Hybrid cyclic libraries and screens thereof

A method of preparing a compound of Formula I:

• or a pharmaceutically acceptable salt or solvate thereof, wherein:
• is a single or double bond;
• X1 is O or NR6;
• Y is —C(O)— or
• X2 is (CH2)m, O, or NR6;
• Z is
• W is O, CH, CH2, CR4, or CR5;
• L1 and L2 are each independently a direct bond, substituted or unsubstituted —(C1-C6)alkyl-, substituted or unsubstituted —(CH2)nO(C1-C6)alkyl-, substituted or unsubstituted —(CH2)nC(O)—, substituted or unsubstituted —(CH2)nC(O)(C1-C6)alkyl-, substituted or unsubstituted —(CH2)nC(O)O(C1-C6)alkyl-, substituted or unsubstituted —(CH2)nNH(C1-C6)alkyl-, substituted or unsubstituted —(CH2)nC(O)NH(C1-C6)alkyl-, substituted or unsubstituted —(CH2)nS(C1-C6)alkyl-, substituted or unsubstituted —(CH2)nC(O)(CH2)nS(C1-C6)alkyl-, substituted or unsubstituted —(C2-C6)alkenyl-, substituted or unsubstituted —(CH2)nO(C2-C6)alkenyl-, substituted or unsubstituted —(CH2)nC(O)(C2-C6)alkenyl-, substituted or unsubstituted —(CH2)nC(O)O(C2-C6)alkenyl-, substituted or unsubstituted —(CH2)nNH(C1-C6)alkenyl-, substituted or unsubstituted —(CH2)nC(O)NH(C2-C6)alkenyl-, substituted or unsubstituted —(CH2)nS(C2-C6)alkenyl-, substituted or unsubstituted —(CH2)nC(O)(CH2)nS(C2-C6)alkenyl-, substituted or unsubstituted —(C2-C6)alkynyl-, substituted or unsubstituted —(CH2)nO(C2-C6)alkynyl-, substituted or unsubstituted —(CH2)nC(O)(C2-C6)alkynyl-, substituted or unsubstituted —(CH2)nC(O)O(C2-C6)alkynyl-, substituted or unsubstituted —(CH2)nNH(C1-C6)alkynyl-, substituted or unsubstituted —(CH2)nC(O)NH(C2-C6)alkynyl-, substituted or unsubstituted —(CH2)nS(C2-C6)alkynyl-, substituted or unsubstituted —(CH2)nC(O)(CH2)nS(C2-C6)alkynyl-, wherein each alkyl, alkenyl and alkynyl group may be optionally substituted with alkyl, alkoxy, amino, carboxyl, cyano, nitro, or trifluoromethyl;
• each m is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;
• each n is independently an integer selected from 0, 1, 2, 3, 4, 5, and 6;
• R1 is hydrogen, hydroxyl, or OPG, wherein PG is a protecting group, or
• R1 is
• wherein
• is a resin;
• R2 is hydrogen, hydroxyl, or alkoxy;
• R3 is hydrogen or alkyl;
• R4 and R5 are each independently hydrogen, hydroxy, alkyl, alkoxy, or OPG, wherein PG is a protecting group;
• R6 is hydrogen or alkyl;
• wherein the Effector Domain has Formula II:
• wherein:
• R7, R9, R11, R13, and R15 are each independently hydrogen or alkyl;
• R8, R10, R12, and R14 are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted perfluoroalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkylaryl, (CH2)nCN, (CH2)nCF3, (CH2)nC2F5, (CH2)nOR16, (CH2)nC(O)R16, (CH2)nC(O)OR16, (CH2)nOC(O)R16, (CH2)nNR17R18, (CH2)nC(O)NR17R18, (CH2)nN19RC(O)R16, (CH2)nN19RC(O)OR16, (CH2)nNR19C(O)NR17R18, (CH2)nSR16, (CH2)nS(O)jNR17R18, (CH2)nN19RS(O)jR16, or —(CH2)nNR19S(O)jNR17R18;
• n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
• j is an integer selected from 0, 1, and 2;
• R16, R17, R18, and R19 are each independently hydrogen, halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, or heteroalkylaryl, or
• R16 and R19 are as described above, and R17 and R18, together with the N atom to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered heterocycloalkyl or a substituted or unsubstituted 5-membered heteroaryl,
• wherein each of the above groups listed for R8, R10, R12, and a R14 may be optionally independently substituted with 1 to 3 groups selected from halogen, amino, cyano, nitro, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, perfluoroalkyl, alkoxy, alkylamino, alkylthio, aryl, alkylaryl, heteroalkyl, heterocycloalkyl, heteroaryl, heteroalkylaryl, (CH2)nCN, (CH2)nCF3, (CH2)nC2F5, (CH2)nOR16, (CH2)nC(O)R16, (CH2)nC(O)OR16, (CH2)nOC(O)R16, (CH2)nNR17R18, (CH2)nC(O)NR17R18, (CH2)nN19RC(O)R16, (CH2)nN19RC(O)OR16, (CH2)nNR19C(O)NR17R18, (CH2)nSR16, (CH2)nS(O)jNR17R18, (CH2)nN19RS(O)jR16, and —(CH2)nNR19S(O)jNR17R18;
• the method comprising the steps of:
• a) coupling and cyclizing a compound of Formula XI with the Effector Domain to provide the compound of Formula I:

A method of identifying compounds from a library of compounds that binds to a protein encoded in a genome in complex with FKBP, the method comprising the steps of:

• a) screening a hybrid combinatorial peptide or non-peptide library of compounds that includes the FKBP-binding domain (FKBP) of the natural product rapamycin or FK506 against the proteins encoded in a genome using a protein chip;
• b) detecting the binding of a compound to a protein on the chip using the anti-V5 antibody together with a fluorescently tagged secondary antibody;
• c) recording the fluorescence pattern of the protein chip on a chip reader;
• d) identifying the proteins based on the physical location of the fluorescent spots on the chip;
• and
• e) determining the function of the protein based on its perturbed biochemical and cellular functions.

A method of generating a lead compound as a high-affinity ligand of the FKBP isoforms, the method comprising the steps of:

• a) screening a hybrid combinatorial peptide or non-peptide library of compounds that includes the FKBP-binding domain (FKBP) of the natural product rapamycin or FK506 against the proteins encoded in a genome using a protein chip;
• b) detecting the binding of a compound to a protein on the chip using the anti-V5 antibody together with a fluorescently tagged secondary antibody;
• c) recording the fluorescence pattern of the protein chip on a chip reader;
• d) identifying the proteins based on the physical location of the fluorescent spots on the chip;
• and
• e) determining the structure of the lead compound.