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US 2014/0275155 A1Published application
Substituted bicyclic 1-carboxylic-acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin c
AssigneeBoehringer Ingelheim International GmbH
InventorsMatthias GRAUERT, Ralf ANDERSKEWITZ, Marc GRUNDL, Thorsten OOST, Alexander PAUTSCH, Stefan PETERS
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Abstract
This invention relates to bicyclic 1-carboxylic-acid (benzyl-cyano-methyl)-amides of formula 1 and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.
Claims16
1:
- A compound of formula 1
- wherein
- X1 is selected from among —NH—, —CH2—NH—, —NH—CH2—, —CH2—CH2—NH— and —NH—CH2—CH2—
- X2 is selected from among —CH2—, —CH2—CH2—, —CH2—CH2—CH2—, —O—CH2—CH2— and —CH2—CH2—O—;
- X3 is selected from among —CH2— and —CH2—CH2—,
- R1 is independently selected from among 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 among
- 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 among 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;
- C5-10-heterocyclyl-;
- containing one, two, three or four heteroatoms independently selected from among 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 among 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 among 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-, C1-16-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 among
- 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 among 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 independently selected from among 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 among 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 among O═, C1-6-alkyl-, C1-16-haloalkyl-;
- C3-8-cycloalkyl-, C1-6-alkyl-O—C1-6-alkyl-, H(O)C—, C1-16-alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-;
- R2.2 is independently selected from among 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
- among —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—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-;
- R2.3.1 is independently selected from among 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 among 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
- among —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)—, —N(R2.4.1)C(R2.4.2)2— and —C1-4-alkylene-;
- and
- R2.4.1 is independently selected from among 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 among 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 among —C(R2.5.1)═, ═C(R2.5.1)—, —N═;
- and
- R2.5.1 is independently selected from among 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, F;
- R4 is independently selected from among H, F, Cl, phenyl-H2C—O—, HO—, C1-6-alkyl-, C1-16-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
- among —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 among H, C1-6-alkyl- and NC—;
- or a salt thereof.
59 more elements
2:
- The compound of formula 1, according to claim 1, wherein
- X1 is selected from among —NH—, —CH2—NH— and —NH—CH2—;
- X2 is selected from among-CH2—, —CH2—CH2—, —CH2—CH2—CH2—, —O—CH2—CH2— and —CH2—CH2—O—;
- and
- X3 is —CH2—CH2—.
2 more elements
3:
- The compound of formula 1, according to claim 1, wherein
- X1 is selected from among —NH—, —CH2—NH—, —NH—CH2—, —CH2—CH2—NH— and —NH—CH2—CH2—;
- X2 is selected from among —CH2—, —CH2—CH2—, —CH2—CH2—CH2—, —O—CH2—CH2— and —CH2—CH2—O—;
- and
- X3 is —CH2—.
2 more elements
4:
- The compound of formula 1, according to claim 1, wherein R1 is R1.a and R1.a is independently selected from among H, C1-4-alkyl-, F and HO—.
5:
- The compound of formula 1, according to claim 1, wherein R4 is R4.a and R4.a is H, F, Cl, phenyl-H2C—O—, HO—, C1-4-alkyl-, C1-4-haloalkyl-, C3-6-cycloalkyl-, C1-4-alkyl-O— and C1-4-haloalkyl-O—.
6:
- The compound of formula 1, according to claim 1, wherein R4 is R4.b and R4.b is H or F.
7:
- The compound of formula 1, according to claim 1,
- wherein A is Aa and Aa is a bond or independently selected from
- among —O—, —C(O)N(R5)—, —N(R5)C(O)—, —S(O)2N(R5)—, —N(R5)S(O)2—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)2—, —(R5)(O)S═N—, —(R5N═)(O)S— and —N═(O)(R5)S— and R5 is R5.a and R5.a is independently selected from among H, C1-4-alkyl- and NC—.
8:
- The compound of formula 1, according to claim 1, wherein R2 is R2.1 and
- R2.1 is R2.a and R2.1.a is selected from among 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 among
- 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 among 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 among 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.
