US2023159525A1PendingUtilityA1
Azetidine and pyrrolidine parp1 inhibitors and uses thereof
Est. expiryOct 1, 2041(~15.2 yrs left)· nominal 20-yr term from priority
A61K 2300/00A61K 45/06A61K 31/4745A61K 31/444A61P 35/00C07D 401/14C07D 491/048C07D 487/04C07D 491/147C07D 519/00C07D 471/04A61K 31/4985A61K 31/498C07B 2200/05
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Claims
Abstract
Described herein are azetidine and pyrrolidine PARP1 inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of cancer.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
R 1 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl;
X is N or CR 2 ;
R 2 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
or R 1 and R 2 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R;
Z is N or CR 4 ;
R 4 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
Y is N or CR 5 ;
R 5 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
R 6 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
each R 7 is independently hydrogen, deuterium, fluoro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
or two R 7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R;
n is 1 or 2;
each R 8 is independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
or two R 8 on the same carbon are taken together to form an oxo;
or two R 8 on the same carbon or adjacent carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R;
p is 0-4;
W is absent, —C(R 9 ) 2 —, —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O)(═NR W )—, or —NR W —;
each R 9 is independently hydrogen, deuterium, halogen, —CN, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
or two R 9 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R;
R W is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 10 is independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;
q is 0-4;
each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;
each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;
each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R;
or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and
each R is independently deuterium, halogen, —CN, —OH, -OC 1 -C 6 alkyl, —S(═O)C 1 -C 6 alkyl, —S(═O) 2 C 1 -C 6 alkyl, —S(═O) 2 NH 2 , —S(═O) 2 NHC 1 -C 6 alkyl, —S(═O) 2 N(C 1 -C 6 alkyl) 2 , —NH 2 , -NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , —NHC(═O)OC 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, —C(═O)OH, —C(═O)OC 1 -C 6 alkyl, —C(═O)NH 2 , —C(═O)N(C 1 -C 6 alkyl) 2 , —C(═O)NHC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
or two R on the same atom form an oxo; provided that the compound of Formula (I) is not
.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 1 is halogen, C 1 -C 6 alkyl, or cycloalkyl.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 1 is cycloalkyl.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 1 is ethyl.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 1 is halogen.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is CR 2 .
7 . The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 2 is hydrogen.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is CR 4 .
9 . The compound of claim 8 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4 is hydrogen.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is N.
11 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 6 is hydrogen.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 7 is hydrogen.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1.
14 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 8 is independently C 1 -C 6 alkyl.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1 or 2.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1.
18 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is —O—.
19 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is aryl or heteroaryl.
20 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-membered heteroaryl.
21 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 10 is independently deuterium, halogen, —CN, —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
22 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 10 is independently —C(═O)NR c R d .
23 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 1 or 2.
24 . The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
25 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
26 . A method of treating cancer in a subj ect in need thereof, the method comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
27 . The method of claim 26 , wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, gastrointestinal cancer, or lung cancer.Join the waitlist — get patent alerts
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