# US 11,897,880 B2 · 7,8-dihydrobenzo[e]pyrido[3,4-c]azocine-2,5(3H,6H)-dione derivatives useful as a factor XIa inhibitors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,897,880 B2 - Document ID: US11897880B2 - Status: Granted - Kind: B2 - Application number: 17/732,724 - Filed: 2022-04-29 - Published: 2022-12-08 - Granted: 2024-02-13 - Earliest claimed: 2021-04-30 - Assignees: Janssen Pharmaceutica NV - Applicants: Janssen Pharmaceutica NV - Inventors: Guozhang Xu; Tianbao Lu; Zhijie Liu; Micheal D. Gaul - Web page: https://patentgrep.com/patent/US11897880B2 ## CPC - C07D 471/04: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract The present invention is directed to 7,8-dihydrobenzo[e]pyrido[3,4-c]azocine-2,5(3H,6H)-dione derivatives, stereoisomers, isotopologues, isotopomers and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds and the use of said compounds in the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders and diseases or conditions in which plasma kallikrein activity is implicated. ## Claims ### Claim 1 A compound of formula (I) wherein R1 is selected from the group consisting of hydrogen, C1-2alkyl, —(C1-2alkylene)-OH and —(C1-2alkylene)-O-(C1-2alkyl); R2 is hydrogen and R3 is cyclopropyl-methyl-; alternatively, R2 and R3 are taken together with the carbon atoms to which they are bound to form R4 is selected from the group consisting of hydrogen and halogen; R5 is selected from the group consisting of phenyl, heteroaryl and pyridin-4-yl-1-oxide; wherein the phenyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, C1-4alkyl, hydroxy substituted C1-4alkyl, NRARB and —NH—C(O)-(C1-4alkyl); wherein RA and RB are each independently selected from the group consisting of hydrogen and C1-2alkyl; a is an integer from 0 to 3; each R6 is independently selected from the group consisting of chloro, fluoro and methyl; R7 is hydrogen, and R8 and R9 are each independently selected from the group consisting of hydrogen, C1-4alkyl, and C1-4alkoxy; alternatively, R7 is hydrogen, and R8 and R9 are taken together with the carbon atom to which they are bound to form a ring structure selected from the group consisting of cycloprop-1,1-diyl, cyclobut-1,1-diyl, cyclopent-1,1-diyl, and cyclohex-1,1-yl; alternatively, R9 is hydrogen, and R7 and R8 are taken together with the carbon atoms to which they are bound to form a ring structure selected from the group consisting of phen-1,2-diyl and pyridin-3,4-diyl; or a stereoisomer, isotopologue, isotopomer, or pharmaceutically acceptable salt or solvate thereof. ### Claim 2 (depends on 1) The compound of claim 1 having the formula (I-A) or a stereoisomer, isotopologue, isotopomer, or pharmaceutically acceptable salt or solvate thereof. ### Claim 3 (depends on 1) The compound of claim 1 having the formula (I-B) or a stereoisomer, isotopologue, isotopomer, or pharmaceutically acceptable salt or solvate thereof. ### Claim 4 (depends on 1) The compound of claim 1, wherein R1 is selected from the group consisting of hydrogen, C1-2alkyl, —(C1-2alkylene)-OH and —(C1-2alkylene)-O-(C1-2alkyl); R2 is hydrogen and R3 is cyclopropyl-methyl-; alternatively, R2 and R3 are taken together with the carbon atoms to which they are bound to form R4 is selected from the group consisting of hydrogen, fluoro and chloro; R5 is selected from the group consisting of phenyl, nitrogen containing heteroaryl and pyridin-4-yl-1-oxide; wherein the phenyl or heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, oxo, C1-2alkyl, hydroxy substituted C1-2alkyl, NRARB and —NH—C(O)-(C1-2alkyl); wherein RA and RB are each independently selected from the group consisting of hydrogen and C1-2alkyl; a is an integer from 1 to 2; each R6 is independently selected from the group consisting of chloro and fluoro; R7 is hydrogen, and R8 and R9 are the same and selected from the group consisting of hydrogen, C1-2alkyl, and C1-2alkoxy; alternatively, R7 is hydrogen, and R8 and R9 are taken together with the carbon atom to which they are bound to form a ring structure selected from the group consisting of cycloprop-1,1-diyl, cyclobut-1,1-diyl, and cyclopent-1,1-diyl; alternatively, R9 is hydrogen, and R7 and R8 are