCO 2R 14b, or –NR 14aSO 2R 14b; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 14d, or
R 14 and R 15 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated or saturated ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R 14e;
R 14e, at each occurrence, is independently -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-to 8-membered heterocyclyl, 5-to 12-membered heteroaryl, oxo, -CN, CF 3, CHF 2, CH 2F, thioxo, -SCF 3, -SCHF 2, -SCH 2F, -SCH 2CF 3, -SCF 2CH 3, -SCF 2CF 3, -SO 2R 14a, -SO 2NR 14aR 14b, -COR 14a, -CO 2R 14a, -CONR 14aR 14b, -NR 14aR 14b, -NR 14aCOR 14b, -NR 14aCO 2R 14b or -NR 14aSO 2R 14b; 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, 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 14d;
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, C 1-C 8alkoxy-C 1-C 8alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl;
R 14d, at each occurrence, is independently halogen, -OH, 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.
Aspect 25. The compound of aspect 20, wherein R 14 and R 15 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated (preferred aromatic) or saturated ring, said ring comprising 1 or 2 nitrogen heteroatoms; said ring is optionally substituted with 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, -CH 2OH, -SCH 3, -SC 2H 5, oxo, thioxo, -CF 3, -CHF 2, -CH 2F, -SCF 3, -OMe, -OC 2H 5, -CN, -C (O) CH 3, 
Figure PCTCN2022100017-appb-000053
Figure PCTCN2022100017-appb-000054
Aspect 26. The compound of aspect 20, wherein R 14 and R 15 together with the carbon atoms to which they are attached, form a 6-membered unsaturated (preferred aromatic) , said ring comprising 1 or 2 nitrogen heteroatoms; said ring is optionally substituted with one substituent -H, -F, -Cl, -Br, -I, methyl, ethyl or cyclopropyl.
Aspect 27. The compound of aspect 20, wherein R 4 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl or -C 1-C 8alkoxy; each of methyl, ethyl, propyl, butyl, pentyl,  hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-C 8alkenyl or -C 2-C 8alkynyl is optionally substituted with -F, -Cl, -Br, -I, oxo, or -CN.
Aspect 28. The compound of aspect 20, wherein R 4 is hydrogen, -F, -Cl, -Br, -I, -CH 3, -CF 3, -CH 2F, or -CHF 2.
Aspect 29. The compound of aspect 20, wherein R 4 is hydrogen, -F, -Cl, -Br or -I.
Aspect 30. The compound of aspect 20, wherein R 9, R 10 and R 11 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR 9aR 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 -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 is optionally substituted with at least one substituent R 9c;
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, each of said 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 is optionally substituted with at least one substituent R 9d;
R 9c and R 9d are each 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-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl.
Aspect 31. The compound of aspect 20, wherein R 9, R 10 and R 11 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, -NH 2, -NHCH 3, -OH, -OCH 3, -OC 2H 5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2OH, -CH 2OMe, oxo, or -CN.
Aspect 32. The compound of aspect 20, wherein R 9, R 10 and R 11 are each independently selected from hydrogen, -CH 3, -F, -Cl, -Br or -I.
Aspect 33. The compound of aspect 20, wherein Z 4, Z 5, Z 6 and Z 7 are each independently -CR 4z;
R 4Z, at each occurrence, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR 4ZaR 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 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 is optionally substituted with at least one R 4Zc;
R 4Za and R 4Zb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl, each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 4Zd;
R 4Zc and R 4Zd are each independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1-C 8alkoxy, -C 2-C 8alkenyl, -C 2-C 8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl, or 5-to 12-membered heteroaryl.
Aspect 34. The compound of aspect 20, wherein R 4z is selected from H, -CH 3, -C 2H 5, F, -CH 2F, -CHF 2, -CF 3, -OCH 3, -OC 2H 5, -C 3H 7, -OCH 2F, -OCHF 2, -OCH 2CF 3, -OCF 3, -SCF 3, -CF 3, -CH (OH) CH 3, 
Figure PCTCN2022100017-appb-000055
Figure PCTCN2022100017-appb-000056
Aspect 35. The compound of any one of aspects 1-19, wherein Warhead is
Figure PCTCN2022100017-appb-000057
wherein
Figure PCTCN2022100017-appb-000058
is a 5-or 6-membered aromatic ring comprising 0-3 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 1-8alkyl, -C 1- 8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 10a, -SO 2R 10a, -COR 10a, -CO 2R 10a, -CONR 10aR 10b, -C (=NR 10a) NR 10bR 10c, -NR 10aR 10b, -NR 10aCOR 10b, -NR 10aCONR 10bR 10c, -NR 10aCO 2R 10b, -NR 10aSONR 10bR 10c, -NR 10aSO 2NR 10bR 10c, or –NR 10aSO 2R 10b, each of said -C 1-8alkyl, -C 2- 8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 109 is 5-or 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur; said aromatic ring is optionally substituted with halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 1-8alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 10a, -SO 2R 10a, -COR 10a, -CO 2R 10a, -CONR 10aR 10b, -C (=NR 10a) NR 10bR 10c, -NR 10aR 10b, -NR 10aCOR 10b, -NR 10aCONR 10bR 10c, -NR 10aCO 2R 10b, -NR 10aSONR 10bR 10c, -NR 10aSO 2NR 10bR 10c, or –NR 10aSO 2R 10b, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2- 8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, 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 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
Aspect 36. The compound of aspect 35, wherein
Figure PCTCN2022100017-appb-000059
is
Figure PCTCN2022100017-appb-000060
Figure PCTCN2022100017-appb-000061
wherein Z 8, Z 9, Z 10 and Z 11 are each independently selected from CH or N; wherein *cy1 refers to the position attached to the
Figure PCTCN2022100017-appb-000062
moiety, and **cy1 refers to the position attached to L 1.
Aspect 37. The compound of aspect 35, wherein
Figure PCTCN2022100017-appb-000063
is selected from
Figure PCTCN2022100017-appb-000064
Figure PCTCN2022100017-appb-000065
Aspect 38. The compound of aspect 35, wherein p3 is 0, 1, or 2, and each R 107 is independently selected from halogen, -C 1-8alkyl, or -C 1-8alkoxy, preferably F, Cl, Br, I, CH 3, or -OCH 3.
Aspect 39. The compound of aspect 35, wherein R 10a and R 10b are independently selected from hydrogen or CH 3; and n1 is 1 or 2.
Aspect 40. The compound of aspect 35, wherein R 101 is methyl, -CH 2OH, -OCH 3, -CH 2OCH 3 or halogen; p1 is 0 or 1, and R 102 is halogen.
Aspect 41. The compound of aspect 35, wherein R 103 and R 105 are hydrogen; and R 104 is selected from hydrogen or methyl.
Aspect 42. The compound of aspect 35, wherein R 109 is
Figure PCTCN2022100017-appb-000066
Y 101, Y 102, Y 103 and Y 104 are selected from CH, O, S or N; R 111 is selected from hydrogen, halogen, -C 1-8alkyl, -C 1-8alkoxy, -C 2- 8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 10a, -SO 2R 10a, -COR 10a, -CO 2R 10a, -CONR 10aR 10b, -C (=NR 10a) NR 10bR 10c, -NR 10aR 10b, -NR 10aCOR 10b, -NR 10aCONR 10bR 10c, -NR 10aCO 2R 10b, -NR 10aSONR 10bR 10c, -NR 10aSO 2NR 10bR 10c, or –NR 10aSO 2R 10b, each of said -C 1-8alkyl, -C 2- 8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 10a, R 10b, and R 10c are each independently hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and p6 is 0, 1, 2, 3 or 4.
Aspect 43. The compound of aspect 35, wherein Y 101 is CH, S, N or O; Y 102 is CH, O or N; Y 103 is O, S or N; and Y 104 is S, CH or N.
Aspect 44. The compound of any one of aspects 1-19, wherein Warhead is
Figure PCTCN2022100017-appb-000067
ring A 201 and B 201 are each independently an aromatic ring comprising 0-3 heteroatoms selected from nitrogen, sulfur and oxygen as ring member (s) ;
Z 201, Z 203 and Z 204 are each independently N or CR 20z;
L 201 is independently a bond, -C 1-8alkylene-, -N (R 204) -, -O-, -S-,  *L201-C 1-8alkylene-O- **L201,  *L201-O-C 1-8alkylene- **L201,  *L201-N (R 204) CO- **L201,  *L201-CON (R 204) - **L201,  *L201-N (R 204) CO-C 1-8alkylene- **L201,  *L201-CON (R 204) -C 1-8alkylene- **L201,  *L201-N (R 204) -C 1-8alkylene- **L201,  *L201-C 1-8alkylene-N (R 204) - **L201, -heterocyclene-, or -heteroarylene-, wherein each of said -C 1-8alkylene-,  *L201-C 1-8alkylene-O- **L201,  *L201-O-C 1-8alkylene- **L201,  *L201-N (R 204) CO-C 1-8alkylene- **L201,  *L201-CON (R 204) -C 1-8alkylene- **L201,  *L201-N (R 204) -C 1-8alkylene- **L201,  *L201-C 1-8alkylene-N (R 204) - **L201, -heterocyclene-and -heteroarylene-is optionally substituted with at least one substituent R 20L;
wherein * L201 refers to the position attached to ring A, and ** L201 refers to the position attached 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 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 20L, R 203, R 205 and R 206 are each independently hydrogen, halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2- 8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 20a, -SO 2R 20a, -COR 20a, -CO 2R 20a, -CONR 20aR 20b, -C (=NR 20a) NR 20bR 20c, -NR 20aR 20b, -NR 20aCOR 20b, -NR 20aCONR 20bR 20c, -NR 20aCO 2R 20b, -NR 20aSONR 20bR 20c, -NR 20aSO 2NR 20bR 20c, or –NR 20aSO 2R 20b, wherein each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one halogen, hydroxy, -C 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 20z is selected from hydrogen, halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 20a, -SO 2R 20a, -COR 20a, -CO 2R 20a, -CONR 20aR 20b, -C (=NR 20a) NR 20bR 20c, -NR 20aR 20b, -NR 20aCOR 20b, -NR 20aCONR 20bR 20c, -NR 20aCO 2R 20b, -NR 20aSONR 20bR 20c, -NR 20aSO 2NR 20bR 20c, or –NR 20aSO 2R 20b, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one halogen, hydroxy, -C 1-8alkyl, -C 1- 8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 20a, R 20b, and R 20c are each independently hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
or two R 20L, together with the atom (s) to which they are attached, form a 3-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent  independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2, -OR 203f, -SO 2R 203f, -SO 2NR 203fR 203g, -COR 203f, -CO 2R 203f, -CONR 203fR 203g, -C (=NR 203f) NR 203gR 203h, -NR 203fR 203g, -NR 203fCOR 203g, -NR 203fCONR 203gR 203h, -NR 203fCO 2R 203f, -NR 203fSONR 203fR 203g, -NR 203fSO 2NR 203gR 203h, or –NR 203fSO 2R 203g, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2- 8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, -C 1-8alkyl, -OR 203i, -NR 203iR 203j, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
or two R 203, together with the atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2, -OR 203f, -SO 2R 203f, -SO 2NR 203fR 203g, -COR 203f, -CO 2R 203f, -CONR 203fR 203g, -C (=NR 203f) NR 203gR 203h, -NR 203fR 203g, -NR 203fCOR 203g, -NR 203fCONR 203gR 203h, -NR 203fCO 2R 203f, -NR 203fSONR 203fR 203g, -NR 203fSO 2NR 203gR 203h, or –NR 203fSO 2R 203g, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2- 8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, -C 1-8alkyl, -OR 203i, -NR 203iR 203j, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
or R 4 and one of R 3, together with the atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2, -OR 203f, -SO 2R 203f, -SO 2NR 203fR 203g, -COR 203f, -CO 2R 203f, -CONR 203fR 203g, -C (=NR 203f) NR 203gR 203h, -NR 203fR 203g, -NR 203fCOR 203g, -NR 203fCONR 203gR 203h, -NR 203fCO 2R 203f, -NR 203fSONR 203fR 203g, -NR 203fSO 2NR 203gR 203h, or –NR 203fSO 2R 203g, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, -C 1-8alkyl, -OR 203i, -NR 203iR 203j, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 203f, R 203g, R 203h, R 203i, and R 203j are each independently hydrogen, -C 1-8alkyl, C 1-8alkoxy-C 1-8alkyl-, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
Aspect 45. The compound according to any one of Aspects 44, wherein L 201 is a bond, -CH 2-, -C 2H 4-, -C 3H 6-, -C 4H 8-, -C 5H 10-, -O-, -NH-,  *L201-NHCH 2- **L201,  *L201-NHC 2H 4- **L201,  *L201-NHC 3H 6- **L201,  *L201-NHC 4H 8- **L201,  *L201-NHC 5H 10- **L201,  *L201-OCH 2- **L201,  *L201-OC 2H 4- **L201,  *L201-OC 3H 6- **L201,  *L201-OC 4H 8- **L201,  *L201-OC 5H 10- **L201,  *L201-CH 2O- **L201,  *L201-C 2H 4O- **L201,  *L201-C 3H 6O- **L201,  *L201-C 4H 8O- **L201,  *L201-C 5H 10O- **L201,  *L201-CONH- **L201,  *L201-NHCO- **L201,  *L201-CONHCH 2- **L201,  *L201-CONHC 2H 4- **L201,  *L201-CONHC 3H 6- **L201,  *L201-CONHC 4H 8- **L201,  *L201-CONHC 5H 10- **L201, 3-to 8-membered -heterocyclene-or 5-to 6-membered -heteroarylene-; wherein each of said -CH 2-, -C 2H 4-, -C 3H 6-, -C 4H 8-, -C 5H 10-, -O-, -NH-,  *L201-NHCH 2- **L201,  *L201-NHC 2H 4- **L201,  *L201-NHC 3H 6- **L201,  *L201-NHC 4H 8- **L201,  *L201-NHC 5H 10- **L201,  *L201-OCH 2- **L201,  *L201-OC 2H 4- **L201,  *L201-OC 3H 6- **L201,  *L201-OC 4H 8- **L201,  *L201-OC 5H 10- **L201,  *L201-CH 2O- **L201,  *L201-C 2H 4O- **L201,  *L201-C 3H 6O- **L201,  *L201-C 4H 8O- **L201,  *L201-C 5H 10O- **L201,  *L201-CONH- **L201,  *L201-NHCO- **L201,  *L201-CONHCH 2- **L201,  *L201-CONHC 2H 4- **L201,  *L201-CONHC 3H 6- **L201,  *L201-CONHC 4H 8- **L201,  *L201-CONHC 5H 10- **L201, 3-to 8-membered heterocyclene-and 5-to 6-membered heteroarylene-is optionally substituted with at least one substituent R 20L; wherein R 20L is defined as above.
Aspect 46. The compound according to Aspect 44, wherein L 201 is a bond, -O-,  *L201-OCH 2- **L201,  *L201-CH 2O- **L201, -NH-,  *L201-CONH- **L201,  *L201-NHCO- **L201,  *L201-CONHCH 2- **L201,  *L201-CONHCH 2CH 2- **L201,  *L201-CONHCH 2CH 2CH 2- **L201,  *L201-CONHCH (CH 3) - **L201,  *L201-CONHCH (C 2H 5) - **L201,  *L201-NHCH 2- **L201,  *L201-NHCH 2CH 2- **L201,  *L201-NHCH 2CH 2CH 2- **L201,  *L201-NHCH (CH 3) - **L201 or  *L-NHCH (C 2H 5) - **L.
Aspect 47. The compound according to Aspect 44, wherein L 201 is  *L201-N (R 204) CO- **L201, R 203 and R 204, together with the atoms to which they are attached, form a 5-, 6-or 7-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, cycloalkyl, heterocyclyl, aryl, heteroaryl, or oxo.
Aspect 48. The compound according to Aspect 44, wherein
Figure PCTCN2022100017-appb-000068
moiety is 
Figure PCTCN2022100017-appb-000069
Figure PCTCN2022100017-appb-000070
wherein Z 205, Z 206, Z 207, Z 208, Z 209, Z 206’, Z 207’, Z 208’ and Z 209’ are each independently N or C (H) ; Z 210 is N (H) , O or S.
Aspect 49. The compound according to Aspect 44, wherein ring A201 is a 5-to 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, sulfur and oxygen as ring member (s) .
Aspect 50. The compound according to Aspect 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.
Aspect 51. The compound according to Aspect 44, wherein the
Figure PCTCN2022100017-appb-000071
moiety is
Figure PCTCN2022100017-appb-000072
Aspect 52. The compound according to Aspect 44, wherein R 203 is hydrogen, oxo, -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9, -OC 5H 11, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyrrolyl or phenyl, wherein each of said -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9, -OC 5H 11, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyrrolyl or phenyl, is optionally substituted with at least one -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9, -OC 5H 11, -OH, cyclopropyl, cyclobutyl or cyclopentyl.
Aspect 53. The compound according to Aspect 44, wherein 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.
Aspect 54. The compound according to Aspect 44, wherein two R 203, together with the atoms to which they are attached, form a 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9, -OC 5H 11, -OH, -CN, cyclopropyl, cyclobutyl or cyclopentyl.
Aspect 55. The compound according to Aspect 44, wherein the
Figure PCTCN2022100017-appb-000073
moiety is
Figure PCTCN2022100017-appb-000074
Figure PCTCN2022100017-appb-000075
Figure PCTCN2022100017-appb-000076
Aspect 56. The compound according to Aspect 44, wherein the
Figure PCTCN2022100017-appb-000077
moiety is 
Figure PCTCN2022100017-appb-000078
wherein Z 205, Z 206, Z 207 and Z 208 are defined as above.
Aspect 57. The compound according to Aspect 44, wherein the
Figure PCTCN2022100017-appb-000079
moiety is
Figure PCTCN2022100017-appb-000080
Aspect 58. The compound according to Aspect 44, wherein 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 substituted with (R 206)  q201.
