Pdz domain modulators

A method for treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of a PDZ domain, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a compound of Formula 1a, 1b, 1c, 1d, 1e or 1f:

• any of its stereoisomers or any mixture of its stereoisomers,
• or a pharmaceutically acceptable salt thereof;
• for the manufacture of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease or disorder or condition is responsive to modulation of a PDZ domain;
• where in Formula 1a, 1b, 1c, 1d, 1e and 1f:
• R1, R2 and R3 are independently selected from the group consisting of:
• hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl, hydroxy, alkoxy, formyl, alkylcarbonyl and —(C≡C)n—Ra;
• wherein
• n is 0 or 1;
• and
• Ra represents an aryl or a heteroaryl group;
• which aryl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
• halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, formyl, alkylcarbonyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, —NR′R″, —(C═O)NR′R″ or —NR′(C═O)R″;
• wherein R′ and R″ independent of each other are hydrogen or alkyl;
• R4 represents hydrogen or alkyl;
• R5, R6, R7 and R8 are independently selected from the group consisting of:
• hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl, hydroxy, alkoxy, formyl, alkylcarbonyl or an aryl or a heteroaryl group;
• which aryl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
• halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, formyl, alkylcarbonyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, —NR′R″, —(C═O)NR′R″ or —NR′(C═O)R″;
• wherein R′ and R″ independent of each other are hydrogen or alkyl;
• R9 and R10 together form —(O—(C═O))—, —O— or —S—;
• or
• R9 represents hydrogen or alkyl;
• and R10 represents hydrogen, cyano or alkyl;
• R11 and R12 together form —(CHR′—CH2)—;
• wherein R′ represents hydrogen, alkyl or phenyl;
• or
• R11 represents hydrogen or alkyl;
• and
• R12 represents hydrogen, alkyl, alkenyl or alkynyl;
• which alkyl, alkenyl or alkynyl is optionally substituted with an aryl or heteroaryl group;
• which aryl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
• halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, formyl, alkylcarbonyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, —NR′R″, —(C═O)NR′R″ or —NR′(C═O)R″;
• wherein R′ and R″ independent of each other are hydrogen or alkyl;
• R13, R14, R15, R16, R17, R18, R19, R20, R21 and R22 are independently selected from the group consisting of:
• hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl, hydroxy, alkoxy, formyl, alkylcarbonyl, hydroxycarbonyl, alkoxycarbonyl, Rb and —C═N—Rb;
• wherein
• Rb represents an aryl or a heteroaryl group;
• which aryl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
• halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, formyl, alkylcarbonyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, —NR′R″, —(C═O)NR′R″ or —NR′(C═O)R″;
• wherein R′ and R″ independent of each other are hydrogen or alkyl;
• -X1-X2- represents —N═(C—R′)— or —NR″—(C═O)—;
• wherein
• wherein R′ and R″ independent of each other are hydrogen or alkyl;
• Y1—Y2— represents
• wherein
• R23, R24, R25 and R26 are independently selected from the group consisting of:
• hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl, hydroxy, alkoxy, formyl, alkylcarbonyl, and Rd;
• Rc and Rd independent of each other represents an aryl or a heteroaryl group;
• which aryl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
• halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, formyl, alkylcarbonyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, Re-alkoxy, —NR′R″, —(C═O)NR′R″ or —NR′(C═O)R″;
• wherein R′ and R″ independent of each other are hydrogen or alkyl;
• Re represents an aryl group;
• which aryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
• halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, formyl, alkylcarbonyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy,
• —NR′″R″″, —(C═O)NR′″R″″ or —NR′″(C═O)R′″;
• wherein R′″ and R″″ independent of each other are hydrogen or alkyl;
• -Z1-Z2- represents —NR′—C(COOR″)— or —(C═O)—(C═O)—;
• wherein
• wherein R′ and R″ independent of each other are hydrogen or alkyl;
• —W1—W2— represents —C(R27R28)— or —CR27═CR28—;
• wherein
• wherein R27 and R28 are independently selected from the group consisting of:
• hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl, hydroxy and alkoxy;
• the bond represents a single or a double bond.

A compound of Formula 1a or 1b:

• any of its stereoisomers or any mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof;
• wherein
• one of R1, R2 and R3 represents —(C≡C)n-Ra;
• wherein
• wherein n is 0 or 1;
• and
• Ra represents an aryl or a heteroaryl group;
• which aryl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
• halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, formyl, alkylcarbonyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, —NR′R″, —(C═O)NR′R″ or —NR′(C═O)R″;
• wherein R′ and R″ independent of each other are hydrogen or alkyl;
• the remaining two of R1, R2 and R3 are independently selected from the group consisting of:
• hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl, hydroxy, alkoxy formyl and alkylcarbonyl;
• R4 represents hydrogen or alkyl;
• R5, R6, R7 and R8 are independently selected from the group consisting of:
• hydrogen, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl, hydroxy, alkoxy or an aryl or a heteroaryl group;
• which aryl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
• halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, formyl, alkylcarbonyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, —NR′R″, —(C═O)NR′R″ or —NR′(C═O)R″;
• wherein R′ and R″ independent of each other are hydrogen or alkyl;
• R9 and R10 together form —(O—(C═O))—, —O— or —S—;
• or
• R9 represents hydrogen or alkyl;
• and R10 represents hydrogen, cyano or alkyl;
• R11 and R12 together form —(CHR′—CH2)—;
• wherein R′ represents hydrogen, alkyl or phenyl;
• or
• R11 represents hydrogen or alkyl;
• and
• R12 represents hydrogen, alkyl, alkenyl or alkynyl;
• which alkyl, alkenyl or alkynyl is optionally substituted with an aryl or heteroaryl group;
• which aryl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
• halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, formyl, alkylcarbonyl, methylenedioxy, ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, sulfanyl, thioalkoxy, —NR′R″, —(C═O)NR′R″ or —NR′(C═O)R″;
• wherein R′ and R″ independent of each other are hydrogen or alkyl.