Novel compounds as cannabinoid receptor ligands

A compound according to formula (I),

• or a pharmaceutically acceptable salt, solvate, prodrug, salt of a prodrug, or a combination thereof, wherein
• X1 is O, S, S(O), S(O)2, or N(Rbx);
• wherein Rbx is hydrogen, alkyl, haloalkyl, alkoxyalkyl, —C(O)O(alkyl), monocyclic cycloalkyl, —(CR1cR1d)q3-(monocyclic cycloalkyl), or haloalkoxyalkyl;
• and
• A1 is -G1a-G1b, —(CR1aR1b)q1-G1c, —(CR1aR1b)q2-A2, —(CR1gR1h)q2-A4, —N(Rb)C(O)Ra, —N(Rb)C(O)ORd, —N(Rb)C(O)N(Rb)(Rc), —N(Rb)(Rc), or —N═C(Rp)(Rq);
• or
• X1 and A1 together is N═N(Rcx);
• wherein Rcx is alkyl, haloalkyl, —(CR1aR1b)q3-A3, G1d, or —(CR1aR1b)q3-G1d;
• Rp is hydrogen, alkyl, haloalkyl, —(CR1aR1b)q3-A3, —C(O)ORd, —C(O)Rd, G1d, or —(CR1aR1b)q3-G1d;
• Rq is hydrogen, alkyl, haloalkyl, —N(Rb)(Rc), —(CR1aR1b)q3-A3, G1d, or —(CR1aR1b)q3-G1d;
• or
• Rp and Rq, together with the carbon atom to which they are attached, form a monocyclic 5-, 6-, 7-, or 8-membered cycloalkyl or heterocycle ring, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, alkyl, haloalkyl, and halogen;
• A2 is —C(O)Ra, —S(O)2Rd, —C(O)N(Rb)(Rc), —C(S)N(Rb)(Rc), —S(O)2N(Rb)(Rc), —C(═NORf)Ra, —CN, —N(Rc)C(O)Rm, —N(Rc)C(O)ORd, —N(Rc)S(O)2Rd, —N(Rc)C(O)N(Rb)(Rc), —N(Rc)S(O)2N(Rb)(Rc), -L1-G1d, -L1-(CR1aR1b)q3-G1d, -L1-(CR1aR1b)q1-A3, —O—(CR1aR1b)q2—O-alkyl, —OH, or —O(haloalkyl);
• A3 is C(O)Rh, —S(O)2Re, —C(O)N(Rh)2, —C(S)N(Rh)2, —S(O)2N(Rh)2, —C(═NORh)Rh, —N(Rh)C(O)Rh, —N(Rh)C(O)ORe, —N(Rh)S(O)2Re, —N(Rh)C(O)N(Rh)2, —N(Rh)S(O)2N(Rh)2, —CN, —ORj, or —N(Rh)2;
• A4 is cycloalkyl, alkoxy, or N(R1m)2;
• Li is O or N(Rb);
• Ra and Rc, at each occurrence, are each independently hydrogen, alkyl, haloalkyl, —(CR1aR1b)q3—O-alkyl, —(CR1aR1b)q3-A3, G1d, or —(CR1aR1b)q3-G1d;
• Rb, at each occurrence, is each independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, cycloalkyl, —(CR1cR1d)q3-(cycloalkyl), or haloalkoxyalkyl;
• Rd, at each occurrence, is alkyl, haloalkyl, —(CR1aR1b)q3—O-alkyl, —(CR1aR1b)q3-A3, G1d, or —(CR1aR1b)q3-G1d;
• Rj is hydrogen, C1-C4 haloalkyl, monocyclic cycloalkyl, or —(CR1cR1d)q3-(monocyclic cycloalkyl);
• Rm is haloalkyl, —(CR1aR1b)q3—O-alkyl, —(CR1aR1b)q3-A3, G1d, or —(CR1aR1b)q3-G1d;
• R1b, at each occurrence, is independently hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, —ORh, —N(Rh)2, —N(Rh)C(O)Rh, —N(Rh)C(O)ORe, or —N(Rh)S(O)2Re;
• R1g, at each occurrence, is independently hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, —ORh, —N(Rh)2, —N(Rh)C(O)Rh, —N(Rh)C(O)ORe, or —N(Rh)S(O)2Re;
• provided that at least one occurrence of R1g is halo, C1-C4 haloalkyl, —ORh, —N(Rh)2, —N(Rh)C(O)Rh, —N(Rh)C(O)ORe, or —N(Rh)S(O)2Re;
• R1m is hydrogen, alkyl, haloalkyl, alkylcarbonyl, formyl, or alkoxyalkyl;
• or two R1m taken together with the nitrogen atom to which they are attached form a heterocyclic ring, optionally substituted with 1, 2, 3, or 4 substituents selected from alkyl, hydroxy, oxo and haloalkyl;
