N-sulfonylpiperidine cannabinoid receptor 1 antagonists

A compound according to Formula I

• including all prodrugs, pharmaceutically acceptable salts and stereoisomers, wherein:
• X is selected from the group consisting of —C(O)— and —S(O)2—;
• Y is selected from the group consisting of —CR5R6— and —CR5R6CR7R8— (in which CR5R6 is attached to nitrogen and CR7R8 is attached to the piperidine ring);
• R1 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, alkoxy, aryloxy, arylalkoxy, alkylamino, dialkylamino, arylamino, arylalkylamino and heterocyclyl, all of which may be optionally mono-, di- or trisubstituted,
• wherein R1 is not an optionally substituted thiazol-2-ylamino or optionally substituted pyrid-3-ylalkyl;
• R2 is selected from the group consisting of substituted alkyl, alkenyl, arylalkyl, arylalkenyl and heteroarylalkyl, all of which may be optionally mono-, di- or trisubstituted,
• wherein when R2 is optionally substituted arylalkyl or optionally substituted arylalkenyl, and R4 is optionally substituted straight or branched chain alkyl, optionally substituted alkenyl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkyl or optionally substituted heteroarylalkenyl, then R1 is not optionally substituted straight or branched chain alkyl, optionally substituted alkenyl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted alkoxy, optionally substituted aryloxy or optionally substituted arylalkoxy;
• R3 is selected from the group consisting of alkyl, alkenyl, arylalkenyl, hydroxy, alkoxy and arylalkoxy, wherein alkyl, alkenyl, arylalkenyl, alkoxy and arylalkoxy may be optionally mono-, di- or trisubstituted, provided that when R3 is alkyl it is not substituted by aryl or heteroaryl;
• R4 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, alkylamino, dialkylamino, arylamino and arylalkylamino, all of which may be optionally mono-, di- or trisubstituted,
• wherein R4 is not alkyl group that is substituted with an acylalkylaminoacyl group;
• R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl and arylalkenyl, all of which may be optionally mono-, di- or trisubstituted;
• wherein the optional substitutents of R1-R8 are independently selected from the group consisting of halo, cyano, nitro, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, oxo (═O), OR9A, OCO2R10, OCONR9AR9B, COR9A, CO2R9A, CONR9AR9B, CONR9AOR9B, CN4R9A (tetrazole), C(NR9A)NR9BR9C, CONR9ASO2R9B, SOR10, SO2R10, SO3H, SO2NR9AR9B, SO2NR9ACOR9B, SO2NR9ACONR9BR9C, POR9AR9B, PO2R9AR9B, PO3R9AR9B, PO2R9ANR9BR9C, NR9AR9B, NR9ACOR9B, NR9AC(NR9B)R9C, NR9ACO2R9B, NR9ACONR9BR9C, NR9AC(NR9B)NR9CR9D, NR9ASO2R9B, NR9ACONR9BSO2R9C, NR9ASO2NR9BR9C, NR9APOR9BR9C, NR9APO2R9BR9C, NR9APO3R9BR9C and NR9APO2R9BNR9CR9D,
• R9A, R9B, R9C and R9D are independently selected from the group consisting of hydrogen and R10;
• and
• R10 is independently selected from the group consisting of alkyl, arylalkyl, heteroarylalkyl and aryl.

A compound according to Formula I

• including all prodrugs, pharmaceutically acceptable salts and stereoisomers, wherein:
• X is —S(O)2—;
• Y is selected from the group consisting of —CR5R6— and —CR5R6CR7R8— (in which CR5R6 is attached to nitrogen and CR7R8 is attached to the piperidine ring);
• R1 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, alkoxy, aryloxy, arylalkoxy, alkylamino, dialkylamino, arylamino, arylalkylamino and heterocyclyl, all of which may be optionally mono-, di- or trisubstituted;
• R2 is selected from the group consisting of substituted alkyl, alkenyl, arylalkyl, arylalkenyl and heteroarylalkyl, all of which may be optionally mono-, di- or trisubstituted,
• wherein R2 is not an optionally substituted aminoethyl group,
• wherein when R2 is optionally substituted arylalkyl or optionally substituted arylalkenyl, and R4 is optionally substituted straight or branched chain alkyl, optionally substituted alkenyl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkyl or optionally substituted heteroarylalkenyl, then R1 is not optionally substituted straight or branched chain alkyl, optionally substituted alkenyl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted alkoxy, optionally substituted aryloxy or optionally substituted arylalkoxy;
• R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkenyl, hydroxy, alkoxy and arylalkoxy, wherein alkyl, alkenyl, arylalkenyl, alkoxy and arylalkoxy may be optionally mono-, di- or trisubstituted, provided that when R3 is alkyl it is not substituted by aryl or heteroaryl;
• R4 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, alkylamino, dialkylamino, arylamino and arylalkylamino, all of which may be optionally mono-, di- or trisubstituted,
• wherein R4 is not alkyl group that is substituted with an acylalkylaminoacyl group;
• R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl and arylalkenyl, all of which may be optionally mono-, di- or trisubstituted;
• wherein the optional substitutents of R1-R8 are independently selected from the group consisting of halo, cyano, nitro, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, oxo (═O), OR9A, OCO2R10, OCONR9AR9B, COR9A, CO2R9A, CONR9AR9B, CONR9AOR9B, CN4R9A (tetrazole), C(NR9A)NR9BR9C, CONR9ASO2R9B, SOR10, SO2R10, SO3H, SO2NR9AR9B, SO2NR9ACOR9B, SO2NR9ACONR9BR9C, POR9AR9B, PO2R9AR9B, PO3R9AR9B, PO2R9ANR9BR9C, NR9AR9B, NR9ACOR9B, NR9AC(NR9B)R9C, NR9ACO2R9B, NR9ACONR9BR9C, NR9AC(NR9B)NR9CR9D, NR9ASO2R9B, NR9ACONR9BSO2R9C, NR9ASO2NR9BR9C, NR9APOR9BR9C, NR9APO2R9BR9C, NR9APO3R9BR9C and NR9AR9BNR9CR9D,
• R9A, R9B, R9C and R9D are independently selected from the group consisting of hydrogen and R10;
• and
• R10 is independently selected from the group consisting of alkyl, arylalkyl, heteroarylalkyl and aryl.

