CN103547577A - 作为盐皮质激素受体拮抗剂的并环类化合物 - Google Patents
作为盐皮质激素受体拮抗剂的并环类化合物 Download PDFInfo
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- CN103547577A CN103547577A CN201180039955.2A CN201180039955A CN103547577A CN 103547577 A CN103547577 A CN 103547577A CN 201180039955 A CN201180039955 A CN 201180039955A CN 103547577 A CN103547577 A CN 103547577A
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- alkyl
- cycloalkyl
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- hydroxyl
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Abstract
Description
Claims (10)
- 权 利 要 求烯基或 C3_6炔基;Y1, Y2和 Y3分别独立地为 N或 CR5, Y1, Y2和 Y3至少有一个为 N; R1为卤素原子、 «、 羟基、 ½、 氨基、 硝基、 磺酸基、 氨基甲酰 基、 烷基、 C3-8环烷基、 C2 烯基、 C5-8环烯基、 C2_6炔基、 烷氧 基、 C3-8环烷 、 -6烷基胺基、 二 (C1-6烷基)胺基、 烷硫基、 Ci-6 烷基羰基、 烷基胺基曱酰基、 烷基酰胺基、 烷基磺酰基、 C1-6 烷基胺基磺酰基、 烷基磺酰胺基、 二 (C^烷基)胺基甲酰基、 二 (Cw 烷基)胺基磺酰基、 烷氧羰基或 C1-6烷基羰氧基, n为 0〜4, 其中 R1 可相同或不同,所述 Cue烷基、 C3-8环烷基、 C2_6烯基、 C5-8环婦基、 C2_6块基、 C1-6 烷氧基、 C3-8环烷氧基、 烷基胺基、 二 (C1-6烷基)胺基、 烷硫基、 C1-6烷基羰基、 C 烷基胺基甲酰基、 C 烷基酰胺基、 C 烷基磺酰基、 烷基胺基磺酰基、 烷基磧酰胺基、二 (c】_6烷基)胺基曱酰基、二 (C^ 烷基)胺基磺酰基、 C1-6烷氧羰基和 C1-6烷基羰氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代: 卤素原子、 氰基、 羟基、 羧基和R5为氢原子、 卤素原子、 ^、 羟基、 、 、 硝基、 磺 、 J ^曱酰基、 烷基、 C3-8环烷基、 C2_6烯基、 C5-8环婦基、 C2 炔基、 烷 tt、 C3.8环烷氧基、 Ci_6烷基胺基、 二 (Cw烷基)胺基、 烷硫 基、 C1-6烷基羰基、 C 烷基胺基曱酰基、 烷基酰胺基、 C1-6烷基磺酰 基、 Cw烷基胺基磺酰基、 烷基磺酰胺基、 二 (Cw烷基)胺基甲酰基、 二 (C 烷基)胺基磺酰基、 烷氧羰基或 C 烷基羰氧基,所述 C1-6烷基、 C3-8环烷基、 C2-6烯基、 〇5-8环烯基、 C2 炔基、 CI-6 烷氧基、 C3-8环烷 L&、 烷基胺基、 二 (Cw烷基)胺基、 烷硫基、 烷基羰基、 烷基胺基曱酰基、 C1-6烷基酰胺基、 C1-6烷基磺酰基、 烷基胺基磺酰基、 烷基磺酰胺基、二 (CM烷基)胺基甲酰基、二 (Cw 烷基)胺基横酰基、 烷氧羰基和 