Method for synthesis of diazabicyclo[6.2.0]decane related compounds

A method of forming a compound given by Formula I:

• wherein:
• R1 is —I, —Cl, —Br, or
• R2 is C(O)R3;
• wherein R3 is —Oalkyl;
• P1 is a nitrogen protecting group;
• wherein the method comprising reacting a reactant of Formula III
• with a chiral sulfinyl imine;
• wherein X1 is a halogen atom.

A method of forming a compound given by Formula IV

• wherein R1 is —I, —Cl, —Br, or
• P1 and P2 are the same or different and represent nitrogen protecting groups;
• wherein the method comprises:
• (i) forming a lactone of Formula V
• from a compound or Formula 1
• wherein R2 is C (O) R3;
• wherein R3 is —OH, —Oalkyl, —O−;
• wherein when R3 is —O−, a positive counterion is ionically associated with Formula I;
• and P1 is a nitrogen protecting group;
• (ii) reducing said lactone of Formula V into a compound of Formula VI
• and
• (iii) converting the alcoholic groups covalently attached to the unsaturated carbons of Formula VI into leaving groups to form an intermediate that reacts with a nitrogen nucleophile to generate a compound of Formula IV.

A method of making a compound given by the following structure

• wherein:
• R1 is —I, —Cl, —Br, or
• R6 and R7 are independently the same or different, and are selected from —H, —OH, alkyl, —Oalkyl, or wherein R6 and R7 together with the atoms to which they are attached form a ring system protecting group for a diol;
• R8 and R9 are independently the same or different, and are selected from —H, -alkyl, —C(O)alkyl, —S(O)2alkyl, or R8 and R9 together with the N to which they are attached form:
• or a nitrogen protecting group;
• R10 is —H, a straight chain or branched alkyl, —C(O) alkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —C(O) aryl, —C(O)O-aryl, —C(O)NH-aryl, —C(O) heteroaryl, —C(O)O-heteroaryl, and —C(O)N-heteroaryl;
• wherein said aryl is a phenyl group optionally substituted with 1-3 groups of —OCH3, —OH, and halogen;
• and said heteroaryl is selected from the group consisting of triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl;
• wherein the method comprises reacting a compound given by Formula IV
• with a substituted γ-hydroxyaldehyde to promote bicyclization.

A method of forming a compound given by Formula IV

• wherein:
• R1 is —I, —Cl, —Br, or
• P1 and P2 are the same or different and represent nitrogen protecting groups;
• wherein the method comprises converting the alcoholic groups covalently attached to the unsaturated carbons of Formula VI
• into leaving groups to form an intermediate that reacts with a nitrogen nucleophile to generate a compound of Formula IV.

A compound or a pharmaceutically acceptable salt thereof of Formula XV:

• wherein R1 is —I, —Cl, —Br, or and
• and
• wherein Z is a substituted 4-membered nitrogen-containing heterocycle selected from the group consisting of:
• wherein P1 and P2 are the same or different and are nitrogen protecting groups or —H, or a pharmaceutically acceptable salt thereof;
• wherein R8 and R9 are independently the same or different, and are selected from —H, -alkyl, —C(O)alkyl, —S(O)2alkyl, or R8 and R9 together with the N to which they are attached form:
• or a nitrogen protecting group,
• wherein the alkyl is substituted by one or more halogens;
• or a pharmaceutically acceptable salt thereof;
• wherein R8 and R9 are independently the same or different, and are selected from —H, -alkyl, —C(O)alkyl, —S(O)2alkyl, or R8 and R9 together with the N to which they are attached form:
• or a nitrogen protecting group,
• wherein the alkyl is substituted by one or more halogens;
• or a pharmaceutically acceptable salt thereof;
• wherein R8 and R9 are independently the same or different, and are selected from —H, -alkyl, —C(O)alkyl, —S(O)2alkyl, or R8 and R9 together with the N to which they are attached form;
• or a nitrogen protecting group,
• wherein the alkyl is substituted by one or more halogens;
• or a pharmaceutically acceptable salt thereof;
• and
• wherein R8 and R9 are independently the same or different, and are selected from —H, —C(O)alkyl, —S(O)2alkyl, or R8 and R9 together with the N to which they are attached form;
• or a nitrogen protecting group,
• wherein the alkyl is optionally substituted by one or more halogens;
• or a pharmaceutically acceptable salt thereof.

A compound or pharmaceutically acceptable salt thereof wherein the compound has Formula XV:

• wherein R1 is —I, —Cl, —Br, or
• wherein Z is selected from the group consisting of:
• wherein R2 is C (O) R3;
• R3 is —O− and a positive counterion ionically associated with Formula XVI, or R3 is —OH;
• and
• P1 is a nitrogen protecting group or —H;
• wherein P1 is a nitrogen protecting group or —H;
• wherein P1 is a nitrogen protecting group or —H;
• wherein P1 is a nitrogen protecting group or —H;
• and
• wherein P1 is a nitrogen protecting group or —H;
• or a pharmaceutically acceptable salt thereof.