Nitrogen-heterocycle-substituted aromatic compound, composition, intermediate, and use thereof

Abstract

Disclosed in the present invention are a nitrogen-heterocycle-substituted aromatic compound, a composition, an intermediate, and a use thereof. Specifically provided is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound of the present invention has one or more of the following advantages: (1) effective AT2R antagonism, (2) good AT2R / AT1R selectivity; (3) good pharmacokinetic properties; and (4) potential for treatment of AT2R-mediated related diseases, such as pain relief.

Description

Aza-cyclic substituted aromatic compounds, compositions, intermediates and uses thereof

[0001] This application claims priority to Chinese patent application 2024109515219 with a filing date of 2024 / 7 / 16; claims priority to Chinese patent application 202510002110.X with a filing date of 2025 / 1 / 2; claims priority to Chinese patent application 2025104744305 with a filing date of 2025 / 4 / 16. This application incorporates the entire text of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application relates to aza-cyclic substituted aromatic compounds, compositions, intermediates and uses thereof. BACKGROUND

[0003] Renin-angiotensin system (RAS) is an important body fluid regulation system in human body, and angiotensin II (Ang II) is the main component thereof, which not only plays an important role in maintaining circulation stability and water and sodium retention, but also participates in other physiological functions, including the growth and development of nervous system. More and more evidence shows that RAS plays an important role in neuroprotection and neuroregeneration, and studies have shown that Ang II metabolic pathway is related to the pain sensitivity of human population. The receptors of Ang II mainly include Angiotensin II type 1 receptor (AT1R) and Angiotensin II type 2 receptor (AT2R), both of which have similar affinity to Ang II. Among them, AT2R is related to the pain mechanism in the nervous system, mainly expressed in the dorsal ganglion and trigeminal ganglion. Compared with normal nerves, damaged nerves and painful neuromas have higher AT2R expression. After the activation of AT2R, the second messenger pathway activated by G protein-coupled receptors can sensitize ion channels in neurons. Sensitization leads to the activation of ion channels and thus the excitation of neurons. AT2R antagonists have been proved to be useful for relieving pain through animal experiments and clinical experiments. SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the shortcomings of the AT2R antagonists in the prior art. To this end, the present application provides aza-cyclic substituted aromatic compounds, compositions, intermediates and uses thereof. The compounds of the present application have one or more of the following advantages: (1) can effectively antagonize AT2R, (2) have good AT2R / AT1R selectivity; (3) have good pharmacokinetic properties; (4) are expected to be used for treating AT2R-mediated related diseases, such as for relieving pain.

[0005] The present application solves the technical problems of the present application by the following technical solutions:

[0006] The present application provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,

[0007] wherein,

[0008] Ring A is a 5-10 membered heteroaryl or a partially saturated 5-12 membered heterocyclyl;

[0009] x2 is 0, 1, 2, 3, 4, 5 or 6;

[0010] R 6 is independently D, halogen, cyano, OH, oxo (=O or -O - ), C 1-6 1-6 alkyl, -O-C 1-6 1-6 alkyl, -C(O)OR 62 , -C 1-6 1-6 alkylene-C 3-6 1-6 cycloalkyl or -C 1-6 1-6 alkylene-3-6 membered heterocycloalkyl; said alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 61 ;

[0011] R 61 is independently D, halogen, OH, oxo (=O or -O - ), -O-C 1-6 1-6 alkyl, C 1-6 1-6 alkyl or C 1-6 1-6 haloalkyl;

[0012] R 62 is C 1-6 1-6 alkyl;

[0013] L 1 is -CR l1a R l1b -; R l1a and R l1b are independently H, D, halogen, cyano, C 1-6 1-6 alkyl or C 3-6 1-6 cycloalkyl; or R l1a and R l1b together form oxo (=O);

[0014] M 2 is N or CR b1 ; M 1 is N or CR b2 ;

[0015] R b1and R b2 independently H, D or C 1-6 alkyl;

[0016] x3 is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0017] R 5 independently D, halogen, cyano, oxo (=0 or -0 - ), C 1-6 alkyl or C 3-6 cycloalkyl;

[0018] or 2 R 5 groups together with the atom to which they are attached form a ring B, ring B is 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; said cycloalkyl and heterocycloalkyl are optionally substituted with one or more R a1 ;

[0019] R a1 independently D, halogen, cyano, oxo (=0 or -0 - ) or C 1-6 alkyl;

[0020] R 4 is H, D, halogen, cyano, C 1-6 alkyl or C 3-6 cycloalkyl;

[0021] or, R 4 and R 5 groups together with the atom to which they are attached form a ring C, ring C is 5-7 membered partially saturated heterocyclyl; said heterocyclyl is optionally substituted with one or more R a2 ;

[0022] R a2 independently D, halogen, cyano, oxo (=0 or -0 - ) or C 1-6 alkyl;

[0023] R 3 is H, halogen, cyano, -L 3 -C 1-6 alkyl, -L 3 -C 2-6 alkenyl, -L 3 -C 3-6 cycloalkyl or -L 3 -3-6 membered heterocycloalkyl;

[0024] L 3 is independently a bond, -0-, -NR l2 -, -0-CH2- or C 1-3 alkylene; R l2 is independently H or C1-6 alkyl;

[0025] R 2 H, D, halogen or C 1-6 alkyl;

[0026] R 1 Halogen, -OH, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; wherein the alkyl, cycloalkyl, and heterocyclic alkyl are optionally surrounded by one or more R c replace;

[0027] R c It can be a halogen or OH on its own;

[0028] L is the connection key, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein the heterocycloalkyl and heteroaryl groups have 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S;

[0029] L 2 For connection key, -O-, -NR l2a -、-C(R l2b R l2b ) y4 -、-CONR l2a -、-NR l2a CO- or -NR l2a -C(R l2b R l2b ) y4 -;

[0030] R l2a Independently H or C 1-6 alkyl;

[0031] R l2b Independent of H, D, halogen or C 1-6 alkyl;

[0032] y4 can be 1, 2, 3, or 4;

[0033] x1 is 0, 1, 2, 3 or 4;

[0034] Or, R 2 With L 2 -L forms a ring D together with the linked groups, and ring D is a partially saturated C. 3-6 Cycloalkyl, partially saturated 5-7 membered heterocyclic or 5-6 membered heteroaryl; wherein the cycloalkyl, heterocyclic or heteroaryl group is optionally surrounded by one or more R a3 replace;

[0035] R a3 Independently, it can be D, halogen, cyano, or oxo group (=O or -O). - ) or C 1-6 alkyl;

[0036] The aforementioned heteroaryl, heterocyclic alkyl, and heterocyclic groups independently have 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S.

[0037] In one embodiment of the present invention, the preceding R of the present invention 3 H, halogen, cyano, -L 3 -C 1-6 Alkyl, -L 3 -C 2-6 alkenyl, -L 3 -C 3- 6-cycloalkyl or -L 3 In the 3-6 membered heterocyclic alkyl group, the alkyl, alkenyl, cycloalkyl, and heterocyclic alkyl groups may optionally be converted by one or more R groups. c1 Replace; R c1 It can be a halogen or OH on its own.

[0038] In one embodiment of the present invention, the preceding L of the present invention 3 Independently for the connector key, -O-, -NR l2 -、-O-CH2- or C 1-3 Alkylene; R l2 Independently H or C 1-6 In alkyl groups, the -CH2- and C 1-3 Alkylenes can also optionally be converted by one or more R c2 Replace; R c2 It can be a halogen or OH on its own.

[0039] In one embodiment of the present invention, the preceding L of the present invention 3 It can also be -CF2-.

[0040] In certain preferred embodiments of the present invention, certain groups in the compound represented by formula (I) or its pharmaceutically acceptable salt are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in some preferred embodiments").

