Sphingosine Kinase Inhibitors and Methods of Their Use

A compound of the formula I

• wherein:
• X is —C(R3,R4)N(R5)—, —C(O)N(R4)—, —N(R4)C(O)—, —C(R4,R5)—, —N(R4)—, —O—, —S—, —C(O)—, —S(O)2—, —S(O)2N(R4)— or —N(R4)S(O)2—;
• R1 is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, oxo (═O), —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, or mono or dialkylthiocarbamoyl;
• R2 is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, oxo (═O), —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, or mono or dialkylthiocarbamoyl;
• wherein the alkyl and ring portion of each of the above R1 and R2 groups is optionally substituted with up to 5 groups that are independently (C1-C6) alkyl, halogen, haloalkyl, —OC(O)(C1-C6 alkyl), —C(O)O(C1-C6 alkyl), —CONR′R″, —OC(O)NR′R″, —NR′C(O)R″, —CF3, —OCF3, —OH, C1-C6 alkoxy, hydroxyalkyl, —CN, —CO2H, —SH, —S-alkyl, —SOR′R″, —SO2R′, —NO2, or NR′R″, wherein R′ and R″ are independently H or (C1-C6) alkyl, and wherein each alkyl portion of a substituent is optionally further substituted with 1, 2, or 3 groups independently selected from halogen, CN, OH, NH2;
• and
• R3 is H, alkyl, preferably lower alkyl, or oxo, provided that when R3 and R4 are on the same carbon, and R3 is oxo, then R4 is absent;
• R4 and R5 are independently H or (C1-C6)alkyl,
• or a pharmaceutically acceptable salt, hydrate or solvate thereof, provided that the compound is not butyric acid 4-{2-[4-(4-chloro-phenyl)-thiazol-2-ylcarbamoyl]-vinyl}-2-methoxy-phenyl ester.

A compound of the formula (III):

• wherein:
• X is —C(R3,R4)N(R5)—, —C(O)N(R4)—, —N(R4)C(O)—, —C(R4,R5)—, —N(R4)—, —O—, —S—, —C(O)—, —S(O)2—, —S(O)2N(R4)— or —N(R4)S(O)2—;
• R1 is halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, or —NH2.
• R2 is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, oxo (═O), —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, or mono or dialkylthiocarbamoyl;
• wherein the alkyl and ring portion of each of the above is optionally substituted with up to 5 groups that are independently (C1-C6) alkyl, halogen, haloalkyl, —OC(O)(C1-C6 alkyl), —C(O)O(C1-C6 alkyl), —CONR4R5, —OC(O)NR4R5, —NR4C(O)R5, —CF3, —OCF3, —OH, C1-C6 alkoxy, hydroxyalkyl, —CN, —CO2H, —SH, —S-alkyl, —SOR4R5, —SO2R4R5, —NO2, or NR4R5;
• and
• R3 is H, alkyl, preferably lower alkyl, or oxo, provided that when R3 and R4 are on the same carbon, and R3 is oxo, then R4 is absent;
• R4 and R5 are independently H or alkyl, preferably lower alkyl,
• or a pharmaceutically acceptable salt, hydrate or solvate thereof.

A compound of the formula (IV):

• wherein:
• X is —C(R3,R4)N(R5)—, —C(O)N(R4)—, —N(R4)C(O)—, —C(R4,R5)—, —N(R4)—, —O—, —S—, —C(O)—, —S(O)2—, —S(O)2N(R4)— or —N(R4)S(O)2—;
• Y is O or S;
• R1 is halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, or —NH2;
• R2 is H, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, aryl, alkylaryl, alkenylaryl, heterocyclyl, heteroaryl, alkylheteroaryl, heterocycloalkyl, alkyl-heterocycloalkyl, acyl, aroyl, halogen, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkanoyl, oxo (═O), —COOH, —OH, —SH, —S-alkyl, —CN, —NO2, —NH2, —CO2(alkyl), —OC(O)alkyl, carbamoyl, mono or dialkylaminocarbamoyl, mono or dialkylcarbamoyl, mono or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl, thiocarbamoyl, or mono or dialkylthiocarbamoyl;
• wherein the alkyl and ring portion of each of the above is optionally substituted with up to 5 groups that are independently (C1-C6) alkyl, halogen, haloalkyl, —OC(O)(C1-C6 alkyl), —C(O)O(C1-C6 alkyl), —CONR4R5, —OC(O)NR4R5, —NR4C(O)R5, —CF3, —OCF3, —OH, C1-C6 alkoxy, hydroxyalkyl, —CN, —CO2H, —SH, —S-alkyl, —SOR4R5, —SO2R4R5, —NO2, or NR4R5;
• and
• R3 is H, alkyl, preferably lower alkyl, or oxo, provided that when R3 and R4 are on the same carbon, and R3 is oxo, then R4 is absent;
• R4 and R5 are independently H or alkyl, preferably lower alkyl,
• or a pharmaceutically acceptable salt, hydrate or solvate thereof.