US2010221261A1PendingUtilityA1
Iap bir domain binding compounds
Est. expiryMar 16, 2026(expired)· nominal 20-yr term from priority
A61P 37/06A61P 35/00A61P 43/00C07D 207/14C07D 207/16A61K 38/08A61K 31/4025A61K 31/40C07K 7/06A61K 38/00C07K 5/0808C07K 5/0806C07K 5/081C07K 5/0812A61K 38/1761A61P 29/00C07D 401/14A61K 31/4439
68
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Claims
Abstract
Disclosed is an isomer, enantiomer, diastereoisomer or tautomer of a compound represented by Formula I or II or a salt thereof, in which R 1 , R 2 , R 3 , R 100 , R 200 , R 300 , A, A 1 , BG, Q and Q 1 are substituents described herein. Also disclosed is the use of compounds of Formula I and II to treat proliferative disorders such as cancer.
Claims
exact text as granted — not AI-modified1 .- 56 . (canceled)
57 . A method of enhancing apoptosis in a cell comprising contacting the cell with a compound of Formula I:
or a salt thereof,
wherein
m is 0, 1 or 2;
Y is NH, O or S;
BG is —X-L-X 1 —;
X and X 1 are independently
1) O,
2) NR 13 ,
3) S,
4) —C 1 -C 6 alkyl-,
5) —C 1 -C 6 alkyl-O,
6) —C 1 -C 6 alkyl-NR 13 —,
7) —C 1 -C 6 alkyl-S—,
L is:
1) —C 1 -C 20 alkyl-,
2) —C 2 -C 6 alkenyl-,
3) —C 2 -C 4 alkynyl-,
4) —C 3 -C 7 cycloalkyl-,
5) -aryl-,
6) -biphenyl-,
7) -heteroaryl-,
8) -heterocyclyl-,
9) —C 1 -C 6 alkyl-(C 2 -C 6 alkenyl)-C 1 -C 6 alkyl-,
10) —C 1 -C 6 alkyl-(C 2 -C 4 alkynyl)-C 1 -C 6 alkyl-,
11) —C 1 -C 6 alkyl-(C 3 -C 7 cycloalkyl)-C 1 -C 6 alkyl-,
12) —C 1 -C 6 alkyl-aryl-C 1 -C 6 alkyl-,
13) —C 1 -C 6 alkyl-biphenyl-C 1 -C 6 alkyl-,
14) —C 1 -C 6 alkyl-heteroaryl-C 1 -C 6 alkyl-,
15) —C 1 -C 6 alkyl-heterocycyl-C 1 -C 6 alkyl-,
16) —C 1 -C 6 alkyl-Y—C 1 -C 6 alkyl-,
17) -aryl-Y-aryl-,
18) -heteroaryl-Y-heteroaryl-,
19) -heterocyclyl-Y-heterocyclyl-,
wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted with one or more R 6 substituents, and the aryl, biphenyl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 10 substituents;
Q and Q 1 are independently
1) NR 4 R 5 ,
2) OR 11 , or
3) S(O) m R 11 ; or
Q and Q 1 are independently
1) aryl, or
2) heteroaryl, the aryl and the heteroaryl being optionally substituted with one or more
R 10 substituents;
A and A 1 are independently
1) —CH 2 —,
2) —CH 2 CH 2 —,
3) —CH(C 1 -C 6 alkyl)-,
4) —CH(C 3 -C 7 cycloalkyl)-,
5) —C 3 -C 7 cycloalkyl-,
6) —CH(C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl)-, or
7) —C(O)—;
R 1 and R 100 are independently
1) H, or
2) C 1 -C 6 alkyl optionally substituted with one or more R 6 substituents;
R 2 and R 200 are independently —CH 3 , —CH 2 CH 3 , or —CH 2 OH;
R 3 and R 300 are independently C 1 -C 6 alkyl optionally substituted with one or more R 6 substituents;
R 4 and R 5 are each independently
1) H,
2) haloalkyl,
3) C 1 -C 6 alkyl,
4) C 2 -C 6 alkenyl,
5) C 2 -C 4 alkynyl,
6) C 3 -C 7 cycloalkyl,
7) C 3 -C 7 cycloalkenyl,
8) aryl,
9) heteroaryl,
10) heterocyclyl,
11) heterobicyclyl,
12) C(O)—R 11 ,
13) C(O)O—R 11 ,
14) C(═Y)NR 8 R 9 , or
15) S(O) 2 —R 11 ,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R 10 substituents;
R 6 is
1) halogen,
2) NO 2 ,
3) CN,
4) haloalkyl,
5) C 1 -C 6 alkyl,
6) C 2 -C 6 alkenyl,
7) C 2 -C 4 alkynyl,
8) C 3 -C 7 cycloalkyl,
9) C 3 -C 7 cycloalkenyl,
10) aryl,
11) heteroaryl,
12) heterocyclyl,
13) heterobicyclyl,
14) OR 7 ,
15) S(O) m R 7 ,
16) NR 8 R 9 ,
17) NR 8 S(O) 2 R 11 ,
18) COR 7 ,
19) C(O)OR 7 ,
20) CONR 8 R 9 ,
21) S(O) 2 NR 8 R 9
22) OC(O)R 7 ,
23) OC(O)Y—R 11 ,
24) SC(O)R 7 , or
25) NC(Y)NR 8 R 9 ,
wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R 10 substituents;
R 7 is
1) H,
2) haloalkyl,
3) C 1 -C 6 alkyl,
4) C 2 -C 6 alkenyl,
5) C 2 -C 4 alkynyl,
