US2011305777A1PendingUtilityA1
Dimeric iap antagonists
Est. expiryJul 24, 2026(~0 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 43/00C07K 5/06191C07K 5/06026C07K 5/06034A61K 38/00C07K 5/06A61K 31/40Y02A50/30
46
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Claims
Abstract
Smac mimetics that inhibit IAPs.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
Wherein
Z 1 a, Z 2 a, Z 1 b, and Z 2 b are independently CH or N;
R 1 a and R 1 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 2 a, R 2 a′, R 2 b and R 2 b′ are independently H or optionally substituted alkyl, cycloalkyl, or heterocycloalkyl; or when R 2 a′ is H then R 2 a and R 1 a can together form an aziridine or azetidine ring and when R 2 b′ is H then R 2 b and R 1 b can together form an aziridine or azetidine ring;
R 3 a, R 3 b, R 4 a and R 4 b are independently H or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or, R 4 a and R 3 a, or R 4 b and R 3 b, or both, are carbon atoms linked by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O
R 5 a, R 6 a, R 5 b, and R 6 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R 5 a and R 6 a or R 5 b and R 6 b, or both, are carbon atoms linked by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O;
R 7 a, R 7 b, R 8 a, R 8 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R 7 a and R 8 a, or R 7 b and R 8 b, or both, can be linked by an optionally-substituted alkylene or alkenylene group of 3 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O;
each n can be the same or different and is 0, 1, or 2;
Xa is —O—, —N(La—R 10 a)-, —S—, optionally-substituted —C(La—R 10 a)=CH—, —C(O)—O—, —C(O)—N(La—R 10 a)-, —N═C(La—R 10 a)-;
Xb is —O—, —N(Lb-R 10 b)-, —S—, optionally-substituted —C(Lb-R 10 b)=CH—, —C(O)—O—, —C(O)—N(Lb-R 10 b)-, —N═C(Lb-R 10 b)-;
La and Lb are independently a covalent bond or C 1 -C 4 alkylene;
Wa, Wb, R 10 a, and R 10 b are defined in paragraphs (a) through (e), which follow:
(a) when Wa and Wb together are a Linker, then Xa or Xb are independently —O—, —S—, or —C(O)—O—; R 10 a and R 10 b, respectively, are absent; or
(b) when Wa and Wb together are a Linker; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, —N═C(La—R 10 a)-, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—, —N═C(Lb-R 10 b)-, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b are independently H or optionally substituted hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or
(c) when Wa and Wb together are a Linker; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, —N═C(La—R 10 a)-, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—, —N═C(Lb-R 10 b)-, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b together are a Linker; or
(d) when Wa and Wb are not covalently bound, Wa and Wb are independently H, Cl, Br, F, CN, COOH, or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, —N═C(La—R 10 a)-, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—, —N═C(Lb-R 10 b)-, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b together are a Linker; or
(e) when Wa and Wb are not covalently bound, Wa is H, Cl, Br, F, CN, COOH, or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, —N═C(La—R 10 a)-, or —C(O)—N(La—R 10 a)-; Xb is —O—, —N(Lb-R 10 b)-, —S—, —C(Lb-R 10 b)=CH—, —C(O)—O—, —N═C(Lb-R 10 b)-, —C(O)—N(Lb-R 10 b)-; and R 10 b is absent or is H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and Wb and LaR10a together are a Linker;
or a pharmaceutically acceptable salt thereof;
provided that
when Z 1 a is N and Z 2 a is CH, and Z 1 b is N and Z 2 b is CH, then at least one of the following is true:
(i) R 5 a and R 6 a are not both carbon atoms linked by a single covalent bond;
(ii) R 5 a and R 6 a are both carbon atoms linked by a single covalent bond and R 5 a is disubstituted;
(iii) R 5 a and R 6 a are both carbon atoms linked by a single covalent bond and R 6 a is mono- or disubstituted;
(iv) R 5 a and R 6 a are both carbon atoms linked by a single covalent bond and R 3 a and R 4 a are both carbon atoms linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O.
(v) R 5 a and R 6 a are both carbon atoms linked by a single covalent bond and neither R 2 a nor R 2 a′ are H.