[0041] In some preferred embodiments, the halogen or halogenated form is F, Cl, or Br; preferably F.

[0042] In some preferred embodiments, the C 1-6 Alkyl (C1-C6 alkyl) and -OC 1-6 C1-C6 alkyl (-O-C1-C6 alkyl) 1-6 Alkyl groups are independently C1-4 alkyl (C1-C4 alkyl); for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl, preferably methyl or ethyl; more preferably methyl.

[0043] In some preferred embodiments, the C 1-6 alkylene (C1-C6 alkylene), C 1-3 alkylene is independently methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2-, -CH2CH(CH3)-, or -C(CH3)2-}, preferably -CH2- or -CH2CH2-.

[0044] In some preferred embodiments, the C 3-6 cycloalkyl (C3-C6 cycloalkyl) is independently cyclopropyl (when an alkyl group, for example ), cyclobutyl (when an alkyl group, for example ), cyclopentyl (when an alkyl group, for example ), or cyclohexyl.

[0045] In some preferred embodiments, the partially saturated C 3-6 cycloalkyl is cyclopentenyl (when an alkyl group, for example ), cyclohexenyl, or cyclohexadienyl.

[0046] In some preferred embodiments, the 3-12 membered heterocyclyl is independently a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl or a partially saturated 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclyl.

[0047] In some preferred embodiments, of the 3-6 membered heterocycloalkyl, the 3- membered heterocycloalkyl can be independently aziridinyl (for example );

[0048] The 4-membered heterocycloalkyl can be independently azetidinyl (for example );

[0049] The 5-membered heterocycloalkyl can be independently tetrahydrofuranyl (for example , or, when an alkyl group, for example ), tetrahydrothiophenyl (for example ), pyrrolidinyl (for example , or, when an alkyl group, for example​​ );

[0050] A 6-membered heterocyclic alkyl group can be independently piperidinyl (e.g.) Or when it is a subunit ), tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl (e.g.) ), piperazine group (e.g.) ).

[0051] In some preferred embodiments, among the partially saturated 5-12 membered heterocyclic groups, the partially saturated 5-7 membered heterocyclic groups, and the 5-6 membered heterocyclic groups, the partially saturated 5-membered heterocyclic group can independently be an N-heterocyclic pentenyl group ( For example When connected in parallel, for example ), O heterocyclopentenyl ( For example When connected in parallel, for example );

[0052] Partially saturated 6-membered heterocyclic groups can independently...

[0053] In some preferred embodiments, among the partially saturated 5-12 membered heterocyclic groups, 5-7 membered heterocyclic groups, and 7-12 membered heterocyclic groups, the partially saturated 7 membered heterocyclic group can be independently […].

[0054] In some preferred embodiments, among the partially saturated 5-12 membered heterocyclic groups and 7-12 membered heterocyclic groups, the partially saturated 9 membered heterocyclic group can be independently […].

[0055] Partially saturated 11-membered heterocyclic groups can independently...

[0056] In some preferred embodiments, the 5-10 heteroaryl group is independently a 5-membered heteroaryl group, a 6-membered heteroaryl group, or a 9-10-membered heteroaryl group.

[0057] In some preferred embodiments, the 5-membered heteroaryl group is a pyrrole group (e.g., ), imidazole group (e.g.) ), pyrazolyl (e.g.) When it is a subunit, for example ), triazole group (when it is a subunit, for example ), oxazolyl (e.g.) ), thiazolyl (e.g.) When it is a subunit, for example ), thiadiazole group (when it is a subunit, for example ), oxadiazolyl (when as a radical, e.g. ).

[0058] In some preferred embodiments, the 6-membered heteroaryl group is pyridyl (e.g. ), pyridyl (when as a radical, e.g. ), pyridyl (when as a radical, e.g. ), pyridyl (when as a radical, e.g. ), pyridyl (when as a radical, e.g. ), pyridyl (when as a radical, e.g. ), pyridyl (when as a radical, e.g. ), pyridyl (when as a radical, e.g. ).

[0059] In some preferred embodiments, the 9-membered heteroaryl group is

[0060] In some preferred embodiments, when substituted, the number of substitutions is 1, 2, or 3.

[0061] In some preferred embodiments, ring A is a 5-membered heteroaryl group and a 6-membered heteroaryl group-, a partially saturated 6-membered heterocyclyl group, a partially saturated 7-membered spirocyclyl group, a partially saturated 5-membered and 6-membered heterocyclyl group, or a partially saturated 7-membered spirocyclyl and 6-membered heterocyclyl group; for example, a 5-membered heteroaryl group and a 6-membered heteroaryl group-, a partially saturated 7-membered spiroheterocyclyl group, a partially saturated 5-membered and 6-membered heterocyclyl group, or a partially saturated 7-membered spirocyclyl and 6-membered heterocyclyl group.

[0062] In some preferred embodiments, 2 R 5 are taken together with the atoms on which they are attached to form ring B.

[0063] In some preferred embodiments, R 4 is taken together with 1 R 5 to form ring C.

[0064] In some preferred embodiments, R 2 is taken together with L 2 to form ring D.

[0065] In some preferred embodiments, when L 2 is a bond, x1 is 1.

[0066] In some preferred embodiments, formula I satisfies at least one of the following conditions:

[0067] (i) ring A is 5-membered and 6-membered heteroaryl-, partially saturated 6-membered heterocyclyl, partially saturated 7-membered spirocyclyl, partially saturated 5-membered and 6-membered heterocyclyl, or partially saturated 7-membered spirocyclyl and 6-membered heterocyclyl;

[0068] (ii) 2 R 5 together with the group to which they are attached form a ring B;

[0069] (iii) R 4 together with the group to which they are attached form a ring C; 5 together with the group to which they are attached form a ring C;

[0070] (iv) R 2 together with L 2 together with the group to which they are attached form a ring D;

[0071] (v) x2 is 1, 2, 3, 4, 5 or 6; R 6 at least one of said alkyl, alkylene, cycloalkyl and heterocycloalkyl groups is substituted with -OH.

[0072] In some preferred embodiments, ring A is a 5-10 membered heteroaryl; for example a 5 membered heteroaryl, a 6 membered heteroaryl or a 9 membered heteroaryl; said 9 membered heteroaryl can be a 5 membered heteroaryl and a 6 membered heteroaryl-.

[0073] In some preferred embodiments, ring A is a partially saturated 5-12 membered heterocyclyl; for example a partially saturated 6, 7, 9 or 11 membered heterocyclyl.

[0074] In some preferred embodiments, ring A is a partially saturated 5-12 membered heterocyclyl; for example a partially saturated 5 membered and 6 membered heterocyclyl, a partially saturated 7 membered spirocyclyl, a partially saturated 5 membered and 6 membered heterocyclyl or a partially saturated 7 membered spirocyclyl and 6 membered heterocyclyl.

[0075] In some preferred embodiments, in ring A, said 5-10 membered heteroaryl is a 5 membered and 6 membered heteroaryl-; for example wherein ring A 1 is a 5 membered heteroaryl; X 11 , X 12 , X 13 and X 14 are independently C, CH, N or NH; X 15 is O, C, CH, N or NH (e.g. O, N or NH); and at least one of X 11 , X 12 , X 13 , X 14 and X 15 is N or NH;

[0076] is a single or double bond;

[0077] For example

[0078] In some preferred embodiments, in ring A, the partially saturated 5-12 membered heterocyclyl is a partially saturated 5-membered and 6-membered heterocyclyl, for example wherein ring A is 2 a partially saturated 5-membered heterocyclyl; X 21 , X 22 , X 23 and X 24 are independently CH, CH2, N or NH, and at least one is N or NH. 24 are independently C, CH or CH2.

