Inhibitors of JMJD2C as Anticancer Agents

Abstract

The present disclosure provides compounds, pharmaceutical compositions and related methods for the treatment of cancer, e.g., castration-resistant prostate cancer (CRPC). Specifically, the present disclosure provides a series of 8-hydroxyquinoline derivatives which show cytotoxic effects on androgen-independent prostate cancer cells.

Claims

1. A compound of Formula I: ##STR00021## wherein X is CH or a bond; R.sup.1 is selected from H, alkyl and substituted alkyl; R.sup.2 is selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl; R.sup.3 is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and R.sup.4 is selected from H, alkyl and substituted alkyl, or a salt or stereoisomer thereof, wherein if X is a bond, then R.sup.2 is H, R.sup.3 is absent and R.sup.1 is aminoalkyl or substituted aminoalkyl, and if R.sup.3 is heteroaryl or substituted aryl, then R.sup.4 is alkyl or substituted alkyl.

2. The compound of claim 1, wherein X is CH and R.sup.1 is H.

3. The compound of claim 1, wherein X is a bond, R.sup.2 is H, R.sup.3 is absent and R.sup.1 is aminoalkyl or substituted aminoalkyl.

4. The compound of claim 1, wherein R.sup.1 and R.sup.3 are each H and R.sup.2 is selected from amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl.

5. The compound of claim 1, wherein R.sup.1 is H, R.sup.2 amino or substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl or substituted alkyl.

6. The compound of claim 1, wherein R.sup.4 is H.

7. The compound of claim 1, wherein R.sup.4 is alkyl or substituted alkyl.

8. The compound of claim 1, wherein the compound is a compound of Formula Ia: ##STR00022##

9. The compound of claim 8, wherein R.sup.2 is selected from amino, substituted amino, heterocyclyl and substituted heterocyclyl.

10. The compound of claim 1, wherein the compound is a compound of Formula Ib: ##STR00023##

11. The compound of claim 10, wherein R.sup.1 is aminoalkyl or substituted aminoalkyl.

12. The compound of claim 1, wherein the compound is a compound of Formula Ic: ##STR00024##

13. The compound of claim 12, wherein R.sup.2 is amino or substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl or substituted alkyl.

14. The compound of claim 1, wherein the compound is selected from: 5-((2-morpholinoethylamino)methyl)quinolin-8-ol (Compound SD70-17); 7-((4-(pyridin-2-yl)piperazin-1-yl)methyl)quinolin-8-ol (Compound SD70-18); 7-((2-morpholinoethylamino)methyl)quinolin-8-ol (Compound SD70-19); and 7-((isopentylamino)methyl)quinolin-8-ol (Compound SD70-21).

15. A pharmaceutical composition comprising: a compound selected from: N-(furan-2-yl(8-hydroxyquinolin-7-yl)methyl)isobutyramide (Compound SD70); N-((5-chloro-8-hydroxyquinolin-7-yl)(furan-2-yl)methyl)propionamide (Compound SD70-1); N-((5-chloro-8-hydroxyquinolin-7-yl)(furan-2-yl)methyl)isobutyramide (Compound SD70-2); N-((5-chloro-8-hydroxyquinolin-7-yl)(furan-2-yl)methyl)acetamide (Compound SD70-3); N-((5-chloro-8-hydroxyquinolin-7-yl)(furan-2-yl)methyl)butyramide (Compound SD70-4); N-((5-chloro-8-hydroxyquinolin-7-yl)(furan-2-yl)methyl)nicotinamide (Compound SD70-5); N-((5-chloro-8-hydroxyquinolin-7-yl)(furan-2-yl)methyl)-4-methoxybenzamide (Compound SD70-6); N-((5-chloro-8-hydroxyquinolin-7-yl)(furan-2-yl)methyl)-2-phenoxyacetamide (Compound SD70-7); N-((5-chloro-8-hydroxyquinolin-7-yl)(2-methoxyphenyl)methyl)propionamide (Compound SD70-8); N-((5-chloro-8-hydroxyquinolin-7-yl)(3,4-dimethoxyphenyl)methyl)propionamide (Compound SD70-9); N-(furan-2-yl(8-hydroxy-5-nitroquinolin-7-yl)methyl)propionamide (Compound SD70-10); N-(furan-2-yl(8-hydroxyquinolin-7-yl)methyl)propionamide (Compound SD70-11); 5-(chloromethyl)quinolin-8-ol hydrochloride (Compound SD70-15); 5-((2-morpholinoethylamino)methyl)quinolin-8-ol (Compound SD70-17); 7-((4-(pyridin-2-yl)piperazin-1-yl)methyl)quinolin-8-ol (Compound SD70-18); 7-((2-morpholinoethylamino)methyl)quinolin-8-ol (Compound SD70-19); 7-(piperidin-1-ylmethyl)quinolin-8-ol (Compound SD70-20); 7-((isopentylamino)methyl)quinolin-8-ol (Compound SD70-21); N-((8-hydroxyquinolin-7-yl)(4-methoxyphenyl)methyl)isobutyramide (Compound SD70-22); N-((3,4-dimethoxyphenyl)(8-hydroxyquinolin-7-yl)methyl)isobutyramide (Compound SD70-24); and N-((8-hydroxyquinolin-7-yl)(4-nitrophenyl)methyl)isobutyramide (Compound SD70-25); and a pharmaceutically acceptable excipient.

16. A method of inhibiting histone demethylase JMJD2C, the method comprising: administering to a subject an effective amount of a compound of any one of claims 1 to 14.

17. A method of inhibiting histone demethylase JMJD2C, the method comprising: administering to a subject an effective amount of a pharmaceutical composition of claim 15.

18. A method of treating prostate cancer, the method comprising: administering to a subject an effective amount of a compound of any one of claims 1 to 14.

19. A method of treating prostate cancer, the method comprising: administering to a subject an effective amount of a pharmaceutical composition of claim 15.

Description

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0076] The present disclosure provides compounds, pharmaceutical compositions and related methods for the treatment of cancer; e.g., castration-resistant prostate cancer (CRPC); and/or the inhibition of histone demethylase JMJD2C. Specifically, the present disclosure provides a series of 8-hydroxyquinoline derivatives which show cytotoxic effects on androgen-independent prostate cancer cells. Particular compounds and pharmaceutical compositions of the present disclosure show activity as inhibitors of the histone demethylase JMJD2C. The human JMJD2C gene (NCBI Gene ID: 23081), also known as lysine (K)-specific demethylase 4C (KDM4C), is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein with one JmjC domain, one JmjN domain, two PHD-type zinc fingers, and two Tudor domains. This nuclear protein functions as a trimethylation-specific demethylase, converting specific trimethylated histone residues to the dimethylated form. As discussed previously herein, human histone demethylases of the KDM4 (JMJD2) family have been associated with diseases such as prostate and breast cancer. Accordingly, these enzymes are considered oncogenes, the selective inhibition of which may provide a possible therapeutic approach for the treatment of cancer. The present disclosure provides related methods and compositions for the treatment of disease, with particular applicability to the treatment of cancers, such as CRPC.

[0077] The following substituents and values are intended to provide representative examples of various aspects and embodiments. These representative values are intended to further define and illustrate such aspects and embodiments and are not intended to exclude other embodiments or to limit the scope of the present disclosure. In this regard, the representation that a particular value or substituent is preferred is not intended in any way to exclude other values or substituents from the present disclosure unless specifically indicated.

[0078] These compounds may contain one or more chiral centers and therefore, the embodiments are directed to racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like unless otherwise indicated. When a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions unless otherwise indicated, provided that the desired utility of the composition as a whole is not eliminated by the presence of such other isomers.

[0079] Embodiments of the present disclosure include compounds of Formula I, shown below. Pharmaceutical compositions and methods of the present disclosure may also include compounds of Formula I.

