AR102436A2 - TRPV1 ANTAGONISTS AND USES OF THE SAME - Google Patents

Abstract

And pharmaceutically acceptable salts thereof, compositions comprising an effective amount of a compound of formula (1) or a pharmaceutically acceptable derivative thereof. Claim 1: A compound of formula (1) or a pharmaceutically acceptable derivative thereof, characterized in that X is O, S, N-CN, N-OH, or N-OR¹⁰; W is N or C; the dotted line denotes the presence or absence of a link, and when the dotted line denotes the presence of a link or W is N, then R⁴ is absent, otherwise R⁴ is -H, -OH, -OCF₃, -halo, -C₁₋₆alkyl, -CH₂OH, -CH₂Cl, -CH₂Br, -CH₂I, -CH₂F, -CH (halo) ₂, -CF₃, -OR¹⁰, -SR¹⁰, -COOH, -COOR¹⁰, -C (O) R¹⁰, - C (O) H, -OC (O) R¹⁰, -OC (O) NHR¹⁰, -NHC (O) R¹³, -CON (R¹³) ₂, -S (O) ₂R¹⁰, or -NO₂; R¹⁰ is -C₁₋₄alkyl; each R¹³ is independently -H, -C₁₋₄alkyl, -C₁₋₄alkenyl, -C₁₋₄alquinyl, or -phenyl; Ar¹ is a remainder of the group of formulas (2); Ar² is a remainder of the group of formulas (3); c is the integer 0, 1, or 2; Y¹, Y², Y³ are independently C, N, or O; where no more than one of Y¹, Y², or Y³ can be O, and for each Y¹, Y², and Y³ that is N, the N is linked to a group R²¹, and for each Y¹, Y², and Y³ that is C , C is linked to two R²⁰ groups, provided there is no more than a total of two substituted C₁₋₆alkyl groups in all Y¹, Y², and Y³; R¹²ᵃ and R¹²ᵇ, are independently -H or -C₁₋₆alkyl; E is = O, = S, = CHC₁₋₅alkyl, = CHC₁₋₅alkenyl, -NHC₁₋₆alkyl, or = N-OR²⁰; R¹ is -H, -halo, -C₁₋₄alkyl, -NO₂, -CN, -OH, -OCH₃, -NH₂, -C (halo) ₃, -CH (halo) ₂, -CH₂ (halo), -OC (halo) ₃, -OCH (halo) ₂, or -OCH₂ (halo); Each R² is independently: (a) -halo, -OH, -OC₁₋₄alkyl, -CN, -NO₂, -NH₂, -C₁₋₁₀alkyl, -C₂₋₁₀alkenyl, -C₂₋₁₀alquinyl, -phenyl, or (b) a group of formula Q; where Q is a remainder selected from the group of formulas (4); Z¹ is -H, -OR⁷, -SR⁷, -CH₂-OR⁷, -CH₂-SR⁷, -CH₂-N (R²⁰) ₂, or -halo; Z² is -H, -C₁₋₆alkyl, -C₂₋₆alkenyl, -C₂₋₆alquinyl, -CH₂-OR⁷, -phenyl, or -halo; each Z³ is independently -H, -C₁₋₆alkyl, -C₂₋₆alkenyl, -C₂₋₆alquinyl, or -phenyl; Z⁴ is -H, -OH, -OR²⁰, -C₁₋₆alkyl, or -N (R²⁰) ₂; J is -OR²⁰, -SR²⁰, -N (R²⁰) ₂, or -CN; as long as at least one group R² is a group of formula Q, and provided that, when Z¹ is -OR⁷ or -SR⁷, then Z² is not -halo; each R³ is independently: (a) -H, C₁₋₆alkyl, or CH₂OR⁷; or (b) two R³ groups together form a C₂₋₆ bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R⁸ groups, and whose bridge optionally contains -HC = CH- within the C₂₋₆ bridge; or (c) two R³ groups together form a bridge -CH₂-N (Rᵃ) -CH₂-, a bridge of formula (5) or, a bridge of formula (6); Rᵃ is selected from -H, -C₁₋₆alkyl, -C₃₋₈cycloalkyl, -CH₂-C (O) -Rᶜ, - (CH₂) -C (O) -ORᶜ, - (CH₂) -C (O) -N (Rᶜ) ₂, - (CH₂) ₂-O-Rᶜ, - (CH₂) ₂-S (O) ₂-N (Rᶜ) ₂, or - (CH₂) ₂-N (Rᶜ) S (O) ₂- Rᶜ; Rᵇ is selected from: (a) -H, -C₁₋₆alkyl, -C₃₋₈cycloalkyl, -3 to 7-membered heterocycle, -N (Rᶜ) ₂, -N (Rᶜ) -C₃₋₈cycloalkyl, or -N ( Rᶜ) -heterocycle of 3 to 7 members; or (b) -phenyl, -5 or 6-membered heteroaryl, -N (Rᶜ) -phenyl, or -N (Rᶜ) -5 to 10-membered heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R⁷ groups; each Rᶜ is independently selected from -H or -C₁₋₄alkyl; each R⁷ is independently -H, -C₁₋₆alkyl, -C₂₋₆alkenyl, -C₂₋₆alquinyl, -C₃₋₈cycloalkyl, -C₅₋₈cycloalkenyl, -phenyl, -C₁₋₆haloalkyl, -C₁₋₆hydroxyalkyl, -C₁₋₆alkoxy- C₁₋₆alkyl, -C₁₋₆alkyl-N (R²⁰) ₂, or -CON (R²⁰) ₂; each R⁸ and R⁹ is independently: (a) -C₁₋₆alkyl, -C₂₋₆alkenyl, -C₂₋₆alquinyl, -C₃₋₈cycloalkyl, -C₅₋₈cycloalkenyl or -phenyl, each of which is unsubstituted or substituted with 1 or 2 -OH groups; or (b) -H, -CH₂C (halo) ₃, -C (halo) ₃, -CH (halo) ₂, -CH₂ (halo), -OC (halo) ₃, -OCH (halo) ₂, -OCH₂ (halo), -SC (halo) ₃, -SCH (halo) ₂, -SCH₂ (halo), -CN, -O-CN, -OH, -halo, -N₃, -NO₂, -CH = NR⁷, - N (R⁷) ₂, -NR⁷OH, -OR⁷, -C (O) R⁷, -C (O) OR⁷, -OC (O) R⁷, -OC (O) OR⁷, -SR⁷, -S (O) R⁷, or -S (O) ₂R⁷; each R¹¹ is independently -CN, -OH, -C₁₋₆alkyl, -C₂₋₆alkenyl, -halo, -N₃, -NO₂, -N (R⁷) ₂, -CH = NR⁷, -NR⁷OH, -OR⁷, -C ( O) R⁷, -C (O) OR⁷, -OC (O) R⁷, or -OC (O) OR⁷; each R¹⁴ is independently -H, -C₁₋₆alkyl, -C₂₋₆alkenyl, -C₂₋₆alquinyl, -C₃₋₈cycloalkyl, -C₅₋₈cycloalkenyl, -C₁₋₆alkoxy-C₁₋₆alkyl, -phenyl, -C (halo) ₃ , -CH (halo) ₂, -CH₂ (halo), 3 to 7-membered heterocycle, -C₁₋₆haloalkyl, -C₂₋₆haloalkenyl, -C₂₋₆haloalquinyl, -C₂₋₆hydroxyalkenyl, -C₂₋₆hydroxyalquinyl, -C₁₋ ₆alkoxy-C₂₋₆alkyl, -C₁₋₆alkoxy-C₂₋₆alkenyl, -C₁₋₆alkoxy-C₂₋₆alquinyl, -C₁₋₆alkoxy-C₃₋₈cycloalkyl, -CN, -OH, -halo, -OC (halo) ₃, - N₃, -NO₂, -CH = NR⁷, -N (R⁷) ₂, -NR⁷OH, -OR⁷, -SR⁷, -O (CH₂) ᵇOR⁷, -O (CH₂) ᵇSR⁷, -O (CH₂) ᵇN (R⁷) ₂ , -N (R⁷) (CH₂) ᵇOR⁷, -N (R⁷) (CH₂) ᵇSR⁷, -N (R⁷) (CH₂) ᵇN (R⁷) ₂, -N (R⁷) COR⁷, -C (O) R⁷, - C (O) OR⁷, -OC (O) R⁷, -OC (O) OR⁷, -S (O) R⁷, or -S (O) ₂R⁷, -S (O) ₂N (R⁷) ₂, -SO₂C (halo ) ₃, -SO₂-3- to 7-membered heterocycle, -CON (R⁷) ₂, -C₁₋₅alkyl-C = NOR⁷, -C ₋₅alquil-C (O) -N (R⁷) ₂, -C₁₋₆alquil-NHSO₂N (R⁷) ₂, or -C₁₋₆alquil-C (= NH) -N (R⁷) ₂; each R²⁰ is independently -H, -C₁₋₆alkyl, or -C₃₋₈cycloalkyl; each R²¹ is independently -H, -C₁₋₆alkyl, or a compound of the group of formulas (7); each halo is independently -F, -Cl, -Br, or -I; n is the integer 1, 2, or 3; p is the integer 1 or 2; each b is independently 1 or 2; q is the integer 0, 1, 2, 3 or 4; r is the integer 0, 1, 2, 3, 4, 5, or 6; s is the integer 0, 1, 2, 3, 4, or 5; t is the integer 0, 1, 2, or 3; and m is the integer 0, 1, or 2.