Aza-ergoline derivative and preparation method therefor and application thereof

1 . A compound as shown in formula I, a pharmaceutically acceptable salt thereof:

wherein L is C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene or —C 1-6 alkylene-C 3-6 cycloalkylene-;

M is —O—, —NH—, —CH 2 —, —(CH—OH)— or —C(═O)—;

Q is C 6-18 aryl, C 6-18 aryl substituted with one or more Q 1-1 , 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryl substituted with one or more Q 1-2 , —C(═O)R 1 or —S(═O) 2 R 2 ; the heteroatoms in the 5 to 10 membered heteroaryl are one or more of N, S or O, and the number is 1, 2 or 3; the heteroatoms in the 5 to 10 membered heteroaryl substituted with one or more Q 1-2 are one or more of N, S or O, and the number is 1, 2 or 3;

when Q is C 6-18 aryl or C 6-18 aryl substituted with one or more Q 1-1 , M is —O—, —NH—, —(CH—OH)— or —C(═O)—;

Q 1-1 is independently halogen or C 1-4 alkyl;

Q 1-2 is independently C 1-4 alkyl, oxo or hydroxyl;

R 1 and R 2 are independently —NR 1-1 R 1-2 , 3 to 6 membered heterocycloalkyl, C 6-18 aryl, C 6-18 aryl substituted with one or more R 1-3 , 5 to 10 membered heteroaryl or 5 to 10 membered heteroaryl substituted with one or more R 1-4 ; the heteroatoms in the 3 to 6 membered heterocycloalkyl are one or more of N, S or O, and the number is 1, 2 or 3; the heteroatoms in the 5 to 10 membered heteroaryl are one or more of N, S or O, and the number is 1, 2 or 3; the heteroatoms in the 5 to 10 membered heteroaryl substituted with one or more R 1-4 are one or more of N, S or O, and the number is 1, 2 or 3;

R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently C 1-4 alkyl;

R is hydrogen or C 1-4 alkyl.

2 . The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound as shown in formula I is described in any one of the following situations:

situation 1:

the compound as shown in formula I is a compound as shown in formula Ia, Ib or Ic:

in formula Ic, “ ” represents a double bond or a single bond; Y is hydrogen, hydroxyl or oxygen;

situation 2:

the compound as shown in formula I is a compound as shown in formula Id and/or Ie;

situation 3:

when the compound as shown in formula I has only one chiral center in

is

3 . The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound as shown in formula I is described in any one of the following schemes:

scheme 1:

L is C 1-10 alkylene or —C 1-6 alkylene-C 3-6 cycloalkylene-;

M is —O—, —NH— or —CH 2 —;

Q is C 6-18 aryl, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryl substituted with one or more Q 1-2 , —C(═O)R 1 or —S(═O) 2 R 2 ;

when Q is C 6-18 aryl, M is —O— or —NH—;

scheme 2:

L is C 1-10 alkylene or —C 1-6 alkylene-C 3-6 cycloalkylene-;

M is —O—, —NH— or —CH 2 —;

Q is C 6-18 aryl, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryl substituted with one or more Q 1-2 , —C(═O)R 1 or —S(═O) 2 R 2 ;

when Q is C 6-18 aryl, M is —O— or —NH—;

when M is —O—, Q 1-2 is C 1-4 alkyl or hydroxyl;

when the heteroatom in the 5 to 10 membered heteroaryl is O, the number of heteroatoms in the 5 to 10 membered heteroaryl is 1;

scheme 3:

L is C 1-10 alkylene or —C 1-6 alkylene-C 3-6 cycloalkylene-;

M is —O—, —NH— or —CH 2 —;

Q is C 6-18 aryl, 5 to 10 membered heteroaryl, 5 to 10 membered heteroaryl substituted with one or more Q 1-2 , —C(═O)R 1 or —S(═O) 2 R 2 ;

when Q is C 6-18 aryl, M is —O— or —NH—;

when L is —C 1-6 alkylene-C 3-6 cycloalkylene-, the C 1-6 alkylene in the —C 1-6 alkylene-C 3-6 cycloalkylene- is ethylene;

scheme 4:

L is C 1-10 alkylene or —C 1-6 alkylene-C 3-6 cycloalkylene-;