[0079] In some preferred embodiments, ring A is

[0080] In some preferred embodiments, in ring A, the partially saturated 5-12 membered heterocyclyl is a partially saturated 7-membered spirocyclic heterocyclyl and 6-membered heterocyclyl, for example wherein ring A is 2 a partially saturated 5-membered heterocyclyl; X 21 , X 22 and X 23 are independently CH, CH2, N or NH, and at least one is N or NH.

[0081] In some preferred embodiments, ring A is

[0082] In some preferred embodiments, in ring A, the partially saturated 5-12 membered heterocyclyl is a partially saturated 6-membered heterocyclyl, for example X 31 , X 32 and X 33 are independently C, CH, N or NH, and at least one is N or NH.

[0083] In some preferred embodiments, ring A is

[0084] In some preferred embodiments, in ring A, the partially saturated 5-12 membered heterocyclyl is a partially saturated 7-membered spirocyclic heterocyclyl, for example

[0085] In some preferred embodiments, ring A is

[0086] In some preferred embodiments, x2 is 0, 1, 2 or 3.

[0087] In some preferred embodiments, R 6 is independently oxo (=0 or -0 - ), C 1-6 alkyl, -C(O)OR 62 , or -C 1-6 alkylene-3-6 membered heterocycloalkyl; said alkyl and heterocycloalkyl are optionally substituted with one or more R 61 .

[0088] In some preferred embodiments, R 61 and R 62 are independently OH or methyl.

[0089] In some preferred embodiments, R 6 is independently methyl, =0, -C(O)O-CH3,

[0090] In some preferred embodiments, is

[0091] In some preferred embodiments, R l1a and R l1b are independently H.

[0092] In some preferred embodiments, L 1 is -CH2-, -CHF-, -CF2-, -CHCH3-, -CO-, or -C(cyclopropyl)-; again, for example, -CH2-.

[0093] In some preferred embodiments, is

[0094] In some preferred embodiments, M 1 is N.

[0095] In some preferred embodiments, M 2 is N.

[0096] In some preferred embodiments, x3 is 0, 1, 2, or 3.

[0097] In some preferred embodiments, R 5 is H or C 1-6 alkyl; for example, H or methyl.

[0098] In some preferred embodiments, 2 R 5 groups together form a ring B, ring B being C3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; said cycloalkyl and heterocycloalkyl are optionally substituted with one or more R a1 substituents;

[0099] said C 3-6 Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl;

[0100] said 3-6 membered heterocycloalkyl can be 5 membered heterocycloalkyl, for example tetrahydrofuranyl, tetrahydrothiophenyl or pyrrolidinyl; for example

[0101] In some preferred embodiments, R a1 is independently C 1-6 alkyl; for example methyl.

[0102] In some preferred embodiments, R is for example

[0103] In some preferred embodiments, R is Z is a bond or NH or NHMe or O or S, m = 0, 1, 2 or 3, n = 0, 1, 2 or 3; y is 0, 1, 2 or 3.

[0104] In some preferred embodiments, R is

[0105] for example

[0106] In some preferred embodiments, R 4 is H.

[0107] In some preferred embodiments, R 4 and R 5 form, together with the linking group, a ring C, in which ring C, said partially saturated 5-7 membered heterocyclyl is a partially saturated 6-7 membered heterocyclyl; said heterocyclyl is optionally substituted with one or more R a2 substituents;

[0108] for example a is a benzenoid ring connected to the indicated ring.

[0109] In some preferred embodiments, R 3 is -L 3 -C 1-6 alkyl, -L 3 -C 3-6 cycloalkyl; said C 1-6 alkyl and C 3-6cycloalkyl is optionally substituted with one or more R c1 substituents; R c1 is independently halogen.

[0110] In some preferred embodiments, R c1 is independently F.

[0111] In some preferred embodiments, R 3 is -L 3 -C 1-6 alkyl; for example C 1-6 alkyl.

[0112] In some preferred embodiments, L 3 is a bond.

[0113] In some preferred embodiments, L 3 is C 1-3 alkylene; said alkylene is optionally substituted with one or more R c2 substituents.

[0114] In some preferred embodiments, L 3 is methylene (-CH2-); said methylene is optionally substituted with one or more R c2 substituents.

[0115] In some preferred embodiments, R c2 is independently F.

[0116] In some preferred embodiments, R 3 is C 1-6 alkyl, cyclopropyl-CH2-, cyclobutyl-CH2-, said C 1-6 alkyl, cyclopropyl, cyclobutyl and -CH2- is optionally substituted with one, two or three F.

[0117] In some preferred embodiments, R 3 is isobutyl.

[0118] In some preferred embodiments, R 3 is selected from

[0119] In some preferred embodiments, R 2 is H.

[0120] In some preferred embodiments, R 1 is halogen, OH, C 1-6 alkyl, -O-C 1-6 alkyl or C 3-6 cycloalkyl; said alkyl and cycloalkyl is optionally substituted with one or more R c substituents.

[0121] In some preferred embodiments, R c is independently halogen; for example F.

[0122] In some preferred embodiments, R 1 is F, Br, methyl, CHF2, CF3, ethyl, -CH2CHF2, isopropyl, cyclopropyl, -O-methyl, OH.

[0123] In some preferred embodiments, L is a bond, C 1-3 alkyl, C 3-6 cycloalkyl, or 5-6 membered heteroaryl; for example a bond, methyl, ethyl, cyclopropyl, cyclopentyl,

[0124] In some preferred embodiments, L is cyclobutyl.

[0125] In some preferred embodiments, L is 3-6 membered heterocycloalkyl, preferably

[0126] In some preferred embodiments, R l2a is independently H.

[0127] In some preferred embodiments, R l2b is independently H or halogen; for example H or F.

[0128] In some preferred embodiments, L 2 is a bond, -O-, -NR l2a -, -C(R l2b R l2b ) y1 -, -CONR l2a -, -NR l2a CO- or -NR l2a -C(R l2b R l2b ) y1 .

[0129] In some preferred embodiments, L 2 is a bond, -O-, -NH-, -CH2-, -CF2-, -CONH-, -NHCO- or -NHCH2-.

[0130] In some preferred embodiments, is F, Br, cyclopropyl, -CHF2, -O-CH3,

[0131] In some preferred embodiments, is

[0132] In some preferred embodiments, For

[0133] In some preferred embodiments, R a3 is independently C 1-6 alkyl; for example methyl.

[0134] In some preferred embodiments, R 2 and L 2 -L together with the linking group forms a ring D, which is a partially saturated C 3-6 cycloalkyl, partially saturated 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl; said cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted with one or more R a3 ; for example partially saturated C 5-6 cycloalkyl, partially saturated 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl; said cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted with one or more R a3 .

[0135] In some preferred embodiments, in ring D, said partially saturated C 3-6 cycloalkyl is b is attached to the indicated benzene ring annulus.

[0136] In some preferred embodiments, in ring D, said partially saturated 5-7 membered heterocycloalkyl or b is attached to the indicated benzene ring annulus.

[0137] In some preferred embodiments, in ring D, said 5-6 membered heteroaryl is b is attached to the indicated benzene ring annulus.

[0138] In some preferred embodiments, ring D is b is attached to the indicated benzene ring annulus.

[0139] In some preferred embodiments, said compound of formula (I) can be a compound of formula (I-1), (I-1.1), (I-2), (I-3), (I-4), (I-4.1), (I-4.1a) or (I-4.1b):

[0140] wherein Z is a bond or NH or NHMe or O or S, m = 0, 1, 2 or 3, n = 0, 1, 2 or 3; y is 0, 1, 2 or 3;

[0141] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, L 1 , L 2 , M 1 , M 2 , A, B, C, D, x1, x2or x3are as defined in any of the Schemes herein.

