发明名称 C2,C6 OXACYCLIC-FUSED THIAZINE DIOXIDE COMPOUNDS AS BACE INHIBITORS, COMPOSITIONS, AND THEIR USE
摘要 In its many embodiments, the present invention provides certain C2-ring-substituted iminothiazine compounds, including compounds Formula (I): (structurally represented) or a tautomers thereof, and pharmaceutically acceptable salts of said compounds and, wherein R1, R2, R3, R4, X, ring A, RA, m, -L1-, and RL are as defined herein. The novel compounds of the invention are useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer's disease, are also disclosed.;
申请公布号 US2015344500(A1) 申请公布日期 2015.12.03
申请号 US201314653685 申请日期 2013.12.16
申请人 MERCK SHARP & DOHME CORP. 发明人 Cumming Jared N.;Kaelin, Jr. David Earl;Scott Jack D.;Wu Wen-Lian;Burnett Duane A.
分类号 C07D513/04 主分类号 C07D513/04
代理机构 代理人
主权项 1. A compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (I):or a tautomer thereof having the structural formula (I′): or a pharmaceutically acceptable salt of said tautomer, wherein: X is selected from the group consisting of —O—, —C(R4H)2O—, and —OC(R4H)2—; R1 is independently selected from the group consisting of: H, halogen, alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R1 is optionally unsubstituted or substituted with one or more halogen; R2 is selected from the group consisting of H, halogen, alkyl, and heteroalkyl, wherein said alkyl and heteroalkyl of R2 are each optionally unsubstituted or substituted with one or more halogen; or, alternatively, R2 is a moiety having the formula wherein k is 0 or 1; -LC- (when present) is a divalent moiety selected from the group consisting of lower alkyl and lower heteroalkyl, wherein each said lower alkyl and lower heteroalkyl is optionally substituted with one or more halogen; ring C (when present) is selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; n is 0 or more; and each RC (when present) is independently selected from the group consisting of: halogen, oxo, —OH, —CN, —SF5, —OSF5, —Si(R5C)3, —N(R6C)2, —NR7CC(O)R6C, —NR7CS(O)2R6C, —NR7CS(O)2R6C, —NR7CC(O)N(R6C)2, —NR7CC(O)OR6C, —C(O)R6C, —C(O)2R6C, —C(O)N(R6C)2, —S(O)R6C, —S(O)2R6C, —S(O)2N(R6C)2, —OR6C, —SR6C, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, of RC are each optionally independently unsubstituted or substituted with one or more groups independently selected from R8; R3 is selected from the group consisting of H, halogen, lower alkyl, and lower heteroalkyl, wherein said lower alkyl and lower heteroalkyl are each optionally unsubstituted or substituted with one or more halogen; each R4 is independently selected from the group consisting of H, halogen, -alkyl-OH, alkyl, heteroalkyl, alkoxy, and cycloalkyl, wherein each said alkyl, heteroalkyl, alkoxy, and cycloalkyl of R4 is optionally substituted with halogen, with the proviso that when R4 is attached to a ring carbon atom adjacent to a ring oxygen atom, said R4 is selected from the group consisting of R4H; R4H (when present) is selected from the group consisting of H, -alkyl-OH, alkyl, heteroalkyl, and cycloalkyl wherein each said alkyl, heteroalkyl, and cycloalkyl of R4H is optionally substituted with halogen; ring A is selected from the group consisting of aryl and heteroaryl; m is 0 or more; each RA (when present) is independently selected from the group consisting of: halogen, oxo, —OH, —CN, —SF5, —OSF5, —Si(R5A)3, —N(R6A)2, —OR6A, —SR6A, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of RA are each optionally independently unsubstituted or substituted with one or more groups independently selected from R8; -L1- is a divalent moiety selected from the group consisting of —NHC(O)— and —C(O)NH—; RL is selected from the group consisting of alkyl and heteroalkyl, wherein said alkyl and heteroalkyl of RL are each optionally unsubstituted or substituted with one or more halogen; or, alternatively, RL is a moiety having the formula wherein q is 0 or 1; -LB- (when present) is a divalent moiety selected from the group consisting of lower alkyl and lower heteroalkyl, wherein each said lower alkyl and lower heteroalkyl is optionally substituted with one or more halogen; ring B is selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl; p is 0 or more; and each RB (when present) is independently selected from the group consisting of: halogen, oxo, —OH, —CN, —SF5, —OSF5, —Si(R5B)3, —N(R6B)2, —NR7BC(O)R6B, —NR7BS(O)2R6B, —NR7BS(O)2N(R6B)2, —NR7BC(O)N(R6B)2, —NR7BC(O)OR6B, —C(O)R6B, —C(O)OR6B, —C(O)N(R6B)2, —S(O)R6B, —S(O)2R6B, —S(O)2N(R6B)2, —OR6B, —SR6B, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, of RB are each optionally independently unsubstituted or substituted with one or more groups independently selected from R9; each R5A, R5B, and R5C (when present) is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl of R5A, R5B, and R5C is unsubstituted or substituted with one or more halogen; each R6A and R6C (when present) is independently selected from the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R6A and R6C is unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, haloalkyl, cycloalkyl, halogen-substituted cycloalkyl, heteroalkyl, halogen-substituted heteroalkyl, alkoxy, halogen-substituted alkoxy, heteroalkoxy, and halogen-substituted heteroalkoxy; each R6B (when present) is independently selected from the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R6B is unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, haloalkyl, cycloalkyl, halogen-substituted cycloalkyl, heteroalkyl, halogen-substituted heteroalkyl, alkoxy, halogen-substituted alkoxy, heteroalkoxy, and halogen-substituted heteroalkoxy; each R7A, R7B, and R7C (when present) is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, cloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R7A, R7B, and R7C is unsubstituted or substituted with one or more halogen; each R8 (when present) is independently selected from the group consisting of halogen, lower alkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, and lower heterocycloalkyl, wherein each said lower alkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, and lower heterocycloalkyl of R8 is optionally substituted with halogen; and each R9 (when present) is independently selected from the group consisting of halogen, —OH, —CN, —SF5, —OSF5, alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and —O-alkyl-heterocycloalkyl, wherein each said alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and —O-alkyl-heterocycloalkyl are optionally substituted with one or more halogen.
地址 Rahway NJ US