taken together with the carbon atoms to which they are bound to form a ring structure selected from the group consisting of phen-1,2-diyl and pyridin-3,4-diyl; or stereoisomer, isotopologue, isotopomer, or pharmaceutically acceptable salt or solvate thereof. ### Claim 5 A compound of formula (I) wherein R1 is selected from the group consisting of hydrogen, methyl, 2-hydroxy-ethyl- and 2-methoxy-ethyl-; R2 is hydrogen and R3 is cyclopropyl-methyl-; alternatively, R2 and R3 are taken together with the carbon atoms to which they are bound to form; R4 is selected from the group consisting of hydrogen and fluoro; R5 is selected from the group consisting of 4-fluoro-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 1-methyl-imidazol-5-yl, 1-methyl-1,2,3-triazol-5-yl, 1-methyl-pyrimidin-4-yl-6-one, 2-fluoro-6-amino-pyridin-3-yl, 2-chloro-6-amino-pyridin-3-yl, 1-methyl-pyridin-3-yl-6-one, pyridin-4-yl, 2-chloro-6-amino-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-fluoro-6-amino-pyridin-4-yl, 1-methyl-pyridin-4-yl-6-one, pyridin-4-yl-1-oxide, 2-chloro-6-amino-pyridin-5-yl, indol-5-yl, indazol-5-yl, benzimidazol-5-yl, benzothiazol-5-yl, 2-methyl-benzothiazol-5-yl, benzo[1,2,3]thiadiazol-5-yl, imidazo[1,2-a]pyridin-7-yl, 3-bromo-imidazo[1,2-a]pyridin-7-yl and [1,2,4]triazolo[4,3-a]pyridin-7-yl; a is an integer from 1 to 2; each R6 is independently selected from the group consisting of 11-chloro and 12-fluoro; R7 is hydrogen, and R8 and R9 are the same and selected from the group consisting of hydrogen, and methyl; alternatively, R7 is hydrogen, and R8 and R9 are taken together with the carbon atom to which they are bound to form a ring structure selected from the group consisting of cycloprop-1,1-diyl, cyclobut-1,1-diyl and cyclopent-1,1-diyl; alternatively, R9 is hydrogen, and R7 and R8 are taken together with the carbon atoms to which they are bound to form a ring structure selected from the group consisting of phen-1,2-diyl and pyridin-3,4-diyl; or stereoisomer or pharmaceutically acceptable salt thereof. ### Claim 6 (depends on 5) The compound of claim 5, wherein R1 is selected from the group consisting of hydrogen, methyl, and 2-hydroxy-ethyl-; R2 is hydrogen and R3 is cyclopropyl-methyl-; alternatively, R2 and R3 are taken together with the carbon atoms to which they are bound to form; R4 is selected from the group consisting of hydrogen and fluoro; R5 is selected from the group consisting of 4-fluoro-phenyl, 4-(methoxy-carbonyl-amino)-phenyl, 2-fluoro-6-amino-pyridin-3-yl, 2-chloro-6-amino-pyridin-3-yl, pyridin-4-yl, 2-chloro-6-amino-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-fluoro-6-amino-pyridin-4-yl, 1-methyl-pyridin-4-yl-6-one, indol-5-yl, indazol-5-yl, benzimidazol-5-yl, benzothiazol-5-yl, 2-methyl-benzothiazol-5-yl, benzo[1,2,3]thiadiazol-5-yl, imidazo[1,2-a]pyridin-7-yl, 3-bromo-imidazo[1,2-a]pyridin-7-yl and [1,2,4]triazolo[4,3-a]pyridin-7-yl; a is an integer from 1 to 2; each R6 is independently selected from the group consisting of 11-chloro and 12-fluoro; R7 is hydrogen, and R8 and R9 are the same and selected from the group consisting of hydrogen, and methyl; alternatively, R7 is hydrogen, and R8 and R9 are taken together with the carbon atom to which they are bound to form a ring structure selected from the group consisting of cycloprop-1,1-diyl, cyclobut-1,1-diyl and cyclopent-1,1-diyl; alternatively, R9 is hydrogen, and R7 and R8 are taken together with the carbon atoms to which they are bound to form a ring structure selected from the group consisting of phen-1,2-diyl and pyridin-3,4-diyl; or a pharmaceutically acceptable salt thereof. ### Claim 7 (depends on 5) The compound of claim 5, wherein R1 is selected from the group consisting of hydrogen, and methyl; R2 is hydrogen and R3 is cyclopropyl-methyl-; alternatively, R2 and R3 are taken together with the carbon atoms to which they are bound to form; R4 is selected from the group consisting of hydrogen and fluoro; R5 is selected from the group consisting of 4-(methoxy-carbonyl-amino)-phenyl, 2-fluoro-6-amino-pyridin-3-yl, 2-chloro-6-amino-pyridin-3-yl, 2-chloro-6-amino-pyridin-4-yl, 2-fluoro-6-amino-pyridin-4-yl, indol-5-yl, indazol-5-yl, benzimidazol-5-yl, benzothiazol-5-yl, 