Patent EA-002817-B1 (EA)
Title: Sulfonic acid or sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds
Inventor: CHOI-SLEDESKI YONG MI
IPC: A61K31/519
Filed: 1997-12-03
Abstract: 1. A compound of formula I     is an isoquinolinyl, quinolinyl, 2-oxo-1,2-dihydroquinolinyl, tetrahydroquinolinyl, quinazolinyl, benzoimidazolyl, pyrrolopyridyl, thienopyrimidyl, thienopyridyl, furopyridyl, imidazopyridyl, at that at least one nitrogen atom of said bicyclic heteroaryls is in the distal ring thereof to the proximal ring thereof that is attached to Z; Z is C1-C3alkylenyl; R1 is hydrogen, C1-C4 alkyl with straight or branched chain, or acetyl; R2 is R3SO2; R3 is naphthyl, optionally substituted with C1-C4 alkoxy group; benzothienyl, optionally substituted with halo; thienyl, optionally substituted with pyridyl; or thienopyridyl. X1, X1a, X3, X4 are H; X2 and X2a, taken together, form oxo; X5, X5a and X5b independently selected from H, NH2, R7O- or halo and one of X5, X5a and X5b is H, hydroxy or NH2, which substitutes the distal ring of the group   at a position alpha to a nitrogen thereof; R7 is H or C1-C4 alkyl with straight or branched chain; m is 1; or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof. 2. The compound of Claim 1 wherein R1 is H or C1-C4 alkyl. 3. The compound of Claim 1 wherein R3 is naphthyl, optionally substituted with methoxy; thienyl, substituted with pyridyl; benzothienyl, optionally substituted with halo; 4. The compound of Claim 1 wherein Z is methylenyl. 5. The compound of Claim 1 wherein   is isoquinolinyl optionally substituted with X5, X5a and X5b. 6. The compound of Claim 5 wherein the isoquinolinyl is attached to Z at the 7-position thereof. 7. The compound of Claim 1 wherein   is quinolinyl optionally substituted with X5, X5a and X5b. 8. The compound of Claim 7 wherein the quinolinyl is attached to Z at the 7-position thereof. 9. The compound of Claim 1 wherein   is quinazolinyl optionally substituted with X5, X5a and X5b. 10. The compound of Claim 9 wherein the quinazolinyl is attached to Z at the 7-position thereof. 11. The compound of Claim 1 wherein one of X5, X5a and X5b is H, hydroxy or amino that is substituted on the proximal ring of   at a position that is adjacent to the position of the proximal ring to which Z is attached. 12. The compound of Claim 11 wherein one of X5, X5a and X5b is hydroxy or amino. 13. The compound of Claim 1 wherein one of X5, X5a and X5b that substitutes the distal ring of   at the position alpha to a nitrogen thereof is H or NH2. 14. A compound according to Claim 1 which is 7-methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [l-(1-aminoisoquinolin-7-ylmethy)-2-oxopyrrolidin-3-(S)-yl] amide hydrochloride; 7-methoxynaphthalene-2-sulfonic acid [l-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(1-hydroxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl] amide; 7-methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl] methylamide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] methylamide trifluoroacetate; Benzo[b]thiophene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 6-chlorobenzo[b]thiophene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide hydrochloride; 7-methoxynaphthalene-2-sulfonic acid [1-(6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 4-(2-chloro-6-nitrophenoxy)benzene sulfonic acid [1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 6-chlorobcnzo[b]thiophene-2-sulfonic acid [1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl) amide trifluoroacetate; 6-chlorobenzo[b]thiophene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; Benzo[b]thiophene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethy1)-2-oxopyrrolidin-3-(S)-yl] methylamide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(2-hydroxyquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] methylamide; 7-methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] methylamide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(2-hydroxyquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] methylamide; 7-methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide; 7-methoxynaphthalene-2-sulfonic acid [1-(2-hydroxyquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide; 7-methoxynaphthalene-2-sulfonic acid [1-(1H-benzimidazol-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [2-(1H-benzimidazol-5-ylethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(4-aminoquinazolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] methylamide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(4-aminothieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [2-(6-aminothieno[2.3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(7-aminothieno[2,3-c]pyridin-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(7-hydroxythieno[2.3-c]pyridin-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(4-aminothieno[3,2-c]pyridin-3-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl] amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(4-hydroxythieno[3.2-c]pyridin-3-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl] amide trifluoroacetate; Benzo[b]thiophene-2-sulfonic acid [1-(4-aminothieno[3,2-c]pyridin-3-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl] amide trifluoroacetate; 5-pyridin-4-yl-thiophene-2-sulfonic acid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 5-pyridin-3-yl-thiophene-2-sulfonic acid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; Benzo[b]thiophene-2-sulfonic acid [1-(4-aminoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 6-chlorobenzo[b]thiophene-2-sulfonic acid [1-(1-amino-isoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate; 6-chlorobenzo[b]thiophene-2-sulfonic acid [2-oxo-1-(1,2,3,4-tetrahydroisoquinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amide trifluoroacetate; 6-chlorobenzo[b]thiophene-2-sulfoiuc acid [1-(4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide; 6-chlorobenzo[b]thiophene-2-sulfonic acid [2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl] amide; 7-methoxynaphthalene-2-sulfonic acid [2-oxo-1-(1H-pyrroIo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl) amide trifluoroacetate; 6-chlorobenzo[b]thiophene-2-sulfonic acid (1-furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl) amide; 6-chlorobenzo[b]thiophene-2-sulfonic acid (1-furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl) amide; 6-chlorobenzo[b]thiophene-2-sulfonic acid [2-oxo-1-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl] amide trifluoroacetate; 6-chlorobenzo[b]thiophene-2-sulfonic acid [2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl] amide trifiuoroacetate; thieno[3,2-b]pyridine-2-sulfonic acid [2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl) pyrrolidin-3-(S)-yl] amide ditrifluoroacetate; benzo[b]thiophene-2-sulfonic acid (2-oxo-1-thieno[3,2-c]pyridin-2-ylmethylpyrrolidin-3-(S)-yl) amide trifluoroacetate; 7-methoxynaphthalene-2-sulfonic acid [1-(1H-imidazo[4,5-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate; or 7-methoxynaphthalene-2-sulfonic acid [1-(2-amino-3H-benzoimidazol-5-methyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate. 15. A compound according to Claim 1 which is 7-methoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate. 16. A compound according to Claim 1 which is 7-metoxynaphthalene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl] amide trifluoroacetate. 17. A compound according to Claim 1 which is 7-methoxynaphthalene-2-sulfonic acid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopynolidin-3-(S)-yl]methylamide trifluoroacetate. 18. A compound according to Claim 1 which is benzo[b]thiophene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate. 19. A compound according to Claim 1 which is 6-chlorobenzo[b]thiophene-2-sulfonic acid [1-(1-aminoisoquinolin-7-ylmethy1)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate. 20. A compound according to Claim 1 which is 7-methoxynaphthalene-2-sulfonic acid-[1-(1,6-diaminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate. 21. A compound according to Claim 1 which is 6-chlorobenzo[b]thiophene-2-sulfonic acid [1-(1,6-diaminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetate. 22. A compound according to Claim 1 which is 7-methoxynaphthalene-2-sulfonic acid [1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl] amide trifluoroacetat