US2006019988A1PendingUtilityA1
Compounds, compositions, and methods
Est. expiryJun 14, 2022(expired)· nominal 20-yr term from priority
Inventors:Andrew McdonaldPu-Ping LuGustave BergnesDavid J. Morgans, Jr.Dashyant DhanakSteven David Knight
A61P 43/00A61P 37/00A61P 35/00A61P 9/00C07D 217/24C07D 401/06A61P 29/00
51
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Claims
Abstract
Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of KSP are disclosed.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting KSP kinesin activity which comprises contacting said kinesin with an effective amount of a compound having the structure represented by Formula I:
wherein:
R 1 is chosen from optionally substituted phenyl-C 1 -C 4 -alkyl-, optionally substituted heteroaryl-C 1 -C 4 -alkyl-, and naphthalenylmethyl-;
R 2 and R 2′ are independently chosen from hydrogen, optionally substituted alkyl-, optionally substituted alkoxy, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heteroaryl-, and optionally substituted heteroaralkyl-; or R 2 and R 2′ taken together form an optionally substituted 3- to 7-membered ring;
R 12 is selected from the group consisting of optionally substituted imidazolyl-, optionally substituted imidazolinyl-, —NHR 4 ; —N(R 4 )(COR 3 ); —N(R 4 )(SO 2 R 3a ); and —N(R 4 )(CH 2 R 3b );
R 3 is chosen from hydrogen, optionally substituted alkyl-, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heteroaryl-, optionally substituted heteroaralkyl-, R 15 O— and R 17 —NH—;
R 3a is chosen from optionally substituted alkyl-, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heteroaryl-, optionally substituted heteroaralkyl-, and R 17 —NH—;
R 3b is chosen from hydrogen, optionally substituted alkyl-, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heteroaryl-, and optionally substituted heteroaralkyl-;
R 4 is chosen from hydrogen, optionally substituted alkyl-, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heterocyclyl-, and optionally substituted heteroaralkyl-;
R 5 , R 6 , R 7 and R 8 are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halogen, hydroxyl, nitro, cyano, dialkylamino, alkylsulfonyl, alkylsulfonamido, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, optionally substituted aryl and optionally substituted heteroaryl;
R 15 is optionally substituted alkyl-, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heteroaryl-, or optionally substituted heteroaralkyl-; and
R 17 is chosen from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
a pharmaceutically acceptable salt of a compound of Formula I;
a pharmaceutically acceptable solvate of a compound of Formula I;
or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of a compound of Formula I.
2 - 5 . (canceled)
6 . A method according to claim 1 , wherein R 1 is benzyl.
7 . A method according to claim 1 , wherein R 2 and R 2′ are independently chosen from hydrogen, optionally substituted alkyl-, optionally substituted alkoxy, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heteroaryl-, and optionally substituted heteroaralkyl-; or R 2 and R 2′ taken together form an optionally substituted 3- to 7-membered ring.
8 . A method according to claim 7 , wherein R 2 is optionally substituted C 1 -C 4 alkyl-, and R 2′ is hydrogen or optionally substituted C 1 -C 4 alkyl-.
9 . A method according to claim 8 , wherein R 2′ is hydrogen and R 2 is optionally substituted C 1 -C 4 alkyl-.
10 . A method according to claim 9 , wherein R 2′ is hydrogen and R 2 is ethyl or propyl.
11 . A method according to claim 10 , wherein R 2 is i-propyl.
12 . A method according to claim 1 , wherein if either R 2 or R 2′ is hydrogen, then the other is not hydrogen.
13 . A method according to claim 1 , wherein R 5 , R 6 , R 7 , and R 8 are independently chosen from hydrogen, hydroxyl, halogen, optionally substituted C 1 -C 4 alkyl-, C 1 -C 4 alkoxy, cyano, amino, substituted amino, or carbamyl-.
14 . A method according to claim 13 , wherein R 5 , R 6 , R 7 , and R 8 are independently methoxy, methyl, trifluoromethyl, cyano, hydrogen or halo.
