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首页> 外国专利> Gonadotropin-releasing hormone receptor antagonists, method for its preparation and pharmaceutical composition comprising the same

Gonadotropin-releasing hormone receptor antagonists, method for its preparation and pharmaceutical composition comprising the same

机译：促性腺激素释放激素受体拮抗剂，其制备方法和包含该拮抗剂的药物组合物

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摘要

A compound of formula (I), or a stereoisomer or a pharmaceutically salt thereof: ** Formula ** wherein, A is CR8aR8b, O, S or NR9; R1 and R2, which may be the same or different, are each independently hydrogen, (C1-C10) alkyl, substituted (C1-C10) alkyl, substituted (C3-C10) cycloalkyl, substituted (C3-C10) cycloalkyl, (C6) aryl -C12), substituted (C6-C10) aryl, (C6-C12) aryl-(C1-C10) alkyl, substituted (C6-C12) -aryl (C1-C10) alkyl, (C1-C20) heteroaryl, heteroaryl ( C1-C20) substituted, (C1-C20) heteroaryl-(C1-C10) alkyl, substituted (C1-C20) heteroaryl-(C1-C10) alkyl, substituted (C1-C20) heterocycle, substituted (C1-C20) heterocycle, (C1-C20) heterocyclyl-(C1-C10) alkyl, substituted (C1-C20) heterocyclyl-(C1-C10) alkyl, or - (CR1aR1b) s-R12; R3a and R3b, which may be the same or different, are each independently hydrogen, (C1-C10) -alkyl, substituted (C1-C10) -alkyl, (C3-C10) -cycloalkyl, substituted (C3-C10) -cycloalkyl, (C1-alkoxy) -C10), (C1-C10) alkylthio, (C1-C10) alkylamino, substituted (C6-C12) aryl, (C6-C12) aryl, (C6-C12) aryl-(C1-C10) alkyl, (C6) aryl -C12) -substituted (C1-C10) alkyl, (C1-C20) heteroaryl, substituted (C1-C20) heteroaryl, (C1-C20) heteroaryl-(C1-C10) alkyl, (C1-C20) heteroaryl-( C1-C10) substituted, (C1-C20) heterocycle, substituted (C1-C20) heterocycle, (C1-C20) heterocyclyl-(C1-C10) alkyl, substituted (C1-C20) -cyclyl (C1-C10) alkyl, -COOR13 or -CONR13R14; R3a and R3b, together with the carbon atom attached to them, form a homocyclic ring, a substituted homocyclic ring, a heterocyclic ring or a substituted heterocyclic ring; or R3a and a carbon bonded thereto, together with R1 and a nitrogen atom bonded thereto, form a heterocyclic ring or a substituted heterocyclic ring; R4 is - (CR9aR9b) r-Z-Y; ç n is an integer of 2, 3 or 4; s is an integer of 1,2, 3 or 4; r is an integer of 0, 1 or 2; Z represents a direct bond, or -O-, -S-, -NR11-, -SO-, -SO2-, -OSO2-, -SO2O-, -SO2NR11-, -NR11SO2-, -CO-, -COO- , -OCO-, -CONR11-, -NR11CO-, -NR11CONR11a-, -OCONR11- or -NR11COO-; Y is hydrogen, halogen, (C1-C10) alkyl, substituted (C1-C10) alkyl, substituted (C3-C10) cycloalkyl, substituted (C3-C10) cycloalkyl, substituted (C6-C12) aryl, (C6-C12) aryl , (C6-C12) aryl-(C1-C10) alkyl, substituted (C6-C12) -aryl (C1-C10) alkyl, (C1-C20) heteroaryl, substituted (C1-C20) heteroaryl, (C1-C20) heteroaryl ) -substituted (C1-C10) alkyl or heteroaryl (C1-C20) -substituted (C1-C10) alkyl; R6 