Pyrazolyl-containing tricyclic derivatives, preparation method and application thereof
阅读说明：本技术 含吡唑基的三并环类衍生物、其制备方法和应用 (Pyrazolyl-containing tricyclic derivatives, preparation method and application thereof ) 是由 刘世强 周远锋 刘扬 吴雪松 刘磊 包如迪 于 2018-10-18 设计创作，主要内容包括：本发明涉及含吡唑基的三并环类衍生物、其制备方法和应用。特别地,本发明涉及通式(I)所示的化合物、其制备方法及含有该化合物的药物组合物,及其作为蛋白酶如ERK(MAPK)抑制剂在治疗癌症、骨病、炎性疾病、免疫疾病、神经系统疾病、代谢性疾病、呼吸性疾病和心脏病的用途,其中通式(I)中的各取代基与说明书中的定义相同。<Image he="345" wi="497" file="DDA0002143239920000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to pyrazolyl-containing tricyclic derivatives, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof as a protease inhibitor such as ERK (MAPK) in treating cancer, bone diseases, inflammatory diseases, immune diseases, nervous system diseases, metabolic diseases, respiratory diseases and heart diseases, wherein each substituent in the general formula (I) is defined as the specification.)
A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
x and Y are each independently selected from N or-CR3；
M is selected from the group consisting of a bond,
Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, oxo, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nR3、-(CH2)nOR3、-(CH2)nSR3、-(CH2)nC(O)R3、-(CH2)nC(O)OR3、-(CH2)nS(O)mR3、-(CH2)nNR3R4、-(CH2)nC(O)NR3R4、-(CH2)nNR3C(O)R4And- (CH)2)nNR3S(O)mR4Is substituted with one or more substituents of (1);
R1selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, and alkoxy groupAlkyl, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nR3、-(CH2)nOR3、-(CH2)nSR3、-(CH2)nC(O)R3、-(CH2)nC(O)OR3、-(CH2)nS(O)mR3、-(CH2)nNR3R4、-(CH2)nC(O)NR3R4、-(CH2)nNR3C(O)R4And- (CH)2)nNR3S(O)mR4(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nR5、-(CH2)nOR5、-(CH2)nSR5、-(CH2)nC(O)R5、-(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR5R6、-(CH2)nC(O)NR5R6、-(CH2)nNR5C(O)R6And- (CH)2)nNR5S(O)mR6Is substituted with one or more substituents of (1);
R2selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nR3、-(CH2)nOR3、-(CH2)nSR3、-(CH2)nC(O)R3、-(CH2)nC(O)OR3、-(CH2)nS(O)mR3、-(CH2)nNR3R4、-(CH2)nC(O)NR3R4、-(CH2)nNR3C(O)R4And- (CH)2)nNR3S(O)mR4Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, oxo, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nR5、-(CH2)nOR5、-(CH2)nSR5、-(CH2)nC(O)R5、-(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR5R6、-(CH2)nC(O)NR5R6、-(CH2)nC(O)NHR5、-(CH2)nNR5C(O)R6And- (CH)2)nNR5S(O)mR6Is substituted with one or more substituents of (1);
R3and R4Are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nR5、-(CH2)nOR5、-(CH2)nSR5、-(CH2)nC(O)R5、-(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR5R6、-(CH2)nC(O)NR5R6、-(CH2)nC(O)NHR5、-(CH2)nNR5C(O)R6And- (CH)2)nNR5S(O)mR6(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium atoms, alkyl groups, halogens, hydroxyl groups, amino groups, nitro groups, cyano groups, ester groups, alkoxy groups, hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups;
R5and R6The same or different, and each is independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyl group, amino group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of deuterium atom, alkyl group, halogen, hydroxyl group, amino group, nitro group, cyano group, alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group;
m is an integer selected from 0, 1 and 2; and is
n is an integer selected from 0, 1,2, 3,4 and 5.
The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
x and Y are each independently selected from N or-CR3(ii) a Preferably CH;
X1and X2Each independently selected from O, -NR3or-CR3；
R2Is selected from- (CH)2)nR3、-(CH2)nOR3、-(CH2)nNR3R4Cycloalkyl, heterocycleAryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, oxo, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nR5、-(CH2)nOR5、-(CH2)nSR5、-(CH2)nC(O)R5、 -(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR5R6、-(CH2)nC(O)NR5R6、-(CH2)nC(O)NHR5、-(CH2)nNR5C(O)R6And- (CH)2)nNR5S(O)mR6Is substituted with one or more substituents of (1);
R7selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nR3、-(CH2)nOR3、-(CH2)nSR3、-(CH2)nC(O)R3、-(CH2)nC(O)OR3、-(CH2)nS(O)mR3、-(CH2)nNR3R4、-(CH2)nC(O)NR3R4、-(CH2)nNR3C(O)R4And- (CH)2)nNR3S(O)mR4(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nR5、-(CH2)nOR5、-(CH2)nSR5、-(CH2)nC(O)R5、-(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR5R6、-(CH2)nC(O)NR5R6、-(CH2)nNR5C(O)R6And- (CH)2)nNR5S(O)mR6Is substituted with one or more substituents of (1);
R3～R6m and n are as defined in claim 1.