• G1a and G1b, are each independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl;
• G1c is cycloalkenyl, heterocycle, aryl, or heteroaryl;
• wherein the ring as represented by G1a is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, ═N—CN, ═N—ORf, —CN, oxo, —ORf, —OC(O)Rf, —OC(O)N(Rf)2, —S(O)2Re, —S(O)2N(Rf)2, —C(O)Rf, —C(O)ORf, —C(O)N(O2, —N(Rf)2, —N(Rf)C(O)Rf, —N(Rf)S(O)2Re, —N(Rf)C(O)O(Re), and —N(Rf)C(O)N(R)2;
• wherein the cycloalkyl of A4 and the rings as represented by G1b and G1c, are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of G1d, —(CR1cR1d)q3-G1d, alkyl, alkenyl, alkynyl, halo, haloalkyl, ═N—CN, ═N—ORf, —CN, oxo, —ORf, —OC(O)Rf, —OC(O)N(Rf)2, —S(O)2Re, —S(O)2N(Rf)2, —C(O)Rf, —C(O)ORf, —C(O)N(Rf)2, —N(Rf)2, —N(Rf)C(O)Rf, —N(Rf)S(O)2Re, —N(Rf)C(O)O(Re), —N(Rf)C(O)N(Rf)2, —(CR1cR1d)q3—C(═NORf)(Ra), —(CR1cR1d)q3—ORf, —(CR1cR1d)q3—OC(O)Rf, —(CR1cR1d)q3—OC(O)N(Rf)2, —(CR1cR1d)q3—S(O)2Re, —(CR1cR1d)q3—S(O)2N(Rf)2, —(CR1cR1d)q3—C(O)Rf, —(CR1cR1d)q3—C(O)ORf, —(CR1cR1d)q3—C(O)N(Rf)2, —(CR1cR1d)q3—N(Rf)2, —(CR1cR1d)q3—N(Rf)C(O)Rf, —(CR1cR1d)q3—N(Rf)S(O)2Re, —(CR1cR1d)q3—N(Rf)C(O)O(Re), —(CR1cR1d)q3—N(Rf)C(O)N(Rf)2, and —(CR1cR1d)q3—CN;
• G1d, at each occurrence, is independently a monocyclic heterocycle, a monocyclic heteroaryl, a phenyl, a monocyclic cycloalkyl, or a monocyclic cycloalkenyl;
• optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of —N(Rh)2, —CN, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, and hydroxy;
• Re and Ri, at each occurrence, are each independently C1-C4 alkyl, C1-C4 haloalkyl, monocyclic cycloalkyl, or —(CR1cR1d)q3-(monocyclic cycloalkyl);
• Rf, at each occurrence, is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —(CR1cR1d)q3—ORg, monocyclic cycloalkyl, monocyclic heterocycle, or —(CR1cR1d)q3-(monocyclic cycloalkyl);
• Rg and Rh, at each occurrence, are each independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, monocyclic cycloalkyl, or —(CR1cR1d)q3-(monocyclic cycloalkyl);
• wherein the cycloalkyl, the monocyclic cycloalkyl, and the monocyclic heterocycle, as a substituent or part of a substituent, of Rb, Rbx, Rc, Ri, Rf, Rg, Rh, and Rj, at each occurrence, are each independently unsubstituted are substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C4 alkyl, halo, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 haloalkyl;
• R2 is —(CR2aR2b)q4—OH, —(CR2aR2b)q4—O-alkyl, —(CR2aR2b)q4—O—(CR2cR2d)q3—O-alkyl, or —(CR2aR2b)q5-G2;
• G2 is a 4-, 5-, 6-, 7-, 8-, or 9-membered monocyclic heterocycle containing zero or one double bond, one or two oxygen, and zero or one nitrogen as ring atoms;
• two non-adjacent atoms of said heterocycle ring can be optionally linked by an alkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms;
• or G2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl;
• each ring G2 is optionally fused with a monocyclic ring selected from the group consisting of benzo, cycloalkyl, cycloalkenyl, heterocycle and heteroaryl;
