Stabilization of amyloidogenic immunoglobulin light chains

A method of treatment of light chain amyloidosis in a patient, comprising administering to the patient an effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof:

• wherein
• A is
• X1 is O or NR0;
• X2 is selected from the group consisting of a bond, NR12, O, C(O), C(O)NR11, and CR12R11;
• X3 is O or NR13
• W is
• m is an integer selected from 1, 2, 3, 4, 5, and 6;
• n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
• p is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
• r is an integer selected from 0, 1, 2, and 3;
• Z1 is selected from the group consisting of
• H,
• C1-C6-alkyl,
• C3-C8-cycloalkyl,
• 3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
• C2-C6-alkenyl,
• C3-C8-cycloalkenyl,
• 3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
• C6-C10-aryl,
• 5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
• —(C1-C6-alkyl)(C6-C10-aryl),
• —(C1-C6-alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S,
• halogen,
• NR16R17,
• COOR18;
• OR18,
• NR16SO2R18,
• NR16COR18,
• X4(CR21R22)aCONR16R17,
• X4(CR21R22)aCOOR18,
• X4(CR21R22)aCOR18,
• X4(CR21R22)aNR16R17,
• X4(CR21R22)aOR18,
• SO2NR16R17,
• X4(CR21R22)aNR16COR18,
• C(N═R23)NR24OH, and
• wherein
• X4 is a bond, O, or NR0;
• and
• a is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
• Z2 is selected from the group consisting of
• H,
• C1-C6-alkyl,
• C3-C8-cycloalkyl,
• 3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
• C2-C6-alkenyl,
• C2-C6-alkynyl,
• C3-C8-cycloalkenyl,
• 3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
• C6-C10-aryl,
• 5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
• —(C1-C6-alkyl)(C6-C10-aryl),
• —(C1-C6-alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S,
• CN,
• OR18 and
• NR19R20;
• Ar1 is a divalent moiety selected from
• C6-C10-arylene and
• 5- to 10-membered heteroarylene wherein 1-4 heteroaryl members are independently selected from N, O, and S;
• R1 is selected from the group consisting of
• H,
• C1-C6-alkyl,
• C3-C8-cycloalkyl,
• 3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
• C2-C6-alkenyl,
• C3-C8-cycloalkenyl,
• 3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
• C6-C10-aryl,
• 5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
• —(C1-C6-alkyl)(C6-C10-aryl),
• —(C1-C6-alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S,
• OH,
• (CR21R22)bOR18 wherein b is an integer selected from 0, 1, 2, 3, 4, 5, and 6,
• halogen, and
• (C1-C6)haloalkyl;
• R2, R3, and R4 are independently selected from the group consisting of
• H,
• C1-C6-alkyl,
• —(C1-C6-alkyl)(C6-C10-aryl),
• OH,
• (CR21R22)bOR18,
• halogen,
• C3-C8-cycloalkyl,
• 3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
• C2-C6-alkenyl,
• C3-C8-cycloalkenyl,
• 3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
• C6-C10-aryl,
• 5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
• —(C1-C6-alkyl)(C6-C10-aryl), and
• —(C1-C6-alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S;
• R0, and R5-R13 and R18-R22 are independently selected from the group consisting of
• H,
• C1-C6-alkyl,
• C1-C6-haloalkyl,
• C3-C8-cycloalkyl,
• 3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
• C2-C6-alkenyl,
• C2-C6-alkynyl,
• C3-C8-cycloalkenyl,
• 3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
• C6-C10-aryl,
• 5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
• —(C1-C6-alkyl)(C6-C10-aryl), and
• —(C1-C6-alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are independently selected from N, O, and S;
• R16 and R17 are independently selected from the group consisting of
• H,
• C1-C6-alkyl,
• C3-C8-cycloalkyl,
• 3- to 6-membered heterocycloalkyl wherein 1-4 ring members are independently selected from N, O, and S,
• C2-C6-alkenyl,
• C3-C8-cycloalkenyl,
• 3- to 6-membered heterocycloalkenyl wherein 1-4 ring members are independently selected from N, O, and S,
• C6-C10-aryl,
• 5- to 10-membered heteroaryl wherein 1-4 heteroaryl members are independently selected from N, O, and S,
• —(C1-C6-alkyl)(C6-C10-aryl),
• —(C1-C6-alkyl)(5- to 10-membered heteroaryl) wherein 1-4 heteroaryl members are
• independently selected from N, O, and S,
• C(O)OR18,
• C(O)R18, and
• SO2R18;
• R16 and R9, together with the atoms to which they are bound, optionally are a 3- to 8-membered ring;
• R16 and R17, together with the atoms to which they are bound, optionally are a 3- to 8-membered ring wherein ring members are selected from C, O and N;
• R19 and R20, together with the atoms to which they are bound, optionally are a 3- to 8-membered ring;
• R21 and R22, together with the atoms to which they are bound, optionally are a 3- to 8-membered ring.