Formula I

[0080] Embodiments of the present disclosure include a compound of Formula I:

##STR00001##

wherein

[0081] X is CH or a bond;

[0082] R.sup.1 is selected from H, alkyl and substituted alkyl;

[0083] R.sup.2 is selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl;

[0084] R.sup.3is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and

[0085] R.sup.4 is selected from H, alkyl and substituted alkyl,

[0086] or a salt or stereoisomer thereof.

[0087] In certain embodiments, if X is a bond, then R.sup.2 is H, R.sup.3 is absent and R.sup.1 is aminoalkyl or substituted aminoalkyl.

[0088] In certain embodiments, if R.sup.3 is heteroaryl or substituted aryl, then R.sup.4 is alkyl or substituted alkyl.

[0089] In certain embodiments, X is CH or a bond. In certain embodiments, X is CH. In certain embodiments, X is a bond. In certain embodiments, if X is a bond, then R.sup.2 is H. In certain embodiments, if X is a bond, then R.sup.3 is absent. In certain embodiments, if X is a bond, then R.sup.2 is H and R.sup.3 is absent. In certain embodiments, if X is a bond, then R.sup.1 is alkyl or substituted alkyl. In certain embodiments, if X is a bond, then R.sup.1 is alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl. In certain embodiments, if X is a bond, then R.sup.1 is substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl (e.g., substituted methyl, substituted ethyl or substituted propyl). In certain embodiments, if X is a bond, then R.sup.1 is substituted methyl. In certain embodiments, if X is a bond, then R.sup.1 is alkyl substituted with one or more amino or substituted amino groups (e.g., R.sup.1 is aminoalkyl or substituted aminoalkyl). In certain embodiments, if X is a bond, then R.sup.1 is aminoalkyl. In certain embodiments, if X is a bond, then R.sup.1 is substituted aminoalkyl. For example, if X is a bond, then R.sup.1 may be substituted aminoalkyl, where the amino is substituted with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, if X is a bond, then R.sup.1 may be substituted aminoalkyl, where the amino is substituted with alkyl or substituted alkyl. In some instances, if X is a bond, then R.sup.1 may be substituted aminoalkyl, where the amino is substituted with substituted alkyl, such as a C.sub.1-6 or C.sub.1-3 alkyl substituted with cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, if X is a bond, then R.sup.1 may be substituted aminoalkyl, where the amino is substituted with substituted alkyl, such as a C.sub.1-3 alkyl (e.g., ethylene) substituted with heterocyclyl or substituted heterocyclyl (e.g., morpholinyl).

[0090] In certain embodiments, R.sup.1 is selected from H, alkyl and substituted alkyl. In certain embodiments, R.sup.1 is H. In certain embodiments, R.sup.1 is alkyl or substituted alkyl. In certain embodiments, R.sup.1 is alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl (e.g., substituted methyl, substituted ethyl or substituted propyl). In certain embodiments, R.sup.1 is substituted methyl. In certain embodiments, R.sup.1 is alkyl substituted with one or more amino or substituted amino groups (e.g., R.sup.1 is aminoalkyl or substituted aminoalkyl). In certain embodiments, R.sup.1 is aminoalkyl. In certain embodiments, R.sup.1 is substituted aminoalkyl. For example, R.sup.1 may be substituted aminoalkyl, where the amino is substituted with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, R.sup.1 is substituted aminoalkyl, where the amino is substituted with alkyl or substituted alkyl. In some instances, R.sup.1 is substituted aminoalkyl, where the amino is substituted with substituted alkyl, such as a C.sub.1-6 or C.sub.1-3 alkyl substituted with cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, R.sup.1 is substituted aminoalkyl, where the amino is substituted with substituted alkyl, such as a C.sub.1-3 alkyl (e.g., ethylene) substituted with heterocyclyl or substituted heterocyclyl (e.g., morpholinyl).

[0091] In certain embodiments, R.sup.2 is selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl. In certain embodiments, R.sup.2 is H. In certain embodiments, R.sup.2 is alkyl or substituted alkyl. In certain embodiments, R.sup.2 is alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is amino or substituted amino. In certain embodiments, R.sup.2 is amino. In certain embodiments, R.sup.2 is substituted amino (e.g., a secondary amino or a tertiary amino). In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with alkyl or substituted alkyl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl (e.g., n-pentyl, tert-pentyl, neo-pentyl, iso-pentyl, sec-pentyl or 3-pentyl), or hexyl (e.g., n-hexyl or branched-chain hexyl). In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with alkyl, such as iso-pentyl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with a substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with a substituted alkyl, where the alkyl is substituted with cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with a substituted alkyl, where the alkyl is substituted with heterocyclyl or substituted heterocyclyl (e.g., morpholinyl).

[0092] In certain embodiments, R.sup.2 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.2 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.2 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.2 is substituted C.sub.3-6 cycloalkyl, such as substituted cyclopentyl or substituted cyclohexyl. In certain embodiments, R.sup.2 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.2 is heterocyclyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl, where one or more carbon atoms in the ring is selected from O, N or S. Examples of heterocyclyl groups include, but are not limited to pyrrolidinyl, pyrazolidinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, oxazolidinyl, and the like. In certain embodiments, R.sup.2 is piperazinyl. In certain embodiments, R.sup.2 is substituted heterocyclyl such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl, where one or more carbon atoms in the ring is selected from O, N or S. In certain embodiments, R.sup.2 is substituted C.sub.3-6 heterocyclyl, such as substituted cyclopentyl or substituted cyclohexyl, where one or more carbon atoms in the ring is selected from O, N or S. Examples of substituted heterocyclyls include, but are not limited to substituted pyrrolidinyl, substituted pyrazolidinyl, substituted imidazolidinyl, substituted imidazolinyl, substituted piperidinyl, substituted piperazinyl, substituted morpholinyl, substituted tetrahydrofuranyl, substituted oxazolidinyl, and the like. In certain embodiments, R.sup.2 is substituted piperazinyl. In some instances, R.sup.2 is a substituted heterocycyl, where the heterocyclyl is substituted with one or more alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, R.sup.2 is a substituted heterocycyl, where the heterocyclyl is substituted with aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, R.sup.2 is a substituted heterocycyl, where the heterocyclyl is substituted with aryl or substituted aryl. In some instances, R.sup.2 is a substituted heterocycyl, where the heterocyclyl is substituted with heteroaryl or substituted heteroaryl, such as, but not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, furanyl, and the like. In some instances, R.sup.2 is a substituted heterocycyl, where the heterocyclyl is substituted with pyridinyl. In some instances, R.sup.2 is a substituted piperazinyl, where the piperazinyl is substituted with pyridinyl.

[0093] In certain embodiments, R.sup.3 is selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In certain embodiments, R.sup.3 is H. In certain embodiments, R.sup.3 is alkyl or substituted alkyl. In certain embodiments, R.sup.3 is alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl. In certain embodiments, R.sup.3 is substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.3 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.3 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.3 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.3 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.3 is heterocyclyl such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl, where one or more carbon atoms in the ring is selected from O, N or S. In certain embodiments, R.sup.3 is substituted heterocyclyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl, where one or more carbon atoms in the ring is selected from O, N or S. In certain embodiments, R.sup.3 is aryl or substituted aryl. In certain embodiments, R.sup.3 is aryl. In certain embodiments, R.sup.3 is substituted aryl. In certain embodiments, R.sup.3 is heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.3 is heteroaryl, such as, but not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, furanyl, and the like. In certain embodiments, R.sup.3 is furanyl. In certain embodiments, R.sup.3 is substituted heteroaryl.

[0094] In certain embodiments, if R.sup.3 is heteroaryl or substituted aryl, then R.sup.4 is alkyl or substituted alkyl. In certain embodiments, if R.sup.3 is heteroaryl, then R.sup.4 is alkyl or substituted alkyl. In certain embodiments, if R.sup.3 is heteroaryl, then R.sup.4 is alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl (e.g., methyl). In certain embodiments, if R.sup.3 is heteroaryl, then R.sup.4 is methyl. In certain embodiments, if R.sup.3 is heteroaryl, then R.sup.4 is substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl. In certain embodiments, if R.sup.3 is substituted aryl, then R.sup.4 is alkyl or substituted alkyl. In certain embodiments, if R.sup.3 is substituted aryl, then R.sup.4 is alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl (e.g., methyl). In certain embodiments, if R.sup.3 is substituted aryl, then R.sup.4 is substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl.