11 more elements
9:
- The compound of formula 1, according to claim 1, wherein R2 is R2.q and R2.q is selected from among the substituents (a1) to (h1)
- wherein carbon atoms of the R2.q ring are optionally and independently from each other substituted by a group selected from among —CN, —SO2Me, —SO2NMe2, Me, ═O, F and —CONH2, and possibly available nitrogen atoms of the ring are optionally and independently from each other substituted by a group selected from among Me, —CH2CH2OMe and —CH2-tetrahydropyranyl, and possibly available sulfur atoms of the ring are optionally and independently from each other substituted by one or two ═O.
10:
- The compound of formula 1 according to claim 1, wherein
- X1 is selected from among —NH—, —CH2—NH— and —NH—CH2—;
- X2 is selected from among —CH2—, —CH2—CH2—, —CH2—CH2—CH2—, —O—CH2—CH2— and —CH2—CH2—O—;
- R1 is R1.b and R1.b is H;
- or two R1 are together —CH2—;
- R2 is selected from among
- R2.1
- phenyl-;
- optionally substituted with one or two residues independently selected from R2.1;
- optionally substituted with one R2.3;
- C5-heteroaryl-;
- containing two or three independently selected from among S, O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one R2.1;
- wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R2.2;
- monocyclic C6-heterocyclyl containing one or two nitrogen atoms, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one R2.1;
- wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R2.2;
- bicyclic C9 or 10-heterocyclyl-;
- containing one, two, three or four heteroatoms independently selected from among 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 R2.1;
- wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one R2.2;
- R2.1 is independently selected from among halogen, NC—, O═, H-A-, H-A-C1-4-alkylene-, R2.1.1-A-, C1-4-alkyl-A-, C3-6-cycloalkyl-A-, R2.1.1—C1-4-alkylene-A-, C1-4-alkyl-A-C1-4-alkylene- and HO—C1-4-alkylene-A-C1-4-alkylene-;
- R2.1.1 is independently selected from among
- phenyl-;
- C5 or 6-heterocyclyl-;
- containing one or two heteroatoms independently selected from among O and N, wherein the ring is fully or partially saturated, wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one C1-4-alkyl-;
- R2.2 is independently selected from among H-A-C1-4-alkylene-, C3-6-cycloalkyl-, C1-4-alkyl-A-C1-4-alkylene-, R2.1.1-A-C1-4-alkylene- and C1-4-alkyl-C(O)—;
- R2.3 and R4 are together a group selected from
- among —N(R2.3.1)—, —C(O)N(R2.3.2)— and —N(R2.3.1)C(O)—;
- R2.3.1 is independently selected from among H and H3C—;
- R3 is H or F;
- R4 is R4.b and R4.b is H or F;
- A is a bond or independently selected from
- among —O—, —C(O)N(R5)—, —N(R5)C(O)—, —S(O)2N(R5)—, —N(R5)S(O)2—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)2— and —N═(O)(R5)S—;
- R5 is independently selected from among H and C1-4-alkyl-;
- or a salt thereof.
30 more elements
11:
- A compound of formula 1′
- wherein X1, X2, X3, R1, R2, R3 and R4 have the meaning in claim 1.
12-13. (canceled)
A pharmaceutical composition, comprising a compound of formula 1 according to claim 1 or a pharmaceutically acceptable salt thereof.
(canceled)
16:
- The pharmaceutical composition according to claim 14 further comprising a pharmaceutically active compound selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors, 5-LO-inhibitors, Histamine receptor antagonists, CCR9 antagonists and SYK-inhibitors, NE-inhibitors, MMP9 inhibitors and MMP12 inhibitors, or combinations of two or three of the pharmaceutically active compound.
17:
- A method of treating asthma and allergic diseases, gastrointestinal inflammatory diseases, eosinophilic diseases, chronic obstructive pulmonary disease, infection by pathogenic microbes, rheumatoid arthritis or atherosclerosis comprising administering to a patient a therapeutically effective amount of a compound according to claim 1.
Dependencies are inferred from the claim text.