Calanolides for inhibiting BTK

A pharmaceutical composition for inhibiting the activity of Tec family tyrosine kinase, comprising an effective amount of a compound of formula I:

• where:
• R7 is —C(═O)R8, —CH(—OH)—R8, or —CH2—R8 wherein R8 is (C1-C4) alkyl, or R7 and X1 together form a fused pyran ring;
• R1, R2, R3, R4, R5, R6, R14, R15 and R16 are the same or different, and are each independently H, OH, SH, CN, halogen, (C1-C4) alkoxy, (C1-C4) alkylthio, (C1-C4) alkyl, (C3-C7) cycloalkyl, aryl, heteroaryl, or NRaRb;
• wherein Ra and Rb are each independently hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl;
• or Ra and Rb together with the nitrogen to which they are attached form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino;
• — — — is an optional bond;
• X1 is a hydrogen bonding group;
• and
• X2 is a hydrogen bonding group, with the proviso that when R16 is absent, x2 is a hydrogen bonding group that is doubly bonded to a ring carbon;
• or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula II:

• where:
• R is (C1-C4) alkyl;
• R1, R2, R3, R4, R5, R6, and R16 are the same or different, and are each independently H, OH, SH, CN, halogen, (C1-C4) alkoxy, (C1-C4) alkylthio, (C1-C4) alkyl, (C3-C7) cycloalkyl, aryl, heteroaryl, or NRaRb;
• wherein Ra and Rb are each independently hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl;
• or Ra and Rb together with the nitrogen to which they are attached form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino;
• X1 is OH, SH, NH2, CONH2, COOH;
• or X1 is (C1-C4) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl, each of which is substituted with one or more of OH, SH, NH2, CONH2, COOH;
• X2 is ═O, ═S, ═NH, ═N—OH, ═N—OR9, where R9 is (C1-C4) alkyl, or (C3-C7) cycloalkyl;
• or X2 is (C1-C4) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl, each of which is substituted with one or more of ═O, ═S, ═NH, ═N—OH, ═N—OR9, where R9 is (C1-C4) alkyl or (C3-C7) cycloalkyl, with the proviso that when R16 is absent, X2 is a hydrogen bonding group that is doubly bonded to a ring carbon;
• or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.

A method for treating a pathological condition regulated by Tec family tyrosine kinase activity, comprising administering a compound of formula I:

• where:
• R7 is —C(═O)R8, —CH(—OH)—R8, or —CH2—R8 wherein R8 is (C1-C4)alkyl, or R7 and X1 together form a fused pyran ring;
• R1, R2, R3, R4, R5, R6, R14, R15, and R16 are the same or different, and are each independently H, OH, SH, CN, halogen, (C1-C4) alkoxy, (C1-C4) alkylthio, (C1-C4) alkyl, (C3-C7) cycloalkyl, aryl, heteroaryl, or NRaRb;
• wherein Ra and Rb are each independently hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl;
• or Ra and Rb together with the nitrogen to which they are attached form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino;
• — — — is an optional bond;
• X1 is a hydrogen bonding group;
• and
• X2 is a hydrogen bonding group, with the proviso that when R16 is absent, X2 is a hydrogen bonding group that is doubly bonded to a ring carbon;
• or a pharmaceutically acceptable salt thereof.