C1-6烷基羰氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代: 卤素原子、 氰基、 羟基、 羧基和R2a为氢原子、 烷基、 C3-8环烷基、 C5-8环烯基、 笨基或包含至少 一个选自 0、 S或 N的 3-8元杂环基, 所迷 烷基、 C3-8环烷基、 C5-8 环烯基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自 以下的取代基取代: 卤素原子、 、 羟基、 羧基、 ½、 C1-6烷基和卤 代 Cj_6燒基;R2b、 R3a和尺31)分别独立地为氢原子、 、 卤素原子、 C1-6烷基、 C3-8环烷基、 C2_6晞基、 C5-8环烯基、 C2_6炔基、 烷氧基或 C3-8环烷氧 基, 所述 烷基、 C3-8环烷基、 烯基、 C5-8环烯基、 C2_6炔基、 C1-6 烷氧基和 C3-8环烷氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的 取 取代: 卤素原子、 tt、 羟基、 和R4为氢原子或 (CR13R14)pR6, R6为 OR7、 C(0)R7、 C(0)OR7、 OC(0)R7、 C(0)NR8R9、 NR8C(0)R7、 N 8R9、 S(0)qR7、 S(0)qOR7 , NHC(0)OR7、 HC(0) R8R9、 S(0)qNR8R9、 NR8S(0)qR7或 C(0)NHS(0)qR7;R7、 R8和 R9分别独立地为氢原子、 C1-6烷基、 C3-8环烷基或 3-8元杂 环基, 其中 R8和 R9可以与它们所连接的氮形成 3-8元杂环基或氧代 3-8 元杂环基, 所述 烷基、 C3-8环烷基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代: 卤素原子、 氰基、 羟基、 烷基、 吡咯烷基、 OR1Q、 C(0)R1G、 C(0)OR10, OC(0)R10. C(0) RnR12, NRUR12、 N nC(0)R10, S O)^10, SiC q R^R12和 NRUs 10;R1G、 R11和 R12分别独立地为氢原子、 C 烷基、 C3-8环烷基或苯基, 其中 R11和 R12可以与它们所连接的氮形成 3-8元杂环基, 所述 烷基、 C 8环烷基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地 选自以下的取代基取代: 卤素原子、 tt、 羟基和羧基;R13和 R14分别独立地为氢原子或 烷基;Cy为 C3-8环烷基、 5-7元杂环基或芳基;P为 0~6的整数;q为 0~2的整数。
- 2、 权利要求 1的化合物, 其药学上可接受的盐, 及其异构体, 其中, X为 0、 NR<sup>5a</sup>或 CR<sup>13</sup>R<sup>14</sup>, 其中 R<sup>5a</sup>为氢原子、 烷基、 C<sub>3</sub>^ 烯基或 炔基;Υ] Υ2和 Υ3分别独立地为 Ν或 CR5, Υ Υ2和 Υ3至少有一个为 Ν; R1为卤素原子、 、 羟基、 羧基、 、 硝基、 磺酸基、 氨基甲酰 基、 烷基、 C3-8环烷基、 C2_6烯基、 C5-8环烯基、 C2_6炔基、 C1-6烷氧 基、 c3-8环烷! LS^、 烷基胺基、 二 (c1-6烷基)胺基、 烷硫基、 Ci.6 烷基羰基、 烷基胺基甲酰基、 Cw烷基酰胺基、 烷基磺酰基、 Ci-6 烷基胺基磺酰基、 烷基磺酰胺基、 二 (Cw垸基)胺基曱酰基、 二 (Cw 烷基)胺基磺酰基、 烷氧羰基或 C1-6烷基羰氧基, n为 0〜4, 其中 R1 