(R)-Glutarimide CRBN Ligands and Methods of Use

2024

Online Patent

Zugriff:

View record in USPTO Patent Applications (Volltext)

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 of tumors and cancers.

Titel:	(R)-Glutarimide CRBN Ligands and Methods of Use
Link:	View record in USPTO Patent Applications (Volltext)
Veröffentlichung:	2024
Medientyp:	Patent
Sonstiges:	Nachgewiesen in: USPTO Patent Applications Sprachen: English Document Number: 20240207267 Publication Date: June 27, 2024 Appl. No: 18/391154 Application Filed: December 20, 2023 Assignees: BeiGene Switzerland GmbH (Basel, CH) Claim: 1. A compound of Formula (I): [chemical expression included] 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 [chemical expression included] moiety; s1 is 0 or 1; s2 is 0 or 1; Z1, Z2 and Z3 are each independently N or CRz, provided that Z1, Z2 and Z3 are not N at the same time; Rz, at each occurrence, is independently selected from hydrogen, halogen, —C1-8alkyl, —NRZaRZb, —ORZa, —SRZa, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl or CN; each of —C1-8alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl is optionally substituted with at least one RZc; the [chemical expression included] moiety is linked to the [chemical expression included] moiety via any one of Z1, Z2 or Z3 which is CRz and Rz is hydrogen; RZa and RZb are each independently selected from hydrogen, —C1-C8alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RZd; RZc and RZd are each independently halogen, hydroxy, —C1-C8alkyl, C3-C8cycloalkyl, —C1-8alkoxy, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl; R1 and R2 are each independently selected from halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —SO2R1a, —SO2NR1aR1b, —COR1a, —CO2R1a, —CONR1aR1b, —NR1aR1b, —NR1aCOR1b, —NR1aCO2R1b, or —NR1aSO2R1b; each of —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, oxo, —CN, —OR1c, —SO2R1c, —SO2NR1cR1d, —COR1c, —CO2R1c, —CONR1cR1d, —NR1cR1d, —NR1cOR1d, —NR1cCO2R1d, or —NR1cSO2R1d; R1a, R1b, R1c and R1d are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl. Claim: 2. The compound of claim 1, wherein at most one of Z1, Z2 and Z3 is N. Claim: 3. The compound of any one of claims 1-2, wherein Z1, Z2 and Z3 are each independently CRz. Claim: 4. The compound of any one of claims 1-3, wherein RZ, at each occurrence, is independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —NRZaRZb, —ORZa, —SRZa, 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 RZc; RZa and RZb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-8alkenyl, —C2-8alkynyl, 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, —C2-8alkenyl, —C2-8alkynyl, 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 RZd; RZc and RZd are each independently —F, —Cl, —Br, —I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl. Claim: 5. The compound of any one of claims 1-4, wherein Rz is selected from H, —CH3, —C2H5, F, —CH2F, —CHF2, —CF3, —OCH3, —OC2H5, —C3H7, —OCH2F, —OCHF2, —OCH2CF3, —OCF3, —SCF3, —CF3 or —CH(OH)CH3. Claim: 6. The compound of any one of claims 1-5, wherein R1 and R2 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, —C2-8alkenyl, —C2-8alkynyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —SO2R1a, —SO2NR1aR1b, —COR1a, —CO2R1a, —CONR1aR1b, —NR1aR1b, —NR1aCOR1b, —NR1aCO2R1b, or —NR1aSO2R1b; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —C2-8alkenyl, —C2-8alkynyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 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, —C2-8alkenyl, —C2-8alkynyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, oxo, —CN, —OR1c, —SO2R1c, —SO2NR1cR1d, —COR1c, —CO2R1c, —CONR1cR1d, —NR1cR1d, —NR1cCOR1d, —NR1cCO2R1d, or —NR1cSO2R1d; R1a, R1b, R1c and R1d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —C2-8alkenyl, —C2-8alkynyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, or 5- to 12-membered heteroaryl. Claim: 7. The compound of any one of claims 1-6, wherein R1 and R2 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, —CH2F, —CHF2, —CF3, —OCH2F, —OCHF2, —OCH2CF3, —OCF3, —SCF3, or phenyl. Claim: 8. The compound of any one of claims 1-7, wherein the compound is Formula (II) [chemical expression included] wherein Warhead and Linker are defined as claim 1. Claim: 9. The compound of any one of claims 1-8, wherein Linker is [chemical expression included] wherein * refers to the position attached to the [chemical expression included] moiety, and ** refers to the position attached to the [chemical expression included] moiety; L1 is selected from a single bond, —O—, —SO2—, —C(O)—, —NRL1a—, —C3-C8cycloalkylene-, L1-O—C1-8alkylene-L1, L1-C1-8alkylene-O-*L1, L1-SO2—C1-8alkylene-*L1, L1-C1-8alkylene-SO2-*L1, L1-CO—C1-8alkylene-*L1, L1-C1-8alkylene-CO-*L1, L1-NRL1a—C1-8alkylene-*L1, L1-C1-8alkylene-NRL1a-*L1, L1-NRL1aC(O)-*L1, L1-C(O)NRL1a-*L1, —C1-8alkylene, —C2-8alkenylene, —C2-8alkynylene, —[O(CRL1aRL1b)m4]m5—, [chemical expression included] wherein each of said —C3-C8cycloalkylene-, L1-C1-8alkylene*L1, L1-C1-8alkylene-O-*L1, L1-SO2—C1-8alkylene-*L1, L1-C1-8-alkylene-SO2-*L1, L1-CO—C1-8alkylene-*L1, L1-C1-8alkylene-CO-*L1, L1-NRL1a—C1-8alkylene-*L1, L1-C1-8alkylene-NRL1a-*L1, —C1-8alkylene-, —C2-8alkenylene-, —C2-8alkynylene-, [chemical expression included] is optionally substituted with at least one RL1c; wherein L1 refers to the position attached to the [chemical expression included] moiety, and *L1 refers to the position attached to the [chemical expression included] moiety; RL1a and RL1b are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RL1d; each of said RL1c and RL1d are independently oxo, halogen, hydroxy, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl; or two RL1c 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 —C1-8alkyl; L2 is selected from a single bond, —O—, —SO2—, —CO—, —NRL2a—, —C3-C8cycloalkylene-, L2-O—C1-8alkylene-*L2, L2-C1-8alkylene-O-*L2, L2-SO2—C1-8alkylene-*L2, L2-C1-8alkylene-SO2-*L2, L2-CO—C1-8alkylene-*L2, L2-C1-8alkylene-CO-*L2, L2-NRL2a—C1-8-alkylene-*L2, L2-C1-8alkylene-NRL2a-*L2, L2-NRL2aC(O)-*L2, L2-C(O)NRL2a-*L2, —C1-8alkylene-, —C2-8alkenylene, —C2-8-alkynylene-, —[O(CRL2aRL2b)m4]m5-, [chemical expression included] wherein each of said —C3-C8cycloalkylene-, L2-O—C1-8alkylene-*L2, L2-C1-8alkylene-O-*L2, L2-SO2—C1-8alkylene-*L2, L2-C1-8alkylene-SO2-*L2, L2-CO—C1-8alkylene-*L2, L2-C1-8alkylene-CO-*L2, L2-NRL2a—C1-8alkylene-*L2, L2-C1-8alkylene-NRL2a-*L2, —C1-8alkylene-, —C2-8alkenylene-, —C2-8alkynylene-, [chemical expression included] is optionally substituted with at least one substiutent RL2c; wherein L2 refers to the position attached to [chemical expression included] moiety, and *L2 refers to the position attached to the [chemical expression included] moiety; RL2a and RL2b are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C-C2aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RL2d; each of said RL2c and RL2d are independently oxo, halogen, hydroxy, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl; or two RL2c 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, —C1-8alkyl; L3 is selected from a single bond, —O—, —SO2—, —CO—, —NRL3a—, —C3-C8cycloalkylene-, L3-OC1-8alkylene-*L3, L3-C1-8alkylene-O-*L3, L3-SO2—C1-8alkylene-*L3, L3-C1-8alkylene-SO2-*L3, L3-CO—C1-8alkylene-*L3, L3-C1-8alkylene-CO-*L3, L3-NRL3a—C1-8alkylene-*L3, L3-C1-8alkylene-NRL3a-*L3, L3-NRL3aC(O)-*L3, L3-C(O)NRL3a-*L3, —C1-8 alkylene- —C2-8alkenylene-, —C2-8alkynylene-, —[O(CRL3aRL3b)m4]m5—, [chemical expression included] wherein each of said —C3-C5cycloalkylene-, L3-O—C1-8alkylene-*L3, L3-C1-8alkylene-O-*L3, L3-SO2—C1-8alkylene-*L3, L3-C1-8alkylene-SO2-*L3, L3-CO—C1-8alkylene-*L3, L3-C1-8alkylene-CO-*L3, L3-NRL3aC1-8alkylene-*L3, L3-C1-8alkylene-NRL3a-*L3-C1-8alkylene-, —C2-8alkenylene-, —C2-8alkynylene-, [chemical expression included] is optionally substituted with at least one substituent RL3c; wherein L3 refers to the position attached to [chemical expression included] moiety, and *L3 refers to the position attached to the [chemical expression included] moiety; RL3a and RL3b are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RL3d; each of said RL3c and RL3d are independently oxo, halogen, hydroxy, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl; or two RL3c 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 —C1-8alkyl; R12 is independently selected from hydrogen, halogen, —C1-8alkyl, —NR12aR12b, —OR12a, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, oxo, or —CN; each of —C1-8alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R12c; or two R12 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 R12c; R12a and R12b are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R12d; or R12c and R12d are each independently halogen, hydroxy, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl; X1, X2, X3 and X4 are each independently selected from —CRa, or N; X5, X6 and X7 are each independently selected from —NRa—, —O—, —S— and —CRaRb—; X12 and X13 are each independently selected from —C(O)—, —NRa— and —O—; Q1, Q2, Q3 and Q4 are each independently selected from CRa or N; Q5 is each independently selected from —O—, —NRa—, —CRa—, —CRaRb—, —S— or —C(O)—; P1 is a single bond, —O—, —NRa—, —CRaRb—, —S—, —SO— or —SO2—; at each occurrence, Ra and Rb are each independently selected from hydrogen, hydroxy, halogen, CN, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl, each of said —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, halogen, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl; or Ra and Rb 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl; m1 is 0 or 1; m2 and m3 is 0, 1, 2, 3, 4, 5, 6, 7 or 8; m4 and m5 are each independently 0, 1, 2 or 3; n, n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3. Claim: 10. The compound of claim 9, wherein L1 is selected from a single bond, —C1-8alkylene- preferably —CH2—, —C2H4—, —C3H6—), —CO—, —O—, —N(CH3)—, —NH—, [chemical expression