Inhibitors for programmed cell necrosis and preparation method therefor and use thereof
Provided in the present invention are inhibitors for programmed cell necrosis, a preparation method therefor and a use thereof. Specifically, provided in the present invention are a compound represented by formula I and a composition comprising same. The described compound may be used to prepare a pharmaceutical composition for the prevention and/or treatment of diseases involving cell death and/or inflammation.
1 . A compound represented by the following Formula (I-c), or pharmaceutically acceptable salts thereof,
wherein:
dashed line is a chemical bond or none;
X is selected from the group consisting of CR 2 , NR, O, S, CR, and N;
R is selected from the group consisting of H, D, and C1-C4 alkyl;
R 1 and R 2 are each independently selected from the group consisting of H and C1-C4 alkyl; or R 1 and R 2 together form a structure of substituted or unsubstituted —(CH 2 ) n —; wherein, n is 1, 2, 3, or 4;
ring A is selected from the group consisting of substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-12 membered heteroaryl;
ring B is selected from the group consisting of substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-12 membered heteroaryl,
wherein the substituted means that at least one hydrogen atom in a group is substituted by one or more substituents selected from the group consisting of halogen, deuterium, C1-C6 alkoxy, halogenated C1-C6 alkoxy, methyl sulfonyl, —S(═O) 2 NH 2 , oxo(═O), —CN, hydroxyl, —NH 2 , carboxyl, C2-C6 amido (—C(—O)—N(Rc) 2 or—NH—C(—O)(Rc), wherein Rc is H or C1-C5 alkyl), C1-C6 alkyl-(C2-C6 amido), and substituted or unsubstituted groups selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 amino, C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, 5-12 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, —(CH 2 )—C6-C10 aryl, and —(CH 2 )-(5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O), and the substituents are selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, oxo, —CN, —NH 2 , —OH, C6-C10 aryl, C1-C6 amino, C2-C6 amido, and 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O.
2 . The compound according to claim 1 , wherein the compound of Formula (I-c) has a structure selected from the group consisting of I-a and I-b:
3 . The compound according to claim 1 , wherein the ring A is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted 5-7 membered heteroaryl; and/or
ring B is selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted 5-7 membered heteroaryl.
4 . The compound according to claim 1 , wherein the compound is selected from the following table:
Com-
Com-
pound
pound
number
Chemical structure
number
Chemical structure
QY-1- 98
QY-4- 6
QY-2- 25
QY-4- 7
QY-2- 26
QY-4- 8
QY-2- 27
QY-4- 11
QY-2- 34
QY-4- 12
QY-2- 38
QY-4- 14
QY-2- 39
QY-4- 27
QY-2- 52
QY-4- 32
QY-2- 53
QY-4- 35
QY-2- 54
QY-4- 39
QY-2- 55
QY-4- 66
QY-2- 56
QY-4- 67
QY-2- 75
QY-4- 69
QY-2- 76
QY-4- 70
QY-2- 77
QY-4- 75
QY-2- 78
QY-4- 78
QY-2- 79
QY-4- 87
QY-2- 100
QY-4- 88
QY-2- 103
QY-4- 96
QY-2- 104
QY-4- 99
QY-3- 4
QY-5- 1
QY-3- 11
QY-5- 4
QY-3- 17
QY-5- 21
QY-3- 26
QY-5- 22
QY-3- 27
QY-5- 79
QY-3- 28
QY-5- 83
QY-3- 29
QY-5- 85
QY-3- 35
QY-6- 47
QY-3- 36
QY-6- 60
QY-3- 39
QY-6- 61
QY-3- 46
QY-6- 62
QY-3- 51
QY-6- 63
QY-3- 65
QY-6- 83
QY-3- 81
QY-6- 84
QY-3- 86
QY-7- 7
QY-3- 94
QY-7- 50
QY-3- 95
QY-7- 60
QY-3- 96
QY-7- 62
QY-3- 99
XHJ-3- 22
QY4-1
ZSQ-13- 56
QY4-2
ZSQ-13- 57
QY-7- 101
QY-8- 101
QY-9- 8
QY-9- 32
QY-9- 43
QY-10- 1
QY-10- 92
QY-10- 96
QY-10- 104
QY-11- 1
QY-11- 9A
QY-11- 9B
QY-11- 11A
QY-11- 11B
QY-11- 15B
QY-11- 16A
QY-11- 16B
QY-11- 36
QY-11- 44
QY-11- 45
QY-12- 11
QY-12- 14
QY-12- 32
QY-13- 42
QY-13- 68
QY-13- 70
QY-13- 86
QY-14- 8
QY-14- 9
QY-14- 17
QY-14- 24
QY-14- 25
QY-14- 27
QY-14- 29
QY-14- 30
QY-14- 31
QY-14- 33
QY-14- 34
QY-14- 35
QY-14- 40
QY-14- 44
QY-14- 59
QY-14- 60
QY-14- 68
QY-15- 11
QY-15- 12
QY-15- 31
QY-16- 60
QY-16- 61
QY-16- 66
QY-16- 75
QY-16- 76
QY-16- 77
QY-16- 82
and
QY-16- 84
.
5 . A pharmaceutical composition comprising: (a) a therapeutically effective amount of the compound according to claim 1 , or pharmaceutically acceptable salts, hydrates or solvates thereof; and (b) a pharmaceutically acceptable carrier.
6 . The pharmaceutical composition according to claim 5 , wherein diseases or conditions to be treated with the pharmaceutical composition are selected from the group consisting of inflammatory diseases, infectious diseases, ischemic or degenerative-related diseases, and tissue damage.
7 . The pharmaceutical composition according to claim 5 , wherein diseases or conditions to be treated with the pharmaceutical composition are related to programmed cell necrosis and/or the activity or expression levels of human receptor interacting protein 1 kinase (RIPK1).
8 . The pharmaceutical composition according to claim 7 , wherein the diseases or conditions are selected from the group consisting of inflammatory diseases, infectious diseases, ischemic or degenerative related diseases, and tissue damage.
9 . A method for treating diseases or conditions related to programmed cell necrosis and/or the activity or expression levels of human receptor interacting protein 1 kinase (RIPK1), comprising administering the compound of Formula (I-c) according to claim 1 to a subject in need thereof, wherein the diseases or conditions are selected from the group consisting of inflammatory diseases, infectious diseases, ischemic or degenerative related diseases, and tissue damage.