Biaril espiroaminooxazolina analogues and espiroaminodiazolina modulators alfa2c adrenergic Receptors, Pharmaceutical compositions containing same and Use thereof in allergic rhinitis, Heart Disorders and other diseases

摘要

Claim 1: a compound represented by the formula (1) or a pharmaceutically acceptable Salt thereof, where J1, J2, J3 and J4 are independently - N -, N - (o) -, - C (R2) - X - C (r6) (r6) -, - N (r6) -, - O -, - S - W is N (R15) -, - or - or - S - Z is independently selected from the Group; Consisting of H, Oh, Halo, - CN, - NO2, - S (o) - PR7, nr7r7 '- [c] (RA) (RB) qyr7' - [c] (RA) (RB) yr7 QN (R7) ',- [c] (RA) (RB) qoyr7 ', and' cr7r7 Wut = (CH2), and alkyl groups, alkoxy, alquenilo, alqueniloxi, alquinilo cicloalcoxi, cycloalkyl, aryl, heteroaryl, ariloxi, arylalkyl heteroarilalquilo heterociclilo,,,, and heterociclilalquilo optionally substituted with at least one R5; where -- - IT's a Single or dual link with the condition that when w IS - or - or - S -,The Double bond is present between n and 2 position, and when W is N (R15), the double bond is present between n and W and the position 2 or 2 position, but not 2 contiguous Double Bonds can form a Ring; r1 is selected from the group consisting cicloalquenilo, cycloalkyl, aryl, I Terociclilo, heterociclenilo and heteroaryl,Each of which is optionally substituted with at least one R12; R2 is absent or is independently selected from the group consisting of H, Halo, - CN, - NO2, - Oh, - S (o) - PR7, nr7r7 '- [c] (RA) (RB) qyr7', - [c] (RA) (RB) QN (R7) yr7 '- [c] (RA) (RB) QN (R7) CN, - [c] (RA) (RB) qo yr7') and - (CH2) = C Wut R7r7 'groups, and alkyl, alkoxy, alquenilo, alqueniloxi, alquinilo, cycloalkyl, aryl, cicloalcoxi,Ariloxi, arylalkyl, heteroaryl, heteroarilalquilo, heterociclilo and heterociclilalquilo substituted with at least one R5, and is selected from the group consisting of a Link, - C (= o) -, - C (= o) nr7 -, - C (= o) -, - C (= o) n (RC) -, - C (= nr7) -, - C (= nor7) -, - C (= nr7 nr7) -, - C (= nr7o nr7) -, - C (= N - S (- CN), or So2nr7) P - - -And - C (= o) - Where nr7; ra and RB are independently selected from the group consisting of H, alkyl, alkoxy, and Halo, and RC is H or alkyl; R3 is independently selected from the group consisting of H, Oh, Halo, - CN, - NO2, or - S (- nr7r7 PR7), 's' pnr7r7 and (OR) (= OR), and alkyl groups, ALCO XI, alquenilo, alqueniloxi, alquinilo, cycloalkyl, aryl, ariloxi arylalkyl cicloalcoxi,,,Heteroaryl, heteroarilalquilo, heterociclilo, and heterociclilalquilo optionally substituted with at least one R5, with the condition that when W is 3, not more than 2 groups can be (= r3 or R4); is independently selected from the group consisting of H, D, - Oh, Halo, - CN, - S (o) - nr7r7 PR7, 'and' pnr7r7 - S (o), and alkyl groups, deuterizado alkyl, alkoxy, alquenilo, alqueniloxi,Alquinilo, cicloalcoxi, cycloalkyl, aryl, heteroaryl, ariloxi, arylalkyl, heteroarilalquilo, heterociclilo, and heterociclilalquilo, optionally substituted with at least one R5; R4 is independently selected from the group consisting of H, D, Halo, - Oh, alkyl and alkyl deuteriz Ado and alkoxy; or R4 R4 'can be taken together to form (= o),With the condition that when M 1, there is no more than 1 Group (= OR); R5 is independently selected from the group consisting of H, Halo, - Oh, - CN, - NO2, nr7r7 