included] [chemical expression included] [chemical expression included] Claim: 11. The compound of any one of claims 9-10, wherein X1 and X2 are each independently selected from —CRa or N; Ra 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, X1 and X2 are each independently selected from CH, C(F), C(CH3) or N); m1=1 or 0; R12 is hydrogen, oxo, methoxymethyl, hydroxymethyl, —CN or —CH3. Claim: 12. The compound of any one of claims 9-11, wherein m1 is 1; preferably, [chemical expression included] moiety is [chemical expression included] wherein X refers to the position attached to [chemical expression included] moeity, and *X refers to the position attached to the [chemical expression included] moiety. Claim: 13. The compound of any one of claims 9-12, wherein m1 is 1, [chemical expression included] moiety is [chemical expression included] Claim: 14. The compound of any one of claims 9-13, wherein L2 is selected from a single bond, —C1-8alkylene-(preferably —CH2—, —C2H4—, —C3H6—), —CO—, —O—, —N(CH3)—, —NH—, [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] Claim: 15. The compound of any one of claims 9-14, wherein L3 is selected from single bond, —C1-8alkylene-(preferably —CH2—, —C2H4—, —C3H6—), —CO—, —O—, —N(CH3)—, —NH—, [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] Claim: 16. The compound of any one of claims 9-15, wherein L2 is a single bond; or L3 is a single bond; or L2 is a single bond and L3 is a single bond. Claim: 17. The compound of any one of claims 9-16, wherein [chemical expression included] is selected from [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] Claim: 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. Claim: 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. Claim: 20. The compound of any one of claims 1-19, wherein Warhead is [chemical expression included] wherein R13 is selected from —P(O)R13aR13b, —SO2R13a, —SO2—NR13aR13b or —N(R13a)—SO2R13b; R13a and R13b are each independently selected from hydrogen, —C1-C8alkyl or C3-C8cycloalkyl, said —C1-C8alkyl or C3-C8cycloalkyl is optionally substituted with at least one halogen; R14 and R15 are each independently selected from hydrogen, halogen, —C1-C8alkyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —OR14a, —SO2R14a, —SO2NR14aR14b, COR14a, —CO2R14a, —CONR14aR14b, —NR14aR14b, —NR14aCOR14b, —NR14aCO2R14b, or —NR14aSO2R14b; each of —C1-C8alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R14d, or R14 and R15 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 R14c; R14e, at each occurrence, is independently hydrogen, halogen, —C1-C8alkyl, —C1-C8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, oxo (═O), —OR14a, thioxo (═S), —SR14a, —CN, —SO2R14a, —SO2NR14aR14b, —COR14a, —CO2R14a, —CONR14aR14b, —NR14aR14b, —NR14aCOR14b, —NR14aCO2R14b or —NR14aSO2R14b; each of —C1-C8alkyl, —C1-C8alkoxy, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R14d; R14a and R14b are each independently selected from hydrogen, —C1-C8alkyl, —C1-C8haloalkyl, —C2-C8alkenyl, —C2-C8alkynyl, C1-C8alkoxy-C1-C8alkyl-, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl; R14d, at each occurrence, is independently halogen, —OH, —CN, oxo, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, or 5- to 12-membered heteroaryl; R4 is selected from hydrogen, halogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C1-C8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —SO2R4a, —SO2NR4aR4b, —COR4a, —CO2R4a, —CONR4aR4b, —NR4aR4b, —NR4aCOR4b, —NR4aCO2R4b or —NR4aSO2R4b; each of —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C1-C8alkoxy, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with halogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, oxo, —CN, —OR4c, —SO2R4c, —SO2NR4cR4d, —COR4c, —CO2R4c, —CONR4cR4d, —NR4cR4d, —NR4cCOR4d, —NR4cCO2R4d or —NR4cSO2R4d; R4a, R4b, R4c and R4d are each independently hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl; R9, R10 and R11 are each independently selected from hydrogen, halogen, —C1-C8alkyl, —NR9aR9b, —OR9a, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl, 5- to 12-membered heteroaryl, oxo or —CN; each of —C1-C8alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R9c; R9a and R9b are each independently selected from hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl; each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R9d; or R9c and R9d are each independently halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, —C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, —C6-C12aryl or 5- to 12-membered heteroaryl; Z4, Z5, Z6 and Z7 are each independently selected from —CRZ4, or N; RZ4, at each occurrence, is independently selected from hydrogen, halogen, —C1-C8alkyl, —NRZ4aRZ4b, —ORZ4a, —SRZ4a, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, 5- to 12-membered heteroaryl, or CN; each of —C1-C8alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one RZ4c; RZ4a and RZ4b are each independently selected from