The compound of formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (III), a stereoisomer, or a pharmaceutically acceptable salt thereof:
wherein:
x and Y are each independently selected from N or-CR3(ii) a Preferably CH;
X3and X4Each independently selected from N, NR3or-CR3；
R2Is selected from- (CH)2)nR3、-(CH2)nOR3、-(CH2)nNR3R4Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, oxo, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nR5、-(CH2)nOR5、-(CH2)nSR5、-(CH2)nC(O)R5、-(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR5R6、-(CH2)nC(O)NR5R6、-(CH2)nC(O)NHR5、-(CH2)nNR5C(O)R6And- (CH)2)nNR5S(O)mR6Substituted with one or more substituents of (a);
M、R1、R3～R6m and n are as defined in claim 1.
The compound of formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (IV), a stereoisomer, or a pharmaceutically acceptable salt thereof:
wherein:
M1selected from the group consisting of a bond, O, NR3、
Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium atom, oxo, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R8selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group; wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium atoms, alkyl groups, haloalkyl groups, halogens, amino groups, nitro groups, cyano groups, hydroxy groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups; and is
x is an integer of 0, 1,2, 3 or 4;
X、Y、X1、X2、R3～R7m and n are as defined in claim 2.
The compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 3, which is a compound of formula (V), a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
X3and X4Each independently selected from N, NR3or-CR3；
M1Selected from the group consisting of a bond, O, NR3、Or- (CH)2)n-, preferably a bond, O, NR3、
Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium atom, oxo, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R8selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group; wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium atoms, alkyl groups, haloalkyl groups, halogens, amino groups, nitro groups, cyano groups, hydroxy groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups;
M、X、Y、R1m, n and x are as defined in claim 3.
The compound of the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 5, which is a compound of the general formula (V-A), (V-B), (V-C), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
ring B, M, M1、X、Y、R1、R8And x is as defined in claim 5.
The compound of the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 5, which is a compound of the general formula (V-D), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
M2selected from the group consisting of a bond, - (CH)2)nCR3R4-、-O(CH2)nCR3R4-、-(CH2)nNR3-、-(CH2)nN(R3)NR4-、-(CH2)nNHCR3R4-or-CR3R4-；
Ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from deuterium atom, oxo, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
the following structure is preferred:
R9selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nR3、-(CH2)nOR3、-(CH2)nSR3、-(CH2)nC(O)R3、-(CH2)nC(O)OR3、-(CH2)nS(O)mR3、-(CH2)nNR3R4、-(CH2)nC(O)NR3R4、-(CH2)nNR3C(O)R4And- (CH)2)nNR3S(O)mR4；
t is an integer of 0, 1,2, 3,4 or 5;
ring B, M1、X、Y、R8And x is as defined in claim 5.
A compound according to claim 4 to 7 of the general formula (I):
wherein:
ring B is selected from the following structures:
the compound of formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 4, which is a compound of formula (VI), a stereoisomer, or a pharmaceutically acceptable salt thereof:
wherein:
X、Y、X1、X2、R7、R8and x is as defined in claim 4.
The compound of formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 5, which is a compound of formula (VII):
wherein:
M、X、Y、X3、X4、R1、R8and x is as defined in claim 5.
The compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (VIII), a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
x and Y are each independently selected from N or-CR3(ii) a Preferably CH;
X1and X2Each independently selected from O, -NR3or-CR3；
R2Is selected from- (CH)2)nR3、-(CH2)nOR3、-(CH2)nNR3R4Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium atom, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxy, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nR5、-(CH2)nOR5、-(CH2)nSR5、-(CH2)nC(O)R5、-(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR5R6、-(CH2)nC(O)NR5R6、-(CH2)nNR5C(O)R6And- (CH)2)nNR5S(O)mR6Is substituted with one or more substituents of (1);
R7selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxy group, cyano group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)nR3、-(CH2)nOR3、-(CH2)nSR3、-(CH2)nC(O)R3、-(CH2)nC(O)OR3、-(CH2)nS(O)mR3、-(CH2)nNR3R4、-(CH2)nC(O)NR3R4、-(CH2)nNR3C(O)R4And- (CH)2)nNR3S(O)mR4(ii) a Wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)nR5、-(CH2)nOR5、-(CH2)nSR5、-(CH2)nC(O)R5、-(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR5R6、-(CH2)nC(O)NR5R6、-(CH2)nNR5C(O)R6And- (CH)2)nNR5S(O)mR6Is substituted with one or more substituents of (1); and is
y is an integer selected from 0, 1,2 and 3, preferably y is 1;
R3～R6m and n are as defined in claim 1.
The compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (VII-a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
X3and X4Each independently selected from N, NH or CH;
ring C is selected from the following structures:
R3selected from hydrogen atom, deuterium atom, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Alkoxy or C1-8A haloalkoxy group;
R8selected from hydrogen atom, deuterium atom, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Alkoxy radical, C1-8Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C3-10Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-12 membered heteroaryl;
R9selected from hydrogen atom, deuterium atom, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Alkoxy radical, C1-8Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C3-10Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-12 membered heteroaryl;
R10and R11Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Alkoxy radical, C1-8Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C3-10Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CH)2)nR5、-(CH2)nOR5、-(CH2)nSR5、-(CH2)nC(O)R5、-(CH2)nC(O)OR5、-(CH2)nS(O)mR5、-(CH2)nNR5R6、-(CH2)nC(O)NR5R6、-(CH2)nC(O)NHR5、-(CH2)nNR5C(O)R6And- (CH)2)nNR5S(O)mR6(ii) a Wherein said C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-12 membered heteroaryl optionally further substituted by a substituent selected from the group consisting of deuterium atom, C1-8Alkyl, halogen, hydroxy, amino, nitro, cyano, ester, C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-12 membered heteroaryl;
R5and R6Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a deuterium atom, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, hydroxy, amino, C3-10Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-12 membered heteroaryl, wherein said C is1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-12 membered heteroaryl optionally further substituted by a substituent selected from deuterium atom, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, halogen, hydroxy, amino, nitro, cyano, C1-8Alkoxy radical, C1-8Hydroxyalkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-12 membered heteroaryl;
m is an integer selected from 0, 1 and 2;
n is an integer selected from 0, 1,2, 3,4 and 5;
x is an integer selected from 0, 1,2, 3 and 4; and is
t is an integer selected from 0, 1,2, 3,4 and 5.
The compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1,3, 5,6, 8, or 10, wherein R is1Selected from hydrogen atoms, C1-8Alkyl, 5-10 membered aryl5-10 membered heteroaryl, - (CH)2)nR3、-(CH2)nOR3、-(CH2)nC(O)R3、-(CH2)nC(O)OR3And- (CH)2)nNR3R4Wherein said C1-8Alkyl, 5-10 membered aryl and 5-10 membered heteroaryl optionally further substituted by C1-8Alkyl, halogen, 5-10 membered aryl, 5-10 membered heteroaryl, - (CH)2)nR5、-(CHR4)nR5And- (CH)2)nOR5Is substituted with one or more substituents of (1);
preferably a hydrogen atom, C1-6Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, - (CH)2)nR3、-(CH2)nOR3、-(CH2)nC(O)R3And- (CH)2)nNR3R4；
More preferably a hydrogen atom, C1-3Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, - (CH)2)nR3、-(CH2)nOR3、-(CH2)nC(O)R3And- (CH)2)nNR3R4。
The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 10, 12 or 13, wherein R is8Selected from hydrogen atom, cyano, C1-8Alkyl radical, C1-8Alkoxy, halogen, oxo and C1-8A haloalkyl group; preferably C1-6Alkyl radical, C1-6Alkoxy or halogen; more preferably C1-3Alkyl radical, C1-3Alkoxy or halogen.
The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, which is selected from the following compounds:
an intermediate for the preparation of a compound of formula (VII-a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
pg is an amino protecting group selected from benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trityl or phthaloyl; preferably a trityl group;
ring C, X3、X4、R3、R8-R11T and x are as defined in claim 12.
A process for the preparation of a compound of formula (VII-a), the process comprising:
deprotecting the compound of formula (IX) under acidic conditions to give a compound of formula (VII-A);
wherein:
ring C, Pg, X3、X4、R3、R8-R11T and x are as defined in claim 16.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 15, in association with one or more pharmaceutically acceptable carriers, diluents or excipients.
The compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, or the pharmaceutical composition of claim 18 for use in the preparation of an ERK inhibitor medicament.
Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 18, for the manufacture of a medicament for the treatment of cancer, bone disorders, inflammatory diseases, immune diseases, neurological diseases, metabolic diseases, respiratory diseases and cardiac diseases; wherein the cancer is a cancer selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer, thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome, acute myeloid leukemia, and colorectal cancer.
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