Compounds as cannabinoid receptor ligands

A compound according to formula (I),

• or a pharmaceutically acceptable salt thereof, wherein
• L1 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, -G1e, —(CR1aR1b)q1-A2, —N(Rb)C(O)Rd, —N(Rb)C(O)N(Rb)(Rc), —N(Rb)(Rc), or —N═C(RP)(Rq);
• or
• L1 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 5-, 6-, 7-, or 8-membered ring selected from the group consisting of monocyclic cycloalkyl and monocyclic heterocycle, 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)Ra, —N(Rc)C(O)ORd, —N(Rc)S(O)2Rd, —N(Rc)C(O)N(Rb)(Rc), —N(Rc)S(O)2N(Rb)(Rc), —N(Rb)(Rc), —O—Rj, or —O—C(O)(alkyl);
• Ra and Rc, at each occurrence, are each independently hydrogen, alkyl, haloalkyl, —(CR1aR1b)q2-A3, G1d, or —(CR1aR1b)q2-G1d;
• Rb, at each occurrence, is independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, monocyclic cycloalkyl, —(CR1cR1d)q2-(monocyclic cycloalkyl), or haloalkoxyalkyl;
• Rd, at each occurrence, is independently alkyl, haloalkyl, —(CR1aR1b)q2-A3, G1d, or —(CR1aR1b)q2-G1d;
• Rj is hydrogen, haloalkyl, —(CR1aR1b)q2-A3, G1d, or —(CR1aR1b)q2-G1d;
• 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, —ORh, or —N(Rh)2;
• G1a, G1b, and G1c, at each occurrence, are each independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl;
• G1e is C4-C8 cycloalkyl, heterocycle, 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, halogen, 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—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)q2—CN;
• wherein 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, halogen, 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—ORf, —(CR1cR1d)q3—OC(O)Rf, —(CR1cR1d)q3—OC(O)N(Rf)2, —(CR1cR1d)q2—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;
• wherein the ring as represented by G1e is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of —(CR1cR1d)q3-G1d, alkyl, alkenyl, alkynyl, halogen, 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—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;
• each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of —N(Rh)2, —CN, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, 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, 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 monocyclic cycloalkyl, as a substituent or part of a substituent, of Rbx, Rb, Re, Ri, Rf, Rg, and Rh, at each occurrence, is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-C4 alkyl, halogen, oxo, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, and C1-C4 haloalkyl;
• R2 is C2-C10 alkyl, alkenyl, alkynyl, haloalkyl, —(CR2aR2b)q4—O-haloalkyl, —(CR2aR2b)q4—O-G2a, —(CR2aR2b)q4—O—(CR2cR2d)q5-G2a, —(CR2aR2b)q5—C(O)—Ra, —(CR2aR2b)q5—C(═N—ORe)Ra, —CR2aR2b)q5—SO2—Rd, —(CR2aR2b)q5-G2b, —(CR2aR2b)q5—C(O)N(Rb)(Rc), —(CR2aR2b)q4—OC(O)N(Rb)(Rc), or —(CR2aR2b)q5—CN;
• G2a, at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl;
• G2b is cycloalkyl, cycloalkenyl, thien-2-yl, or thien-3-yl;
• wherein the rings as represented by G2a and G2b are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, alkyl, halogen, hydroxy, alkoxy, haloalkoxy, and haloalkyl;
• R3 and R4 are the same or different, and are each independently G3, hydrogen, alkyl, alkenyl, alkynyl, —NO2, —CN, halogen, —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);
• or
• R3 and R4, together with the carbon atoms to which they are attached, form a 4-, 5-, 6-, or 7-membered monocyclic ring that contains zero, one, or two additional double bond, optionally containing one or two nitrogen atom as ring atoms;
• two non-adjacent atoms of the monocyclic ring are 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, the monocyclic ring is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, alkyl, halogen, hydroxy, alkoxy, haloalkoxy, 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 independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen, C1-C4 haloalkyl, ═N—CN, ═N—ORh, —CN, oxo, —ORh, —OC(O)Rh, —OC(O)N(Rh)2, —S(O)2Ri, —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)2Ri, —N(Rh)C(O)O(Ri), and —N(Rh)C(O)N(Rh)2;
• R1a, R1c, R1d, R2a, R2b, R2c, R2d, R3a, and R3b, at each occurrence, are each independently hydrogen, halogen, C1-C4 alkyl, or C1-C4 haloalkyl;
• R1b, at each occurrence, is independently hydrogen, halogen, 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 each independently chosen from the group consisting of G1d, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen, C1-C4 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(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, or —(CR1cR1d)q3—CN;
• q1 and q2, at each occurrence, are each independently 1, 2, 3, or 4;
• q3, at each occurrence, is independently 1, 2 or, 3;
• q4, at each occurrence, is independently 2, 3, 4, or 5;
• 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 when
• L1 is N(Rbx) wherein Rbx is hydrogen, alkyl, or alkoxyalkyl;
• and
• R2 is C2-C10 alkyl, alkenyl, alkynyl, haloalkyl, —(CR2aR2b)q5—C(O)—Ra wherein Ra is heterocycle, —(CR2aR2b)q5—C(O)N(Rb)(Rc) wherein Rb and Rc are hydrogen or alkyl, —(CR2aR2b)q5—CN, or —(CR2aR2b)q5-G2b wherein G2b is cycloalkyl;
• then A1 is not —(CR1aR1b)q1—OH or heterocycle;
• and with the further proviso that when L1 is S(O)2;
• and
• R2 is C2-C10 alkyl, alkenyl, alkynyl, haloalkyl, —(CR2aR2b)q5—C(O)—Ra wherein Ra is monocyclic heterocycle, —(CR2aR2b)q5—C(O)N(Rb)(Rc) wherein Rb and Rc are hydrogen or alkyl, —(CR2aR2b)q5—CN, or —(CR2aR2b)q5-G2b wherein G2b is cycloalkyl;
• then A1 is not heterocycle, N(H)2, N(H)(alky), or N(alkyl)2.