Aspect 59. The compound according to Aspect 44, wherein R 206 is hydrogen, -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -CN, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9 or -OC 5H 11, wherein each of said -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9 or -OC 5H 11 is optionally substituted with -F, -Cl, -Br, -I, hydroxy, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
Aspect 60. The compound according to Aspect 44, wherein the
Figure PCTCN2022100017-appb-000081
moiety is
Figure PCTCN2022100017-appb-000082
Aspect 61. The compound according to Aspect 44, wherein R 201 and R 202 are each independently hydrogen, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -C 2-8alkenyl, -C 2-8alkynyl or aryl.
Aspect 62. The compound according to Aspect 44, wherein R 201 and R 202 are both H.
Aspect 63. The compound according to Aspect 44, wherein R 205 is independently hydrogen, -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -C 2-8alkenyl, -C 2-8alkynyl or aryl.
Aspect 64. The compound according to Aspect 44, wherein R 20z is hydrogen, -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9 or -C 5H 11.
Aspect 65. The compound according to any one of Aspects 44 to 64, wherein the 
Figure PCTCN2022100017-appb-000083
moiety is
Figure PCTCN2022100017-appb-000084
Figure PCTCN2022100017-appb-000085
Figure PCTCN2022100017-appb-000086
Figure PCTCN2022100017-appb-000087
Aspect 66. The compound of any one of aspects 1-19, wherein Warhead is
Figure PCTCN2022100017-appb-000088
wherein:
Cy302 is a 5-or 6-membered saturated ring or unsaturated ring (preferably aromatic ring) comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member (s) ;
each of occurrence, R 301, R 302, R 303, R 304 and R 308 are each independently hydrogen, halogen, -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O) , -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 306 and R 307 are each independently hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 305 is 5-or 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member (s) ; said aromatic ring is optionally substituted with halogen, -C 1-8alkyl, -C 2- 8alkenyl, -C 2-8alkynyl, -C 1-8alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said -C 1-8alkyl, -C 2- 8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with -C 1-8alkyl, halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, 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 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
(R 30c and R 30d) or (R 30d and R 30e) together with the atom (s) to which they are attached, form a 3-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2.
Aspect 67. The compound of Aspect 66, wherein
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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, - NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, -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 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2.
Aspect 68. The compound of any aspect of Aspects 66-67, wherein 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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO 2; preferably R1 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl.
Aspect 69. The compound of any aspect of Aspects 66-68, wherein
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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, -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 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2.
Aspect 70. The compound of any aspect of Aspects 66-69, wherein 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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO 2; preferably R 302 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN or -NO 2.
Aspect 71. The compound of any aspect of Aspects 66-70, wherein
R 303 and R 304 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8alkenyl, -C 2- 8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, -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 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2.
Aspect 72. The compound of any aspect of Aspects 66-71, wherein 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 are each independently hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl or cyclopentyl.
Aspect 73. The compound of any aspect of Aspects 66-72, wherein the
Figure PCTCN2022100017-appb-000089
moiety is
Figure PCTCN2022100017-appb-000090
wherein *303 refers to the position attached to the
Figure PCTCN2022100017-appb-000091
moiety, and **303 refers to the position attached to
Figure PCTCN2022100017-appb-000092
moiety.
Aspect 74. The compound of any aspect of Aspects 66-73, wherein R 306 and R 307 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; preferably, R 306 and R 307 are each independently H, methyl, ethyl, propyl butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Aspect 75. The compound of any aspect of Aspects 66-74, wherein R 305 is
Figure PCTCN2022100017-appb-000093
Y 301, Y 302, Y 303 and Y 304 are each independently selected from CH, O, S or N; R 315 is each independently selected from hydrogen, halogen, -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 30c, R 30d, and R 30e are each independently defined as in aspect 66; and p307 is 0, 1, 2, 3 or 4.
Aspect 76. The compound of Aspect 75, wherein Y 301 is CH, S, N or O; Y 302 is CH, S, O or N; Y 303 is CH, O, S or N; and Y 304 is CH, O, S or N.
Aspect 77. The compound of Aspect 75, wherein
Figure PCTCN2022100017-appb-000094
is selected from
Figure PCTCN2022100017-appb-000095
Figure PCTCN2022100017-appb-000096
Aspect 78. The compound according to Aspect 75, wherein, R 315 is selected from -H, -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -C 6H 13, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8alkenyl, -C 2-8alkynyl, -CH 2OH, -CH 2CH 2OH, -CH (OH) CH 3, -CH 2CH 2CH 2OH, -CH (OH) CH 2CH 3, -CH 2CH (OH) CH 3, -CH 2OCH 3, -CFH 2, -CF 2H, -CF 3, -CH 2CF 3, -CH 2CH 2CF 3, each of said -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -C 6H 13, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8alkenyl, -C 2-8alkynyl is optionally substituted with at least one F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
Aspect 79. The compound according to Aspect 75, wherein, R 315 is selected from
Figure PCTCN2022100017-appb-000097
Figure PCTCN2022100017-appb-000098
Aspect 80. The compound of any aspect of Aspects 66-79, wherein the
Figure PCTCN2022100017-appb-000099
moiety is
Figure PCTCN2022100017-appb-000100
Aspect 81. The compound of any aspect of Aspects 66-80, wherein Cy302 is a 5-or 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member (s) .
Aspect 82. The compound of any aspect of Aspects 66-81, wherein
Figure PCTCN2022100017-appb-000101
is
Figure PCTCN2022100017-appb-000102
Y 301, Y 302, Y 303 and Y 304 are each independently defined as in aspect 66;
wherein *Cy302 refers to the position attached to -N (R 307) -in the
Figure PCTCN2022100017-appb-000103
moiety, and **Cy302 refers to the position attached to
Figure PCTCN2022100017-appb-000104
moiety.
Aspect 83. The compound of any aspect of Aspects 66-82, wherein
Figure PCTCN2022100017-appb-000105
is
Figure PCTCN2022100017-appb-000106
Figure PCTCN2022100017-appb-000107
Aspect 84. The compound of any aspect of Aspects 66-83, wherein
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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, -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 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2.
Aspect 85. The compound of any aspect of Aspects 66-84, wherein 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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO 2; preferably R 308 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN or -NO 2.
Aspect 86. The compound of any aspect of Aspects 66-85, wherein
Figure PCTCN2022100017-appb-000108
is
Figure PCTCN2022100017-appb-000109
Aspect 87. The compound of any aspect of Aspects 66-85, wherein the
Figure PCTCN2022100017-appb-000110
moiety is selected from
Figure PCTCN2022100017-appb-000111
Figure PCTCN2022100017-appb-000112
Figure PCTCN2022100017-appb-000113
Aspect 88. A pharmaceutical composition comprising a compound of any one of Aspects 1-87 or a pharmaceutically acceptable salt, tautomer or prodrug thereof, together with a pharmaceutically acceptable excipient.
Aspect 89. A method of treating a disease that can be treated by degrading the target protein that the Warhead can combine by using a compound of any one of Aspects 1-87 .
Aspect 90. The method of aspect 89, wherein said target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism) , antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate) , receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, 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, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity and translation regulator activity.
Aspect 91. The method of aspect 89, wherein Warhead is a moiety which binds to a target protein, wherein said target protein is selected from the group consisting of ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apotosis 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 (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug 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-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) ,  protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7) , farnesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channels, Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor associated kinase-3 (IRAK-3 or IRAK-M) or enolpyruvyl-shikimate-phosphate synthase.
Aspect 92. The method of Aspect 89, wherein the disease is a cancer.
Aspect 93. A compound of Formula (I) :
Figure PCTCN2022100017-appb-000114
or a pharmaceutically acceptable salt thereof, or a deuterated analog thereof, or a prodrug thereof, wherein:
Warhead, Linker, s2, Z 1, Z 2, Z 3, R 1 and R 2 are defined as in any preceding aspects;
s1 is 0.
Aspect 94. A method of binding and altering the specificity of cereblon complex to induce the degradation of a complex-associated protein by using the compound of Claim 93, wherein the protein is selected from ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apotosis 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 (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug 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-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) , protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1,  P2Y2, P2Y4, P2Y6, P2X 1-7) , farnesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channels, Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor associated kinase-3 (IRAK-3 or IRAK-M) , enolpyruvyl-shikimate-phosphate synthase or neo-substrates (like IKZF1, IKZF3, and CK1a) .
Aspect 95. A method of treating an CRBN-mediated disorder, disease, or condition in a patient comprising administering to said patient the pharmaceutical composition of claim 93, preferably, the disorder disease, or condition is selected from proliferative disorders, neurological disorders and disorder associated with transplantation.
In one of another aspects, the compound is selected from
Figure PCTCN2022100017-appb-000115
Figure PCTCN2022100017-appb-000116
Figure PCTCN2022100017-appb-000117
Figure PCTCN2022100017-appb-000118
DETAILED DESCRIPTION OF THE INVENTION
The following terms have the indicated meanings throughout the specification:
Unless specifically defined elsewhere in this document, 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.
The following terms have the indicated meanings throughout the specification:
As used herein, including the appended Aspects, the singular forms of words such as "a" , "an" , and "the" , include their corresponding plural references unless the context clearly indicates otherwise.
The term "or" is used to mean, and is used interchangeably with, the term “and/or” unless the context clearly dictates otherwise.
The term “subject” used herein refers to mammal and human, preferably human.
The term "alkyl" includes a hydrocarbon group selected from linear and branched, saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms. Examples of alkyl groups comprising from 1 to 6 carbon atoms (i.e., C 1-6 alkyl) include, but 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, 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.
The term “propyl” includes 1-propyl or n-propyl ( "n-Pr" ) , 2-propyl or isopropyl ( "i-Pr" ) .
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" ) , 1, 1-dimethylethyl or t-butyl ( "t-Bu" ) .
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.
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.
The term “alkylene” refers to a divalent alkyl group by removing two hydrogen from alkane. Alkylene includes but not limited to methylene, ethylene, propylene, and so on.
The term "halogen” includes fluoro (F) , chloro (Cl) , bromo (Br) and iodo (I) .
The term "alkenyl" includes a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one C=C double bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkenyl group, e.g., C 2-6 alkenyl, include, but not limited to ethenyl or vinyl, 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 hexa-1, 3-dienyl groups.
The term “alkenylene” refers to a divalent alkenyl group by removing two hydrogen from alkene. Alkenylene includes but not limited to, vinylidene, butenylene, and so on.
The term "alkynyl" includes a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C≡C triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkynyl group, e.g., C 2-6 alkynyl, include, but not limited to ethynyl, 1-propynyl, 2-propynyl (propargyl) , 1-butynyl, 2-butynyl, and 3-butynyl groups.
The term “alkynylene” refers to a divalent alkynyl group by removing two hydrogen from alkyne. Alkenylene includes but not limited to ethynylene and so on.
The term "cycloalkyl" includes a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl.
For example, the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, examples of the saturated monocyclic cycloalkyl group, e.g., C 3- 8cycloalkyl, include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C 3-6 cycloalkyl) , including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the bicyclic cycloalkyl groups include those having from 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 the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5, 6] and [6, 6] ring systems.
The term "spiro cycloalkyl" includes a cyclic structure which contains carbon atoms and is formed by at least two rings sharing one atom.
The term "fused cycloalkyl" includes a bicyclic cycloalkyl group as defined herein which is saturated and is formed by two or more rings sharing two adjacent atoms.
The term "bridged cycloalkyl" includes a cyclic structure which contains carbon atoms and is formed by two rings sharing two atoms which are not adjacent to each other. The term "7 to 10 membered  bridged cycloalkyl" includes a cyclic structure which contains 7 to 12 carbon atoms and is formed by two rings sharing two atoms which are not adjacent to each other.
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, as well as benzo 3 to 8 membered cycloalkyl, benzo C 4- 6 cycloalkenyl, 2, 3-dihydro-1H-indenyl, 1H-indenyl, 1, 2, 3, 4-tetralyl, 1, 4-dihydronaphthyl, etc. Preferred embodiments are 8 to 9 membered fused rings, which refer to cyclic structures containing 8 to 9 ring atoms within the above examples.
The term "aryl" used alone or in combination with other terms includes a group selected from:
5-and 6-membered carbocyclic aromatic rings, e.g., phenyl;
bicyclic ring systems such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and,
tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, e.g., fluorenyl.
The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl) . Examples of a monocyclic or bicyclic aromatic hydrocarbon ring includes, but 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 phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.
Specifically, the term "bicyclic fused aryl" includes a bicyclic aryl ring as defined herein. The typical bicyclic fused aryl is naphthalene.
The term "heteroaryl" includes a group selected from:
5-, 6-or 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N) , sulfur (S) and oxygen (O) , with the remaining ring atoms being carbon;
7-to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and
11-to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.
When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring (s) of the heteroaryl group can be oxidized to form N-oxides.
Specifically, the term "bicyclic fused heteroaryl" includes a 7-to 12-membered, preferably 7-to 10-membered, more preferably 9-or 10-membered fused bicyclic heteroaryl ring as defined herein. Typically, a bicyclic fused heteroaryl is 5-membered/5-membered, 5-membered/6-membered, 6-membered/6-membered, or 6-membered/7-membered bicyclic. The group can be attached to the remainder of the molecule through either ring.
"Heterocyclyl" , "heterocycle" or "heterocyclic" are interchangeable and include a non-aromatic heterocyclyl group comprising 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 ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.
The term H or hydrogen disclosed herein includes Hydrogen and the non-radioisotope deuterium.
The term "at least one substituent" disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents, provided that the theory of valence is met. For example, "at least one substituent F" disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents F.
The term “divalent” refers to a linking group capable of forming covalent bonds with two other moieties. For example, “a divalent cycloalkyl group” refers to a cycloalkyl group obtained by removing two hydrogen from the corresponding cycloalkane to form a linking group. the term “divalent aryl group” , “divalent heterocyclyl group” or “divalent heteroaryl group” should be understood in a similar manner.
Compounds disclosed herein may contain an asymmetric center and may thus exist as enantiomers. “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.
When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are meant to include both E and Z geometric isomers.
When compounds disclosed herein contain a di-substituted cyclic ring system, substituents found on such ring system may adopt cis and trans formations. Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides. For example, the di-substituted cyclic ring system may be cyclohexyl or cyclobutyl ring.
It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for  example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium 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 techniques of small scale thin layer and flash chromatography. One skilled in the art could select and apply the techniques most likely to achieve the desired separation.
“Diastereomers” refer to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.
A single stereoisomer, e.g., a substantially pure enantiomer, may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers 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 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 reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
Some of the compounds disclosed herein may exist with different points of attachment of hydrogen, referred to as tautomers. For example, compounds including carbonyl -CH 2C (O) -groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C (OH) -groups (enol forms) . Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.
“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 an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
“deuterated analog” refers to a derivative of an active agent that an arbitrary hydrogen is substituted with deuterium. In some embodiments, the deuterated site is on the Warhead moiety. In some embodiments, the deuterated site is on the Linker moiety. In some embodiments, the deuterated site is on the Degron moiety.
"Pharmaceutically acceptable salts" refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A pharmaceutically acceptable salt may be prepared in situ during the final isolation and  purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base. The term also includes salts of the stereoisomers (such as enantiomers and/or diastereomers) , tautomers and prodrugs of the compound of the invention.
In addition, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.
The terms “administration” , “administering” , “treating” and “treatment” herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell. The term “administration” and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.
The term "effective amount" or “therapeutically effective amount” refers to an amount of the active ingredient, such as compound that, when administered to a subject for treating 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 symptom. The term “therapeutically effective amount” can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, 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. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments. In some embodiments, “therapeutically effective amount” is an amount of at least one compound and/or at least one stereoisomer, tautomer or prodrug thereof, and/or at least one pharmaceutically acceptable salt thereof disclosed herein effective to “treat” as defined herein, a disease or disorder in a subject. In the case of combination therapy, the term “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
The term “disease” refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition” .
Throughout this specification and the Aspects which follow, unless the context requires otherwise, the term "comprise" , and variations such as "comprises" and "comprising" are intended to specify the presence of the features thereafter, but do not exclude the presence or addition of one or more other features. When used herein the term "comprising" can be substituted with the term "containing" , "including" or sometimes "having" .
Throughout this specification and the Aspects which follow, the term “C n-m” or “C n-C m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-8, C 1-6, C 1-C 8, C 1-C 6, and the like.
Unless specifically defined elsewhere in this document, 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
The examples below are intended to be purely exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc. ) , but some experimental errors and deviations should be accounted for. Unless indicated otherwise, temperature is in degrees Centigrade. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless indicated otherwise. Unless indicated otherwise, the reactions set forth below were performed under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents; the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven dried and/or heat dried.
1H NMR spectra were recorded on an Agilent instrument operating at 400 MHz.  1HNMR
spectra were obtained using CDCl 3, CD 2Cl 2, CD 3OD, D 2O, d 6-DMSO, d 6-acetone or (CD 3)  2CO as solvent and tetramethylsilane (0.00 ppm) or residual solvent (CDCl 3: 7.25 ppm; CD 3OD: 3.31 ppm; D 2O: 4.79 ppm; d 6-DMSO: 2.50 ppm; d 6 -acetone: 2.05; (CD 3)  3CO: 2.05) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet) , d (doublet) , t (triplet) , q (quartet) , qn (quintuplet) , sx (sextuplet) , m (multiplet) , br (broadened) , dd (doublet of doublets) , dt (doublet of triplets) . Coupling constants, when given, are reported in Hertz (Hz) .
LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190-400 nm) , Mass detector: 6120 SQ Mobile phase: A: water with 0.1%Formic acid, B: acetonitrile with 0.1%Formic acid Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7pm Gradient method: Flow: 1.8 mL/min Time (min) A (%) B (%)
Time (min) A (%) B (%)
0.00 95 5
1.5 5 95
2.0 5 95
2.1 95 5
3.0 95 5
LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190-400 nm) , Mass detector: G6125C SQ Mobile phase: A: water with 0.1%Formic acid, B: acetonitrile with 0.1%Formic acid Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7pm Gradient method: Flow: 1.8 mL/min Time (min) A (%) B (%)
Time (min) A (%) B (%)
0.00 95 5
1.5 5 95
2.0 5 95
2.1 95 5
3.0 95 5
LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II) Detector: MWD (190-400 nm) , Mass detector: G6125C SQ Mobile phase: A: water with 0.1%Formic acid, B: acetonitrile with 0.1%Formic acid Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7pm Gradient method: Flow: 1.2 mL/min Time (min) A (%) B (%)
Time (min) A (%) B (%)
0.00 90 10
1.5 5 95
2.0 5 95
2.1 90 10
3.0 90 10
Preparative HPLC was conducted on a column (150 x 21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml/min, injection volume 2 ml, at room temperature and UV Detection at 214 nm and 254 nm. 
