US2014100169A1PendingUtilityA1
Compounds for enzyme inhibition
Est. expiryJun 19, 2026(expired)· nominal 20-yr term from priority
Inventors:Kevin D. ShenkFrancesco ParlatiHan-Jie ZhouCatherine SylvainMark S. SmythMark K. BennettGuy J. Laidig
A61P 37/06A61P 37/00A61P 37/08A61P 9/10A61P 37/02A61P 3/10A61P 43/00A61P 9/04A61P 31/18A61P 35/02A61P 35/00A61P 33/00A61P 25/00A61P 3/12A61P 33/02A61P 29/00A61P 31/00A61P 31/04A61P 25/16A61P 27/02A61P 31/12A61P 25/28A61P 21/00A61P 19/02A61P 17/14A61P 11/06A61P 17/00A61P 1/18A61P 1/16A61P 19/00A61P 17/06A61P 11/08A61P 13/12A61P 11/00A61P 1/04C07K 5/0812C07K 5/0808C07D 409/12C07K 5/08C07K 5/06086C07K 5/06034A61K 38/00C07K 5/0821C07K 5/06113C07K 5/06043C07K 5/0806C07K 5/06052C07D 303/32C07K 5/06026C07K 5/0606C07K 5/1008C07K 5/06C07D 405/12C07K 5/0819C07K 5/06078C07K 5/1016C07K 5/06095A61K 31/336Y02A50/30A61P 1/00
66
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Claims
Abstract
One aspect of the invention relates to inhibitors that preferentially inhibit immunoproteasome activity over constitutive proteasome activity. In certain embodiments, the invention relates to the treatment of immune related diseases, comprising administering a compound of the invention. In certain embodiments, the invention relates to the treatment of cancer, comprising administering a compound of the invention.
Claims
exact text as granted — not AI-modified1 . (canceled)
2 . A method for the treatment of an immune-related disease, comprising administering a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
B is absent;
L is C═O;
M is absent or is C 1-12 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is O;
R 1 is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl;
R 2 and R 3 are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl;
R 4 is N(R 5 )L-Q-R 6 ;
R 5 is selected from hydrogen, OH, C 1-6 aralkyl, and C 1-6 alkyl;
R 6 is selected from hydrogen and C 1-6 alkyl;
R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl;
R 9 is selected from hydrogen, OH, and C 1-6 alkyl; and
R 10 is an N-terminal protecting group;
R 11 and R 12 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
each R 13 is independently selected from hydrogen and C 1-6 alkyl; and
R 14 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
R 15 is C 1-6 alkyl.
3 . A method for the treatment of cancer, comprising administering a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
B is absent;
L is C═O;
M is absent or is C 1-12 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is O;
R 1 is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl;
R 2 and R 3 are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl;
R 4 is N(R 5 )L-Q-R 6 ;
R 5 is selected from hydrogen, OH, C 1-6 aralkyl, and C 1-6 alkyl;
R 6 is selected from hydrogen and C 1-6 alkyl;
R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl;
R 9 is selected from hydrogen, OH, and C 1-6 alkyl; and
R 10 is an N-terminal protecting group;
R 11 and R 12 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
each R 13 is independently selected from hydrogen and C 1-6 alkyl; and
R 14 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
R 15 is C 1-6 alkyl.
4 . A method for treating infection, comprising administering a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
B is absent;
L is C═O;
M is absent or is C 1-12 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is O;
R 1 is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl;
R 2 and R 3 are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl;
R 4 is N(R 5 )L-Q-R 6 ;
R 5 is selected from hydrogen, OH, C 1-6 aralkyl, and C 1-6 alkyl;
R 6 is selected from hydrogen and C 1-6 alkyl;
R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl;
R 9 is selected from hydrogen, OH, and C 1-6 alkyl; and
R 10 is an N-terminal protecting group;
R 11 and R 12 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
each R 13 is independently selected from hydrogen and C 1-6 alkyl; and
R 14 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
R 15 is C 1-6 alkyl.
