Heterocyclic Compounds for the Treatment of CF

A compound of Formula I

• wherein:
• A is N or CR4a;
• X is
• R1 is selected from H;
• C1-C8 alkyl optionally substituted by one or more halogen atoms;
• C2-C8 alkenyl;
• C2-C8 alkynyl;
• C3-C10 cycloalkyl;
• C5-C10 cycloalkenyl;
• —C1-C4 alkyl-C3-C8 cycloalkyl;
• C1-C8 alkoxy optionally substituted by one or more halogen atoms;
• halogen;
• SO2NR8R9;
• SO2R10;
• S—C1-C8alkyl optionally substituted by one or more halogen atoms;
• S—C6-C14 aryl;
• —(C0-C4 alkyl)-C6-C14 aryl;
• and —(C0-C4 alkyl)-3 to 14 membered heterocyclyl;
• wherein the heterocyclyl contains at least one heteroatom selected from N, O and S;
• CN;
• NR11R12;
• CONR13R14;
• NR13SO2R15;
• NR13C(O)R15 and CO2R15, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents;
• R2 is C1-C4 haloalkyl;
• R3 is H or C1-C8 alkyl optionally substituted by one or more halogen atoms;
• R4 is H;
• C1-C8 alkyl optionally substituted by one or more halogen atoms;
• C2-C8 alkenyl;
• C2-C8 alkynyl;
• C3-C10 cycloalkyl;
• C5-C10 cycloalkenyl;
• —C1-C4 alkyl-C3-C8 cycloalkyl;
• C1-C8 alkoxy optionally substituted by one or more halogen atoms;
• C1-C4 alkoxy C1-C4 alkyl;
• C1-C8 hydroxyalkyl;
• OH;
• CN;
• fluorine;
• —(CH2)m—NR17R18;
• —(C0-C4 alkyl)-C6-C14 aryl;
• —(C0-C4 alkyl)-3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S;
• or —(C0-C4 alkyl)-CO2R15, wherein the cycloalkyl, cycloalkenyl, —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclyl groups are each optionally substituted by one or more Z substituents;
• R4a is selected from H;
• C1-C4 alkyl optionally substituted by one or more halogen atoms;
• C2-C8 alkenyl;
• —(C0-C4 alkyl)-C6-C14 aryl;
• —(C0-C4 alkyl)-3 to 14 membered heterocyclyl;
• C1-C8 hydroxyalkyl;
• halogen;
• —(CH2)m—NR17R18;
• —(C0-C4 alkyl)-CO2R15 and —(C0-C4 alkyl)-C(O)NR17R18;
• wherein the —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclyl groups are each optionally substituted by one or more Z substituents;
• R5 is C1-C8 alkyl optionally substituted by one or more halogen atoms;
• C2-C8 alkenyl;
• C2-C8 alkynyl;
• C3-C10 cycloalkyl;
• C5-C10 cycloalkenyl;
• —C1-C4 alkyl-C3-C8 cycloalkyl;
• C1-C8 alkoxy optionally substituted by one or more halogen atoms;
• fluorine;
• —(CH2)m—NR17R18;
• —(CH2)m—OR4;
• —(C0-C4 alkyl)-C6-C14 aryl;
• —(C0-C4 alkyl)-3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S;
• or —(C0-C4 alkyl)-CO2R15, wherein the cycloalkyl, cycloalkenyl, —(C0-C4 alkyl)-C6-C14 aryl and —(C0-C4 alkyl)-3 to 14 membered heterocyclyl groups are each optionally substituted by one or more Z substituents;
• or
• R3 and R4 together form an oxo group (C═O);
• or
• R3 and R5 together with the carbon atoms to which they are bound form a 3 to 8 membered cycloalkyl;
• or
• R4 and R5 together with the carbon atoms to which they are bound form a 5 to 8 membered cycloalkyl or a 5 to 8 membered heterocyclyl containing one or more heteroatoms selected from N, O and S, wherein the ring system is optionally substituted by one or more Z substituents;
• m is 0, 1, 2 or 3;
• R8, R11, R13 and R17 are each independently H, C1-C8 alkyl optionally substituted by one or more halogen atoms, C3-C10 cycloalkyl or —(C1-C4 alkyl)-C3-C8 cycloalkyl;
• R9, R10, R12, R14, R15, R16 and R18 are each independently H;
• C1-C8 alkyl optionally substituted by one or more halogen atoms;
• C2-C8 alkenyl;
• C2-C8 alkynyl;
• C3-C10 cycloalkyl;
• C5-C10 cycloalkenyl;
• —C1-C4 alkyl-C3-C8 cycloalkyl;
• —(C0-C4 alkyl)-C6-C14 aryl;
• or —(C0-C4 alkyl)-3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are each optionally substituted by one or more Z substituents;
• or
• R8 and R9, R11 and R12, R13 and R14, and R17 and R18 together with the nitrogen atom to which they are attached may form a 4 to 14 membered heterocyclyl optionally substituted by one or more Z substituents;
• Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C1-C6 alkyl optionally substituted by one or more OH groups or NH2 groups, C1-C6 alkyl optionally substituted by one or more halogen atoms, C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy, NR30(SO2)R32, (SO2)NR31R32, (SO2)R32, NR30C(O)R32, C(O)NR31R32, NR30C(O)NR31R32, NR30C(O)OR19, NR31R32, C(O)OR31, C(O)R31, SR31, OR31, oxo, CN, NO2, halogen or a 3 to 14 membered heterocyclyl, wherein the heterocyclyl contains at least one heteroatom selected from N, O and S;
• R30 is H or C1-C6 alkyl;
• R31 and R32 are each independently H;
• C1-C8 alkyl;
• C3-C8 cycloalkyl;
• C1-C4 alkoxy-C1-C4 alkyl;
• (C0-C4 alkyl)-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen;
• (C0-C4 alkyl)- 3- to 14-membered heterocyclyl, the heterocyclyl including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, oxo, C1-C6 alkyl and C(O)C1-C6 alkyl;
• (C0-C4 alkyl)-O-aryl optionally substituted by one or more groups selected from C1-C6 alkyl, C1-C6 alkoxy and halogen;
• and (C0-C4 alkyl)-O-3- to 14-membered heterocyclyl, the heterocyclyl including one or more heteroatoms selected from N, O and S, optionally substituted by one or more groups selected from halogen, C1-C6 alkyl or C(O)C1-C6 alkyl;
• wherein the alkyl groups are optionally substituted by one or more halogen atoms, C1-C4 alkoxy, C(O)NH2, C(O)NHC1-C6 alkyl or C(O)N(C1-C6 alkyl)2;
• or
• R31 and R32 together with the nitrogen atom to which they attached form a 5- to 10-membered heterocyclyl, the heterocyclyl including one or more further heteroatoms selected from N, O and S, the heterocyclyl being optionally substituted by one or more substituents selected from OH;
• halogen;
• aryl;
• 5- to 10-membered heterocyclyl including one or more heteroatoms selected from N, O and S;
• S(O)2-aryl;
• S(O)2—C1-C6 alkyl;
• C1-C6 alkyl optionally substituted by one or more halogen atoms;
• C1-C6 alkoxy optionally substituted by one or more OH groups or C1-C4 alkoxy;
• and C(O)OC1-C6 alkyl, wherein the aryl and heterocyclic substituent groups are themselves optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;
• or a pharmaceutically acceptable salt thereof.