[0142] In some preferred embodiments, the compound of formula (I) is any of the following structures:

[0143] The present application provides a compound of formula (II) (an intermediate for preparing a compound of formula (I)),

[0144] wherein: M 1 , M 2 , L, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , x1, x2and x3are as defined in any of the Schemes herein.

[0145] In some preferred embodiments, the compound of formula (II) is any of the following structures:

[0146] In some preferred embodiments, the compound of formula (II) is any of the following structures:

[0147] The present application provides a pharmaceutical composition comprising:

[0148] (1) an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and

[0149] (2) a pharmaceutically acceptable excipient.

[0150] The present application provides use of a substance A in the manufacture of a medicament for preventing and / or treating a disease, disorder or condition.

[0151] The substance A is the above-mentioned compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0152] In the use, the disease, disorder or condition can be a drug for AT2R-mediated related disease, disorder or condition.

[0153] In the use, the disease, disorder or condition can be pain, etc.

[0154] The AT2R-mediated related disease, disorder or condition is preferably pain, etc.

[0155] Preferably, the AT2R-mediated related disease, disorder or condition is sciatica.

[0156] Preferably, the pain is sciatica.

[0157] The present application provides a use of a substance A in the preparation of an AT2R antagonist.

[0158] The substance A is the above-mentioned compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0159] The present application provides a kit comprising the above-mentioned compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0160] The present application provides a method for preventing and / or treating a disease, disorder or condition mediated by AT2R, comprising administering to a patient a prophylactically and / or therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0161] The present application provides a method for preventing and / or treating pain, comprising administering to a patient a prophylactically and / or therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0162] The present application provides a method for antagonizing AT2R in a patient or a biological sample, comprising administering to the patient or contacting the biological sample with the above-mentioned compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0163] Term explanation

[0164] In addition to the foregoing, the following terms have the meanings ascribed to them below, unless specifically indicated otherwise.

[0165] As used herein, the compounds of Formula I of the present application can contain one or more chiral centers and exist as different optically active forms. When the compounds contain one chiral center, the compounds comprise enantiomers. The present application includes both enantiomeric forms and mixtures of enantiomers, such as racemic mixtures. The enantiomers can be resolved using methods known in the art, such as crystallization and chiral chromatography. When the compounds of Formula I contain more than one chiral center, diastereomers can exist. The present application includes resolved optically pure individual isomers as well as mixtures of diastereomers. The diastereomers can be resolved using methods known in the art, such as crystallization and chiral chromatography.

[0166] The term "stereoisomers" includes conformational isomers and configurational isomers, wherein configurational isomers include primarily cis-trans isomers and optical isomers. The compounds of the present application can exist in stereoisomeric forms and therefore encompass all possible stereoisomeric forms, including but not limited to, cis-trans isomers, enantiomers, diastereomers, atropisomers, and the like, as well as any combination or mixture of any of the foregoing, such as, for example, mesomers, racemates, equal mixtures of atropisomers, single enantiomers, single diastereomers, or mixtures thereof, or single atropisomers or mixtures thereof.

[0167] The term "tautomers" refers to functional group isomers that result from the rapid movement of an atom in a molecule between two positions.

[0168] When the compounds of the present application contain an olefinic double bond, unless specified otherwise, the compounds include both the cis- and trans-isomers, as well as any combination thereof.

[0169] In the present application, "pharmaceutical composition" refers to a preparation containing a compound of the present application and a medium generally accepted for the delivery of biologically active compounds to mammals, such as humans. The medium includes a pharmaceutically acceptable carrier. The object of a pharmaceutical composition is to facilitate administration of an active ingredient to an organism and to facilitate its absorption into the organism for the exercise of a biological activity.

[0170] In the present application, "pharmaceutically acceptable" means a substance (such as a pharmaceutical carrier) that does not affect the biological activity or properties of a compound of the present application, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0171] In the present application, the term "pharmaceutically acceptable salt" refers to a salt of a compound with a pharmaceutically acceptable acid or base. When a compound contains relatively acidic functionalities, base addition salts can be obtained by contacting the compound with a sufficient amount of the desired pharmaceutically acceptable base in a suitable inert solvent. Where the compound contains relatively basic functionalities, acid addition salts can be obtained by contacting the compound with the desired pharmaceutically acceptable acid in a suitable inert solvent.

[0172] The term "pharmaceutical excipient / carrier" or "pharmaceutically acceptable excipient / carrier" refers to excipients and adjuvants used in the production of pharmaceutical products and dispensing of prescriptions, and all substances contained in pharmaceutical preparations other than active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 Edition) Volume 4).

[0173] The pharmaceutical compositions of the present application can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, dragee-making, encapsulating, entrapping or lyophilizing processes.

[0174] The term "treatment" refers to therapeutic treatment or ameliorative measures. In reference to a particular condition, treatment refers to: (1) alleviating the disease or condition, or one or more of the biological manifestations thereof, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more of the biological manifestations of the condition, (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment, or (4) slowing the development of the condition or one or more of the biological manifestations thereof. "Treatment" can also refer to prolonging the survival compared to the expected survival without treatment.

[0175] The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0176] The term "therapeutically effective amount" refers to the amount of a compound that, when administered to a patient, is sufficient to effect treatment of a disease or condition as described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by one of ordinary skill in the art as needed.

[0177] The term "patient" refers to any animal, mammal, and most preferably a human, to which the compounds or compositions according to the embodiments of the present application will be administered. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.

[0178] Unless otherwise indicated, the present application employs conventional methods of mass spectroscopy, elemental analysis, and the like, and the various substituents and conditions can be in accordance with conventional procedures known in the art.

[0179] Unless otherwise indicated, the present application employs standard nomenclature used in analytical chemistry, organic synthesis chemistry, and optics. In certain instances, standard techniques are used for chemical synthesis, chemical analysis.

[0180] Further, it should be noted that the descriptive manner "independently" as employed in the present application is to be interpreted broadly, i.e. that each individual described is independent of the other, and can be the same or different specific group. In more detail, the descriptive manner "independently" can mean that the specific options expressed by the same symbols in different groups do not influence each other; or that the specific options expressed by the same symbols in the same group do not influence each other.

[0181] In the present specification, groups and substituents thereof can be chosen by one skilled in the art to provide stable moieties and compounds. When a substituent is described as being "selected from a group," this term is to be interpreted as meaning that the substituent is to be independently selected from the group.

[0182] Certain chemical groups defined herein are preceded by a simplified symbol indicating the total number of carbon atoms in the group. For example, C1-C4alkyl or C 1-4 Alkyl means an alkyl group having a total of 1, 2, 3, or 4 carbon atoms as defined below. The total number of carbon atoms in the simplified symbol does not include carbon that can be present in substituents of the group.

[0183] In the present text, numerical ranges as 0 to 10, 1-6, 1-3 etc. in the definition of substituents indicate the integers within the range, e.g. 1-6 is 1, 2, 3, 4, 5, 6.

[0184] The term "optionally substituted with one or more R a Substituted" means not substituted and substituted with one or more R a Substituted" means not substituted and substituted with one or more R a Substituted" means not substituted and substituted with one or more R

[0185] The term "comprising" is to be interpreted as an open-ended term, i.e. it includes but is not limited to the listed features.

[0186] The term "substituted" or "by" means that any one or more hydrogen atoms on the specified atom are replaced with a substituent, provided that the valency of the specified atom is normal and that the resulting compound is stable.

[0187] In general, the terms "substituted" or "substitution" mean that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Further, when a group is substituted with more than one of such substituents, the substituents are independent of each other, i.e., the substituents can be the same or different from each other. Unless otherwise indicated, a substituent group can be substituted at any available substitutable position. When more than one position in a given structure can be substituted with one or more substituents selected from a particular group of substituents, then the substituents can be the same or different at each occurrence.

