Functionally selective alpha2c adrenoreceptor agonists

A compound of the Formula

• or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof
• wherein:
• J4 is:
• where
• Z is —[C(Rc)(Rc)]x—, and
• x is 1, 2, or 3;
• wherein:
• A is a 5-membered heteroaryl, heterocyclyl or heterocyclenyl ring containing 1-3 heteroatoms, preferably selected from the group consisting of —O—, —S— and —N—, and is optionally substituted with at least one R5 and/or 1 or 2 (═O) (carbonyl);
• J1, J2, and J3 are independently —N—, —N(O)— or —C(R2)—;
• is a single or double bond provided that there cannot be two continuous double bonds and further provided that when atoms 1 and 2 form a double bond in Formula I, R4′ and R6 are not present;
• R1 is selected from the group consisting of —[C(Ra)(Rb)]qYR7′, —[C(Ra)(Rb)]q(R7)YR7′, —[C(Ra)(Rb)]qNR7R7′, —[C(Ra)(Rb)]qOYR7′, —[C(Ra)(Rb)]qON═CR7R7′, —P(═O)(OR7)(OR7′), —P(═O)(NR7R7′)2, and —P(═)R82;
• Y is independently selected from the group consisting of a —C(═O)—, —C(═O)NR7—, —C(═O)O—, —C(═O)—[C(Ra)(Rb)]n—O—C(═O)—, —C(═O)N(Rc)—O—, —C(═NR7)—, —C(═NOR7)—, —C(═NR7)NR7—, —C(═NR7)N(Rc)O—, —S(O)p—, —SO2NR7—, and —C(═S)NR7;
• wherein Ra and Rb are independently selected from the group consisting of H, alkyl, alkoxy, and halo, and
• Rc is H or alkyl;
• R2 is independently selected from the group consisting of H, —OH, halo, —CN, —NO2, —S(O)pR7, —NR7R7′, —(CH2)qYR7′, —(CH2)qN(R7)YR7′, —(CH2)qOYR7′, and —(CH2)qON═CR7R7′, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R5;
• R3 is independently selected from the group consisting of H, halo and (═O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R5, provided that when w is 3, no more than 2 of the R3 groups may be (═O);
• R4 is independently selected from the group consisting of H, —CN, and halo and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R5;
• R4′ is absent or independently selected from the group consisting of H, and halo, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R5;
• R5 is independently selected from the group consisting of H, halo, —OH, —CN, —NO2, —NR7R7′, and —S(O)pR7, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one of halo, —OH, —CN, —NO2, —NR7R7′, and —S(O)pR7 substituents and/or 1 or 2 (═O);
• R6 is absent or independently selected from the group consisting of H, —CN, and halo, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each of which is optionally substituted with at least one of halo, —OH, —CN, —NO2, —NR7R7′, and —S(O)pR7 substituents and/or 1 or 2 (═O), and —C(═O)R7, —C(═O)OR7, —C(═O)NR7R7′, —SO2R7 and —SO2NR7R7′;
• R7 is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times by R12;
• R7′ is independently selected from the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted one or more times by R12;
• or
• a) when a variable is —NR7R7′, —[C(Ra)(Rb)]qYR7′, —[C(Ra)(Rb)]4N(R7)YR7′, —[C(Ra)(Rb)]qNR7R7′, —[C(Ra)(Rb)]qOYR7′, —(CH2)qNR7R7′, —C(O)NR7R7′ or —SO2NR7R7′, R7 and R7′ together with the nitrogen atom to which they are attached independently form a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl ring having, in addition to the N atom, 1 or 2 additional hetero atoms independently selected from the group consisting of O, N, —N(R9)— and S, wherein said rings are optionally substituted by 1 to 5 independently selected R5 moieties and/or 1 or 2 (═O), or
• b) when a variable is —(CH2)qON═CR7R7′ or —[C(Ra)(Rb)]qON═CR7R7, R7 and R7′ together with the carbon atom to which they are attached independently form a 3- to 8-membered cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocyclenyl or heteroaryl ring, wherein said hetroacyclyl, heterocyclenyl or heteroaryl rings have 1-3 heteroatoms which are independently selected from the group consisting of O, N, —N(R9)— and S, wherein said rings are optionally substituted by 1 to 5 independently selected R5 moieties and/or 1 or 2 (═O);
