Hinokitiol analogues, methods of preparing and pharmaceutical compositions thereof

A method of preparing a compound of the following structural formula or a salt thereof:

• comprising reacting a compound of the following structural formula or a salt thereof:
• with 2-bromo-7-methoxycyclohepta-2,4,6-trien-1-one or a salt thereof:
• thereby providing the compound of structural formula or a salt thereof:
• wherein:
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is independently optionally substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having sp3 hybridization.

A method of preparing a compound of structural formula or a salt thereof:

• comprising combining a compound having structural formula or a salt thereof:
• with a demethylating agent;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy.

A method of preparing a compound of structural formula:

• or a salt thereof;
• comprising:
• (1) reacting a compound of structural formula;
• or a salt thereof;
• with a compound of structural formula:
• or a salt thereof;
• thereby providing a compound having structural formula:
• or a salt thereof;
• and
• (2) contacting the compound having structural formula:
• or a salt thereof;
• with a demethylating agent;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is optionally and independently substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having sp3 hybridization.

A method of preparing a compound of structural formula:

• or a salt thereof;
• comprising reacting a compound of structural formula:
• or a salt thereof;
• with a compound of structural formula:
• or a salt thereof;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy;
• Rb is hydrogen or methyl;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is optionally and independently substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having sp3 hybridization.

A method of preparing a compound of structural formula:

• or a salt thereof;
• comprising combining a compound having structural formula:
• or a salt thereof;
• with a demethylating agent;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy.

A method of preparing a compound of structural formula:

• or a salt thereof;
• comprising:
• (1) reacting 2-methoxycyclohepta-2,4,6-trien-1-one:
• or a salt thereof, with a brominating agent, thereby forming 3-bromo-2-methoxycyclohepta-2,4,6-trien-1-one:
• or a salt thereof,
• (2) reacting a compound of structural formula:
• or a salt thereof;
• with 3-bromo-2-methoxycyclohepta-2,4,6-trien-1-one:
• or a salt thereof, thereby forming a compound having structural formula:
• or a salt thereof;
• and
• (3) contacting the compound having structural formula:
• or a salt thereof;
• with a demethylating agent;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is optionally and independently substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having sp3 hybridization.

A method of preparing a compound of structural formula:

• or a salt thereof;
• comprising reacting a compound of structural formula:
• or a salt thereof;
• with a compound of structural formula:
• or a salt thereof;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy;
• Rb is hydrogen or methyl;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is optionally and independently substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having sp3 hybridization.

A method of preparing a compound of structural formula:

• or a salt thereof;
• comprising combining a compound having structural formula:
• or a salt thereof;
• with a demethylating agent;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-haloalkyl, and C1-6-alkoxy.

A method of preparing a compound of structural formula:

• or a salt thereof comprising:
• (1) contacting 7,7-dibromobicyclo[4.1.0]heptane-2,3-diol:
• or a salt thereof, with an oxidizing agent, thereby forming 4-bromo-2-hydroxycyclohepta-2,4,6-trien-1-one:
• or a salt thereof,
• (2) reacting a compound of structural formula:
• or a salt thereof;
• with 4-bromo-2-hydroxycyclohepta-2,4,6-trien-1-one:
• or a salt thereof, thereby forming a compound having structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is optionally and independently substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having sp3 hybridization.

A method of preparing a compound of structural formula:

• or a salt thereof comprising reacting a compound of structural formula:
• or a salt thereof;
• with a compound of structural formula:
• or a salt thereof;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-haloalkyl, and C1-6-alkoxy;
• Rb is hydrogen or methyl;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is optionally and independently substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having sp3 hybridization.

A method of preparing a compound of structural formula:

• or a salt thereof;
• comprising combining a compound having structural formula:
• or a salt thereof;
• with a demethylating agent;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-haloalkyl, and C1-6-alkoxy.

A method of preparing a compound of structural formula:

• or a salt thereof comprising:
• (1) contacting 7,7-dibromobicyclo[4.1.0]heptane-3,4-diol:
• or a salt thereof, with an oxidizing agent, thereby forming 5-bromo-2-hydroxycyclohepta-2,4,6-trien-1-one:
• or a salt thereof;
• and
• (2) reacting a compound of structural formula:
• or a salt thereof;
• with 5-bromo-2-hydroxycyclohepta-2,4,6-trien-1-one:
• or a salt thereof, thereby forming a compound having structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is optionally and independently substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having sp3 hybridization.

A method of preparing a compound of structural formula:

• or a salt thereof comprising reacting a compound of structural formula:
• or a salt thereof;
• with a compound of structural formula:
• or a salt thereof;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-haloalkyl, and C1-6-alkoxy;
• Rb is hydrogen or methyl;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is optionally and independently substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having sp3 hybridization.

A method of preparing a compound of structural formula:

• or a salt thereof;
• comprising reacting a compound of structural formula:
• or a salt thereof;
• with a compound of structural formula:
• or a salt thereof;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-haloalkyl, and C1-6-alkoxy;
• Rb is hydrogen or methyl;
• Xa is
• or —Sn(C1-6-alkyl);
• and
• Xb is halo or pseudohalo.

A method of preparing a compound of structural formula:

• or a salt thereof;
• comprising reacting a compound of structural formula:
• or a salt thereof;
• with 3-bromo-7-methoxycyclohepta-2,4,6-trien-1-one:
• or a salt thereof;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is optionally and independently substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having spa hybridization.

A method of preparing a compound of structural formula:

• or a salt thereof;
• comprising combining a compound having structural formula:
• or a salt thereof;
• with a demethylating agent;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy.

A method of preparing a compound of structural formula:

• or a salt thereof comprising:
• (1) contacting 7,7-dibromo-3-methoxybicyclo[4.1.0]hept-3-en-2-one:
• or a salt thereof;
• with a base;
• thereby forming 6-bromo-2-methoxycyclohepta-2,4,6-trien-1-one:
• or a salt thereof;
• (2) reacting a compound of structural formula:
• or a salt thereof;
• with 6-bromo-2-methoxycyclohepta-2,4,6-trien-1-one, or a salt thereof;
• thereby providing a compound having structural formula:
• or a salt thereof;
• and
• (3) contacting the compound having structural formula:
• or a salt thereof;
• with a demethylating agent;
• thereby providing the compound of structural formula:
• or a salt thereof;
• wherein
• Ra is C1-20-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy;
• R1′ and R2′ are each, independently hydrogen or C1-6-alkyl;
• or
• R1′ and R2′, together with atoms to which they are attached, form a ring having 2 to 4 carbon atoms, each of which is optionally and independently substituted with C1-3-alkyl or C═O;
• and
• B is a boron atom having sp3 hybridization.

A compound having a structure according to Formula (I):

• or a salt thereof;
• wherein
• Ra is C1-2-alkyl, C2-20-alkenyl, C2-20-alkynyl, C3-9-cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of halo, NO2, CN, C1-6-alkyl, C1-6-haloalkyl, and C1-6-alkoxy;
• and
• Rb is hydrogen or methyl;
• provided the compound is not hinokitiol.