US2014336222A1PendingUtilityA1
SUBSTITUTED PIPERIDINES THAT INCREASE p53 ACTIVITY AND THE USES THEREOF
Est. expiryOct 14, 2029(~3.3 yrs left)· nominal 20-yr term from priority
Inventors:Stephane L. BogenYao-Dong MaYaolin WangBrian Robert LahueLatha G. NairManami ShizukaMatthew E. VossMargarita Kirova-SnoverWeidong PanYuan TianBheemashankar A. KulkarniCraig R. GibeauYuan LiuGiovanna ScapinDiane RindgenRonald J. DollTimothy J. GuziDanny J. HicklinAmin NomeirCynthia Seidel-DuganGerald W. Shipps, Jr.Malcolm Maccoss
A61P 43/00A61P 37/02A61P 9/00A61P 35/02A61P 37/00A61P 35/00A61P 9/10A61P 31/04A61P 31/10A61P 37/06A61P 1/04A61P 19/02A61P 13/12A61P 17/06C07D 401/14C07D 409/14A61K 31/4436
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Claims
Abstract
The present invention provides a compound of Formula 1 as described herein or a pharmaceutically acceptable salt, solvate or ester thereof. The compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compositions comprising the above compounds and methods of treating cancer using the same.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method of treating cancer in a patient, comprising the step of administering an effective amount of a compound under Formula 1:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is:
wherein
E is either present or absent, and when present is selected from the group consisting of H, halo, OH, CN, —O(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl, —C(O)OH, —C(O)NR 8 R 8′ , —(C 1 -C 6 )alkyl-C(O)OH, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-C(O)NR 8 R 8′ , (C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, heterocyclyl, and heteroaryl;
each J independently is selected from the group consisting of H and halogen;
Y and R may or may not be present, when Y is present, it is selected from the group consisting of O, S, NR 8 , SO 2 , and CR 8 R 8′ ;
R when present is one or more moieties independently selected from the group consisting of —(C 1 -C 6 )alkyl, and —(CR 8 R 8′ ) n —C(O)OH;
G is present and is selected from the group consisting of —(CR 8 R 8′ ) n —C(O)OH, —(CR 8 R 8′ ) n —C(O)NR 8 R 9 , —(CR 8 R 8′ ) n —(C 3 -C 8 )Cycloalkyl-C(O)NR 8 R 9 , —(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OH, —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OH, —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —C(O)OH, —(CR 8 R 8′ ) n —S—(CR 8 R 8′ ) n —C(O)OH, C(O)OH, —(CR 8 R 8′ ) n —NH—(CR 8 R 8′ ) n —C(O)OH, —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —CH 3 , —(CR 8 R 8′ ) n —S—(CR 8 R 8′ ) n —CH 3 , —(CR 8 R 8′ ) n —NH—(CR 8 R 8′ ) n —CH 3 , —(CR 8 R 8′ ) n —CH 3 , —(CR 8 R 8′ ) n -heteroaryl, —(CR 8 R 8′ ) n —P(O)OR 8 OR 8′ , and —(CR 8 R 8′ ) n —OH;
each R 8 and R 8′ is independently selected from the group consisting of H, D, and (C 1 -C 6 )alkyl; or wherein R 8 and R 8′ together with the carbon to which each is attached form (C 3 -C 8 )cycloalkyl;
each R 9 independently is SO 2 (C 1 -C 6 )alkyl or SO 2 (C 3 -C 8 )cycloalkyl;
each n independently is 0-10; provided that when n is 0, any oxygen, nitrogen or sulfur atom of Y is not directly linked to any oxygen, nitrogen, sulfur or phosphorus atom of G;
represents a single or a double bond, provided that when E is present, represents a single bond;
R 2 is
R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 7 , and R 7′ independently are selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl; and
X is
2 . The method of claim 1 , wherein said —(CR 8 R 8′ ) n —C(O)OH is selected from the group consisting of —(CH 2 ) 1-5 C(O)OH, —CH(CH 3 )—(CH 2 ) 2-3 —C(O)OH, —(CH 2 ) 1-3 C(CH 3 ) 2 C(O)OH, —(CH 2 ) 3 CH(CH(CH 3 ) 2 )—C(O)OH, —(CD 2 ) 3 C(O)OH, —(CH 2 ) 1-2 —CH(CH 3 )—(CH 2 ) 1-2 —C(O)OH, CH(CH 3 )—(CH 2 ) 2-3 —C(O)OH,
wherein said —(CR 8 R 8′ ) n —C(O)NR 8 R 9 is —(CH 2 ) 1-4 —C(O)NH—S(O) 2 CH 3 or —(CH 2 ) 3-4 —C(O)NH—S(O) 2 -cyclopropyl; said —(CR 8 R 8′ ) n —(C 3 -C 8 )Cycloalkyl-C(O)NR 8 R 9 is -cyclopentyl-C(O)NH—S(O) 2 —CH 3 or
said —(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OH is selected from the group consisting of —CH 2 -cyclopentyl-C(O)OH, -cyclobutyl-C(O)OH, -cyclopentyl-C(O)OH, -cyclohexyl-C(O)OH, and -cyclopentyl-CH 2 —C(O)OH; said —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OH is —O-cyclopentyl-C(O)OH or —O-cyclobutyl-C(O)OH; said —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —C(O)OH is selected from the group consisting of —CH 2 —O—(CH 2 ) 3 —C(O)OH, —O—(CH 2 ) 2 —C(CH 3 ) 2 —C(O)OH, and —O—(CH 2 ) 3 —C(O)OH; said —(CR 8 R 8′ ) n —NH—(CR 8 R 8′ ) n —C(O)OH is —NH(CH 2 ) 3 C(O)OH; said —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —CH 3 is —(CH 2 ) 2 —O—CH 3 ; said —(CR 8 R 8′ ) n —CH 3 is —CH 3 ; said —(CR 8 R 8′ ) n -heteroaryl is —(CH 2 ) 2 -(alkyl substituted pyrazolyl); said —(CR 8 R 8′ ) n —P(O)OR 8 OR 8′ is —(CH 2 ) 3 P(O)(OH)(OH) or —(CH 2 ) 3 P(O)(OCH 3 )(OCH 3 ); and said —(CR 8 R 8′ ) n —OH is —(CH 2 ) 2 —OH.