可相同或不同,所述 烷基、 C3-8环烷基、 C2_6烯基、 C5-8环烯基、 炔基、 C1-6 烷 &、 C3-8环烷 、 d_6烷基胺基、 二 (Cw烷基)胺基、 烷硫基、 烷基羰基、 烷基胺基甲酰基、 烷基酰胺基、 c 烷基磺酰基、 C1-6烷基胺基磺酰基、 C 烷基磺酰胺基、二 (C 烷基)胺基甲酰基、二 烷基)胺基碌酰基、 d_6烷氧羰基和 C1-6烷基羰氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代: 卤素原子、 氰基、 羟基、 羧基和R5为氢原子、 卤素原子、 氰基、 羟基、 、 tt、 硝基、 磺½、 氨基甲酰基、 _6烷基、 C3-8环烷基、 C2_e烯基、 C5-8环烯基、 炔基、 烷氧基、 C3-8环烷氧基、 烷基胺基、 二 (C1-6烷基)胺基、 烷硫 基、 CW烷基羰基、 烷基胺基甲酰基、 烷基酰胺基、 烷基磺酰 基、 烷基胺基磺酰基、 d-6烷基磺酰胺基、 二 (Cw烷基)胺基甲酰基、 二 烷基)胺基磺酰基、 C 烷氧羰基或 C 烷基羰氧基,所述 烷基、 C3-8环烷基、 C2_6烯基、 C5-8环烯基、 C2_6块基、 c1-6 烷 L^、 C3.8环烷 IL^、 烷基胺基、 二 (Cw烷基)胺基、 烷石克基、 烷基羰基、 烷基胺基甲酰基、 C1-6烷基酰胺基、 烷基磺酰基、 d_6烷基胺基磺酰基、 C 烷基磺酰胺基、二 (C 烷基)胺基曱酰基、二 (C 烷基)胺基磺酰基、 烷氧羰基和 C1-6烷基羰氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代: 卤素原子、 氰基、 羟基、 羧基和R2a为氢原子、 C1-6烷基、 C3_8环烷基、 C5-8环烯基、 苯基或包含至少 一个选自 0、 S或 N的 3-8元杂环基, 所述 C 垸基、 C3-8环烷基、 C5-8 环烯基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自 以下的取代基取代: 卤素原子、 、 羟基、 羧基、 氨基、 C1-6烷基和卤 代 C1-6燒基;R2b、 尺 和 R3b分别独立地为氢原子、 tt、 卤素原子、 C1-6 基、 C3-8环烷基、 C2_6烯基、 C5-8环烯基、 C2_e炔基、 C1-6烷氧基或 C3-8环烷氧 基, 所述 烷基、 C3-8环烷基、 C2_6烯基、 C5-8环烯基、 炔基、 C1-6 烷氧基和 C3-8环烷氧基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的 取代基取代: 卤素原子、 、 羟基、 ½和 ^;R4为氢原子或 (CR13R14)pR6, R6为 OR7、 C(0)R7、 C(0)OR7、 OC(0)R7、 C(0)NR8R9、 NR8C(0)R7、 NR8R9、 S(0)qR7 S(0)qOR7、 NHC(0)OR7、 NHC(0)NR8R9、 S(0)qNR8R9、 R8S(0)qR7或 C(0)NHS(0)qR7;R7、 R8和 R9分别独立地为氢原子、 C1-6烷基、 3-8元杂环基或 C^8环 烷基, 其中 R8和 R9可以与它们所连接的氮形成 3-8元杂环基或氧代 3-8 元杂环基, 所述 烷基、 C3-8环烷基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代: 卤素原子、 氰基、 羟基、 烷基、 吡咯烷基、 OR10. C(0)R1G、 C(0)OR10, OC(0)R1G、 C(0)NRnR12 NRnR12, NRnC(0)R10^ S(0)qR10, S