6) C 3 -C 7 cycloalkyl,
7) C 3 -C 7 cycloalkenyl,
8) aryl,
9) heteroaryl,
10) heterocyclyl,
11) heterobicyclyl,
12) R 8 R 9 NC(═Y), or
13) C 1 -C 6 alkyl-C 2 -C 4 alkenyl, or
14) C 1 -C 6 alkyl-C 2 -C 4 alkynyl,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R 10 substituents;
R 8 and R 9 are independently
1) H,
2) haloalkyl,
3) C 1 -C 6 alkyl,
4) C 2 -C 6 alkenyl,
5) C 2 -C 4 alkynyl,
6) C 3 -C 7 cycloalkyl,
7) C 3 -C 7 cycloalkenyl,
8) aryl,
9) heteroaryl,
10) heterocyclyl,
11) heterobicyclyl,
12) C(O)R 11 ,
13) C(O)Y—R 11 , or
14) S(O) 2 —R 11 ,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R 10 substituents;
or R 8 and R 9 together with the nitrogen atom to which they are bonded form a five, six or seven membered heterocyclic ring optionally substituted with one or more R 6 substituents;
R 10 is
1) halogen,
2) NO 2 ,
3) CN,
4) B(OR 13 )(OR 14 ),
5) C 1 -C 6 alkyl,
6) C 2 -C 6 alkenyl,
7) C 2 -C 4 alkynyl,
8) C 3 -C 7 cycloalkyl,
9) C 3 -C 7 cycloalkenyl,
10) haloalkyl,
11) OR 7 ,
12) NR 8 R 9 ,
13) SR 7 ,
14) COR 7 ,
15) C(O)OR 7 ,
16) S(O) m R 7 ,
17) CONR 8 R 9 ,
18) S(O) 2 NR 8 R 9 ,
19) aryl,
20) heteroaryl,
21) heterocyclyl, or
22) heterobicyclyl,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R 6 substituents;
R 11 is
1) haloalkyl,
2) C 1 -C 6 alkyl,
3) C 2 -C 6 alkenyl,
4) C 2 -C 4 alkynyl,
5) C 3 -C 7 cycloalkyl,
6) C 3 -C 7 cycloalkenyl,
7) aryl,
8) heteroaryl,
9) heterocyclyl, or
10) heterobicyclyl,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R 1 ° substituents;
R 13 and R 14 are independently
1) H, or
2) C 1 -C 6 alkyl; or
R 13 and R 14 are combined to form a heterocyclic ring or a heterobicyclic ring;
whereby apoptosis in the cell is enhanced.
58 . The method of claim 57 , wherein the cell is a cancer cell.
59 . The method of claim 57 , wherein the cell is an immune cell.
60 . The method of claim 57 , wherein the cell is a neutrophil, monocyte, or T-cell.
61 . The method of claim 57 , wherein the cell is in a subject, and the cell is contacted with the compound of Formula I or salt thereof by administering the compound of Formula I or salt thereof to the subject.
62 . The method of claim 61 , further comprising administering to the subject a chemotherapeutic agent prior to, simultaneously with, or after administration of the compound of Formula I or salt thereof.
63 . The method of claim 61 , further comprising administering to the subject a death receptor agonist prior to, simultaneously with, or after administration of the compound of Formula I or salt thereof.
64 . The method of claim 63 , wherein the death receptor agonist is TRAIL.
65 . The method of claim 63 , wherein the death receptor agonist is a TRAIL receptor antibody.
66 . The method of claim 63 , in which the death receptor agonist is administered in an amount that produces a synergistic effect.
67 . The method of claim 61 , in which the subject is a human.
68 . The method of claim 67 , wherein the subject is afflicted with a proliferative disease.
69 . The method of claim 68 , wherein the proliferative disease is cancer.
70 . The method of claim 68 , wherein the proliferative disease is an autoimmune disease or inflammatory disorder.
71 . The method of claim 57 , wherein the compound is a pharmaceutically acceptable salt of Formula I.
72 . The method of claim 57 comprising administering a compound of any of Formulas 1a through 1c, or salt thereof:
73 . The method of claim 57 comprising administering a compound of any of Formulas 1.1 through 1.18, or salt thereof:
wherein r is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
74 . The method of claim 57 , wherein R 1 and R 100 are both CH 3 .