5 . A method for treating proliferative disease, comprising administering a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
B is absent;
L is C═O;
M is absent or is C 1-12 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is O;
R 1 is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl;
R 2 and R 3 are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl;
R 4 is N(R 5 )L-Q-R 6 ;
R 5 is selected from hydrogen, OH, C 1-6 aralkyl, and C 1-6 alkyl;
R 6 is selected from hydrogen and C 1-6 alkyl;
R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl;
R 9 is selected from hydrogen, OH, and C 1-6 alkyl; and
R 10 is an N-terminal protecting group;
R 11 and R 12 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
each R 13 is independently selected from hydrogen and C 1-6 alkyl; and
R 14 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
R 15 is C 1-6 alkyl.
6 . A method for treating neurodegenerative disease, compromising administering a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
B is absent;
L is C═O;
M is absent or is C 1-12 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is O;
R 1 is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl;
R 2 and R 3 are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl;
R 4 is N(R 5 )L-Q-R 6 ;
R 5 is selected from hydrogen, OH, C 1-6 aralkyl, and C 1-6 alkyl;
R 6 is selected from hydrogen and C 1-6 alkyl;
R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl;
R 9 is selected from hydrogen, OH, and C 1-6 alkyl; and
R 10 is an N-terminal protecting group;
R 11 and R 12 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
each R 13 is independently selected from hydrogen and C 1-6 alkyl; and
R 14 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
R 15 is C 1-6 alkyl.
7 . A compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof,
each Ar is independently an aromatic or heteroaromatic group optionally substituted with 1 to 4 substituents;
each A is independently selected from C═O, C═S, and SO 2 ; or
A is optionally a covalent bond when adjacent to an occurrence of Z;
B is absent or is N(R 9 )R 10 ;
L is absent or is selected from C═O, C═S, and SO 2 ;
M is absent or is C 1-12 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is selected from O, S, NH, and N—C 1-6 alkyl;
Y is absent or is selected from C═O and SO 2 ;
each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or
Z is optionally a covalent bond when adjacent to an occurrence of A;
R 2 and R 3 are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl;
R 4 is N(R 5 )L-Q-R 6 ;
R 5 is selected from hydrogen, OH, C 1-6 aralkyl, and C 1-6 alkyl;
R 6 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, Ar—Y—, carbocyclyl, heterocyclyl, an N-terminal protecting group, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, R 11 ZAZ—C 1-8 alkyl-, R 14 Z—C 1-8 alkyl-, (R 11 O)(R 12 O)P(═O)O—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, R 11 ZAZ—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, heterocyclylMZAZ—C 1-8 alkyl-, (R 11 O)(R 12 O)P(═O)O—C 1-8 alkyl-, (R 13 ) 2 N—C 1-12 alkyl-, (R 13 ) 3 N + —C 1-12 alkyl-, heterocyclylM-, carbocyclylM-, R 14 SO 2 C 1-8 alkyl-, and R 14 SO 2 NH; or
R 5 and R 6 together are C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZAZ—C 1-6 alkyl, ZAZ—C 1-6 alkyl-ZAZ—C 1-6 alkyl, ZAZ—C 1-6 alkyl-ZAZ, or C 1-6 alkyl-A, thereby forming a ring;
R 8 is selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl;
R 9 is selected from hydrogen, OH, and C 1-6 alkyl; and
R 10 is an N-terminal protecting group;
R 11 and R 12 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl, or R 11 and R 12 together are C 1-6 alkyl, thereby forming a ring;
each R 13 is independently selected from hydrogen and C 1-6 alkyl; and
R 14 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
R 15 is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)NHC 1-6 alkyl, and C 1-6 aralkyl;
provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.
8 . A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
each Ar is independently an aromatic or heteroaromatic group optionally substituted with 1 to 4 substituents;
B is absent or is N(R 9 )R 10 ;
L is C═O;
M is absent or is C 1-12 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is selected from O, S, NH, and N—C 1-6 alkyl;
Y is absent or is selected from C═O and SO 2 ;
R 1 is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl;
R 2 and R 3 are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl;
R 4 is N(R 5 )L-Q-R 6 ;
R 5 is selected from hydrogen;
R 6 is selected from Ar—Y— and aryl;
R 7 and R 8 are hydrogen; and
R 15 is C 1-6 alkyl;
provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.Cited by (0)
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