O^NRUR12和 ΝΙ^^θ ΐ 10;R1Q、 R11和 R12分别独立地为氢原子、 C1-6烷基、 C3-8环烷基或苯基, 其中 R11和 R12可以与它们所连接的氮形成 3-8元杂环基, 所述 烷基、 C3-8环烷基、 苯基和 3-8元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地 选自以下的取代基取代: 卤素原子、 、 羟基和羧基;R13和 R14分别独立地为氢原子或 烷基;Cy为 C3.8环烷基、 5-7元杂环基或芳基;p为 0〜6的整数;q为 0~2的整数。
- 3、 权利要求 1的化合物, 其药学上可接受的盐, 及其异构体, X为 0或 CH<sub>2</sub>;Y1, Y2和 Y3分别独立地为 N或 CR5, Υ1, Y2和 Y3至少有一个为 N;R5为氢原子、 卤素原子、 羟基、 羧基、 烷基、 C3_8环烷基或 C1-6 烷氧基, 所述的 C1-6烷基、 C3-8环烷基和 C1-6烷氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代: 卤素原子、 羟基、 羧基和氨基;R1为卤素原子、 、 硝基、 羧基、 磺 、 C1-6烷基、 6烷氧基、 C2_6烯基、 C2-6炔基、 烷基胺基、 二 (Cw烷基)胺基、 烷基羰基、 C1-6烷基胺基甲酰基、 C 烷基酰胺基、 C 烷基磺酰基、 C 烷基胺基磺 酰基、 烷基磺酰胺基、 烷氧羰基或 烷基羰氧基, n为 0〜4的整 数, 其中 R1可相同或不同,所述的 烷基、 烷氧基、 C2-6浠基、 C2_6炔基、 烷基胺基、 二 (。1-6烷基)胺基、 烷基羰基、 C1-6烷基胺基甲酰基、 C1-6烷基酰胺基、 烷基磺酰基、 烷基胺基横酰基、 C 烷基磺酰胺基、 C 烷氧羰基 和 烷基羰氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代: 卤素原子、 «、 羟基、 « ^和R2a为氢原子、 C3-8环烷基、 C5_7环烯基、苯基或包含至少一个选自 0、 S或 N的 5-6元杂环基, 所述的 C3-8环烷基、 C5-7环烯基、 苯基和 5-6元 杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代: 卤 素原子、 ½、 羟基、 羧基、 、 烷基和卤代 烷基;R2b、 1 和 1 31)分别独立地为氢原子、 tt、 鹵素原子、 C1-6坑基、 C3-7环烷基、 C2_e烯基或 C1-6烷氧基, 所述的 烷基、 C3-7环烷基、 烯基和 烷氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代: 卤素原子、 氰基和羧基;R4为氢原子或 (CH2)pR6, R6为 C(0)OR7、 OC(0)R7、 C(0)NR8R9、 NR8C(0)R7、 S(0)qR7、 S(0)qOR7、 NHC(0)NR8R9、 S(0)qNR8R9、 N 8S(0)qR7 或 C(0)NHS(0)qR7;R7、 R8和 R9分别独立地为氢原子、 4-7元杂环基、 C4-7环烷基或 CM 烷基, 其中 R8和 R9可以与它们所连接的氮形成 4-7元杂环基或氧代 4-7 元杂环基, 所述(^_4烷基、 Ομ7环烷基和 4-7元杂环基可任选被 1、 2、 3 或 4个独立地选自以下的取代基取代:鹵素原子、羟基、 C 烷基、 C(0)R1Q、 C(O)OR10、 OC(O)R10、 C(0)NRnR12, NR"R12、 NRnC(0)R10, S(O)qR10、 S(0)qNRnR12和 NR^S O^R10;R1Q、 R11和 R12分别独立地为氢原子, 或未被取代或被 1、 2、 3或 4 个独立地选自卤素原子、 、 羟基和½的取代基取代的 C1-6烷基;Cy为苯基或吡啶基;p为 0~4的整数;q为 0~2的整数。
