US2005124604A1PendingUtilityA1
Substituted naphthyridine derivatives as inhibitors of macrophage migration inhibitory factor and their use in the treatment of human diseases
Priority: Aug 22, 2003Filed: Aug 17, 2004Published: Jun 9, 2005
Est. expiryAug 22, 2023(expired)· nominal 20-yr term from priority
A61P 37/02A61P 3/10A61P 7/00A61P 9/00A61P 37/06A61P 43/00A61P 37/00A61P 7/06A61P 9/14A61P 9/04A61P 9/10A61P 3/04A61P 25/16A61P 29/00A61P 31/12A61P 25/00A61P 29/02A61P 25/28A61P 35/00A61P 27/16A61P 31/04A61P 13/12A61P 1/18A61P 17/14A61P 11/00A61P 19/02A61P 1/04A61P 11/06C07D 471/04
51
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Claims
Abstract
Inhibitors of MIF having a naphthyridine backbone are provided which have utility in the treatment of a variety of disorders, including the treatment of pathological conditions associated with MIF activity. The inhibitors of MIF have the following structures: including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein n, R, R 1 , R 2 , X, Y and Z are as defined herein. Compositions containing an inhibitor of MIF in combination with a pharmaceutically acceptable carrier are also provided, as well as methods for use of the same.
Claims
exact text as granted — not AI-modified1 . A compound for inhibiting macrophage migration inhibitory factor, the compound having a structure selected from the group consisting of:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, substituted heterocycle, —(CH 2 ) m C(═O)Ar, and —(CH 2 ) m NR 4 R 5 ;
R 1 is selected from the group consisting of —CN, —NO, —NO 2 , —C(═O)R 3 , —C(═O)OH, —NHC(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —SO 2 NR 4 R 5 , —NR 3 SO 2 R 3 , —NHSO 2 R 3 , —S(O) m R 3 , —(CH 2 ) m NR 4 R 5 , and —(CH 2 ) m C(═O)Ar;
R 2 is selected from the group consisting —CH 2 R 3 , —NR 4 R 5 , —OR 3 , and —R 3 ;
R 3 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, substituted heterocycle;
R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, and substituted heterocycle, or R 4 and R 5 taken together comprise heterocycle or substituted heterocycle;
X is selected from the group consisting of hydrogen, halogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ;
Y is selected from the group consisting of hydrogen, halogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ;
Z is selected from the group consisting of hydrogen, halogen, —F, l, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ;
Ar is selected from the group consisting of aryl and substituted aryl;
m is independently 0, 1, 2, 3, or 4; and
n is 0, 1, or 2.
2 . The compound of claim 1 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
R is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, C 7 -C 12 arylalkyl, C 7 -C 12 alkylaryl, C 2 -C 12 acylalkyl, C 3 -C 12 heterocyclealkyl, C 3 -C 12 alkylheterocycle, and C 2 -C 12 heterocycle, wherein R is substituted with one or more substituents selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —C(═O)NR 3 R 3 , —NR 3 C(═O)R 3 , —SO 2 NR 3 R 3 , —NR 3 SO 2 R 3 , —OR 3 , —SR 3 , —NHSO 2 R 3 , —S(O) m R 3 , —C(═O)OH, —NHC(═O)R 3 , —(CH 2 ) m C(═O)Ar, and —(CH 2 ) m NR 3 R 3 ;
R 1 is selected from the group consisting of —CN, —NO, —NO 2 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —C(═O)NR 3 R 3 , —NR 3 C(═O)R 3 , —SO 2 NR 3 R 3 , —NR 3 SO 2 R 3 , —OR 3 , —SR 3 , —NHSO 2 R 3 , —S(O) m R 3 , —C(═O)OH, —NHC(═O)R 3 , —(CH 2 ) m C(═O)Ar, and —(CH 2 ) m NR 3 R 3 ;
R 2 is selected from the group consisting —NR 4 R 5 , —OR 3 , and —R 3 ;
R 3 is independently selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, C 7 -C 12 arylalkyl, C 7 -C 12 alkylaryl, C 2 -C 12 acylalkyl, C 3 -C 12 heterocyclealkyl, C 3 -C 12 alkylheterocycle, and C 2 -C 12 heterocycle, wherein R 3 is substituted with one or more substituents selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —CN, —NO, —NO 2 , C 1 -C 12 alkoxy, and C 1 -C 12 alkylthio;
R 4 and R 5 are independently selected from the group consisting C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, C 7 -C 12 arylalkyl, C 7 -C 12 alkylaryl, C 2 -C 12 acylalkyl, C 3 -C 12 heterocyclealkyl, C 3 -C 12 alkylheterocycle, and C 2 -C 12 heterocycle substituted with one or more substituents selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —CN, —NO, —NO 2 , C 1 -C 12 alkoxy, and C 1 -C 12 alkylthio, or R 4 and R 5 together comprise a C 2 -C 12 heterocycle substituted with one or more substituents selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , C 1 -C 12 alkoxy, and C 1 -C 12 alkylthio;
