Aryl substituted indoles and the use thereof

A method for treating a condition in a mammal, wherein the condition is stroke, neuronal damage resulting from head trauma, epilepsy, seizures, general epilepsy with febrile seizures, severe myoclonic epilepsy in infancy, neuronal loss following global and focal ischemia, migraine, familial primary erythromelalgia, paroxysmal extreme pain disorder, cerebellar atrophy, ataxia, distonia, tremor, mental retardation, autism, a neurodegenerative disorder, manic depression, tinnitus, myotonia, a movement disorder, or cardiac arrhythmia,

• said method comprising administering to the mammal identified as in need thereof an effective amount of a compound of Formula I:
• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• Z1 is CR2 or N, Z2 is CR3 or N, Z3 is CR4 or N, Z4 is CR5 or N, and Z5 is CR6 or N, provided that Z2, Z3, Z4, and Z5 are not all N at the same time;
• G is G1, G2, or G3, wherein
• G1 is
• G2 is
• G3 is
• m is 0, 1, 2, or 3;
• p is 0, 1, 2, or 3;
• r is 0 or 1;
• s is 1 or 2;
• provided that when r is 1, then s is 1;
• R7 is selected from the group consisting of
• a) —C(═O)NR1iR11, wherein R10 and R11 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;
• b) —C(═O)OR12, wherein R12 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;
• c) —(CH2)nOR13, wherein n is 1-5 and R13 is hydrogen;
• and
• d) hydrogen;
• R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionally substituted arylcarbonyl;
• or
• NR8R9 is —NO2;
• or
• R9 is hydrogen, R7 is —(CH2)nOR13, R8 and R13 together form a bridge —C(═O)— to form a heterocyclic ring, n is 1-5, and m is 1, 2 or 3;
• R7a is selected from the group consisting of
• a) —(CH2)qOH, wherein q is 1, 2, 3, 4, or 5;
• b) —C(═O)OR12a, wherein R12a is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;
• and
• c) hydrogen;
• R8a is hydrogen or a bond;
• provided that when R7a is hydrogen, then R8a is hydrogen;
• R7b and R8b are are each independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionally substituted arylcarbonyl;
• R9b is hydrogen, alkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkyl, cyanoalkyl, or hydroxyalkyl;
• one of R1, R2, R3, R4, R5, and R6 is A, wherein
• A is
• wherein
• A1 is aryl or heteroaryl, any of which is optionally substituted;
• X is —O—, —S—, —SO—, —SO2—, —CH2—, —NR27—, —N(R28)SO2—, or —SO2N(R29)—, wherein
• R27, R28, and R29 are each independently hydrogen or alkyl;
• and
• R14 and R15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl;
• R1, when not A, is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonylalkyl, (alkylaminocarbonyl)alkyl, or (dialkylaminocarbonyl)alkyl;
• and
• R2, R3, R4, R5, and R6, when not A, are each independently selected from the group consisting of hydrogen;
• optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
• halogen;
• hydroxy;
• cyano;
• amino;
• alkylamino;
• dialkylamino;
• alkoxy;
• aminocarbonyl;
• alkylaminocarbonyl;
• dialkylaminocarbonyl;
• alkylcarbonylamino;
• alkylcarbonyloxy;
• carboxy;
• aminosulfonyl;
• alkylsulfonylamino;
• and alkoxycarbonyl.

A method for providing local anesthesia in a subject, comprising administering to the subject identified as in need thereof an effective amount of a compound of Formula I:

• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• Z1 is CR2 or N, Z2 is CR3 or N, Z3 is CR4 or N, Z4 is CR5 or N, and Z5 is CR6 or N, provided that Z2, Z3, Z4, and Z5 are not all N at the same time;
• G is G1, G2, or G3, wherein
• G1 is
• G2 is
• and
• G3 is
• m is 0, 1, 2, or 3;
• p is 0, 1, 2, or 3;
• r is 0 or 1;
• s is 1 or 2;
• provided that when r is 1, then s is 1;
• R7 is selected from the group consisting of
• a) —C(═O)NR10R11, wherein R10 and R11 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;
• b) —C(═O)OR12, wherein R12 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;
• c) —(CH2)nOR13, wherein n is 1-5 and R13 is hydrogen;
• and
• d) hydrogen;
• R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionally substituted arylcarbonyl;
• or
• NR8R9 is —NO2;
• or
• R9 is hydrogen, R7 is —(CH2)nOR13, R8 and R13 together form a bridge —C(═O)— to form a heterocyclic ring, n is 1-5, and m is 1, 2 or 3;
• R7a is selected from the group consisting of
• a) —(CH2)qOH, wherein q is 1, 2, 3, 4, or 5;
• b) —C(═O)OR12a, wherein R12a is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl;
• and
• c) hydrogen;
• R8a is hydrogen or a bond;
• provided that when R7a is hydrogen, then R8a is hydrogen;
• R7b and R8b are are each independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionally substituted arylcarbonyl;
• R9b is hydrogen, alkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkyl, cyanoalkyl, or hydroxyalkyl;
• one of R1, R2, R3, R4, R5, and R6 is A, wherein
• A is
• wherein
• A1 is aryl or heteroaryl, any of which is optionally substituted;
• X is —O—, —S—, —SO—, —SO2—, —CH2—, —NR27—, —N(R28)SO2—, or —SO2N(R29)—, wherein
• R27, R28, and R29 are each independently hydrogen or alkyl;
• and
• R14 and R15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl;
• R1, when not A, is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonylalkyl, (alkylaminocarbonyl)alkyl, or (dialkylaminocarbonyl)alkyl;
• and
• R2, R3, R4, R5, and R6, when not A, are each independently selected from the group consisting of hydrogen;
• optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
• halogen;
• hydroxy;
• cyano;
• amino;
• alkylamino;
• dialkylamino;
• alkoxy;
• aminocarbonyl;
• alkylaminocarbonyl;
• dialkylaminocarbonyl;
• alkylcarbonylamino;
• alkylcarbonyloxy;
• carboxy;
• aminosulfonyl;
• alkylsulfonylamino;
• and alkoxycarbonyl.