Novel heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators

A compound of formula (I)

• 239
• wherein
• represents a single or double bond,
• X is selected from the group consisting of O and S and Y is selected from the group consisting of CRARB, CRARB(CH2)1-2, CRARBC(O) and C(O);
• alternatively Y is selected from the group consisting of O and S and X is selected from the group consisting of CRARB and C(O);
• provided that when X is S, then Y is selected from the group consisting of CRARB and CRARB(CH2)1-2;
• provided further that when Y is S, then X is selected from the group consisting of CRARB;
• wherein each RA and RB is independently selected from hydrogen, hydroxy, alkyl or alkoxy;
• provided that RA and RB are not each hydroxy;
• Z is selected from the group consisting of O and S;
• R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaryl-alkyl;
• wherein the cycloalkyl, aryl, aralkyl, heteroaryl or heteroaryl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO2, NO2, CN, CO2H, RC, —ORC, —SO2—NRDRE, —NRDRE, NRD—SO2—RF, -(alkyl)0-4-C(O)NRDRE, (alkyl)0-4-NRD—C(O)—RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—NRDRE or -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)—ORF;
• wherein RC is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl;
• wherein the cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO2, NO2, CN, CO2H, RC, —SO2—NRDRE, NRDRE, NRDSO2—RF, -(alkyl)0-4-C(O)—NRDRE, -(alkyl)0-4—NRD—C(O)—RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—NRDRE or -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)—ORF;
• wherein Q is selected from the group consisting of O, S, NH, N(alkyl) and —CH═CH—;
• wherein RD and RE are each independently selected from the group consisting of hydrogen and alkyl;
• alternatively RD and RE are taken together with the nitrogen atom to which they are bound to form a 4 to 8 membered ring selected from the group consisting of heteroaryl or heterocycloalkyl;
• wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
• wherein RF is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl;
• wherein the cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
• R2 is selected from the group consisting of hydroxy, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaryl-alkyl;
• wherein the cycloalkyl, aryl, aralkyl, heteroaryl or heteroaryl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO2, NO2, CN, CO2H, RC, —ORC, —SO2—NRDRE, NRDRE, NRD—SO2—RF, -(alkyl)0-4-C(O)NRDRE, (alkyl)0-4-NRD—C(O)—RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—NRDRE or -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)—ORF;
• alternatively, R1 and R2 are taken together with the carbon atom to which they are bound to form C(O);
• provided that when R1 and R2 are taken together with the carbon atom to which they are bound to form C(O) and X is selected from the group consisting of O and S, then Y is selected from the group consisting of CRARB and CRARB(CH2)1-2;
• provided that when R1 and R2 are taken together with the carbon atom to which they are bound to form C(O) and Y is selected from the group consisting of O and S, then X is selected from the group consisting of CRARB;
• n is an integer selected from 0 to 4;
• each R3 is independently selected from the group consisting of halogen, hydroxy, RC, amino, alkylamino, dialkylamino, nitro, cyano, SO2, —C(O)RG, —C(O)ORG, —OC(O)RG, —OC(O)ORG, —OC(O)N(RG)2, —N(RG)C(O)RG, —OSi(RG)3, —ORG, —SO2N(RG)2, —O-(alkyl)1-4-C(O)RG and —O-(alkyl)1-4-C(O)ORG;
• wherein each RG is independently selected from hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one;
• wherein the alkyl, aryl or aralkyl group is optionally substituted with one or more substituents independently selected from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, —OC(O)-alkyl or —C(O)O-alkyl;
• alternatively two RG groups are taken together with the nitrogen atom to which they are bound to form a heterocycloalkyl group;
• wherein the heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
• m is an integer selected from 0 to 4;
• each R4 is independently selected from the group consisting of halogen, hydroxy, RC, amino, alkylamino, dialkylamino, nitro, cyano, SO2, —C(O)RG, —C(O)ORG, —OC(O)RG, —OC(O)ORG, —OC(O)N(RG)2, —N(RG)C(O)RG, —OSi(RG)3, —ORG, —SO2N(alkyl)2, —O-(alkyl)1-4-C(O)RG and —O-(alkyl)1-4-C(O)ORG;
• provided that when is a double bond, X is CH2, Y is O, Z is O and R1 and R2 are taken together with the carbon atom to which they are bound to form C(O), then at least one of n or m is an integer selected from 1 to 4;
• provided further that when is a single bond, X is O, Y is CH(alkyl), Z is O, R1 is hydrogen and R2 is alkyl, then at least one of n or m is an integer selected from 1 to 4;
• provided further that when is a single bond, X is O, Y is CH(alkyl), Z is O, R1 is hydrogen, R2 is alkyl, n is 1 and m is 1, then R3 and R4 are other than methoxy or ethoxy;
• provided further that when is a double bond, X is O, Y is CH2, Z is O, R1 and R2 are taken together with the carbon atom to which they are bound to form C(O), n is 0 and m is 2, then each R4 is not hydroxy or alkoxy.
• or a pharmaceutically acceptable salt thereof.