75 . The method of claim 57 , wherein R 3 and R 300 are both C(CH 3 ) 3 .
76 . The method of claim 57 , wherein A and A 1 are both C═O, and Q and
77 . The method of claim 57 , wherein A and A 1 are both CH 2 and Q and Q 1 are:
78 . The method of claim 57 , wherein
X and X 1 are independently
79 . The method of claim 78 , wherein L is:
and r is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
80 . The method of claim 57 , wherein Q and Q 1 are both NR 4 R 5 .
81 . The method of claim 57 , wherein A and A 1 are both CH 2 .
82 . The method of claim 57 , wherein A and A 1 are both C═O.
83 . The method of claim 57 , wherein A and A 1 are both C═O, and Q and Q 1 are both NR 4 R 5 , wherein R 4 is H and R 5 is
1) C 1 -C 6 alkyl, 2) C 2 -C 6 alkenyl, 3) C 2 -C 4 alkynyl, 4) C 3 -C 7 cycloalkyl, 5) C 3 -C 7 cycloalkenyl, 6) aryl, 7) heteroaryl, 8) heterocyclyl, or 9) heterobicyclyl,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R 10 substituents.
84 . The method of claim 57 , wherein A and A 1 are both CH 2 , and Q and Q 1 are both NR 4 R 5 , wherein R 4 and R 5 are each independently
1) haloalkyl, 2) C 1 -C 6 alkyl, 3) C 2 -C 6 alkenyl, 4) C 2 -C 4 alkynyl, 5) C 3 -C 7 cycloalkyl, 6) C 3 -C 7 cycloalkenyl, 7) aryl, 8) heteroaryl, 9) heterocyclyl, 10) heterobicyclyl, 11) C(O)—R 11 , 12) C(O)O—R 11 , 13) C(═Y)NR 8 R 9 , or 14) S(O) 2 —R 11 ,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R 6 substituents; and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R 10 substituents.
85 . The method of claim 81 , wherein Q and Q 1 are NR 4 R 5 .
86 . The method of claim 85 , wherein R 4 and R 5 are independently
1) H, 2) haloalkyl, 3) C 1 -C 6 alkyl, 4) C 2 -C 6 alkenyl, 5) C 2 -C 4 alkynyl, 6) C 3 -C 7 cycloalkyl, 7) C 3 -C 7 cycloalkenyl, 8) aryl, 9) heteroaryl, 10) heterocyclyl, 11) heterobicyclyl, 12) C(O)—R 11 , 13) C(O)O—R 11 , 14) C(═Y)NR 8 R 9 , or 15) S(O) 2 —R 11 ,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more R 6 substituents; and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl is optionally substituted with one or more R 10 substituents.
87 . The method of claim 86 , wherein R 4 and R 5 are independently
1) C 1 -C 6 alkyl, 2) C(O)—R 11 , 3) C(O)O—R 11 , or 5) S(O) 2 —R 11 ,
wherein the alkyl is substituted with one or more R 6 substituents.
88 . The method of claim 82 , wherein Q and Q 1 are NR 4 R 5 .
89 . The method of claim 88 , wherein R 4 is H and R 5 is
1) C 1 -C 6 alkyl, 2) C 2 -C 6 alkenyl, 3) C 2 -C 4 alkynyl, 4) C 3 -C 1 cycloalkyl, 5) C 3 -C 7 cycloalkenyl, 6) aryl, 7) heteroaryl, 8) heterocyclyl, or 9) heterobicyclyl,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more R 6 substituents; and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl is optionally substituted with one or more R 10 substituents.
90 . The method of claim 89 , wherein R 5 is C 1 -C 6 alkyl optionally substituted with one or more R 6 substituents or aryl optionally substituted with one or more R 10 substituents.
91 . The compound of claim 89 , wherein R 5 is:
wherein n is 0, 1, or 2 and X is O, S or SO 2 .
92 . The method of claim 88 , wherein Q and Q 1 are:
93 . The method of claim 57 , wherein the compound of Formula I or salt thereof is:
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or a salt thereof
94 . The method of claim 57 , wherein the compound is
or a salt thereof.
95 . The method of claim 57 , wherein the compound is
or a salt thereof.
96 . The method of claim 57 , wherein the compound is
or a salt thereof.
97 . The method of claim 57 , wherein the compound is
or a salt thereof.
98 . The method of claim 57 , wherein the compound is
or a salt thereof.
99 . The method of claim 57 , wherein the compound is
or a salt thereof.
100 . The method of claim 57 , wherein the compound is
or a salt thereof.
101 . The method of claim 57 , wherein the compound is
or a salt thereof.
102 . The method of claim 57 , wherein the compound is
or a salt thereof.
103 . The method of claim 57 , wherein the compound of Formula I or salt thereof is in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluents, or excipient.
104 . The method of claim 103 , wherein the pharmaceutical composition further comprises a compound that increases the circulating level of one or more death receptor agonists.Cited by (0)
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