Indole derivatives and use thereof

1. A compound of Formula IV:

wherein:

X is NR 4a , O, and S; Y is CR 3a ; and Z is CR 3b ;

R 4a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxyalkyl, optionally-substituted (cycloalkyl)alkyl, optionally-substituted (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, optionally-substituted aralkyl, optionally-substituted (heteroaryl)alkyl, optionally substituted aryl, —COR 11a , and —SO 2 R 11b ;

R 3a is selected from the group consisting of hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R 3b is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, optionally substituted aryl, (heterocycloamino)alkyl, —CO 2 H, and —C(═O)NR 12a R 12b ;

R 11a is selected from the group consisting of alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R 11b is selected from the group consisting of alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, amino, alkylamino, dialkylamino, and heterocyclo;

R 12a is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heterocyclo)alkyl, optionally substituted (heteroaryl)alkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (carboxamido)alkyl, (cyano)alkyl, alkoxyalkyl, hydroxyalkyl, and heteroalkyl;

R 12b is selected from the group consisting of hydrogen and alkyl; or

R 12a and R 12b taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclo group;

R 1e and R 1f are hydrogen;

W 4 is CH;

G is —C(═O)E;

R 5 is selected from the group consisting of hydrogen, halo, hydroxy, alkyl, hydroxyalkyl, cyano, heterocyclo, and —X 1 —R 7 ;

X 1 is selected from the group consisting of —O—, —NR 8a —, and —(CH 2 ) t —Y 1 —;

Y 1 is selected from the group consisting of —O— and —NR 8b —;

t is 1 or 2;

R 7 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl,

R 8a is selected from the group consisting of hydrogen and alkyl;

R 8b is selected from the group consisting of hydrogen and alkyl; or

R 8b and R 7 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;

R 9 is selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl; and

R 10a and R 10b are independently selected from the group consisting of hydrogen and alkyl; or

R 10a and R 10b taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;

E is —NR 1 R 2 ;

R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, heteroaryl, and optionally substituted (cycloalkyl)alkyl; and

R 2 is hydrogen;

or a pharmaceutically acceptable salt or solvate thereof.

2. A compound selected from the group consisting of:

6-(1-methyl-3-(3-(trifluoromethyl) phenyl)-1H-indol-5-yl)picolinamide;

6-(1-methyl-3-(4-(trifluoromethyl) phenyl)-1H-indol-5-yl)picolinamide;

6-(1-(2-(diethylamino)ethyl)-3-(4-fluorophenyl)-1H-indol-6-yl)picolinamide;

6-(1H-indol-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide;

6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;

6-(1-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-indol-5-yl)picolinamide;

6-(1H-indol-5-yl)picolinamide;

6-(1-methyl-1H-indol-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide;

N-cyclohexyl-6-(1H-indol-5-yl)picolinamide;

(S)-6-(1H-indol-5-yl)-4-((2-oxopyrrolidin-3-yl)amino)-N-(4-(trifluoromethyl)-phenyl)picolinamide;

6-(1-(cyclohexylmethyl)-1H-indol-5-yl)picolinamide;

6-(benzofuran-5-yl)-N-(4-(trifluoromethyl)phenyl)picolinamide;

5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxamide;

5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxylic acid;

(S)-2-(5-(6-((4-(trifluoromethyl)phenyl)carbamoyl)pyridin-2-yl)-1H-indole-3-carboxamido)pentanediamide;

5-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide;

(S)—N-(1-amino-1-oxopropan-2-yl)-5-(6-carbamoylpyridin-2-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide;

N-(cyclohexylmethyl)-6-(1H-indol-5-yl)picolinamide;

6-(1-(4-fluorobenzyl)-1H-indol-5-yl)picolinamide;

N-cyclopentyl-6-(1H-indol-5-yl)picolinamide;

6-(1-(2-cyclohexylethyl)-1H-indol-5-yl)picolinamide;

6-(1H-indol-5-yl)-N-(1H-tetrazol-5-yl)picolinamide;

6-(1-((2-methylthiazol-4-yl)methyl)-1H-indol-5-yl)picolinamide;

6-(1-isobutyl-1H-indol-5-yl)picolinamide;

6-(1-(4-m ethylbenzyl)-1H-indol-5-yl)picolinamide;

6-(1-(pyridin-4-ylmethyl)-1H-indol-5-yl)picolinamide;

6-(1-(cyclohexylsulfonyl)-1H-indol-5-yl)picolinamide;

6-(1-(2-morpholinoethyl)-1H-indol-5-yl)picolinamide;

(S)-6-(3-(((2-oxopyrrolidin-3-yl)amino)methyl)-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;

6-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-indol-5-yl)picolinamide;

(S)-6-(1-(cyclohexylmethyl)-3-(((2-oxopyrrolidin-3-yl)amino)methyl)-1H-indol-5-yl)picolinamide;

(R)-4-(1,2-dihydroxyethyl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;

(S)-4-(1,2-dihydroxyethyl)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)picolinamide;

(S)-4-(1,2-dihydroxyethyl)-6-(1-isobutyl-1H-indol-5-yl)picolinamide;

(R)-4-(1,2-dihydroxyethyl)-6-(1-isobutyl-1H-indol-5-yl)picolinamide;

and a pharmaceutically acceptable salt or solvate thereof.

3. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

4. A method for treating pain in a mammal, comprising administering an effective amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need of such treatment.

5. The method of claim 4 , wherein said pain is selected from the group consisting of chronic pain, inflammatory pain, neuropathic pain, acute pain, and surgical pain.

6. A method of modulating Nav1.7 sodium channels in a mammal, comprising administering to the mammal at least one compound as claimed in claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

7. A compound as claimed in claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is 3 H, 11 C, or 14 C radiolabeled.

8. A pharmaceutical composition comprising the compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.