阅读说明：本技术 具有β2受体激动及M受体拮抗活性的杂环衍生物及其医药用途 (Heterocyclic derivative with beta 2 receptor agonistic and M receptor antagonistic activities and medical application thereof ) 是由 殷惠军 闫旭 沙汉明 刘国标 司春枫 于 2020-05-29 设计创作，主要内容包括：一种具有β-(2)受体激动及M受体拮抗活性的杂环衍生物及其医药用途。杂环衍生物为通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐,其制备方法,含有其的药物组合物,及其在制备用于治疗气道阻塞性疾病的药物中的应用。(Has beta 2 Heterocyclic derivatives with receptor agonistic and M receptor antagonistic activities and medical uses thereof. The heterocyclic derivative is a compound shown in the general formula (I) or a racemate, an enantiomer, a diastereoisomer, a mixture form thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof, a preparation method thereof and a medicament containing the sameA pharmaceutical composition and application thereof in preparing medicaments for treating airway obstructive diseases.)

A compound of the general formula (I):

or a racemate, enantiomer, diastereomer or mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

R ¹is composed of

R ^1aAnd R^1bEach independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or (CH)₂) _pR ^aSaid alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, OR^a、SR ^aAlkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OC (O) R^bor-C (O) R^bWith the proviso that R is^1a、R ^1bNot hydrogen at the same time;

R ^1cselected from hydrogen, hydroxy, cyano, amino, alkyl, OR^a、SR ^aor-C (O) NR^bR ^c；

R ²、R ³Each independently selected from hydrogen or alkyl;

b is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, oxo, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, - (CH)₂) _pOR ^a、-C(O)OR ^a、-C(O)R ^b、-NR ^bC(O)R ^c、-NR ^bS(O) ₂R ^c、-NR ^bS(O) ₂NR ^bR ^c、-S(O) ₂NR ^bR ^c、-OC(O)R ^bor-NR^b(CH ₂) _pR ^cWherein said alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxySubstituted with one or more groups selected from the group consisting of alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

A ¹and A²Each independently selected from alkylene, alkenylene, or alkynylene; said alkylene, alkenylene OR alkynylene group is optionally further selected from halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, haloalkyl, OR^a、SR ^a、-OC(O)R ^b、-C(O)R ^bCycloalkyl, heterocyclyl, aryl or heteroaryl;

L ¹selected from single bonds, -NR^b-or-O-;

L ²selected from single bonds, -O-, -NR^b-、-S(O) _m-、-NR ^bC(O)-、-C(O)NR ^b-、-NR ^bC(O)(CH ₂) _pO-、-O(CH ₂) _pC(O)NR ^b-、-NR ^b(CH ₂) _pO-、-O(CH ₂) _pNR ^b-、-NR ^bC(O)NR ^c-、-C(O)-、-C(O)O-、-OC(O)-、-S(O) _mNR ^b-、-NR ^bS(O) _m-、-NR ^bS(O) _mNR ^c-、-NR ^bS(O) _m(CH ₂) _pS-、-S(CH ₂) _pS(O) _mNR ^b-、-NR ^b(CH ₂) _pS-、-S(CH ₂) _pNR ^b-、-C(O)NR ^bS(O) _m-or-S (O)_mNR ^bC(O)-；

Ring C is selected from cycloalkyl or heterocyclyl, said cycloalkyl or heterocyclyl being optionally further selected from hydrogen, halo-NR, -C, -O, and-O^bR ^c、-C(O)R ^b、-OC(O)R ^b、-C(O)OR ^a、-C(O)NR ^bR ^c、-NHC(O)R ^b、-S(O) _mR ^b、-S(O) _mNR ^bR ^c、-NHS(O) _mR ^band-P (O) (R)^b) ₂Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halo, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

with the proviso that,is not that

Wherein, represents a site linked to O; is represented by formula A¹The site of ligation;

g is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR^bR ^c、-C(O)R ^b、-OC(O)R ^b、-C(O)OR ^a、-C(O)NR ^bR ^c、-NHC(O)R ^b、-S(O) _mR ^b、-S(O) _mNR ^bR ^c、-NHS(O) _mR ^band-P (O) (R)^b) ₂Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halo, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

with the proviso that when G is phenyl, L²Not directly linked thereto by an-O-, -NHC (O) -, -C (O) NH-or-NHC (O) O-group;