In the following examples, the abbreviations below are used:
Figure PCTCN2022100017-appb-000119
Figure PCTCN2022100017-appb-000120
Figure PCTCN2022100017-appb-000121
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
Figure PCTCN2022100017-appb-000122
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 in 20 min at -65 ℃, the reaction solution was stirred for 1 hour at this temperature, then to this was added ethyl 3-bromopropanoate (9.4 g, 51.7 mmol) in THF (30 mL) dropwise in 10 min. The resulting solution was stirred for 30 min at -65 ℃, then the temperature was allowed to rise to room temperature naturally. The reaction was quenched by the addition of sat. aq. NH 4Cl (50 mL) , and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL x  3) , the organic layers were combined and washed with brine, and dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure to afford the product (13.8 g, 96.5%) . [M+H]  + = 332.0.
Step 2: 4- (4-bromo-2, 6-difluorophenyl) -4-cyanobutanoic acid
Figure PCTCN2022100017-appb-000123
To a solution of ethyl 4- (4-bromo-2, 6-difluorophenyl) -4-cyanobutanoate (13.5 g, 40.7 mmol) in THF/H 2O (90 mL/30 mL) was added LiOH (2.9 g, 0.122 mol) . The reaction mixture was stirred for 12 h at room temperature. 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) , dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure to afford the product (10.2 g, 82.5%) . [M+H]  + = 304.2.
Step 3: 3- (4-bromo-2, 6-difluorophenyl) piperidine-2, 6-dione
Figure PCTCN2022100017-appb-000124
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 conc. H 2SO 4 (2 mL, 36.9 mmol) . The resulting solution was stirred at 100 ℃for 3 h. The reaction mixture was concentrated under vacuum, then the mixture was poured into water. The pH value was adjusted to 7-8 with sat. aq. NaHCO 3, and then the mixture was extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with water (50 mL) and brine (50 mL) , dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure to afford the product (8.2 g, 80.4%) . [M+H]  + = 304.3.
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
Figure PCTCN2022100017-appb-000125
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/H 2O (100 mL/20 mL) were added Pd (dtbpf) Cl 2 (883 mg, 1.35 mmol) and CsF (8.2 g, 54.0 mmol) . The resulting mixture was stirred for 2 h at 80 ℃ under nitrogen atmosphere. The reaction solution was diluted with water (400 mL) , and extracted with EtOAc (100 mL x 2) . The combined organic layers were washed with water (100 mL) and brine (100 mL) , dried over anhydrous Na 2SO 4, filtered and concentrated under reduced pressure. The residue was purified by SFC ( (IH (3*25cm, 5um) , 13%EtOH/87%CO 2, 100 bar, 100 ml/min) to afford (S, E) -3- (4- (2-ethoxyvinyl) -2, 6-difluorophenyl) piperidine-2, 6-dione corresponded 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 corresponded 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 had the same  1H NMR and LCMS data.  1H 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.
Example 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
Figure PCTCN2022100017-appb-000126
To the 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 K 3PO 4 (20 g, 94 mmol) in 250 mL DMSO, CuI (893 mg, 4.7 mmol) and L-Proline (1 g, 9.4 mmol) was added. The mixture was stirred at 80 ℃ for 16 hours. After LCMS showed the reaction was completed, the mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL x 3) . The combined organic layers were washed with brine and separated. The organic phase was concentrated and purified by silica column chromatography (PE: EA=50: 1-30: 1) to afford the product (4.9 g, 32.5%) . [M+H]  + = 320.1.
Step 2: methyl (R) -1- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) -3, 5-difluorophenyl) pyrrolidine-3-carboxylate
Figure PCTCN2022100017-appb-000127
To the 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 DMF and 15 mL water, Pd (dtbpf) Cl 2 (498 mg, 0.8 mmol) was added. The mixture was stirred at 80 ℃ for 4 hours. After LCMS showed the reaction was completed, 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 combi-flash (EA: PE=1: 10) to afford the product (7.9 g, 97.4%) . [M+H]  + = 531.3.
Step 3: (R) -1- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) -3, 5-difluorophenyl) pyrrolidine-3-carboxylic acid
Figure PCTCN2022100017-appb-000128
To the 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 completed, the mixture was concentrated in vacuum at room temperature. The residue was diluted with water and adjust to pH < 5 with 1 N HCl aqueous. The liquid was extracted with EtOAc and separated. The organic phase was dried with Na 2SO 4 and concentrated in vacuum to afford the product (7.4 g, 96.0%) . [M+H]  + = 517.2.
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)
Figure PCTCN2022100017-appb-000129
To the 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, Pd/C (7.4 g, 10%) was added. The mixture was stirred at 40 ℃ for 16 hours under hydrogen atmosphere (balloon) . After LCMS showed the reaction was completed, the mixture was cooled to room temperature and filtered by celite directly. The filtrate was concentrated in vacuum to afford the crude product which was purified by SFC ( (IH (3*25cm, 5um) , 13%EtOH/87%CO 2, 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%)  1H 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. and (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.
Example 7: (R) -3- (2, 6-difluoro-4- ( (R) -3- (hydroxymethyl) pyrrolidin-1-yl) phenyl) piperidine-2, 6-dione
Figure PCTCN2022100017-appb-000130
The title compound was prepared in a procedure similar to 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%CO 2, 100 bar, 100 ml/min) and corresponded to peak A @2.028 min/254 nm (230 mg, 31%) .  1H 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.
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
Figure PCTCN2022100017-appb-000131
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 LiAlH 4 (1 M in THF, 4.27 mL, 4.27 mmol) dropwise at 0 ℃. Then the mixture was stirred for 2 hours, the reaction was quenched with water (10 mL) at 0 ℃. The resulting mixture was extracted with EtOAc (3 x 50 mL) . The combined organic layers were washed with brine, dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure to afford the product (1.4 g, 87%) [M+H]  += 489.2.
Step 2: 3- (2, 6-difluoro-4- (3- (hydroxymethyl) azetidin-1-yl) phenyl) piperidine-2, 6-dione
Figure PCTCN2022100017-appb-000132
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 hours. The resulting mixture was filtered, and the solid was washed with MeOH (20 mL) . The filtrate was concentrated under reduced pressure to afford 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.
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
Figure PCTCN2022100017-appb-000133
To a stirred mixture of 2, 6-bis (benzyloxy) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (The intermediate can be prepared according to the way described in WO2017197046) (8.3 g, 20 mmol) and 4-bromoiodobenzene (5.6 g, 20 mmol) in 1, 4-dioxane (100 mL) and H 2O (10 mL) was added K 2CO 3 (5.5 g, 40 mmol) and Pd (dppf) Cl 2 (1.4 g, 2 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 80 ℃ under nitrogen atmosphere. The reaction mixture was allowed to cool down 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 Na 2SO 4,  filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA: PE=1: 10) to afford the product (4.5 g, 50%) . [M+H]  + = 446.2.
Step 2: methyl (R) -1- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) phenyl) pyrrolidine-3-carboxylate
Figure PCTCN2022100017-appb-000134
To the 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 Cs 2CO 3 (15 g, 45 mmol) in 50 mL 1, 4-dioxane, was added Pd 2 (dba)  3 (915 mg, 1 mmol) and Xantphos (1.16 g, 2 mmol) . The mixture was stirred at 80 ℃ for 16 hours under nitrogen atmosphere. After LCMS shown the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica column chromatography (EA: PE=1: 10) to afford the product (2.1 g, 42.5%) . [M+H]  + = 494.9.
Step 3: (R) -1- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) phenyl) pyrrolidine-3-carboxylic acid
Figure PCTCN2022100017-appb-000135
To the 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 THF and 10 mL water, was added LiOH·H 2O (178 mg, 4.25 mmol) in 2 mL water dropwise at room temperature. The mixture was stirred at room temperature for 15 minutes. Once the reaction was completed determined by TLC, the mixture was concentrated under reduced pressure. The residue was diluted with water and adjust to pH<5 with 1 N HCl aqueous. The liquid was extracted with EtOAc (100 mL x 3) . The combined organic layers were washed with brine (60 mL x 3) , dried over anhydrous Na 2SO 4, filtered and concentrated in vacuum to afford the product (2 g, 98%) . [M+H]  + = 481.6.
Step 4: (3R) -1- (4- (2, 6-dioxopiperidin-3-yl) phenyl) pyrrolidine-3-carboxylic acid
Figure PCTCN2022100017-appb-000136
To the 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, Pd/C (2 g, 10%) was added. The mixture was stirred at 45 ℃f or 16 hours under hydrogen atmosphere (balloon) . Once the reaction has completed determined by LCMS, the mixture was cooled to room temperature and filtered through celite directly. The solid was dispensed in DCM (5 mL) and MeOH (50 mL) , which was sonicated for 5 min. The mixture was then filtered through celite and the combined filtrate was concentrated in vacuum to afford the product (1.2 g, 95%) .  1H 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.
Example 14: (S) -1- (4- ( (R) -2, 6-dioxopiperidin-3-yl) -3, 5-difluorophenyl) -4, 4-dimethylpyrrolidine-3-carboxylic acid
Figure PCTCN2022100017-appb-000137
The title compound was prepared in a procedure similar 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%CO 2, 100 bar, 100 ml/min) and corresponded to peak A @1.165 min/254 nm (670 mg, 26%) .  1H 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.
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
Figure PCTCN2022100017-appb-000138
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) Cl 2 (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 ℃ and stirred for 2 h. The mixture was cooled to room temperature. After filtration, the filtrate was concentrated in vacuum to afford the crude product (28 g, crude) which was used directly without further purification.
[M+H]  +=249.2.
Step 2: 2- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) phenyl) ethan-1-ol
Figure PCTCN2022100017-appb-000139
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) Cl 2 (7.3 g, 10 mmol) , 2, 6-bis (benzyloxy) -3-bromopyridine (36.9 g, 100 mmol) and Cs 2CO 3 (65.2 g, 200 mmol) in 1, 4-dioxane (300 mL) and water (30 mL) was stirred at 100 ℃ overnight under nitrogen atmosphere. The reaction was cooled down to room temperature, the solids were filtered out, the filtrate was concentrated and purified with silica gel column (eluted with EtOAc/Hexane=1: 2) to give the crude product which was used directly in the next step. [M+H]  +=412.2.
Step 3: 3- (4- (2-hydroxyethyl) phenyl) piperidine-2, 6-dione
Figure PCTCN2022100017-appb-000140
2- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) phenyl) ethan-1-ol (the crude from last step) was dissolved in MeOH (500 mL) , 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 out, the filtrate was concentrated in vacuum to give a crude product. The crude was triturated with MTBE (50 mL) to give desire product (13.5 g, 57.9 %yield over 3 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
Step 1: tert-butyl 4- (1- (2-bromo-5-methoxy-4-nitrophenyl) piperidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2022100017-appb-000141
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) , K 2CO 3 (4.4 g, 32mmol) in DMF (50 mL) was stirred in a flask at 80 ℃ overnight. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3 x 500 mL) . The combined organic layers were washed with brine (500 mL) , dried over anhydrous Na 2SO 4. 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 afford the product (7 g, 90%) . [M+H]  + = 499.0.
Step 2: tert-butyl 4- (1- (5-methoxy-4-nitro-2-vinylphenyl) piperidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2022100017-appb-000142
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) Cl 2 (1.1 g, 1.4 mmol) and K 3PO 4 (8.9 g, 42mmol) in DMF (160 mL) and water (20 mL) was stirred in a flask at 90 ℃ under nitrogen atmosphere for 16 hrs. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 1000 mL) . The combined organic layers were washed with brine (500 mL) , dried over anhydrous Na 2SO 4. 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 afford the product (5 g, 80%) . [M+H]  + = 447.0.
Step 3: tert-butyl 4- (1- (4-amino-2-ethyl-5-methoxyphenyl) piperidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2022100017-appb-000143
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) was added Pd/C (wet, 10%) (1 g) under nitrogen atmosphere. The resulting mixture was stirred for 16 hrs at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the solid was washed with DCM/CH 3OH (10: 1, 200 mL) . The filtrate was concentrated under reduced pressure to afford the product (4.0 g, 85.3%) . [M+H]  + = 419.1.
Step 4: (6-aminoquinoxalin-5-yl) dimethylphosphine oxide
Figure PCTCN2022100017-appb-000144
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 K 3PO 4 (28 g, 134 mmol) in DMF (250 mL) and water (50 mL) was stirred in a flask at 130 ℃ under nitrogen atmosphere for 16 hrs. The reaction mixture was allowed to cool down to room temperature. The resulting mixture was extracted with DCM (3 x 1000 mL) . The combined organic layers were washed with brine (1000 mL) , dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10: 1) to afford the product (6 g, 60%) , [M+H]  + = 222.0.
Step 5: (6- ( (5-bromo-2-chloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide
Figure PCTCN2022100017-appb-000145
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 ℃ under nitrogen atmosphere, before 54 mL KHMDS (1M in THF) was added. The reaction mixture was allowed to warm up to room temperature for 2 hours. The reaction was quenched with water and the mixture was extracted with DCM, washed three times with saturated brine, dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10: 1) to afford the product (4 g, 35%) . [M+H]  + = 412.0.
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
Figure PCTCN2022100017-appb-000146
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 ℃ under nitrogen atmosphere for overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH=10: 1) to afford the product (2 g, 60%) . [M+H]  + = 694.0.
Step 7: (R) -2- (4- (2, 6-dioxopiperidin-3-yl) -3, 5-difluorophenyl) acetaldehyde
Figure PCTCN2022100017-appb-000147
(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 for 2 h at room temperature. The reaction solution was evaporated to dryness to afford the product (2.6 g, 91.8%) . [M+H]  + = 268.1.
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
Figure PCTCN2022100017-appb-000148
The title compound (34 mg, 25%) was prepared in a manner similar to that in Example 21 step 9 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.  1H 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 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
Figure PCTCN2022100017-appb-000149
The title compound was synthesized in a manner similar to that in Example 16.  1H 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 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
Figure PCTCN2022100017-appb-000150
The title compound was synthesized in a manner similar to that in Example 16.  1H 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
Figure PCTCN2022100017-appb-000151
The title compound was synthesized in a manner similar to that in 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, 12 H) , 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.
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
Figure PCTCN2022100017-appb-000152
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, the compound was obtained through the similar way with “ (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 hour. To the mixture was added sodium triacetoxyborohydride (146.34 mg, 0.694 mmol) and the reaction was stirred at room temperature for another 2 h. The resulting mixture was diluted with H 2O (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 Na 2SO 4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the crude product (600 mg) , which was purified with HPLC chromatography (0.1%FA in water: acetonitrile = 90: 10 ～ 50: 50 gradient elution) to give the product (475mg, 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.
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
Figure PCTCN2022100017-appb-000153
To a solution of quinolin-2-ol (6 g, 41.3mmol) in conc. H 2SO 4 (98%) (50 mL) was added dropwise a solution of conc. HNO 3 (63%) (3.12g, 49.6mmol) with stirring at 0℃ , Then the mixture was stirred at rt for 1h . The mixture was diluted with water (200 mL) at 0 ℃, the reaction mixture was filtered and the solid was washed with H 2O (500 ml) , dried in vacuum to afford 6-nitroquinolin-2-ol (5.5g 69.9%) [M+H]  + =191.1.
Step 2: 2-chloro-6-nitroquinoline
Figure PCTCN2022100017-appb-000154
A solution of 6-nitroquinolin-2-ol (5.5 g, 28.78 mmol) in POCl 3 (50 mL) was stirred at 100 ℃ for 2 hrs. Then the mixture was cooled to rt, then concentrated in vacuo. The residue was purified by Combi-Flash (silica column, 40 g, DCM: MeOH=15: 1) to give 2-chloro-6-nitroquinoline (5g 82.9%) [M+H]  + =209.1.
Step 3: 6-nitro-2-vinylquinoline
Figure PCTCN2022100017-appb-000155
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 (40mL) and water (10 mL) was added K 2CO 3 (9.91 g, 71.77 mmol) and Pd (dppf) Cl 2 (1.74g, 2.39 mmol) under N 2 The mixture was warmed to 100℃ and stirred for 16 hrs. Then the mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo. The residue was purified by Combi-Flash (silica column, 40 g, DCM: MeOH=15: 1) to give 6-nitro-2-vinylquinoline (4.5 g, 93.9%) . [M+H]  + = 201.1.
Step 4: 2-ethylquinolin-6-amine
Figure PCTCN2022100017-appb-000156
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 rt for 16 hrs under hydrogen atmosphere. Then the mixture was filtered and the solid was washed with MeOH. The filtrate was concentrated in vacuo to afford 2-ethylquinolin-6-amine (3.84 g, 99.2%) . [M+H]  + = 173.1.
Step 5: 2-ethyl-5-iodoquinolin-6-amine
Figure PCTCN2022100017-appb-000157
The title compound (4.5g, 75.3%) was prepared in a manner similar to that in Example 22 step 1 from 2-ethylquinolin-6-amine and ICl. [M+H]  + = 299.1.
Step 6: (6-amino-2-ethylquinolin-5-yl) dimethylphosphine oxide
Figure PCTCN2022100017-appb-000158
The title compound (3.5g, 93.5%) . was prepared in a manner similar to that in Example 22 step 2 from 2-ethyl-5-iodoquinolin-6-amine and dimethylphosphineoxide. [M+H]  + = 249.1.
Step 7: (6- ( (5-bromo-2-chloropyrimidin-4-yl) amino) -2-ethylquinolin-5-yl) dimethylphosphine oxide
Figure PCTCN2022100017-appb-000159
The title compound (2.5g, 40.38%) . was prepared in a manner similar to that in Example 22 step 3 from (6-amino-2-ethylquinolin-5-yl) dimethylphosphine oxide and 5-bromo-2, 4-dichloropyrimidine. [M+H]  + = 439.6.