X is selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —C(═O)NR 3 R 3 , —NR 3 C(═O)R 3 , —SO 2 NR 3 R 3 , —NR 3 SO 2 R 3 , —OR 3 , —S(O) m R 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , —(CH 2 ) m C(═O)Ar, and —(CH 2 ) m NR 3 R 3 ;
Y is selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —C(═O)NR 3 R 3 , —NR 3 C(═O)R 3 , —SO 2 NR 3 R 3 , —NR 3 SO 2 R 3 , —OR 3 , —S(O) m R 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , —(CH 2 ) m C(═O)Ar, and —(CH 2 ) m NR 3 R 3 ;
Z is selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —C(═O)NR 3 R 3 , —NR 3 C(═O)R 3 , —SO 2 NR 3 R 3 , —NR 3 SO 2 R 3 , —OR 3 , —S(O) m R 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , —(CH 2 ) m C(═O)Ar, and —(CH 2 ) m NR 3 R 3 ;
Ar is independently selected from the group consisting of C 6 -C 12 aryl substituted with one or more substituents selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —CN, —NO, —NO 2 , C 1 -C 12 alkyl, C 1 -C 12 alkoxy, and C 1 -C 12 alkylthio; and
m is independently 0, 1, 2, 3, or 4.
3 . The compound of claim 1 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, wherein:
R is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, C 7 -C 12 arylalkyl, C 7 -C 12 alkylaryl, C 2 -C 12 acylalkyl, C 3 -C 12 heterocyclealkyl, C 3 -C 12 alkylheterocycle, and C 2 -C 12 heterocycle, wherein R is substituted with one or more substituents selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —C(═O)NR 3 R 3 , —NR 3 C(═O)R 3 , —SO 2 NR 3 R 3 , —NR 3 SO 2 R 3 , —OR 3 , —SR 3 , —S(O) m R 3 , —(CH 2 ) m C(═O)Ar, and —(CH 2 ) m NR 3 R 3 ;
R 1 is selected from the group consisting of —CN, —NO, —NO 2 , —C(═O)R 3 , —C(═O)OR 3 , —OC(═O)R 3 , —NHSO 2 R 3 , —C(═O)NR 3 R 3 , —NR 3 C(═O)R 3 , —SO 2 NR 3 R 3 , —NR 3 SO 2 R 3 , —OR 3 , —SR 3 , —S(O) m R 3 , —(CH 2 ) m C(═O)Ar, and CH 2 ) m NR 3 R 3 ;
R 2 is selected from the group consisting —NR 4 R 5 , —OR 3 , and —R 3 ;
R 3 is independently selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, C 7 -C 12 arylalkyl, C 7 -C 12 alkylaryl, C 2 -C 12 acylalkyl, C 3 -C 12 heterocyclealkyl, C 3 -C 12 alkylheterocycle, and C 2 -C 12 heterocycle, wherein R 3 is substituted with one or more substituents selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —CN, —NO, —NO 2 , C 1 -C 12 alkoxy, and C 1 -C 12 alkylthio;
R 4 and R 5 are independently selected from the group consisting C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 3 -C 12 cycloalkyl, C 6 -C 12 aryl, C 7 -C 12 arylalkyl, C 7 -C 12 alkylaryl, C 2 -C 12 acylalkyl, C 3 -C 12 heterocyclealkyl, C 3 -C 12 alkylheterocycle, and C 2 -C 12 heterocycle substituted with one or more substituents selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —CN, —NO, —NO 2 , C 1 -C 12 alkoxy, and C 1 -C 12 alkylthio, or R 4 and R 5 together comprise a C 2 -C 12 heterocycle substituted with one or more substituents selected from the group consisting of hydrogen, —F, —Cl, —CN, —NO, —NO 2 , —CN, —NO, —NO 2 , C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 alkylthio, and C 1 -C 12 alkyl substituted with one or more substituents selected from the group consisting of hydrogen, —F, and —Cl;
X is selected from the group consisting of hydrogen, —F, —Cl, —OCF 3 , —CF 3 , C 1 -C 12 alkyl, and C 1 -C 12 alkyl substituted with one or more substituents selected from the group consisting of hydrogen, —F, and —Cl;
Y is selected from the group consisting of hydrogen, —F, —Cl, —OCF 3 , —CF 3 , C 1 -C 12 alkyl, and C 1 -C 12 alkyl substituted with one or more substituents selected from the group consisting of hydrogen, —F, and —Cl;
Z is selected from the group consisting of hydrogen, —F, —Cl, —OCF 3 , —CF 3 , C 1 -C 12 alkyl, and C 1 -C 12 alkyl substituted with one or more substituents selected from the group consisting of hydrogen, —F, and —Cl;
Ar is selected from the group consisting of C 6 -C 12 aryl substituted with one or more substituents selected from the group consisting of hydrogen, —F, —Cl, C 1 -C 12 alkyl, and C 1 -C 12 alkyl substituted with one or more substituents selected from the group consisting of hydrogen, —F, and —Cl; and
m is independently 0, 1, 2, 3, or 4.
