Benzyl(idene)-lactam derivatives

A method of preparing a compound having the formula 1A′:

• or a pharmaceutically acceptable salt thereof
• wherein a is zero to eight;
• m is one;
• R6 is selected from the group consisting of hydrogen, (C1-C6)alkyl optionally substituted with (C1-C6)alkoxy or one to three fluorine atoms, or ((C1-C4)alkyl)aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH2)q-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and —SOt(C1-C6)alkyl, wherein t is zero, one or two;
• each R13 is, independently, (C1-C4)alkyl;
• X is hydrogen, chioro, fluoro, bromo, iodo, cyano, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, —SOt(C1-C6)alkyl wherein t is zero, one or two, —CO2R10 or —CONR11R12,
• each of R10, R11 and R12 is selected, independently, from hydrogen, (C1-C4)alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and —SOt(C1-C6)alkyl wherein t is zero to two;
• or R11 and R12, together with the nitrogen to which they are attached, form a 4 to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;
• R3 is phenyl or pyridyl substituted with one to three substituents independently selected from (C1-C8)hydroxyalkyl-, (C1-C8)alkoxy-(C1-C8)alkyl-, (C3-C8)hydroxycycloalkyl-, (C3-C8)cycloalkoxy-, (C1-C8)alkoxy-(C3-C8)cycloalkyl-, heterocycloalkyl, hydroxyheterocycloalkyl, and (C1-C8)alkoxy-heterocycloalkyl, wherein each (C3-C8)cycloalkyl or heterocycloalkyl moiety may be independently substituted with from one to three (C1-C6)alkyl or benzyl groups;
• or
• substituted with one to three substituents independently selected from phenyl, naphthyl and a 5- to 6-membered heteroaryl ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be substituted with from one to three (C1-C8)alkyl or C3-C8 cycloalkyl substituents;
• or
• substituted with one to three substituents independently selected from (a) lactone formed from —CH2)tOH with an ortho —COOH, wherein t is one, two or three;
• (b) —CONR14R15 wherein R14 and R15 are independently selected from (C1-C8)alkyl and benzyl, or R14 and R15 together with the nitrogen to which they are attached form a 5- to 7-membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the —CONR14R15 group, wherein when any of said heteroatoms is nitrogen it may be optionally substituted with (C1-C8)alkyl or benzyl, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms;
• (c) —(CH2)v NCOR16R17 wherein v is zero, one, two or three and —COR16 and R17 taken together with the nitrogen to which they are attached form a 4- to 6-membered lactam ring;
• and, (d) —(C1-C8)NR18R19 where each of R18 and R19 is selected, independently, from hydrogen and (C1-C4)alkyl, or R18 and R19, together with the nitrogen to which they are attached, form a 4- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;
• wherein the broken lines indicate optional double bonds;
• and,
• n is one, two, or three;
• or, a pharmaceutically acceptable salt or optical isomer thereof which comprises (a) preparing a compound having the formula 1B′:
• and either (b) treating the compound prepared in step (a) with hydrogen gas in a reaction-inert solvent selected from the group consisting of a lower alcohol, THF, dioxane, ethyl acetate, methanol and ethanol, in the presence of a noble metal catalyst on a solid support selected from the group consisting of palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO4), platinum on carbon (Pt/C), tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), and 1000 palladium on carbon, at a pressure of from about 1 to about 5 atmospheres, preferably about 3 to about 4 atmospheres, at a temperature of about 10° C. to about 100° C., under conditions suitable to form the compound having the formula 1A;
• or, (b′) treating the compound prepared in step (a) under transfer hydrogenation conditions with a hydride donor selected from the group consisting of cyclohexadiene and ammonium formate, in a reaction-inert solvent selected from a lower alcohol, THF, dioxane, ethyl acetate, methanol and ethanol, in the presence of a noble metal catalyst on a solid support selected from the group consisting of palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO4), platinum on carbon (Pt/C), tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), and 10% palladium on carbon, at a temperature of about 20° C. to about 150° C., under conditions suitable to form the compound having the formula 1A, optionally preparing a pharmaceutically acceptable salt thereof.