M is —O— or —NH—;

Q is —C(═O)R 1 or 5 to 10 membered heteroaryl substituted with one or more Q 1-2 ;

R 1 is —NR 1-1 R 1-2 ;

scheme 5:

the molecular structure of formula I is as shown in formula Ia:

L is C 1-10 alkylene or C 2-10 alkenylene;

Q is C 6-18 aryl substituted with one or more Q 1-1 , 5 to 10 membered heteroaryl or 5 to 10 membered heteroaryl substituted with one or more Q 1-2 ;

Q 1-1 is halogen;

scheme 6:

the molecular structure of formula I is as shown in formula Ib:

L is —C 1-6 alkylene-C 3-6 cycloalkylene-;

Q is —C(═O)R 1 or —S(═O) 2 R 2 ;

R 1 and R 2 are independently —NR 1-1 R 1-2 , 3 to 6 membered heterocycloalkyl, C 6-18 aryl or 5 to 10 membered heteroaryl;

scheme 7:

the molecular structure of formula I is as shown in formula Ic:

“ ” represents a double bond or a single bond;

Y is hydrogen, hydroxyl or oxygen;

L is C 1-10 alkylene;

Q is C 6-18 aryl substituted with one or more Q 1-1 or 5 to 10 membered heteroaryl substituted with one or more Q 1-2 ;

when Q is C 6-18 aryl substituted with one or more Q 1-1 , Y is hydroxyl or oxygen;

Q 1-1 is halogen;

Q 1-2 is independently C 1-4 alkyl or oxo;

scheme 8:

L is C 1-10 alkylene, C 2-10 alkenylene or —C 1-6 alkylene-C 3-6 cycloalkylene-;

when M is —(CH—OH)— or —C(═O)—, R is hydrogen;

scheme 9:

L is C 1-10 alkylene;

M is —O—;

Q is 5 to 10 membered heteroaryl substituted with one or more Q 1-2 ;

scheme 10:

L is —C 1-6 alkylene-C 3-6 cycloalkylene-;

M is —NH—;

Q is —C(═O)R 1 ;

R 1 is —NR 1-1 R 1-2 ;

scheme 11:

the molecular structure of formula I is as shown in formula Ia:

L is C 1-10 alkylene or C 2-10 alkenylene;

Q is 5 to 10 membered heteroaryl, or 5 to 10 membered heteroaryl substituted with one or more Q 1-2 :

scheme 12:

the molecular structure of formula I is as shown in formula Ic-1:

L is C 1-10 alkylene;

Q is C 6-18 aryl substituted with one or more Q 1-1 ;

Q 1-1 is halogen;

R is hydrogen;

scheme 13:

the molecular structure of formula I is as shown in formula Ic-2:

L is C 1-10 alkylene;

Q is C 6-18 aryl substituted with one or more Q 1-1 ;

Q 1-1 is halogen;

R is hydrogen;

scheme 14:

the molecular structure of formula I is as shown in formula Ic-3:

L is C 1-10 alkylene;

Q is 5 to 10 membered heteroaryl substituted with one or more Q 1-2 ;

Q 1-2 is C 1-4 alkyl or oxo;

R is hydrogen.

4 . The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein when L is C 1-10 alkylene, the C 1-10 alkylene is methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene or tert-butylene;

or, when L is C 2-10 alkenylene, the C 2-10 alkenylene is C 2-4 alkenylene;

or, when L is —C 1-6 alkylene-C 3-6 cycloalkylene-, the C 1-6 alkylene is connected to N, and the C 3-6 cycloalkylene is connected to Q;

or, when L is —C 1-6 alkylene-C 3-6 cycloalkylene-, the C 1-6 alkylene in the —C 1-6 alkylene-C 3-6 cycloalkylene- is methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene or tert-butylene;

or, when L is —C 1-6 alkylene-C 3-6 cycloalkylene-, the C 3-6 cycloalkylene in the —C 1-6 alkylene-C 3-6 cycloalkylene is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene;

or, when Q is C 6-18 aryl, the C 6-18 aryl is phenyl, naphthyl, anthracenyl or phenanthryl;

or, when Q is C 6-18 aryl substituted with Q 1-1 , the C 6-18 aryl is phenyl, naphthyl, anthracenyl or phenanthryl;

