Phenyl derivatives and methods of use

A method of binding cannabinoid receptors in a patient in need thereof, comprising the step of:

• administering to said patient an effective amount of a compound of formula I:
• wherein:
• R1, R2, R3, and R4 are each independently H, alkyl, —OR9a, —N(R10)(R11), —C(═O)N(R12)(R13), —C(═O)—OR9b, —OP(═O)(OR9c)(OR9d), —CN, or
• R5 and R6 are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a 3- to 8-membered carbocyclic ring, wherein 1 to 3 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, or —N(R9e)—;
• each R7 and R8 is independently H, alkyl, halogen, or —OR9f;
• A, B, D, and E are each independently N, CR14a, C—[C(R15a)(R16a)]p—N(R17)-G1, or C—[C(R15b)(R16b)]p—OC(═O)—N(R18a)(R18b);
• J is N or CR14b, provided that no more than two of A, B, D, E, and J are N;
• each G1 is independently —S(═O)2R19, —S(═O)2N(R20a)(R20b), —C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, —C(═O)-N(R18c)(R18d), —C(═CHNO2)—N(R18c)(R18d), or —C(═N—CN)—N(R18e)(R18f);
• G2 is alkyl, acyl, aryl, heteroaryl, heterocycloalkyl, —S(═O)2R19, —S(═O)2N(R20a)(R20b), —C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, —C(═O)—N(R18c)(R18d), —C(═O)—OR9b, —C(═CHNO2)—N(R18c)(R18d), or —C(═N—CN)—N(R18e)(R18f);
• each R9a, R9b, R9c, R9d, R9e, and R9f is independently H or alkyl;
• each R10, R11, R12, and R13 is independently H, alkyl, alkenyl, aryl, or heteroaryl, or each R10 and R11 or R12 and R13, taken together with the nitrogen atom to which they are attached, independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• each R14a and R14b is independently H, halogen, alkyl, —CH2F, —CHF2, —CF3, —CN, —(CH2)r—OH, or —(CH2)r—O-alkyl;
• each R18a, R18b, R18c, R18d, R18e, R18f, R20a, and R20b is independently H, alkyl, alkenyl, or aryl, or each R18a and R18b or R18c and R18d or R20a and R20b, taken together with the nitrogen atom to which they are attached independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• each R19 is independently H, alkyl, aryl, OH, or —O-alkyl;
• W is a single bond, —O—, —S—, —CH2—, —CF2—, alkylidene, —CH(halogen)-, —CH(OH)—, or —CH(O-alkyl)-, provided that when W is —O— or —S—, then n≧2 and each R7 and R8 is independently H or alkyl;
• X is a single bond, —CH═CH—, —O—, or —N(R21)—, provided that when X is —O—, G2 is other than —C(═N—CN)—N(R18e)(R18f);
• and provided that when X is —O— or —N(R21)—, then R8 is H or alkyl;
• and provided that when G2 is —C(═CHNO2)—N(R18c)(R18d), then X is —N(R21)—;
• and
• provided that when G2 is heterocycloalkyl or heteroaryl and attached to X through a ring heteroarom, then X is a single bond;
• R15a, R15b, R16a, R16b, R17, and R21 is independently H or alkyl;
• or R17 and R18c, taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• or R18c and R21, taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2-alkyl)-;
• m and n are each independently an integer from 1 to 5;
• each p is independently an integer from 0 to 5;
• and
• each r is independently an integer from 0 to 4;
• with the proviso that:
• at least one of A, B, D, and E is C—[C(R15a)(R16a)]p—N(R17)-G1 or C—[C(R15b)(R16b)]p—OC(═O)—N(R18a)(R18b);
• or a pharmaceutically acceptable salt thereof.

A method of providing cardioprotection against ischemic and reperfusion effects in a patient in need thereof, comprising the step of:

• administering to said patient an effective amount of a compound of formula I:
• wherein:
• R1, R2, R3, and R4 are each independently H, alkyl, —OR9a, —N(R10)(R11), —C(═O)N(R12)(R13), —C(═O)—OR9b, —OP(═O)(OR9c)(OR9d), —CN, or
• R5 and R6 are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a 3- to 8-membered carbocyclic ring, wherein 1 to 3 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, or —N(R9e)—;
• each R7 and R8 is independently H, alkyl, halogen, or —OR9f;
• A, B, D, and E are each independently N, CR14a, C—[C(R15a)(R16a)]p—N(R17)-G1, or C—[C(R15b)(R16b)]p—OC(═O)—N(R18a)(R18b);
• J is N or CR14b, provided that no more than two of A, B, D, E, and J are N;
• each G1 is independently —S(═O)2R19, —S(═O)2N(R20a)(R201), —C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, —C(═O)—N(R18c)(R18d), —C(═CHNO2)—N(R18c)(R18d), or —C(═N—CN)—N(R18e)(R18f);
• G2 is alkyl, acyl, aryl, heteroaryl, heterocycloalkyl, —S(═O)2R19, —S(═O)2N(R20a)(R20b), —C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, —C(═O)—N(R18c)(R18d), —C(═O)—OR9b, —C(═CHNO2)—N(R18c)(R18d), or —C(═N—CN)—N(R18e)(R18f);
• each R9a, R9b, R9c, R9d, R9e, and R9f is independently H or alkyl;
• each R10, R11, R12, and R13 is independently H, alkyl, alkenyl, aryl, or heteroaryl, or each R10 and R11 or R12 and R13, taken together with the nitrogen atom to which they are attached, independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• each R14a and R14b is independently H, halogen, alkyl, —CH2F, —CHF2, —CF3, —CN, —(CH2), —OH, or —(CH2), —O-alkyl;
• each R18a, R18b, R18c, R18d, R18e, R18f, R20a, and R20b is independently H, alkyl, alkenyl, or aryl, or each R18a and R18b or R18c and R18d or R20a and R20b, taken together with the nitrogen atom to which they are attached independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• each R19 is independently H, alkyl, aryl, OH, or —O-alkyl;
• W is a single bond, —O—, —S—, —CH2—, —CF2—, alkylidene, —CH(halogen)-, —CH(OH)—, or —CH(O-alkyl)-, provided that when W is —O— or —S—, then n≧2 and each R7 and R8 is independently H or alkyl;
• X is a single bond, —CH═CH—, —O—, or —N(R21)—, provided that when X is —O—, G2 is other than —C(═N—CN)—N(R18e)(R18f);
• and provided that when X is —O— or —N(R21)—, then R8 is H or alkyl;
• and provided that when G2 is —C(═CHNO2)—N(R18c)(R18d), then X is —N(R21)—;
• and provided that when G2 is heterocycloalkyl or heteroaryl and attached to X through a ring heteroarom, then X is a single bond;
• each R15a, R15b, R16a, R16b, R17, and R21 is independently H or alkyl;
• or R17 and R18c, taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• or R18c and R21, taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2-alkyl)-;
• m and n are each independently an integer from 1 to 5;
• each p is independently an integer from 0 to 5;
• and
• each r is independently an integer from 0 to 4;
• with the proviso that:
• at least one of A, B, D, and E is C—[C(R15a)(R16a)]p—N(R17)-G1 or C—[C(R15b)(R16b)]p—OC(═O)—N(R18a)(R18b);
• or a pharmaceutically acceptable salt thereof.

A method of inducing apoptosis in malignant cells, comprising the step of:

• contacting said cells with an effective amount of a compound of formula I:
• wherein:
• R1, R2, R3, and R4 are each independently H, alkyl, —OR9a, —N(R10)(R11), —C(═O)N(R12)(R13), —C(═O)—OR9b, —OP(═O)(OR9c)(OR9d), —CN, or
• R5 and R6 are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a 3- to 8-membered carbocyclic ring, wherein 1 to 3 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, or —N(R9e)—;
• each R7 and R8 is independently H, alkyl, halogen, or —OR9f;
• A, B, D, and E are each independently N, CR14a, C—[C(R15a)(R16a)]p—N(R17)-G1, or C—[C(R15b)(R16b)]p—OC(═O)—N(R18a)(R18b);
• J is N or CR14b, provided that no more than two of A, B, D, E, and J are N;
• each G1 is independently —S(═O)2R19, —S(═O)2N(R20a)(R20b), —C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, —C(═O)—N(R18c)(R18d), —C(═CHNO2)—N(R18c)(R18d), or —C(═N—CN)—N(R18e)(R18f);
• G2 is alkyl, acyl, aryl, heteroaryl, heterocycloalkyl, —S(═O)2R19, —S(═O)2N(R20a)(R20b), —C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, —C(═O)—N(R18c)(R18d), —C(═O)—OR9b, —C(═CHNO2)—N(R18c)(R18d), or —C(═N—CN)—N(R18e)(R18f);
• each R9a, R9b, R9c, R9d, R9e, and R9f is independently H or alkyl;
• each R10, R11, R12, and R13 is independently H, alkyl, alkenyl, aryl, or heteroaryl, or each R10 and R11 or R12 and R13, taken together with the nitrogen atom to which they are attached, independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• each R14a and R14b is independently H, halogen, alkyl, —CH2F, —CHF2, —CF3, —CN, —(CH2)r—OH, or —(CH2)r—O-alkyl;
• each R18a, R18b, R18c, R18d, R18e, R18f, R20a, and R20b is independently H, alkyl, alkenyl, or aryl, or each R18a and R18b or R18c and R18d or R20a and R20b, taken together with the nitrogen atom to which they are attached independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• each R19 is independently H, alkyl, aryl, OH, or —O-alkyl;
• W is a single bond, —O—, —S—, —CH2—, —CF2—, alkylidene, —CH(halogen)-, —CH(OH)—, or —CH(O-alkyl)-, provided that when W is —O— or —S—, then n≧2 and each R7 and R8 is independently H or alkyl;
• X is a single bond, —CH═CH—, —O—, or —N(R21)—, provided that when X is —O—, G2 is other than —C(═N—CN)—N(R18e)(R18f);
• and provided that when X is —O— or —N(R21)—, then R8 is H or alkyl;
• and provided that when G2 is —C(═CHNO2)—N(R18c)(R18d), then X is —N(R21)—;
• and provided that when G2 is heterocycloalkyl or heteroaryl and attached to X through a ring heteroarom, then X is a single bond;
• each R15a, R15b, R16a, R16b, R17, and R21 is independently H or alkyl;
• or R17 and R18c, taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• or R18c and R21, taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2-alkyl)-;
• m and n are each independently an integer from 1 to 5;
• each p is independently an integer from 0 to 5;
• and
• each r is independently an integer from 0 to 4;
• with the proviso that:
• at least one of A, B, D, and E is C—[C(R15a)(R16a)]p—N(R17)-G1 or C—[C(R15b)(R16b)]p—OC(═O)—N(R18a)(R18b);
• or a pharmaceutically acceptable salt thereof.

