Proteostasis regulators

A compound having the Formula (II):

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• D is hydrogen, S(O)2Ra, S(O)2NRaRa, C(O)NRaRa, C(O)Ra, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 cycloalkenyl, or is a monocyclic or polycyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C4-C12 cycloalkenyl, optionally substituted 4- to 12-membered heterocyclic, optionally substituted aryl or optionally substituted heteroaryl, each optionally substituted;
• each Ra is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• Q is C(Rd) or N;
• each Ri is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcC(O)Rc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• R5 and R6 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcC(O)Rc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• alternatively, R5 and R6 can be taken together with the carbon to which they are attached to form a C(O), C3-C8 cycloalkyl, C3-C8 cycloalkenyl or a 3- to 8-membered heterocyclic;
• Z1 is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• or alternatively, R5 or R6 can be taken together with Z1 to form a C3-C12 cycloalkyl, C3-C12 cycloalkenyl, 3- to 12-membered heterocyclic, aryl, or heteroaryl, each optionally substituted;
• each Rc is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• or alternatively, two Rc groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted;
• Rd is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• alternatively, Rd and D can be taken together to form a fused monocyclic or polycyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted 3- to 12-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl and
• n is 0, 1 or 2.

A compound having the Formula (IIIa):

• or a pharmaceutically acceptable salt thereof, prodrug or solvate thereof, wherein:
• Ring W is a 5-membered heteroaryl or a 5-membered heterocyclic, wherein each ring carbon atom of said 5-membered heteroaryl is substituted with one Rd and wherein each ring nitrogen atom of said 5-membered heteroaryl is substituted with zero or one Rd when said nitrogen atom is present, and wherein each ring carbon atom of said 5-membered heterocyclic is substituted with one or two Rd and each ring nitrogen atom of said 5-membered heterocyclic is substituted with zero or one Rd, when said nitrogen atom or atoms are present;
• A2 is S(O)2Ra, S(O)2NRaRa, C(O)NRaRa, C(O)Ra, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 cycloalkenyl, or is a monocyclic or polycyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C4-C12 cycloalkenyl, optionally substituted 3- to 12-membered heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl;
• each Ra is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• each Rd is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• alternatively, two vicinal Rd groups can be taken together to form a fused monocyclic or polycyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
• or yet alternatively, a vicinal Rd and A2 can be taken together to form a fused monocyclic or polycyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted 3- to 12-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl;
• R7 and R8 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcC(O)Rc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc, wherein at least one of R7 and R8 is not hydrogen, and further wherein when one of R7 and R8 is hydrogen, the other of R7 and R8 is not methyl;
• alternatively, R7 and R8 can be taken together with the carbon atom to which they are attached to form C(O), C3-C8 cycloalkyl, C3-C8 cycloalkenyl or a 3- to 8-membered heterocyclic;
• or yet alternatively, R7 and an Rd can be taken together to form a fused monocyclic group selected from the group consisting of C5-C12 cycloalkyl, C5-C12 cycloalkenyl, 5- to 12-membered heterocyclic, C5-C12 aryl, and 5- to 12-membered heteroaryl, each substituted with Rs and Z2, and optionally further substituted;
• Z2 is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcC(O)Rc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• or further alternatively, R7 or R8 can be taken together with Z2 form a C3-C12 cycloalkyl, C3-C12 cycloalkenyl, 3- to 12-membered heterocyclic, aryl, and heteroaryl, each optionally substituted;
• each Rc is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• alternatively, two Rc groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted;
• and
• n is 0, 1 or 2.