[0188] Throughout various portions of the specification, substituents of compounds disclosed herein are presented by group type or range. In particular, it is specifically intended that the present application include each and every independent combination of members of the groups and ranges specified. The term "C x -C y "alkyl" or "C x-y "alkyl" means a straight or branched chain saturated hydrocarbon containing x to y carbon atoms. For example, the term "Ci-C6alkyl" or "C 1-6 "alkyl" specifically means methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl, each of which is independently disclosed. 1-4 "alkyl" specifically means methyl, ethyl, C3alkyl (i.e., propyl, including n-propyl and isopropyl), C4alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl).

[0189] The terms "moiety," "structural moiety," "chemical moiety," "group," and "chemical group" as used herein refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity that is embedded in or appended to a molecule.

[0190] When an enumerated substituent does not specify through which atom of the chemical structure formula (including but not specifically mentioned compounds) it is attached, the substituent can be bonded through any atom thereof. Combinations of substituents, and / or variables, are permissible only if such combinations result in stable compounds.

[0191] When any variable (e.g., R 1-a ) occurs more than one time in a compound, its definition in each occurrence is independent of its definition at every other occurrence. Thus, if a group is substituted with one, two, or three R 1-a groups, then such R 1-a groups can be the same or different at each occurrence. 1-a 1-a ​The definitions of the various substituents and variables are independent of one another. In addition, combinations of substituents and / or variables are specifically allowed only if the combination results in stable compounds.

[0192] When a group is recited without explicit indication that it bears a substituent, the group refers to the unsubstituted version of the group. For example, when "C 1-6 alkyl" is recited without the qualification "substituted or unsubstituted," it refers only to "C 1-6 alkyl" per se or "unsubstituted C 1-6 alkyl."

[0193] In various portions of the application, connecting substituents are described. When the structure clearly requires a connecting group, the Markush variable recited for that group is to be understood as a connecting group. For example, if the structure requires a connecting group and the Markush group definition recites "alkyl" for that variable, then it is to be understood that the "alkyl" represents a connecting alkylene group.

[0194] In some specific structures, when an alkyl group is clearly indicated as a connecting group, then the alkyl group represents a connecting alkylene group, for example, the group "halo-C 1-6 alkyl-" represents a connecting C 1-6 alkyl group. 1-6 alkylene group.

[0195] In the present application, the notation in a structural fragment means that the remainder of the molecule is connected to the structural fragment through the bond. For example, means cyclopropyl.

[0196] In the present application, the notation "-" at the end of a group means that the group is connected to the remainder of the molecule through the site. For example, -OH means hydroxyl.

[0197] As will be understood by those skilled in the art, the use of in the structural formulae of the groups described herein means that the corresponding group is connected to the remainder of the molecule through the bond.

[0198] As will be understood by those skilled in the art, the use of in the structural formulae of the groups described herein means that the connecting bond, the corresponding group is connected to the remainder of the molecule through the bond. When the group is O, it represents either a double bond (e.g., =0) or a single bond (e.g., O - ); unless otherwise specified, it is a single bond.

[0199] The term "oxo," used herein alone or in combination with other radicals, means =0 (e.g., C=0, S=0 / S02when attached to a C, S, respectively) or O - The term "thioxo," used herein alone or in combination with other radicals, means =S (e.g., when attached to a C, S, respectively). + O - ).

[0200] It should be understood that the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise.

[0201] The term "one or more" or "one or more than one" means 1, 2, 3, 4, 5, 6, 7, 8, 9, or more. For example, 1, 2, or 3.

[0202] In the present application, the term "B substituted by one or more A" when B is substituted by "more" A, A is the same or different.

[0203] In the present application, the term "halogen" means fluorine, chlorine, bromine, or iodine, especially F, Cl, or Br.

[0204] In the present application, the term "alkyl," as a group or as part of another group (e.g., used in haloalkyl, deuterated alkyl, etc.), means includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms, consisting solely of carbon and hydrogen atoms, having, for example, from 1 to 12 (preferably 1 to 8, more preferably 1 to 6, most preferably 1 to 4) carbon atoms, and zero valence, which is attached to the rest of the molecule by a single bond, where propyl is a C3alkyl group (including structural isomers, e.g., n-propyl or isopropyl); butyl is a C4alkyl group (including structural isomers, e.g., n-butyl, sec-butyl, isobutyl, or t-butyl); pentyl is a C5alkyl group (including structural isomers, e.g., n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, t-pentyl, or neopentyl); and hexyl is a C6alkyl group (including structural isomers, e.g., n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl, and decyl, and the like.

[0205] In the present application, the term "alkylene" as a group or part of a group refers to a saturated divalent hydrocarbon radical derived by the removal of two hydrogen atoms from a straight- chain or branched-chain hydrocarbon; i.e., one hydrogen from each of two carbon atoms of an alkyl group, the definition of which is given above. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2-, -CH2CH(CH3)-, or -C(CH3)2-}, and the like.

[0206] In the present application, the term "heteroalkylene" as a group or part of a group refers to an alkylene in which one or more (e.g., 1, 2, 3, or 4) CH2 or CH units are replaced by O, S, or N; for example, -CH2-O-, -O-CH2-O-, -CH2CH2-O-, -O-CH2CH2-O-, -C(CH3)-O-, -CH(CH3)CH2-O-, -CH2C(CH3)-O-, or -C(CH3)2-O-.

[0207] In the present application, the term "alkoxy" as a group or part of a group refers to -O-alkyl, the definition of which is given above.

[0208] In the present application, the term "hydroxyalkyl" as a group or part of a group refers to HO-alkyl-, the definition of which is given above.

[0209] In the present application, the term "alkenyl" as a group or part of a group refers to a straight-chain or branched-chain hydrocarbon group having at least one double bond, consisting solely of carbon and hydrogen atoms, having, for example, from 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and being attached to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl, or pent-1,4-dienyl, and the like.

[0210] In the present application, the term "alkynyl" as a group or part of a group refers to a straight-chain or branched-chain hydrocarbon group having at least one triple bond, consisting solely of carbon and hydrogen atoms, having, for example, from 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and being attached to the rest of the molecule by a single bond, such as, but not limited to, ethynyl, 1-propynyl, n-propargyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, or pent-1,4-diynyl, and the like.

[0211] In the present application, the term "cycloalkyl" as a group or part of a group refers to a saturated carbocyclic ring substituent which is either monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring bridged, fused or spiro ring systems) and which can be attached to the rest of the molecule by a single bond through any suitable carbon atom; such as 3- to 15-membered cycloalkyl having 3 to 15 carbon atoms, preferably 3- to 12-membered cycloalkyl having 3 to 12 carbon atoms, more preferably 3- to 8-membered cycloalkyl having 3 to 8 carbon atoms, most preferably 3- to 6-membered cycloalkyl having 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like.

[0212] In the present application, the term "partially saturated cycloalkyl" as a group or part of a group refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring bridged, fused or spiro ring systems) carbocyclic ring substituent which contains at least one unsaturated bond and which can be attached to the rest of the molecule by a single bond through any suitable carbon atom; such as 3- to 15-membered cycloalkenyl having 3 to 15 carbon atoms, preferably 3- to 12-membered cycloalkenyl having 3 to 12 carbon atoms, more preferably 3- to 8-membered cycloalkenyl having 3 to 8 carbon atoms, most preferably 3- to 6-membered partially saturated cycloalkyl having 3 to 6 carbon atoms. Examples of partially saturated cycloalkyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cyclooctenyl and the like.