R ^aselected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^band R^cEach independently selected from hydrogen, halogen, hydroxy, cyano, amino, carboxy, ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester group, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

or R^bAnd R^cTogether with the atom to which they are attached form a heterocyclic radicalSaid heterocyclyl is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

m is 0, 1 or 2;

p is an integer of 0 to 6.

The compound of the general formula (I) according to claim 1,

wherein the content of the first and second substances,

ring C is selected from cycloalkyl or heterocyclyl, preferably 5-12 membered spirocycloalkyl, 6-12 membered bridged cycloalkyl, 5-12 membered spiroheterocyclyl, 6-12 membered bridged heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally further selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR^bR ^c、-C(O)R ^b、-OC(O)R ^b、-C(O)OR ^a、-C(O)NR ^bR ^c、-NHC(O)R ^b、-S(O) _mR ^b、-S(O) _mNR ^bR ^c、-NHS(O) _mR ^band-P (O) (R)^b) ₂Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halo, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^aselected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercaptoOne or more substituents selected from the group consisting of a group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ^band R^cEach independently selected from hydrogen, halogen, hydroxy, cyano, amino, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

or R^bAnd R^cTogether with the atoms to which they are attached form a heterocyclyl, which heterocyclyl is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

m is 0, 1 or 2.

The compound represented by the general formula (I) according to claim 1 or 2, which is a compound represented by the general formula (II),

wherein the content of the first and second substances,

ring D is selected from the group consisting of heterocyclyl, preferably 5-12 membered spiroheterocyclyl and 6-12 membered bridged heterocyclyl, wherein said heterocyclyl is optionally further selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR^bR ^c、-C(O)R ^b、-OC(O)R ^b、-C(O)OR ^a、 -C(O)NR ^bR ^c、-NHC(O)R ^b、-S(O) _mR ^b、-S(O) _mNR ^bR ^c、-NHS(O) _mR ^band-P (O) (R)^b) ₂Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more groups selected from halo, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^aselected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^band R^cEach independently selected from hydrogen, halogen, hydroxy, cyano, amino, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

or R^bAnd R^cTogether with the atoms to which they are attached form a heterocyclic group optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, arylHeteroaryl, or substituted with one or more groups;

m is 0, 1 or 2;

A ¹、A ²、R ¹、R ²、R ³、L ¹、L ²g and B are as defined in claim 1.

A compound of the general formula (I) according to any one of claims 1 to 3,

wherein the content of the first and second substances,

b is selected fromPreference is given to

Wherein:

each R⁴Each independently selected from hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, alkoxy, -C (O) OR^a、-C(O)R ^b、-NR ^bC(O)R ^c、-NR ^bS(O) ₂R ^c、-NR ^bS(O) ₂NR ^bR ^c、-OC(O)R ^bor-NR^b(CH ₂) _pR ^c(ii) a Wherein said alkyl, alkoxy is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

each R⁵Each independently selected from hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, alkoxy, -C (O) OR^a、-C(O)R ^b、-NR ^bC(O)R ^c、-NR ^bS(O) ₂R ^c、NR ^bS(O) ₂NR ^bR ^c、-OC(O)R ^bor-NR^b(CH ₂) _pR ^c(ii) a Wherein said alkyl, alkoxy is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ⁶selected from hydrogen, halogen, hydroxy, amino, carboxy, cyano, nitro, alkyl, alkoxy, -C (O) OR^a、-C(O)R ^b、-NR ^bC(O)R ^c、-NR ^bS(O) ₂R ^c、NR ^bS(O) ₂NR ^bR ^c、-OC(O)R ^bor-NR^b(CH ₂) _pR ^c(ii) a Wherein said alkyl, alkoxy is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