A compound according to Formula I

• including all prodrugs, pharmaceutically acceptable salts and stereoisomers, wherein:
• X is selected from the group consisting of —C(O)— and —S(O)2—;
• Y is selected from the group consisting of —CR5R6— and —CR5R6CR7R8— (in which CR5R6 is attached to nitrogen and CR7R8 is attached to the piperidine ring);
• R1 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, alkoxy, aryloxy, arylalkoxy, alkylamino, dialkylamino, arylamino, arylalkylamino and heterocyclyl, all of which may be optionally mono-, di- or trisubstituted,
• wherein R1 is not an optionally substituted thiazol-2-ylamino or optionally substituted pyrid-3-ylalkyl;
• R2 is selected from the group consisting of substituted alkyl, substituted alkenyl, arylalkyl, arylalkenyl and heteroarylalkyl, all of which may be optionally mono-, di- or trisubstituted,
• wherein R2 is not an optionally substituted aminoethyl group,
• wherein when R2 is optionally substituted arylalkyl or optionally substituted arylalkenyl, and R4 is optionally substituted straight or branched chain alkyl or optionally substituted alkenyl, then R1 is not optionally substituted straight or branched chain alkyl, optionally substituted alkenyl, optionally substituted arylalkyl, optionally substituted arylalkenyl, optionally substituted alkoxy, optionally substituted aryloxy or optionally substituted arylalkoxy;
• R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkenyl, hydroxy, alkoxy and arylalkoxy, wherein alkyl, alkenyl, arylalkenyl, alkoxy and arylalkoxy may be optionally mono-, di- or trisubstituted, provided that when R3 is alkyl it is not substituted by aryl or heteroaryl;
• R4 is selected from the group consisting of optionally substituted alkyl and optionally substituted alkenyl, wherein both the optionally substituted alkyl and optionally substituted alkenyl contain six or more carbon atoms;
• R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl and arylalkenyl, all of which may be optionally mono-, di- or trisubstituted;
• wherein the optional substitutents of R1-R8 are independently selected from the group consisting of halo, cyano, nitro, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, oxo (═O), OR9A, OCO2R10, OCONR9AR9B, COR9A, CO2R9A, CONR9AR9B, CONR9AOR9B, CN4R9A (tetrazole), C(NR9A)NR9BR9C, CONR9ASO2R9B, SOR10, SO2R10, SO3H, SO2NR9AR9B, SO2NR9ACOR9B, SO2NR9ACONR9BR9C, POR9AR9B, PO2R9AR9B, PO3R9AR9B, PO2R9ANR9BR9C, NR9AR9B, NR9ACOR9B, NR9AC(NR9B)R9C, NR9ACO2R9B, NR9ACONR9BR9C, NR9AC(NR9B)NR9CR9D, NR9ASO2R9B, NR9ACONR9BSO2R9C, NR9ASO2NR9BR9C, NR9APOR9BR9C, NR9APO2R9BR9C, NR9APO3R9BR9C and NR9APO2R9BNR9CR9D,
• R9A, R9B, R9C and R9D are independently selected from the group consisting of hydrogen and R10;
• and
• R10 is independently selected from the group consisting of alkyl, arylalkyl, heteroarylalkyl and aryl.

