# US 8,772,504 B2 · Substituted benzoxazole, benzimidazole, oxazolopyridine and imidazopyridine derivatives as gamma secretase modulators > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,772,504 B2 - Document ID: US8772504B2 - Status: Granted - Kind: B2 - Application number: 13/144,557 - Filed: 2010-02-15 - Published: 2012-01-26 - Granted: 2014-07-08 - Earliest claimed: 2009-02-19 - Assignees: Janssen Pharmaceuticals, Inc.; Cellzome Limited - Applicants: Henricus Jacobus Maria Gijsen; François Paul Bischoff; Wei Zhuang; Sven Franciscus Anna Van Brandt; Michel Surkyn; Mirko Zaja; Didier Jean-Claude Berthelot; Michel Anna Jozef De Cleyn; Gregor James MacDonald; Daniel Oehlrich - Inventors: Henricus Jacobus Maria Gijsen; François Paul Bischoff; Wei Zhuang; Sven Franciscus Anna Van Brandt; Michel Surkyn; Mirko Zaja; Didier Jean-Claude Berthelot; Michel Anna Jozef De Cleyn; Gregor James MacDonald; Daniel Oehlrich - Web page: https://patentgrep.com/patent/US8772504B2 ## CPC - C07D 413/12: linked by a chain containing hetero atoms as chain links - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/16: Anti-Parkinson drugs - A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 401/14: containing three or more hetero rings - C07D 403/12: linked by a chain containing hetero atoms as chain links - C07D 403/14: containing three or more hetero rings - C07D 405/14: containing three or more hetero rings - C07D 413/14: containing three or more hetero rings - C07D 471/04: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention is concerned with novel substituted benzoxazole, benzimidazole, oxazolopyridine and imidazopyridine derivatives of Formula (I) wherein R1, R2, R3, R4, X, A1, A2, A3, A4, Y1, Y2, Y3 and Z have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament. ## Claims ### Claim 1 A compound of formula (I) or a stereoisomeric form thereof, wherein R1 is hydrogen, cyano, CF3, halo, or C1-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl and C1-4alkyloxy; R2 is hydrogen, C1-4alkyl or halo; X is CR5 or N; R5 is hydrogen or halo; A1 is CR6 or N; R6 is hydrogen, halo or C1-4alkyloxy; A2, A3 and A4 each independently are CH, CF or N; provided that no more than two of A1, A2, A3 and A4 are N; Y1 is CH Y2 is CR4; Y3 is CH; R4 is hydrogen, halo, C1-4alkyloxy, cyano, cycloC3-7alkyl, C2-4alkenyl, or C1-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and C1-4alkyloxy; R3 is C2-6alkyl substituted with one or more halo substituents; C1-6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, morpholinyl, pyrrolidinyl, Ar, C1-6alkyloxy, tetrahydropyranyl, cycloC3-7alkyloxy and cycloC3-7alkyl; cycloC3-7alkyl substituted with one or more phenyl substituents optionally substituted with one or more halo substituents; cycloC3-7alkyl; piperidinyl; morpholinyl; pyrrolidinyl; tetrahydropyranyl; O—Ar; NR7R8; C1-6alkyloxy; C1-6alkylthio; Ar; CH2—O—Ar; S—Ar; NCH3—Ar; NH—Ar; or 1,6-dihydro-1-methyl-6-oxo-3-pyridinyl; wherein each piperidinyl, morpholinyl and pyrrolidinyl may be substituted with one or more substituents each independently selected from the group consisting of C1-4alkyl, C2-6alkenyl, C1-4alkylcarbonyl, halo and C1-4alkyloxycarbonyl; wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyloxy, cyano, NR7R8, morpholinyl, C1-4alkyl, C1-4alkyloxy substituted with one or more halo substituents, and C1-4alkyl substituted with one or more halo substituents; or a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyloxy, cyano, C1-4alkyl, C1-4alkyloxy substituted with one or more halo substituents, and C1-4alkyl substituted with one or more halo substituents; each R7 is selected independently from hydrogen or C1-4alkyl; each R8 is selected independently from hydrogen, C1-4alkyl or C1-4alkylcarbonyl; Z is NR9; R9 is hydrogen, or C1-6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, phenyl, cycloC3-7alkyl and C1-4alkyloxy; or a pharmaceutically acceptable addition salt thereof. ### Claim 2 (depends on 1) The compound according to claim 1 or a stereoisomeric form thereof, wherein R1 is hydrogen, C1-4alkyl, cyano, CF3, or halo; R2 is hydrogen or C1-4alkyl; X is CR5 or N; R5 is hydrogen or halo; A1 is CR6 or N; R6 is hydrogen, halo or