[0213] In the present application, the term "heterocyclyl" as a group or as part of a group refers to a stable saturated or partially saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring bridged, fused or spiro ring systems) non-aromatic ring-like group consisting of carbon atoms and 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O and S; preferably a 3- to 12-membered heterocyclyl group comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, more preferably a 3- to 10-membered heterocyclyl group comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, most preferably a 3- to 8-membered heterocyclyl group comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S. When it is a bicyclic, tricyclic or more ring fused (annellated) heterocyclyl group, it can also include a fusion with a cycloalkyl, aryl, heteroaryl group as defined herein, provided that the heterocyclyl group is attached to the rest of the molecule through a single bond via any suitable atom in the saturated or partially saturated heterocyclic ring. When it is a bicyclic, tricyclic or more ring spiro heterocyclyl group, it can also include a spirofused with a cycloalkyl group as defined herein, provided that the heterocyclyl group is attached to the rest of the molecule through a single bond via any suitable atom in the saturated or partially saturated heterocyclic ring. In certain aspects of the application, the heterocyclyl group includes "heterocycloalkyl" and "heterocycloalkenyl", the latter referring to a stable partially saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring bridged, fused or spiro ring systems) non-aromatic ring-like group consisting of carbon atoms and 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O and S, having at least one double bond. For example, the 3- to 10-membered heterocyclyl groups described include 3- to 10-membered heterocycloalkyl or 3- to 10-membered heterocycloalkenyl groups. In some embodiments, "heterocycloalkyl" is a 3- to 7-membered monocyclic heterocycloalkyl group, a 4- to 8-membered annelated heterocycloalkyl group, a 4- to 8-membered bridged heterocycloalkyl group, or a 5- to 10-membered spirocyclic heterocycloalkyl group. Exemplary 3-membered heterocycloalkyl groups include, but are not limited to, aziridinyl, epoxidoethylidene, and thiiridinyl, or stereoisomers thereof; exemplary 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl (e.g., ), epoxido-propylidene, oxetanyl (e.g., ), thietanyl, or isomers and stereoisomers thereof; exemplary 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl (e.g., ), tetrahydrothiophenyl (e.g., ), pyrrolidinyl (e.g., ), or isomers and stereoisomers thereof. Exemplary 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl (e.g. ), tetrahydropyranyl, sulfidylcyclopentyl, morpholinyl (e.g. ), thiomorpholinyl, dithianyl, dioxanyl, piperazinyl (e.g. ), triazinanyl, or isomers and stereoisomers thereof. Exemplary 7-membered heterocycloalkyl groups include, but are not limited to, oxepinyl, or isomers and stereoisomers thereof. Exemplary 8-membered heterocycloalkyl groups include, but are not limited to, or isomers and stereoisomers thereof. Exemplary partially saturated heterocycloalkyl groups:

[0214] In the present application, the term "aryl" as a group or as part of another group refers to an aromatic group consisting of a conjugated hydrocarbon ring system of carbon atoms satisfying the 4n+2 rule, each ring having aromaticity. In one aspect, "aryl" refers to an aromatic group having 6 to 12 (preferably 6 to 10) carbon atoms. Examples of aryl groups include, but are not limited to, phenyl or naphthyl, and the like.

[0215] In the present application, the term "heteroaryl" as a group or as part of another group means a conjugated ring system group having carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur within the ring. Unless otherwise specifically indicated herein, the heteroaryl group can be a monocyclic, bicyclic, tricyclic, or more ring system. Preferred are 5-12 membered heteroaryl groups comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S, more preferred are 5-6 membered heteroaryl groups, 8-10 membered heteroaryl groups comprising 1, 2, 3, or 4 heteroatoms selected from N, O, and S. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl (e.g. ), pyrazolyl (e.g. ), thiazolyl, oxazolyl (e.g. ), oxadiazolyl, isoxazolyl, pyridyl (e.g. ), pyrimidinyl (e.g. ), pyrazinyl, pyridazinyl (e.g. ), benzimidazolyl, benzopyrazolyl, indolyl furanyl, pyrrolyl, triazolyl (e.g. oxazolyl, benzoxazolyl, benzisoxazolyl, benzothiophenyl, oxatriazolyl, cinnolinyl, quinazolinyl, indolizinyl, phenoxazinyl, phenothiazinyl, benzoxazolyl, benzisoxazolyl, or naphthylidinyl (for example ).

[0216] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. If there is an inconsistency between the definitions of terms as defined herein and as used in the art, the definition as used in the art prevails.

[0217] The above-mentioned preferred conditions can be combined arbitrarily without departing from the common knowledge in the art, thereby obtaining various preferred embodiments of the present application.

[0218] The reagents and raw materials used in the present application are commercially available.

[0219] The positive progress effect of the present application is that the compounds of the present application have one or more of the following effect advantages: (1) can effectively antagonize AT2R, (2) AT2R / AT1R selectivity is good; (3) has good pharmacokinetic characteristics; (4) is expected to be used for treating AT2R-mediated related diseases, such as for treating pain relief. BRIEF DESCRIPTION OF DRAWINGS

[0220] Figure 1 is a test flow timeline in test example 5

[0221] Figure 2 is a test flow timeline in test example 6 DETAILED DESCRIPTION

[0222] The present application will be further described by way of examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples are not specified, and the methods are selected according to the conventional methods and conditions, or according to the instructions of the commercial products. For example, the compounds A1-1, A4-2 and 2-1 in the present application can be prepared by referring to the methods disclosed in WO 2023006893A1.

[0223] General preparation method one:

[0224] wherein: X is halogen, M 1 , M 2 , L, L 1 , L 2 , R 1 , R 2R 3 R 4 R 5 R 6 x1, x2 and x3 are defined as the same as the definition described above.

[0225] Preparation of intermediates

[0226] Synthesis of intermediate A1

[0227] To a solution of A1-1 (500.0 mg, 1.95 mmol, 1.0 equiv) in dimethyl sulfoxide (5 mL) was added N,N-diisopropylethylamine (756.96 mg, 5.86 mmol, 3.0 equiv) and cyclopropanamine (222.9 mg, 3.90 mmol, 2.0 equiv) under nitrogen protection at room temperature. The reaction mixture was heated to 120 °C and stirred for 16 h. After the reaction was completed, the reaction mixture was added to ice water (20 mL) to quench and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography, ethyl acetate / petroleum ether (0-20%) to give the product A1 (160.0 mg, yield 27.95%) as yellow oil. LCMS: (ESI, m / z): 293.0 [M+H] + .

[0228] Synthesis of intermediate A2

[0229] Step 1: Synthesis of compound A2-2

[0230] To a solution of A2-1 (1 g, 5.78 mmol, 1 equiv) in super dry dichloromethane (15 mL) was added O-(trimethylsilyl)hydroxylamine (1.24 g, 5.78 mmol, 1 equiv) at room temperature under nitrogen protection. The reaction was carried out at 30 °C for 16 h. The desired product was found in the liquid chromatography-mass spectrometry (LC-MS). The reaction solution was filtered to give yellow solid A2-2 (800 mg, 73%). LCMS (ESI, m / z): 188.0 [M] + .

[0231] Step 2: Synthesis of compound A2-3

[0232] To a solution of A2-2 (750 mg, 3.97 mmol, 1 equiv) in anhydrous pyridine (10 mL) was added oxalyl chloride methyl ester (973 mg, 7.93 mmol, 2.0 equiv) at room temperature under nitrogen protection. The reaction was stirred at 100 °C for 5 h. The desired product was found in LCMS. The reaction was poured into water (100 mL). The system was extracted with ethyl acetate (2*40 mL). The organic phase was combined and washed with 1 N aqueous hydrochloric acid (2*30 mL), dried over anhydrous sodium sulfate and concentrated to dryness to give yellow solid A2-3 (350 mg, 35%). LCMS (ESI, m / z): 256.0 [M+H] + .