hydrogen, —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl, each of said —C1-C8alkyl, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent RZ4d; RZ4c and RZ4d are each independently halogen, hydroxy, —C1-C8alkyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, C3-C8cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12aryl, or 5- to 12-membered heteroaryl. Claim: 21. The compound of claim 20, wherein R13 is selected from —P(O)R13aR13b or —N(R13a)—SO2R13b, wherein R13a and R13b are each independently selected from hydrogen, —C1-C8alkyl (preferably —CH3, —C2H5, —C3H7, —C4H9 or —C5H11; more preferably —CH3, —CH2CH3, —CH2CH2CH3, -iso-C3H7, —CH2CH2CH2CH3, -iso-C4H9, -sec-C4H9 or -tert-C4H9) or C3-C8cycloalkyl (preferably cyclopropyl, cyclobutyl or cyclopentyl). Claim: 22. The compound of claim 20, wherein R13 is selected from —P(O)(CH3)2, —NH—SO2CH3 or —N(CH3)—SO2CH3. Claim: 23. The compound of claim 20, wherein R13 is —P(O)(CH3)2. Claim: 24. The compound of claim 20, wherein R14 and R15 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, C6-C12aryl, 5- to 12-membered heteroaryl, —CN, —OR14a, —SO2R14a, —SO2NR14aR14b, COR14a, —CO2R14a, —CONR14aR14b, —NR14aR14b, —NR14aCOR14b, —NR14aCO2R14b, or —NR14aSO2R14b; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C12aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R14d, or R14 and R15 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 R14e; R14e, 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, CF3, CHF2, CH2F, thioxo, —SCF3, —SCHF2, —SCH2F, —SCH2CF3, —SCF2CH3, —SCF2CF3, —SO2R14a, —SO2NR14aR14b, —COR14a, —CO2R14a, —CONR14aR14b, —NR14aR14b, —NR14aCOR14b, —NR14aCO2R14b or —NR14aSO2R14b; 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 R14d; R14a and R14b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, C1-C8alkoxy-C1-C8alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; R14d, 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. Claim: 25. The compound of claim 20, wherein R14 and R15 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, —CH2OH, —SCH3, —SC2H5, oxo, thioxo, —CF3, —CHF2, —CH2F, —SCF3, —OMe, —OC2H5, —CN, —C(O)CH3, [chemical expression included] Claim: 26. The compound of claim 20, wherein R14 and R15 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. Claim: 27. The compound of claim 20, wherein R4 is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —C2-C8alkenyl, —C2-C8alkynyl or —C1-C8alkoxy; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —C2-C8alkenyl or —C2-C8alkynyl is optionally substituted with —F, —Cl, —Br, —I, oxo, or —CN. Claim: 28. The compound of claim 20, wherein R4 is hydrogen, —F, —Cl, —Br, —I, —CH3, —CF3, —CH2F, or —CHF2. Claim: 29. The compound of claim 20, wherein R4 is hydrogen, —F, —Cl, —Br or —I. Claim: 30. The compound of claim 20, wherein R9, R10 and R11 are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —NR9aR9b, —OR9a, 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 R9c; R9a and R9b 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 R9d; R9c and R9d 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. Claim: 31. The compound of claim 20, wherein R9, R10 and R11 are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, —NH2, —NHCH3, —OH, —OCH3, —OC2H5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH2OH, —CH2OMe, oxo, or —CN. Claim: 32. The compound of claim 20, wherein R9, R10 and R11 are each independently selected from hydrogen, —CH3, —F, —Cl, —Br or —I. Claim: 33. The compound of claim 20, wherein Z4, Z5, Z6 and Z7 are each independently —CR4z; R4Z, at each occurrence, is independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —NR4ZaR4Zb, —OR4Za, —SR4Za 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 R4Zc; R4Za and R4Zb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-C8alkenyl, —C2-C8alkynyl, 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, —C2-C8alkenyl, —C2-C8alkynyl, 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 R4Zd; R4Zc and R4Zd are each independently —F, —Cl, —Br, —I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C1-C8alkoxy, —C2-C8alkenyl, —C2-C8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl. Claim: 34. The compound of claim 20, wherein R4z is selected from H, —CH3, —C2H5, F, —CH2F, —CHF2, —CF3, —OCH3, —OC2H5, —C3H7, —OCH2F, —OCHF2, —OCH2CF3, —OCF3, —SCF3, —CF3, —CH(OH)CH3, [chemical expression included] Claim: 35. The compound of any one of claims 1-19, wherein Warhead is [chemical expression included] wherein [chemical expression included] is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms selected from nitrogen, oxygen and sulfur; R101, R102, R103, R104, R105, R106 and R107 are each independently hydrogen, halogen, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR10a, —SO2R10a, —COR10a, —CO2R10a, —CONR10aR10b, —C(═NR10a)NR10bR10c, —NR10aR10b, —NR10aCOR10b, —NR10cCONR10bR10c, —NR10aCO2R10b, —NR10aSONR10bR10c, —NR10aSO2NR10bR10c, or —NR10aSO2R10b, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC1-8alkyl, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R109 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR10a, —SO2R10a, —COR10a, —CO2R10a, —CONR10aR10b, —C(═NR10a)NR10bR10c, —NR10aR10b, —NR10aCOR10b, —NR10aCONR10bR10c, —NR10aCO2R10b, —NR10aSONR10bR10c, —NR10aSO2NR10bR10c, or —NR10aSO2R10b, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC1-8alkyl, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p1, p2 and p3 are each independently 0, 1, 2, 3 or 4; R10a, R10b and R10c are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Claim: 36. The compound of claim 35, wherein [chemical expression included] wherein Z8, Z9, Z10 and Z11 are each independently selected from CH or N; wherein cy1 refers to the position attached to the [chemical expression included] moiety, and *cy1 refers to the position attached to L1. Claim: 37. The compound of claim 35, wherein [chemical expression included] is selected from [chemical expression included] Claim: 38. The compound of claim 35, wherein p3 is 0, 1, or 2, and each R107 is independently selected from halogen, —C1-8alkyl, or —C1-8alkoxy, preferably F, Cl, Br, I, CH3, or —OCH3. Claim: 39. The compound of claim 35, wherein R10a and R10b are independently selected from hydrogen or CH3; and n1 is 1 or 2. Claim: 40. The compound of claim 35, wherein R101 is methyl, —CH2OH, —OCH3, —CH2OCH3 or halogen; p1 is 0 or 1, and R102 is halogen. Claim: 41. The compound of claim 35, wherein R103 and R105 are hydrogen; and R104 is selected from hydrogen or methyl. Claim: 42. The compound of claim 35, wherein R109 is [chemical expression included] Y101, Y102, Y103 and Y104 are selected from CH, O, S or N; R111 is selected from hydrogen, halogen, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR10a, —SO2R10a, —COR10a, —CO2R10a, —CONR10aR10b, —C(═NR10a)NR10bR10c, —NR10aR10b, —NR10aCOR10b, —NR10aCONR10bR10c, —NR10aCO2R10b, —NR10aSONR10bR10c, —NR10aSO2NR10bR10c, or —NR10aSO2R10b, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC1-8alkyl, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R10a, R10b, and R10c are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and p6 is 0, 1, 2, 3 or 4. Claim: 43. The compound of claim 35, wherein Y101 is CH, S, N or O; Y102 is CH, O or N; Y103 is O, S or N; and Y104 is S, CH or N. Claim: 44. The compound of any one of claims 1-19, wherein Warhead is [chemical expression included] ring A201 and B201 are each independently an aromatic ring comprising 0-3 heteroatoms selected from nitrogen, sulfur and oxygen as ring member(s); Z201, Z203 and Z204 are each independently N or CR20z; L201 is independently a bond, —C1-8alkylene-, —N(R204)—, —O—, —S—, L201-C1- 8alkylene-O-*L201, L201-O—C1-8alkylene-*L201, L201-N(R204)CO-*L201, L201-CON(R204)-*L201, L201-N(R204)CO—C1-8alkylene-*L201, L201-CON(R204)—C1-8alkylene-*L201, L201-N(R204)—C1-8alkylene-*L201, L201-C1- 8alkylene-N(R204)-*L201, -heterocyclene-, or -heteroarylene-, wherein each of said —C1-8alkylene-, L201-C1- 8alkylene-O-*L201, L201-O—C1-8alkylene-*L201, L201-N(R204)CO—C1-8alkylene-*L201, L201-CON(R204)—C1-8alkylene-*L201, L201-N(R204)—C1-8alkylene-*L201, L201-C1- 8alkylene-N(R204)-*L201, -heterocyclene- and -heteroarylene- is optionally substituted with at least one substituent R20L; 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; R201, R202, and R204 are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R20L, R203, R205 and R206 are each independently hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR20a, —SO2R20a, —COR20a, —CO2R20a, —CONR20aR20b, —C(═NR20a)NR20bR20c, —NR20aR20b, —NR20aCOR20b, —NR20aCONR20bR20c, —NR20aCO2R20b, —NR20aSONR20bR20c, —NR20aSO2NR20bR20c, or —NR20aSO2R20b, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one halogen, hydroxy, —C1-8alkyl, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R20z is selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR20a, —SO2R20a, —COR20a, —CO2R20a, —CONR20aR20b, —C(═NR20a)NR20bR20c, —NR20aR20b, —NR20aCOR20b, —NR20aCONR20bR20c, —NR20aCO2R20b, —NR20aSONR20bR20c, —NR20aSO2NR20bR20c, or —NR20aSO2R20b, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one halogen, hydroxy, —C1-8alkyl, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R20a, R20b, and R20c are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or two R20L, 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO2, —OR203f, —SO2R203f, -SO2NR203fR203g, —COR203f, —CO2R203f, —CONR203fR203g, —C(═NR203f)NR203gR203h, —NR203fR203g, —NR203fCOR203g, —NR203fCONR203gR203h, —NR203fCO2R203f, NR203fSONR203fR203g, NR203fSO2NR203gR203h, or —NR203fSO2R203g, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, —C1-8alkyl, —OR203i, —NR203iR203j, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or two R203, 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO2, —OR203f, —SO2R203f, -SO2NR203fR203g, —COR203f, —CO2R203f, —CONR203fR203g, —C(═NR203f)NR203gR203h, —NR203fR203g, —NR203fCOR203g, —NR203fCONR203gR203h, —NR203fCO2R203f, —NR203fSONR203fR203g, NR203fSO2NR203gR203h, or —NR203fSO2R203g, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, —C1-8alkyl, —OR203i, —NR203iR203j, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R4 and one of R3, 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO2, —OR203f, —SO2R203f, -SO2NR203fR203g, —COR203f, —CO2R203f, —CONR203fR203g, —C(═NR203f)NR203gR203h, —NR203fR203g, —NR203fCOR203g, —NR203fCONR203gR203h, —NR203fCO2R203f, —NR203fSONR203fR203g, —NR203fSO2NR203gR203h, or -NR203fSO2R203g, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, —C1-8alkyl, —OR203i, —NR203iR203j, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R203f, R203g, R203h, R203i, and R203j are each independently hydrogen, —C1-8alkyl, C1-8alkoxy-C1-8alkyl-, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Claim: 45. The compound according to any one of claim 44, wherein L201 is a bond, —CH2—, —C2H4—, —C3H6—, —C4H8—, —C5H10—, —O—, —NH—, L201-NHCH2-*L201, L201-NHC2H4-*L201, L201-NHC3H6-*L201, L201-NHC4H8-*L201, L201-NHC5H10-*L201, L201-OCH2-*L201, L201-OC2H4-*L201, L201-OC3H6-*L201, L201-OC4H8-*L201, L201-OC5H10-*L201, L201-CH2O-*L201, L201-C2H4O-*L201, L201-C3H6O-*L201, L201-C4H8-*L201, L201-C5H10-*L201, L201-CONH-*L201, L201-NHCO-*L201, L201-CONHCH2-*L201, L201-CONHC2H4-*L201, L201-CONHC3H6-*L201, L201-CONHC4H8-*L201, L201-CONHC5H10-*L201, 3- to 8-membered -heterocyclene- or 5- to 6-membered -heteroarylene-; wherein each of said —CH2—, —C2H4-, —C3H6—, —C4H8-, —C5H10—, —O—, —NH—, L201-NHCH2*L201, L201-NHC2H4-*L201, L201-NHC3H6-*L201, L201-NHC4H8-*L201, L201-NHC5H10-*L201, L201-OCH2-*L201, L201-OC2H4-*L201, L201-OC3H6-*L201, L201-OC4H8-*L201, L201-OC5H10-*L201, L201-CH2O-*L201, L201-C2H4O-*L201, L201-C3H6O-*L201, L201-C4H8O-*L201, L201-C5H10O-*L201, L201-CONH-*L201, L201-NHCO-*L201, L201-CONHCH2*L201, L201-CONHC2H4-*L201, L201-CONHC3H6-*L201, L201-CONHC4H8-*L201, L201-CONHC5H10-*L201, 3- to 8-membered heterocyclene- and 5- to 6-membered heteroarylene- is optionally substituted with at least one substituent R20L; wherein R20L is defined as above. Claim: 46. The compound according to claim 44, wherein L201 is a bond, —O—, L201-OCH2-*L201, L201-CH2O-*L201, —NH—, L201-CONH-*L201, L201-NHCO-*L201, L201-CONHCH2-*L201, L201-CONHCH2CH2-*L201, L201-CONHCH2CH2CH2-*L201, L201-CONHCH(CH3)-*L201, L201-CONHCH(C2H5)-*L201, L201-NHCH2-*L201, L201-NHCH2CH2-*L201, L201-NHCH2CH2CH2-*L201, L201-NHCH(CH3)-*L201 or L-NHCH(C2H5)-*L. Claim: 47. The compound according to claim 44, wherein L201 is L201-N(R204)CO-*L201, R203 and R204, 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, —CH3, —C2H5, —C3H7, —C4H9, —C5H11, cycloalkyl, heterocyclyl, aryl, heteroaryl, or oxo. Claim: 48. The compound according to claim 44, wherein [chemical expression included] moiety is [chemical expression included] wherein Z205, Z206, Z207, Z208, Z209, Z206′, Z207′,% Z208′ and Z209′ are each independently N or C(H); Z210 is N(H), O or S. Claim: 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). Claim: 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. Claim: 51. The compound according to claim 44, wherein the [chemical expression included] moiety is [chemical expression included] Claim: 52. The compound according to claim 44, wherein R203 is hydrogen, oxo, —F, —Cl, —Br, —I, —CH3, —C2H5, —C3H7, —C4H9, —C5H11, —OCH3, —OC2H5, —OC3H7, —OC4H9, —OC5H11, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyrrolyl or phenyl, wherein each of said —CH3, —C2H5, —C3H7, —C4H9, —C5H11, —OCH3, —OC2H5, —OC3H7, —OC4H9, —OC5H11, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyrrolyl or phenyl, is optionally substituted with at least one —F, —Cl, —Br, —I, —CH3, —C2H5, —C3H7, —C4H9, —C5H11, —OCH3, —OC2H5, —OC3H7, —OC4H9, —OC5H11, —OH, cyclopropyl, cyclobutyl or cyclopentyl. Claim: 53. The compound according to claim 44, wherein R203 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. Claim: 54. The compound according to claim 44, wherein two R203, 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, —CH3, —C2H5, —C3H7, —C4H9, —C5H11, —OCH3, —OC2H5, —OC3H7, —OC4H9, —OC5H11, —OH, —CN, cyclopropyl, cyclobutyl or cyclopentyl. Claim: 55. The compound according to claim 44, wherein the [chemical expression included] moiety is [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] Claim: 56. The compound according to claim 44, wherein the [chemical expression included] moiety is [chemical expression included] wherein Z205, Z206, Z207 and Z208 are defined as above. Claim: 57. The compound according to claim 44, wherein the [chemical expression included] moiety is [chemical expression included] Claim: 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 (R206)q201. Claim: 59. The compound according to claim 44, wherein R206 is hydrogen, —F, —Cl, —Br, —I, —CH3, —C2H5, —C3H7, —C4H9, —C5H11, —CN, —OCH3, —OC2H5, —OC3H7, —OC4H9 or —OC5H11, wherein each of said —CH3, —C2H5, —C3H7, —C4H9, —C5H11, —OCH3, —OC2H5, —OC3H7, —OC4H9 or —OC5H11 is