2 . The compound of claim 1 , wherein R 3 a, R 4 a, R 3 b, and R 4 b are independently H, methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally-substituted with hydroxyl, mercapto, sulfonyl, alkylsulfonyl, halogen, pseudohalogen, amino, carboxyl, alkyl, haloalky, pseudohaloalkyl, alkoxy, or alkylthio.
3 . The compound of claim 1 wherein R 2 a and R 2 b are independently —H, methyl, fluoromethyl, difluoromethyl, ethyl, fluoroethyl, hydroxyethyl, or cycloalkyl.
4 . The compound of claim 1 wherein R 1 a and R 1 b are independently H, methyl, allyl, propargyl, ethyl, hydroxyethyl, cycloalkyl, or cycloalkylmethyl.
5 . The compound of claim 1 wherein R 3 a, R 4 a, R 3 b, and R 4 b are independently optionally substituted lower alkyl or C 3 -C 8 cycloalkyl wherein the optional substituents are hydroxy or lower alkoxy.
6 . The compound of claim 1 wherein Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; and Xa and Xb are independently —O—, —S—, or —C(O)—O—.
7 . The compound of claim 1 wherein Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
8 . The compound of claim 1 wherein Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-,—C(Lb-R 10 b)=CH—, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b together are an optionally-substituted alkylene, cycloalkyl, or aryl of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n .
9 . The compound of claim 1 wherein Wa and Wb are not covalently bound, and Wa and Wb are independently H, Cl, Br, F, CN, COOH, or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-,—C(Lb-R 10 b)=CH—, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b together are an optionally-substituted alkylene, cycloalkyl, or aryl of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n .
10 . The compound of claim 1 wherein Wa and Wb are not covalently bound, Wa is H, Cl, Br, F, CN, COOH, or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —O—, —N(Lb-R 10 b)-, —S—,—C(Lb-R 10 b)=CH—, —C(O)—O—, —C(O)—N(Lb-R 10 b)-; and R 10 b is H or optionally-substituted alkyl; and Wb and R 10 a together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n .
11 . The compound of claim 1 wherein Wa and Wb are not covalently bound, Wb is H, Cl, Br, F, CN, COOH, or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—, or —C(O)—N(Lb-R 10 b)-; Xa is —O—, —N(La—R 10 a)-, —S—, —C(La—R 10 a)=CH—, —C(O)—O—, —C(O)—N(La—R 10 a)-; and R 10 a is H or optionally-substituted alkyl; and Wa and R 10 b together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n .
12 . The compound of claim 1 wherein Z 1 a and Z 1 b are both N and Z 2 a and Z 2 b are both C and wherein R 5 a and R 6 a, and R 5 b and R 6 b, are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O.
13 . The compound of 1 wherein Z 1 a and Z 1 b are both N and Z 2 a and Z 2 b are both C and wherein R 3 a and R 4 a, and R 3 b and R 4 b, are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O.
14 . The compound of claim 1 wherein R 10 a and R 10 b are not heterocycloalkyl or heteroaryl.
15 . The compound of claim 1 having formula (II):
wherein
Xa is —N—, —C═C(R 16 a)-, —N═C— or —C(O)N—;
Xb is —N—, —C═C(R 16 b)-, —N═C— or —C(O)N—;
La and Lb are independently a covalent bond or C 1 -C 4 alkylene;
Ya is —C—, —N—, or —N + —; such that,
When Ya is —C— then R 10 a, R 11 a, R 12 a, R 13 a, R 14 a, R 15 a, and R 16 a are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime; provided that when Xa is —N— or —C(O)—N—, -L 1 -R 10 a is bound to the —N— atom; and, when Xa is —C═C(R 16 a)- or —N═C—, -L 1 -R 10 a is bound to the —C═ atom; and
When Ya is —N— or —N + —, then R11a is absent or —O—, and R 10 a, R 11a , R 13 a, R 14 a, R 15 a, and R 16 a are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime; provided that when X is —N— or —C(O)—N—, -L 1 -R 10a is bound to the —N— atom; and, when X is —C═C(R 16 a)- or —N═C—, -L 1 -R 10 a is bound to the —C═ atom;
Yb is —C—, —N—, or —N + —; such that,
When Yb is —C— then R 10 b, R 11 b, R 12 b, R 13 b, R 14 b, R 15 b, and R 16 b are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime; provided that when Xb is —N— or —C(O)—N—, -L 1 -R 10 b is bound to the —N— atom; and, when Xb is —C═C(R 16 b)- or —N═C—, -L 1 -R 10 b is bound to the —C═ atom; and
When Yb is —N— or —N + —, then R 11 b is absent or —O—, and R 10 b, R 12 b, R 13 b, R 14 b, R 15 b, and R 16 b are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime; provided that when Xb is —N— or —C(O)—N—, -L 1 -R 10 b is bound to the —N— atom; and, when Xb is —C═C(R 16 b)- or —N═C—, -L 1 -R 10 b is bound to the —C═ atom.
