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US 9,540,322 B2Granted
MIF modulators
AssigneeYale University
InventorsWilliam L. Jorgensen, Richard J. Bucala
Life of this patent
Estimating the term…
Abstract
The invention provides novel heterocyclic compounds, pharmaceutical compositions and methods of treatment that modulate levels of MIF expression and treat disorders associated with high or low levels of MIF expression.
Claims29
A compound according to formula III H:
- wherein
- each X1 is selected from —H, Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each X2 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each X3 is —OH or —O(C1-C6 alkyl);
- each X4 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each X5 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each Y1 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each Y2 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each Y3 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each Y4 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- and
- each Y5 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- provided that X3 is OH or Y3 is —O(C1-C6)alkyl or —OH;
- each Ra is independently unsubstituted (C1-C6)alkyl or (C1-C6)alkyl substituted with up to five halogen atoms and up to two substituents selected from the group consisting of —C≡N;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NR42;
- —ORb;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)NRc2;
- —S(C1-C6)alkyl;
- —S(O)(C1-C6)alkyl;
- and —SO2(C1-C6)alkyl;
- each Rb is independently hydrogen or (C1-C6)alkyl;
- each Rc is independently hydrogen;
- (C1-C6)alkyl;
- —(C2-C6)alkylene-ORb;
- —(C1-C6)alkylene-C(═O)ORb;
- —(C1-C6)alkylene-OC(═O)Rb;
- —(C2-C6)alkylene-NRb2;
- —(C1-C6)alkylene-C(═O)NRb2;
- —(C1-C6)alkylene-NRbC(═O)Rb;
- —(C1-C6)alkylene-NRbC(═O)NRb2;
- or, optionally, within any occurrence of NRc2, independently of any other occurrence of NRc2, the two Rc groups in combination are —(CH2)α— or —(CH2)βQ(CH2)2—;
- each α is independently selected from the group consisting of 4, 5, and 6;
- each β is independently selected from the group consisting of 2 and 3;
- each Q is independently selected from the group consisting of O, S, NRb;
- NC(═O)Rb;
- NSO2Rb;
- N(C2-C6)alkylene-ORb;
- N(C1-C6)alkylene-C(═O)ORb;
- N(C1-C6)alkylene-OC(═O)Rb;
- N(C2-C6)alkylene-NRb2;
- N(C1-C6)alkylene-C(═O)NRb2;
- N(C1-C6)alkylene-NRbC(═O)Rb;
- and N(C1-C6)alkylene-NRbC(═O)NRb2,
- or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.
264 more elements
A compound according to formula III-B:
- wherein
- B is selected from the group consisting of —Ar2 and —CH2Ar2;
- Ar2 is an unsubstituted or substituted aromatic ring which is a 5, 6, 8, 9, or 10-membered monocyclic or bicyclic heteroaryl group containing 0, 1, 2, 3 or 4 nitrogen atoms, 0, 1 or 2 oxygen atoms, and 0, 1 or 2 sulfur atoms as heteroatoms;
- wherein the optional substituents of Ar2 are each independently selected from —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each X1 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each X2 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each X3 is —OH or —O(C1-C6 alkyl);
- each X4 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each X5 is selected from —H, —Ra;
- —OH;
- —ORa;
- (C2-C6)alkenyl;
- (C2-C6)alkynyl;
- halogen;
- —C≡N;
- —NO2;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NRc2;
- —C(═NRb)NRc2;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)O(C1-C6)alkyl;
- —NRbC(═O)NRc2;
- —NRbSO2Rb;
- —SRb;
- —S(O)Rb;
- —SO2Rb;
- —OSO2(C1-C6)alkyl;
- and —SO2NRc2;
- each Ra is independently unsubstituted (C1-C6)alkyl or (C1-C6)alkyl substituted with up to five halogen atoms and up to two substituents selected from the group consisting of —C≡N;
- —C(═O)Rb;
- —C(═O)ORb;
- —C(═O)NR42;
- —ORb;
- —OC(═O)(C1-C6)alkyl;
- —OC(═O)O(C1-C6)alkyl;
- —OC(═O)NRc2;
- —NRc2;
- —NRbC(═O)Rb;
- —NRbC(═O)NRc2;
- —S(C1-C6)alkyl;
- —S(O)(C1-C6)alkyl;
- and —SO2(C1-C6)alkyl;
- each Rb is independently hydrogen or (C1-C6)alkyl;
- each Rc is independently hydrogen;
- (C1-C6)alkyl;
- —(C2-C6)alkylene-ORb;
- —(C1-C6)alkylene-C(═O)ORb;
- —(C1-C6)alkylene-OC(═O)Rb;
- —(C2-C6)alkylene-NRb2;
- —(C1-C6)alkylene-C(═O)NRb2;
- —(C1-C6)alkylene-NRbC(═O)Rb;
- —(C1-C6)alkylene-NRbC(═O)NRb2;
- or, optionally, within any occurrence of NRc2, independently of any other occurrence of NRc2, the two Rc groups in combination are —(CH2)α— or —(CH2)βQ(CH2)2—;
- each α is independently selected from the group consisting of 4, 5, and 6;
- each β is independently selected from the group consisting of 2 and 3;
- and
- each Q is independently selected from the group consisting of O, S, NRb;
- NC(═O)Rb;
- NSO2Rb;
- N(C2-C6)alkylene-ORb;
- N(C1-C6)alkylene-C(═O)ORb;
- N(C1-C6)alkylene-OC(═O)Rb;
- N(C2-C6)alkylene-NRb2;
- N(C1-C6)alkylene-C(═O)NRb2;
- N(C1-C6)alkylene-NRbC(═O)Rb;
- and N(C1-C6)alkylene-NRbC(═O)NRb2,
- or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.
165 more elements
A compound of the following formula:
- or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.
Dependencies are inferred from the claim text.