Compounds as modulators of a mutant CFTR protein and their use for treating diseases associated with CFTR protein malfunction

1. A pharmaceutical composition comprising:

a compound of general formula (IIIb) used for the manufacture of a medication for the treatment of diseases associated with CFTR protein malfunction:

its tautomers, E and Z geometric isomers, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof or complexes thereof;

wherein any occurrence of Z 1 independently represents the following optional substituents, —OR B , —OC(═O)R C , —OC(═O)OR B , —OC(═O)N(R A )R A ′, —C(═O)R C , —C(═O)N(R A )R A ′, —C(═O)N(OR B )R A , —C(═O)OR B , —C(═S)R C , —C(═O)C(═O)R C , —CH 2 OR B , —CH 2 CH 2 OR B , —CH 2 N(R A )R A ′, —CH 2 CH 2 N(R A )R A ′, —CH 2 OCH 2 R C , —CH 2 N(R A )CH 2 R C , —SR D , —S(═O)R D , —SO 2 R D , —SO 2 N(R A )R A ′, —SO 3 R B , —N(R A )C(═O)R C , —N(R A )C(═O)OR B , —N(R A )C(═O)N(R A ′)R A ″, —N(R A )SO 2 R D , —N(R A )SO 2 N(R A ′)R A ″, —N(R A )R A ′, —N(R A )C(═O)R C , —N(R A )C(═O)OR B , —N(R A )N(R A ′)R A ″, —N(R A ′)N(R A )C(═O)R C , —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —SCN, —SO 2 CN, —F, Cl, —Br, —I, —C n H 2n R C which is branched or unbranched wherein n is an integer from 1 to 5; —C n H (2n-2) R C in E or Z geometrical conformation which is branched or unbranched wherein n is an integer from 2 to 5; —C n H (2n-4) R C which is branched or unbranched wherein n is an integer from 2 to 5, —PO 3 H 2 , or —OPO 3 H 2 ;

wherein R A , R A ′, R A ″ are each independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, and —OH;

wherein R B is independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 Cl, —CH 2 Br, and —CH 2 I;

wherein R C is independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 Cl, —CH 2 Br, —CH 2 I, —F, —Cl, —Br, —I, and —NH 2 ;

wherein R D is independently selected from the group consisting of: —H and lower alkyl group

wherein R 5 and R 6 are optional substituents which are independently selected from the group consisting of: OH, NH 2 , COOH, Cl, Br, I, CH 3 , and C 2 H 5 ;

wherein R 7 is an optional substituent which is independently selected from the group consisting of: —F, —Cl, —Br, —I, —CH 3 , and —C 2 H 5 ;

wherein R 8 is an optional substituent which is independently selected from the group consisting of: —NH 2 , —NHAr, —OH, —CH 2 Ar, —C(═O)Ar, and —OAr;

wherein Ar is an aromatic group or heteroaromatic group, and

wherein the compound of formula (IIIb) is present in a pharmaceutical composition.

2. The pharmaceutical composition according to claim 1 , wherein the compound has an effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II, and wherein a mutation ΔF508-CFTR, or another mutation of class II are involved in CFTR protein malfunction.

3. The pharmaceutical composition according to claim 1 , wherein the compound is characterized in that it has effect on CFTR-dependent ion transport across a cellular membrane and/or it has the ability to increase the number of mutant CFTR proteins that reach a cell surface.

4. The pharmaceutical composition according to claim 1 , wherein the compound is characterized in that it has a stabilizing effect on the structure of the mutant CFTR protein and/or blocks interaction with cellular proteins responsible for the premature degradation of mutant CFTR.

5. The pharmaceutical composition according to claim 1 , wherein the compound is characterized in that it has an effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II.

6. A pharmaceutical composition comprising:

a compound used for the manufacture of a medication for the treatment of diseases associated with CFTR protein malfunction:

its tautomers, E and Z geometric isomers, enantiomers, diastereomers or its pharmaceutically acceptable salts thereof, or complexes thereof,

wherein the compound is present in a pharmaceutical composition.