15 . A method according to claim 14 , wherein only one of R 5 , R 6 , R 7 , and R 8 is not hydrogen.
16 . A method according to claim 1 , wherein R 12 is an optionally substituted imidazolyl- having the formula:
wherein
R 9 is chosen from hydrogen, optionally substituted C 1 -C 8 alkyl-, optionally substituted aryl-, optionally substituted aryl-C 1 -C 4 -alkyl-, optionally substituted heteroaryl-C 1 -C 4 -alkyl-, optionally substituted aryl-C 1 -C 4 -alkoxy, optionally substituted heteroaryl-C 1 -C 4 -alkoxy, and optionally substituted heteroaryl-; and
R 13 and R 13′ are independently hydrogen, optionally substituted C 1 -C 8 alkyl-, optionally substituted aryl-, or optionally substituted aryl-C 1 -C 4 -alkyl-.
17 . A method according to claim 16 , wherein R 9 is lower-alkyl; phenyl-; or phenyl- substituted with one or more of the following groups: methyl, methoxy, trifluoromethyl, or halo.
18 . A method according to claim 16 , wherein R 13 is hydrogen and R 13′ is optionally substituted substituted C 1 -C 4 alkyl-.
19 . A method according to claim 1 , wherein R 12 is an optionally substituted imidazoline having the formula
wherein,
R 14 is chosen from hydrogen, optionally substituted C 1 -C 8 alkyl-, optionally substituted aryl-, optionally substituted aryl-C 1 -C 4 -alkyl-, optionally substituted heteroaryl-, optionally substituted heteroaryl-C 1 -C 4 -alkyl-; and
R 10 , R 10′ , R 11 and R 11′ are independently chosen from hydrogen, optionally substituted C 1 -C 8 alkyl-, optionally substituted aryl-, and optionally substituted aryl-C 1 -C 4 -alkyl-.
20 . A method according to claim 19 , wherein R 10 , R 10′ , R 11′ , and R 11 are independently hydrogen or optionally substituted C 1 -C 4 alkyl-.
21 . A method according to claim 1 wherein R 12 is —NHR 4, —NR 4 (COR 3 ), NR 4 (SO 2 R 3a ), or —NR 4 (CH 2 R 3b ) and R 4 is R 16 -alkylene-, and R 16 is chosen from alkoxy, amino, alkylamino, dialkylamino, carboxy, guanidine, hydroxyl-, and N-heterocyclyl-.
22 . A method according to claim 1 wherein R 12 is —NR 4 (COR 3 ) and R 3 is selected from hydrogen, optionally substituted alkyl-, optionally substituted aralkyl-, optionally substituted heteroaralkyl-, optionally substituted heteroaryl-, optionally substituted aryl-, R 15 O— and R 17 —NH—, wherein R 15 is chosen from optionally substituted alkyl and optionally substituted aryl and R 17 is chosen from hydrogen, optionally substituted alkyl and optionally substituted aryl-.
23 . A method according to claim 22 wherein R 12 is —NR 4 (COR 3 ) and R 3 is tolyl-, halophenyl-, halomethylphenyl-, hydroxymethylphenyl-, methylenedioxyphenyl-, formylphenyl or cyanophenyl-.
24 . A method according to claim 21 wherein R 3a is chosen from C 1 -C 13 alkyl-; phenyl-; naphthyl-; phenyl substituted with cyano, halo, lower-alkyl-, lower-alkoxy, nitro, methylenedioxy, or trifluoromethyl-; biphenylyl and heteroaryl-.
25 . A method according to claim 21 wherein R 3b is chosen from C 1 -C 13 alkyl-; substituted lower-alkyl-; phenyl-; naphthyl-; phenyl substituted with cyano, halo, lower-alkyl-, lower-alkoxy, nitro, methylenedioxy, or trifluoromethyl-; biphenylyl-, benzyl and heterocyclyl-.