's, and (OR) alkyl and alkoxy groups, PR7, alquenilo alqueniloxi,,, alquinilo, cicloalcoxi, cycloalkyl, aryl, ariloxi, arylalkyl, het Eroarilo, heteroarilalquilo, heterociclilo, and heterociclilalquilo,Each of which is optionally substituted with at least one of the Halo Substituent, - Oh, - CN, - NO2, nr7r7 '-, and - S (o) and / or PR7 1 or 2 groups (= OR); R6 is selected from the group consisting of H, Oh, Halo, - CN, - NO2, - S (o) - nr7r7 PR7,' s' (or pnr7r7) -, - C (o) - R10, - C (o) - or10, and groups Alkyl, alkoxy, alquenilo, alqueniloxi, alquinilo, cycloalkyl, aryl, ariloxi, cicloalcoxi,Aralquilo, heteroaryl, heteroarilalquilo, heterociclilo and heterociclilalquilo, each of which is optionally substituted with at least one (preferably 1 to 5, preferably 1 to 3) of Halo substituents, - Oh, - CN, - NO2, nr7r7 '-, and - S (o) and / or PR7 1 or 2 groups (= O) - C (= o R7), or7 - C (= o) - C (= o) - so2r7 nr7r7 ', and' - so2nr7r7; r6 'is selected from the group consisting of H,- S (o) PR7, pnr7r7 's (o) -, - C (o) - R10, or10 - C (o) -, - C (o) - N (R7) R10 groups and alkyl, alkoxy, alquenilo, alqueniloxi, alquinilo, cycloalkyl, aryl, ariloxi arylalkyl cicloalcoxi,,, heteroaryl, heteroarilalquilo heterociclilo, and heterociclilalquilo, each of which is optionally substituted With at least one (preferably 1 to 5More preferably 1 to 3) of the Halo Substituent groups, - Oh, - CN, - NO2, nr7r7 '-, and - S (o) and / or PR7 1 or 2 (= o) - C (= o) R7, - C (= o) - C (= or7, or nr7r7'), so2r7 - and - so2nr7r7 '; or' R6 and R6 can be taken together to form (= OR); R7 is independently selected from the group consisting of H And alkyl groups, alquenilo, alquinilo, cycloalkyl, cicloalquilalquilo, cicloclenilo,Ciclociclenilalquilo, arylalkyl, heterociclilo, aryl, heteroaryl heterociclenilalquilo heterociclenilo heterociclilalquilo,,,, and heteroarilalquilo, each of which is optionally substituted by one or more times with R12; R7 is independently selected from the group consisting of H and alkyl groups, alquenilo, alquinilo, cycloalkyl, cicloalquilalquilo, cicloclenilo,Cicloclenilalquilo, arylalkyl, heterociclilo, aryl, heteroaryl heterociclenilalquilo heterociclenilo heterociclilalquilo,,,, and heteroarilalquilo, each of which is optionally substituted by one or more times with R12; or when a variable is nr7r7) -, - C (o) - so2nr7r7 nr7r7 'Or',R6 and R7 'in conjunction with the nitrogen Atom to which together form a Ring heterociclilo Regardless, heterociclenilo or heteroaryl 3 to 8 members, which also has the Atom n, 1 or 2 additional heteroatoms independently selected from the group consisting of o, n (R9) -, - N and SSuch Rings which are optionally substituted with 1 to 5 remains R12 independently selected and / or 1 or 2 groups (= o), or (b) when a variable is - (CH2) = cr7r7 Wut, R7 and R7 'in conjunction with the carbon Atom to which they are United to form a cycloalkyl Ring Regardless, Ci Cloalquenilo, aryl or heteroaryl, heterociclilo, heterociclenilo 3 to 8 members,Where such Rings heterociclilo heterociclenilo heteroaryl, or have 1 to 3 heteroatoms are independently selected from the group consisting of o, N, N - (R9) - and S, where the Rings are optionally substituted with 1 to 5 remains R12 independently selected and / or 1 or 2 (= o) groups; R9 is independently selected from