US 11,999,734 B2
Compounds and compositions for the treatment of cystic fibrosis
Tiziano Bandiera, Genoa (IT); Fabio Bertozzi, Genoa (IT); Francesca Giacomina, Genoa (IT); Simone Giovani, Genoa (IT); Federico Sorana, Verona (IT); Emanuela Caci, Verona (IT); Loretta Ferrera, Verona (IT); Nicoletta Pedemonte, Genoa (IT); and Luis Juan Vicente Galietta, Genoa (IT)
Assigned to Fondazione Istituto Italiano Di Tecnologia, Genoa (IT); Istituto Giannina Gaslini, Genoa (IT); and Fondazione Per La Ricerca Sulla Fibrosi Cistica—Onlus, Verona (IT)
Appl. No. 17/259,221
Filed by Fondazione Istituto Italiano Di Tecnologia, Genoa (IT); Istituto Giannina Gaslini, Genoa (IT); and Fondazione Per La Ricerca Sulla Fibrosi Cistica-Onlus, Verona (IT)
PCT Filed Jul. 12, 2019, PCT No. PCT/IB2019/055955
§ 371(c)(1), (2) Date Jan. 11, 2021,
PCT Pub. No. WO2020/012427, PCT Pub. Date Jan. 16, 2020.
Claims priority of application No. 102018000007183 (IT), filed on Jul. 13, 2018.
Prior Publication US 2021/0292324 A1, Sep. 23, 2021
Int. Cl. C07D 471/18 (2006.01); C07D 471/04 (2006.01)
CPC C07D 471/18 (2013.01) [C07D 471/04 (2013.01)] 11 Claims
 
1. A compound of Formula (Ia):

OG Complex Work Unit Chemistry
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

OG Complex Work Unit Chemistry
represents one of the structures selected from the group consisting of:

OG Complex Work Unit Chemistry
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:

OG Complex Work Unit Chemistry
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).
 
8. A compound of Formula (Ib)

OG Complex Work Unit Chemistry
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

OG Complex Work Unit Chemistry
represents one of the structures selected from the group consisting of:

OG Complex Work Unit Chemistry
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:

OG Complex Work Unit Chemistry
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.