US2023128041A1PendingUtilityA1
Parp1 inhibitors and uses thereof
Est. expiryApr 19, 2041(~14.8 yrs left)· nominal 20-yr term from priority
Inventors:Lynnie TrzossQing DongStephen W. KaldorRobert Louis HoffmanPorino Jinjo VaJoseph Robert Pinchman
C07D 498/14C07D 471/04C07D 519/00C07D 491/048A61P 35/00C07D 401/12C07D 491/147C07D 491/14C07D 498/08C07D 513/04C07D 487/04C07D 491/052A61K 31/496
68
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Claims
Abstract
Described herein are 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 (III″), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
R C1 is halogen;
R C2 is hydrogen, deuterium, halogen, —CN, —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, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl;
R C3 is 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, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl;
each R 7 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, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl;
or two R 7 are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with 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;
each R 8 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R 8 on the same carbon are taken together to form an oxo;
or two R 8 on the same carbon, adjacent carbons, or opposite carbons are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more 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;
n is 0-6;
R 12 is C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , 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;
each R 11 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, or heterocycloalkyl;
q is 0-3;
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 optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , 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;
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 optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , 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; and
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 optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , 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 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 oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , 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.
2 . (canceled)
3 . (canceled)
4 . (canceled)
5 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C1 is chloro.
6 . (canceled)
7 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C2 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
8 . (canceled)
9 . (canceled)
10 . (canceled)
11 . (canceled)
12 . (canceled)
13 . (canceled)
14 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C3 is hydrogen.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein
is
16 . (canceled)
17 . The compound of claim 15 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein
is
18 . The compound of claim 15 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein
is
19 . (canceled)
20 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 7 is hydrogen.
21 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 8 is C 1 -C 6 alkyl; or two R 8 on the same carbon are taken together to form an oxo.
22 . (canceled)
23 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0.
24 . (canceled)
25 . (canceled)
26 . (canceled)
27 . (canceled)
28 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 11 is independently halogen or C 1 -C 6 alkyl.
29 . (canceled)
30 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0 or 1.
31 . (canceled)
32 . (canceled)
33 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 12 is C 1 -C 6 alkyl or cycloalkyl.
34 . (canceled)
35 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 12 is cycloalkyl.
36 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
37 . (canceled)
38 . (canceled)
39 . (canceled)
40 . The compound of claim 36 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
41 . The compound of claim 36 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
42 . The compound of claim 36 , wherein the compound is:
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
43 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
44 . A method of treating cancer in a subject in need thereof, the method comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, gastrointestinal cancer, or lung cancer.
45 . (canceled)
46 . (canceled)
47 . (canceled)Cited by (0)
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