Mannose 6-phosphate or asgpr receptor binding compounds for the degradation of extracellular proteins

A compound of Formula:

• or a salt thereof,
• wherein:
• Mannose 6-Phosphate LigandC is selected from the group consisting of:
• wherein
• X1 is 1 to 5 contiguous atoms independently selected from the group consisting of O, S, S(O), S(O)2, N(R6), and C(R4)(R4), wherein if X1 is 1 atom then X1 is O, S, S(O), S(O)2, N(R6), or C(R4)(R4), if X1 is 2 atoms then no more than 1 atom of X1 is O, S, or N(R6), if X1 is 3, 4, or 5 atoms then no more than 2 atoms of X1 are O, S, or N(R6);
• R1 is hydrogen, heteroalkyl, C1-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-P(O)(R3)2, C1-C6alkyl-OP(O)(R3)2, C0-C6alkyl-NR8P(O)(R3)2, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8)—C(O)R3, C0-C6alkyl-N(R8)—S(O)R3, C0-C6alkyl-N(R8)—C(S)R3, C0-C6alkyl-N(R8)—S(O)2R3, C1-C6alkyl-O—C(O)R3, C1-C6alkyl-O—S(O)R3, C0-C6alkyl-O—C(S)R3, —N═S(O)(R3)2, C0-C6alkylN3, or C1-C6alkyl-O-S(O)2R3;
• R3 at each occurrence is independently selected from hydrogen, alkyl, heteroalkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, —OR8, and —NR8R9;
• R4 is independently selected at each occurrence from hydrogen, halogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, —OR6, —NR6R7, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3;
• R5 is selected from
• heteroaryl, heterocycle, and R55;
• R55 is selected from
• m is 1, 2, or 3;
• R6 and R7 are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3;
• R8 and R9 are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle;
• R41 and R42 are independently selected from hydrogen, halogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle;
• R43 is selected from alkyl, alkenyl, alkynyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycle, and -alkyl-heterocycle, each of which is optionally substituted with 1, 2, 3, or 4 substituents;
• R44 is selected from hydrogen, alkyl, cyano, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle each of which except hydrogen and cyano is optionally substituted with 1, 2, or 3 substituents;
• R45 is selected from cycloalkyl, aryl, heteroaryl, and heterocycle each of which is optionally substituted with 1, 2, or 4 substituents;
• R46 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle each of which except hydrogen is optionally substituted with 1, 2, or 4 substituents;
• LinkerE is selected from
• R11, R12, R13, R14, R15, R16, R17, R18, and R19 are independently at each occurrence selected from the group consisting of a bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —SO2—, —S(O)—, —C(S)—, —C(O)NR6—, —NR6C(O)—, —C(O)N(OH)—, —N(OH)C(O)—, —O—, —S—, —NR6—, —S(O)(═N—R44)—, —S(O)(═NR), —P(O)(R3)O—, —P(O)(R3)—, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, —CH2CH2—[O—(CH2)2]n—O—, —CH2CH2—[O—(CH2)2]n—NR6—, —CH2CH2—[O—(CH2)2]n—, —[—(CH2)2—O—]n—, —[O—(CH2)2]n—, —[O—CH(CH3)C(O)]n—, —[C(O)—CH(CH3)—O]n—, —[O—CH2C(O)]n—, —[C(O)—CH2—O]n—, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid;
• each of which is optionally substituted with 1 or 2 substituents independently selected from R21;
• n is independently selected at each instance from 0, 1, 2, 3, 4, or 5;
• R21 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, —NR6R7, —NR8SO2R3, —NR8S(O)R3, haloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycle, wherein the 1 or 2 R21 substituents are selected such that a stable compound results;
• and
• each optional substituent is independently selected from alkyl, alkenyl, alkynyl, haloalkyl, —OR6, F, Cl, —NR6R7, heteroalkyl, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, —SR3, —S(O)(NR6)R3, —NR8C(O)R3, —C(O)NR6R7, —C(O)OR3, —C(O)R3,
• as allowed by valence wherein the optional substituent is selected such that a stable compound results.