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
Figure PCTCN2022100017-appb-000160
The title compound (2.0g, 48.78%) was prepared in a manner similar to that in Example 22 step 4 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. [M+H]  + = 721.5.
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
Figure PCTCN2022100017-appb-000161
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 in a flask at room temperature for 2 hour. To the mixture was added sodium triacetoxyborohydride (146.34 mg, 0.694 mmol) and the reaction was stirred at room temperature for another 2 h. The resulting mixture was diluted with H 2O (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 Na 2SO 4, filtered and concentrated under reduced pressure. The residue was purified with HPLC chromatography (0.1%FA in water: acetonitrile = 90: 10 ～50: 50 gradient elution) 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.
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
Figure PCTCN2022100017-appb-000162
To a solution of 2-methylquinolin-6-amine (5g, 31.62 mmol) in AcOH (50 mL) was added dropwise a solution of ICl (8.85g, 37.95 mmol) in AcOH (10 mL) . The mixture was stirred at 5℃～10℃. Then the mixture was stirred at rt for 1h. The reaction solution was concentrated to dryness and the mixture was diluted with water (200 mL) , neutralized with solid K 2CO 3. The mixture was extracted with DCM (3×150 mL) . The combined organic phase was washed with brine (2×100 mL) , dried over Na 2SO 4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (DCM: MeOH=20: 1) to afford product (7.1g, 79.06%) . [M+H]  + = 285.2.
Step 2: (6-amino-2-methylquinolin-5-yl) dimethylphosphine oxide
Figure PCTCN2022100017-appb-000163
To a solution of 5-iodo-2-methylquinolin-6-amine (7.1g, 24.99mmol) and dimethylphosphine oxide (2.93g, 37.49mmol) in dioxane (100 mL) was added Pd (OAc)  2 (0.55g, 2.45mmol) , Xantphos (2.89g, 4.99mmol) , and K 3PO 4 (10.61g, 49.98mmol) under nitrogen atmosphere. The mixture was degassed under vacuum and purged with nitrogen several times. The mixture was stirred under nitrogen balloon at 100℃for 6 h. The reaction mixture was extracted with DCM (3×50mL) . The combined organic phase was washed with brine (100 mL) , dried over Na 2SO 4 and concentrated in vacuum. The residue was purified by column chromatography (DCM: MeOH=15: 1) to afford the product (4.5 g, 76.9%) . [M+H]  + = 235.2.
Step 3: (6- ( (5-bromo-2-chloropyrimidin-4-yl) amino) -2-methylquinolin-5-yl) dimethylphosphine oxide
Figure PCTCN2022100017-appb-000164
A solution of (6-amino-2-methylquinolin-5-yl) dimethylphosphine oxide (4.5g, 19.21mmol) , 5-bromo-2, 4-dichloropyrimidine (13.13g, 57.64mmol) and DIEA (7.45g, 57.64mmol) in n-BuOH (100 mL) was stirred at 120 ℃ for 12 h. The reaction solution was concentrated to dryness, then the crude product was purified by re-crystallization from EA: PE=5: 1 (50mL) . 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 Na 2SO 4 and concentrated in vacuum to afford product (5.5g, 67.3%) . [M+H]  + = 425.2.
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
Figure PCTCN2022100017-appb-000165
A solution of (6- ( (5-bromo-2-chloropyrimidin-4-yl) amino) -2-methylquinolin-5-yl) dimethylphosphine oxide (5.5g, 12.91 mmol) , TsOH (6.67g, 38.73 mmol) and tert-butyl 4- (1- (4-amino-2-ethyl-5-methoxyphenyl) piperidin-4-yl) piperazine-1-carboxylate (5.67g, 13.56 mmol) in n-BuOH (80 mL) was stirred at 100℃ for 12 h. The reaction mixture was adjusted to pH=8 with 1M NaOH, and then extracted with DCM (3×80 mL) . The combined organic phase was washed with brine (2×100 mL) , dried over Na 2SO 4 and concentrated in vacuum, The residue was purified by column chromatograph (DCM: MeOH=8: 1) to afford the product (5.2 g, 57.01%) . [M+H]  + = 707.3.
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
Figure PCTCN2022100017-appb-000166
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, 50%w. t. T 3P in EtOAc solution (64 mg, 0.1 mmol) was added. The mixture was stirred at 25 ℃ for 16 hours. After LCMS showed the reaction was completed, the mixture was quenched with 10 mL water. The organic phase was concentrated in vacuum and purified by prep-HPLC with C-18 column chromatography (0.1%FA in water : acetonitrile = 90 : 10 ～ 60 : 40 gradient elution) to afford 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.
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
Figure PCTCN2022100017-appb-000167
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 T 3P (763 mg, 2.4 mmol) in dichloromethane (8 mL) was stirred in a flask at room temperature for 0.5h. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with prep-HPLC chromatography (0.1%FA in water: acetonitrile = 90: 10 ～ 50: 50 gradient elution) to give the product (800 mg, 48.3%) .  1H 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.
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
Figure PCTCN2022100017-appb-000168
The title compound was prepared in the procedure similar to Example 24.  1H NMR (500 MHz, DMSO) δ11.80 (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.
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
Figure PCTCN2022100017-appb-000169
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 K 2CO 3 (4.34 g, 31.4 mmol) at 20 ℃. Then the mixture was warmed to 70℃ and stirred for 16 hrs. Then the mixture was diluted with EA (200 mL) , washed with water (100 mL x 2) and brine (100 mL x 2) . Then the organic layer was combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Combi-Flash (silica column, 80 g, PE: EA=10: 1) to give the product (3.5 g, 76.2%) .
Step 2: tert-butyl 4- (1- (2-bromo-5-cyclopropoxy-4-nitrophenyl) piperidin-4-yl) piperazine-1- carboxylate
Figure PCTCN2022100017-appb-000170
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 K 2CO 3 (3.31 g, 24.0 mmol) at 25 ℃. Then the mixture was stirred at 80 ℃ for 16 hrs. Then the mixture was cooled to rt and filtered. The solid was washed with EA. Then the filtrate was concentrated in vacuo. The residue was purified by Combi-Flash (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.
Step 3: tert-butyl 4- (1- (5-cyclopropoxy-4-nitro-2-vinylphenyl) piperidin-4-yl) piperazine-1- carboxylate
Figure PCTCN2022100017-appb-000171
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 K 2CO 3 (1.57 g, 11.4 mmol) and Pd (dppf) Cl 2 (139 mg, 0.19 mmol) under nitrogen atmosphere. The mixture was warmed to 100℃ and  stirred for 16 hrs. Then the mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo. The residue was purified by Combi-Flash (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.
Step 4: tert-butyl 4- (1- (4-amino-5-cyclopropoxy-2-ethylphenyl) piperidin-4-yl) piperazine-1- carboxylate
Figure PCTCN2022100017-appb-000172
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 rt for 16 hrs under hydrogen atmosphere. Then the mixture was filtered and the solid was washed with MeOH. The filtrate was concentrated in vacuo to afford 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.
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
Figure PCTCN2022100017-appb-000173
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 ℃. 4-Methylbenzenesulfonic acid (783 mg, 4.6 mmol) was added to the reaction mixture at 20 ℃. Then the mixture was stirred at 100 ℃ for 13 hrs. The mixture was diluted with water (100 mL) , adjusted to pH = 8 with 5N NaOH solution and then extracted with DCM (150 mL x 3) . The combined organic layers were washed with brine (150 mL x 3) , dried over Na 2SO 4, filtered and concentrated in vacuum. 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.
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
Figure PCTCN2022100017-appb-000174
The title compound (32 mg, 48%) was prepared in a manner similar to that in Example 21 step 9 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.  1H 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.
Example 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)
Figure PCTCN2022100017-appb-000175
To the 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 anhydrous DCM, T 3P (190 mg, 0.3 mmol, 50%w. t. EtOAc solution) was added. The mixture was stirred at room temperature for 30 minutes. Once the reaction has completed determined by LCMS, the mixture was diluted with 10 mL 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 Na 2SO 4, filtered and concentrated in vacuum. Purification by prep-TLC (DCM: MeOH=15: 1) afforded the mixture of two diastereomers, which could be seperated by chiral-HPLC (IF (2*25cm, 5um) , 60%MtBE/40%MeOH: DCM=1: 1/0.1%DEA, 80 bar , 20ml/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. 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) 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.
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
Figure PCTCN2022100017-appb-000176
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 the reaction was  completed, the solvent was removed under reduced pressure to give the desired product (850 mg, 99%) . [M+H]  + = 248.1.
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
Figure PCTCN2022100017-appb-000177
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 Na 2SO 4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (PE: EtOAc = 10: 1～2: 1 gradient elution) to give the product (1.0 g, 73%) . [M+H] + = 400.2.
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
Figure PCTCN2022100017-appb-000178
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) Cl 2 (95 mg, 0.13 mmol) and Cs 2CO 3 (638 mg, 1.95 mmol) in dioxane (15 mL) /H 2O (3 mL) was stirred in a round bottom flask at 80 ℃ for 1 h under nitrogen atmosphere. The solvent was removed under reduced pressure and the crude product was purified with silica gel column chromatography (PE: EtOAc = 10: 1～4: 1 gradient elution) to give the product (390 mg, 53%) . [M+H]  + = 569.1.
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
Figure PCTCN2022100017-appb-000179
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) Cl 2 (50 mg, 0.068 mmol) and Cs 2CO 3 (335 mg, 1.03 mmol) in dioxane (15 mL) /H 2O (3 mL) was stirred in a round bottom flask at 90 ℃ for 3 h under N 2. The solvent was removed under reduced pressure and the crude product was purified with silica gel column chromatography (DCM: MeOH = 100: 1～10: 1 gradient elution) to give the product (270 mg, 53%) . [M+H]  + = 750.5.
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
Figure PCTCN2022100017-appb-000180
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 the reaction was completed, the solvent was removed under reduced pressure to give the desired product (220 mg, 99%) . [M+H]  + = 550.3.
Step 6: 2- (4- (2, 6-dioxopiperidin-3-yl) phenyl) acetaldehyde
Figure PCTCN2022100017-appb-000181
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 ℃ for 2hrs. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2SO 4, and evaporated in vacuum to afford the product (200 mg, 86%) . [M+H] + = 232.1.
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
Figure PCTCN2022100017-appb-000182
The title compound (12 mg, 25%) was prepared in a manner similar to that in Example 21 step 9 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.
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
Figure PCTCN2022100017-appb-000183
The title compound was prepared in the procedure similar to that in 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, 5.0 Hz, 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.
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
Figure PCTCN2022100017-appb-000184
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 K 2CO 3 (29.6 g, 214 mmol) in DMF (300.0 mL) was stirred at 80 ℃ overnight. The mixture was treated with water (500 mL) , extracted with dichloromethane (3 x 30 mL) , and washed with brine (500 mL) . The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product, which was purified with silica gel column chromatography (DCM: MeOH = 100: 0 ～ 93: 7 gradient elution) to give the product (8.0 g, 16.8%) . [M+H]  + = 448.0.
Step 2: 2, 7-dibromo-9, 10-dihydro-4H-benzo [d] pyrazolo [1, 5-a] [1, 3] diazepine-3-carbonitrile
Figure PCTCN2022100017-appb-000185
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 ℃ overnight under nitrogen. The mixture was treated with water (300 mL) and filtered to give the crude product, which was purified with silica gel column chromatography (PE: EA = 80: 20 ～ 50: 50 gradient elution) to give the product (2.2 g, 33.3%) .  1H 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.
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
Figure PCTCN2022100017-appb-000186
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 at 75 ℃ for 6 hours in sealed tube. Then the mixture was evaporated in vacuum to afford the crude product, which was purified with silica gel column chromatography (PE: EA = 80: 20 ～ 50: 50 gradient elution) to give the product (350 mg, 15.9%) .  1H 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.
Step 4: 4-bromo-5-fluoro-2-methyl-N- (6-methylpyridin-2-yl) benzamide
Figure PCTCN2022100017-appb-000187
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 ℃ ～5 ℃ for 5 mins, then LiHMDS (6.2 mL, 0.00812 mol, 1.3 M) was added dropwise. The mixture was stirred at room temperature overnight. Then the mixture was quenched by NH 4Cl solution, extracted with EA (3 x 50 mL) and washed with brine (100 mL) . The organic phase was dried over anhydrous Na 2SO 4, filtered, and concentrated under reduced pressure to afford the product (1.67 g, crude) . [M+H]  + = 323.0.
Step 5: 5-fluoro-2-methyl-N- (6-methylpyridin-2-yl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl) benzamide
Figure PCTCN2022100017-appb-000188
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) Cl 2 (170 mg, 0.000233 mol) and KOAc (915 mg, 0.00934 mol) in dioxane (30.0 mL) was stirred at 93 ℃ overnight under N 2. The mixture was cooled down to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography PE: EA = 100%: 0%～ 50%: 50%to afford the product (530 mg, 31%) . [M+H]  + = 371.0.
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
Figure PCTCN2022100017-appb-000189
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) , Na 2CO 3 (303 mg, 1.86 mmol) and Pd (PPh 3)  4 (165 mg, 0.143 mmol) in dioxane/water (20 mL/4 mL) was stirred at 95 ℃ overnight under N 2. The mixture was cooled down to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography PE: EA = 100%: 0%～ 0%: 100%to afford the desired product (347 mg, 36%) . [M+H]  + = 671.0.
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
Figure PCTCN2022100017-appb-000190
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 ℃ for 30 mins. The mixture was then cooled, basified with aqueous sodium hydroxide solution to pH 12, extracted with dichloromethane (3 x 30 mL) and  washed with water (3x 30 mL) . The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the product (225 mg, crude) .
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
Figure PCTCN2022100017-appb-000191
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 mins. 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 hours. The reaction mixture was concentrated in vacuum, and the residue was purified by silica gel column chromatography (DCM: MeOH = 100%: 0%～90%: 10%gradient elution) to give crude product, which was further purified by prep-TLC (DCM: MeOH = 10: 1) to afford 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.
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
Figure PCTCN2022100017-appb-000192
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 rt for 16 hours. Then the mixture was washed by water and extracted with dichloromethane (3 x 60 mL) . The organic phase was combined and washed by brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was  purified with silica gel column chromatography (PE: EA = 80: 20 ～ 30: 70 gradient elution) to give the product (40 mg, 42%) . [M+H]  + = 315.2.
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
Figure PCTCN2022100017-appb-000193
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 (the compound was synthesized through the similar way of the intermediate in 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 hours, and then NaBH (OAc)  3 (110 mg, 0.52 mmol) was added and stirred at room temperature for 1 hour. The mixture was treated with water (30 mL) , extracted with dichloromethane (3 x 30 mL) , and washed with brine (30 mL) . The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was purified with silica gel column chromatography (DCM: MeOH = 100: 0 ～ 90: 10 gradient elution) to give the product (14 mg, 16%) .  1H 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.
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
Figure PCTCN2022100017-appb-000194
The titled compound was synthesized in the procedures similar to Example B34.  1H 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.
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
Figure PCTCN2022100017-appb-000195
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 ℃. The mixture was stirred at room temperature for 3 h. The mixture was washed by water and extracted with DCM. The organic layers were combined and dried over Na 2SO 4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc =9: 1) to afford the product (14.6 g, 78%) . [M+H]  + = 204.1.
Step 2: methyl 4-amino-3-fluoro-2-methylbenzoate
Figure PCTCN2022100017-appb-000196
To a solution of 4-bromo-2-fluoro-3-methylaniline (10.2 g, 50mmol) , Pd (dppf) Cl 2 (1.83 g, 2.50 mmol) dissolved in MeOH (140 mL) was dropwise added Et 3N (10.1 g, 100 mmol) . The mixture was stirred at 90 ℃ for 16 h under CO atmosphere. The mixture was concentrated in vacuum. The mixture was washed by water and extracted with EtOAc. The organic layers were combined and dried over Na 2SO 4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 4: 1) to afford the product (2.53 g, 28%) . [M+H]  + = 184.1.
Step 3: methyl 3-fluoro-2-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate
Figure PCTCN2022100017-appb-000197
To a solution of methyl 4-amino-3-fluoro-2-methylbenzoate (2.53 g, 13.8 mmol) , tert-butyl nitrite (2.84 g, 27.6 mmol) and BPO (334 mg, 1.38 mmol) dissolved 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 vacuum. The mixture was washed by water and extracted with EtOAc. The organic layers were combined, dried over Na 2SO 4 and filtered. The filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 12: 1) to afford the product (1.83 g, 45%) .  1H NMR (500 MHz, CDCl 3) δ 7.67-7.53 (m, 2H) , 3.90 (s, 3H) , 2.47 (d, J = 2.1 Hz, 3H) , 1.37 (s, 12H) .
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
Figure PCTCN2022100017-appb-000198
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) Cl 2 (0.124 g, 0.17 mmol) and Na 2CO 3 (0.352 g, 3.32 mmol) in dioxane (25 mL) and H 2O (3 mL) was stirred at 95 ℃ for 16 hours under N 2. Then the mixture was washed by water and extracted with dichloromethane (3 x 60 mL) . The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was purified with silica gel column chromatography (PE: EA = 80: 20 ～ 50: 50 gradient elution) to give the product (345 mg, 35%) . [M+H]  + = 595.3.
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
Figure PCTCN2022100017-appb-000199
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 (0.077g, 0.581 mmol) in THF (8.0 mL) was added LiHMDS (1.74 mL, 1 M) dropwise. The reaction was stirred at 60 ℃ for 2 hours and then cooled. The mixture was washed by water and extracted with dichloromethane (3 x 30 mL) . The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the product (365 mg, 95%) . [M+H]  + =660.2.
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
Figure PCTCN2022100017-appb-000200
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 ℃ for 1 hour. The mixture was then cooled, acidified with aqueous sodium hydroxide solution to pH 12 and extracted with dichloromethane (3 x 30 mL) and water (3x 30 mL) . The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the product (290 mg, 97%) . [M+H]  + = 544.1.