A compound of the fornula (D)

• 240
• wherein
• represents a single or double bond,
• A is selected from the group consisting of O and S;
• D is selected from the group consisting of hydrogen, methyl, acetyl, benzyl, benzoyl, SEM, MOM, BOM, TBS, TMSpivaloyl and —C(O)R;
• wherein R is selected from alkyl, aryl, and substituted aryl;
• wherein the substituents on the aryl group are one or more independently selected from halogen, hydroxy, alkyl, alkoxy, amino, alkylamino, di(alkyl)amino, nitro or cyano;
• each R10 and R11 is independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, —CH(OH)-aryl, —CHO, —C(O)-(alky), —C(O)-aryl, —C(O)O-alkyl, —C(O)O-aryl, SEM, MOM, BOM, —CH2CH2—O-benzyl, —CH2CH2—OCH3 and pivaloyl;
• wherein the alkyl group, whether alone or as part of a large substiutent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen or phenyl);
• wherein the aryl group, whether alone or as part of a larger substituents group is optionally substituted with one or more substituents independently selected from hydroxy, alkoxy or alkoxy-carbonyl);
• provided that R10 and R11 are not each hydrogen or each hydroxy;
• Z is selected from the group consisting of O and S;
• n is an integer selected from 0 to 4;
• each R12 is independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkyloxy, SEMoxy, MOMoxy and pivaloyloxy;
• m is an integer selected from 0 to 4;
• each R13 is independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkyloxy, SEMoxy, MOMoxy and pivaloyloxy;
• or a pharmaceutically acceptable salt thereof.

A compound of the formula (DI)

• 241
• wherein
• represents a single or double bond,
• X is selected from the group consisting of O and S and Y is selected from the group consisting of CRARB, CRARB(CRARB)1-2, CRARBC(O), CRARBC(O)CRARB and C(O);
• alternatively Y is selected from the group consisting of O and S and X is selected from the group consisting of CRARB and C(O);
• provided that when X is S, then Y is selected from the group consisting of CRARB, CRARB(CRARB)1-2 and CH2C(O)CH2;
• provided further that when Y is S, then X is selected from the group consisting of CRARB;
• wherein each RA and RB is independently selected from hydrogen, hydroxy, alkyl or alkoxy;
• provided that RA and RB are not each hydroxy;
• T is selected from the group consisting of -(aryl)-O-(alkyl)-NRDRE and -(aryl)-O-(alkyl)-OH;
• n is an integer selected from 0 to 4;
• each R3 is independently selected from the group consisting of halogen, hydroxy, RC, amino, alkylamino, dialkylamino, nitro, cyano, —C(O)RG, —C(O)ORG, —OC(O)RG, —OC(O)ORG, —OC(O)N(RG)2, —N(RG)C(O)RG, —OSi(RG)3, —ORG, —SO2N(RG)2, —O-(alkyl)1-4-C(O)RG and —O-(alkyl)1-4-C(O)ORG;
• wherein RC is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl;
• wherein the cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO2, NO2, CN, CO2H, RC, —SO2—NRDRE, NRDRE, NRD—SO2—RF, -(alkyl)0-4-C(O)—NRDRE, -(alkyl)0-4-NRD—C(O)—RF, -(alkyl)0-4-(Q)0-1,-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—NRDRE or -(alkyl)0-4-C(O)(alkyl)0-4-C(O)—ORF;
• wherein Q is selected from the group consisting of O, S, NH, N(alkyl) and —CH═CH—;
• wherein RD and RE are each independently selected from the group consisting of hydrogen and alkyl;
• alternatively RD and RE are taken together with the nitrogen atom to which they are bound to form a 3 to 10 membered ring selected from the group consisting of heteroaryl or heterocycloalkyl;
• wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, oxo, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
• wherein RF is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl;
• wherein the cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
• wherein each RG is independently selected from hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one;
• wherein the alkyl, aryl or aralkyl group is optionally substituted with one or more substituents independently selected from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, —OC(O)-alkyl or —C(O)O-alkyl;
• alternatively two RG groups are taken together with the nitrogen atom to which they are bound to form a heterocycloalkyl group;
• wherein the heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
• m is an integer selected from 0 to 4;
• each R4 is independently selected from the group consisting of halogen, hydroxy, RC, amino, alkylamino, dialkylamino, nitro, cyano, —C(O)RG, —C(O)ORG, —OC(O)RG, —OC(O)ORG, —OC(O)N(RG)2, —N(RG)C(O)RG, —OSi(RG)3, —ORG, —SO2N(alkyl)2, —O-(alkyl)1-4-C(O)RG and —O-(alkyl)1-4-C(O)ORG;
• or a pharmaceutically acceptable salt thereof.

