CPC C07D 471/18 (2013.01) [C07D 471/04 (2013.01)] | 11 Claims |
1. 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).
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8. A compound of Formula (Ib)
![]() or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, or stereoisomers thereof, for the use to potentiate CFTR protein or ABC protein activities 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, CONHRviii, CONRixRx, 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, NRixRx, N(Rx)CORviii, N(Rx)COORviii, N(Rx)CONRixRx, N(Rx)SO2Rxi, SO2Rxi, SO2NRixRx, 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, B 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, CORviii, 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;
provided that at least one of Riii or Riv of at least one of A1, A2, A3 or A4 is not H.
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