A method of preparing a compound having formula 1B′:

• wherein a is zero to eight;
• m is one;
• R6 is selected from the group consisting of hydrogen, (C1-C6)alkyl optionally substituted with (C1-C6)alkoxy or one to three fluorine atoms, or ((C1-C4)alkyl)aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH2)q-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and —SOt(C1-C6)alkyl, wherein t is zero, one or two;
• each R13 is, independently, (C1-C4)alkyl;
• X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, —SOt(C1-C6)alkyl wherein t is zero, one or two, —CO2R10 or —CONR11R12;
• each of R10, R11 and R12 is selected, independently, from hydrogen, (C1-C4)alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and —SOt(C1-C6)alkyl wherein t is zero to two;
• or R11 and R12, together with the nitrogen to which they are attached, form a 4 to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;
• R3 is phenyl or pyridyl substituted with one to three substituents independently selected from (C1-C8)hydroxyalkyl-, (C1-C8)alkoxy-(C1-C8)alkyl-, (C3-C8)hydroxycycloalkyl-, (C3-C8)cycloalkoxy-, (C1-C8)(C3-C8)cycloalkyl-, heterocycloalkyl, hydroxyheterocycloalkyl, and (C1-C8)alkoxy-heterocycloalkyl, wherein each (C3-C8)cycloalkyl or heterocycloalkyl moiety may be independently substituted with from one to three (C1-C6)alkyl or benzyl groups;
• or
• substituted with one to three substituents independently selected from phenyl, naphthyl and a 5- to 6-membered heteroaryl ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be substituted with from one to three (C1-C8)alkyl or C3-C8 cycloalkyl substituents;
• or
• substituted with one to three substituents independently selected from (a) lactone formed from —CH3)tOH with an ortho —COOH, wherein t is one, two or three;
• (b) —CONR14R15 wherein R14 and R15 are independently selected from (C1-C8)alkyl and benzyl, or R14 and R15 together with the nitrogen to which they are attached form a 5- to 7-membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the —CONR14R15 group, wherein when any of said heteroatoms is nitrogen it may be optionally substituted with (C1-C8)alkyl or benzyl, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms;
• (c) —(CH2)vNCOR16R17 wherein v is zero, one, two or three and —COR16 and R17 taken together with the nitrogen to which they are attached form a 4- to 6-membered lactam ring;
• and, (d) —C1-C8)NR18R19 where each of R18 and R19 is selected, independently, from hydrogen and (C1-C4)alkyl, or R18 and R19, together with the nitrogen to which they are attached, form a 4- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;
• wherein the broken lines indicate optional double bonds;
• and,
• n is one, two, or three;
• or, a pharmaceutically acceptable salt or optical isomer thereof which comprises (a) preparing a compound having the formula 1B:
• and treating the compound prepared in step (a) with a reagent R3-Y, wherein R3 is as defined above and Y is chloro, bromo, fluoro, iodo or sulfonate, in a suitable reaction inert solvent selected from the group consisting of 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene and toluene, in the presence of (1) a base selected from the group consisting of potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium tert-butoxide, lithium tert-butoxide, or sodium tert-butoxide, a diamine, 1,2-ethylenediamine, N,N′-dimethylethylenediamine, N,N-dimethylethylenediamine, and cis-1 ,2-diaminocyclohexane, (2) a copper(I) salt selected from the group consisting of cuprous chloride, cuprous bromide and cuprous iodide, and (3) an amount of water comprising from about 10% to about 4% w/w, optionally in the presence of a polar co-solvent selected from the group consisting of N,N-dimethyl formamide and N,N-dimethyl acetamide in the order of 5-15% v/v relative to the first solvent, at a temperature from about 40° C. to about 150° C., under suitable conditions to form the compound having formula 1B′′.