16 . The compound of claim 15 wherein Z 1 a and Z 1 b are both N and Z 2 a and Z 2 b are both C and wherein (i) R 5 a and R 6 a, and R 5 b and R 6 b, are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O or (ii) R 3 a and R 4 a, and R 3 b and R 4 b, are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O or (iii) both (i) and (ii) are true.
17 . The compound of claim 15 wherein R 3 a and R 4 a, and R 3 b and R 4 b, are carbon atoms and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 3 carbon atoms of which one or more can be replaced by N, O, S(O) n , or C═O
18 . The compound of claim 15 wherein
R 4 a and R 3 a or R 4 b and R 3 b, or both, are linked by an alkylene or alkenylene group of 1 to 3 atoms;
R 2 a and R 2 b are independently selected from methyl, fluoromethyl, difluoromethyl, ethyl, fluoroethyl, and cycloalkyl;
Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; and Xa and Xb are independently —O—, —S—, or —C(O)—O—; or
Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; Xa is —N(La—R 10 a)-, —C(La—R 10 a)=CH—, or —C(O)—N(La—R 10 a)-; Xb is —N(Lb-R 10 b)-, —C(Lb-R 10 b)=CH—, or —C(O)—N(Lb-R 10 b)-; R 10 a and R 10 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or, heteroaryl.
19 . The compound of claim 15 wherein R 10 a and R 10 b are not optionally substituted 5-, 6-, or 7-membered heterocycloalkyl or heteroaryl.
20 . The compound of claim 1 having formula (IV), or a pharmaceutically acceptable salt thereof:
wherein —La—R 10 a-Wb- is a covalent bond.
21 . The compound of claim 1 that is selected from compounds A through N, as follows:
R13a/
R12a/
R11a/
Compound
R1a
R2a
R3a
R17a
R17b
R3b
R2b
R1b
R13b
R12b
R11b
A
Me
S—Me
S—(2R—
S—OH
S—OH
S—(2R—
S—Me
Me
H
F
H
MeCHOMe)
MeCHOMe)
B
Me
S—CH 2 OH
S—(2R—
S—OH
S—OH
S—(2R—
S—CH 2 OH
Me
H
F
H
MeCHOMe)
MeCHOMe)
C
Me
S—Me
S—tBu
S—OH
S—OH
S—tBu
S—Me
Me
H
F
H
D
Me
S—Et
S—tBu
S—OH
S—OH
S—tBu
S—Et
Me
H
F
H
E
Et
S—Me
S—(2R—
S—OH
S—OH
S—(2R—
S—Me
Et
H
F
H
MeCHOMe)
MeCHOMe)
F
Me
S—Et
S—(2R—
S—OH
S—OH
S—(2R—
S—Et
Me
H
F
H
MeCHOMe)
MeCHOMe)
G
Me
S—Me
S—(2R—
S—OMe
S—OMe
S—(2R—
S—Me
Me
H
F
H
MeCHOMe)
MeCHOMe)
H
Me
S—Et
S—(2R—
S—OMe
S—OMe
S—(2R—
S—Et
Me
H
F
H
MeCHOMe)
MeCHOMe)
I
Me
S—Me
S—tBu
S—OMe
S—OMe
S—tBu
S—Me
Me
H
F
H
J
Me
S—Et
S—tBu
S—OMe
S—OMe
S—tBu
S—Et
Me
H
F
H
K
Et
S—Me
S—(2R—
S—OMe
S—OMe
S—(2R—
S—Me
Et
H
F
H
MeCHOMe)
MeCHOMe)
L
Et
S—Me
S—tBu
S—OMe
S—OMe
S—tBu
S—Me
Et
H
F
H
M
Me
S—Me
S—(2R—
S—Me
S—Me
S—(2R—
S—Me
Me
H
F
H
MeCHOMe)
MeCHOMe)
R1a/
R2a/
R3a/
R17a/
R12a/
Compound
R1b
R2b
R3b
R17b
R12b
N
Me
Me
R—
(S)—OH
6-F
(Me)CHOMe
22 . The compound of claim 1 having the formula
wherein R 1 a, R 1 b, R 2 a, R 2 b, R 3 a, and R 3 b are independently lower alkyl, lower alkoxy, lower alkanol, or C 3 -C 6 cycloalkyl; R 17 a and R 17 b are independently —OH, lower alkoxy or lower alkyl; R 11 a, R 11 b, R 12 a, R 12 b, R 13 a, R 13 b, R 14 a, and R 14 b are independently —H or halogen.
