Compounds and compositions for the treatment of cystic fibrosis

A compound of Formula (Ia):

• or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, or stereoisomers thereof wherein:
• Z is selected from the group consisting of C═O, SO2 or CONRi;
• Ri is selected from the group consisting of hydrogen, C1-6alkyl, C3-6cycloalkyl, and heterocycloalkyl;
• X1, X2, X3 and X4 are independently selected from the group consisting of CRii and N, with the proviso that the number of nitrogen atoms in the ring is comprised from 0 to 2;
• each Rii is independently selected from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-aryl, O-heteroaryl, CORviii, COORviii, CONHRc, CONRdRe, OH, O—C1-6alkyl, O—C3-6cycloalkyl, O-heterocycloalkyl, O-haloC1-6alkyl, C1-6alkyl-O—C1-6alkyl, C1-6alkyl-O—C3-6cycloalkyl, C1-6alkyl-O-heterocycloalkyl, CN, NO2, NHRc, NRdRe, N(Re)CORc, N(Re)COORc, N(Rx)CONRixRx, N(Rx)SO2Rxi, SO2Rxi, SO2NHRc, SO2NRdRe, halogen, and hydroxy-C1-6alkyl;
• A1 and A4 are CRiiiRiv,
• A2 and A3 are selected from a bond and CRiiiRiv;
• Riii and Riv are independently selected from the group consisting of hydrogen, C1-6alkyl, C3-6cycloalkyl, heterocycloalkyl, haloC1-6alkyl, CORviii, COORviii, CONHRviii, CONRixRx, OH, and O—C1-6alkyl, C1-6alkyl-O—C1-6alkyl, CN, halogen, NRixRx, and N(Rix)CORviii, or Riii and Riv form a C3-C6 cycloalkyl with the C to which they are linked;
• or, when A3 is a bond, two groups Riv on A1 and A2, or on A1 and A4 are linked together to form a ring and thus the moiety
• represents one of the structures selected from the group consisting of:
• wherein Ra and Rb are independently selected from the group consisting of hydrogen, C1-6alkyl, halogen, OH, O—C1-6alkyl, and C1-6alkyl-O—C1-6alkyl,
• B is selected from the group consisting of:
• wherein
• Y and W are independently selected from the group consisting of O, S, CRv, CRvRvi, N, and NRvii, wherein
• Rv and Rvi are selected form the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O—C1-6alkyl, O—C1-6alkylaryl, O—C3-6cycloalkyl, O-heterocycloalkyl, O-haloC1-6alkyl, C1-6alkyl-O—C1-6alkyl, C1-6alkyl-O—C3-6cycloalkyl, C1-6alkyl-O-heterocycloalkyl, C1-6alkyl-O-aryl, C1-6alkyl-O-heteroaryl, hydroxy-C1-6alkyl, CORvii, COORviii, CONHRviii, and CONRixRx;
• Rvii is selected form the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C2-6alkyl-O—C1-6alkyl, C2-6alkyl-O—C3-6cycloalkyl, C2-6alkyl-O-heterocycloalkyl, C2-6alkyl-O-aryl, and C2-6alkyl-O-heteroaryl;
• R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, CORviii, COORviii, CONHRviii, CONRixRx, OH, O—C1-6alkyl, O—C1-6alkylaryl, O—C3-6cycloalkyl, O-heterocycloalkyl, O-heteroaryl, O-aryl, O-haloC1-6alkyl, C1-6alkyl-O—C1-6alkyl, C1-6alkyl-O—C3-6cycloalkyl, C1-6alkyl-O-heterocycloalkyl, C1-6alkyl-O-aryl, C1-6alkyl-O-heteroaryl, hydroxy-C1-6alkyl, CN, NO2, NRixRx, N(Rx)CORviii, N(Rx)COORviii, N(Rx)CONRixRx, N(Rx)SO2Rxi, SO2Rxi, SO2NRixRx, and halogen;
• Rviii is selected from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6alkyl-O—C1-6alkyl, and C1-6alkyl-O-heterocycloalkyl;
• Rix is selected from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
• Rx is selected from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6alkyl-O—C2-6alkyl, and hydroxy-C2-6alkyl;
• Rxi is selected from the group consisting of C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
• Rc is selected from the group consisting of hydrogen, C1-6alkyl, haloC1-6alkyl, C2-6alkyl-O—C1-6alkyl, and C2-6alkyl-O-heterocycloalkyl;
• Rd is selected from the group consisting of C1-6alkyl, haloC1-6alkyl, aryl, and heteroaryl;
• Re is selected from the group consisting of C1-6alkyl, haloC1-6alkyl, aryl, heteroaryl, C1-6alkyl-O—C2-6alkyl, and hydroxy-C2-6alkyl;
• provided that at least one of Riii or Riv of at least one of A1, A2, A3 or A4 is not H and that, when Z is C═O, A1 is not CH(C1-6alkyl) when A4 is CH2 or A1 is not CH2 when A4 is CH(C1-6alkyl).