m is selected from-C (R)^d)＝C(R ^e)、-CR ^dR ^eCR ^dR ^e、-O-、-S-、-OCR ^dR ^e-、-CR ^dR ^eO-、-SCR ^dR ^e-and-CR^dR ^eS-, in which R^dAnd R^eEach independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, oxo, mercapto, carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclic group, - (CH)₂) _pOR ^a、-C(O)OR ^a、-C(O)R ^b、-NR ^bC(O)R ^c、-NR ^bS(O) ₂R ^c、-NR ^bS(O) ₂NR ^bR ^c、-S(O) ₂NR ^bR ^c、-OC(O)R ^bor-NR^b(CH ₂) _pR ^cWherein said alkyl, alkoxy, cycloalkyl and heterocyclyl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^aselected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^band R^cEach independently selected from hydrogen, halogen, hydroxy, cyano, amino, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

or R^bAnd R^cTogether with the atoms to which they are attached form a heterocyclic group, said heterocyclic group optionally being further selected from halogen, amino, heteroaryl, and the like,Nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

n is an integer of 0 to 4;

q is an integer of 0 to 4.

The compound of the general formula (I) according to claim 4,

wherein the content of the first and second substances,

m is selected from-C (R)^d)＝C(R ^e)、-CR ^dR ^eCR ^dR ^e、-O-、-S-、-OCR ^dR ^e-、-CR ^dR ^eO-、-SCR ^dR ^e-and-CR^dR ^eS-, in which R^dAnd R^eEach independently selected from hydrogen or alkyl.

The compound represented by the general formula (I) according to any one of claims 1 to 5,

wherein the content of the first and second substances,

b is selected from Preference is given to More preferably

The compound represented by the general formula (I) according to any one of claims 1 to 6,

wherein the content of the first and second substances,

R ^1aand R^1bEach independently selected from hydrogen and C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, 3-to 8-membered heterocyclyl, C_5-10Aryl, 3-to 10-membered heteroaryl, C_3-10cycloalkyl-C_1-6Alkylene or 3-to 10-membered heterocyclyl-C_1-6Alkylene, preferably C_3-7Cycloalkyl, 3-to 6-membered heterocyclyl, C_5-6Aryl and 5-to 6-membered heteroaryl, more preferably 5-to 6-membered heteroaryl, said alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally further selected from halogen, hydroxy, amino, carboxy, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylthio, -OC (O) C_1-6Alkyl, -C (O) C_1-6Alkyl, or-C_3-6One or more groups of cycloalkoxy; provided that R is^1a、R ^1bNot hydrogen at the same time;

R ^1cselected from hydrogen, hydroxy, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio or-C (O) NH₂Preferably a hydroxyl group.

The compound of the general formula (I) according to any one of claims 1 to 7,

wherein the content of the first and second substances,

R ¹is selected fromPreference is given to More preferably

The compound of the general formula (I) according to any one of claims 1 to 8,

wherein the content of the first and second substances,

g is selected from C_5-10Aryl or 5-10 membered heteroaryl, preferably phenyl and 7-10 membered fused heteroaryl, more preferably phenyl andwherein, represents and A²The site of attachment represents a group with L²The site of attachment of the peptide,

wherein said aryl or heteroaryl is optionally further substituted with a group selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR^bR ^c、-C(O)R ^b、-OC(O)R ^b、-C(O)OR ^a、-C(O)NR ^bR ^c、-NHC(O)R ^b、-S(O) _mR ^b、-S(O) _mNR ^bR ^c、-NHS(O) _mR ^band-P (O) (R)^b) ₂Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more groups ofOne step is substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester group, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

x, Y and Z are each independently selected from-N-, -C-, -S-, -O-or-C (O) -, wherein Z is preferably N, X is preferably N, O, C or S, Y is preferably N, C or-C (O) -;

R ^aselected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^band R^cEach independently selected from hydrogen, halogen, hydroxy, cyano, amino, carboxy, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

or R^bAnd R^cTogether with the atoms to which they are attached form a heterocyclyl, which heterocyclyl is optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

m is 0, 1 or 2.