3 . The method of claim 1 , wherein R 4 is hydrogen and R 4′ is 1-propyl, such that Formula 1 is represented by Formula 1A:
wherein R 1 , R 2 , R 5 , R 5′ , R 6 , R 6′ , R 7 , R 7′ , and X are as set forth in Formula 1.
4 . The method of claim 3 , wherein R 5 , R 5′ , R 6 , R 6′ , R 7 , and R 7′ are all hydrogen.
5 . The method of claim 4 , wherein:
R 1 is
R 2 is
and
either (i) each J in R 1 is H, or (ii) one J in R 1 is halo, and the remaining three Js are H.
6 . The method of claim 4 , wherein:
R 1 is
R 2 is
and
each J in R 1 is H.
7 . The method of claim 5 , wherein E is CN or OH, each J in R 1 is H, Y is O, and G is —(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OH.
8 . The method of claim 5 , wherein E is CN or OH, each J in R 1 is H, Y is O, and G is selected from the group consisting of
—CH 2 -cyclopentyl-C(O)OH, -cyclobutyl-C(O)OH, -cyclopentyl-C(O)OH, -cyclohexyl-C(O)OH, and -cyclopentyl-CH 2 —C(O)OH.
9 . The method of claim 5 , wherein E is CN or OH, each J in R 1 is H, Y is O, and G is selected from the group consisting of —CH(CH 3 )—(CH 2 ) 2-3 —C(O)OH, —(CH 2 ) 3 CH(CH(CH 3 ) 2 )—C(O)OH, —(CD 2 ) 3 C(O)OH, —(CH 2 ) 1-2 —CH(CH 3 )—(CH 2 ) 1-2 —C(O)OH, and —CH(CH 3 )—(CH 2 ) 2-3 —C(O)OH.
10 . The method of claim 5 , wherein G is selected from the group consisting of —(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OH and —(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —(C 3 -C 8 )cycloalkyl-(CR 8 R 8′ ) n —C(O)OH.
11 . The method of claim 5 , wherein G is —(CR 8 R 8′ ) n —P(O)OR 8 OR 8′ or —(CR 8 R 8′ ) n —S—(CR 8 R 8′ ) n —C(O)OH.
12 . The method of claim 1 , wherein R 1 is
E is present, G is present and is selected from the group consisting of —(CR 8 R 8′ ) n —C(O)OH, wherein n is 3, 4, 5 or 6, —CH(CH 3 )—(CH 2 ) 2-3 —C(O)OH, —(CH 2 ) 3 CH(CH(CH 3 ) 2 )—C(O)OH, —(CD 2 ) 3 C(O)OH, —(CH 2 ) 1-2 —CH(CH 3 )—(CH 2 ) 1-2 —C(O)OH,
—(CR 8 R 8′ ) n —O—(CR 8 R 8′ ) n —C(O)OH, wherein the first n is 0 or 1, and the second n is 3, —CH 2 —O—(CH 2 ) 3 —C(O)OH, —O—(CH 2 ) 2 —C(CH 3 ) 2 —C(O)OH, and —O—(CH 2 ) 3 —C(O)OH.
13 . The method of claim 1 , wherein G is present and is selected from the group consisting of —(CH 2 ) 0-4 CH((C 1 -C 6 )alkyl)-(CH 2 ) 1-5 —C(O)OH, —(CH 2 ) 1-5 —CH((C 1 -C 6 )alkyl)-C(O)OH, —(CH 2 ) 0-5 —(C 3 -C 8 )cycloalkyl-C(O)OH, —(CH 2 ) 0-5 —(C 3 -C 8 )cycloalkyl-(CH 2 ) 1-6 —C(O)OH,
14 . A method of treating cancer in a patient, comprising the step of administering an effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15 . The method of claim 14 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
16 . The method of claim 14 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
17 . The method of claim 14 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
18 . The method of claim 14 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
19 . The method of claim 14 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
20 . The method of claim 1 , wherein the cancer is selected from the group consisting of lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, melanoma, sarcoma, liposarcoma, glioblastoma, colorectal cancer and cancer of the breast, stomach, prostate, endometrium, kidney, colon, ovary or lung.Cited by (0)
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