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
Figure PCTCN2022100017-appb-000201
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 hours, and then NaBH (OAc)  3 (220 mg, 1.04 mmol) was added and stirred at room temperature for 1 hour. The mixture was treated with water (30 mL) , extracted with dichloromethane (3 x 30 mL) , and washed with brine (30 mL) . The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was purified with silica gel column chromatography (DCM: MeOH = 100: 0 ～ 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.
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
Figure PCTCN2022100017-appb-000202
The titled compound was synthesized in the procedures similar to 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) , 3.12-3.06 (m, 4H) , 2.85-2.77 (m, 3H) , 2.65-2.53 (m, 7H) , 2.28 (d, J = 2.0 Hz, 3H) , 2.18-2.08 (m, 1H) , 2.04-1.97 (m, 1H) ; [M+H]  + = 795.5.
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
Figure PCTCN2022100017-appb-000203
The titled compound was synthesized in the procedures similar to 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.
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
Figure PCTCN2022100017-appb-000204
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 K 2CO 3 (2.6 g, 18.9 mmol) in EtOH (50 mL) was stirred at 80 ℃ for 16 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with hexane/EtOAc (1: 1) to afford the product (660 mg, 24%) . [M+H]  + = 432.3.
Step 2: tert-butyl 4- (3- ( (6-chloropyrimidin-4-yl) amino) phenyl) piperazine-1-carboxylate
Figure PCTCN2022100017-appb-000205
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 for 6 h at 78 ℃ under nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 5%-50%EtOAc in petroleum ether to afford the product (1.4 g, 65%) . [M+H]  + = 390.1.
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
Figure PCTCN2022100017-appb-000206
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 H 2O (3 mL) were added K 2CO 3 (210 mg, 1.52 mmol) and Pd (dppf) Cl 2 (31 mg, 0.038 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 89 ℃ under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10%-90%EtOAc in petroleum ether to afford the product (290 mg, 58%) . [M+H]  + = 659.3.
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
Figure PCTCN2022100017-appb-000207
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 for 2 h at room temperature and concentrated under vacuum. The residue (234 mg, crude) was used directly for next step without any further purification. [M+H]  + = 559.3.
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
Figure PCTCN2022100017-appb-000208
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 in a round bottom flask at room temperature for 0.5 hour. To the mixture was added NaBH (OAc)  3 (0.222 g, 1.04 mmol) and stirred at room temperature for 12 hours. Then the mixture was evaporated in vacuum to afford the crude product, which was purified by pre-HPLC to afford 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.
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
Figure PCTCN2022100017-appb-000209
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 for 16 h at 80 ℃ and diluted with water (500 mL) . The resulting mixture was extracted with EtOAc (3 x 300 mL) . The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the titled product (8.1 g, 81%) . [M+H]  + = 299.1.
Step 2: tert-butyl 4- (6- ( (diphenylmethylene) amino) pyridazin-3-yl) piperazine-1-carboxylate
Figure PCTCN2022100017-appb-000210
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) were added Pd 2 (dba)  3 (0.31 g, 0.34 mmol) , BINAP (0.42 g, 0.67 mmol) and Cs 2CO 3 (4.36 g, 13.39 mmol) in portions at room temperature. The resulting mixture was stirred for 16 h at 100 ℃ under nitrogen atmosphere and concentrated under vacuum. The residue was purified by silica gel column chromatography to give the titled product (1.4 g, 47%) . [M+H]  + = 444.2.
Step 3: tert-butyl 4- (6-aminopyridazin-3-yl) piperazine-1-carboxylate
Figure PCTCN2022100017-appb-000211
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 H 2O (13.5 mL) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography to give the titled product (710 mg, 83%) . [M+H]  + = 280.2.
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
Figure PCTCN2022100017-appb-000212
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 (the compound was obtained through the similar way of example C39) (858.90 mg, 2.15 mmol) in dioxane (10 mL) were added XPhos (170.66 mg, 0.36 mmol) , XPhos Pd G 3 (151.51 mg, 0.18 mmol) and Cs 2CO 3 (1.17 g, 3.58 mmol) in portions at room temperature. The resulting mixture was stirred for 16 h at 100 ℃ under nitrogen atmosphere and concentrated under vacuum. The residue was purified by silica gel column chromatography to give the titled product (314 mg, 27%) . [M+H]  + = 643.2.
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
Figure PCTCN2022100017-appb-000213
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 for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was triturated with Et 2O to afford the titled product (254 mg, 89%) . [M+H]  + = 543.3.
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
Figure PCTCN2022100017-appb-000214
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 titled product (50 mg, 36%) .  1H 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.
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
Figure PCTCN2022100017-appb-000215
The titled compound was synthesized in the procedures similar to Example C40.  1H 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.
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
Figure PCTCN2022100017-appb-000216
A solution of 1, 3-difluoro-2-nitrobenzene (50.0 g, 314.4 mmol) in NMP (300 mL) were cooled to -20  ℃ under N 2 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 at -10 ℃ to -20 ℃ over 2 h. After being stirred for 2 h, the reaction was quenched by pouring into 1M HCl (200mL) and ice-water. The mixture was extracted with EA (300 mL x 3) . The combined organic layer was washed by brine, dried with Na 2SO 4. The solution was concentrated in vacuum and the residue was purified by silica gel column chromatography (PE/EA = 200/1 to 100/1) to provide product (13.7 g, 18%) .  1H NMR (400 MHz, CDCl 3) 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) .
Step 2: ethyl 2- (4-amino-3, 5-difluorophenyl) acetate
Figure PCTCN2022100017-appb-000217
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 r. t. The mixture was stirred at r. t under H 2 atmosphere for 5 h. Filtrated on vacuum to remove Pd/C and concentrated in vacuum to provide the prodcut (12.2 g) , which was used in next step without further purification.  1H NMR (400 MHz, DMSO_d 6) 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.
Step 3: ethyl 2- (3, 5-difluoro-4-iodophenyl) acetate
Figure PCTCN2022100017-appb-000218
A solution of ethyl 2- (4-amino-3, 5-difluorophenyl) acetate (12.2 g, 56 mmol) in MeCN (150 mL) was cooled to 0 ℃ under N 2 atmosphere and CuI (21.2 g, 112 mmol) was added. After stirring for 10 min, tert-butylnitrite (11.5 g, 112 mmol) was added dropwise over 30 min. Then the mixture was stirred at r. t for overnight. The reaction was quenched by pouring into water and extracted with EA (300 mL x 3) . All organic layers were combined and washed by brine, dried with Na 2SO 4. The solution was concentrated in vacuum and the residue was purified by silica gel column chromatography (PE/EA = 500/1 to 100/1) to provide the product (8.8 g, 48%) . [M+H]  + = 326.5.
Step 4: ethyl 2- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) -3, 5-difluorophenyl) acetate
Figure PCTCN2022100017-appb-000219
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/H 2O (100 mL /20 mL) were added K 2CO 3 (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) Cl 2 (2.9 g, 4.0 mmol) under N 2 atmosphere. The resulting solution was stirred for 6 h at 100 ℃. The mixture was diluted with water (300 mL) and extracted with EA (300 mL x 3) . All organic layers were combined and washed with brine (300 mL) , dried over Na 2SO 4. The solution was concentrated in vacuum and the residue was purified by silica gel column chromatography (PE/EA = 200/1) to give the product (8.2 g, 62%) .  1H NMR (400 MHz, CDCl 3) 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) .
Step 5: 2- (4- (2, 6-bis (benzyloxy) pyridin-3-yl) -3, 5-difluorophenyl) ethanol
Figure PCTCN2022100017-appb-000220
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 ℃ under N 2 atmosphere and 1.5 M DIBAL-H (45 mL, 67.5 mol) in THF was added dropwise over 30 min. Then the mixture was stirred at r. t for 2 h. The reaction was quenched by pouring into water and extracted with EA (300 mLx 3) . All organic layers were combined and washed by brine, dried with Na 2SO 4. The solution was concentrated in vacuum and the residue was purified by column chromatography (PE/EA = 10/1 to 3/1) to provide the product (6.6 g, 88%) .  1H NMR (400 MHz, CDCl 3) 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.
Step 6: 3- (2, 6-difluoro-4- (2-hydroxyethyl) phenyl) piperidine-2, 6-dione
Figure PCTCN2022100017-appb-000221
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 stirred overnight, the mxiture was concentrated in vacuo. The residue was dissolved in MeOH (200 mL) and 10%Pd/C (1.0 g) was added. The resulted mixture was stirred for 2 days at r. t under H 2 atmosphere. The mixture was filtered and the filtrate was concentracted to give a residue which was purified by reversed flash C18 chromatography (ACN/water = 0%to 30%) to give the title compound (2.1 g, 53%) . [M+H]  + = 270.1.
Step 7: 4- (2, 6-dioxopiperidin-3-yl) -3, 5-difluorophenethyl methanesulfonate
Figure PCTCN2022100017-appb-000222
To the 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, MsCl (510 mg, 4.46 mmol) was added dropwise at 0 ℃. The mixture was stirred at room temperature for 4 hours. The mixture was quenched with NaHCO 3 aqueous and extracted by DCM. The organic layer was separated and concentrated. The residue was purified by silica column chromatography (MeOH: DCM=0-6%) to afford the product (1.1 g, 85.3%yield) . [M+H]  +=348.1.
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
Figure PCTCN2022100017-appb-000223
To the 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, KI (46 mg, 0.28 mmol) and DIEA (60 mg, 0.46 mmol) was added. The mixture was stirred at 85 ℃ for 16 hours. After LCMS shown the reaction was completed, the mixture was concentrated in vacuum. The residue was washed with water and extracted by DCM. The organic layer was separated and concentrated. The residue was purified by prep-TLC (DCM: MeOH=10: 1)  to afford the crude. The crude product was purified by prep-HPLC to afford the product (8.1 mg, 11%yield) .  1H NMR (500 MHz, DMSO-d 6) 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.
Test Example 1
Cell Degradation
Cell line generation
H1975-clone#28 (Del19/T790M/C797S) was stably expressed in H1975 cell lines (from ATCC) by lentivirus-mediated over-expression. The EGFR over-expressed cells then underwent gene knockout, in which the EGFR targeting sgRNA was designed to only target the endogenous EGFR copies and preserve the exogenous EGFR copies. Followed by the gene knockout, the edited H1975 cells were seeded in 96 well plates at the concentration of 1 cell/cell, cultured for about 2 weeks to allow single clones formation. The formed clones were screened by DNA sequencing and whole exon sequencing analysis for the desired edition. H1975-clone#28 was finally confirmed as homozygous Del19/T790M/C797S EGFR clone
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#11835-030) , 10%heat-inactive FBS, 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3799) .
1b) . On day 1, H1975-clone#28 (Del19/T790M/C797S) 10000 cells/well correspondingly in cell culture medium [RPMI1640 (Gibco, Cat#72400-047) , 10%heat-inactive FBS, 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3599) .
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 incubate for 16h, 37℃, 5%CO 2, H1975-#28 cells are treated with compounds diluted in 0.2%DMSO cell culture medium on day 2, incubate for 16h, 37℃, 5%CO 2 . the final concentriation of compounds in all assay is start with 10uM, 5-fold dilution, total 8 doses were included.
1c) . TMD-8 cells are seeded at 20000 cells/well at a volume of 15μl/well in cell culture medium [RPMI1640 (Gibco, phenol red free, Cat#11835-030) , 10%heat-inactive FBS, 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3799) . TMD-8 cells are treated with compounds diluted in 0.2%DMSO, dilution is done according to the following protocol: (1) make 500× stock solution in DMSO from 1mM by 6-fold dilution, total 8 doses were included; (2) make 2× solution in cell culture medium by transferring 0.5μl 500× stock solution into 125μl medium; (3) 15μl of 2× solution is added to cells and incubate for 6h.
HTRF assay (EGFR degradation)
After 16h treatment, add HTRF lysis buffer to each well ; seal the plate and incubate 1 hour at room temperature on a plate shaker; Once the cells are lysed, 16 μL of cell lysate are transferred to a PE 384-well HTRF detection plate; 4 μL of pre-mixed HTRF antibodies are added to each well ; Cover the plate with a plate sealer, spin 1000 rpm for 1 min, Incubate overnight at room temperature; Read on BMG PheraStar with HTRF protocol (337nm-665nm-620nm) .
The inhibition (degradation) percentage of the compound was calculated by the following equation: Inhibition percentage of Compound = 100-100 × (Signal-low control) / (High control-low control) , wherein signal = each test compound group
Low control = only lysis buffer without cells, indicating that EGFR is completely degraded;
High control = Cell group with added DMSO and without compound, indicating microplate readings without EGFR degradation;
Dmax is the maximum percentage of inhibition (degradation) .
HTFR assay (BTK degradation)
After 6h treatment, add 10μl 4xlysis buffer to each well; seal the plate and incubate 30min at room temperature on a plate shaker; Once the cells are lysed, 16 μL of cell lysate are transferred to a PE 384-well HTRF detection plate; 4 μL of pre-mixed HTRF antibodies are added to each well; Cover the plate with a plate sealer, spin 1000 rpm for 1 min, Incubate overnight at room temperature; Read on BMG PheraStar with HTRF protocol (337nm-665nm-620nm) .
The inhibition (degradation) percentage of the compound was calculated by the following equation: Inhibition percentage of Compound = 100-100 × (Signal-low control) / (High control-low control) , wherein signal = each test compound group
Low control = only lysis buffer without cells, indicating that BTK is completely degraded;
High control = Cell group with added DMSO and without compound, indicating microplate readings without BTK degradation;
Dmax is the maximum percentage of inhibition (degradation) .
The IC 50 (DC 50) value of a compound can be obtained by fitting the following equation
Y = Bottom + (TOP-Bottom) / (1 + ( (IC 50 /X) ^ hillslope) )
Wherein, X and Y are known values, and IC 50, Hillslope, Top and Bottom are the parameters obtained by fitting with software. Y is the inhibition percentage (calculated from the equation) , X is the concentration of the compound; IC 50 is the concentration of the compound when the 50%inhibition is reached. The smaller the IC 50 value is, the stronger the inhibitory ability of the compound is. Vice versa, the higher the IC 50 value is, the weaker the ability the inhibitory ability of the compound is; Hillslope represents the slope of the fitted curve, generally around 1 *; Bottom represents the minimum value of the curve obtained by data fitting, which is generally 0%± 20%; Top represents the maximum value of the curve obtained by data fitting, which is generally 100%± 20%. The experimental data were fitted by calculating and analyzing with Dotmatics data analysis software.
Table 1. Degradation (BaF3) result for Example 16 to Example 19
Figure PCTCN2022100017-appb-000224
Table 2. Degradation (H1975 #28 DTC and BaF3-LTC) result for Example 20 to Example 29
Figure PCTCN2022100017-appb-000225
Figure PCTCN2022100017-appb-000226
Table 3. Degradation (TMD-8) result for Example 31 and 32
Example DC 50 (nM) Dmax (%)
31 >2000.0 11.99
32 5.33 97.38
Test example 2
HTRF (Homogeneous Time-Resolved Fluorescence) assay
Biochemical potency of compound was determined by using CRBN&DDB1 protein (His Tag) .
Compounds were tested for blocking the binding of CRBN&DDB1 protein (CRBN, aa 40-442, DDB1, 1-1140, Viva Biotech) with biotin labeled thalidomide in an assay based on the time-resolved fluorescence-resonance energy transfer (TR-FRET) methodology. The assay was carried out in 384-well low volume black plates in a reaction mixture containing CRBN&DDB1 protein, 30 nM biotin labeled thalidomide and 0-10 μM compound in buffer containing 50 mM HEPES pH7.5, 50 mM NaCl, 0.01%BSA, 1 mM DTT and 0.015%Brij-35. The protein was preincubated with compound for 60 minutes at room temperature and biotin labeled thalidomide was added to plate. After further incubation at room temperature for 60 minutes detection reagents Mab Anti-6His Eu cryptate Gold (Cisbio, Cat#61HI2KLB) and Streptavidin-XL665 (Cisbio, Cat#610SAXLG) were added to plate. Plates were sealed and incubated at room temperature for 1 hour, and the TR-FRET signals (ex337nm, em665nm/620nm) were recorded on a PHERAstar FSX plate reader (BMG Labtech) . The inhibition percentage of CRBN&DDB1 protein interaction with biotin labeled thalidomide in presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 665 nm to that at 620 nm. IC 50 was derived from fitting the dose-response %inhibition data to the four-parameter logistic model by Dotmatics.
Four-parameter logistic equation: Y=Bottom + (Top-Bottom) / (1+10^ ( (LogIC 50-X) *HillSlope) ) . While X is Log of compound concentration. Y is %inhibition at X. Bottom is the bottom of the curve effect. Top is the top of the curve effect. HillSlope is the hill slope factor.
Table 4. HTRF assay result for Example 2 to Example 15
Example IC 50 (nM)
2 406
5 26
6 1070
7 22
9 64
12 178
13 27
14 24
15 239
Test Example 3
Cell Degradation
Cell treatment
TMD-8 cells were seeded at 20000 cells/well at a volume of 15μl/well in cell culture medium [RPMI1640 (Gibco, phenol red free, Cat#11835-030) , 10%heat-inactive FBS, 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3799) . TMD-8 cells were treated with compounds diluted in 0.2%DMSO, dilution was done according to the following protocol: (1) making 500× stock solution in DMSO from 1mM by 6-fold dilution, total 8 doses were included; (2) making 2× solution in cell culture medium by transferring 0.5μl 500× stock solution into 125μl medium; (3) adding 15μl of 2× solution to cells for incubation of 6h.
HTFR assay
After 6h treatment, 10μl 4xlysis buffer was added to each well; the plate was sealed and incubated for 30min at room temperature on a plate shaker; Once the cells was lysed, 16 μL of cell lysate were transferred to a PE 384-well HTRF detection plate; 4 μL of pre-mixed HTRF antibodies were added to each well; the plate was covered with a plate sealer, and then spinned at 1000 rpm for 1 min, then incubated overnight at room temperature; the results were read on BMG PheraStar with HTRF protocol (337nm-665nm-620nm) .
The inhibition (degradation) percentage of the compound was calculated by the following equation:
Inhibition percentage of Compound = 100-100 × (Signal-low control) / (High control-low control) , wherein signal = each test compound group
Low control = only lysis buffer without cells, indicating that BTK is completely degraded;
High control = Cell group with added DMSO and without compound, indicating microplate readings without BTK degradation;
Dmax is the maximum percentage of inhibition (degradation) .