4 . The compound of claim 2 , wherein R 1 comprises —(CH 2 ) m C(═O)Ar.
5 . The compound of claim 2 , wherein R 1 comprises —C(═O)OCH 2 CH 3 .
6 . The compound of claim 2 , wherein R 1 comprises —NH—C(═O)CH 3 .
7 . The compound of claim 2 , wherein R 1 comprises —CN.
8 . The compound of claim 2 , wherein R 1 comprises —NO 2 .
9 . The compound of claim 2 , wherein R 1 comprises —NH 2 .
10 . The compound of claim 2 , wherein R 2 comprises
11 . The compound of claim 2 , wherein R 2 comprises
12 . The compound of claim 2 , wherein R comprises —(CH 2 ) m C(═O)Ar.
13 . The compound of claim 2 , wherein X is selected from the group consisting of hydrogen, fluorine, and chlorine; wherein Y is selected from the group consisting of hydrogen, fluorine, and chlorine; and wherein Z is selected from the group consisting of hydrogen, fluorine, and chlorine.
14 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
15 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
16 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
19 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
20 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
21 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
22 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
23 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
24 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
25 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
26 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
27 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
28 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
29 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
30 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
31 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
32 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
33 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
34 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
35 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
36 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
37 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
38 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
39 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
40 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
41 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
42 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
43 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
44 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
45 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
46 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
47 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
48 . The compound of claim 2 , having a structure:
or a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof.
49 . A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier or diluent.
50 . A method for reducing MIF activity in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 1 , whereby MIF activity is reduced.
51 . A method for treating inflammation in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
52 . A method for treating septic shock in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
53 . A method for treating arthritis in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
54 . A method for treating cancer in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
55 . A method for treating acute respiratory distress syndrome in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
56 . A method for treating an inflammatory disease in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
57 . The method of claim 56 , wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, and asthma.
58 . A method for treating a cardiac disease in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
59 . The method of claim 58 , wherein the cardiac disease is selected from the group consisting of cardiac dysfunction, myocardial infarction, congestive heart failure, restenosis, and atherosclerosis.
60 . A method for treating an autoimmune disorder in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
61 . The method of claim 60 , wherein the autoimmune disorder is selected from the group consisting of diabetes, asthma, and multiple sclerosis.
62 . A method for suppressing an immune response in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
63 . A method for decreasing angiogenesis in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
64 . A method for treating a disease associated with excess glucocorticoid levels in a warm-blooded animal, comprising administering to the animal an effective amount of the compound of claim 1 .
65 . The method of claim 64 , wherein the disease is Cushing's disease.