optionally substituted with —F, —Cl, —Br, —I, hydroxy, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Claim: 60. The compound according to claim 44, wherein the [chemical expression included] moiety is [chemical expression included] Claim: 61. The compound according to claim 44, wherein R201 and R202 are each independently hydrogen, —CH3, —C2H5, —C3H7, —C4H9, —C5H11, —C2-8alkenyl, —C2-8alkynyl or aryl. Claim: 62. The compound according to claim 44, wherein R201 and R202 are both H. Claim: 63. The compound according to any one of claims 1-27, wherein R205 is independently hydrogen, —F, —Cl, —Br, —I, —CH3, —C2H5, —C3H7, —C4H9, —C5H11, —C2-8alkenyl, —C2-8alkynyl or aryl. Claim: 64. The compound according to claim 44, wherein R20z is hydrogen, —F, —Cl, —Br, —I, —CH3, —C2H5, —C3H7, —C4Hg or —C5H11. Claim: 65. The compound according to any one of claims 44 to 64, wherein the [chemical expression included] moiety is [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] Claim: 66. The compound ofany one of claims 1-19, wherein Warhead is [chemical expression included] 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, R301, R302, R303, R304 and R308 are each independently hydrogen, halogen, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (═O), —CN, —NO2, —OR30c, —SO2R30c, —COR30c, —CO2R30c, —CONR30cR30d, —C(═NR30c)NR30dR30e, —NR30cR30d, —NR30cCOR30d, —NR30cCONR30dR30e, —NR30cCO2R30d, —NR30cSONR30dR30e, —NR30cSO2NR30dR30e, or —NR30cSO2R30d, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC1-8alkyl, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R306 and R307 are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC1-8alkyl, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R305 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR30c, —SO2R30c, —COR30c, —CO2R30c, —CONR30cR30d, —C(═NR30c)NR30dR30e, —NR30cR30d, —NR30cCOR30d, —NR30cCONR30dR30e, —NR30cCO2R30d, —NR30cSONR30dR30e, —NR30cSO2NR30dR30e, or —NR30cSO2R30d, each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with —C1-8alkyl, halogen, hydroxy, -haloC1-8alkyl, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p301 and p302 are each independently 0, 1, 2, 3 or 4; R30c, R30d and R30e are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R30c and R30d) or (R30d and R30e) 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN or —NO2. Claim: 67. The compound of claim 66, wherein R301 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR30c, —SO2R30c, —COR30c, —CO2R30c, —CONR30cR30d, —C(═NR30c)NR30dR30e, —NR30cR30d, —NR30cCOR30d, —NR30cCONR30dR30e, —NR30cCO2R30d, —NR30cSONR30dR30e, —NR30cSO2NR30dR30e, or —NR30c SO2R30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC1-8alkyl, - methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R30c, R30d and R30e are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R30c and R30d) or (R30d and R30e) 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN or —NO2. Claim: 68. The compound of any claim of claims 66-67, wherein R301 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, —CN or —NO2; preferably RI is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl. Claim: 69. The compound of any claim of claims 66-68, wherein R302 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR30c, —SO2R30c, —COR30c, —CO2R30c, —CONR30cR30d, —C(═NR30c)NR30dR30e, —NR30cR30d, —NR30cCOR30d, —NR30cCONR30dR30e, —NR30cCO2R30d, —NR30cSONR30dR30e, —NR30cSO2NR30dR30e, or —NR30c SO2R30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC1-8alkyl, - methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R30c, R30d and R30e are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R30c and R30d) or (R30d and R30e) 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN or —NO2. Claim: 70. The compound of any claim of claims 66-69, wherein R302 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, —CN or —NO2; preferably R302 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, —CN or —NO2. Claim: 71. The compound of any claim of claims 66-70, wherein R303 and R304 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR30c, —SO2R30c, —COR30c, —CO2R30c, —CONR30cR30d, —C(═NR30c)NR30dR30e, —NR30cR30d, —NR30cCOR30d, —NR30cCONR30dR30e, —NR30cCO2R30d, —NR30cSONR30dR30e, —NR30cSO2NR30dR30e, or —NR30cSO2R30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC1-8alkyl, - methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R30c, R30d and R30e are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R30c and R30d) or (R30d and R30e) 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN or —NO2. Claim: 72. The compound of any claim of claims 66-71, wherein R303 and R304 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 R303 and R304 are each independently hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl or cyclopentyl. Claim: 73. The compound of any claim of claims 66-72, wherein the [chemical expression included] moiety is [chemical expression included] wherein 303 refers to the position