US 2020/0138780 A1 · 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

1:

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
R2.1;
aryl-;
optionally substituted with one, two or three residues independently selected from R2.1;
optionally substituted with one R2.3;
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;
wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.2;
wherein a carbon atom of the ring is optionally substituted with one R2.3;
a nitrogen atom of the ring is optionally substituted with one R2.4;
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;
wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.2;
wherein a carbon atom of the ring is optionally substituted with one R2.3 or one R2.5;
a nitrogen atom of the ring is optionally substituted with one R2.4 or
R2 and R4 are together with two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three 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;
wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.2;
R2.1 is independently selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C1-6-alkylene-, R2.1.1-A-, C1-6-alkyl-A-, C3-8-cycloalkyl-A-, C1-6-haloalkyl-A-, R2.1.1—C1-6-alkylene-A-, C1-6-alkyl-A-C1-6-alkylene-, C3-8-cycloalkyl-A-C1-6-alkylene-, C1-6-haloalkyl-A-C1-6-alkylene-, R2.1.1—C1-6-alkylene-A-C1-6-alkylene-, R2.1.1-A-C1-6-alkylene-, HO—C1-6-alkylene-A-, HO—C1-6-alkylene-A-C1-6-alkylene-, C1-6-alkyl-O—C1-6-alkylene-A- and C1-6-alkyl-O—C1-6-alkylene-A-C1-6-alkylene-
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═, C1-6-alkyl-, C1-6-alkyl-O—, C1-6-haloalkyl-, C1-6-haloalkyl-O— and C3-8-cycloalkyl-;
R2.1.1.2 is independently selected from O═, C1-6-alkyl-, C1-6-haloalkyl-;
C3-8-cycloalkyl-, C1-6-alkyl-O—C1-6-alkyl-, H(O)C—, C1-6-alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-;
R2.2 is independently selected from H-A-C1-6-alkylene-, C3-8-cycloalkyl-, C1-6-alkyl-A-C1-6-alkylene-, C3-8-cycloalkyl-A-C1-6-alkylene-, C1-6-haloalkyl-A-C1-6-alkylene-, R2.1.1-A-C1-6-alkylene-, C1-6-alkyl-S(O)2— and C1-6-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(R2.42)—, —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.

58 more elements

7:

The compound of formula 1, according to claim 1, wherein R2 is R2.d and R2.d is phenyl;
optionally substituted with one, two or three residues independently selected from R2.1 and
R2.1 is R2.1.a and R2.1.a is 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 R2.1.1.a and R2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2.1.1.1;
C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently 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 selected independently from S, S(O), S(O)2, O and N and 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 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
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 O═, 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.

13 more elements

8:

The compound of formula 1, according to claim 1, wherein R2 is R2.g and R2.g 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 R2.1.a and R2.1.a is 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-allylene-, 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 R2.1.1.a and R2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2.1.1.1;
C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently 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 selected independently from S, S(O), S(O)2, O and N and 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 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
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 O═, 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 R2.2.a and R2.2.a 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-.

17 more elements

9:

The compound of formula 1, according to claim 1, wherein R2 is R2.j and R2.j 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 R2.l.a and R2.1.a is 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 R2.1.1.a and R2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2.1.1.1;
C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently 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 selected independently from S, S(O), S(O)2, O and N and 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 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
R2.1.1.1 is independently selected from halogen, HO—, O═, C1-4-alkyl-, C1-4-alkyl-O—, C1-4-haloalkyl- and C1-4-haloalkyl-O—, C3-6-cycloalkyl-;
and
R2.1.1.2 is independently selected from O═, 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 R2.2.a and R2.2.a 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—, C1-4-alkyl-C(O)— and R2.1.1-A-.

17 more elements

10:

The compound of formula 1, according to claim 1, wherein R2 is R2.m and R2.m is together with R4 and two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three 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, wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R2.2;
and
R2.1 is R2.1.a and R2.1.a is 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 R2.1.1.a and R2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2.1.1.1;
C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently 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 selected independently from S, S(O), S(O)2, O and N and 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 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
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 O═, 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 R2.2.a and R2.2.a 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—, C1-4-alkyl-C(O)— and R2.1.1-A-.

15 more elements

11:

The compound of formula 1, according to claim 1, wherein R2 is R2.n and R2.n is selected from aryl-, pyrazole, thiophene, furane;
wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R2.1;
wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.2;
wherein a carbon atom of the ring is optionally substituted with one R2.3;
a nitrogen atom of the ring is optionally substituted with one R2.4;
or R2.n is selected from
wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R2.1;
wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R2.2;
wherein a carbon atom of the ring is optionally substituted with one R2.3 or one R2.5;
a nitrogen atom of the ring is optionally substituted with one R2.4;
and
R2.1 is R2.1.a and R2.1.a is 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—C4-alkylene-A-C1-4-alkylene-, R2.1.1-A-C4-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 R2.1.1.a and R2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2.1.1.1;
C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently 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 selected independently from S, S(O), S(O)2, O and N and 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 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
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 O═, 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 R2.2.a and R2.2.a 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—, C1-4-alkyl-C(O)— and R2.1.1-A-;
and
R2.3 is together with R4 a group R2.3.a and R2.3.a is 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—, —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)—, —N(R2.3.1)C(R2.3.2)2— and —C1-4-alkylene-;
and
R2.3.1 is independently selected from H, C1-4-alkyl-, C1-4-haloalkyl-, C3-6-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, C1-4-alkyl-, C1-4-haloalkyl-, C3-6-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-;
and
R2.4 is together with R4 a group R2.4.a and R2.4.a is 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(R2.42)—, —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, C1-4-alkyl-, C1-4-haloalkyl-, C3-6-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, C1-4-alkyl-, C1-4-haloalkyl-, C3-6-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-;
and
R2.5 is together with R4 a group R2.5.a and R2.5.a is selected from —C(R2.5.1)═, ═C(R2.5.1)— and —N═;
and
R2.5.1 is independently selected from H, C1-4-alkyl-, C1-4-haloalkyl-, C3-6-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-.

38 more elements

13:

The compound of formula 1 according to claim 1, wherein R2 is R2.s and R2.s is Phenyl-R2.3,
wherein the phenyl ring is optionally substituted with one or two residues R2.1, wherein
R2.1 is R2.1.a and R2.1.a is 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-C114-alkylene-;
and
R2.1.1 is R2.1.1.a and R2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R2.1.1.1;
C5-10-heteroaryl-, containing one, two, three or four heteroatoms selected independently 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;
C5-10-heterocyclyl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O)2, O and N, and 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 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
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 O═, 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.s and R4 together denote a group (r1),
wherein the N-atom is optionally substituted with —R2.2, wherein
R2.2 is independently selected from H-A-C1-6-alkylene-, C3-8-cycloalkyl-, C1-6-alkyl-A-C1-6-alkylene-, C3-8-cycloalkyl-A-C1-6-alkylene-, C1-6-haloalkyl-A-C1-6-alkylene-, R2.1.1-A-C1-6-alkylene-, C1-6-alkyl-S(O)2—, C1-6-alkyl-C(O)— and R2.1.1-A-;
or a salt thereof.

16 more elements

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

Life of this patent

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

Life of this patent

Abstract

Claims19