23 . The compound of claim 1 having the formula
wherein R 1 a, R 1 b, R 2 a, R 2 b, R 3 a, and R 3 b are independently lower alkyl, lower alkoxy, lower alkanol, or C 3 -C 6 cycloalkyl; R 17 a and R 17 b are independently —OH, lower alkoxy or lower alkyl; R 12 a and R 12 b are independently —H or halogen.
24 . A method for inducing apoptosis in a cell comprising contacting the cell with a compound of claim 1 in an amount sufficient to induce apoptosis in the cell.
25 . The method of claim 24 , wherein said cell is neoplastic.
26 . The method of claim 24 , wherein said cell overexpresses an inhibitor of caspase.
27 . The method of claim 24 , wherein the inhibitor inhibits activation or activity of one or more of a caspase selected from caspase-3, caspase-7 and caspase-9.
28 . A method of stimulating apoptosis in a cell comprising contacting the cell with a compound of claim 1 in an amount sufficient to stimulate apoptosis in the cell.
29 . The method of claim 28 , wherein said cells are cancer cells.
30 . A method of enhancing apoptosis of pathogenic cells in vivo in an individual comprising administering to the individual a therapeutically effective amount of a compound of claim 1 .
31 . The method of claim 30 further comprising administering a second therapy selected from radiation, chemotherapy, immunotherapy, photodynamic therapy and combinations thereof.
32 . A method of treating a disease associated with the overexpression of IAP in an individual comprising administering to said individual an effective amount of a compound of claim 1 .
33 . A method of treating cancer comprising administering a therapeutically effective amount of a compound of claim 1 .
34 . A pharmaceutical composition comprising: a compound selected from a compound of claim 1 and a pharmaceutically acceptable excipient.
35 . The composition of claim 34 further comprising a second chemotherapeutic agent.
36 . The composition of claim 34 , wherein said second chemotherapeutic agent is selected from alkylating agents, plant alkaloids, antitumor antibiotics, antimetabolites, topoisomerase inhibitors and combinations thereof.
37 . The composition of claim 36 , wherein said chemotherapeutic agent is selected from altretamine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphomide, dacarbazine, hexamethylmelamine, ifosfamide, lomustine, melphalan, mechlorethamine, oxaliplatin, procarbazine, streptozocin, temozolomide, thiotepa, uramustine, docetaxel, etoposide, irinotecan, paclitaxel, tenisopide, topotecan, vincristine, vinblastine, vindesine, vinorelbine, bleomycin, dactinomycin, daunorubicin, epirubicin, hydroxyurea, idarubicin, mitomycin, mitoxantrone, plicamycin, azathioprine, capecitabine, cladribine, cytarabine, fludarabine, fluorouracil, floxuridine, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pentostatin, thioguanine, camptothecan, irinotecan, topotecan, BNP 1350, SN 38, 9-amino-camptothecan, lurtotecan, gimatecan, diflomotecan, an anthracycline, anthraquinone, podophyllotoxin, doxorubicin, epirubicin, idarubicin, nemorubicin, mitoxantrone, loxoxantrone, etoposide, teniposide and combinations thereof.Cited by (0)
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