LZK-targeting degraders and methods of use

A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, having a general formula:

• Q-L-Z
• where
• Z is an E3-ligase binding moiety having a structure
• where each Re independently is substituted or unsubstituted C1-C3 alkyl or H;
• Rf is substituted or unsubstituted C1-C3 alkyl or —N(Re)2;
• and
• Y is O or N(Re);
• L is a linker having a general formula
• wherein
• L1 is —C(O)—, —S(O)2—, —CH2—, —C(Rb)(Rc)—, —(CH2)nC(O)—, —C(O)—(CH2)n—, —N(Re)—, —N(Re)—(C(H)(Ra))s—C(O)—, or —C(O)—(C(H)(Ra))s—N(Re)—, and L1 binds to Q, or L1 is absent and L2 binds to Q;
• L3 is —C(O)—, —S(O)2—, —CH2—, —C(Rb)(Rc)—, —C(O)—(CH2)n—, —(CH2)n—C(O)—, —N(Re)—, —N(Re)—(C(H)(Ra))s—C(O)—, or —C(O)—(C(H)(Ra))s—N(Re)—, and -L3 binds to Z, or L3 is absent and L2 binds to Z;
• L2 is —(Rd)p—, —N(Rb)—(Rd)p—, —(Rd)p—N(Rb)—, —N(Rb)—(Rd)p—N(Rb)—, —(N(Rb)—(C(H)(Ra))s—C(O))m—N(Rb)—C(H)(Ra)—, or —C(H)(Ra)—N(Rb)—(C(O)—(C(H)(Ra))s—N(Rb)m—;
• each Ra independently is an amino acid side chain;
• each Rb independently is H or Rc;
• each Rc independently is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted alkylaryl;
• each Rd independently is substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH2—CH2—O)r—, —(C(H)(Ra))s—C(O)—, —C(O)N(Rb)—, or —N(Rb)C(O)—;
• each Re independently is substituted or unsubstituted C1-C3 alkyl or H;
• m is an integer from 0-11;
• n is an integer from 1-10;
• p is an integer from 0-5;
• r is an integer from 2-20;
• and
• s is an integer from 1-20,
• wherein (i) L2 is not solely —C(O)N(Rb)— or —N(Rb)C(O)—, (ii) if L2 terminates in —C(H)(Ra)—C(O)— or —N(Rb)C(O)—, then L3 is not —C(O)— or —S(O)2—, and (iii) if L3 is absent, L2 is —(Rd)p— and p is 0, then L1 binds directly to Z;
• Q is a leucine zipper kinase (LZK) binding moiety having a structure (Q1)
• where each bond represented by is a single or double bond as needed to satisfy valence requirements;
• X5 is —N(H)— or absent;
• ring A
• R1 is cyano, perhaloalkyl, H, alkyl, or perhaloalkoxy;
• R2 is H, alkoxy, perhaloalkyl, perhaloalkoxy, haloalkoxy, haloalkyl, cyano, alkyl, cyanoalkyl, amino, or heteroarylalkoxy, or R1 and R2 together with the atoms to which they are attached form a 5- or 6-membered substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl ring;
• R3 is H, amino, alkylamino, aminoalkyl, alkoxy, or R′C(O)N(H)— where R′ is alkyl, or R2 and R3 together with the atoms to which they are attached form a 5- or 6-membered substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl ring:
• R7 and R8 independently are H, alkyl, alkoxy, perhaloalkyl, perhaloalkoxy, or cyano;
• each R9 independently is H or alkyl;
• each R10 independently is H, alkyl, or cyano,
• R11 and R12 are H, alkyl, perhaloalkyl, alkoxy, perhaloalkoxy, cyano, or amino and
• is:
• wherein R4 is 3,3-difluoro-1-pyrrolidinyl, isopropyl, —C(H)(OH)—C(CH3)2, cyclopropyl, or
• R5 is
• or where X is a bond or alkyl group binding Q to L.