Inhibitor of btk and mutants thereof

A compound of Formula (1), or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (1) or N-oxide thereof:

• wherein
• Warhead is chemical group that can covalently bind to Cys481 of BTK;
• each of L1, L2, L3, L4, L5, and L6, independently, is absent, a bond, N(Ra), O, S, C(O), S(O2), OC(O), C(O)O, OSO2, S(O2)O, C(O)S, SC(O), C(O)C(O), C(O)N(Ra), N(Ra)C(O), S(O2)N(Ra), N(Ra)S(O2), OC(O)O, OC(O)S, OC(O)N(Ra), N(Ra)C(O)O, N(Ra)C(O)S, N(Ra)C(O)N(Ra), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, spiro-heterocyclic, fused-heterocyclic, or bridged-heterocyclic, in which said alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, spiro-heterocyclic, fused-heterocyclic, or bridged-heterocyclic is optionally substituted with one or more Rd;
• Q0 is a 5-9 membered aryl or heteroaryl;
• Q1 is a 5-7 membered heteroaryl or heterocycloalkyl;
• Q2 is a 5-9 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• Q3 is a 5-9 membered aryl or heteroaryl;
• Q4 is a 5-9 membered aryl or heteroaryl;
• W is —C(O)—, —P(O)(RaRb)—, or —S(O2)—;
• Z is NH or O;
• Z1 is absent, bond, alkyl, alkenyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, or bridged-heterocyclic, each of which is independently optionally substituted with one or more Rd;
• each of R0, R1, R4, R5, R6, and R7, independently, is H, D, alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, halo, nitro, oxo, cyano, ORa, SRa, alkyl-Ra, NH(CH2)PRa, C(O)Ra, S(O)Ra, SO2Ra, C(O)ORa, OC(O)Ra, NRbRc, C(O)N(Rb)Rc, N(Rb)C(O)Rc, —P(O)RbRc, —OP(O)RbRc, —NP(O)RbRc, -alkyl-P(O)RbRc, -alkyl-O—P(O)(Ra)(Rb), -alkyl-N(Ra)—P(O)(Ra)(Rb), -alkyl-OC(O)N(Ra)(Rb), —S(O)(=N(Rb))Rc, —N═S(O)RbRc, =NRb, SO2N(Rb)Rc, or N(Rb)SO2Rc, in which said alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, spiro-heterocyclic, fused-heterocyclic, or bridged-heterocyclic is optionally substituted with one or more Rd;
• R3 is H, halo, alkyl, —C(RaRbRc), haloalkyl, or hydroxyalkyl;
• two of R1 groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl optionally substituted with one or more Rd;
• two of R4 groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl optionally substituted with one or more Rd;
• two of R5 groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally substituted with one or more Rd;
• two of R6 groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl optionally substituted with one or more Rd;
• two of R7 groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally substituted with one or more Rd;
• RA is H, D, alkyl, alkylene-Ra, alkylene-P(O)RbRc, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;
• RB is independently H, D, halo, cyano, nitro, alkyl, alkylene-Ra, alkylene-P(O)RbRc, alkenyl, alkynyl, C(O)Ra, C(O)NRbRc, C(O)ORa, NH(CH2)PRa, NRbRc, NRbC(O)Rc, ═NRb, NRbS(O)2Rc, N═S(O)RbRc, ORa, OC(O)Ra, ═O, P(O)RbRc, SRa, S(O)Ra, S(O)(NRb)Rc, S(O)2Ra, S(O)2NRbRc, cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;
• or
• RA and RB, taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rd substituents;
• Ra, Rb, Rc and Rd, independently, is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, oxo, -alkyl-O—P(O)(OH)(OH), C(O)NHOH, C(O)OH, C(O)NH2, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, spiro-heterocyclic, fused-heterocyclic, or bridged-heterocyclic, in which said H, D, amine, hydroxy, alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more Re;
• Re is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, ═O, -alkyl-O—P(O)(OH)(OH), C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said H, D, amine, hydroxy, alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more Rf;
• and
• Rf is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, ═O, -alkyl-O—P(O)(OH)(OH), C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
• two of Rd groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl optionally substituted with one or more Re;
• two of Re groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl optionally substituted with one or more Rf;
• and
• two of Rf groups, taken together with the atom to which they are attached, may optionally form a cycloalkyl or heterocycloalkyl optionally substituted with one or more Rf;
• and D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, ═O, -alkyl-O—P(O)(OH)(OH), C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;
• each of i, j, k, m, n, p, and q, independently, is 0, 1, 2, 3, or 4.