is hydrogen, (C1-C10) alkyl, substituted (C1-C10) alkyl, substituted (C3-C10) cycloalkyl, substituted (C3-C10) cycloalkyl, substituted (C6-C12) aryl, (C6-C12) aryl, aryl (C6-C12) -C1-C10-alkyl, substituted (C6-C12) -aryl-C1-C10-alkyl, substituted (C1-C20) heteroaryl, substituted (C1-C20) heteroaryl, (C1-C20) heteroaryl - (C1-C10) alkyl or (C1-C20) heteroaryl-substituted (C1-C10) alkyl; R9 is hydrogen, (C1-C10) alkyl or (C1-C10) acyl; R12 is -CO2R13 or -COOH; R1a and R1b, which may be the same or different, are each independently hydrogen, (C1-C10) acyl, hydroxyl, halogen, cyano, (C1-C10) alkyl, substituted (C1-C10) alkyl, (C3-C10 cycloalkyl). ), substituted (C3-C10) cycloalkyl, (C1-C10) alkoxy, (C1-C10) alkylthio, (C1-C10) alkylamino, -COOR13- or CONR13R14-; or R1a and R1b, together with the atom or atoms to which they are attached, independently form a homocyclic ring, a substituted homocyclic ring, a heterocyclic ring or a substituted heterocyclic ring; R5a, R5b, R7a, R7b, R8a and R8b, which may be the same or different, are each independently hydrogen, (C1-C10) acyl, hydroxyl, amino, halogen, cyano, (C1-C10) alkyl, (C1-alkyl) -C10) substituted, (C3-C10) cycloalkyl, substituted (C3-C10) cycloalkyl, substituted (C1-C10) aryl, (C1-C10) substituted aryl, (C1-C10) alkoxy, (C1-C10) alkylthio, alkylamino (C1-C10), -COOR13 or -CONR14R15; and R9a, R9b, R11, R11b, R13, R14 and R15, which may be the same or different, are each independently hydrogen (C1-C10) alkyl, aryl (C6-C12) or aryl (C6-C12) -alkyl ( C1-C10); wherein the heterocyclic ring, the heterocycle, the heterocyclylalkyl, heteroaryl, and heteroarylalkyl contain at least one heteroatom selected from the group consisting of N, O, and S; and "substituted" is intended to mean replacement with at least one substituent selected from the group consisting of halogen, acetylene, vinyl, hydroxy, cyano, nitro, amino, (C1-C10) alkylamino, di-C1-C10 alkylamino, (C1-C10) alkyl, (C3-C10) cycloalkyl, (C1-C10) alkoxy, (C1-C10) alkylthio, (C1-C10) haloalkyl, (C6-C12) aryl, (C6-C12) aryl-alkyl (C1-C10), (C1-C20) heteroaryl, (C1-C20) heteroaryl-(C1-C10) alkyl, (C1-C20) heterocycle, (C1-C20) heterocyclyl (C1-C10) alkyl, -NRaRb , -NRaC ( = O) Rb, -NRaC ( = O) NRaORb, -NRaC ( = O) NRaRb, -NRaC ( = O) ORb, -NRaSO2Rb, -C ( = O) Ra, - C ( = O) ORa, -OC ( = O) Ra, -C ( = O) NRaRb, -OC ( = O) NRaRb, -ORa, -SRa, -SORa, -S ( = O ) 2Ra, -OS ( = O) 2Ra and -S ( = O) 2ORa, where Ra and Rb, which may be the same or different, are each independently hydrogen, (C1-C10) alkyl, (C1- haloalkyl) C10), (C3-C10) cycloalkyl, (C6-C12) aryl, (C6-C12) aryl-(C1-C10) alkyl, (C1-C20) heteroaryl, (C1-C20) heteroaryl (C1-C10) alkyl ), heterocycle (C1-C20), (C1-C20) heterocyclyl-(C1-C10) alkyl or - (CH2) zC ( = O) Rc, z is an integer of 1, 2, 3 or 4, and Rc is hydroxyl, (C1-C10 alkyl) ), (C3-C10) cycloalkyl or (C1-C10) alkoxy.