or, when Q is C 6-18 aryl substituted with Q 1-1 , the number of Q 1-1 is 1 or 2;

or, when Q 1-1 is halogen, the halogen is F, Cl, Br or I;

or, when Q is 5 to 10 membered heteroaryl, the 5 to 10 membered heteroaryl is 9 or 10 membered heteroaryl, and the number of heteroatoms is 1 or 2;

or, when Q is 5 to 10 membered heteroaryl substituted with one or more Q 1-2 , the 5 to 10 membered heteroaryl is 9 or 10 membered heteroaryl, the heteroatom is N and/or O, the number of heteroatoms is 1 or 2;

or, when Q is C 6-18 aryl substituted with Q 1-1 , the number of Q 1-1 is 1 or 2;

or, when Q 1-2 is C 1-4 alkyl, the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

or, when R 1 and R 2 are independently 3 to 6 membered heterocycloalkyl, the 3 to 6 membered heterocycloalkyl is piperidinyl or pyrrolidinyl;

or, when R 1 is 3 to 6 membered heterocycloalkyl, the 3 to 6 membered heterocycloalkyl is connected to carbonyl through a heteroatom;

or, when R 1 and R 2 are independently C 6-18 aryl, the C 6-18 aryl is phenyl, naphthyl, anthracenyl or phenanthryl;

or, when R 1 and R 2 are independently C 6-18 aryl substituted with R 1-3 , the C 6-18 aryl is phenyl, naphthyl, anthracenyl or phenanthryl;

or, when R 1 and R 2 are independently 5 to 10 membered heteroaryl, the 5 to 10 membered heteroaryl is 9 or 10 membered heteroaryl, the heteroatom is N, and the number of heteroatoms is 1 or 2;

or, when R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently C 1-4 alkyl, the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

or, when R is C 1-4 alkyl, the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

5 . The compound or the pharmaceutically acceptable salt thereof according to claim 4 , wherein when L is —C 1-6 alkylene-C 3-6 cycloalkylene-, the —C 1-6 alkylene-C 3-6 cycloalkylene- is

wherein a end is connected to Q, and b end is connected to N;

or, when Q is C 6-18 aryl substituted with Q 1-1 , the C 6-18 aryl substituted with Q 1-1 is

or, when Q is 5 to 10 membered heteroaryl substituted with one or more Q 1-2 , the 5 to 10 membered heteroaryl substituted with one or more Q 1-2 is

or, when R 1 is 3 to 6 membered heterocycloalkyl, the 3 to 6 membered heterocycloalkyl is

or,

is

and when Q is C 6-18 aryl or C 6-18 aryl substituted with one or more Q 1-1 ,

is

6 . The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein L is C 1-10 alkylene, C 2-10 alkenylene or —C 1-6 alkylene-C 3-6 cycloalkylene;

or, M is —O—, —NH— or —CH 2 —; and when Q is C 6-18 aryl or C 6-18 aryl substituted with one or more Q 1-1 , M is —O— or —NH—;

or, Q 1-1 is halogen;

or, R 1 is —NR 1-1 R 1-2 , 3 to 6 membered heterocycloalkyl, C 6-18 aryl or 5 to 10 membered heteroaryl;

or, R is hydrogen.

7 . The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound as shown in formula I is any one of the following compounds:

8 . A crystal as shown in the formula pNs-(+)-I-10, wherein the crystal system of which belongs to the triclinic crystal system, the P1 space group, and the unit cell parameters are a=9.315 Å, b=6.564 Å, c=23.792 Å, α=90.15°, β=99.368°, γ=90.25°;

9 . A pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutical adjuvant.

10 . A method for treating diseases related to dopamine D2 receptors or disease M, which comprises administering to a subject a therapeutically effective amount of substance A;

the disease M is Parkinson's disease, schizophrenia, depression or prolactinoma;

the substance A is the compound or the pharmaceutically acceptable salt thereof according to claim 1 .

11 . The method according to claim 10 , wherein the disease M is schizophrenia or depression.

12 . A method for treating diseases related to dopamine D2 receptors or disease M, which comprises administering to a subject a therapeutically effective amount of the crystal as shown in formula pNs-(+)-I-10 according to claim 8 ;

the disease M is Parkinson's disease, schizophrenia, depression or prolactinoma.