26 . A method according to claim 1 wherein,
R 1 is optionally substituted aryl-C 1 -C 4 -alkyl-, optionally substituted heteroaryl-C 1 -C 4 -alkyl-, or naphthalenylmethyl R 2 is optionally substituted C 1 -C 4 -alkyl-; R 2′ is hydrogen; R 7 is hydrogen, methyl, or cyano; R 5 , R 6 , and R 8 are hydrogen; and R 12 is optionally substituted imidazolyl-, optionally substituted imidazolinyl-, —NHR 4 ; —N(R 4 )(COR 3 ); —N(R 4 )(SO 2 R 3a ); and —N(R 4 )(CH 2 R 3b ).
27 . A method according to claim 26 wherein R 12 is optionally substituted imidazolyl- having the formula:
wherein
R 9 is lower-alkyl; phenyl-; or phenyl- substituted with one or more of the following groups: methyl, methoxy, trifluoromethyl, or halo;
R 13 is hydrogen; and
R 13′ is substituted C 1 -C 4 alkyl-.
28 . A method according to claim 26 wherein R 12 is optionally substituted imidazolinyl- having the formula:
wherein
R 14 is lower-alkyl; phenyl-; or phenyl- substituted with one or more of the following groups: methyl, methoxy, trifluoromethyl, or halo; and
R 10 , R 10′ , R 11′ , and R 11 are independently hydrogen or optionally substituted C 1 -C 4 alkyl-.
29 . A method according to claim 26 wherein R 12 is —NHR 4 ; and
R 4 is chosen from hydrogen, optionally substituted alkyl-, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heteroaralkyl-, and optionally substituted heterocyclyl-.
30 . A method according to claim 26 wherein R 3 is selected from hydrogen, optionally substituted alkyl-, optionally substituted aralkyl-, optionally substituted heteroaralkyl-, optionally substituted heteroaryl-, optionally substituted aryl-, R 15 O— and R 17 —NH—, wherein R 15 is chosen from optionally substituted alkyl and optionally substituted aryl and R 17 is chosen from hydrogen, optionally substituted alkyl and optionally substituted aryl.
31 . A method according to claim 30 wherein R 4 is is R 16 -alkylene-, and R 16 is chosen from alkoxy, amino, alkylamino, dialkylamino, carboxy, hydroxyl-, and N-heterocyclyl-.
32 . A method according to claim 31 , wherein
R 4 is chosen from hydrogen, optionally substituted alkyl-, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heteroaralkyl-, and optionally substituted heterocyclyl- and R 3 is selected from optionally substituted alkyl-; aryl-; substituted aryl-; benzyl-; and optionally substituted heteroaryl-.
33 . A method according to claim 32 , wherein R 3 is tolyl-, halophenyl-, halomethylphenyl-, hydroxymethylphenyl-, methylenedioxyphenyl-, formylphenyl or cyanophenyl-.
34 . A method according to claim 26 , wherein R 12 is —N(R 4 )(CH 2 R 3b );
R 4 is chosen from hydrogen, optionally substituted alkyl-, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heteroaralkyl-, and optionally substituted heterocyclyl- and R 3b is chosen from phenyl substituted with one or more halo, methyl-, cyano, trifluoromethyl-, trifluoromethoxy, carboxy, or methoxycarbonyl groups; piperidinyl-; and naphthyl-.
35 . A method according to claim 1 , wherein R 12 is —NR 4 (SO 2 R 3a );
R 4 is chosen from hydrogen, optionally substituted alkyl-, optionally substituted aryl-, optionally substituted aralkyl-, optionally substituted heteroaralkyl-, and optionally substituted heterocyclyl- and R 3a is chosen from phenyl substituted with halo, lower-alkyl-, lower-alkoxy, cyano, nitro, methlenedixoy, or trifluoromethyl-; and naphthyl-.
36 . A method according to claim 1 , wherein R 2 and R 2′ are each attached to a stereogenic center having an R-configuration.
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