C1-4alkyloxy; A2, A3 and A4 each independently are CH, CF or N; provided that no more than two of A1, A2, A3 and A4 are N; Y1 is CH; Y2 is CR4; Y3 is CH; R4 is hydrogen, halo, C1-4alkyloxy, cyano, cycloC3-7alkyl, C2-4alkenyl, or C1-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and C1-4alkyloxy; R3 is C2-6alkyl substituted with one or more halo substituents; C1-6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, Ar, C1-6alkyloxy, tetrahydropyranyl, cycloC3-7alkyloxy and cycloC3-7alkyl; cycloC3-7alkyl; piperidinyl; morpholinyl; pyrrolidinyl; tetrahydropyranyl; O—Ar; NR7R8; C1-6alkyloxy; C1-6alkylthio; Ar; CH2—O—Ar; S—Ar; NCH3—Ar; or NH—Ar; wherein each piperidinyl, morpholinyl and pyrrolidinyl may be substituted with one or more substituents each independently selected from the group consisting of C1-4alkyl, C2-6alkenyl, C1-4alkylcarbonyl, halo and C1-4alkyloxycarbonyl; wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyloxy, cyano, NR7R8, morpholinyl, C1-4alkyl and C1-4alkyl substituted with one or more halo substituents; or a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyloxy, cyano, C1-4alkyl and C1-4alkyl substituted with one or more halo substituents; each R7 is selected independently from hydrogen or C1-4alkyl; each R8 is selected independently from hydrogen or C1-4alkyl; Z is NR9; R9 is hydrogen, or C1-6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, phenyl and C1-4alkyloxy; or a pharmaceutically acceptable addition salt thereof. ### Claim 3 (depends on 1) The compound according to claim 1 or a stereoisomeric form thereof, wherein R1 is hydrogen, C1-4alkyl, cyano, CF3, or halo; R2 is hydrogen or C1-4alkyl; X is CR5 or N; R5 is hydrogen or halo; A1 is CR6 or N; R6 is hydrogen, halo or C1-4alkyloxy; A2, A3 and A4 each independently are CH, CF or N; provided that no more than two of A1, A2, A3 and A4 are N; Y1 is CH; Y2 is CR4; Y3 is CH; R4 is hydrogen, halo, C1-4alkyloxy, cyano, or C1-4alkyl optionally substituted with one or more halo substituents; R3 is C2-6alkyl substituted with one or more halo substituents; C1-6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, Ar, C1-6alkyloxy, tetrahydropyranyl, cycloC3-7alkyloxy and cycloC3-7alkyl; cycloC3-7alkyl; piperidinyl; morpholinyl; pyrrolidinyl; tetrahydropyranyl; O—Ar; NR7R8; C1-6alkyloxy; C1-6alkylthio; Ar; CH2—O—Ar; S—Ar; NCH3—Ar; or NH—Ar; wherein each piperidinyl, morpholinyl and pyrrolidinyl may be substituted with one or more substituents each independently selected from the group consisting of C1-4alkyl, C2-6alkenyl, C1-4alkylcarbonyl, halo and C1-4alkyloxycarbonyl; wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyloxy, cyano, NR7R8, morpholinyl, C1-4alkyl and C1-4alkyl substituted with one or more halo substituents; or a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl and pyrazinyl; wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyloxy, cyano, C1-4alkyl and C1-4alkyl substituted with one or more halo substituents; each R7 is selected independently from hydrogen or C1-4alkyl; each R8 is selected independently from hydrogen or C1-4alkyl; Z is NR9; R9 is hydrogen, or C1-6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, phenyl and C1-4alkyloxy; or a pharmaceutically acceptable addition salt thereof. ### Claim 4 (depends on 1) The compound according to claim 1 or a stereoisomeric form thereof, wherein R1 is hydrogen, cyano, halo, or C1-4alkyl optionally substituted with one or more hydroxyl radicals; R5 is hydrogen; Y1 is CH; Y2 is CR4; Y3 is CH; provided that only one of Y1 and Y2 may represent N; R4 is hydrogen, halo, C1-4alkyloxy, cycloC3-7alkyl, C2-4alkenyl, or C1-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and C1-4alkyloxy; R3 is C2-6alkyl substituted with one or more halo substituents; C1-6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of piperidinyl, Ar, C1-6alkyloxy, tetrahydropyranyl and cycloC3-7alkyl; cycloC3-7alkyl substituted with one or more phenyl substituents optionally substituted with one or more halo substituents; cycloC3-7alkyl; piperidinyl; morpholinyl; tetrahydropyranyl; O—Ar; C1-6alkyloxy; C1-6alkylthio; Ar; CH2—O—Ar; NH—Ar; or 1,6-dihydro-1-methyl-6-oxo-3-pyridinyl; wherein each piperidinyl and