2-methyl-benzothiazol-5-yl, benzo[1,2,3]thiadiazol-5-yl, and imidazo[1,2-a]pyridin-7-yl; a is an integer from 1 to 2; each R6 is independently selected from the group consisting of 11-chloro and 12-fluoro; R7 is hydrogen, and R8 and R9 are the same and selected from the group consisting of hydrogen, and methyl; alternatively, R7 is hydrogen, and R8 and R9 are taken together with the carbon atom to which they are bound to form a ring structure selected from the group consisting of cycloprop-1,1-diyl, cyclobut-1,1-diyl and cyclopent-1,1-diyl; or a pharmaceutically acceptable salt thereof. ### Claim 8 (depends on 5) The compound of claim 5, wherein R1 is hydrogen; R2 is hydrogen and R3 is cyclopropyl-methyl-; alternatively, R2 and R5 are taken together with the carbon atoms to which they are bound to form; R4 is hydrogen; R5 is selected from the group consisting of 4-(methoxy-carbonyl-amino)-phenyl, 2-fluoro-6-amino-pyridin-3-yl, 2-chloro-6-amino-pyridin-3-yl, 2-fluoro-6-amino-pyridin-4-yl, indazol-5-yl, benzimidazol-5-yl, and benzothiazol-5-yl; a is 2; one R6 is 11-chloro and the other R6 is 12-fluoro; R7 is hydrogen, and R8 and R9 are each methyl; alternatively, R7 is hydrogen, and R8 and R9 are taken together with the carbon atom to which they are bound to form a ring structure selected from the group consisting of cycloprop-1,1-diyl, cyclobut-1,1-diyl and cyclopent-1,1-diyl; or a pharmaceutically acceptable salt thereof. ### Claim 9 (depends on 1) The compound of claim 1, selected from the group consisting of (R*)-12-(5-(1H-benzo[d]imidazol-5-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopropane]-1,10(4H,12H)-dione; (S*)-12-(5-(1H-indol-5-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopropane]-1,10(4H,12H)-dione; (S)-12-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopropane]-1,10(4H,12H)-dione; (S*)-12-(5-(6-amino-2-chloropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopropane]-1,10(4H,12H)-dione; (R*)-12-(5-(6-amino-2-chloropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-3,4,13,14-tetrahydrobenzo[5,6]azocino[4,3-g]indolizine-1,10(2H,12H)-dione; (S*)-12-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-3,3-dimethyl-3,4,13,14-tetrahydrobenzo[5,6]azocino[4,3-g]indolizine-1,10(2H,12H)-dione; (S*)-12-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclobutane]-1,10(4H,12H)-dione; (S*)-12-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopentane]-1,10(4H,12H)-dione; (S*)-12-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-2-methyl-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopropane]-1,10(4H,12H)-dione; and pharmaceutically acceptable salt thereof. ### Claim 10 (depends on 5) The compound of claim 5, selected from the group consisting of (R*)-12-(5-(1H-benzo[d]imidazol-5-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopropane]-1,10(4H,12H)-dione, (S*)-12-(5-(1H-indol-5-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopropane]-1,10(4H,12H)-dione; (S)-12-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopropane]-1,10(4H,12H)-dione; (S*)-12-(5-(6-amino-2-chloropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopropane]-1,10(4H,12H)-dione; (R*)-12-(5-(6-amino-2-chloropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-3,4,13,14-tetrahydrobenzo[5,6]azocino[4,3-g]indolizine-1,10(2H,12H)-dione; (S*)-12-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-3,3-dimethyl-3,4,13,14-tetrahydrobenzo[5,6]azocino[4,3-g]indolizine-1,10(2H,12H)-dione; (S*)-12-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclobutane]-1,10(4H,12H)-dione; (S*)-12-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopentane]-1,10(4H,12H)-dione; (S*)-12-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-chloro-8-fluoro-2-methyl-13,14-dihydro-2H-spiro[benzo[5,6]azocino[4,3-g]indolizine-3,1′-cyclopropane]-1,10(4H,12H)-dione; methyl (S*)-(4-(2-(1-(11-chloro-12-fluoro-2,5-dioxo-2,5,6,8-tetrahydro-3H-spiro[benzo[e]pyrido[3,4-c]azocine-7,1′-cyclopropan]-3-yl)-2-cyclopropylethyl)-1H-imidazol-5-yl)phenyl)carbamate; and pharmaceutically acceptable salt thereof. ### Claim 11 (depends on 1) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1.