Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of Cathepsin C

A method of treating Wegener Granulomatosis comprising administering to a patient a therapeutically effective amount of a compound of formula 1

• wherein
• R1 is independently selected from H, C1-6-alkyl-, halogen, HO—, C1-6-alkyl-O—, H2N—, C1-6-alkyl-HN—, (C1-6-alkyl)2N- and C1-6-alkyl-C(O)HN—;
• or two R1 are together C1-4-alkylene;
• R2 is selected from
• wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1;
• wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.2;
• and
• R2.1 is independently selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C1-4-alkylene-, R2.1.1-A-, C1-4-alkyl-A-, C3-6-cycloalkyl-A-, C1-4-haloalkyl-A-,
• R2.1.1—C1-4-alkylene-A-, C1-4-alkyl-A-C1-4-alkylene-, C3-6-cycloalkyl-A-C1-4-alkylene-,
• C1-4-haloalkyl-A-C1-4-alkylene-, R2.1.1—C1-4-alkylene-A-C1-4-alkylene-,
• R2.1.1-A-C1-4-alkylene-, HO—C1-4-alkylene-A-, HO—C1-4-alkylene-A-C1-4-alkylene-,
• C1-4-alkyl-O—C1-4-alkylene-A- and C1-4-alkyl-O—C1-4-alkylene-A-C1-4-alkylene-;
• and
• R2.1.1 is independently selected from
• aryl-;
• optionally substituted independently from each other with one, two or three R2.1.1.1;
• C5-10-heteroaryl-;
• containing one, two, three or four heteroatoms independently selected from S, S(O), S(O)2, O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1.1.1;
• wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1.1.2;
• and
• C5-10-heterocyclyl-;
• containing one, two, three or four heteroatoms independently selected from S, S(O), S(O)2, O and N, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three or four R2.1.1.1;
• wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.1.1.2;
• R2.1.1.1 is independently selected from halogen, HO—, O═, C1-4-alkyl-, C1-4-alkyl-O—, C1-4-haloalkyl-, C1-4-haloalkyl-O— and C3-6-cycloalkyl-;
• and
• R2.1.1.2 is independently selected from C1-4-alkyl-, C1-4-haloalkyl-;
• C3-6-cycloalkyl-, C1-4-alkyl-O—C1-4-alkyl-, H(O)C—, C1-4-alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-;
• and
• R2.2 is independently selected from H-A-C1-4-alkylene-, C3-6-cycloalkyl-, C1-4-alkyl-A-C1-4-alkylene-, C3-6-cycloalkyl-A-C1-4-alkylene-, C1-4-haloalkyl-A-C1-4-alkylene-, R2.1.1-A-C1-4-alkylene-, C1-4-alkyl-S(O)2— and C1-4-alkyl-C(O)—, R2.1.1-A-;
• R2.3 and R4 are together selected
• from —O—, —S—, —N(R2.3.1)—, —C(O)N(R2.3.1)—, —N(R2.3.1)C(O)—, —S(O)2N(R2.3.1)—, —N(R2.3.1)S(O)2—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)2—, R2.3,
• R2.3, —C(R2.3.2)═C(R2.3.2)—, —C═N—, —N═C—, —C(R2.3.2)2—O—, —O—C(R2.3.2)2—, —C(R2.3.2)2N(R2.3.1)—, and —N(R2.3.1)C(R2.3.2)2— and —C1-4-alkylene-;
• R2.3.1 is independently selected from H, C1-6-alkyl-, C1-6-haloalkyl-;
• C3-8-cycloalkyl-, HO—C1-4-alkylene-, (C1-4-alkyl)-O—C1-4-alkylene-, H2N—C1-4-alkylene-, (C1-4-alkyl) HN—C1-4-alkylene- and (C1-4-alkyl)2N—C1-4-alkylene-;
• R2.3.2 is independently selected from H, C1-6-alkyl-, C1-6-haloalkyl-;
• C3-8-cycloalkyl-, HO—C1-4-alkylene-, (C1-4-alkyl)-O—C1-4-alkylene-, H2N—C1-4-alkylene-, (C1-4-alkyl) HN—C1-4-alkylene- and (C1-4-alkyl)2N—C1-4-alkylene-;
• R2.4 and R4 are together selected
• from —N(R2.4.1)—, —C(O)N(R2.4.1)—, —N(R2.4.1)C(O)—, —S(O)2N(R2.4.1)—, —N(R2.4.1)S(O)2—, —C(O)—, —S(O)—, —S(O)2—, —C(R2.4.2)═C(R2.4.2)—, —C═N—, —N═C—, —C(R2.4.2)2N(R2.4.1)— and —N(R2.4.1)C(R2.4.2)2—, —C1-4-alkylene-;
• and
• R2.4.1 is independently selected from H, C1-6-alkyl-, C1-6-haloalkyl-;
• C3-8-cycloalkyl-, HO—C1-4-alkylene-, (C1-4-alkyl)-O—C1-4-alkylene-, H2N—C1-4-alkylene-, (C1-4-alkyl) HN—C1-4-alkylene- and (C1-4-alkyl)2N—C1-4-alkylene-;
• R2.4.2 is independently selected from H, C1-6-alkyl-, C1-6-haloalkyl-;
• C3-8-cycloalkyl-, HO—C1-4-alkylene-, (C1-4-alkyl)-O—C1-4-alkylene-, H2N—C1-4-alkylene-, (C1-4-alkyl) HN—C1-4-alkylene- and (C1-4-alkyl)2N—C1-4-alkylene-;
• R2.5 and R4 are together selected from —C(R2.5.1)=, ═C(R2.5.1)—, —N═;
• and
• R2.5.1 is independently selected from H, C1-6-alkyl-, C1-6-haloalkyl-;
• C3-8-cycloalkyl-, HO—C1-4-alkylene-, (C1-4-alkyl)-O—C1-4-alkylene-, H2N—C1-4-alkylene-, (C1-4-alkyl) HN—C1-4-alkylene- and (C1-4-alkyl)2N—C1-4-alkylene-;
• R3 is H or F;
• R4 is independently selected from F, Cl, phenyl-H2C—O—, HO—, C1-6-alkyl-, C1-6-haloalkyl-, C3-8-cycloalkyl-, C1-6-alkyl-O—, C1-6-haloalkyl-O—, C1-6-alkyl-HN—, (C1-6-alkyl)2-HN—, C1-6-alkyl-HN—C1-4-alkylene- and (C1-6-alkyl)2-HN—C1-4-alkylene-;
• A is a bond or independently selected
• from —O—, —S—, —N(R5)—, —C(O)N(R5)—, —N(R5)C(O)—, —S(O)2N(R5)—, —N(R5)S(O)2—, —S(O)(═NR5)—N(R5)—, —N(R5)(NR5═) S(O)—, —S(═NR5)2—N(R5)—, —N(R5)(NR5=)2S—, —C(R5)═C(R5)—, —C≡C—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)2—, —S(═NR5)—, —S(O)(═NR5)—, —S(═NR5)2—, —(R5)(O)S═N—, —(R5N═)(O)S—, and —N═(O)(R5)S—;
• R5 is independently selected from H, C1-6-alkyl- and NC—;
• or a salt thereof.