A compound having the Formula (IVa):

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• Ring W is a 5-membered heteroaryl or a 5-membered heterocyclic, wherein each ring carbon atom of said 5-membered heteroaryl is substituted with one Rd and wherein each ring nitrogen atom of said 5-membered heteroaryl is substituted with zero or one Rd when said nitrogen atom is present, and wherein each ring carbon atom of said 5-membered heterocyclic is substituted with one or two Rd and each ring nitrogen atom of said 5-membered heterocyclic is substituted with zero or one Rd, when said nitrogen atom or atoms are present;
• X is selected from the group consisting of C(Rf)2, C(Rg)═C(Rg), S, S(O), S(O)2, and B(ORg);
• Rf is halo;
• each Rg is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• A3 is S(O)2Ra, S(O)2NRaRa, C(O)NRaRa, C(O)Ra, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 cycloalkenyl, or is a monocyclic or polycyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C4-C12 cycloalkenyl, optionally substituted 3- to 12-membered heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl;
• each Ra is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• each Rd is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORS, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcC(O)Rc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• alternatively, two vicinal Rd groups can be taken together to form a fused monocyclic or polycyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
• or yet alternatively, a vicinal Rd and A3 can be taken together to form a fused monocyclic or polycyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted 3- to 12-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl;
• R9 and R10 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcC(O)Rc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• alternatively, R9 and R10 can be taken together with the carbon atom to which they are attached to form a C(O), C3-C8 cycloalkyl, C3-C8 cycloalkenyl or a 3- to 8-membered heterocyclic;
• or yet alternatively, R9 and Rd can be taken together to form a fused monocyclic group selected from the group consisting of C5-C12 cycloalkyl, C5-C12 cycloalkenyl, 5- to 12-membered heterocyclic, C5-C12 aryl, and 5- to 12-membered heteroaryl, each substituted with R10 and Z3, and optionally further substituted;
• Z3 is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• or alternatively, R9 or R10 can be taken together with Z3 form a C3-C12 cycloalkyl, C3-C12 cycloalkenyl, 3- to 12-membered heterocyclic, aryl, and heteroaryl, each optionally substituted;
• each Rc is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• alternatively, two Rc groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted;
• and
• n is 0, 1 or 2.

A compound having the Formula (VII):

• or a pharmaceutically acceptable, salt or prodrug thereof;
• wherein
• Ring T is a ring selected from the group consisting of:
• A6 is S(O)2Ra, S(O)2NRaRa, C(O)NRaRa, C(O)Ra, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C3-C12 cycloalkenyl, or is a monocyclic or polycyclic group selected from the group consisting of optionally substituted C4-C12 cycloalkyl, optionally substituted C4-C12 cycloalkenyl, optionally substituted 4- to 12-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl;
• each Ra is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• each Rd is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORS, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcC(O)Rc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• alternatively, two vicinal Rd groups can be taken together to form a fused monocyclic or polycyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
• or yet alternatively, a vicinal Rd and A6 can be taken together to form a fused monocyclic or polycyclic group selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted 3- to 12-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl;
• R16 and R17 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcC(O)Rc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• alternatively, R16 and R17 can be taken together with the carbon atom to which they are attached to form a C(O), C3-C8 cycloalkyl, C3-C8 cycloalkenyl or a 3- to 8-membered heterocyclic;
• or yet alternatively, R16 or R17 can be taken together with Rd to form a fused monocyclic group selected from the group consisting of C5-C12 cycloalkyl, C5-C12 cycloalkenyl, 5- to 12-membered heterocyclic, C5-C12 aryl, and 5- to 12-membered heteroaryl, each substituted with R17 and Z, and optionally further substituted;
• Z6 is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORc, SRc, NRcRc, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRcRc, NRcC(O)Rc, NRcS(O)nRc, N(Rc)(COORc), NRcC(O)C(O)Rc, NRcC(O)NRcRc, NRcS(O)nNRcRc, NRcS(O)nRc, S(O)nRc, S(O)nNRcRc, OC(O)ORc and (C═NRc)Rc;
• or further alternatively, R16 or R17 can be taken together with Z6 form a C3-C12 cycloalkyl, C3-C12 cycloalkenyl, 3- to 12-membered heterocyclic, aryl, and heteroaryl, each optionally substituted;
• each Rc is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
• alternatively, two Rc groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted;
• and
• n is 0, 1 or 2.