morpholinyl may be substituted with one or more substituents each independently selected from the group consisting of C1-4alkyl, C1-4alkylcarbonyl, halo and C1-4alkyloxycarbonyl; wherein each Ar independently is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyloxy, cyano, NR7R8, C1-4alkyl, C1-4alkyloxy substituted with one or more halo substituents, and C1-4alkyl substituted with one or more halo substituents; or a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl and thiophenyl; wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo and C1-4alkyl substituted with one or more halo substituents; each R8 is selected independently from C1-4alkyl or C1-4alkylcarbonyl or a pharmaceutically acceptable addition salt thereof. ### Claim 5 (depends on 1) The compound according to claim 1, or a stereoisomeric form thereof, wherein R1 is methyl; R2 is hydrogen; or a pharmaceutically acceptable addition salt thereof. ### Claim 6 (depends on 1) The compound according to claim 1, or a stereoisomeric form thereof, wherein R1 is C1-4alkyl; R2 is hydrogen; X is CH or N; A1 is CR6; R6 is hydrogen, methoxy or halo; A2 is CH or N; A3 and A4 are CH; Y1 is CH; Y2 is CR4; Y3 is CH; R4 is hydrogen, halo or C1-4alkyl; R3 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo, C1-4alkyloxy, NR7R8 and C1-4alkyl substituted with one or more halo substituents; R7 is hydrogen; R8 is C1-4alkylcarbonyl; Z is NR9; R9 is C1-6alkyl; or a pharmaceutically acceptable addition salt thereof. ### Claim 7 (depends on 1) The compound according to claim 1, or a stereoisomeric form thereof, wherein R1 is C1-4alkyl; R2 is hydrogen; X is CH; A1 is CR6; R6 is F or methoxy; A2 is N or CH; A3 and A4 are CH; Y1 is CH; Y2 is CR4; Y3 is CH; R4 is hydrogen or methyl; R3 is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and methoxy; Z is NR9; R9 is C1-6alkyl; or a pharmaceutically acceptable addition salt thereof. ### Claim 8 (depends on 1) The compound according to claim 1, or a stereoisomeric form thereof, wherein R1 is C1-4alkyl; R2 is hydrogen; X is CH; A1 is COCH3; A2 is N; A3 is CH; A4 is CH; Y1, Y2 and Y3 are CH; R3 is phenyl optionally substituted with one or more halo substituents; Z is NR9; R9 is C1-6alkyl; or a pharmaceutically acceptable addition salt thereof. ### Claim 9 (depends on 1) The compound according to claim 1, wherein the compound is N-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-(4-fluorophenyl)-1,6-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine, N-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-(4-fluorophenyl)-1,6-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine.2CH3SO3H, N-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-(4-fluorophenyl)-1,6-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine.2HCl, 2-(4-fluorophenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine, 2-(4-fluorophenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine.2HCl, 2-(2,3-difluorophenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine.2HCl.H2O, 2-(2,3-difluorophenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine, 2-(4-fluoro-3-methoxyphenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine.2HCl.H2O, 2-(4-fluoro-3-methoxyphenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine, 2-(3,5-dimethoxyphenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine.2HCl.H2O, or 2-(3,5-dimethoxyphenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine, including any stereochemically isomeric form thereof or a pharmaceutically acceptable addition salt thereof. ### Claim 10 (depends on 1) The compound according to claim 1, wherein the compound is 2-(4-fluorophenyl)-N-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-2-pyridinyl]-1-methyl-1H-benzimidazol-4-amine, or a pharmaceutically acceptable addition salt thereof. ### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1 to 10. ### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) A method for the treatment of a disease or condition selected from, traumatic brain injury, mild cognitive impairment, senility, dementia, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid, comprising administering to a subject a compound as defined in any one of claims 1 to 10.