the group consisting of H, - C (o) - R10- C (o) - or10, and - S (o) P - R10 and alkyl groups, alquenilo, alquinilo, cycloalkyl, aryl, heteroaryl heteroarilalquilo arylalkyl,, and, each of which is optionally substituted with at least one Halo Substituent, - Oh, - CN, - NO2 - N (R11 - S) 2 and (OR) PR11 and / or 1 or 2 groups (= OR) and R10 is Independently selected from the group consisting of H, alkyl groups, alquenilo, alquinilo,Arylalkyl, cycloalkyl, aryl, heteroaryl, and heteroarilalquilo, each of which is optionally substituted with at least one of the Halo Substituent, - Oh, - CN, - NO2 - N (R11) 2 and (OR) - S, PR11 and / or 1 or 2 groups (= o); R11 is an independently Selected the Group consis I in H and alkyl groups, alkoxy, alquenilo, alqueniloxi, alquinilo, cycloalkyl, cicloalcoxi,Ariloxi, aryl, heteroaryl heteroarilalquilo heterociclilo arylalkyl,,,, and heterociclilalquilo, each of which is optionally substituted with at least one Substituent selected from the group consisting of Halo, - Oh, - CN, - NO2 - N (R11 '- S) 2 and (OR) PR11' and / or 1 or 2 groups (= OR) R11 '; Is independently selected from the group consisting of H, alkyl, alkoxy, alquenilo,Alqueniloxi, alquinilo cicloalcoxi, cycloalkyl, aryl, heteroaryl, ariloxi, arylalkyl heteroarilalquilo heterociclilo,,,, and heterociclilalquilo; R12 is independently selected from the group consisting of H, Halo, - Oh, - CN, - NO2 - N (R11) 2, - C (o) - N - (or14, R14) - C (o) - R14, - N (R14) - C (o) - R1 2 4, - C (o) - n 2 - N (R11) (R14) - S (o) 2 - (R11, - s or - N (R11) 2 -) 2 and (OR) PR11 and / or 1 or 2 groups (= o),Alkyl and alkoxy groups,, alquenilo, alqueniloxi, alquinilo, cycloalkyl, cicloalquenilo, cicloalcoxi, aryl, heteroaryl, ariloxi, arylalkyl, heteroariloxi, heteroarilalquilo, heterociclilo, heterociclenilo, heterocicleniloxi, heterociclilalquilo, heteroclenilalquilo, ariialcoxi, heteroarilalco XI, heterocicliialcoxi and heterociclenilalcoxi,Each of which is optionally replaced at least once by a Substituent selected from the group consisting of H, alkyl, Halo, haloalquilo, - Oh, ariloxi alkoxy optionally substituted, optionally substituted, optionally substituted cicloalcoxi, heteroariloxi option Finally heterocicleniloxi substituted, optionally substituted, - CN, - NO2 - N (R11) 2And - S (o) PR11 and / or 1 or 2 groups (= o), where such ariloxi alkoxy optionally substituted, optionally substituted, cicloalcoxi, heteroariloxi optionally substituted, and when they are heterocicleniloxi replaced one or more times with R11, R14 is independently h, alkyl, or aryl; R 15 is absent or is independently selected from the group consisting of H, - C (o) - R10Or10 - C (o) -, - C (= o) - N (R7) (R7), and - S (o) P - R10 - SO2 - nr7r7 'and alkyl groups, alkoxy, alquenilo, alqueniloxi, alquinilo cicloalcoxi, cycloalkyl, aryl, heteroaryl ariloxi arylalkyl,,,, heteroarilalquilo heterociclilo heterociclilalquilo,, and, each of which is optionally substituted C On at least one of Halo, - Oh, - CN, - NO2 - nr7r7 ',And - S (o) and / or PR7 1 or 2 Substituent groups (= o) - C (= o) R7, - C (= o) or7, - C (= o) - so2r7 nr7r7 ', and' - so2nr7r7; Q is independently an integer from 0 to 10; n is independently an integer of 0 - 2; M is an integer of 1 - 3 independently; whether p is an integer of 0 - 2, and W is an integer of 0 - 3.