Phthalazinone based modulators for the treatment of disease
The disclosure herein provides compounds and pharmaceutical compositions of Formula (II) for killing a cancer cell or inhibiting cancer cell proliferation. Further, the compounds and pharmaceutical compositions of Formula (II) are useful in methods for the inhibition of cancer cell proliferation.
1. A compound represented by the structure of Formula (II):
or a pharmaceutically acceptable salt thereof wherein:
X 1 is N;
R 4 is independently selected at each occurrence from (a), (b), and (c):
(a) halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —OC(O)R 20 , —OC(O)N(R 20 ) 2 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)OR 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )S(O) 2 (R 20 ), —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —NO 2 , and —CN;
(b) C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —OC(O)R 20 , —OC(O)N(R 20 ) 2 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)OR 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )S(O) 2 (R 20 ), —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —NO 2 , ═S, ═O, and —CN; and
(c) C 3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR 20 , —SR 20 , —N(R 20 ) 2 , —C(O)R 20 , —C(O)OR 20 , —OC(O)R 20 , —OC(O)N(R 20 ) 2 , —C(O)N(R 20 ) 2 , —N(R 20 )C(O)R 20 , —N(R 20 )C(O)OR 20 , —N(R 20 )C(O)N(R 20 ) 2 , —N(R 20 )S(O) 2 (R 20 ), —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 N(R 20 ) 2 , —NO 2 , ═S, ═O, and —CN;
R 5 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR 21 , —SR 21 , —N(R 21 ) 2 , —C(O)R 21 , —C(O)OR 21 , —OC(O)R 21 , —OC(O)N(R 21 ) 2 , —C(O)N(R 21 ) 2 , —N(R 21 )C(O)R 21 , —N(R 21 )C(O)OR 21 , —N(R 21 )C(O)N(R 21 ) 2 , —N(R 21 )S(O) 2 (R 21 ), —S(O)R 21 , —S(O) 2 R 21 , —S(O) 2 N(R 21 ) 2 , —NO 2 , ═S, ═O, and —CN;
R 6 is independently selected at each occurrence from:
C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 22 , —SR 22 , —N(R 22 ) 2 , —C(O)R 22 ,—C(O)OR 22 , —OC(O)R 22 , —OC(O)N(R 22 ) 2 , —C(O)N(R 22 ) 2 , —N(R 22 )C(O)R 22 , —N(R 22 )C(O)OR 22 , —N(R 22 )C(O)N(R 22 ) 2 , —N(R 22 )S(O) 2 (R 22 ), —S(O)R 22 , —S(O) 2 R 22 , —S(O) 2 N(R 22 ) 2 , —NO 2 , ═S, ═O, and —CN;
Ring B is selected from C 3-10 carbocycle and 3- to 10-membered heterocycle;
R 7 is independently selected at each occurrence from:
halogen, —OR 23 , —SR 23 , —N(R 23 ) 2 , —C(O)R 23 , —OC(O)R 23 , —OC(O)N(R 23 ) 2 , —C(O)N(R 23 ) 2 , —N(R 23 )C(O)R 23 , —N(R 23 )C(O)OR 23 , —N(R 23 )C(O)N(R 23 ) 2 , —N(R 23 )S(O) 2 (R 23 ), —S(O)R 23 , —S(O) 2 R 23 , —S(O) 2 N(R 23 ) 2 , —NO 2 , and —CN; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 23 , —SR 23 , —N(R 23 ) 2 , —C(O)R 23 , —C(O)OR 23 , —OC(O)R 23 , —OC(O)N(R 23 ) 2 , —C(O)N(R 23 ) 2 , —N(R 23 )C(O)R 23 , —N(R 23 )C(O)OR 23 , —N(R 23 )C(O)N(R 23 ) 2 , —N(R 23 )S(O) 2 (R 23 ), —S(O)R 23 , —S(O) 2 R 23 , —S(O) 2 N(R 23 ) 2 , —NO 2 , ═S, ═O, and —CN;
R 20 , R 21 , R 22 , and R 23 , are each independently selected at each occurrence from (d), (e), and (f):
(d) hydrogen;
(e) C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —NH 2 , —NO 2 , ═O, —CN, C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, —OH, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —NH 2 , —NO 2 , ═O, and —CN; and
(f) C 3-10 carbocycle and 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, —OH, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —NH 2 , —NO 2 , ═O, and —CN;
x is selected from 0, 1, 2, 3, and 4;
y is selected from 0, 1, 2, 3, and 4; and
z is selected from 0, 1, 2, 3, 4 and 5; wherein
at least one of x or y is selected from 1, 2, 3, and 4.
2. The compound or salt of claim 1 , wherein x is selected from 0 and 1.
3. The compound or salt of claim 1 , wherein R 4 is selected from:
halogen, —OR 20 , —N(R 20 ) 2 , —C(O)R 20 , —NO 2 , and —CN; and
C 1-3 alkyl, C 3-6 carbocycle, and 3- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR 20 , —N(R 20 ) 2 , —C(O)R 20 , —NO 2 , and —CN; and
each R 20 is independently selected from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
4. The compound or salt of claim 1 , wherein each R 4 is independently selected from: fluoro, chloro, bromo, —O—C 1-6 alkyl, —N(CH 3 ) 2 , —CN,
5. The compound or salt of claim 1 , wherein y is selected from 0 and 1.
6. The compound or salt of claim 1 , wherein R 5 is C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 21 , —N(R 21 ) 2 , —C(O)R 21 , —NO 2 , ═S, ═O, and —CN; and R 21 is selected from hydrogen and C 1-3 alkyl.
7. The compound or salt of claim 1 , wherein z is selected from 0, 1, and 2.
8. The compound or salt of claim 1 , wherein R 7 is selected from halogen, —OR 23 , —N(R 23 ) 2 , —C(O)R 23 , —NO 2 , —CN; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 23 , —N(R 23 ) 2 , —C(O)R 23 , —NO 2 , and —CN; and R 23 is selected from hydrogen and C 1-3 alkyl.
9. The compound or salt of claim 1 , wherein
is selected from:
10. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any one thereof.