The IC 50 (DC 50) value of a compound can be obtained by fitting the following equation
Y = Bottom + (TOP-Bottom) / (1 + ( (IC 50 /X) ^ hillslope) )wherein, X and Y are known values, and IC 50, Hillslope, Top and Bottom are the parameters obtained by fitting with software. Y is the inhibition percentage (calculated from the equation) , X is the concentration of the compound; IC 50 is the concentration of the compound when the 50%inhibition is reached. The smaller the IC 50 value is, the stronger the inhibitory ability of the compound is. Vice versa, the higher the IC 50 value is, the weaker the ability the inhibitory ability of the compound is; Hillslope represents the slope of the fitted curve, generally around 1 *; Bottom represents the minimum value of the curve obtained by data fitting, which is generally 0%± 20%; Top represents the maximum value of the curve  obtained by data fitting, which is generally 100%± 20%. The experimental data were fitted by calculating and analyzing with Dotmatics data analysis software.
HEK-293 Cell treatment
HEK-293 cells were seeded at 2000 cells/well at a volume of 50ul/well in cell culture medium [DMEM (Gibco, Cat#11965-092) , 10%heat-inactive FBS (Gibco, Cat#10099) , 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3903) , and then incubated overnight. HEK-293 cells were treated with compounds diluted in 0.2%DMSO, dilution was done according to the following protocol: (1) making 500× stock solution in DMSO from 5mM by 4-fold dilution, total 8 doses were included; (2) making 2×solution in cell culture medium by transferring 0.5ul 500× stock solution into 125ul medium; (3) adding 50ul of 2× solution to cells for incubation of 72h.
Cytotoxicity detection
25μl of the 
Figure PCTCN2022100017-appb-000227
Reagent [ (Promega) -Cat No. G7572] was added to each well in the 96-well plate. The contents were mixed for 2 minutes on an orbital shaker to induce cell lysis. The plate was then allowed to incubate at room temperature for 10 minutes to stabilize luminescent signal. Luminescence was recorded on BMG PheraStar with luminescence protocol.
IC50 calculation
The inhibition percentage of the compound was calculated by the following equation: Inhibition percentage of Compound = 100-100 × (Signal-low control) / (High control-low control) , wherein signal =each test compound group
Low control = only medium group (without cells) , indicating that cells proliferation is completely inhibited;
High control = Cell group with added DMSO and without compound, indicating cells proliferation with no inhibition;
Imax is the maximum percentage of inhibition.
The IC50 value of a compound can be obtained by fitting the following equation
Y = Bottom + (TOP-Bottom) / (1 + ( (IC50 /X) ^ hillslope) )
Wherein, X and Y are known values, and IC50, Hillslope, Top and Bottom are the parameters obtained by fitting with software. Y is the inhibition percentage (calculated from the equation) , X is the concentration of the compound; IC50 is the concentration of the compound when the 50%inhibition is reached. The smaller the IC50 value is, the stronger the inhibitory ability of the compound is. Vice versa, the higher the IC50 value is, the weaker the ability the inhibitory ability of the compound is; Hillslope represents the slope of the fitted curve, generally around 1 *; Bottom represents the minimum value of the curve obtained by data fitting, which is generally 0%± 20%; Top represents the maximum value of the curve obtained by data fitting, which is generally 100%± 20%. The experimental data were fitted by calculating and analyzing with Dotmatics data analysis software.
Table 5. Degradation and HEK293 result for Example B35 to Example C41
Example IC50 of HEK293 (nM) DC50 (nM)
B35 >10000.0 2.32
Example IC50 of HEK293 (nM) DC50 (nM)
B37 >10000.0 0.414
B38 26.78 1.7
C39 >10000.0 242.2
C41 >10000.0 2.73
Test Example 4
Cell treatment
THP-1 cells are seeded at 100000 cells/well at a volume of 15μl/well in cell culture medium [RPMI1640 (Gibco, phenol red free, Cat#11835-030) , 10%heat-inactive FBS, 1%PS (Gibco, Cat#10378) ] in Corning 96 well plate (Cat#3799) . THP-1 cells are treated with compounds diluted in 0.2%DMSO, dilution is done according to the following protocol: (1) make 500× stock solution in DMSO from 5mM by 5-fold dilution, total 8 doses were included; (2) make 2×solution in cell culture medium by transferring 0.5μl 500× stock solution into 125μl medium; (3) 15μl of 2× solution is added to cells and incubate for 6h.
HTFR assay
After 6h treatment, add 10μl 4xlysis buffer to each well ; seal the plate and incubate 1 hour at room temperature on a plate shaker; Once the cells are lysed, 16 μL of cell lysate are transferred to a PE 384-well HTRF detection plate (for triple mutant cells , the lysate were diluted by the qual volume 1xlysis buffer before transfer) ; 4 μL of pre-mixed HTRF antibodies are added to each well ; Cover the plate with a plate sealer, spin 1000 rpm for 1 min, Incubate overnight at room temperature; Read on BMG PheraStar with HTRF protocol (337nm-665nm-620nm) .
The inhibition (degradation) percentage of the compound was calculated by the following equation: Inhibition percentage of Compound = 100-100 × (Signal-low control) / (High control-low control) , wherein signal = each test compound group
Low control = only lysis buffer without cells, indicating that IRAKM is completely degraded;
High control = Cell group with added DMSO and without compound, indicating microplate readings without IRAKM degradation;
Dmax is the maximum percentage of inhibition (degradation) .
The IC 50 (DC 50) value of a compound can be obtained by fitting the following equation
Y = Bottom + (TOP-Bottom) / (1 + ( (IC 50 /X) ^ hillslope) )
Wherein, X and Y are known values, and IC 50, Hillslope, Top and Bottom are the parameters obtained by fitting with software. Y is the inhibition percentage (calculated from the equation) , X is the concentration of the compound; IC 50 is the concentration of the compound when the 50%inhibition is reached. The smaller the IC 50 value is, the stronger the inhibitory ability of the compound is. Vice versa, the higher the IC 50 value is, the weaker the ability the inhibitory ability of the compound is; Hillslope represents the slope of the fitted curve, generally around 1 *;
Bottom represents the minimum value of the curve obtained by data fitting, which is generally 0%± 20%; Top represents the maximum value of the curve obtained by data fitting, which is  generally 100%± 20%. The experimental data were fitted by calculating and analyzing with Dotmatics data analysis software.
Table 6. Degradation result for Example D42
Example DC 50 (nM) Dmax
D42 2.8 88
The foregoing examples and description of certain embodiments should be taken as illustrating, rather than as limiting the present invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims. All such variations are intended to be included within the scope of the present invention. All references cited are incorporated herein by reference in their entireties.
It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country.

Claims (95)

  1. A compound of Formula (I) :
    Figure PCTCN2022100017-appb-100001
    or a pharmaceutically acceptable salt thereof, or a deuterated analog thereof, or a prodrug thereof, wherein:
    Warhead is a targeting moiety that binds to a target protein; wherein the target protein is a mediator of a disease in a subject;
    Linker is a divalent chemical group that connects the Warhead moiety and the
    Figure PCTCN2022100017-appb-100002
    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 N at the same time;
    R z, at each occurrence, is independently selected from hydrogen, halogen, -C 1-8alkyl, -NR ZaR Zb, -OR Za, -SR Za, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl or CN; each of -C 1-8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl is optionally substituted with at least one R Zc;
    the
    Figure PCTCN2022100017-appb-100003
    moiety is linked to the
    Figure PCTCN2022100017-appb-100004
    moiety via any one of Z 1, Z 2 or Z 3 which is CR z and R z is hydrogen;
    R Za and R Zb are each independently selected from hydrogen, -C 1-C 8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 2- 8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 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-C 8alkyl, C 3-C 8cycloalkyl, -C 1-8alkoxy, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl;
    R 1 and R 2 are each independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 1- 8alkoxy, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, -CN, -SO 2R 1a, -SO 2NR 1aR 1b, -COR 1a, -CO 2R 1a, -CONR 1aR 1b, -NR 1aR 1b, -NR 1aCOR 1b, -NR 1aCO 2R 1b, or –NR 1aSO 2R 1b; each of -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 1-8alkoxy, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo, -CN, -OR 1c, -SO 2R 1c, -SO 2NR 1cR 1d, -COR 1c, -CO 2R 1c, -CONR 1cR 1d, -NR 1cR 1d, -NR 1cCOR 1d, -NR 1cCO 2R 1d, or –NR 1cSO 2R 1d;
    R 1a, R 1b, R 1c and R 1d are each independently hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl.
  2. The compound of claim 1, wherein at most one of Z 1, Z 2 and Z 3 is N.
  3. The compound of any one of claims 1-2, wherein Z 1, Z 2 and Z 3 are each independently CR z.
  4. The compound of any one of claims 1-3, wherein R Z, at each occurrence, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR ZaR 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 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 is optionally substituted with at least one R Zc;
    R Za and R Zb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl, each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R Zd;
    R Zc and R Zd are each independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl, or 5-to 12-membered heteroaryl.
  5. The compound of any one of claims 1-4, wherein R z is selected from H, -CH 3, -C 2H 5, F, -CH 2F, -CHF 2, -CF 3, -OCH 3, -OC 2H 5, -C 3H 7, -OCH 2F, -OCHF 2, -OCH 2CF 3, -OCF 3, -SCF 3, -CF 3 or -CH (OH) CH 3.
  6. The compound of any one of claims 1-5, wherein R 1 and R 2 are each 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, -C 2-8alkenyl, -C 2-8alkynyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, -CN, -SO 2R 1a, -SO 2NR 1aR 1b, -COR 1a, -CO 2R 1a, -CONR 1aR 1b, -NR 1aR 1b, -NR 1aCOR 1b, -NR 1aCO 2R 1b, or –NR 1aSO 2R 1b; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8alkenyl, -C 2-8alkynyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl is optionally substituted with 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 2-8alkenyl, -C 2- 8alkynyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo, -CN, -OR 1c, -SO 2R 1c, -SO 2NR 1cR 1d, -COR 1c, -CO 2R 1c, -CONR 1cR 1d, -NR 1cR 1d, -NR 1cCOR 1d, -NR 1cCO 2R 1d, or –NR 1cSO 2R 1d;
    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- 8alkenyl, -C 2-8alkynyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, or 5-to 12-membered heteroaryl.
  7. The compound of any one of claims 1-6, wherein R 1 and R 2 are each 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, -CH 2F, -CHF 2, -CF 3, -OCH 2F, -OCHF 2, -OCH 2CF 3, -OCF 3, -SCF 3, or phenyl.
  8. The compound of any one of claims 1-7, wherein the compound is Formula (II)
    Figure PCTCN2022100017-appb-100005
    wherein Warhead and Linker are defined as claim 1.
  9. The compound of any one of claims 1-8, wherein Linker is
    Figure PCTCN2022100017-appb-100006
    wherein *refers to the position attached to the
    Figure PCTCN2022100017-appb-100007
    moiety, and ** refers to the position attached to the
    Figure PCTCN2022100017-appb-100008
    moiety;
    L 1 is selected from a single bond, -O-, -SO 2-, -C (O) -, -NR L1a-, -C 3-C 8cycloalkylene-, * L1-O-C 1- 8alkylene-** L1, * L1-C 1-8alkylene-O-** L1, * L1-SO 2-C 1-8alkylene-** L1, * L1-C 1-8alkylene-SO 2-** L1, * L1-CO-C 1-8alkylene-** L1, * L1-C 1-8alkylene-CO-** L1, * L1-NR L1a-C 1-8alkylene-** L1, * L1-C 1-8alkylene-NR L1a-** L1, * L1-NR L1aC (O) -** L1, * L1-C (O) NR L1a-** L1, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2-8alkynylene-, - [O (CR L1aR L1b)  m4]  m5-, 
    Figure PCTCN2022100017-appb-100009
    Figure PCTCN2022100017-appb-100010
    wherein each of said -C 3-C 8cycloalkylene-, * L1-O-C 1-8alkylene-** L1, * L1-C 1-8alkylene-O-** L1, * L1-SO 2-C 1-8alkylene-** L1, * L1-C 1-8alkylene-SO 2-** L1, * L1-CO-C 1-8alkylene-** L1, * L1-C 1-8alkylene-CO-** L1, * L1-NR L1a-C 1-8alkylene-** L1, * L1-C 1-8alkylene-NR L1a-** L1, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2- 8alkynylene-, 
    Figure PCTCN2022100017-appb-100011
    Figure PCTCN2022100017-appb-100012
    Figure PCTCN2022100017-appb-100013
    is optionally substituted with at least one R L1c;
    wherein * L1 refers to the position attached to the
    Figure PCTCN2022100017-appb-100014
    moiety, and ** L1 refers to the position attached to the
    Figure PCTCN2022100017-appb-100015
    moiety;
    R L1a and R L1b are each independently selected from hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R L1d;
    each of said R L1c and R L1d are independently oxo, halogen, hydroxy, -C 1-8alkyl, -C 1-8alkoxy, -C 2- 8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl; or
    two R L1c together with the atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, or -C 1-8alkyl;
    L 2 is selected from a single bond, -O-, -SO 2-, -CO-, -NR L2a-, -C 3-C 8cycloalkylene-, * L2-O-C 1- 8alkylene-** L2, * L2-C 1-8alkylene-O-** L2, * L2-SO 2-C 1-8alkylene-** L2, * L2-C 1-8alkylene-SO 2-** L2, * L2-CO-C 1-8alkylene-** L2, * L2-C 1-8alkylene-CO-** L2, * L2-NR L2a-C 1-8alkylene-** L2, * L2-C 1-8alkylene-NR L2a-** L2,  * L2-NR L2aC (O) -** L2, * L2-C (O) NR L2a-** L2, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2-8alkynylene-, - [O (CR L2aR L2b)  m4]  m5-, 
    Figure PCTCN2022100017-appb-100016
    Figure PCTCN2022100017-appb-100017
    wherein each of said -C 3-C 8cycloalkylene-, * L2-O-C 1-8alkylene-** L2, * L2-C 1-8alkylene-O-** L2, * L2-SO 2-C 1-8alkylene-** L2, * L2-C 1-8alkylene-SO 2-** L2, * L2-CO-C 1-8alkylene-** L2, * L2-C 1-8alkylene-CO-** L2, * L2-NR L2a-C 1-8alkylene-** L2, * L2-C 1-8alkylene-NR L2a-** L2, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2- 8alkynylene-, 
    Figure PCTCN2022100017-appb-100018
    Figure PCTCN2022100017-appb-100019
    Figure PCTCN2022100017-appb-100020
    is optionally substituted with at least one substituent R L2c;
    wherein * L2 refers to the position attached to
    Figure PCTCN2022100017-appb-100021
    moiety, and ** L2 refers to the position attached to the
    Figure PCTCN2022100017-appb-100022
    moiety;
    R L2a and R L2b are each independently selected from hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R L2d;
    each of said R L2c and R L2d are independently oxo, halogen, hydroxy, -C 1-8alkyl, -C 1-8alkoxy, -C 2- 8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl; or
    two R L2c together with the atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, -C 1-8alkyl;
    L 3 is selected from a single bond, -O-, -SO 2-, -CO-, -NR L3a-, -C 3-C 8cycloalkylene-, * L3-O-C 1- 8alkylene-** L3, * L3-C 1-8alkylene-O-** L3, * L3-SO 2-C 1-8alkylene-** L3, * L3-C 1-8alkylene-SO 2-** L3, * L3-CO-C 1-8alkylene-** L3, * L3-C 1-8alkylene-CO-** L3, * L3-NR L3a-C 1-8alkylene-** L3, * L3-C 1-8alkylene-NR L3a-** L3, * L3-NR L3aC (O) -** L3, * L3-C (O) NR L3a-** L3, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2-8alkynylene-, - [O (CR L3aR L3b)  m4]  m5-, 
    Figure PCTCN2022100017-appb-100023
    Figure PCTCN2022100017-appb-100024
    wherein each of said -C 3-C 8cycloalkylene-, * L3-O-C 1-8alkylene-** L3, * L3-C 1-8alkylene-O-** L3, * L3-SO 2-C 1-8alkylene-** L3, * L3-C 1-8alkylene-SO 2-** L3, * L3-CO-C 1-8alkylene-** L3, * L3-C 1-8alkylene-CO-** L3, * L3-NR L3a-C 1-8alkylene-** L3, * L3-C 1-8alkylene-NR L3a-** L3, -C 1-8alkylene-, -C 2-8alkenylene-, -C 2- 8alkynylene-, 
    Figure PCTCN2022100017-appb-100025
    Figure PCTCN2022100017-appb-100026
    Figure PCTCN2022100017-appb-100027
    is optionally substituted with at least one substituent R L3c;
    wherein * L3 refers to the position attached to
    Figure PCTCN2022100017-appb-100028
    moiety, and ** L3 refers to the position attached to the
    Figure PCTCN2022100017-appb-100029
    moiety;
    R L3a and R L3b are each independently selected from hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R L3d;
    each of said R L3c and R L3d are independently oxo, halogen, hydroxy, -C 1-8alkyl, -C 1-8alkoxy, -C 2- 8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl; or
    two R L3c together with the atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, or -C 1-8alkyl;
    R 12 is independently selected from hydrogen, halogen, -C 1-8alkyl, -NR 12aR 12b, -OR 12a, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo, or -CN; each of -C 1-8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 12c; or
    two R 12 together with the carbon atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R 12c;
    R 12a and R 12b are each independently selected from hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 12d; or
    R 12c and R 12d are each independently halogen, hydroxy, -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2- 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl;
    X 1, X 2, X 3 and X 4 are each independently selected from -CR a, or N;
    X 5, X 6 and X 7 are each independently selected from -NR a-, -O-, -S-and -CR aR b-;
    X 12 and X 13 are each independently selected from -C (O) -, -NR a-and -O-;
    Q 1, Q 2, Q 3 and Q 4 are each independently selected from CR a or N;
    Q 5 is each independently selected from -O-, -NR a-, -CR aR b-, -S-or -C (O) -;
    P 1 is a single bond, -O-, -NR a-, -CR aR b -, -S-, -SO-or -SO 2-;
    at each occurrence, R a and R b are each independently selected from hydrogen, hydroxy, halogen, CN, -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl, each of said -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2- 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, halogen, -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl; or
    R a and R b together with the carbon atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent halogen, hydroxy, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl;
    m 1 is 0 or 1;
    m 2 and m3 is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
    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 are each independently 0, 1, 2 or 3.