• and each G2 is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl;
• R3 and R4 are each independently G3, hydrogen, alkyl, alkenyl, alkynyl, —NO2, —CN, halo, —ORh, —N(Rh)2, —C(O)Rh, —C(O)O(Rh), haloalkyl, —(CR3aR3b)q6—ORh, —(CR3aR3b)q6—N(Rh)2, —(CR3aR3b)q6—C(O)Rh, or —(CR3aR3b)q6—C(O)O(Rh);
• R3 and R4, together with the carbon atoms to which they are attached, optionally form a 4-, 5-, 6-, or 7-membered monocyclic ring that contains zero, one or two additional double bond, zero or one oxygen atom, and zero, one or two nitrogen atom as ring atoms;
• two non-adjacent atoms of said monocyclic ring can be optionally linked by an alkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, said monocyclic ring is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, alkyl, halo, —OH, alkoxy, and haloalkyl;
• two substituents on the same carbon atom of said monocyclic ring, together with the carbon atom to which they are attached, optionally form a 3-, 4-, 5-, or 6-membered monocyclic cycloalkyl ring, wherein the monocyclic cycloalkyl ring is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of alkyl and haloalkyl;
• G3 is cycloalkyl, cycloalkenyl, aryl, heterocycle, or heteroaryl, each of which is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, C1-C4 haloalkyl, ═N—CN, ═N—ORh, —CN, oxo, —ORh, —OC(O)Rh, —OC(O)N(Rh)2, —S(O)2R1, —S(O)2N(Rh)2, —C(O)Rh, —C(O)ORh, —C(O)N(Rh)2, —N(Rh)2, —N(Rh)C(O)Rh, —N(Rh)S(O)2R1, —N(Rh)C(O)O(R1), and —N(Rh)C(O)N(Rh)2;
• R1a, R1h R1c, R1d, R2a, R2b, R2c, R2d, R3a and R3b, at each occurrence, are each independently hydrogen, halo, C1-C4 alkyl, or C1-C4 haloalkyl;
• Rx, at each occurrence, is independently G1d, alkyl, alkenyl, alkynyl, halo, haloalkyl, —CN, —ORf, —OC(O)Rf, —OC(O)N(Rf)2, —S(O)2Re, —S(O)2N(Rf)2, —C(O)Rf, —C(O)ORf, —C(O)N(Rf)2, —N(Rf)2, —N(Rf)C(O)Rf, —N(Rf)S(O)2Re, —N(Rf)C(O)O(Re), —N(Rf)C(O)N(Rf)2, —(CR1cR1d)q3—ORf, —(CR1cR1d)q3—OC(O)Rf, —(CR1cR1d)q3—OC(O)N(Rf)2, —(CR1cR1d)q3—S(O)2Re, —(CR1cR1d)q3—S(O)2N(Rf)2, —(CR1cR1d)q3—C(O)Rf, —(CR1cR1d)q3—C(O)ORf, —(CR1cR1d)q3—C(O)N(Rf)2, —(CR1cR1d)q3—N(O2, —(CR1cR1d)q3—N(Rf)C(O)Rf, —(CR1cR1d)q3—N(Rf)S(O)2Re, —(CR1cR1d)q3—N(Rf)C(O)O(Re), —(CR1cR1d)q3—N(Rf)C(O)N(Rf)2, or —(CR1cR1d)q3—CN;
• q1 is 1, 2, 3, or 4;
• q2 and q4, at each occurrence, are each independently 2, 3, 4, or 5;
• q3 is 1, 2 or, 3;
• q5 and q6, at each occurrence, are each independently 1, 2, 3, 4, 5, or 6;
• and
• z is 0, 1, 2, 3, or 4;
• with the proviso that
• (i) when X1 is N(Rbx) wherein Rbx is hydrogen, alkyl, haloalkyl or alkoxyalkyl;
• and R2 is —(CR2aR2b)q4—OH or —(CR2aR2b)q4—O-alkyl;
• then A1 is not —(CR1aR1b)q1—OH;
• (ii) when X1 is O;
• and G1b and G1c are heterocycle, then G1b and G1c are each connected to the parent moiety through the ring carbon atom;
• and
• (iii) when X1 is S(O)2 and R2 is —(CR2aR2b)q4—OH or —(CR2aR2b)q4—O-alkyl;
• then A1 is not N(H)2, N(alkyl)(H), or N(alkyl)2.