机译：式（I）的化合物或其立体异构体或其药学上的盐：**式**，其中，A是CR8aR8b，O，S或NR9; R1和R2可以相同或不同，分别独立地为氢，（C1-C10）烷基，取代的（C1-C10）烷基，取代的（C3-C10）环烷基，取代的（C3-C10）环烷基，（C6 ）芳基-（C12），取代的（C6-C10）芳基，（C6-C12）芳基-（C1-C10）烷基，取代的（C6-C12）-芳基（C1-C10）烷基，（C1-C20）杂芳基，杂芳基（C1-C20）取代的，（C1-C20）杂芳基-（C1-C10）烷基，取代的（C1-C20）杂芳基-（C1-C10）烷基，取代的（C1-C20）杂环，取代的（C1-C20 ）杂环，（C1-C20）杂环基-（C1-C10）烷基，取代的（C1-C20）杂环基-（C1-C10）烷基或-（CR1aR1b）s-R12;可以相同或不同的R 3a和R 3b各自独立地为氢，（C 1 -C 10）-烷基，取代的（C 1 -C 10）-烷基，（C 3 -C 10）-环烷基，取代的（C 3 -C 10）-环烷基，（C1-C10烷氧基）-C10），（C1-C10）烷硫基，（C1-C10）烷基氨基，取代的（C6-C12）芳基，（C6-C12）芳基，（C6-C12）芳基-（C1-C10 ）烷基，（C6）芳基-C12）-取代的（C1-C10）烷基，（C1-C20）杂芳基，取代的（C1-C20）杂芳基，（C1-C20）杂芳基-（C1-C10）烷基，（C1 -C20）杂芳基-（C1-C10）取代的，（C1-C20）杂环，取代的（C1-C20）杂环，（C1-C20）杂环基-（C1-C10）烷基，取代的（C1-C20）-环基（ C1-C10）烷基，-COOR13或-CONR13R14; R 3a和R 3b以及与它们相连的碳原子一起形成同环，取代的同环，杂环或取代的杂环; R 3a和与其键合的碳与R 1和与其键合的氮原子一起形成杂环或取代的杂环。 R4是-（CR9aR9b）r-Z-Y; çn是2、3或4的整数; s是1、2、3或4的整数; r是0、1或2的整数; Z代表直接键，或-O-，-S-，-NR11-，-SO-，-SO2-，-OSO2-，-SO2O-，-SO2NR11-，-NR11SO2-，-CO-，-COO- ，-OCO-，-CONR11-，-NR11CO-，-NR11CONR11a-，-OCONR11-或-NR11COO-; Y是氢，卤素，（C1-C10）烷基，取代的（C1-C10）烷基，取代的（C3-C10）环烷基，取代的（C3-C10）环烷基，取代的（C6-C12）芳基，（C6-C12）芳基，（C6-C12）芳基-（C1-C10）烷基，取代的（C6-C12）-芳基（C1-C10）烷基，（C1-C20）杂芳基，取代的（C1-C20）杂芳基，（C1-C20 ）杂芳基）-取代的（C1-C10）烷基或杂芳基（C1-C20）-取代的（C1-C10）烷基; R6为氢，（C1-C10）烷基，取代的（C1-C10）烷基，取代的（C3-C10）环烷基，取代的（C3-C10）环烷基，取代的（C6-C12）芳基，（C6-C12）芳基，芳基（C6-C12）-C1-C10-烷基，取代的（C6-C12）-芳基-C1-C10-烷基，取代的（C1-C20）杂芳基，取代的（C1-C20）杂芳基，（C1-C20）杂芳基-（C1-C10）烷基或（C1-C20）杂芳基取代的（C1-C10）烷基; R9是氢，（C1-C10）烷基或（C1-C10）酰基; R12为-CO2R13或-COOH; R1a和R1b可以相同或不同，分别独立地为氢，（C1-C10）酰基，羟基，卤素，氰基，（C1-C10）烷基，取代的（C1-C10）烷基，（C3-C10环烷基） ）。 ），取代的（C3-C10）环烷基，（C1-C10）烷氧基，（C1-C10）烷硫基，（C1-C10）烷氨基，-COOR13-或CONR13R14-; R1a和R1b与它们所连接的一个或多个原子独立地形成同环，取代的同环，杂环或取代的杂环;可以相同或不同的R 5a，R 5b，R 7a，R 7b，R 8a和R 8b各自独立地为氢，（C 1 -C 10）酰基，羟基，氨基，卤素，氰基，（C 1 -C 10）烷基，（C 1-烷基）-C10）取代的，（C3-C10）环烷基，取代的（C3-C10）环烷基，取代的（C1-C10）芳基，（C1-C10）取代的芳基，（C1-C10）烷氧基，（C1-C10）烷硫基，烷氨基（C1-C10），-COOR13或-CONR14R15;可以相同或不同的R 9a，R 9b，R 11，R 11b，R 13，R 14和R 15各自独立地为氢（C 1 -C 10）烷基，芳基（C 6 -C 12）或芳基（C 6 -C 12）-烷基（ C1-C10）;其中杂环，杂环，杂环基烷基，杂芳基和杂芳基烷基包含至少一个选自N，O和S的杂原子; “被取代的”和“被取代的”是指被选自卤素，乙炔基，乙烯基，羟基，氰基，硝基，氨基，（C1-C10）烷基氨基，二-C1-C10烷基氨基，（C1 -C10）烷基，（C3-C10）环烷基，（C1-C10）烷氧基，（C1-C10）烷硫基，（C1-C10）卤代烷基，（C6-C12）芳基，（C6-C12）芳基-烷基（C1 -C10），（C1-C20）杂芳基，（C1-C20）杂芳基-（C1-C10）烷基，（C1-C20）杂环，（C1-C20）杂环基（C1-C10）烷基，-NRaRb，-NRaC （> = O）Rb，-NRaC（> = O）NRaORb，-NRaC（> = O）NRaRb，-NRaC（> = O）ORb，-NRaSO2Rb，-C（> = O）Ra，-C（> = O）ORa，-OC（> = O）Ra，-C（> = O）NRaRb，-OC（> = O）NRaRb，-ORa，-SRa，-SORa，-S（> = O）2Ra， -OS（> = O）2Ra和-S（> = O）2ORa，其中Ra和Rb可以相同或不同各自独立地是氢，（C 1 -C 10）烷基，（C 1-卤代烷基）C 10），（C 3 -C 10）环烷基，（C 6 -C 12）芳基，（C 6 -C 12）芳基-（C 1 -C 10）烷基，（ C1-C20）杂芳基，（C1-C20）杂芳基（C1-C10）烷基），杂环（C1-C20），（C1-C20）杂环基-（C1-C10）烷基或-（CH2）zC（> = O R c，z是1、2、3或4的整数，并且R c是羟基，（C 1 -C 10烷基）），（C 3 -C 10）环烷基或（C 1 -C 10）烷氧基。

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