A process for the preparation of a compound of formula (DX)

• 242
• wherein
• represents a single or double bond,
• X is selected from the group consisting of O and S;
• p is an integer from 0 to 2;
• RA and RB are each independently selected from hydrogen, hydroxy, alkyl or alkoxy;
• provided that RA and RB are not each hydroxy;
• Z is selected from the group consisting of O and S;
• n is an integer from 0 to 4;
• each R12 is independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkyloxy, SEMoxy, MOMoxy and pivaloyloxy;
• m is an integer selected from 0 to 4;
• each R13 is independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkyloxy, SEMoxy, MOMoxy and pivaloyloxy;
• or a pharmaceutically acceptable salt thereof;
• comprising
• 243
• reacting a suitable substituted compound of formula (VIII), a known compound or compound prepared by known methods, wherein Pg10 is a protecting group, with an organic base selected from the group consisting of NaHMDS, LiHMDS, KHMDS, LDA and di(lower alkyl)amino lithium, to yield the corresponding compound of formula (C), wherein y is the corresponding base cation;
• 244
• reacting the compound of formula (C) with a suitably substituted compound of formula (Cl), wherein E is an electrophile and L is a leaving group, to yield the corresponding compound of formula (CII);
• 245
• de-protecting the compound of formula (CII), to yield the corresponding compound of formula (CIII);
• 246
• cyclizing the compound of formula (CIII), to yield the corresponding compound of formula (DX).

A process for the preparation of a compound of formula (DXI)

• 247
• wherein
• represents a single or double bond,
• X is selected from the group consisting of O and S;
• U is selected from the group consisting of hydrogen and alkyl;
• RA and RB are each independently selected from hydrogen, hydroxy, alkyl or alkoxy;
• provided that RA and RB are not each hydroxy;
• Z is selected from the group consisting of O and S;
• n is an integer from 0 to 4;
• each R12 is independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkyloxy, SEMoxy, MOMoxy and pivaloyloxy;
• m is an integer selected from 0 to 4;
• each R13 is independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkyloxy, SEMoxy, MOMoxy and pivaloyloxy;
• or a pharmaceutically acceptable salt thereof;
• comprising
• 248
• reacting a suitable substituted compound of formula (VIII), a known compound or compound prepared by known methods, wherein Pg10 is a protecting group, with an organic base selected from the group consisting of NaHMDS, LiHMDS, KHMDS, LDA and di(lower alkyl)amino lithium, to yield the corresponding compound of formula (C), wherein V is the corresponding base cation;
• 249
• reacting the compound of formula (C) with a suitably substituted aldehyde, a compound of formula (CIV), to yield the corresponding compound of formula (CV);
• 250
• de-protecting the compound of formula (CV), to yield the corresponding compound of formula (CVI);
• 251
• cyclizing the compound of formula (CIVI), to yield the corresponding compound of formula (DXI).

A process for the preparation of a compound of formula (Ca)

• 252
• wherein
• represents a single or double bond,
• X is selected from the group consisting of O and S;
• Pg11 is a protecting group selected from the group consisting of alkyl, allyl, benzyl, benzoyl, SEM, MOM, BOM and pivaloyl;
• V is selected from the group consisting of Li, Na and K;
• RA and RB are each independently selected from hydrogen, hydroxy, alkyl or alkoxy;
• provided that RA and RB are not each hydroxy;
• Z is selected from the group consisting of O and S;
• n is an integer from 0 to 4;
• each R12 is independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkyloxy, SEMoxy, MOMoxy and pivaloyloxy;
• m is an integer selected from 0 to 4;
• each R13 is independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, trialkylsilyl, acyloxy, benzoyloxy, aryloxy, aralkyloxy, SEMoxy, MOMoxy and pivaloyloxy;
• or a pharmaceutically acceptable salt thereof;
• comprising
• 253
• reacting a suitable substituted compound of formula (VIIIa), a known compound or compound prepared by known methods, with an organic base selected from the group consisting of NaHMDS, LiHMDS, KHMDS, LDA and di(lower alkyl)amino lithium, to yield the corresponding compound of formula (Ca).