Degradation of Bruton's tyrosine kinase (BTK) by conjugation of BTK inhibitors with E3 ligase ligand and methods of use

A compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
• wherein:
• ring A and B are each independently an aromatic ring comprising 0-3 heteroatoms selected from nitrogen, sulfur and oxygen as ring member(s);
• Z1, Z2, Z3 and Z4 are each independently N or CRz;
• L is independently a bond, —C1-8alkylene-, —N(R4)—, —O—, —S—, *L—C1-8alkylene-O—**L, *L—O—C1-8alkylene-**L, *L—N(R4)CO—**L, *L—CON(R4)—**L, *L—N(R4)CO—C1-8alkylene-**L, *L—CON(R4)—C1-8alkylene-**L, *L—N(R4)—C1-8alkylene-**L, *L—C1-8alkylene-N(R4)—**L, -heterocyclene-, or -heteroarylene-, wherein each of said —C1-8alkylene-, *L—C1-8alkylene-O—**L, *L—O—C1-8alkylene-**L, *L—N(R4)CO—C1-8alkylene-**L, *L—CON(R4)—C1-8alkylene-**L, *L—N(R4)—C1-8alkylene-**L, *L—C1-8alkylene-N(R4)—**L, -heterocyclene- and -heteroarylene- is optionally substituted with at least one substituent RL;
• wherein *L refers to the position attached to ring A, and **L refers to the position attached to ring B;
• m, n and q are each independently 0, 1, 2, 3 or 4;
• t is 0, 1 or 2;
• R1, R2, and R4 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;
• RL, R3, R5 and R6 are each independently hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —ORa, —SO2Ra, —CORa, —CO2Ra, —CONRaRb, —C(═NRa)NRbRc, —NRaRb, —NRaCORb, —NRaCONRbRc, —NRaCO2Rb, —NRaSONRbRc, —NRaSO2NRbRc, or —NRaSO2Rb, 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;
• Rz is selected from the bond between
• moiety and
• moiety, hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO2, —ORa, —SO2Ra, —CORa, —CO2Ra, —CONRaRb, —C(═NRa)NRbRc, —NRaRb, —NRaCORb, —NRaCONRbRc, —NRaCO2Rb, —NRaSONRbRc, —NRaSO2NRbRc, or —NRaSO2Rb, 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;
• Ra, Rb, and Rc are each independently hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• or two RL, 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, —OR3f, —SO2R3f, —SO2NR3fR3g, —COR3f, —CO2R3f, —CONR3fR3g, —C(═NR3f) NR3gR3h, —NR3fR3g, —NR3fCOR3g, —NR3fCONR3gR3h, —NR3fCO2R3f, —NR3fSONR3fR3g, —NR3fSO2NR3gR3h, or —NR3fSO2R3g, 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, —OR3i, —NR3iR3j, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• or two 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, —OR3f, —SO2R3f, —SO2NR3fR3g, —COR3f, —CO2R3f, —CONR3fR3g, —C(═NR3f)NR3gR3h, —NR3fR3g, —NR3fCOR3g, —NR3CONR3gR3h, —NR3fCO2R3f, —NR3fSONR3fR3g, —NR3fSO2NR3gR3h, or —NR3fSO2R3g, 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, —OR3i, —NR3iR3j, 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, —OR3f, —SO2R3f, —SO2NR3fR3g, —COR3f, —CO2R3f, —CONR3fR3g, —C(═NR3f)NR3gR3h, —NR3fR3g, —NR3fCOR3g, —NR3fCONR3gR3h, —NR3fCO2R3f, —NR3fSONR3fR3g, —NR3fSO2NR3gR3h, or —NR3fSO2R3g, 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, —OR3i, —NR3iR3j, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• R3f, R3g, R3h, R3i, and R3j are each independently hydrogen, —C1-8alkyl, C1-8alkoxy-C1-8alkyl-, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• the Linker is a bond or a divalent linking group, and
• the Degron is an E3 Ubiquitin ligase moiety.