  10. The compound of claim 9, wherein L 1 is selected from a single bond, -C 1-8alkylene- (preferably -CH 2-, -C 2H 4-, -C 3H 6-) , -CO-, -O-, -N (CH 3) -, -NH-, 
    Figure PCTCN2022100017-appb-100030
    Figure PCTCN2022100017-appb-100031
    Figure PCTCN2022100017-appb-100032
  11. The compound of any one of claims 9-10, wherein X 1 and X 2 are each independently selected from -CR a or N;
    R a is selected from hydrogen, -F, -Cl, -Br, -I, CN, methyl, ethyl, methoxy, ethoxy, or cyclopropyl, wherein each of said methyl, ethyl, methoxy, ethoxy, and 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=1 or 0;
    R 12 is hydrogen, oxo, methoxymethyl, hydroxymethyl, -CN or -CH 3.
  12. The compound of any one of claims 9-11, wherein m 1 is 1; preferably, 
    Figure PCTCN2022100017-appb-100033
    moiety is
    Figure PCTCN2022100017-appb-100034
    Figure PCTCN2022100017-appb-100035
    Figure PCTCN2022100017-appb-100036
    Figure PCTCN2022100017-appb-100037
    wherein * X refers to the position attached to
    Figure PCTCN2022100017-appb-100038
    moiety, and ** X refers to the position attached to the
    Figure PCTCN2022100017-appb-100039
    moiety.
  13. The compound of any one of claims 9-12, wherein m 1 is 1, 
    Figure PCTCN2022100017-appb-100040
    moiety is
    Figure PCTCN2022100017-appb-100041
  14. The compound of any one of claims 9-13, wherein L 2 is selected from a single bond, -C 1-8alkylene- (preferably -CH 2-, -C 2H 4-, -C 3H 6-) , -CO-, -O-, -N (CH 3) -, -NH-, 
    Figure PCTCN2022100017-appb-100042
    Figure PCTCN2022100017-appb-100043
    Figure PCTCN2022100017-appb-100044
  15. The compound of any one of claims 9-14, wherein L 3 is selected from single bond, -C 1-8alkylene- (preferably -CH 2-, -C 2H 4-, -C 3H 6-) , -CO-, -O-, -N (CH 3) -, -NH-, 
    Figure PCTCN2022100017-appb-100045
    Figure PCTCN2022100017-appb-100046
    Figure PCTCN2022100017-appb-100047
  16. The compound of any one of claims 9-15, wherein L 2 is a single bond; or L 3 is a single bond; or L 2 is a single bond and L 3 is a single bond.
  17. The compound of any one of claims 9-16, wherein
    Figure PCTCN2022100017-appb-100048
    is selected from
    Figure PCTCN2022100017-appb-100049
    Figure PCTCN2022100017-appb-100050
    Figure PCTCN2022100017-appb-100051
    Figure PCTCN2022100017-appb-100052
  18. The compound of any one of claims 1-17, wherein Warhead is a moiety which binds to a target protein, wherein said target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism) , antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate) , receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, 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, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity and translation regulator activity.
  19. The compound of any one of claims 1-18, wherein Warhead is a moiety which binds to a target protein, wherein said target protein is selected from the group consisting of ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apotosis 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 (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH  trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug 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-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) , protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7) , farnesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channels, Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor associated kinase-3 (IRAK-3 or IRAK-M) or enolpyruvyl-shikimate-phosphate synthase.
  20. The compound of any one of claims 1-19, wherein Warhead is
    Figure PCTCN2022100017-appb-100053
    wherein R 13 is selected from -P (O) R 13aR 13b, -SO 2R 13a, -SO 2-NR 13aR 13b or -N (R 13a) -SO 2R 13b;
    R 13a and R 13b are each independently selected from hydrogen, -C 1-C 8alkyl or C 3-C 8cycloalkyl, said -C 1-C 8alkyl or C 3-C 8cycloalkyl is optionally substituted with at least one halogen;
    R 14 and R 15 are each independently selected from hydrogen, halogen, -C 1-C 8alkyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, -CN, -OR 14a, -SO 2R 14a, -SO 2NR 14aR 14b, -COR 14a, -CO 2R 14a, -CONR 14aR 14b, -NR 14aR 14b, -NR 14aCOR 14b, -NR 14aCO 2R 14b, or –NR 14aSO 2R 14b; each of -C 1-C 8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 14d, or
    R 14 and R 15 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated or saturated ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R 14e;
    R 14e, at each occurrence, is independently hydrogen, halogen, -C 1-C 8alkyl, -C 1-C 8alkoxy, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo (=O) , - OR 14a, thioxo (=S) , -SR 14a, -CN, -SO 2R 14a, -SO 2NR 14aR 14b, -COR 14a, -CO 2R 14a, -CONR 14aR 14b, -NR 14aR 14b, -NR 14aCOR 14b, -NR 14aCO 2R 14b or -NR 14aSO 2R 14b; each of -C 1-C 8alkyl, -C 1-C 8alkoxy, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 14d;
    R 14a and R 14b are each independently selected from hydrogen, -C 1-C 8alkyl, -C 1-C 8haloalkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 1-C 8alkoxy-C 1-C 8alkyl-, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl;
    R 14d, at each occurrence, is independently halogen, -OH, -CN, oxo, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, or 5-to 12-membered heteroaryl;
    R 4 is selected from hydrogen, halogen, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 1-C 8alkoxy, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, -CN, -SO 2R 4a, -SO 2NR 4aR 4b, -COR 4a, -CO 2R 4a, -CONR 4aR 4b, -NR 4aR 4b, -NR 4aCOR 4b, -NR 4aCO 2R 4b or -NR 4aSO 2R 4b; each of -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 1-C 8alkoxy, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with halogen, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo, -CN, -OR 4c, -SO 2R 4c, -SO 2NR 4cR 4d, -COR 4c, -CO 2R 4c, -CONR 4cR 4d, -NR 4cR 4d, -NR 4cCOR 4d, -NR 4cCO 2R 4d or -NR 4cSO 2R 4d;
    R 4a, R 4b, R 4c and R 4d are each independently hydrogen, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl;
    R 9, R 10 and R 11 are each independently selected from hydrogen, halogen, -C 1-C 8alkyl, -NR 9aR 9b, -OR 9a, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl, 5-to 12-membered heteroaryl, oxo or -CN; each of -C 1-C 8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 9c;
    R 9a and R 9b are each independently selected from hydrogen, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl; each of said -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 9d; or
    R 9c and R 9d are each independently halogen, hydroxy, -C 1-C 8alkyl, -C 1-C 8alkoxy, -C 2-C 8alkenyl, -C 2-C 8alkynyl, -C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, -C 6-C 12aryl or 5-to 12-membered heteroaryl;
    Z 4, Z 5, Z 6 and Z 7 are each independently selected from -CR Z4, or N;
    R Z4, at each occurrence, is independently selected from hydrogen, halogen, -C 1-C 8alkyl, -NR Z4aR Z4b, -OR Z4a, -SR Z4a, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, or CN; each of -C 1-C 8alkyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl is optionally substituted with at least one R Z4c;
    R Z4a and R Z4b are each independently selected from hydrogen, -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl,  each of said -C 1-C 8alkyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R Z4d;
    R Z4c and R Z4d are each independently halogen, hydroxy, -C 1-C 8alkyl, -C 1-C 8alkoxy, -C 2-C 8alkenyl, -C 2-C 8alkynyl, C 3-C 8cycloalkyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, or 5-to 12-membered heteroaryl.
  21. The compound of claim 20, wherein R 13 is selected from -P (O) R 13aR 13b or -N (R 13a) -SO 2R 13b, wherein R 13a and R 13b are each independently selected from hydrogen, -C 1-C 8alkyl (preferably -CH 3, -C 2H 5, -C 3H 7, -C 4H 9 or -C 5H 11; more preferably -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -iso-C 3H 7, -CH 2CH 2CH 2CH 3, -iso-C 4H 9, -sec-C 4H 9 or -tert-C 4H 9) or C 3-C 8cycloalkyl (preferably cyclopropyl, cyclobutyl or cyclopentyl) .
  22. The compound of claim 20, wherein R 13 is selected from -P (O) (CH 3)  2, -NH-SO 2CH 3 or -N (CH 3) -SO 2CH 3.
  23. The compound of claim 20, wherein R 13 is -P (O) (CH 3)  2.
  24. The compound of claim 20, wherein R 14 and R 15 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl, 5-to 12-membered heteroaryl, -CN, -OR 14a, -SO 2R 14a, -SO 2NR 14aR 14b, -COR 14a, -CO 2R 14a, -CONR 14aR 14b, -NR 14aR 14b, -NR 14aCOR 14b, -NR 14aCO 2R 14b, or –NR 14aSO 2R 14b; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, C 6-C 12aryl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 14d, or
    R 14 and R 15 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated or saturated ring, said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R 14e;
    R 14e, at each occurrence, is independently -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-to 8-membered heterocyclyl, 5-to 12-membered heteroaryl, oxo, -CN, CF 3, CHF 2, CH 2F, thioxo, -SCF 3, -SCHF 2, -SCH 2F, -SCH 2CF 3, -SCF 2CH 3, -SCF 2CF 3, -SO 2R 14a, -SO 2NR 14aR 14b, -COR 14a, -CO 2R 14a, -CONR 14aR 14b, -NR 14aR 14b, -NR 14aCOR 14b, -NR 14aCO 2R 14b or -NR 14aSO 2R 14b; 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, 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 14d;
    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, C 1-C 8alkoxy-C 1-C 8alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl;
    R 14d, at each occurrence, is independently halogen, -OH, 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.
  25. The compound of claim 20, wherein R 14 and R 15 together with the carbon atoms to which they are attached, form a 5 or 6-membered unsaturated (preferred aromatic) or saturated ring, said ring comprising 1 or 2 nitrogen heteroatoms; said ring is optionally substituted with 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, -CH 2OH, -SCH 3, -SC 2H 5, oxo, thioxo, -CF 3, -CHF 2, -CH 2F, -SCF 3, -OMe, -OC 2H 5, -CN, -C (O) CH 3, 
    Figure PCTCN2022100017-appb-100054
  26. The compound of claim 20, wherein R 14 and R 15 together with the carbon atoms to which they are attached, form a 6-membered unsaturated (preferred aromatic) , said ring comprising 1 or 2 nitrogen heteroatoms; said ring is optionally substituted with one substituent -H, -F, -Cl, -Br, -I, methyl, ethyl or cyclopropyl.
  27. The compound of claim 20, wherein R 4 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl or -C 1-C 8alkoxy; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-C 8alkenyl or -C 2-C 8alkynyl is optionally substituted with -F, -Cl, -Br, -I, oxo, or -CN.
  28. The compound of claim 20, wherein R 4 is hydrogen, -F, -Cl, -Br, -I, -CH 3, -CF 3, -CH 2F, or -CHF 2.
  29. The compound of claim 20, wherein R 4 is hydrogen, -F, -Cl, -Br or -I.
  30. The compound of claim 20, wherein R 9, R 10 and R 11 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR 9aR 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 -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 is optionally substituted with at least one substituent R 9c;
    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, each of said 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 is optionally substituted with at least one substituent R 9d;
    R 9c and R 9d are each 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-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl.
  31. The compound of claim 20, wherein R 9, R 10 and R 11 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, -NH 2, -NHCH 3, -OH, -OCH 3, -OC 2H 5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2OH, -CH 2OMe, oxo, or -CN.
  32. The compound of claim 20, wherein R 9, R 10 and R 11 are each independently selected from hydrogen, -CH 3, -F, -Cl, -Br or -I.
  33. The compound of claim 20, wherein Z 4, Z 5, Z 6 and Z 7 are each independently -CR 4z;
    R 4Z, at each occurrence, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR 4ZaR 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 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 is optionally substituted with at least one R 4Zc;
    R 4Za and R 4Zb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl, each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-C 8alkenyl, -C 2-C 8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl or 5-to 12-membered heteroaryl is optionally substituted with at least one substituent R 4Zd;
    R 4Zc and R 4Zd are each independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1-C 8alkoxy, -C 2-C 8alkenyl, -C 2-C 8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-to 8-membered heterocyclyl, phenyl, or 5-to 12-membered heteroaryl.
  34. The compound of claim 20, wherein R 4z is selected from H, -CH 3, -C 2H 5, F, -CH 2F, -CHF 2, -CF 3, -OCH 3, -OC 2H 5, -C 3H 7, -OCH 2F, -OCHF 2, -OCH 2CF 3, -OCF 3, -SCF 3, -CF 3, -CH (OH) CH 3, 
    Figure PCTCN2022100017-appb-100055
    Figure PCTCN2022100017-appb-100056
  35. The compound of any one of claims 1-19, wherein Warhead is
    Figure PCTCN2022100017-appb-100057
    wherein
    Figure PCTCN2022100017-appb-100058
    is a 5-or 6-membered aromatic ring comprising 0-3 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 1-8alkyl, -C 1- 8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 10a, -SO 2R 10a, -COR 10a, -CO 2R 10a, -CONR 10aR 10b, -C (=NR 10a) NR 10bR 10c, -NR 10aR 10b, -NR 10aCOR 10b, -NR 10aCONR 10bR 10c, -NR 10aCO 2R 10b, -NR 10aSONR 10bR 10c, -NR 10aSO 2NR 10bR 10c, or –NR 10aSO 2R 10b, each of said -C 1-8alkyl, -C 2- 8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    R 109 is 5-or 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur; said aromatic ring is optionally substituted with halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, -C 1-8alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 10a, -SO 2R 10a, -COR 10a, -CO 2R 10a, -CONR 10aR 10b, -C (=NR 10a) NR 10bR 10c, -NR 10aR 10b, -NR 10aCOR 10b, -NR 10aCONR 10bR 10c, -NR 10aCO 2R 10b, -NR 10aSONR 10bR 10c, -NR 10aSO 2NR 10bR 10c, or –NR 10aSO 2R 10b, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2- 8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, 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 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  36. The compound of claim 35, wherein
    Figure PCTCN2022100017-appb-100059
    is
    Figure PCTCN2022100017-appb-100060
    Figure PCTCN2022100017-appb-100061
    wherein Z 8, Z 9, Z 10 and Z 11 are each independently selected from CH or N; wherein *cy1 refers to the position attached to the
    Figure PCTCN2022100017-appb-100062
    moiety, and **cy1 refers to the position attached to L 1.
  37. The compound of claim 35, wherein
    Figure PCTCN2022100017-appb-100063
    is selected from
    Figure PCTCN2022100017-appb-100064
    Figure PCTCN2022100017-appb-100065
  38. The compound of claim 35, wherein p3 is 0, 1, or 2, and each R 107 is independently selected from halogen, -C 1-8alkyl, or -C 1-8alkoxy, preferably F, Cl, Br, I, CH 3, or -OCH 3.
  39. The compound of claim 35, wherein R 10a and R 10b are independently selected from hydrogen or CH 3; and n1 is 1 or 2.
  40. The compound of claim 35, wherein R 101 is methyl, -CH 2OH, -OCH 3, -CH 2OCH 3 or halogen; p1 is 0 or 1, and R 102 is halogen.
  41. The compound of claim 35, wherein R 103 and R 105 are hydrogen; and R 104 is selected from hydrogen or methyl.
  42. The compound of claim 35, wherein R 109 is
    Figure PCTCN2022100017-appb-100066
    Y 101, Y 102, Y 103 and Y 104 are selected from CH, O, S or N; R 111 is selected from hydrogen, halogen, -C 1-8alkyl, -C 1-8alkoxy, -C 2- 8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 10a, -SO 2R 10a, -COR 10a, -CO 2R 10a, -CONR 10aR 10b, -C (=NR 10a) NR 10bR 10c, -NR 10aR 10b, -NR 10aCOR 10b, -NR 10aCONR 10bR 10c, -NR 10aCO 2R 10b, -NR 10aSONR 10bR 10c, -NR 10aSO 2NR 10bR 10c, or –NR 10aSO 2R 10b, each of said -C 1-8alkyl, -C 2- 8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 10a, R 10b, and R 10c are each independently hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and p6 is 0, 1, 2, 3 or 4.
  43. The compound of claim 35, wherein Y 101 is CH, S, N or O; Y 102 is CH, O or N; Y 103 is O, S or N; and Y 104 is S, CH or N.
