Methods for making central nervous system agents that are TRPV1 antagonists

1. A method of making a compound of formula XXIV,

or salt thereof, comprising:

reacting a compound of formula XII or XIIa,

R 10 —CN  (XII)

or

R 10 —NH 2   (XIIa)

with hydrogen in the presence of Ra—Ni, and then an acid HX, to produce a compound of formula XIII or XIIIa,

reacting the freebase of compound of formula XIII or XIIIa with PhOCONH 2 in the presence of a first base and a first solvent, to produce a compound of formula IV,

optionally, reacting a compound of formula XII or XIIa,

R 10 —CN  (XII)

or

R 10 —NH 2   (XIIa)

with PhOCONH 2 in the presence of a first base and a first solvent, to produce a compound of formula IV,

or further optionally reacting a compound of formula XII or XIIa, in situ,

R 10 —CN  (XII)

or

R 10 —NH 2   (XIIa)

with hydrogen in the presence of Ra—Ni, and an acid HX, and PhOCONH 2 in the presence of a first base and a first solvent, to produce a compound of formula IV,

and further reacting the compound of formula IV with a compound of formula II

in the presence of a palladium catalyst, a second base, a second solvent, and a ligand,

wherein X 2 is selected from the group consisting of: halogen and sulfonate, wherein the sulfonate is independently substituted with fluorine or C 1 -C 8 fluorinated alkanes;

wherein the compound of formula II includes at least one R 1 group;

wherein R 1 may be present more than once on the indicated ring;

wherein each wherein each R 1 is independently selected from the group consisting of: hydrogen, hydroxyl, alkoxy, amino, substituted amino, substituted sulfur, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, substituted C 1 -C 8 alkyl, substituted C 2 -C 8 alkenyl, substituted —C 2 -C 8 alkynyl; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, —C 3 -C 12 cycloalkenyl, and substituted —C 3 -C 12 cycloalkenyl; each containing 0, 1, 2, or 3 heteroatoms selected from the group consisting of: O, S, and N;

R 2 is selected from the group consisting of: hydrogen, alkyl, and aryl;

R 3 is selected from the group consisting of: hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, substituted —C 2 -C 8 alkynyl; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, —C 3 -C 12 cycloalkenyl, and substituted —C 3 -C 12 cycloalkenyl; each containing 0, 1, 2, or 3 heteroatoms selected from the group consisting of: O, S, and N; and

R 10 is selected from the group consisting of: aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, substituted —C 2 -C 8 alkynyl; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, —C 3 -C 12 cycloalkenyl, and substituted —C 3 -C 12 cycloalkenyl; each containing 0, 1, 2, or 3 heteroatoms selected from the group consisting of: O, S, and N.

2. The method of claim 1 , wherein X 2 is Cl, R 3 is hydrogen or methyl, and R 10 is aryl or alkyl.

3. The method of claim 1 , wherein R 10 is a group of formula VIII or VIIIa

4. The method of claim 1 , wherein the first base is N,N-diisopropyl ethyl amine, and the second base is potassium phosphate tribasic.

5. The method of claim 1 , wherein the first solvent is Me-THF, and the second solvent is DME.

6. The method of claim 1 , wherein the palladium catalyst is selected from the group consisting of: Pd 2 (dba) 3 , Pd 2 Cl 2 (dba), Pd(OAc) 2 , Pd(OTFA) 2 , PdCl 2 , PdCl 2 (CH 3 CN) 2 , and PdCl 2 (PhCN) 2 .

7. The method of claim 6 , wherein the palladium catalyst is Pd 2 dba 3 .

8. The method of claim 1 , wherein the ligand is selected from the group consisting of the compounds of formulas XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, and VII:

PdCl 2 (dppf), and PdCl 2 (dppf)CH 2 Cl 2 .

9. The method of claim 8 , wherein the ligand is a compound of formula VII