[0095] In certain embodiments, R.sup.4 is selected from H, alkyl and substituted alkyl. In certain embodiments, R.sup.4 is H. In certain embodiments, R.sup.4 is alkyl or substituted alkyl. In certain embodiments, R.sup.4 is alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl (e.g., methyl). In certain embodiments, R.sup.4 is methyl. In certain embodiments, R.sup.4 is substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl.

[0096] In certain embodiments, X is CH and R.sup.1 is H.

[0097] In certain embodiments, X is a bond, R.sup.2 is H, R.sup.3 is absent and R.sup.1 is aminoalkyl or substituted aminoalkyl. In certain embodiments, X is a bond, R.sup.2 is H, R.sup.3 is absent and R.sup.1 is aminoalkyl, such as a C.sub.1-6 alkyl, or C.sub.1-3 alkyl substituted with an amino group. In certain embodiments, X is a bond, R.sup.2 is H, R.sup.3 is absent and R.sup.1 is aminoalkyl, such as a methylene substituted with an amino group. In certain embodiments, X is a bond, R.sup.2 is H, R.sup.3 is absent and R.sup.1 is substituted aminoalkyl, such as a C.sub.1-6 alkyl, or C.sub.1-3 alkyl substituted with a substituted amino group. In certain embodiments, X is a bond, R.sup.2 is H, R.sup.3 is absent and R.sup.1 is substituted aminoalkyl, such as a methylene substituted with a substituted amino group. In certain embodiments, X is a bond, R.sup.2 is H, R.sup.3 is absent and R.sup.1 is substituted aminoalkyl, where the amino is substituted with alkyl or substituted alkyl. In some instances, X is a bond, R.sup.2 is H, R.sup.3 is absent and R.sup.1 is substituted aminoalkyl, where the amino is substituted with substituted alkyl, such as a C.sub.1-6 or C.sub.1-3 alkyl substituted with cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, X is a bond, R.sup.2 is H, R.sup.3 is absent and R.sup.1 is substituted aminoalkyl, where the amino is substituted with substituted alkyl, such as a C.sub.1-3 alkyl (e.g., ethylene) substituted with heterocyclyl or substituted heterocyclyl (e.g., morpholinyl).

[0098] In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is selected from amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocyclyl and substituted heterocyclyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is amino or substituted amino. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is amino. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is substituted amino (e.g., a secondary amino or a tertiary amino). In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted amino, where the amino is substituted with alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted amino, where the amino is substituted with alkyl or substituted alkyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted amino, where the amino is substituted with alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted amino, where the amino is substituted with alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl (e.g., n-pentyl, tert-pentyl, neo-pentyl, iso-pentyl, sec-pentyl or 3-pentyl), or hexyl (e.g., n-hexyl or branched-chain hexyl). In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted amino, where the amino is substituted with alkyl, such as iso-pentyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted amino, where the amino is substituted with a substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted amino, where the amino is substituted with a substituted alkyl, where the alkyl is substituted with cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted amino, where the amino is substituted with a substituted alkyl, where the alkyl is substituted with heterocyclyl or substituted heterocyclyl (e.g., morpholinyl).

[0099] In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is substituted C.sub.3-6 cycloalkyl, such as substituted cyclopentyl or substituted cyclohexyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is heterocyclyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl, where one or more carbon atoms in the ring is selected from O, N or S. Examples of heterocyclyls include, but are not limited to pyrrolidinyl, pyrazolidinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, oxazolidinyl, and the like. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is piperazinyl. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is substituted heterocyclyl such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl, where one or more carbon atoms in the ring is selected from O, N or S. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is substituted C.sub.3-6 heterocyclyl, such as substituted cyclopentyl or substituted cyclohexyl, where one or more carbon atoms in the ring is selected from O, N or S. Examples of substituted heterocyclyls include, but are not limited to substituted pyrrolidinyl, substituted pyrazolidinyl, substituted imidazolidinyl, substituted imidazolinyl, substituted piperidinyl, substituted piperazinyl, substituted morpholinyl, substituted tetrahydrofuranyl, substituted oxazolidinyl, and the like. In certain embodiments, R.sup.1 and R.sup.3 are each H and R.sup.2 is substituted piperazinyl. In some instances, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted heterocycyl, where the heterocyclyl is substituted with one or more alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted heterocycyl, where the heterocyclyl is substituted with aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted heterocycyl, where the heterocyclyl is substituted with aryl or substituted aryl. In some instances, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted heterocycyl, where the heterocyclyl is substituted with heteroaryl or substituted heteroaryl, such as, but not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, furanyl, and the like. In some instances, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted heterocycyl, where the heterocyclyl is substituted with pyridinyl. In some instances, R.sup.1 and R.sup.3 are each H and R.sup.2 is a substituted piperazinyl, where the piperazinyl is substituted with pyridinyl.

[0100] In certain embodiments, R.sup.1 is H, R.sup.2 is amino or substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl or substituted alkyl. In certain embodiments, R.sup.1 is H, R.sup.2 is amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl or substituted alkyl. In certain embodiments, R.sup.1 is H, R.sup.2 is substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl or substituted alkyl. In certain embodiments, R.sup.1 is H, R.sup.2 is substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl or substituted alkyl. In certain embodiments, R.sup.1 is H, R.sup.2 is substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl. In certain embodiments, R.sup.1 is H, R.sup.2 is substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is substituted alkyl. In certain embodiments, R.sup.1 is H, R.sup.2 is substituted amino, R.sup.3 is aryl or substituted aryl, and R.sup.4 is alkyl. In certain embodiments, R.sup.1 is H, R.sup.2 is substituted amino, R.sup.3 is heteroaryl or substituted heteroaryl, and R.sup.4 is alkyl. In certain embodiments, R.sup.1 is H, R.sup.2 is substituted amino, R.sup.3 is heteroaryl, and R.sup.4 is alkyl. In certain embodiments, R.sup.1 is H, R.sup.2 is substituted amino, R.sup.3 is substituted heteroaryl, and R.sup.4 is alkyl. In certain embodiments, where R.sup.3 is heteroaryl, R.sup.3 is selected from pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and furanyl, and the like. In certain embodiments, R.sup.3 is furanyl. In certain embodiments, R.sup.1 is H, R.sup.2 is substituted amino, R.sup.3 is furanyl, and R.sup.4 is alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl (e.g., methyl). In certain embodiments, where R.sup.2 is substituted amino, R.sup.2 is an amino substituted with one or more alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In certain embodiments, where R.sup.2 is substituted amino, R.sup.2 is an amino substituted with alkyl or substituted alkyl. In certain embodiments, where R.sup.2 is substituted amino, R.sup.2 is an amino substituted with alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl. In certain embodiments, where R.sup.2 is substituted amino, R.sup.2 is an amino substituted with a substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl, where the substituted alkyl is substituted with one or more cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo or oxo. In certain embodiments, where R.sup.2 is substituted amino, R.sup.2 is an amino substituted with a substituted alkyl, where the substituted alkyl is substituted with an oxo.

[0101] Particular compounds of interest of Formula I, and salts or solvates or stereoisomers thereof, include:

##STR00002##

5-((2-morpholinoethylamino)methyl)quinolin-8-ol (Compound SD70-17);

##STR00003##

7-((4-(pyridin-2-yl)piperazin-1 -yl)methyl)quinolin-8-ol (Compound SD70-18);

##STR00004##

7-((2-morpholinoethylamino)methyl)quinolin-8-ol (Compound SD70-19); and

##STR00005##

7-((isopentylamino)methyl)quinolin-8-ol (Compound SD70-21).

[0102] Particular compounds of interest of Formula I, and salts or solvates or stereoisomers thereof, include:

##STR00006##

N-(furan-2-yl(8-methoxyquinolin-7-yl)methyl)isobutyramide (Compound SD70-23).