A method for modulating appetite, comprising the step of:

• administering to said patient an effective amount of a compound of formula I:
• wherein:
• R1, R2, R3, and R4 are each independently H, alkyl, —OR9a, —N(R10)(R11), —C(═O)N(R12)(R13), —C(═O)—OR9b, —OP(═O)(OR9c)(OR9d), —CN, or
• R5 and R6 are each independently H or alkyl, or taken together with the carbon atom to which they are attached form a 3- to 8-membered carbocyclic ring, wherein 1 to 3 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, or —N(R9e)—;
• each R7 and R8 is independently H, alkyl, halogen, or —OR9f;
• A, B, D, and E are each independently N, CR14a, C—[C(R15a)(R16a)]p—N(R17)-G1, or C—[C(R15b)(R16b)]pOC(═O)—N(R18a)(R18b);
• J is N or CR14b, provided that no more than two of A, B, D, E, and J are N;
• each G1 is independently —S(═O)2R19, —S(═O)2N(R20a)(R20b)C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, —C(═O)—N(R18c)(R18d), —C(═CHNO2)—N(R18c)(R18d), or —C(═N—CN)—N(R18e)(R18f);
• G2 is alkyl, acyl, aryl, heteroaryl, heterocycloalkyl, —S(═O)2R19, —S(═O)2N(R20a)(R20b), —C(═O)-heterocycloalkyl, —C(═O)-heteroaryl, —C(═O)—N(R18c)(R18d), —C(═O)—OR9b, —C(═CHNO2)—N(R18c)(R18d), or —C(═N—CN)—N(R18e)(R18f);
• each R9a, R9b, R9c, R9d, R9e, and R9f is independently H or alkyl;
• each R10, R11, R12, and R13 is independently H, alkyl, alkenyl, aryl, or heteroaryl, or each R10 and R11 or R12 and R13, taken together with the nitrogen atom to which they are attached, independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• each R14a and R14b is independently H, halogen, alkyl, —CH2F, —CHF2, —CF3, —CN, —(CH2)r—OH, or —(CH2)r—O-alkyl;
• each R18a, R18b, R18c, R18d, R18e, R18f, R20a, and R20b is independently H, alkyl, alkenyl, or aryl, or each R18a and R18b or R18c and R18d or R20a and R20b, taken together with the nitrogen atom to which they are attached independently form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• each R19 is independently H, alkyl, aryl, OH, or —O-alkyl;
• W is a single bond, —O—, —S—, —CH2—, —CF2—, alkylidene, —CH(halogen)-, —CH(OH)—, or —CH(O-alkyl)-, provided that when W is —O— or —S—, then n≧2 and each R7 and R8 is independently H or alkyl;
• X is a single bond, —CH═CH—, —O—, or —N(R21)—, provided that when X is —O—, G2 is other than —C(═N—CN)—N(R18e)(R18f);
• and provided that when X is —O— or —N(R21)—, then R8 is H or alkyl;
• and provided that when G2 is —C(═CHNO2)—N(R18c)(R18d), then X is —N(R21)—;
• and
• provided that when G2 is heterocycloalkyl or heteroaryl and attached to X through a ring heteroarom, then X is a single bond;
• each R15a, R15b, R16a, R16b, R17, and R21 is independently H or alkyl;
• or R17 and R18c, taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2—R9a)—;
• or R18c and R21, taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring wherein 1 or 2 of the ring carbon atoms independently may be optionally replaced by —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(alkyl)-, —N(C(═O)—R9a)—, or —N(S(═O)2-alkyl)-;
• m and n are each independently an integer from 1 to 5;
• each p is independently an integer from 0 to 5;
• and
• each r is independently an integer from 0 to 4;
• with the proviso that:
• at least one of A, B, D, and E is C—[C(R15a)(R16a)]p—N(R17)-G1 or C—[C(R15b)(R16b)]p—OC(═O)—N(R18a)(R18b);
• or a pharmaceutically acceptable salt thereof.