The compound of the general formula (I) according to any one of claims 1 to 9,

wherein the content of the first and second substances,

g is selected from

Wherein, represents and A²The site of attachment represents a group with L²The site of ligation.

The compound of the general formula (I) according to any one of claims 1 to 10,

wherein the content of the first and second substances,

L ¹selected from single bonds, -NR^b-and-O-, preferably a single bond and-NR^b-；

R ^bSelected from the group consisting of hydrogen, halogen, alkyl, wherein said alkyl is optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The compound of the general formula (I) according to any one of claims 1 to 11,

wherein the content of the first and second substances,

L ²selected from single bonds, -NR^b-、-S-、-SO ₂-、-C(O)-、-C(O)O-、-S(O) ₂NR ^b-、-NR ^bS(O) ₂-、-NR ^bC(O)(CH ₂)O-、-O(CH ₂)C(O)NR ^b-、-NR ^bC(O)NR ^cand-C (O) NR^bS(O) ₂-; preference is given to single bonds, -NH-, -S-, -SO₂-、-C(O)-、-NR ^bC(O)NR ^c-and-O (CH)₂)(CO)NR ^bMore preferably a single bond and-O (CH)₂)(CO)NR ^b；

Wherein R is^bAnd R^cEach independently selected from hydrogen, halogen, alkyl, wherein said alkyl is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The compound of the general formula (I) according to any one of claims 1 to 12,

wherein A is¹And A²Each independently selected from C_1-10Alkylene, preferably C_1-6An alkylene group; said alkylene is optionally further selected from halogen, hydroxy, amino, carboxy, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylthio, -OC (O) C_1-6Alkyl, -C (O) C_1-6Alkyl radical, C_3-6Cycloalkoxy, C_5-6Aryl and C_3-7One or more groups of the cycloalkyl group are substituted.

A compound of formula (I) according to any one of claims 1 to 13, wherein the compound is selected from:

a process for the preparation of a compound of general formula (I) according to any one of claims 1 to 14, comprising the steps of:

when-L¹-A ¹is-CH₂-CH ₂-CH ₂-，A ²is-CH₂When the pressure in the air is higher than the preset pressure,

1) reacting a compound Ie with a compound If in the presence of a catalyst and a reducing agent to obtain a compound Ig, wherein the catalyst is preferably anhydrous zinc chloride, and the reducing agent is preferably sodium cyanoborohydride;

2) in the presence of a catalyst, carrying out deprotection reaction on a compound Ig to obtain a compound with a general formula (I), wherein the protecting group is preferably TBS, and the catalyst is preferably triethylamine hydrofluoride;

wherein R is¹、R ²、R ³、B、G、L ²And C is as defined in claim 1.

A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 14, and a pharmaceutically acceptable carrier.

Use of a compound of general formula (I) according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 16, for the preparation of a muscarinic receptor antagonist and a β -adrenergic receptor agonist.

Use of a compound of general formula (I) according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 16, for the preparation of a medicament for the prevention and/or treatment of a disease associated with muscarinic and β -adrenergic receptor activity; the disease is preferably a respiratory disease, such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema.

Use of a compound of general formula (I) according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 16, in combination with another therapeutic agent or agents, preferably selected from PDE4 inhibitors, muscarinic receptor antagonists, corticosteroids and β -adrenergic receptor agonists, for the preparation of a medicament for the prevention and/or treatment of a respiratory disease such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema.