Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators for treating respiratory and non-respiratory diseases

A method of treating a respiratory or non-respiratory leukocyte-activation associated disease in a mammal comprising administering to said mammal an effective amount of at least one cannabinoid receptor modulator having the formula (I):

• 542
• or a pharmaceutically acceptable salt or hydrate thereof, in which:
• A and B are selected from carbon and nitrogen so that ring X defines a pyrrole, pyrazole, or imidazole ring;
• wherein when A is nitrogen, the group —C(═O)NR1R2 is attached to atom C-3 and R5 does not exist;
• and when A is carbon, one of the group —C(═O)NR1R2 and R5 is attached to A and the other of —C(═O)NR1R2 and R5 is attached to atom C-3;
• and when B is carbon, two R4 groups attached to B and atom C-5, respectively, optionally form a fused 6-membered aryl or 6-membered heteroaryl having one heteroatom which is nitrogen, wherein said aryl or heteroaryl has three or four substituents R6;
• f is 0 or 1;
• g is 1 or 2;
• R1 and R2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, cycloalkyl, aryl, heterocyclo, or alkoxyalkyl;
• or R2 together with R1 or R5 forms a five or six membered heterocyclo;
• R3is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heterocyclo, or alkoxy;
• or forms a heterocyclo with one of R6;
• R4 is attached to atom C-5 and optionally B and at each occurrence independent of each other R4 is selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, NR8C(═O)R9, and S(O)uR10;
• or when B is carbon, optionally two R4 groups taken together form a six-membered aryl or heteroaryl having three or four R6;
• R5 is attached to A or atom C-3 and is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkoxy, aryl, or heterocyclo;
• or R5 together with R2 forms a heterocyclo;
• R6 at each occurrence independent of each other R6 is selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted aryl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, nitro, NR8C(═O)R9, S(O)uR10, —C(═O)R8, —CO2R8, —S(O)2NR8R10, —C(═O)N(R8)O(R9), —C(═O)NR8R9, and —OC(═O)R10;
• and/or one R6 group together with R3 forms a heterocyclo;
• R8 and R9 at each occurrence independent of each other R8 and R9 are selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo;
• or R8 and R9 together form a three-to-eight membered heterocyclo;
• or R8 together with R10 forms a three-to-eight membered heterocyclo;
• and
• R10 at each occurrence independent of each other R10 is selected from alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl, or forms a heterocyclo with R8;
• and
• u is 0, 1, 2 or 3.

A compound having the formula:

• 545
• or a pharmaceutically acceptable salt or hydrate thereof, in which:
• A is carbon or nitrogen;
• wherein when A is nitrogen, the group —C(═O)NR1R2 is attached to atom C-3 and R5 does not exist;
• and when A is carbon, one of the group —C(═O)NR1R2 and R5 is attached to A and the other of —C(═O)NR1R2 and R5 is attached to atom C-3;
• Q is nitrogen or CR6a and J, L, and M are carbon or nitrogen, provided that only one of J, L, M and Q is nitrogen;
• R1 and R2 are independently selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, cycloalkyl, aryl, and heterocyclo, wherein said heterocyclo has for its heteroatom or heteroatoms sulfur or at least one of nitrogen and oxygen;
• or R2 together with R1 forms a heterocyclo that is unsaturated or selected from optionally-substituted 1,2,3,4-tetrahydroquinoline, triazaspirodecane, morpholine, piperidine, pyrrolidine, and diazapine;
• or R2 together with R5 forms a five or six-membered heterocyclo;
• R3is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heterocyclo, or alkoxy;
• or forms a heterocyclo with R6a;
• R5 is attached to A or atom C-3 and is hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkoxy, or heterocyclo;
• or R5 together with R2 forms a five to six membered heterocyclo;
• R6 at each occurrence independent of each other R6 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, heterocyclo, hydroxy, alkoxy, amino, aminoalkyl, cyano, halogen, alkylamide, nitro, NR8C(═O)R9, S(O)uR10, —C(═O)R8, —CO2R8, —S(O)2NR8R10, —C(═O)N(R8)O(R9), —C(═O)NR8R9, and —OC(═O)R10, provided only one of said R6 groups is selected from amino and aminoalkyl;
• R6a is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, heterocyclo, hydroxy, alkoxy, cyano, halogen, alkylamide, nitro, NR8C(═O)R9, S(O)uR10, —C(═O)R8, —CO2R8, —S(O)2NR8R10, —C(═O)N(R8)O(R9), —C(═O)NR8R9, and —OC(═O)R10;
• or forms a six-membered heterocyclo with R3;
• R8 and R9 at each occurrence selected independently are selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, or heterocyclo;
• or R8 and R9 together form a three-to-eight membered heterocyclo;
• or R8 with R10 forms a three-to-eight membered heterocyclo;
• and
• R10 at each occurrence independent of each other R10 is selected from alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl, or forms a heterocyclo with R8;
• and
• u is 0, 1, 2 or 3.

A compound having the formula:

• 550
• or a pharmaceutically acceptable salt or hydrate thereof, in which:
• A is nitrogen or CR5;
• B is nitrogen or CR4b, provided that A and B are not both nitrogen;
• R1 is —CHR17R18;
• R2 is hydrogen, lower alkyl, phenyl, or forms a five or six membered heterocyclo with R5;
• R4a is hydrogen, alkyl, aryl, or OR13;
• R4b is hydrogen, alkyl, alkoxy, amino, cyano, halogen, or aryl;
• R5 is hydrogen, methyl or ethyl, or forms a heterocyclo with R2;
• R13 is hydrogen, C1-6alkyl, phenyl, benzyl, or —CH2— which together with R14 forms a six membered heterocyclo ring;
• R14 is hydrogen or when R13 is —CH2—, a bond linked to R13;
• R17 and R18 are (i) selected independently from hydrogen and —(CH2)s—(CR21R22)v—(CH2)t—W;
• or (ii) R17 and R18 together form cycloalkyl, aryl, or heterocyclo having as its heteroatom or heteroatoms sulfur or at least one of oxygen and nitrogen;
• W at each occurrence is selected from CH3, alkylamide, aminoalkyl, alkylthio, alkoxy, hydroxy, cyano, —CO2R19, —C(═O)R19, —C(═O)N(R19)O(R20), —NR19(C═O)R20, aryl, cycloalkyl, and heterocyclo having as its heteroatom or heteroatoms sulfur or at least one of oxygen and nitrogen;
• R19 and R20 are selected from hydrogen, alkyl, substituted alkyl, heterocycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, and heterocyclo;
• R21 and R22 are independently hydrogen, alkyl, hydroxy, or hydroxyalkyl;
• s and t are 0, 1 or 2;
• and
• v is 0 or 1.