[0103] In some instances, Compound SD70-23 finds use as a control compound, where the activities of other compounds of the present disclosure may be compared to the level of activity (or substantial lack thereof) of Compound SD70-23. As such, in certain embodiments, particular compounds and pharmaceutical compositions of the present disclosure, which show activity as inhibitors of histone demethylase JMJD2C and/or cytotoxic effects on androgen-independent prostate cancer cells, do not include Compound SD70-23.

[0104] Embodiments of the present disclosure include a compound of Formula Ia:

##STR00007##

[0105] In certain embodiments, R.sup.2 is selected from amino, substituted amino, heterocyclyl and substituted heterocyclyl. In certain embodiments, R.sup.2 is amino. In certain embodiments, R.sup.2 is substituted amino (e.g., a secondary amino or a tertiary amino). In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with alkyl or substituted alkyl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl (e.g., n-pentyl, tert-pentyl, neo-pentyl, iso-pentyl, sec-pentyl or 3-pentyl), or hexyl (e.g., n-hexyl or branched-chain hexyl). In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with alkyl, such as iso-pentyl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with a substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with a substituted alkyl, where the alkyl is substituted with cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.2 is a substituted amino, where the amino is substituted with a substituted alkyl, where the alkyl is substituted with heterocyclyl or substituted heterocyclyl (e.g., morpholinyl).

[0106] Particular compounds of interest of Formula Ia, and salts or solvates or stereoisomers thereof, include:

##STR00008##

7-((4-(pyridin-2-yl)piperazin-1-yl)methyl)quinolin-8-ol (Compound SD70-18);

##STR00009##

7-((2-morpholinoethylamino)methyl)quinolin-8-ol (Compound SD70-19); and

##STR00010##

7-((isopentylamino)methyl)quinolin-8-ol (Compound SD70-21).

[0107] Embodiments of the present disclosure include a compound of Formula Ib:

##STR00011##

[0108] In certain embodiments, R.sup.1 is aminoalkyl or substituted aminoalkyl (e.g., alkyl substituted with one or more amino or substituted amino groups). In certain embodiments, R.sup.1 is aminoalkyl. In certain embodiments, R.sup.1 is substituted aminoalkyl. For example, R.sup.1 may be substituted aminoalkyl, where the amino is substituted with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, R.sup.1 is substituted aminoalkyl, where the amino is substituted with alkyl or substituted alkyl. In some instances, R.sup.1 is substituted aminoalkyl, where the amino is substituted with substituted alkyl, such as a C.sub.1-6 or C.sub.1-3 alkyl substituted with cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some instances, R.sup.1 is substituted aminoalkyl, where the amino is substituted with substituted alkyl, such as a C.sub.1-3 alkyl (e.g., ethylene) substituted with heterocyclyl or substituted heterocyclyl (e.g., morpholinyl).

[0109] Particular compounds of interest of Formula Ib, and salts or solvates or stereoisomers thereof, include:

##STR00012##

5-((2-morpholinoethylamino)methyl)quinolin-8-ol (Compound SD70-17).

[0110] Embodiments of the present disclosure include a compound of Formula Ic:

##STR00013##

[0111] In certain embodiments, R.sup.2 is amino or substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl or substituted alkyl. In certain embodiments, R.sup.2 is amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl or substituted alkyl. In certain embodiments, R.sup.2 is substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl or substituted alkyl. In certain embodiments, R.sup.2 is substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl or substituted alkyl. In certain embodiments, R.sup.2 is substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is alkyl. In certain embodiments, R.sup.2 is substituted amino, R.sup.3 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R.sup.4 is substituted alkyl. In certain embodiments, R.sup.2 is substituted amino, R.sup.3 is aryl or substituted aryl, and R.sup.4 is alkyl. In certain embodiments, R.sup.2 is substituted amino, R.sup.3 is heteroaryl or substituted heteroaryl, and R.sup.4 is alkyl. In certain embodiments, R.sup.2 is substituted amino, R.sup.3 is heteroaryl, and R.sup.4 is alkyl. In certain embodiments, R.sup.2 is substituted amino, R.sup.3 is substituted heteroaryl, and R.sup.4 is alkyl. In certain embodiments, where R.sup.3 is heteroaryl, R.sup.3 is selected from pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and furanyl, and the like. In certain embodiments, R.sup.3 is furanyl. In certain embodiments, R.sup.2 is substituted amino, R.sup.3 is furanyl, and R.sup.4 is alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl (e.g., methyl). In certain embodiments, where R.sup.2 is substituted amino, R.sup.2 is an amino substituted with one or more alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In certain embodiments, where R.sup.2 is substituted amino, R.sup.2 is an amino substituted with alkyl or substituted alkyl. In certain embodiments, where R.sup.2 is substituted amino, R.sup.2 is an amino substituted with alkyl, such as C.sub.1-6 alkyl, or C.sub.1-3 alkyl. In certain embodiments, where R.sup.2 is substituted amino, R.sup.2 is an amino substituted with a substituted alkyl, such as substituted C.sub.1-6 alkyl, or substituted C.sub.1-3 alkyl, where the substituted alkyl is substituted with one or more cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo or oxo. In certain embodiments, where R.sup.2 is substituted amino, R.sup.2 is an amino substituted with a substituted alkyl, where the substituted alkyl is substituted with an oxo.

[0112] Particular compounds of interest of Formula Ic, and salts or solvates or stereoisomers thereof, include:

##STR00014##

N-(furan-2-yl(8-methoxyquinolin-7-yl)methyl)isobutyramide (Compound SD70-23).

[0113] In some instances, Compound SD70-23 finds use as a control compound, where the activities of other compounds of the present disclosure may be compared to the level of activity (or substantial lack thereof) of Compound SD70-23. As such, in certain embodiments, particular compounds and pharmaceutical compositions of the present disclosure, which show activity as inhibitors of histone demethylase JMJD2C and/or cytotoxic effects on androgen-independent prostate cancer cells, do not include Compound SD70-23.

[0114] Embodiments of the present disclosure include compounds of Formula II, shown below. Pharmaceutical compositions and methods of the present disclosure may also include compounds of Formula II.

Formula II

[0115] Embodiments of the present disclosure include a compound of Formula II:

##STR00015##

wherein

[0116] R.sup.7 is H or (CH.sub.2).sub.nYR.sup.3, wherein n is an integer from 1 to 6, and Y is selected from O, NH, and NR.sup.9; and

[0117] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8 and R.sup.9 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl,or a salt or stereoisomer thereof.

[0118] In certain embodiments, R.sup.7 is H or (CH.sub.2).sub.nYR.sup.3. In certain embodiments, R.sup.7 is H. In certain embodiments, R.sup.7 is (CH.sub.2).sub.nYR.sup.3. In certain embodiments, n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6). In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, Y is selected from O, NH, and NR.sup.9. In certain embodiments, Y is O. In certain embodiments, Y is NH. In certain embodiments, Y is NR.sup.9.

[0119] In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8 and R.sup.9 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.

[0120] In certain embodiments, R.sup.1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In certain embodiments, R.sup.1 is H. In certain embodiments, R.sup.1 is alkyl or substituted alkyl. In certain embodiments, R.sup.1 is alkyl, such as C.sub.1-6 alkyl or C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is substituted alkyl, such as substituted C.sub.1-6 alkyl or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is alkenyl or substituted alkenyl. In certain embodiments, R.sup.1 is alkynyl or substituted alkynyl. In certain embodiments, R.sup.1 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.1 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.1 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.1 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.1 is heterocyclyl, such as C.sub.3-10 heterocyclyl, C.sub.3-8 heterocyclyl or C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.1 is substituted heterocyclyl, such as substituted C.sub.3-10 heterocyclyl, substituted C.sub.3-8 heterocyclyl or substituted C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.1 is aryl or substituted aryl. In certain embodiments, R.sup.1 is aryl, such as C.sub.3-10 aryl, C.sub.4-8 aryl or C.sub.5-6 aryl. In certain embodiments, R.sup.1 is substituted aryl, such as substituted C.sub.3-10 aryl, substituted C.sub.4-8 aryl or substituted C.sub.5-6 aryl. In certain embodiments, R.sup.1 is heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.1 is heteroaryl, such as C.sub.3-10 heteroaryl, C.sub.4-8 heteroaryl or C.sub.5-6 heteroaryl. In certain embodiments, R.sup.1 is substituted heteroaryl, such as substituted C.sub.3-10 heteroaryl, substituted C.sub.4-8 heteroaryl or substituted C.sub.5-6 heteroaryl.

[0121] In certain embodiments, R.sup.2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In certain embodiments, R.sup.2 is H. In certain embodiments, R.sup.2 is alkyl or substituted alkyl. In certain embodiments, R.sup.2 is alkyl, such as C.sub.1-6 alkyl or C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is substituted alkyl, such as substituted C.sub.1-6 alkyl or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is alkenyl or substituted alkenyl. In certain embodiments, R.sup.2 is alkynyl or substituted alkynyl. In certain embodiments, R.sup.2 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.2 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.2 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.2 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.2 is heterocyclyl, such as C.sub.3-10 heterocyclyl, C.sub.3-8 heterocyclyl or C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.2 is substituted heterocyclyl, such as substituted C.sub.3-10 heterocyclyl, substituted C.sub.3-8 heterocyclyl or substituted C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.2 is aryl or substituted aryl. In certain embodiments, R.sup.2 is aryl, such as C.sub.3-10 aryl, C.sub.4-8 aryl or C.sub.5-6 aryl. In certain embodiments, R.sup.2 is substituted aryl, such as substituted C.sub.3-10 aryl, substituted C.sub.4-8 aryl or substituted C.sub.5-6 aryl. In certain embodiments, R.sup.2 is heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.2 is heteroaryl, such as C.sub.3-10 heteroaryl, C.sub.4-8 heteroaryl or C.sub.5-6 heteroaryl. In certain embodiments, R.sup.2 is substituted heteroaryl, such as substituted C.sub.3-10 heteroaryl, substituted C.sub.4-8 heteroaryl or substituted C.sub.5-6 heteroaryl.

[0122] In certain embodiments, R.sup.3 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In certain embodiments, R.sup.3 is H. In certain embodiments, R.sup.3 is alkyl or substituted alkyl. In certain embodiments, R.sup.3 is alkyl, such as C.sub.1-6 alkyl or C.sub.1-3 alkyl. In certain embodiments, R.sup.3 is substituted alkyl, such as substituted C.sub.1-6 alkyl or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.3 is alkenyl or substituted alkenyl. In certain embodiments, R.sup.3 is alkynyl or substituted alkynyl. In certain embodiments, R.sup.3 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.3 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.3 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.3 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.3 is heterocyclyl, such as C.sub.3-10 heterocyclyl, C.sub.3-8 heterocyclyl or C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.3 is substituted heterocyclyl, such as substituted C.sub.3-10 heterocyclyl, substituted C.sub.3-8 heterocyclyl or substituted C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.3 is aryl or substituted aryl. In certain embodiments, R.sup.3 is aryl, such as C.sub.3-10 aryl, C.sub.4-8 aryl or C.sub.5-6 aryl. In certain embodiments, R.sup.3 is substituted aryl, such as substituted C.sub.3-10 aryl, substituted C.sub.4-8 aryl or substituted C.sub.5-6 aryl. In certain embodiments, R.sup.3 is heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.3 is heteroaryl, such as C.sub.3-10 heteroaryl, C.sub.4-8 heteroaryl or C.sub.5-6 heteroaryl. In certain embodiments, R.sup.3 is substituted heteroaryl, such as substituted C.sub.3-10 heteroaryl, substituted C.sub.4-8 heteroaryl or substituted C.sub.5-6 heteroaryl.

[0123] In certain embodiments, R.sup.4 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In certain embodiments, R.sup.4 is H. In certain embodiments, R.sup.4 is alkyl or substituted alkyl. In certain embodiments, R.sup.4 is alkyl, such as C.sub.1-6 alkyl or C.sub.1-3 alkyl. In certain embodiments, R.sup.4 is substituted alkyl, such as substituted C.sub.1-6 alkyl or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.4 is alkenyl or substituted alkenyl. In certain embodiments, R.sup.4 is alkynyl or substituted alkynyl. In certain embodiments, R.sup.4 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.4 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.4 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.4 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.4 is heterocyclyl, such as C.sub.3-10 heterocyclyl, C.sub.3-8 heterocyclyl or C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.4 is substituted heterocyclyl, such as substituted C.sub.3-10 heterocyclyl, substituted C.sub.3-8 heterocyclyl or substituted C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.4 is aryl or substituted aryl. In certain embodiments, R.sup.4 is aryl, such as C.sub.3-10 aryl, C.sub.4-8 aryl or C.sub.5-6 aryl. In certain embodiments, R.sup.4 is substituted aryl, such as substituted C.sub.3-10 aryl, substituted C.sub.4-8 aryl or substituted C.sub.5-6 aryl. In certain embodiments, R.sup.4 is heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.4 is heteroaryl, such as C.sub.3-10 heteroaryl, C.sub.4-8 heteroaryl or C.sub.5-6 heteroaryl. In certain embodiments, R.sup.4 is substituted heteroaryl, such as substituted C.sub.3-10 heteroaryl, substituted C.sub.4-8 heteroaryl or substituted C.sub.5-6 heteroaryl.

[0124] In certain embodiments, R.sup.5 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In certain embodiments, R.sup.5 is H. In certain embodiments, R.sup.5 is alkyl or substituted alkyl. In certain embodiments, R.sup.5 is alkyl, such as C.sub.1-6 alkyl or C.sub.1-3 alkyl. In certain embodiments, R.sup.5 is substituted alkyl, such as substituted C.sub.1-6 alkyl or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.5 is alkenyl or substituted alkenyl. In certain embodiments, R.sup.5 is alkynyl or substituted alkynyl. In certain embodiments, R.sup.5 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.5 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.5 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.5 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.5 is heterocyclyl, such as C.sub.3-10 heterocyclyl, C.sub.3-8 heterocyclyl or C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.5 is substituted heterocyclyl, such as substituted C.sub.3-10 heterocyclyl, substituted C.sub.3-8 heterocyclyl or substituted C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.5 is aryl or substituted aryl. In certain embodiments, R.sup.5 is aryl, such as C.sub.3-10 aryl, C.sub.4-8 aryl or C.sub.5-6 aryl. In certain embodiments, R.sup.5 is substituted aryl, such as substituted C.sub.3-10 aryl, substituted C.sub.4-8 aryl or substituted C.sub.5-6 aryl. In certain embodiments, R.sup.5 is heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.5 is heteroaryl, such as C.sub.3-10 heteroaryl, C.sub.4-8 heteroaryl or C.sub.5-6 heteroaryl. In certain embodiments, R.sup.5 is substituted heteroaryl, such as substituted C.sub.3-10 heteroaryl, substituted C.sub.4-8 heteroaryl or substituted C.sub.5-6 heteroaryl.

[0125] In certain embodiments, R.sup.6 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In certain embodiments, R.sup.6 is H. In certain embodiments, R.sup.6 is alkyl or substituted alkyl. In certain embodiments, R.sup.6 is alkyl, such as C.sub.1-6 alkyl or C.sub.1-3 alkyl. In certain embodiments, R.sup.6 is substituted alkyl, such as substituted C.sub.1-6 alkyl or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.6 is alkenyl or substituted alkenyl. In certain embodiments, R.sup.6 is alkynyl or substituted alkynyl. In certain embodiments, R.sup.6 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.6 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.6 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.6 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.6 is heterocyclyl, such as C.sub.3-10 heterocyclyl, C.sub.3-8 heterocyclyl or C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.6 is substituted heterocyclyl, such as substituted C.sub.3-10 heterocyclyl, substituted C.sub.3-8 heterocyclyl or substituted C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.6 is aryl or substituted aryl. In certain embodiments, R.sup.6 is aryl, such as C.sub.3-10 aryl, C.sub.4-8 aryl or C.sub.5-6 aryl. In certain embodiments, R.sup.6 is substituted aryl, such as substituted C.sub.3-10 aryl, substituted C.sub.4-8 aryl or substituted C.sub.5-6 aryl. In certain embodiments, R.sup.6 is heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.6 is heteroaryl, such as C.sub.3-10 heteroaryl, C.sub.4-8 heteroaryl or C.sub.5-6 heteroaryl. In certain embodiments, R.sup.6 is substituted heteroaryl, such as substituted C.sub.3-10 heteroaryl, substituted C.sub.4-8 heteroaryl or substituted C.sub.5-6 heteroaryl.