attached to the [chemical expression included] moiety, and *303 refers to the position attached to [chemical expression included] moiety. Claim: 74. The compound of any claim of claims 66-73, wherein R306 and R307 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC1-8alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; preferably, R306 and R307 are each independently H, methyl, ethyl, propyl butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Claim: 75. The compound of any claim of claims 66-74, wherein R305 is [chemical expression included] Y301, Y302, Y303 and Y304 are each independently selected from CH, O, S or N; R315 is each independently selected from hydrogen, halogen, —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR30c, —SO2R30c, —COR30c, —CO2R30c, —CONR30cR30d, —C(═NR30c)NR30dR30e, —NR30cR30d, —NR30cCOR30d, —NR30cCONR30dR30e, —NR30cCO2R30d, —NR30cSONR30dR30e, —NR30cSO2NR30dR30e, or —NR30cSO2R30d, each of said —C1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -haloC1-8alkyl, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R30c, R30d, and R30e are each independently defined as in claim 66; and p307 is 0, 1, 2, 3 or 4. Claim: 76. The compound of claim 75, wherein Y301 is CH, S, N or O; Y302 is CH, S, O or N; Y303 is CH, O, S or N; and Y304 is CH, O, S or N. Claim: 77. The compound of claim 75, wherein [chemical expression included] is selected from [chemical expression included] Claim: 78. The compound according to claim 75, wherein, R315 is selected from —H, —F, —Cl, —Br, —I, —CH3, —C2H5, —C3H7, —C4H9, —C5H11, —C6H13, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C2-8alkenyl, —C2-8alkynyl, —CH2OH, —CH2CH2OH, —CH(OH)CH3, —CH2CH2CH2OH, —CH(OH)CH2CH3, —CH2CH(OH)CH3, —CH2OCH3, —CFH2, —CF2H, —CF3, —CH2CF3, —CH2CH2CF3, each of said —CH3, —C2H5, —C3H7, —C4H9, —C5H11, —C6H13, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C2-8alkenyl, —C2-8alkynyl is optionally substituted with at least one F, Cl, Br, I, hydroxy, -haloC1-8alkyl, —C1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Claim: 79. The compound according to claim 75, wherein, R315 is selected from [chemical expression included] Claim: 80. The compound of any claim of claims 66-79, wherein the [chemical expression included] moiety is [chemical expression included] Claim: 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). Claim: 82. The compound of any claim of claims 66-81, wherein [chemical expression included] Y301, Y302, Y303 and Y304 are each independently defined as in claim 66; wherein Cy302 refers to the position attached to —N(R307) in the [chemical expression included] moiety, and **Cy302 refers to the position attached to [chemical expression included] moiety. Claim: 83. The compound of any claim of claims 66-82, wherein [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] Claim: 84. The compound of any claim of claims 66-83, wherein R308 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —OR30c, —SO2R30c, —COR30c, —CO2R30c, —CONR30cR30d, —C(═NR30c)NR30dR30e, —NR30cR30d, —NR30cCOR30d, —NR30cCONR30dR30e, —NR30cCO2R30d, —NR30cSONR30dR30e, —NR30cSO2NR30dR30e, or —NR30cSO2R30d, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally substituted with F, Cl, Br, I, hydroxy, -haloC1-8alkyl, - methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R30c, R30d and R30e are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; or (R30c and R30d) or (R30d and R30e) 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, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN or —NO2. Claim: 85. The compound of any claim of claims 66-84, wherein R308 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C2-8alkenyl, —C2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, —CN or —NO2; preferably R2 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, —CN or —NO2. Claim: 86. The compound of any claim of claims 66-85, wherein [chemical expression included] Claim: 87. The compound of any claim of claims 66-85 wherein the [chemical expression included] moiety is selected from [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] Claim: 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. Claim: 89. A method of treating a disease that can be treated by degrading the target protein that the Warhead can combine. Claim: 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. Claim: 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. Claim: 92. The method of claim 89, wherein the disease is cancer. Claim: 93. A compound of Formula (I): [chemical expression included] or a pharmaceutically acceptable salt thereof, or a deuterated analog thereof, or a prodrug thereof, wherein: Warhead, Linker, s2, Z1, Z2, Z3, R1 and R2 are as defined as any preceding claims; s1 is 0. Claim: 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). Claim: 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. Current International Class: 61; 61; 61

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