A method of preparing a compound having formula 1A′:

• or a pharmaceutically acceptable salt thereof;
• wherein a is zero to eight;
• m is one;
• R6 is selected from the group consisting of hydrogen, (C1-C6)alkyl optionally substituted with (C1-C6)alkoxy or one to three fluorine atoms, or ((C1-C4)alkyl)aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH2)q-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and —SOt(C1-C6)alkyl, wherein t is zero, one or two;
• each R13 is, independently, (C1-C4)alkyl;
• X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, —SOt(C1-C6)alkyl wherein t is zero, one or two, —CO2R10 or —CONR11R12;
• each of R10, R11 and R12 is selected, independently, from hydrogen, (C1-C4)alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and —SOt(C1-C6)alkyl wherein t is zero to two;
• or R11 and R12, together with the nitrogen to which they are attached, form a 4 to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;
• R1 is phenyl or pyridyl substituted with one to three substituents independently selected from (C1-C8)hydroxyalkyl-, (C1-C8)alkoxy-(C1-C8)alkyl-, (C3-C8)hydroxycycloalkyl-, (C3-C8)cycloalkoxy-, (C1-C8)alkoxy-(C3-C8)cycloalkyl-, heterocycloalkyl, hydroxyheterocycloalkyl, and (C1-C8)alkoxy-heterocycloalkyl, wherein each (C3-C8)cycloalkyl or heterocycloalkyl moiety may be independently substituted with from one to three (C1-C6)alkyl or benzyl groups;
• or
• substituted with one to three substituents independently selected from phenyl, naphthyl and a 5- to 6-membered heteroaryl ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be substituted with from one to three (C1-C8)alkyl or C3-C8 cycloalkyl substituents;
• or
• substituted with one to three substituents independently selected from (a) lactone formed from —(CH2)tOH with an ortho —COOH, wherein t is one, two or three;
• (b) —CONR14R15, wherein R14 and R15 are independently selected from (C1-C8)alkyl and benzyl, or R14 and R15 together with the nitrogen to which they are attached form a 5- to 7-membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the —CONR14R15 group, wherein when any of said heteroatoms is nitrogen it may be optionally substituted with (C1-C8)alkyl or benzyl, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms;
• (c) —(CH2)vNCOR16 R17 wherein v is zero, one two or three and —COR16 and R17 taken together with the nitrogen to which they are attached form a 4- to 6-membered lactam ring;
• and, (d) —(C1-C8)NR18R19, where each of R18 and R19 is selected, independently, from hydrogen and (C1-C4)alkyl, or R18 and R19, together with the nitrogen to which they are attached, form a 4- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;
• wherein the broken lines indicate optional double bonds;
• and,
• n is one, two, or three;
• or, a pharmaceutically acceptable salt or optical isomer thereof;
• which comprises (a) preparing a compound having the formula 1A:
• and treating the compound prepared in step (a) with a reagent R3-Y, wherein R3 is as defined above and Y is chioro, bromo, fluoro, iodo or sulfonate, in a suitable reaction inert solvent selected from the group consisting of 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran, benzene and toluene, in the presence of (1) a base selected from the group consisting of potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium tert-butoxide, lithium tert-butoxide, or sodium tert-butoxide, a diamine, 1,2-ethylenediamine, N,N′-dimethylethylenediamine, N,N-dimethylethylenediamine, and cis-1,2-diaminocyclohexane, (2) a copper(I) salt selected from the group consisting of cuprous chloride, cuprous bromide and cuprous iodide, and (3) an amount of water comprising from about 1% to about 4% w/w, optionally in the presence of a polar co-solvent selected from the group consisting of N,N-dimethyl formamide and N,N-dimethyl acetamide in the order of 5-15% v/v relative to the first solvent, at a temperature from about 40° C. to about 150° C., under suitable conditions to form the compound having formula 1A′, optionally preparing a pharmaceutically acceptable salt thereof.