Spirocyclic MDM2 modulator and uses thereof

A compound of Formula (I), 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 (I) or N-oxide thereof:

• wherein
• Z is CH2, —SO2—, or —P(O)(Ra)—;
• or Z is C(O) when R0 is not H;
• V is C(O);
• W is C(Ra) or N;
• R is H or a small molecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase;
• each of L1, L2, L3, L4, L5, and L6, independently, is absent, a bond, (CRaRb)p, N(Ra), O, S, C(O), S(O2), —O(CRaRb)p—, —N(Ra)(CRaRb)p—, 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), (CRaRb)pN(Ra)(CRaRb)q, (CRaRb)pN(Ra)C(O)(CRaRb)q, OC(O)N(Rb)(CRaRb)p+1N(Rb)(CRaRb)q, (CRaRb)pC(O)N(Ra)(CRaRb)q, bivalent alkyl, bivalent alkenyl, bivalent alkynyl, bivalent cycloalkyl, bivalent cycloalkenyl, bivalent heterocycloalkyl, bivalent heterocycloalkenyl, bivalent aryl, or bivalent heteroaryl, in which said bivalent alkyl, bivalent cycloalkyl, bivalent cycloalkenyl, bivalent heterocycloalkyl, bivalent spiro-heterocyclic, bivalent fused-heterocyclic, bivalent bridged-heterocyclic, bivalent heterocycloalkenyl, bivalent aryl, or bivalent heteroaryl is optionally substituted with one or more Rd;
• each of R0, R1, R2, R3, R4, R5, and R6, independently, H, D, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, cyano, —ORa, —SRa, -alkyl-Ra, -alkyl-O—P(O)(Ra)(Rb), -alkyl-OC(O)N(Ra)(Rb), —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, in which said alkyl, spiroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl is optionally substituted with one or more Rd;
• each of Q1, and Q2, independently, is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spiroheterocyclyl, fused heterocyclyl, bridged heterocyclyl, aryl, or heteroaryl;
• Ra, Rb, Rc and Rd, independently, is H, D, alkyl, spiroalkyl, alkenyl, alkynyl, halo, cyano, amine, nitro, hydroxy, ═O, -alkyl-O—P(O)(OH)(OH), C(O)NHOH, C(O)OH, C (O)NH2, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which said 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 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 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 R2 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 R3 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 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;
• R3 and 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;
• R4 and R5 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;
• R5 and 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 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
• each of m, n, r, and s, independently, is 0, 1, 2, or 3.