7. The pharmaceutical composition according to claim 6 , wherein the compound has an effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR or another mutation of class II, and wherein the mutation ΔF508-CFTR or another mutation of class II are involved in CFTR protein malfunction.

8. The pharmaceutical composition according to claim 6 , wherein the compound is characterized in that it has effect on CFTR-dependent ion transport across a cellular membrane and/or it has the ability to increase mutant CFTR proteins that reach a cell surface.

9. The pharmaceutical composition according to claim 6 , wherein the compound is characterized in that it has a stabilizing effect on the structure of the mutant CFTR protein and/or blocks interaction with cellular proteins responsible for premature degradation of mutant CFTR protein.

10. The pharmaceutical composition according to claim 6 , wherein the compound is characterized in that it has an effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II.

11. A method comprising:

treating a disease associated with CFTR protein malfunction in a patient by administering a therapeutically effective amount of a composition comprising:

a compound:

its tautomers, E and Z geometric isomers, enantiomers, diastereomers or its pharmaceutically acceptable salts thereof, or complexes thereof,

as a modulator of a mutant CFTR protein to the patient.

12. The method according to claim 11 , wherein the CTFR protein malfunction is a mutation of ΔF508-CFTR.

13. A method comprising:

treating a disease associated with CFTR protein malfunction in a patient by administering to the patient a therapeutically effective amount of a composition comprising:

a compound of general formula (IIIb):

its tautomers, E and Z geometric isomers, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof or complexes thereof;

wherein any occurrence of Z 1 independently represents the following optional substituents, —OR B , —OC(═O)R C , —OC(═O)OR B , —OC(═O)N(R A )R A ′, —C(═O)R C , —C(═O)N(R A )R A ′, —C(═O)N(OR B )R A , —C(═O)OR B , —C(═S)R C , —C(═O)C(═O)R C , —CH 2 OR B , —CH 2 CH 2 OR B , —CH 2 N(R A )R A ′, —CH 2 CH 2 N(R A )R A ′, —CH 2 OCH 2 R C , —CH 2 N(R A )CH 2 R C , —SR D , —S(═O)R D , —SO 2 R D , —SO 2 N(R A )R A ′, —SO 3 R B , —N(R A )C(═O)R C , —N(R A )C(═O)OR B , —N(R A )C(═O)N(R A ′)R A ″, —N(R A )SO 2 R D , —N(R A )SO 2 N(R A ′)R A ″, —N(R A )R A ′, —N(R A )C(═O)R C , —N(R A )C(═O)OR B , —N(R A )N(R A ′)R A ″, —N(R A ′)N(R A )C(═O)R C , —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —SCN, —SO 2 CN, —F, Cl, —Br, —I, —C n H 2n R C which is branched or unbranched wherein n is an integer from 1 to 5; —C n H (2n-2) R C in E or Z geometrical conformation which is branched or unbranched wherein n is an integer from 2 to 5; —C n H (2n-4) R C which is branched or unbranched wherein n is an integer from 2 to 5, —PO 3 H 2 , or —OPO 3 H 2 ;

wherein R A , R A ′, R A ″ are each independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, and —OH;

wherein R B is independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 Cl, —CH 2 Br, and —CH 2 I;

wherein R C is independently selected from the group consisting of: —H, lower alkyl group, —CN, —CF 3 , —CHF 2 , —CH 2 Cl, —CH 2 Br, —CH 2 I, —F, —Cl, —Br, —I, and —NH 2 ;

wherein R D is independently selected from the group consisting of: —H and lower alkyl group

wherein R 5 and R 6 are optional substituents which are independently selected from the group consisting of: OH, NH 2 , COOH, Cl, Br, I, CH 3 , and C 2 H 5 ;

wherein R 7 is an optional substituent which is independently selected from the group consisting of: —F, —Cl, —Br, —I, —CH 3 , and —C 2 H 5 ;

wherein R 8 is an optional substituent which is independently selected from the group consisting of: —NH 2 , —NHAr, —OH, —CH 2 Ar, —C(═O)Ar, and —OAr;

wherein Ar is an aromatic group or heteroaromatic group.

14. The method according to claim 13 , wherein the CTFR protein malfunction is a mutation of ΔF508-CFTR.