[0126] In certain embodiments, R.sup.8 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In certain embodiments, R.sup.8 is H. In certain embodiments, R.sup.8 is alkyl or substituted alkyl. In certain embodiments, R.sup.8 is alkyl, such as C.sub.1-6 alkyl or C.sub.1-3 alkyl. In certain embodiments, R.sup.8 is substituted alkyl, such as substituted C.sub.1-6 alkyl or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.8 is alkenyl or substituted alkenyl. In certain embodiments, R.sup.8 is alkynyl or substituted alkynyl. In certain embodiments, R.sup.8 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.8 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.8 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.8 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.8 is heterocyclyl, such as C.sub.3-10 heterocyclyl, C.sub.3-8 heterocyclyl or C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.8 is substituted heterocyclyl, such as substituted C.sub.3-10 heterocyclyl, substituted C.sub.3-8 heterocyclyl or substituted C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.8 is aryl or substituted aryl. In certain embodiments, R.sup.8 is aryl, such as C.sub.3-10 aryl, C.sub.4-8 aryl or C.sub.5-6 aryl. In certain embodiments, R.sup.8 is substituted aryl, such as substituted C.sub.3-10 aryl, substituted C.sub.4-8 aryl or substituted C.sub.5-6 aryl. In certain embodiments, R.sup.8 is heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.8 is heteroaryl, such as C.sub.3-10 heteroaryl, C.sub.4-8 heteroaryl or C.sub.5-6 heteroaryl. In certain embodiments, R.sup.8 is substituted heteroaryl, such as substituted C.sub.3-10 heteroaryl, substituted C.sub.4-8 heteroaryl or substituted C.sub.5-6 heteroaryl. In certain embodiments, R.sup.9 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. In certain embodiments, R.sup.9 is H. In certain embodiments, R.sup.9 is alkyl or substituted alkyl. In certain embodiments, R.sup.9 is alkyl, such as C.sub.1-6 alkyl or C.sub.1-3 alkyl. In certain embodiments, R.sup.9 is substituted alkyl, such as substituted C.sub.1-6 alkyl or substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.9 is alkenyl or substituted alkenyl. In certain embodiments, R.sup.9 is alkynyl or substituted alkynyl. In certain embodiments, R.sup.9 is cycloalkyl or substituted cycloalkyl. In certain embodiments, R.sup.9 is cycloalkyl, such as C.sub.3-10 cycloalkyl, C.sub.3-8 cycloalkyl or C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.9 is substituted cycloalkyl, such as substituted C.sub.3-10 cycloalkyl, substituted C.sub.3-8 cycloalkyl or substituted C.sub.3-6 cycloalkyl. In certain embodiments, R.sup.9 is heterocyclyl or substituted heterocyclyl. In certain embodiments, R.sup.9 is heterocyclyl, such as C.sub.3-10 heterocyclyl, C.sub.3-8 heterocyclyl or C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.9 is substituted heterocyclyl, such as substituted C.sub.3-10 heterocyclyl, substituted C.sub.3-8 heterocyclyl or substituted C.sub.3-6 heterocyclyl. In certain embodiments, R.sup.9 is aryl or substituted aryl. In certain embodiments, R.sup.9 is aryl, such as C.sub.3-10 aryl, C.sub.4-8 aryl or C.sub.5-6 aryl. In certain embodiments, R.sup.9 is substituted aryl, such as substituted C.sub.3-10 aryl, substituted C.sub.4-8 aryl or substituted C.sub.5-6 aryl. In certain embodiments, R.sup.9 is heteroaryl or substituted heteroaryl. In certain embodiments, R.sup.9 is heteroaryl, such as C.sub.3-10 heteroaryl, C.sub.4-8 heteroaryl or C.sub.5-6 heteroaryl. In certain embodiments, R.sup.9 is substituted heteroaryl, such as substituted C.sub.3-10 heteroaryl, substituted C.sub.4-8 heteroaryl or substituted C.sub.5-6 heteroaryl.

General Synthetic Procedures

[0127] Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith and March, March s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0128] Compounds as described herein can be purified by any purification protocol known in the art, including chromatography, such as HPLC, preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. In certain embodiments, the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, edE. Stahl, Springer-Verlag, New York, 1969.

[0129] During any of the processes for preparation of the subject compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as J. F. W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third edition, Wiley, New York 1999, in The Peptides; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in Methoden der organischen Chemie, Houben-Weyl, 4.sup.th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, Aminosauren, Peptide, Proteine, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and/or in Jochen Lehmann, Chemie der Kohlenhydrate: Monosaccharide and Derivate, Georg Thieme Verlag, Stuttgart 1974. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0130] The subject compounds can be synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods. Exemplary synthetic methods for the 8-hydroxyquinoline derivatives described herein are described below. Those of skill in the art will also be able to readily adapt these methods for the synthesis of specific 8-hydroxyquinoline derivatives as described herein.

General Synthetic Scheme for 8-Hydroxyquinoline Derivatives

[0131] ##STR00016##

Representative Synthesis of Compound SD70 and Derivatives Thereof

[0132] In certain embodiments, 8-hydroxyquinoline (1, 580 mg, 4.0 mmol), furfural (2, 768 mg, 8.0 mmol), and isobutyramide (3, 523 mg, 6.0 mmol) are mixed in ethanol (2 mL) in a glass, pressure tube. The mixtures are heated at 150 C. for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The residue may be chromatographed on silica gel (hexane/ethyl acetate 6/1, 1/1) to afford SD70 as a solid. In certain embodiments, SD70 can be further purified by recrystallization in the mixtures of hexane/ethyl acetate (1/1).

Pharmaceutical Compositions

[0133] In certain embodiments, the disclosed compounds are useful for the inhibition of histone demethylase JMJD2C activity and/or the treatment of a disease or disorder that is mediated through the activity of histone demethylase JMJD2C, such as prostate cancer. In certain embodiments, the disclosed compounds are useful for the treatment of cancer, e.g., the treatment of a castration-resistant prostate cancer (CRPC). Accordingly, pharmaceutical compositions comprising at least one disclosed compound are also described herein.

[0134] A pharmaceutical composition that includes a subject compound may be administered to a patient alone, or in combination with other supplementary active agents. The pharmaceutical compositions may be manufactured using any of a variety of processes, including, but not limited to, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing, and the like. The pharmaceutical composition can take any of a variety of forms including, but not limited to, a sterile solution, suspension, emulsion, lyophilisate, tablet, pill, pellet, capsule, powder, syrup, elixir or any other dosage form suitable for administration.

[0135] A subject compound may be administered to a subject using any convenient means capable of resulting in the desired reduction in disease condition or symptom. Thus, a subject compound can be incorporated into a variety of formulations for therapeutic administration. More particularly, a subject compound can be formulated into pharmaceutical compositions by combination with appropriate pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, aerosols, and the like

[0136] Formulations for pharmaceutical compositions are described in, for example, Remingtons Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, Pa., 19th Edition, 1995, which describes examples of formulations (and components thereof) suitable for pharmaceutical delivery of disclosed compounds. Pharmaceutical compositions that include at least one of the subject compounds can be formulated for use in human or veterinary medicine. Particular formulations of a disclosed pharmaceutical composition may depend, for example, on the mode of administration and/or on the location of the subject to be treated. In some embodiments, formulations include a pharmaceutically acceptable carrier in addition to at least one active ingredient, such as a subject compound. In other embodiments, other medicinal or pharmaceutical agents, for example, with similar, related or complementary effects on the disease or condition being treated can also be included as active ingredients in a pharmaceutical composition.