[0233] Step 3: Synthesis of compound A2-4

[0234] To a solution of A2-3 (280 mg, 1.09 mmol, 1 equiv) in 1.4-dioxane (3 mL) and water (0.5 mL) was added (S)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-l-yl)methyl)potassium trifluoroborate (1.4 g, 4.37 mmol, 4.0 equiv), cesium carbonate (888 mg, 2.73 mmol, 2.5 equiv), palladium acetate (25 mg, 0.1 mmol, 0.1 equiv), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (52 mg, 0.1 mmol, 0.1 equiv) respectively at room temperature under nitrogen protection. The reaction was heated to 90 °C for 16 h. The desired product was found in LCMS. The reaction was poured into water (20 mL). The system was extracted with ethyl acetate (2*30 mL). The organic phase was combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The residue was directly purified by column (methanol / dichloromethane = 5%) to give yellow solid A2-4 (200 mg, 47%). LCMS (ESI, m / z): 390.1 [M+H] + .

[0235] Step 4: Synthesis of compound A2

[0236] A2-4 (200 mg, 0.51 mmol, 1 equiv) was dissolved in 1.4-dioxane (3 mL) under nitrogen protection. 4 M hydrochloric acid dioxane solution (3 mL) was added at 0 °C. The reaction was stirred at room temperature for 1 h. The desired product was found in LCMS. The reaction was concentrated under reduced pressure to give white solid crude A2 hydrochloride (200 mg). LCMS (ESI, m / z): 290.1 [M+H] + .

[0237] Synthesis of intermediate A3

[0238] Step 1: Synthesis of compound A3-1

[0239] To a solution of A2-3 (600.0 mg, 2.34 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) was added (tributylstannyl)methanol (1.5 g, 4.69 mmol, 2.0 equiv), tetrakis(triphenylphosphine)palladium (234.3 mg, 0.234 mmol, 0.1 equiv) at room temperature. The reaction mixture was heated to 110 °C and stirred for 16 h under nitrogen protection. After the reaction was completed, the reaction mixture was added to ice water (20 mL) to quench and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel, methanol / methylene chloride (0-10%) to give yellow solid A3-1 (110.0 mg, yield 22.66%). LCMS: (ESI, m / z): 207.9 [M+H] + .

[0240] Step 2: Synthesis of compound A3

[0241] To a solution of A3-1 (90.0 mg, 0.434 mmol, 1.0 equiv) in dichloromethane (3 mL) was added methyl sulfonyl chloride (99.5 mg, 0.868 mmol, 2.0 equiv), triethylamine (131.8 mg, 1.30 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h under nitrogen protection. After the reaction was completed, the reaction mixture was added to ice water (20 mL) to quench and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel, methanol / dichloromethane (0-10%) to give yellow solid product A3 (100.0 mg, yield 80.70%). LCMS: (ESI, m / z): 286.0 [M+H] + .

[0242] Synthesis of intermediate A4

[0243] Step 1: Synthesis of compound A4-3

[0244] To a solution of A4-2 (100 mg, 0.47 mmol, 1 equiv) in anhydrous 1.4-dioxane (5 mL) was added A4-1 (125 mg, 0.47 mmol, 1.0 equiv), cesium carbonate (461 mg, 1.42 mmol, 3.0 equiv), [2-(dicyclohexylphosphino)-2'-(N,N-dimethylamino)-1,1'-biphenyl]palladium(II) (2'-amino-1,1'-biphenyl-2-yl) (36 mg, 0.047 mmol, 0.1 equiv) under nitrogen protection. The reaction was heated to 110 °C for 5 h. The desired product was found in LCMS. The reaction mixture was poured into water (20 mL). The system was extracted with ethyl acetate (2*30 mL), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The resulting residue was directly purified by column (methanol / methylene chloride = 5%) to give yellow oil A4-3 (130 mg, 70%). LCMS (ESI, m / z): 399.1 [M+H] + .

[0245] Step 2: Synthesis of compound A4

[0246] A4-3 (130 mg, 0.33 mmol, 1 equiv) was dissolved in hydrochloric acid dioxane solution (4 M, 5 mL) under nitrogen protection. The reaction was carried out at room temperature for 2 hours. The desired product was found in LCMS. Concentration under reduced pressure gave white solid A4 hydrochloride (150 mg). LCMS: (ESI, m / z): 299.2 [M+H] +

[0247] Synthesis of intermediate A5

[0248] Step 1: Synthesis of compound A5-1

[0249] To a solution of A1-1 (100.0 mg, 0.392 mmol, 1.0 equiv) in methanol (5 mL) was added sodium methoxide in methanol (mass fraction 30%) (212 mg, 1.176 mmol, 3.0 equiv) under nitrogen protection at room temperature. The reaction mixture was heated to 70 °C and stirred for 16 hours. After the reaction was completed, it was extracted with ethyl acetate (20 mL x 3), the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography, ethyl acetate / petroleum ether (0-20%) to give white solid product A5-1 (60.0 mg, yield 57.3%).

[0250] 1H NMR (400 MHz, DMSO-d6) δ 7.25 (s, 1H), 7.10 (s, 1H), 3.92 (s, 3H), 2.52 (d, J = 4.8 Hz, 2H), 1.95 - 1.88 (m, 1H), 0.87 (d, J = 6.4 Hz, 6H).

[0251] Step 2: Synthesis of compound A5

[0252] Synthesized by referring to the preparation method of intermediate A4, using A5-1 instead of A2-4 to give compound A5 hydrochloride (40.0 mg, crude) as a white solid. LCMS: (ESI, m / z): 300.2 [M+H] + .

[0253] Synthesis of intermediate A6

[0254] Synthesized by referring to the preparation method of intermediate A1, using 2,2-difluoroethanamine instead of cyclopropylalkylamine to give compound A6-1, then by referring to the preparation method of intermediate A4, using A6-1 instead of A4-2 to give compound A6 hydrochloride (25.0 mg, crude). LCMS: (ESI, m / z): 349.1 [M+H] + .

[0255] Synthesis of intermediate A7

[0256] Synthesized by referring to the preparation method of intermediate A4, using A1-1 instead of A4-2 to give compound A7 hydrochloride (83.0 mg, crude) as a white solid. LCMS: (ESI, m / z): 348.0 [M+H] + .

[0257] Synthesis of intermediate A8

[0258] Step 1: Synthesis of compound A8-2

[0259] A4-1 (220 mg, 1.04 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (5 mL) under nitrogen protection, N,N-diisopropyl ethylamine (469 mg, 3.63 mmol, 3.5 equiv) was added at 0 °C, after 10 minutes, 3-chloromethyl pyridazine hydrochloride (205 mg, 1.24 mmol, 12 equiv) was added. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL x 3), the organic phase was combined and washed with saturated brine (10 mL x 4), dried over anhydrous sodium sulfate and concentrated, the obtained residue was purified by silica gel column chromatography, dichloromethane / methanol (5%), to obtain yellow oil A8-2 (202 mg, 64%). LCMS: (ESI, m / z): 305.2 [M+H] + .

[0260] Step 2: Synthesis of compound A8

[0261] A8-2 (202 mg, 0.69 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL) under nitrogen protection, then trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain brown oil A8 (519 mg, crude). LCMS: (ESI, m / z): 205.2 [M+H] + .

[0262] Synthesis of intermediate A9

[0263] Step 1: Synthesis of compound A9-2

[0264] A9-1 (2 g, 11.56 mmol, 1.0 equiv) was dissolved in acetone (16 mL) under nitrogen protection, ethyl bromoacetate (2.12 g, 12.72 mmol, 1.1 equiv) was added, and the reaction was carried out at 65 °C for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with acetone (20 mL) to obtain white solid A9-2 (2.93 g, 75%). LCMS (ESI, m / z): 338.1 [M] + .