- 4、 权利要求 1的化合物, 其药学上可接受的盐, 及其异构体, X为 CH<sub>2</sub>;Y1. Y2和 Y3分别独立地为 N或 CR5, Υ Υ2和 Υ3至少有一个为 Ν;R5为氢原子、 卤素原子、 羟基、 羧基、 烷基或 C3-8环烷基, 所述 的 烷基和 C3-8环烷基可任选被 1、 2、 3或 4个独立地选自以下的取代 基取代: 卤素原子、 羟基、 羧基和氨基;R1为卤素原子、 ·«、 硝基、 羧基、 磺^、 烷基、 烷氧基、 C2_e烯基、 C2-6炔基、 烷基胺基、 二 (C^烷基)胺基, 烷基胺基甲 酰基、 烷基酰胺基、 烷基横酰基、 烷基磺酰胺基、 烷氧羰 基或 烷基狻氧基, n为 0~3的整数, 其中 R1可相同或不同,所述的 烷基、 烷氧基、 C2_6烯基、 C2_6炔基、 烷基胺基、 二 烷基)胺基、 烷基胺基甲酰基、 C 烷基酰胺基、 C 烷基磺酰 基、 烷基磺酰胺基、 烷氧羰基和 C^e烷基羰氧基可任选被 1、 2、 3 或 4个独立地选自以下的取代基取代: 鹵素原子、 氰基、 羟基、 羧基和氨 基;R2a为氢原子、 环烷基、 苯基或包含至少一个选自 0、 S或 N的 5-6元杂环基,所述的 C3-7环烷基、苯基和 5-6元杂环基可任选被 1、 2、 3、 4、 5或 6个独立地选自以下的取代基取代: 卤素原子、 氰基、 羟基、 羧 基、 氨基、 d.6烷基和卤代 烷基;R2b、 R3a和 R3b分别独立地为氢原子、 氰基、 鹵素原子、 6 基或 Cw环烷基, 所述的 烷基和 C3-7环烷基可任选被 1、 2、 3或 4个独立 地选自以下的取代基取代: 卤素原子、 ^&和R4为氢原子或 (CH2)pR6, R6为 C(0)OR7、 C(0)NR8R9、 NR8C(0)R7、 S(0)qR7、 S(0)qOR7、 S(0)q R8R9或 NR8S(0)qR7;R7、 R8和 R9分别独立地为氢原子、 5-6元杂环基、 C5-6环烷基或 CM 烷基, 其中 R8和 R9可以与它们所连接的氮形成 5-6元杂环基或氧代 5-6 元杂环基, 所述。14烷基、 C5_6环烷基和 5-6元杂环基可任选被 1、 2、 3 或 4个独立地选自以下的取代基取代:卤素原子、羟基、 烷基、 C(0)R1Q、 C(O)OR10、 OC(O)R10、 C(0) R"R12、 NRnR12, NR11^)^^ S(O)qR10、 S(0)qNRnR12和R1Q、 R11和 R12分别独立地为氢原子, 或未被取代或任选被 1、 2、 3 或 4个独立地选自卤素原子、 tt、羟基和羧基的取代基取代的 C1-4烷基;Cy为苯基或吡啶基; p为 0~3的整数;q为 0~2的整数。
- 5、 权利要求 1的化合物, 其药学上可接受的盐, 及其异构体, 其中, X为 CH<sub>2</sub>;Y1为 N;Y2和 Y3分别独立地为 CR5;R5为氢原子、 鹵素原子、 羟基、 羧基、 CM烷基或 C4.7环烷基, 所述 的 _4烷基和 环烷基可任选被 1、 2或 3个独立地选自以下的取代基 取代: 卤素原子、 羟基、 和R1为卤素原子、 、 硝基、 羧基、磺 、 CM烷基、 CM烷氧基、C2_4炔基、 烷基胺基、 二 (d_4烷基)胺基、 〇μ4烷基胺基甲酰基、 CM 烷基横酰基、 C1-4烷基磺酰胺基或 CM烷基羰氧基, n为 1或 2, 其中 R1 可相同或不同,所述的 CM烷基、 