[0137] Pharmaceutically acceptable carriers useful for the disclosed methods and compositions may depend on the particular mode of administration being employed. For example, parenteral formulations may include injectable fluids, such as, but not limited to, pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. For solid compositions (e.g., powder, pill, tablet, or capsule forms), non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, pharmaceutical compositions to be administered can optionally contain minor amounts of non-toxic auxiliary substances (e.g., excipients), such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like; for example, sodium acetate or sorbitan monolaurate. Other examples of excipients include, nonionic solubilizers, such as cremophor, or proteins, such as human serum albumin or plasma preparations.

[0138] Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) water (e.g., pyrogen-free water); (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0139] The disclosed pharmaceutical compositions may be formulated as a pharmaceutically acceptable salt of a disclosed compound. Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids. Non-limiting examples of suitable inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydroiodic acid, and phosphoric acid. Non-limiting examples of suitable organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, methyl sulfonic acid, salicylic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, asparagic acid, aspartic acid, benzenesulfonic acid, para-tolucncsulfonic acid, naphthalenesulfonic acid, and the like. In certain embodiments, the pharmaceutically acceptable salt includes formic acid. In certain embodiments, the pharmaceutically acceptable salt includes trifluoroacetic acid. Other suitable pharmaceutically acceptable salts are found in Remingtons Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985. A pharmaceutically acceptable salt may also serve to adjust the osmotic pressure of the composition.

[0140] A subject compound can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents. Such preparations can be used for oral administration.

[0141] A subject compound can be formulated into preparations for injection by dissolving, suspending or emulsifying the compound in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives. The preparation may also be emulsified or the active ingredient encapsulated in liposome vehicles. Formulations suitable for injection can be administered by an intravitreal, intraocular, intramuscular, subcutaneous, sublingual, or other route of administration, e.g., injection into the gum tissue or other oral tissue. Such formulations are also suitable for topical administration.

[0142] In some embodiments, a subject compound can be delivered by a continuous delivery system. The term continuous delivery system is used interchangeably herein with controlled delivery system and encompasses continuous (e.g., controlled) delivery devices (e.g., pumps) in combination with catheters, injection devices, and the like, a wide variety of which are known in the art.

[0143] A subject compound can be utilized in aerosol formulation to be administered via inhalation. A subject compound can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.

[0144] Furthermore, a subject compound can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. A subject compound can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are substantially solid at room temperature.

[0145] The term unit dosage form, as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of a subject compound calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for a subject compound depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0146] The dosage form of a disclosed pharmaceutical composition may be determined by the mode of administration chosen. For example, in addition to injectable fluids, topical or oral dosage forms may be employed. Topical preparations may include eye drops, ointments, sprays and the like. Oral formulations may be liquid (e.g., syrups, solutions or suspensions), or solid (e.g., powders, pills, tablets, or capsules). Methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art.

[0147] Certain embodiments of the pharmaceutical compositions that include a subject compound may be formulated in unit dosage form suitable for individual administration of precise dosages. The amount of active ingredient administered may depend on the subject being treated, the severity of the affliction, and the manner of administration, and is known to those skilled in the art. In certain instances, the formulation to be administered contains a quantity of the compounds disclosed herein in an amount effective to achieve the desired effect in the subject being treated.

[0148] Each therapeutic compound can independently be in any dosage form, such as those described herein, and can also be administered in various ways, as described herein. For example, the compounds may be formulated together, in a single dosage unit (that is, combined together in one form such as capsule, tablet, powder, or liquid, etc.) as a combination product. Alternatively, when not formulated together in a single dosage unit, an individual subject compound may be administered at the same time as another therapeutic compound or sequentially, in any order thereof.

Methods of Administration

[0149] Compounds disclose herein can inhibit histone demethylase JMJD2C activity. Accordingly, such compounds are useful for treating a disease or disorder that is mediated through the activity of histone demethylase JMJD2C in a subject. In certain embodiments, the subject compounds are useful for treating a disease or disorder that is associated with the histone demethylase JMJD2C activity in a subject, such as prostate cancer. Compounds disclose herein exhibit cytotoxic effects on androgen-independent prostate cancer cells. Accordingly, such compounds are useful for treating castration-resistant prostate cancer (CRPC).

[0150] The route of administration may be selected according to a variety of factors including, but not limited to, the condition to be treated, the formulation and/or device used, the patient to be treated, and the like. Routes of administration useful in the disclosed methods include but are not limited to oral and parenteral routes, such as intravenous (iv), intraperitoneal (ip), rectal, topical, ophthalmic, nasal, and transdermal. Formulations for these dosage forms are described herein.

[0151] An effective amount of a subject compound may depend, at least, on the particular method of use, the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition. A therapeutically effective amount of a composition is a quantity of a specified compound sufficient to achieve a desired effect in a subject (e.g., patient) being treated. For example, this may be the amount of a subject compound necessary to prevent, inhibit, reduce or relieve a disease or disorder, such as prostate cancer, in a subject. Ideally, a therapeutically effective amount of a compound is an amount sufficient to prevent, inhibit, reduce or relieve a disease or disorder that is mediated through histone demethylase JMJD2C activity in a subject without causing a substantial cytotoxic effect on other types of cells (e.g., non-cancerous cells) in the subject. For example, a therapeutically effective amount of a compound is an amount sufficient to prevent, inhibit, reduce or relieve a disease or disorder, such as prostate cancer, in a subject without causing a substantial cytotoxic effect on other types of cells (e.g., non-cancerous cells) in the subject.

[0152] Therapeutically effective doses of a subject compound or pharmaceutical composition can be determined by one of skill in the art, with a goal of achieving local (e.g., tissue) concentrations that are at least as high as the IC.sub.50 of an applicable compound disclosed herein.

[0153] An example of a dosage range is from 0.1 to 200 mg/kg body weight orally in single or divided doses. In some embodiments, a dosage range is from 1.0 to 100 mg/kg body weight orally in single or divided doses, including from 1.0 to 50 mg/kg body weight, from 1.0 to 25 mg/kg body weight, from 1.0 to 10 mg/kg body weight (assuming an average body weight of approximately 70 kg; values may be adjusted accordingly for persons weighing more or less than average). For oral administration, the compositions are, for example, provided in the form of a tablet containing from about 10 to about 1000 mg of the active ingredient, such as 25 to 750 mg, or 50 to 500 mg, for example 75 mg, 100 mg, 200 mg, 250 mg, 400 mg, 500 mg, 600 mg, 750 mg, or 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject being treated. In certain embodiments of an oral dosage regimen, a tablet containing from 500 mg to 1000 mg active ingredient is administered once (e.g., a loading dose) followed by administration of (i.e., half) dosage tablets (e.g., from 250 to 500 mg) each 6 to 24 hours for 3 days or more.

[0154] The specific dose level and frequency of dosage for any particular subject may be varied and may depend upon a variety of factors, including the activity of the subject compound, the metabolic stability and length of action of that compound, the age, body weight, general health, sex and diet of the subject, mode and time of administration, rate of excretion, drug combination, and severity of the condition of the host undergoing therapy.

[0155] Embodiments of the present disclosure also include combinations of one or more disclosed compounds with one or more other agents or therapies useful in the treatment of a disease or disorder. In certain instances, the disease or disorder is cell proliferative disorder, such as prostate cancer. For example, one or more disclosed compounds may be administered in combination with therapeutically effective doses of other medicinal and pharmaceutical agents, or in combination other non-medicinal therapies, such as hormone or radiation therapy. The term administration in combination with refers to both concurrent and sequential administration of the active agents.