• R8 is independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one of halo, alkoxy, —OH, —CN, —NO2, —N(R11)2, and —S(O)pR11 substituents and/or 1 or 2 (═O);
• R9 is independently selected from the group consisting of H, —C(O)—R10, —C(O)—OR10, and —S(O)p—OR10 and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one of halo, —OH, —CN, —NO2, —N(R11)2, and —S(O)pR11 substituents and/or 1 or 2 (═O);
• R10 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is optionally substituted with at least one of halo, —OH, —CN, —NO2, —N(R11)2, and —S(O)pR11 substituents and/or 1 or 2 (═O);
• R11 is a moiety independently selected from the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each of which is optionally substituted by at least one substituent independently selected from the group consisting of halo, —OH, —CN, —NO2, —N(R11′)2, and —S(O)pR11 substituents and/or 1 or 2 (═O);
• R11′ is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
• R12 is independently selected from the group consisting of H, halo, —OH, —CN, —NO2, —N(R11)2, and —S(O)pR11, and/or 1 or 2 (═O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl, heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl, heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, and heterocyclenylalkoxy groups, each of which in turn is optionally substituted by at least once by a substituent selected from the group consisting of H, alkyl, haloalkyl, halo, —OH, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, optionally substituted heterocyclenyloxy, —CN, —NO2, —N(R11)2, and —S(O)pR11 and/or 1 or 2 (═O), wherein said optionally substituted alkoxy, aryloxy, optionally substituted cycloalkoxy, optionally substituted heteroaryloxy, and heterocyclenyloxy when substituted are substituted one or more times by R11;
• R13 is independently selected from the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R5;
• R14 is independently selected from the group consisting of H, alkyl, halo, —CN, and alkoxy;
• m is 0 or 1;
• n is independently 1, 2, or 3;
• p is independently 0, 1, or 2;
• q is independently an integer from 0 to 10;
• w is 1, 2, or 3;
• and
• z is 0, 1, 2, 3, 4, or 5,
• provided that
• a) when m is 0, z cannot be 0;
• b) if J1-J3 are —C(H)—, R1 is —[C(Ra)(Rb)]qOYR7′, q is 0, and A is unsubstituted imidazolyl, then Y cannot be a bond or —C(═O)—;
• c) if J1-J3 are —C(H)—, R1 is —[C(Ra)(Rb)]qYR7′, q is 0, and A is unsubstituted imidazolyl, then Y cannot be a bond, —C(═O)— or —C(═O)O—;
• d) if J1-J3 are —C(H)—, R1 is —[C(Ra)(Rb)]qYR7′, q is 0, and A is unsubstituted imidazolyl, and Y is S(O)p—, then p is other than 0;
• e) if J1-J3 are —C(H)—, R1 is —[C(Ra)(Rb)]qYR7′, q is 1, A is unsubstituted imidazolyl, and Y is a bond, then R7′ cannot be H;
• f) if J1-J3 are —C(H)—, R1 is —[C(Ra)(Rb)]qNR7R7′, A is unsubstituted imidazolyl, then q is other than zero;
• g) if J1-J3 are —C(H)—, R1 is —[C(Ra)(Rb)]qNR7YR7′, A is unsubstituted imidazolyl, q is 0, then Y is other than a bond;
• h) if J1-J3 are —C(H)—, R1 is —[C(Ra)(Rb)]qOYR7′, q is 1, Y is a bond and A is unsubstituted imidazolyl, then R7′ is other than alkyl.
• i) if R1 is —[C(Ra)(Rb)]qYR7′, q=0, and Y═—C(═NR7)—, —C(═NOR7)—, —C(═NR7)NR7—, or —C(═NR7)N(Rc)O—, then R7 and R7′ may not be taken together to form a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl ring;
• and
• j) if R1 is —[C(Ra)(Rb)]qN(R7)YR7′ or —[C(Ra)(Rb)]qNR7R7′ and q=0, then R7 and R7′ may not be taken together to form a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl ring.