CM烷氧基、 C2-4炔基、 CM烷基胺基、二 (CM烷基) 胺基、 Ci.4烷基胺基甲酰基、 C 烷基磺酰基、 C 烷基横酰胺基和 CM 烷基羰氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代: 卤素 原子、 氰基、 羟基、 羧基和氨基;R2a为氢原子、 C4_6环烷基或苯基,所述的 C4_6环烷基和苯基可任选被 1、 2或 3个独立地选自以下的取代基取代: 卤素原子、 氰基、 羟基、 羧 基、 氨基、 CM烷基和卤代 CM烷基;R2b、 R3a和 R3b分别独立地为氢原子、 、 卤素原子、 CM烷基或 环烷基, 所述。"烷基和 C4_6环烷基可任选被 1、 2、 3或 4个独立地 选自以下的取代基取代: 卤素原子、 *^和«;R4为氢原子或 (CH2)pR6, R6为 C(0)OR7、 C(0) R8R9或 NR8C(0)R7;R7、 R8和 R9分别独立地为氢原子、 C5-6环烷基、 5-6元杂环基或 Cw 烷基, 其中 R8和 R9可以与它们所连接的氮形成 5-6元杂环基或氧代 5-6 元杂环基, 所述 CM烷基、 C5_e环烷基和 5-6元杂环基可任选被 1、 2、 3 或 4 个独立地选自以下的取代基取代: 卤素原子、 羟基、 烷基、 C(0)OR10, OC(0)R10, C(0)NRnR12, NRnR12, N nC(0)R10, S(0)qR1(、 S(0)qNRnR12和 N uS(0)qR10;R1G、 R11和 R12分别独立地为氢原子, 或未被取代或任选被 1、 2、 3 或 4个独立地选自卤素原子、氰基、羟基和羧基的取代基取代的 d_4烷基; Cy为笨基或吡。定基;p为 0, 1或 2;q为 0, 1或 2。
- 6、 权利要求 1的化合物, 其药学上可接受的盐, 及其异构体, 其中, X为 CH<sub>2</sub>;Y1为 N;Y2和 Y3分别独立地为 CR5, 其中 R5为氢原子、 氟原子、 氯原子、 羟 基、 羧基、 曱基、 乙基、 三氟甲基、 羟甲基、 羧曱基或氨曱基;R1为鹵素原子、 、 硝基、羧基、磺 、 C1-3烷基、 C 1-3烷! L^、 烷基胺基或二 (C1-3烷基)胺基, n为 2, 其中 R1可相同或不同, 所迷的 d_3烷基、 C1-3烷氧基、 C1-3烷基胺基和二 (C1-3烷基)胺基可任 选被 1、 2或 3个独立地选自以下的取代基取代: 氟原子、 氯原子、 氰基、 羟基和羧基;R2a为氢原子、 环丁烷、 环戊烷、 环己烷或苯基, 所述的环丁烷、 环 戊烷、环己烷和笨基可任选被 1、 2或 3个独立地选自以下的取代基取代: 氟原子、 氯原子、 、 羟基、 羧基、 .3烷基和卤代 d.3烷基;R2b、 R3a和 R3b分别独立地为氢原子、 曱基、 乙基、 三氟甲基或羧曱 基;R4为氢原子或 (CH2)pR6, R6为 C(0)OR7、 C(0)NR8R9或 NR8C(0)R7;R7、 R8和 R9分别独立地为氢原子、 C5-6环烷基、 5-6元杂环基或 C1-3 烷基, 其中 R8和 R9可以与它们所连接的氮形成 5-6元杂环基或氧代 5-6 元杂环基, 所述 C1-3烷基、 环烷基和 5-6元杂环基可任选被 1、 2、 3 或 4 个独立地选自以下的取代基取代: 卤素原子、 羟基、 烷基、 C(O)OR10、 C(0)NRHR12, NRUR12、 NRHC(0)R10. S(O)QR10、 S(0)QNRNR12 和 NRUS C qR10;R1Q、 R11和 R12分别独立地为氢原子, 或未被取代或任选被 1、 2、 3 或 4个独立地选自卤素原子、氰基、羟基和羧基的取代基取代的 烷基; Cy为苯基;p为 0或 1。q为 0, 1或 2。