66 . A process for preparing a compound of claim 1 , the process comprising the steps of:
reacting POCl 3 with a compound of Formula (3): wherein R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, substituted heterocycle, —(CH 2 ) m C(═O)Ar, and CH 2 ) m NR 4 R 5 ; R 1 is selected from the group consisting of —CN, —NO, —NO 2 , —C(═O)R 3 , —C(═O)OH, —NHC(═O)R 3 , —C (═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —SO 2 NR 4 R 5 , —NR 3 SO 2 R 3 , —NHSO 2 R 3 , —S(O) m R 3 , —(CH 2 ) m NR 4 R 5 , and CH 2 ) m C(═O)Ar; R 3 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, substituted heterocycle; R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, and substituted heterocycle, or R 4 and R 5 taken together comprise heterocycle or substituted heterocycle; X is selected from the group consisting of hydrogen, halogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ; Y is selected from the group consisting of hydrogen, halogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ; Z is selected from the group consisting of hydrogen, halogen, —F, —Cl, N, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , C(═O)OR 3 , —C(═O)NR 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ; Ar is selected from the group consisting of aryl and substituted aryl; and m is independently 0, 1, 2, 3, or 4; thereby yielding a compound of Formula (4): reacting the compound of Formula (4) with piperazine, thereby yielding a compound of Formula (5): reacting the compound of Formula (5) with a compound having the formula R 2 —C(═O)Cl, wherein R 2 is selected from the group consisting —CH 2 R 3 , —NR 4 R 5 , —OR 3 , and —R 3 , thereby yielding a compound of Formula (6): wherein the compound of Formula (6) is suitable for use as a MIF inhibitor.
67 - 76 . (canceled)
77 . A process for preparing a compound of claim 1 , the process comprising the steps of:
reacting a compound of Formula (13): wherein R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, substituted heterocycle, —(CH 2 ) m C(═O)Ar, and —(CH 2 ) m NR 4 R 5 ; R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, and substituted heterocycle, or R 4 and R 5 taken together comprise heterocycle or substituted heterocycle; X is selected from the group consisting of hydrogen, halogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ; Y is selected from the group consisting of hydrogen, halogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ; Z is selected from the group consisting of hydrogen, halogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ; R 3 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, substituted heterocycle; Ar is selected from the group consisting of aryl and substituted aryl; and m is independently 0, 1, 2, 3, or 4, with cyclohexylamine, thereby yielding a compound of Formula (14): reacting the compound of Formula (14) with POCl 3 , thereby yielding a compound of Formula (15): reacting the compound of Formula (15) with piperazine, thereby yielding a compound of Formula (16): reacting the compound of Formula (16) with a compound having the formula R 2 —C(═O)Cl, wherein R 2 is selected from the group consisting —CH 2 R 3 , —NR 4 R 5 , —OR 3 , and —R 3 , thereby yielding a compound of Formula (17): wherein the compound of Formula (17) is suitable for use as a MIF inhibitor.
78 - 81 . (canceled)
82 . A process for preparing a compound of claim 1 , the process comprising the steps of:
reacting a compound of Formula (23): wherein R 1 is selected from the group consisting of —CN, —NO, —NO 2 , —C(═O)R 3 , —C(═O)OH, —NHC(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —SO 2 NR 4 R 5 , —NR 3 SO 2 R 3 , —NHSO 2 R 3 , —S(O) m R 3 , —(CH 2 ) m NR 4 R 5 , and —(CH 2 ) m C(═O)Ar; R 3 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, substituted heterocycle; R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, and substituted heterocycle, or R 4 and R 5 taken together comprise heterocycle or substituted heterocycle; X is selected from the group consisting of hydrogen, halogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ; Y is selected from the group consisting of hydrogen, halogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ; Z is selected from the group consisting of hydrogen, halogen, —F, —Cl, —CN, —NO, —NO 2 , —OCF 3 , —CF 3 , —NHSO 2 R 3 , —C(═O)R 3 , —C(═O)OR 3 , —C(═O)NR 4 R 5 , —NR 3 C(═O)R 3 , —NR 3 SO 2 R 3 , —S(O) m R 3 , —R 3 , —OR 3 , —SR 3 , —C(═O)OH, —NHC(═O)R 3 , and —NR 4 R 5 ; Ar is independently selected from the group consisting of aryl and substituted aryl; and m is independently 0, 1, 2, 3, or 4, with POCl 3 and trifluoroacetic acid, thereby yielding a compound of Formula (24): reacting the compound of Formula (24) with a compound of formula: wherein R 2 is selected from the group consisting —CH 2 R 3 , —NR 4 R 5 , —OR 3 , and —R 3 , thereby yielding a compound of Formula (25): reacting the compound of Formula (25) with a compound having the formula RX′ wherein X′ comprises halogen and wherein R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acylalkyl, subtituted acylalkyl, heterocycle, substituted heterocycle, —(CH 2 ) m C(═O)Ar, and —(CH 2 ) m NR 4 R 5 , thereby yielding a compound of Formula (26): wherein the compound of Formula (26) is suitable for use as a MIF inhibitor.
83 - 102 . (canceled)Join the waitlist — get patent alerts
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