[0156] In some embodiments, a suitable subject for treatment with one or more of the compounds described herein is a subject, e.g., a mammalian subject, e.g. a human subject, suffering from castration-resistant prostate cancer or at risk of developing castration-resistant prostate cancer. For example, a suitable subject may be one who has been diagnosed as having castration-resistant prostate cancer or at risk of developing castration-resistant prostate cancer. In some embodiments, a suitable subject may be one who has undergone androgen deprivation treatment but exhibits progressive signs of disease following such treatment.

[0157] Aspects, including embodiments, of the present subject matter described above may be beneficial alone or in combination, with one or more other aspects or embodiments. This is intended to provide support for all such combinations of aspects.

EXAMPLES

[0158] The following example is put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used.

Example 1

Synthesis of Compound SD70-17

[0159] ##STR00017##

[0160] SD70-15 (0.40 g, 1.7 mmol) and a 2-morpholinoethylamine (4, 0.27 ml, 2.1 mmol) were dissolved in acetonitrile, to which NaHCO.sub.3 (0.17 g, 2.1 mmol) was added. The mixtures were stirred at room temperature for 10 h and then concentrated in vacuo. Chromatography on silica gel afforded SD70-17.

Example 2

Synthesis of Compound SD70-18

[0161] ##STR00018##

[0162] 8-Hydroxyquinoline (1, 2.0 g, 14 mmol), paraformaldehyde (0.93 g, 31 mmol), and 4-(2-pyridinyl)piperazine (5, 2.4 mL, 16 mmol) were dissolved in ethanol (125 mL) and then refluxed for 4 hours. The reaction mixtures were cooled to room temperature, concentrated under reduced pressure, and chromatographed on silica gel to afford SD70-18.

Example 3

Synthesis of Compound SD70-19

[0163] ##STR00019##

[0164] 8-Hydroxyquinoline (1, 2.0 g, 14 mmol), paraformaldehyde (0.93 g, 31 mmol), and 2-morpholinoethylamine (4, 2.7 ml, 21 mmol) were dissolved in ethanol (125 mL) and then refluxed for 4 hours. The reaction mixtures were cooled to room temperature, concentrated under reduced pressure, and chromatographed on silica gel to afford SD70-19.

Example 4

Synthesis of Compound SD70-21

[0165] ##STR00020##

[0166] 8-Hydroxyquinoline (1, 2.0 g, 14 mmol), paraformaldehyde (0.93 g, 31 mmol), and isoamylamine (6, 1.8 ml, 15 mmol) were dissolved in ethanol (125 mL) and then refluxed for 4 hours. The reaction mixtures were cooled to room temperature, concentrated under reduced pressure, and chromatographed on silica gel to afford SD70-21.

Example 5

Effect of Selected 8-hydroquinoline Derivatives on Androgen-Independent Prostate Cancer Cells

[0167] Cell viability assays were performed on three representative prostate cancer cell lines (i.e., CWR22Rvl, PC3 and DU145) to determine the effect of treatment with a series of 8-hydroxyquinoline derivatives.

Materials and Methods

[0168] Cell viability was assessed 48 hours after compound treatment with the CellTiter-Glo Luminescent Cell Viability Assay (Promega), according to the manufacturer's protocol. Briefly, 5000 cells were plated into 96-well cell culture plates in DMEM supplemented with 10% FBS. After overnight incubation, compounds at indicated concentrations were added and the treatment was maintained for two days. At the end of compound treatment, 5.0 L of CellTiter-Glo Reagent was added to each well. Plates were returned to the incubator for 2 hours. Plates were then removed from the incubator and luminescence was measured in a standard luminescence plate reader. The luminescence signal was then used to calculate % of survival normalized to DMSO control treatment.

Results

[0169] The results of the cell viability assays are provided below in Table 1.

TABLE-US-00001 TABLE 1 Cytotoxic effects of 8-hydroxyquinoline derivatives on androgen-independent prostate cancer cells % CWR22Rv1 % PC3 % DU145 Survival Survival Survival (Compound (Compound (Compound Compound Compound Identification and Source at 10 M) at 2 M) at 2 M) DMSO 100 100 100 SD70 N-(furan-2-yl(8-hydroxyquinolin-7- 9 14 26 yl)methyl)isobutyramide (available from Chem Div, Inc., Catalog No. K839-0073) SD70-1 N-((5-chloro-8-hydroxyquinolin-7- 93 47 87 yl)(furan-2-yl)methyl)propionamide (available from ChemBridge Corp., Catalog No. 6955265) SD70-2 N-((5-chloro-8-hydroxyquinolin-7- 100 9 32 yl)(furan-2-yl)methyl)isobutyramide (available from ChemBridge Corp., Catalog No. 7119963) SD70-3 N-((5-chloro-8-hydroxyquinolin-7- 110 88 110 yl)(furan-2-yl)methyl)acetamide (available from ChemBridge Corp., Catalog No. 6968435) SD70-4 N-((5-chloro-8-hydroxyquinolin-7- 110 7 29 yl)(furan-2-yl)methyl)butyramide (available from ChemBridge Corp., Catalog No. 7203222) SD70-5 N-((5-chloro-8-hydroxyquinolin-7- 94 23 31 yl)(furan-2-yl)methyl)nicotinamide (available from ChemBridge Corp., Catalog No. 6403782) SD70-6 N-((5-chloro-8-hydroxyquinolin-7- 21 24 50 yl)(furan-2-yl)methyl)-4- methoxybenzamide (available from ChemBridge Corp., Catalog No. 6383468) SD70-7 N-((5-chloro-8-hydroxyquinolin-7- 28 21 21 yl)(furan-2-yl)methyl)-2- phenoxyacetamide (available from ChemBridge Corp., Catalog No. 6420252) SD70-8 N-((5-chloro-8-hydroxyquinolin-7- 10 61 42 yl)(2- methoxyphenyl)methyl)propionamide (available from ChemBridge Corp., Catalog No. 6983050) SD70-9 N-((5-chloro-8-hydroxyquinolin-7- 18 21 10 yl)(3,4- dimethoxyphenyl)methyl)propionamide (available from ChemBridge Corp., Catalog No. 6988304) SD70-10 N-(furan-2-yl(8-hydroxy-5- 110 93 100 nitroquinolin-7-yl)methyl)propionamide (available from ChemBridge Corp., Catalog No. 6993246) SD70-11 N-(furan-2-yl(8-hydroxyquinolin-7- 16 79 120 yl)methyl)propionamide (available from ChemBridge Corp., Catalog No. 5927497) SD70-15 5-(chloromethyl)quinolin-8-ol 91 96 100 hydrochloride (available from Matrix Scientific, Inc., Catalog No. 060183) SD70-16 5-(benzyloxymethyl)quinolin-8-ol 20 14 19 (available from Chem Div, Inc., Catalog No. BB57-4916) SD70-17 5-((2- 7 98 100 morpholinoethylamino)methyl)quinolin- 8-ol SD70-18 7-((4-(pyridin-2-yl)piperazin-1- 27 125 110 yl)methyl)quinolin-8-ol SD70-19 7-((2- 107 98 94 morpholinoethylamino)methyl)quinolin- 8-ol SD70-20 7-(piperidin-1-ylmethyl)quinolin-8-ol 99 98 88 (available from Sigma-Aldrich, Catalog No. CDS017373) SD70-21 7-((isopentylamino)methyl)quinolin-8- 93 93 100 ol SD70-22 N-((8-hydroxyquinolin-7-yl)(4- 18 13 21 methoxyphenyl)methyl)isobutyramide isobutyramide (available from Chem Div, Inc., Catalog No. K839-0080) SD70-23 N-(furan-2-yl(8-methoxyquinolin-7- 96 N/A N/A yl)methyl)isobutyramide SD70-24 N-((3,4-dimethoxyphenyl)(8- 12 N/A N/A hydroxyquinolin-7- yl)methyl)isobutyramide (available from ChemBridge Corp., Catalog No. 5930428) SD70-25 N-((8-hydroxyquinolin-7-yl)(4- 16 N/A N/A nitrophenyl)methyl)isobutyramide (available from Ambinter Stock Screening Collection (Greenpharma S.A.S.), Catalog No. Amb10820457)