- 7、 权利要求 1的化合物, 其药学上可接受的盐, 及其异构体, 其中, X为 CH<sub>2</sub>; Y<sup>1</sup>为 N;Y2和 Y3为 CH;R1为卤素原子、 氰基或 C1-3烷基, n为 2, 其中 R1可相同或不同; R2a为环丁烷、 环戊烷、 环己烷或 4-氟苯基;R2b、 R3a和 R3b分别独立地为氢原子或甲基;R4为 C(0)OR7或 C(0)NR8R9;R7、 R8和 R9分别独立地为氢原子、 5-6元杂环基或 C1-3烷基, 其中 R8和 R9可以与它们所连接的氮形成 5-6元杂环基或氧代 5-6元杂环基, 所迷 Cw烷基和 5-6元杂环基可任选被 1、 2、 3或 4个独立地选自以下的 取 取代:卤素原子、羟基、 烷基、 C(O)OR10、 C(0)NRnR12. NRnR12, NRUC(0)R10, S C qR1。和 N nS(0)qR10;R1Q、 R11和 R12分别独立地为氢原子, 或未被取代或任选被 1、 2、 3 或 4个独立地选自卤素原子、氰基、羟基和羧基的取代基取代的 CM烷基;Cy为苯基;q为 0, 1或 2。
- 8、 权利要求 1的化合物, 其药学上可接受的盐, 及其异构体, 其中, X为 CH<sub>2</sub>;Y1为 N;Y2和 Y3为 CH;R1为卤素原子、 氰基或 C1-3烷基, n为 2, 其中 R1可相同或不同; R2a为环丁烷、 环戊烷、 环己烷或 4-氟苯基;R2b、 1 和1 315分别独立地为氢原子或甲基;R4为 C(0)OR7或 C(0)NR8R9;R7、 R8和 R9分别独立地为氢原子、 5-6元杂环基或 C1-3烷基, 其中 R8和 R9可以与它们所连接的氮形成 5-6元杂环基或氧代 5-6元杂环基, 所述 烷基和 5-6 元杂环基可任选被羟基、 C 烷基、 NRUR12、 NRHSiC qRW或 S(0)qR1Q取代;其中所述 5-6元杂环基或氧代 5-6元杂环基包含 1或 2个选自 N、 0 和 S的杂原子;R1Q、 R11和 R12分别独立地为氢原子或 d_4烷基;Cy为苯基;q为 2。 9、 通式(VI )所示的化合物, 其药学上可接受的盐, 及其异构体,其中, X为 CH2;Y1为 N;Y2和 Y3分别独立地为 CR5;R5为氢原子、 卤素原子、 羟基、 羧基、 CM烷基或 C4-7环烷基, 所述 的 烷基和 C4-7环烷基可任选被 1、 2或 3个独立地选自以下的取代基 取代: 鹵素原子、 羟基、 和 ^;R1为卤素原子、 、 硝基、 羧基、 磺^、 烷基、 C1-4烷氧基、 C24炔基、 CM烷基胺基、 二 (CM烷基)胺基、 CM烷基胺基甲酰基、 C 烷基磺酰基、 (^_4烷基磺酰胺基或 CM烷基羰氧基, n为 1或 2 , 其中 R1 可相同或不同,所述的 CM烷基、。"烷氧基、 C2-4炔基、 C 烷基胺基、二 (CM烷基) 胺基、 烷基胺基甲酰基、 C1-4烷基磺酰基、 烷基磺酰胺基和 CM 烷基羰氧基可任选被 1、 2、 3或 4个独立地选自以下的取代基取代: 卤素 原子、 氰基、 羟基、 羧基和氨基;R2a为氢原子、 C4 环烷基或笨基,所述的 C4 环烷基和笨基可任选被 1、 2或 3个独立地选自以下的取代基取代: 卤素原子、 氰基、 羟基、 羧 基、 氨基、 CM烷基和卤代 CM烷基;R2b、 R3a、 1 ¾和1 15分别独立地为氢原子、 氰基、 鹵素原子、 (:1-4烷 基或 C«环烷基, 所述 CM烷基和 C4-6环烷基可任选被 1、 2、 3或 4个独 立地选自以下的取 取代: 卤素原子、 和羧基;R4为氢原子或 (C¾)pR6, R6为 C(0)OR7、 C(0)NR8R9或 NR8C(0)R7;R7、 R8和 R9分别独立地为氢原子、 C5-6环烷基、 5-6元杂环基或 CM 烷基, 其中 R8和 R9可以与它们所连接的氮形成 5-6元杂环基或氧代 5-6 元杂环基, 所述 CM烷基、 C5_6环烷基和 5-6元杂环基可任选被 1、 2、 3 或 4 个独立地选自以下的取代基取代: 卤素原子、 羟基、 烷基、 C(O)OR10、 OC(O)R10、 C^NR^R12, NR"R12、 NRUC(0)R10, S(O)qR10、 S(0)qNRnR12和 >^„ ;R1Q、 R11和 R12分别独立地为氢原子, 或未被取代或任选被 1、 2、 3 或 4个独立地选自卤素原子、氰基、羟基和羧基的取代基取代的 烷基;Cy为苯基或吡啶基;p为 0, 1或 2;q为 0, 1或 2。其药学上可接受的盐, 及其异构体,;R4为 C(0)OH或 C(0)NR8R9;R8和 R9分别独立地为氢原子、 Cw烷基,其中 R8和 R9可以与它们所 连接的氮形成哌啶、 哌嗪、 吡咯烷、 呋喃、 吗啉或二氧化硫代吗啉, 所述 d_3烷基、 哌啶、 哌嗪、 吡咯烷、 呋喃、 吗啉和二氧化硫代吗啉可任选被 羟基、 乙基、 NRUR12或 S(0)qR1()取代;R1Q、 R11和 R12分别独立地为氢原子、 甲基、 乙基;q为 2。其药学上可接受的盐, 及其异构体,;R4为 C(0)OH或 C(0)NR8R9;R8和 R9分別独立地为氢原子、 C1-3烷基、 四氢呋喃或 1-甲基吡咯烷, 其中 R8和 R9可以与它们所连接的氮形成哌啶、 哌秦、 吡咯烷、 呋喃、 吗 啉或二氧化硫代吗啉, 所述 Cw烷基、 哌啶、 哌嗪、 吡咯烷、 呋喃、 吗啉 和二氧化硫代吗啉可任选被羟基、乙基、 NRUSCC^qR10或 S(0)qR1() 取代;R1Q、 R11和 R12分别独立地为氢原子、 甲基、 乙基;q为 2。12、 下述化合物:其药学上可接受的盐, 及其异构体。 所示的化合物, 其药学上可接受的盐,或其中, X、 Υ1, Y2、 Y R R2a、 R2b、 R3a、 R3b、 R4、 Cy和 n是如 权利要求 1-8中任一项所述的。14、 含有权利要求卜 13任一项所述的化合物、 其药学上可接受的盐 或其异构体的药物制剂 , 其特征在于包括一种或多种药用载体。
- 15、 含有权利要求 1~13任一项所述的化合物、 其药学上可接受的盐 或其异构体在制备治疗和 /或预防肾损伤和 /或心血管疾病包括高血压、 心 力衰竭、 心肌梗塞、 心绞痛、 心脏肥大、 心肌炎、 心脏血管纤维化、 压力 感受器官能障碍、 过多的体液和心律不齐, 或内分泌疾病, 包括原发 /继 发性醛 酮增多症、 阿狄森氏病、库兴氏综合症和巴特式综合症的药物中 的应用。
- 16、 药物组合物, 其特征在于包含权利要求 1-13任一项所述的化合 物、其药学上可接受的盐或其异构体和一种或多种治疗活性物质, 所述治 疗活性物质选自血管紧张素 II拮抗剂或其药学上可接受的盐; HMG-Co-A 还原酶抑制剂或其药学上可接受的盐; 钙通道阻滞剂(CCB )或其药学上 可接受的盐; 血管紧张素转化酶 /中性内肽酶(ACE/NEP )双重抑制剂或 其药学上可接受的盐; 抗糖尿病药; 减肥药; 醛固酮受体阻滞剂; 内皮素 受体阻滞剂; CETP抑制剂; Na-K-ATP酶膜泵抑制剂; β-肾上腺素能受体 抑制剂或 α-肾上腺素能受体阻断剂; 中性内肽酶( ΝΕΡ )抑制剂和变力剂。
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