Heteroaryl compounds as inhibitors of RIP2 kinase, composition and application thereof
The present disclosure provides heterocycle compounds with RIP2 kinase inhibitory activity, pharmaceutical compositions comprising the same, methods using the same and applications thereof. The present disclosure provides compounds of Formula (I), as inhibitors of RIP2 kinase. These compounds can be used for preventing and/or treating RIP2 kinase-related diseases and/or conditions.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
n is 0, 1, 2 or 3;
L is a bond, —O—, —N(R 6 )—, or
wherein # denotes a connection to R 3 ;
ring A is C 6-10 aryl and 5-10 membered heteroaryl;
R 1 is independently H, deuterium, halide, —OH, amino, —CN, C 1-6 alkyl, C 3-6 cycloalkyl, —O(C 1-6 alkyl), —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , C 2-6 alkenyl or C 2-6 alkynyl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from R a ;
R 2 is independently H, deuterium, C 1-3 alkyl or C 3-6 cycloalkyl, wherein C 1-3 alkyl and C 3-6 cycloalkyl are unsubstituted or substituted with 1 to 3 groups independently selected from R b ;
R 3 is independently H, halide, —OH, amino, C 1-6 alkyl, C 3-6 cycloalkyl, —O(C 1-6 alkyl), 3-6 membered cycloheteroalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered cycloheteroalkyl, C 6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted with 1 to 3 groups independently selected from R c ;
R 4 is C 1-3 alkyl, wherein C 1-3 alkyl is unsubstituted or substituted with 1 to 3 groups independently selected from R d ,
R 5 is C 1-3 alkyl, wherein C 1-3 alkyl is unsubstituted or substituted with 1 to 3 groups independently selected from R e ,
or R 4 and R 5 together with the phosphorus atom attached thereto form 5-6 membered cycloheteroalkyl or 5-8 members cycloheteroalkenyl, wherein 5-6 membered cycloheteroalkyl and 5-8 members cycloheteroalkenyl are unsubstituted or substituted with 1 to 3 groups independently selected from R d ,
R 6 is H, C 1-3 alkyl, or C 3-6 cycloalkyl, wherein C 1-3 alkyl and C 3-6 cycloalkyl are unsubstituted or substituted with 1 to 3 groups independently selected from R f ,
R 7 is independently H, deuterium, F, Cl, Br, —OH, amino, —CN, C 1-6 alkyl, C 3-6 cycloalkyl, —O(C 1-6 alkyl), —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , C 2-6 alkenyl or C 2-6 alkynyl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from R a ,
R a , R b , R d , R e and R f are independently F, Cl, Br, I, —OH, amino, methyl or methoxy; and
R c is independently deuterium, F, Cl, Br, I, —OH, amino, methyl, methoxy or
wherein each of 3-6 membered cycloheteroalkyl 5-6 membered cycloheteroalkyl, 5-8 members cycloheteroalkenyl, and 5-10 membered heteroaryl comprises 1 to 3 heteroatoms or heteroatom groups independently selected from N, NH, O, S and P(═O).
2 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
R 2 is H.
3 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
L is a bond, —O, or
and
R 6 is defined in claim 1 .
4 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein
is selected from the group consisting of:
5 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein
is selected from the group consisting of:
6 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein
is selected from the group consisting of:
7 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
R 3 is independently H, halide, —OH, amino, C 1-6 alkyl, C 3-6 cycloalkyl, —O(C 1-6 alkyl), 3-6 membered cycloheteroalkyl, and 5-10 membered heteroaryl, wherein C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered cycloheteroalkyl, or 5-10 membered heteroaryl are unsubstituted or substituted with 1 to 3 groups independently selected from R c ; and
R c is defined in claim 1 .
8 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
R 3 is independently H, F, methyl, ethyl, n-propyl, i-propyl, methoxy, —OCD 3 , —OCF 3 , —OCHF 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
wherein * denotes a connection to L.
9 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
R 3 is independently H, methyl, ethyl, n-propyl, i-propyl, methoxy, —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
wherein * denotes a connection to L.
10 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
R 3 is independently H, F, methyl, methoxy, —OCD 3 , —OCF 3 , —OCHF 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
wherein * denotes a connection to L.
11 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
R 3 is independently F, methoxy, —OCD 3 , —OCF 3 , —OCHF 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
wherein * denotes a connection to L.
12 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
R 3 is independently methoxy, —OCD 3 , —OCF 3 , and —OCHF 2 , wherein * denotes a connection to L.
13 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
R 3 -L is independently H, F, methyl, ethyl, n-propyl, i-propyl, methoxy, —OCD 3 , —OCF 3 , —OCHF 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 ,
wherein * denotes a connection to quinoline.
14 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
R 4 is methyl;
R 5 is methyl; and
R 6 is H or C 1-3 alkyl.
15 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein:
R 7 is H, deuterium, F, Cl or Br.
16 . The compound of claim 1 , or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein the compound is selected from the group consisting of:
17 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.
18 . A composition comprising:
(i) the compound of claim 1 or the pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, stereoisomer or tautomer thereof; and
(ii) at least one additional therapeutic agent selected from the group consisting of anti-tumor agent, agent treating autoimmune disease, anti-neurodegenerative agent, agent treating metabolic disease, and agent treating genetic disease.