  44. The compound of any one of claims 1-19, wherein Warhead is
    Figure PCTCN2022100017-appb-100067
    ring A 201 and B 201 are each independently an aromatic ring comprising 0-3 heteroatoms selected from nitrogen, sulfur and oxygen as ring member (s) ;
    Z 201, Z 203 and Z 204 are each independently N or CR 20z;
    L 201 is independently a bond, -C 1-8alkylene-, -N (R 204) -, -O-, -S-,  *L201-C 1-8alkylene-O- **L201,  *L201-O-C 1-8alkylene- **L201,  *L201-N (R 204) CO- **L201,  *L201-CON (R 204) - **L201,  *L201-N (R 204) CO-C 1-8alkylene- **L201,  *L201-CON (R 204) -C 1-8alkylene- **L201,  *L201-N (R 204) -C 1-8alkylene- **L201,  *L201-C 1-8alkylene-N (R 204) - **L201, -heterocyclene-, or -heteroarylene-, wherein each of said -C 1-8alkylene-,  *L201-C 1-8alkylene-O- **L201,  *L201-O-C 1-8alkylene- **L201,  *L201-N (R 204) CO-C 1-8alkylene- **L201,  *L201-CON (R 204) -C 1-8alkylene- **L201,  *L201-N (R 204) -C 1-8alkylene- **L201,  *L201-C 1-8alkylene-N (R 204) - **L201, -heterocyclene-and -heteroarylene-is optionally substituted with at least one substituent R 20L;
    wherein * L201 refers to the position attached to ring A, and ** L201 refers to the position attached 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 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    R 20L, R 203, R 205 and R 206 are each independently hydrogen, halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2- 8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 20a, -SO 2R 20a, -COR 20a, -CO 2R 20a, - CONR 20aR 20b, -C (=NR 20a) NR 20bR 20c, -NR 20aR 20b, -NR 20aCOR 20b, -NR 20aCONR 20bR 20c, -NR 20aCO 2R 20b, -NR 20aSONR 20bR 20c, -NR 20aSO 2NR 20bR 20c, or –NR 20aSO 2R 20b, wherein each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one halogen, hydroxy, -C 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    R 20z is selected from hydrogen, halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 20a, -SO 2R 20a, -COR 20a, -CO 2R 20a, -CONR 20aR 20b, -C (=NR 20a) NR 20bR 20c, -NR 20aR 20b, -NR 20aCOR 20b, -NR 20aCONR 20bR 20c, -NR 20aCO 2R 20b, -NR 20aSONR 20bR 20c, -NR 20aSO 2NR 20bR 20c, or –NR 20aSO 2R 20b, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one halogen, hydroxy, -C 1-8alkyl, -C 1- 8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    R 20a, R 20b, and R 20c are each independently hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    or two R 20L, together with the atom (s) to which they are attached, form a 3-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2, -OR 203f, -SO 2R 203f, -SO 2NR 203fR 203g, -COR 203f, -CO 2R 203f, -CONR 203fR 203g, -C (=NR 203f) NR 203gR 203h, -NR 203fR 203g, -NR 203fCOR 203g, -NR 203fCONR 203gR 203h, -NR 203fCO 2R 203f, -NR 203fSONR 203fR 203g, -NR 203fSO 2NR 203gR 203h, or –NR 203fSO 2R 203g, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2- 8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, -C 1-8alkyl, -OR 203i, -NR 203iR 203j, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    or two R 203, together with the atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2, -OR 203f, -SO 2R 203f, -SO 2NR 203fR 203g, -COR 203f, -CO 2R 203f, -CONR 203fR 203g, -C (=NR 203f) NR 203gR 203h, -NR 203fR 203g, -NR 203fCOR 203g, -NR 203fCONR 203gR 203h, -NR 203fCO 2R 203f, -NR 203fSONR 203fR 203g, -NR 203fSO 2NR 203gR 203h, or –NR 203fSO 2R 203g, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2- 8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, -C 1-8alkyl, -OR 203i, -NR 203iR 203j, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    or R 4 and one of R 3, together with the atoms to which they are attached, form a 3-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2, -OR 203f, -SO 2R 203f, -SO 2NR 203fR 203g, -COR 203f, -CO 2R 203f, -CONR 203fR 203g, -C (=NR 203f) NR 203gR 203h, -NR 203fR 203g, -NR 203fCOR 203g, -NR 203fCONR 203gR 203h, -NR 203fCO 2R 203f, -NR 203fSONR 203fR 203g, -NR 203fSO 2NR 203gR 203h, or –NR 203fSO 2R 203g, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, -C 1-8alkyl, -OR 203i, -NR 203iR 203j, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    R 203f, R 203g, R 203h, R 203i, and R 203j are each independently hydrogen, -C 1-8alkyl, C 1-8alkoxy-C 1-8alkyl-, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  45. The compound according to any one of Claims 44, wherein L 201 is a bond, -CH 2-, -C 2H 4-, -C 3H 6-, -C 4H 8-, -C 5H 10-, -O-, -NH-,  *L201-NHCH 2- **L201,  *L201-NHC 2H 4- **L201,  *L201-NHC 3H 6- **L201,  *L201-NHC 4H 8- **L201,  *L201-NHC 5H 10- **L201,  *L201-OCH 2- **L201,  *L201-OC 2H 4- **L201,  *L201-OC 3H 6- **L201,  *L201-OC 4H 8- **L201,  *L201-OC 5H 10- **L201,  *L201-CH 2O- **L201,  *L201-C 2H 4O- **L201,  *L201-C 3H 6O- **L201,  *L201-C 4H 8O- **L201,  *L201-C 5H 10O- **L201,  *L201-CONH- **L201,  *L201-NHCO- **L201,  *L201-CONHCH 2- **L201,  *L201-CONHC 2H 4- **L201,  *L201-CONHC 3H 6- **L201,  *L201-CONHC 4H 8- **L201,  *L201-CONHC 5H 10- **L201, 3-to 8-membered -heterocyclene-or 5-to 6-membered -heteroarylene-; wherein each of said -CH 2-, -C 2H 4-, -C 3H 6-, -C 4H 8-, -C 5H 10-, -O-, -NH-,  *L201-NHCH 2- **L201,  *L201-NHC 2H 4- **L201,  *L201-NHC 3H 6- **L201,  *L201-NHC 4H 8- **L201,  *L201-NHC 5H 10- **L201,  *L201-OCH 2- **L201,  *L201-OC 2H 4- **L201,  *L201-OC 3H 6- **L201,  *L201-OC 4H 8- **L201,  *L201-OC 5H 10- **L201,  *L201-CH 2O- **L201,  *L201-C 2H 4O- **L201,  *L201-C 3H 6O- **L201,  *L201-C 4H 8O- **L201,  *L201-C 5H 10O- **L201,  *L201-CONH- **L201,  *L201-NHCO- **L201,  *L201-CONHCH 2- **L201,  *L201-CONHC 2H 4- **L201,  *L201-CONHC 3H 6- **L201,  *L201-CONHC 4H 8- **L201,  *L201-CONHC 5H 10- **L201, 3-to 8-membered heterocyclene-and 5-to 6-membered heteroarylene-is optionally substituted with at least one substituent R 20L; wherein R 20L is defined as above.
  46. The compound according to Claim 44, wherein L 201 is a bond, -O-,  *L201-OCH 2- **L201,  *L201-CH 2O- **L201, -NH-,  *L201-CONH- **L201,  *L201-NHCO- **L201,  *L201-CONHCH 2- **L201,  *L201-CONHCH 2CH 2- **L201,  *L201-CONHCH 2CH 2CH 2- **L201,  *L201-CONHCH (CH 3) - **L201,  *L201-CONHCH (C 2H 5) - **L201,  *L201-NHCH 2- **L201,  *L201-NHCH 2CH 2- **L201,  *L201-NHCH 2CH 2CH 2- **L201,  *L201-NHCH (CH 3) - **L201 or  *L-NHCH (C 2H 5) - **L.
  47. The compound according to Claim 44, wherein L 201 is  *L201-N (R 204) CO- **L201,
    R 203 and R 204, together with the atoms to which they are attached, form a 5-, 6-or 7-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, cycloalkyl, heterocyclyl, aryl, heteroaryl, or oxo.
  48. The compound according to Claim 44, wherein
    Figure PCTCN2022100017-appb-100068
    moiety is
    Figure PCTCN2022100017-appb-100069
    Figure PCTCN2022100017-appb-100070
    Figure PCTCN2022100017-appb-100071
    wherein Z 205, Z 206, Z 207, Z 208, Z 209, Z 206’, Z 207’, Z 208’ and Z 209’ are each independently N or C (H) ; Z 210 is N (H) , O or S.
  49. The compound according to Claim 44, wherein ring A201 is a 5-to 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, sulfur and oxygen as ring member (s) .
  50. The compound according to Claim 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.
  51. The compound according to Claim 44, wherein the
    Figure PCTCN2022100017-appb-100072
    moiety is
    Figure PCTCN2022100017-appb-100073
  52. The compound according to Claim 44, wherein R 203 is hydrogen, oxo, -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9, -OC 5H 11, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyrrolyl or phenyl, wherein each of said -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9, -OC 5H 11, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyrrolyl or phenyl, is optionally substituted with at least one -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9, -OC 5H 11, -OH, cyclopropyl, cyclobutyl or cyclopentyl.
  53. The compound according to Claim 44, wherein 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.
  54. The compound according to Claim 44, wherein two R 203, together with the atoms to which they are attached, form a 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9, -OC 5H 11, -OH, -CN, cyclopropyl, cyclobutyl or cyclopentyl.
  55. The compound according to Claim 44, wherein the
    Figure PCTCN2022100017-appb-100074
    moiety is
    Figure PCTCN2022100017-appb-100075
    Figure PCTCN2022100017-appb-100076
  56. The compound according to Claim 44, wherein the
    Figure PCTCN2022100017-appb-100077
    moiety is
    Figure PCTCN2022100017-appb-100078
    wherein Z 205, Z 206, Z 207 and Z 208 are defined as above.
  57. The compound according to Claim 44, wherein the
    Figure PCTCN2022100017-appb-100079
    moiety is
    Figure PCTCN2022100017-appb-100080
  58. The compound according to Claim 44, wherein 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 substituted with (R 206)  q201.
  59. The compound according to Claim 44, wherein R 206 is hydrogen, -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -CN, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9 or -OC 5H 11, wherein each of said -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -OCH 3, -OC 2H 5, -OC 3H 7, -OC 4H 9 or -OC 5H 11 is optionally substituted with -F, -Cl, -Br, -I, hydroxy, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  60. The compound according to Claim 44, wherein the
    Figure PCTCN2022100017-appb-100081
    moiety is
    Figure PCTCN2022100017-appb-100082
    Figure PCTCN2022100017-appb-100083
  61. The compound according to Claim 44, wherein R 201 and R 202 are each independently hydrogen, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -C 2-8alkenyl, -C 2-8alkynyl or aryl.
  62. The compound according to Claim 44, wherein R 201 and R 202 are both H.
  63. The compound according to any one of Claims 1-27, wherein R 205 is independently hydrogen, -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -C 2-8alkenyl, -C 2-8alkynyl or aryl.
  64. The compound according to Claim 44, wherein R 20z is hydrogen, -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9 or -C 5H 11.
  65. The compound according to any one of Claims 44 to 64, wherein the
    Figure PCTCN2022100017-appb-100084
    moiety is
    Figure PCTCN2022100017-appb-100085
    Figure PCTCN2022100017-appb-100086
    Figure PCTCN2022100017-appb-100087
    Figure PCTCN2022100017-appb-100088
    Figure PCTCN2022100017-appb-100089
  66. The compound of any one of claims 1-19, wherein Warhead is
    Figure PCTCN2022100017-appb-100090
    wherein:
    Cy302 is a 5-or 6-membered saturated ring or unsaturated ring (preferably aromatic ring) comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member (s) ;
    each of occurrence, R 301, R 302, R 303, R 304 and R 308 are each independently hydrogen, halogen, -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O) , -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    R 306 and R 307 are each independently hydrogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    R 305 is 5-or 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member (s) ; said aromatic ring is optionally substituted with halogen, -C 1-8alkyl, -C 2- 8alkenyl, -C 2-8alkynyl, -C 1-8alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said -C 1-8alkyl, -C 2- 8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with -C 1-8alkyl, halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, 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 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
    (R 30c and R 30d) or (R 30d and R 30e) together with the atom (s) to which they are attached, form a 3-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one  substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2.
  67. The compound of Claim 66, wherein
    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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, -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 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2.
  68. The compound of any claim of Claims 66-67, wherein 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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO 2; preferably R1 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl.
  69. The compound of any claim of Claims 66-68, wherein
    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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, -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 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,  octyl, -C 2-8alkenyl, -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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2.
  70. The compound of any claim of Claims 66-69, wherein 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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO 2; preferably R 302 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN or -NO 2.
  71. The compound of any claim of Claims 66-70, wherein
    R 303 and R 304 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8alkenyl, -C 2- 8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, -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 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2.
  72. The compound of any claim of Claims 66-71, wherein 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 are each independently hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl or cyclopentyl.
  73. The compound of any claim of Claims 66-72, wherein the
    Figure PCTCN2022100017-appb-100091
    moiety is
    Figure PCTCN2022100017-appb-100092
    Figure PCTCN2022100017-appb-100093
    wherein *303 refers to the position attached to the
    Figure PCTCN2022100017-appb-100094
    moiety, and **303 refers to the position attached to
    Figure PCTCN2022100017-appb-100095
    moiety.
  74. The compound of any claim of Claims 66-73, wherein R 306 and R 307 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; preferably, R 306 and R 307 are each independently H, methyl, ethyl, propyl butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  75. The compound of any claim of Claims 66-74, wherein R 305 is
    Figure PCTCN2022100017-appb-100096
    Y 301, Y 302, Y 303 and Y 304 are each independently selected from CH, O, S or N; R 315 is each independently selected from hydrogen, halogen, -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said -C 1-8alkyl, -C 1-8alkoxy, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 30c, R 30d, and R 30e are each independently defined as in claim 66; and p307 is 0, 1, 2, 3 or 4.
  76. The compound of Claim 75, wherein Y 301 is CH, S, N or O; Y 302 is CH, S, O or N; Y 303 is CH, O, S or N; and Y 304 is CH, O, S or N.
  77. The compound of Claim 75, wherein
    Figure PCTCN2022100017-appb-100097
    is selected from
    Figure PCTCN2022100017-appb-100098
    Figure PCTCN2022100017-appb-100099
  78. The compound according to Claim 75, wherein, R 315 is selected from -H, -F, -Cl, -Br, -I, -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -C 6H 13, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8alkenyl, -C 2-8alkynyl, -CH 2OH, -CH 2CH 2OH, -CH (OH) CH 3, -CH 2CH 2CH 2OH, -CH (OH) CH 2CH 3, -CH 2CH (OH) CH 3, -CH 2OCH 3, -CFH 2, -CF 2H, -CF 3, -CH 2CF 3, -CH 2CH 2CF 3, each of said -CH 3, -C 2H 5, -C 3H 7, -C 4H 9, -C 5H 11, -C 6H 13, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8alkenyl, -C 2-8alkynyl is optionally substituted with at least one F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, -C 1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  79. The compound according to Claim 75, wherein, R 315 is selected from
    Figure PCTCN2022100017-appb-100100
    Figure PCTCN2022100017-appb-100101
  80. The compound of any claim of Claims 66-79, wherein the
    Figure PCTCN2022100017-appb-100102
    moiety is
    Figure PCTCN2022100017-appb-100103
    Figure PCTCN2022100017-appb-100104
  81. The compound of any claim of Claims 66-80, wherein Cy302 is a 5-or 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur as ring member (s) .
  82. The compound of any claim of Claims 66-81, wherein
    Figure PCTCN2022100017-appb-100105
    is
    Figure PCTCN2022100017-appb-100106
    Figure PCTCN2022100017-appb-100107
    Y 301, Y 302, Y 303 and Y 304 are each independently defined as in claim 66;
    wherein *Cy302 refers to the position attached to -N (R 307) -in the
    Figure PCTCN2022100017-appb-100108
    moiety, and **Cy302 refers to the position attached to
    Figure PCTCN2022100017-appb-100109
    moiety.
  83. The compound of any claim of Claims 66-82, wherein
    Figure PCTCN2022100017-appb-100110
    is
    Figure PCTCN2022100017-appb-100111
    Figure PCTCN2022100017-appb-100112
  84. The compound of any claim of Claims 66-83, wherein
    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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, -OR 30c, -SO 2R 30c, -COR 30c, -CO 2R 30c, -CONR 30cR 30d, -C (=NR 30c) NR 30dR 30e, -NR 30cR 30d, -NR 30cCOR 30d, -NR 30cCONR 30dR 30e, -NR 30cCO 2R 30d, -NR 30cSONR 30dR 30e, -NR 30cSO 2NR 30dR 30e, or –NR 30cSO 2R 30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC 1-8alkyl, -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 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8alkenyl, -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 atom (s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with at least one substituent independently selected from halogen, -C 1-8alkyl, -C 2-8alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2.
  85. The compound of any claim of Claims 66-84, wherein 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 2-8alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO 2; preferably R2 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN or -NO 2.
  86. The compound of any claim of Claims 66-85, wherein
    Figure PCTCN2022100017-appb-100113
    is
    Figure PCTCN2022100017-appb-100114
  87. The compound of any claim of claims 66-85, wherein the
    Figure PCTCN2022100017-appb-100115
    moiety is selected from
    Figure PCTCN2022100017-appb-100116
    Figure PCTCN2022100017-appb-100117
    Figure PCTCN2022100017-appb-100118
  88. A pharmaceutical composition comprising a compound of any one of Claims 1-87 or a pharmaceutically acceptable salt, tautomer or prodrug thereof, together with a pharmaceutically acceptable excipient.
  89. A method of treating a disease that can be treated by degrading the target protein that the Warhead can combine.
  90. The method of claim 89, wherein said target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism) , antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate) , receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, 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, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity and translation regulator activity.
  91. The method of claim 89, wherein Warhead is a moiety which binds to a target protein, wherein said target protein is selected from the group consisting of ErbB receptors, B7.1 and B7, TINFR1m, TNFR2,  NADPH oxidase, Bcl-Bax and other partners in the apotosis 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 (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug 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-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) , protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7) , farnesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channels, Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor associated kinase-3 (IRAK-3 or IRAK-M) or enolpyruvyl-shikimate-phosphate synthase.
  92. The method of claim 89, wherein the disease is cancer.
  93. A compound of Formula (I) :
    Figure PCTCN2022100017-appb-100119
    or a pharmaceutically acceptable salt thereof, or a deuterated analog thereof, or a prodrug thereof, wherein:
    Warhead, Linker, s2, Z 1, Z 2, Z 3, R 1 and R 2 are as defined as any preceding claims;
    s1 is 0.
  94. A method of binding and altering the specificity of cereblon complex to induce the degradation of a complex-associated protein by using the compound of Claim 93, wherein the protein is selected from ErbB receptors, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl-Bax and other partners in the apotosis 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 (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G  Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug 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-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RAS-RAF-MEK-ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) , protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X 1-7) , farnesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channels, Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, L-1 receptor associated kinase-3 (IRAK-3 or IRAK-M) , enolpyruvyl-shikimate-phosphate synthase or neo-substrates (like IKZF1, IKZF3, and CK1a) .
  95. A method of treating an CRBN-mediated disorder, disease, or condition in a patient comprising administering to said patient the pharmaceutical composition of claim 93, preferably, the disorder disease, or condition is selected from proliferative disorders, neurological disorders and disorder associated with transplantation.
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