A compound according to Formula I

• including all prodrugs, pharmaceutically acceptable salts and stereoisomers, wherein:
• X is selected from the group consisting of —C(O)— and —S(O)2—;
• Y is selected from the group consisting of —CR5R6— and —CR5R6CR7R8— (in which CR5R6 is attached to nitrogen and CR7R8 is attached to the piperidine ring);
• R1 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, alkoxy, aryloxy, arylalkoxy, alkylamino, dialkylamino, arylamino, arylalkylamino and heterocyclyl, all of which may be optionally mono-, di- or trisubstituted,
• wherein R1 is not an optionally substituted benzoxadiazole, optionally substituted benzothiadiazole or optionally substituted pyrid-3-ylalkyl;
• R2 is selected from the group consisting of substituted alkyl, alkenyl, arylalkyl, arylalkenyl and heteroarylalkyl, all of which may be optionally mono-, di- or trisubstituted,
• wherein R2 is not an optionally substituted aminoethyl group;
• R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkenyl, hydroxy, alkoxy and arylalkoxy, wherein alkyl, alkenyl, arylalkenyl, alkoxy and arylalkoxy may be optionally mono-, di- or trisubstituted, provided that when R3 is alkyl it is not substituted by aryl or heteroaryl;
• R4 is aryl substituted with aryl or heteroaryl;
• R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl and arylalkenyl, all of which may be optionally mono-, di- or trisubstituted;
• wherein the optional substitutents of R1-R8 are independently selected from the group consisting of halo, cyano, nitro, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, oxo (═O), OR9A, OCO2R10, OCONR9AR9B, COR9A, CO2R9A, CONR9AR9B, CONR9AOR9B, CN4R9A (tetrazole), C(NR9A)NR9BR9C, CONR9ASO2R9B, SOR10, SO2R10, SO3H, SO2NR9AR9B, SO2NR9ACOR9B, SO2NR9ACONR9BR9C, POR9AR9B, PO2R9AR9B, PO3R9AR9B, PO2R9ANR9BR9C, NR9AR9B, NR9ACOR9B, NR9AC(NR9B)R9C, NR9ACO2R9B, NR9ACONR9BR9C, NR9AC(NR9B)NR9CR9D, NR9ASO2R9B, NR9ACONR9BSO2R9C, NR9ASO2NR9BR9C, NR9APOR9BR9C, NR9APO2R9BR9C, NR9APO3R9BR9C and NR9APO2R9BNR9CR9D,
• R9A, R9B, R9C and R9D are independently selected from the group consisting of hydrogen and R10;
• and
• R10 is independently selected from the group consisting of alkyl, arylalkyl, heteroarylalkyl and aryl.

A method for treating a cannabinoid receptor mediated disease or disorder, comprising:

• administering to a patient in need of treatment a therapeutically effective amount of a compound according to Formula I:
• including all prodrugs, pharmaceutically acceptable salts and stereoisomers, wherein:
• X is selected from the group consisting of —C(O)— and —S(O)2—;
• Y is selected from the group consisting of —CR5R6— and —CR5R6CR7R8— (in which CR5R6 is attached to nitrogen and CR7R8 is attached to the piperidine ring);
• R1 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, alkoxy, aryloxy, arylalkoxy, alkylamino, dialkylamino, arylamino, arylalkylamino and heterocyclyl, all of which may be optionally mono-, di- or trisubstituted;
• R2 is selected from the group consisting of alkyl, alkenyl, arylalkyl, arylalkenyl and heteroarylalkyl, all of which may be optionally mono-, di- or trisubstituted;
• R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkenyl, hydroxy, alkoxy and arylalkoxy, wherein alkyl, alkenyl, arylalkenyl, alkoxy and arylalkoxy may be optionally mono-, di- or trisubstituted;
• R4 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, alkylamino, dialkylamino, arylamino and arylalkylamino, all of which may be optionally mono-, di- or trisubstituted;
• R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl and arylalkenyl, all of which may be optionally mono-, di- or trisubstituted;
• wherein the optional substitutents of R1-R8 are independently selected from the group consisting of halo, cyano, nitro, alkyl, alkenyl, aryl, heteroaryl, arylalkyl, arylalkenyl, heteroarylalkyl, heteroarylalkenyl, oxo (═O), OR9A, OCO2R10, OCONR9AR9B, COR9A, CO2R9A, CONR9AR9B, CONR9AOR9B, CN4R9A (tetrazole), C(NR9A)NR9BR9C, CONR9ASO2R9B, SOR10, SO2R10, SO3H, SO2NR9AR9B, SO2NR9ACOR9B, SO2NR9ACONR9BR9C, POR9AR9B, PO2R9AR9B, PO3R9AR9B, PO2R9ANR9BR9C, NR9AR9B, NR9ACOR9B, NR9AC(NR9B)R9C, NR9ACO2R9B, NR9ACONR9BR9C, NR9AC(NR9B)NR9CR9D, NR9ASO2R9B, NR9ACONR9BSO2R9C, NR9ASO2NR9BR9C, NR9APOR9BR9C, NR9APO2R9BR9C, NR9APO3R9BR9C and NR9APO2R9BNR9DR9D,
• R9A, R9B, R9C and R9D are independently selected from the group consisting of hydrogen and R10;
• and
• R10 is independently selected from the group consisting of alkyl, arylalkyl, heteroarylalkyl and aryl.