13 . A method for activating dopamine D2 receptors, which comprises administering to a subject the compound or the pharmaceutically acceptable salt thereof according to claim 1 .

14 . The compound or the pharmaceutically acceptable salt thereof according to claim 2 , wherein

in situation 2:

the compound as shown in formula I is a compound as shown in formula Id;

in situation 3:

when the compound as shown in formula I has only one chiral center in

is

15 . The compound or the pharmaceutically acceptable salt thereof according to claim 4 , wherein when L is C 1-10 alkylene, the C 1-10 alkylene is

or, when L is C 2-10 alkenylene, the C 2-10 alkenylene is

or, when L is —C 1-6 alkylene-C 3-6 cycloalkylene-, the C 1-6 alkylene in the —C 1-6 alkylene-C 3-6 cycloalkylene- is methylene or

or, when L is —C 1-6 alkylene-C 3-6 cycloalkylene-, the C 3-6 cycloalkylene in the —C 1-6 alkylene-C 3-6 cycloalkylene is

or, when Q is C 6-18 aryl, the C 6-18 aryl is phenyl;

or, when Q is C 6-18 aryl substituted with Q 1-1 , the C 6-18 aryl is phenyl;

or, when Q 1-1 is halogen, the halogen is F;

or, when Q is 5 to 10 membered heteroaryl, the 5 to 10 membered heteroaryl is

or, when Q is 5 to 10 membered heteroaryl substituted with one or more Q 1-2 , the 5 to 10 membered heteroaryl is tetrahydroquinolyl, quinolinyl, benzoxazolyl, benzisoxazolyl or tetrahydropyridopyrimidinyl;

or, when Q 1-2 is C 1-4 alkyl, the C 1-4 alkyl is methyl;

or, when R 1 and R 2 are independently 3 to 6 membered heterocycloalkyl, the 3 to 6 membered heterocycloalkyl is pyrrolidinyl;

or, when R 1 and R 2 are independently C 6-18 aryl, the C 6-18 aryl is phenyl;

or, when R 1 and R 2 are independently C 6-18 aryl substituted with R 1-3 , the C 6-18 aryl is phenyl;

or, when R 1 and R 2 are independently 5 to 10 membered heteroaryl, the 5 to 10 membered heteroaryl is indolyl;

or, when R 1-1 , R 1-2 , R 1-3 and R 1-4 are independently C 1-4 alkyl, the C 1-4 alkyl is methyl;

or, when R is C 1-4 alkyl, the C 1-4 alkyl is methyl.

16 . The compound or the pharmaceutically acceptable salt thereof according to claim 15 , wherein when L is C 1-10 alkylene, the C 1-10 alkylene is

or, when L is —C 1-6 alkylene-C 3-6 cycloalkylene-, the C 1-6 alkylene in the —C 1-6 alkylene-C 3-6 cycloalkylene- is

17 . The compound or the pharmaceutically acceptable salt thereof according to claim 5 , wherein when L is —C 1-6 alkylene-C 3-6 cycloalkylene-, the —C 1-6 alkylene-C 3-6 cycloalkylene- is

wherein a end is connected to Q, and b end is connected to N.

18 . The compound or the pharmaceutically acceptable salt thereof according to claim 6 , wherein L is C 1-10 alkylene or —C 1-6 alkylene-C 3-6 cycloalkylene;

or, R 1 is —NR 1-1 R 1-2 , 3 to 6 membered heterocycloalkyl or C 6-18 aryl.

19 . The compound or the pharmaceutically acceptable salt thereof according to claim 7 , wherein the compound as shown in formula I is any one of the following compounds:

with optical rotation of +50.33° and/or retention time of 5.805 min under the following chiral preparation conditions” or

with optical rotation of −45.00° and/or retention time of 7.60 min under the following chiral preparation conditions”;

the chiral preparation conditions: chromatographic column: chiral column CHIRALCEL OD, column volume: 5.0 cm×25 cm, 10 μm filler; mobile phase: MeOH/diethylamine=100/0.1; flow rate: 30 mL/min; wavelength: UV 214 nm; temperature: 38° C.

20 . The method according to claim 12 , wherein the disease M is schizophrenia or depression.