COMPOUNDS AS MODULATORS OF A MUTANT CFTR PROTEIN AND THEIR USE FOR TREATING DISEASES ASSOCIATED WITH CFTR PROTEIN MALFUNCTION

1 . A composition comprising:

a modulator of a mutant CFTR protein adapted for use in the manufacture of a medication for the treatment of diseases associated with CFTR protein malfunction including:

a compound of general formula (I)

its tautomers, E and Z geometrical isomers, optically active forms such as enantiomers, diastereomers and their racemate forms or a mixture of stereoisomeric forms or its pharmaceutically acceptable salts thereof or complexes thereof;

wherein Z 1 is independently selected from the group consisting of:

—C n H (2n) —, which is branched or unbranched wherein n is an integer from 1 to 5;

—C n H (2n−2) — 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) — which is branched or unbranched wherein n is an integer from 2 to 5; —CR′H—, —C 2 H 3 R′—, E or Z—C 2 HR′—, —C 3 H 5 R′—, E or Z—C 3 H 3 R′—, —OCH 2 —, —CH 2 O—, —NR″CH 2 —, —CH 2 NR″—;

wherein R′ is independently selected from the group consisting of: —H, halogen, —NH 2 , —OH, —CN, CF 3 , —CHF 2 , —CH 2 F, —SH, —SCN, —CH 3 , —C 2 H 5 ;

wherein R″ is independently selected from the group consisting of: —H, —CH 3 , —C 2 H 5 ; wherein R 1 and R 2 are independently selected from the group consisting of aromatic ring or heteroaromatic ring.

2 . The composition of claim 1 , wherein R 1 and R 2 are independently selected from the group of sub-formula (Ia):

wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 is independently selected N or C atoms wherein ring contain 0-3 nitrogen atoms;

wherein E 1 , E 2 , E 3 , E 4 , E 5 represents optional substituents, which are selected from: —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, —PO 3 H 2 , —OPO 3 H 2 , —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 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;

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, —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, —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 F, —CH 2 Cl, —CH 2 Br, —CH 2 I, —F, —Cl, —Br, —I, —NH 2 ,

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

3 . The composition of claim 1 , wherein the compound is represented by the following structures:

4 . The composition of claim 2 , wherein the compound is represented by the following structures:

5 . The composition of claim 1 , wherein the compound has an effect on mutant CFTR protein, wherein the mutant CFTR protein 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.

6 . The composition of claim 2 , wherein the compound has an effect on mutant CFTR protein, wherein the mutant CFTR protein 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.

7 . The composition of claim 3 , wherein the compound has an effect on mutant CFTR protein, wherein the mutant CFTR protein 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.

8 . The composition of claim 4 , wherein the compound has an effect on mutant CFTR protein, wherein the mutant CFTR protein 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.

9 . The composition of claim 5 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis.

10 . The composition of claim 6 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis.

11 . The composition of claim 7 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis.

12 . The composition of claim 8 , wherein the disease associated with CFTR protein malfunction is cystic fibrosis.

13 . The compound of claim 1 , wherein said compound is a modulator for use in the treatment of cystic fibrosis wherein it has effect on CFTR-dependent ion transport across cellular membrane and/or it has the ability to increase the number of mutant CFTR proteins that reach the cell surface.

14 . The compound of claim 1 , wherein said compound is a modulator for use in the treatment of cystic fibrosis wherein it has stabilizing effect on the structure of the mutant CFTR protein and/or blocks the interaction with cellular proteins responsible for the premature degradation of mutant CFTR.

15 . The compound of claim 1 , wherein said compound is a modulator for use in the treatment of cystic fibrosis wherein it has effect on mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II.

16 . A method comprising:

treating cystic fibrosis in a patient including administering a therapeutically effective amount of a compound of a general formula (I), as a modulator of a mutant CFTR protein to the patient having cystic fibrosis:

its tautomers, E and Z geometrical isomers, optically active forms such as enantiomers, diastereomers and their racemate forms or a mixture of stereoisomeric forms or its pharmaceutically acceptable salts thereof or complexes thereof;

wherein Z 1 is independently selected from the group consisting of:

—C n H (2n) —, which is branched or unbranched wherein n is an integer from 1 to 5; —C n H (2n−2) — 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) — which is branched or unbranched wherein n is an integer from 2 to 5; —CR′H—, —C 2 H 3 R′—, E or Z—C 2 HR′—, —C 3 H 5 R′—, E or Z—C 3 H 3 R′—, —OCH 2 —, —CH 2 O—, —NR″CH 2 —, —CH 2 NR″—;

wherein R′ is independently selected from the group consisting of: —H, halogen, —NH 2 , —OH, —CN, CF 3 , —CHF 2 , —CH 2 F, —SH, —SCN, —CH 3 , —C 2 H 5 ;

wherein R″ is independently selected from the group consisting of: —H, —CH 3 , —C 2 H 5 ; wherein R 1 and R 2 are independently selected from the group consisting of aromatic ring or heteroaromatic ring and

wherein the compound of effects CFTR-dependent ion transport across a cellular membrane and/or the compound increases the number of mutant CFTR proteins reaching the cell surface.

17 . The method according to claim 16 wherein the compound has a stabilizing effect on the structure of the mutant CFTR protein and/or blocks the interaction with cellular proteins responsible for the premature degradation of mutant CFTR.

18 . The method according to claim 16 wherein the compound is effecting a mutant CFTR protein, wherein said CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II.