[0265] Step 2: Synthesis of compound A9-3

[0266] A9-2 (2.73 g, 8.03 mmol, 1.0 equiv) was dissolved in methanol (40 mL) under nitrogen protection, sodium methoxide (3.7 mL, 20.08 mmol, 5.4 M, 2.5 equiv) was added, after stirring at room temperature for 1 hour, iodomethane (6.84 g, 48.19 mmol, 6.0 equiv) was added, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was rotary evaporated, and the obtained residue was purified by silica gel column chromatography, methanol / dichloromethane (5%), to obtain yellow solid A9-3 (869 mg, 45%). LCMS (ESI, m / z): 241 [M+1] + .

[0267] Step 3: Synthesis of compound A9-4

[0268] A9-3 (500 mg, 2.07 mmol, 1.0 equiv) was dissolved in dioxane (10 mL) and water (1 mL) under nitrogen protection, (S)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)potassium trifluoroborate (996 mg, 3.11 mmol, 1.5 equiv), cesium carbonate (2027 mg, 6.22 mmol, 3.0 equiv), 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl (99 mg, 0.21 mmol, 0.1 equiv), palladium acetate (47 mg, 0.21 mmol, 0.1 equiv) were added, and the reaction was carried out at 90°C for 16 hours. After the reaction was completed, the reaction solution was directly concentrated, and the obtained residue was purified by silica gel column chromatography, methanol / dichloromethane (5%), to obtain yellow solid A9-4 (567 mg, 73%). LCMS (ESI, m / z): 375.2 [M+H] + Step 4: Synthesis of compound A9

[0269] A9-4 (567 mg, 1.51 mmol, 1.0 equiv) was dissolved in hydrochloric acid-dioxane solution (10 mL) under nitrogen protection, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain white solid A9 (713 mg, crude). LCMS (ESI, m / z): 275.2 [M+H] + .

[0270] Synthesis of intermediate A10

[0271] Referring to the preparation method of intermediate A4, A1-1 was used to replace A4-2 to obtain intermediate A10 (80 mg, crude), which was directly used in the next reaction. LCMS: (ESI, m / z): 288.2 [M+H] + .

[0272] Synthesis of intermediate A11

[0273] Step 1 : Synthesis of compound A11-2

[0274] To a solution of (S)-tert-butyl 3-methylpiperazine-l-carboxylate (2.5 g, 12.48 mmol, 1.0 equiv) in N,N-dimethylformamide (20 mL) was added N,N- diisopropylethylamine (4.8 g, 37.45 mmol, 3.0 equiv) and 2-bromoacetonitrile (2.99 g, 24.96 mmol, 2.0 equiv) under nitrogen protection at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was quenched into ice water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (0-10%) to give compound A11-2 (2.7 g, yield 90.38%) as yellow oil.

[0275] 1 H NMR (400 MHz, CDC13) δ 4.00 (s, 1H), 3.84 (d, J = 17.6 Hz, 1H), 3.46 (d, J = 17.6 Hz, 1H), 2.97 (s, 1H), 2.68-2.42 (m, 4H), 1.47 (s, 9H), 1.08 (d, J = 6.0 Hz, 3H).

[0276] Step 2: Synthesis of compound A11-3

[0277] To a solution of A11-2 (2.7 g, 11.28 mmol, 1.0 equiv) in methanol (30 mL) was added sodium methoxide in methanol (30% W, 4.06 g, 22.56 mmol, 2.0 equiv) at room temperature. The reaction mixture was heated to 70 °C with nitrogen protection and stirred for 16 hours. After the reaction was completed, the desired product was found but most of the starting material remained. The reaction mixture was quenched into ice water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was evaporated to give compound A11-3 (2.0 g, crude) as yellow solid. LCMS: (ESI, m / z): 272.2 [M+H] + .

[0278] Step 3: Synthesis of compound A11-4

[0279] To a solution of A11-3 (2.0 g, 7.37 mmol, 1.0 equiv) in xylene (20 mL) was added methyl 1- aminocyclopropane-1-carboxylate (848.5 mg, 7.37 mmol, 1.0 equiv) and glacial acetic acid (44.26 mg, 0.737 mmol, 0.1 equiv) at room temperature in a microwave tube, the reaction was heated to 140 °C under nitrogen protection and stirred for 16 hours. After the reaction was completed, the reaction mixture was added to ice water (20 mL) to quench, extracted with ethyl acetate (20 mL x 3), the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, the obtained residue was purified by silica gel column chromatography, methanol / methylene chloride (0-10%), to give compound A11-4 (127 mg, yield 5.34%) as yellow oil. LCMS: (ESI, m / z): 323.1 [M+H] + .

[0280] Step 4: Synthesis of compound A11-5

[0281] To a solution of A11-4 (127.0 mg, 0.394 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added sodium hydride (60% W, 31.5 mg, 0.788 mmol, 2.0 equiv) under ice water bath, and the reaction was stirred for 30 minutes under ice water bath, then iodomethane (111.8 mg, 0.788 mmol, 2.0 equiv) dissolved in tetrahydrofuran was added dropwise into the reaction. The reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was added to ice water (20 mL) to quench, and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated, the obtained residue was purified by silica gel column chromatography, methanol / methylene chloride (0-10%), to give compound A11-5 (116.0 mg, yield 87.53%) as yellow oil. LCMS: (ESI, m / z): 337.2 [M+H] + Step 5: Synthesis of compound A11

[0282] To a solution of A11-5 (116.0 mg, 0.345 mmol, 1.0 equiv) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) under ice water bath, and the reaction was stirred for 2 hours at room temperature. After the reaction was completed, the reaction mixture was rotary evaporated to dryness to give product A11 (135.0 mg, crude) as yellow oil. LCMS: (ESI, m / z): 237.1 [M+H] + .

[0283] Synthesis of intermediate A12

[0284] Step 1 : Synthesis of compound A12-2

[0285] To a solution of (2-bromoethoxy)(tert-butyl)dimethylsilane (223 mg, 0.931 mmol, 1.5 equiv) in N,N-dimethylformamide (7 mL) was added A11-4 (200 mg, 0.620 mmol, 1.0 equiv) and cesium carbonate (606 mg, 1.86 mmol, 3.0 equiv) under nitrogen protection at room temperature. The above mixture was stirred at 100 °C for 4 h. The desired product was found in LCMS. The reaction mixture was diluted with ethyl acetate (30 mL) and backwashed with saturated brine (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, methanol / dichloromethane (1 :20) to give A12-2 (230 mg, 77%) as a yellow solid. LCMS: (ESI, m / z): 481.4 [M+H] + .

[0286] Step 2: Synthesis of compound A12

[0287] To a solution of A12-2 (180 mg, 0.374 mmol, 1 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) under nitrogen protection at room temperature. The reaction was stirred at room temperature for 18 h. The desired product was found in LCMS. Concentration under reduced pressure gave colorless A12 (120 mg, crude). The crude was used directly in the next step without further purification. LCMS: (ESI, m / z): 267.3 [M+H] + .

[0288] Synthesis of intermediate A13

[0289] Following the procedure for the preparation of compound A12, using A13-1 instead of A12-1, gave intermediate A13 (165 mg, crude). It was used directly in the next step. LCMS: (ESI, m / z): 293.2 [M+H] + .

[0290] Synthesis of intermediate A14

[0291] Following the procedure for the preparation of intermediate A8, using A14-1 instead of A4-1, gave intermediate A14 (90 mg, crude). LCMS: (ESI, m / z): 219 [M+H] + .

[0292] Synthesis of intermediate A15

[0293] Referring to the preparation method of intermediate A6, 1-methyl-1H-pyrazol-4-amine was used to replace 2,2-difluoroethanamine to obtain intermediate A15 (80 mg, crude), which was directly used in the next reaction. LCMS: (ESI, m / z): 365.2 [M+H] + .

[0294] Synthesis of intermediate A16

[0295] Referring to the preparation method of intermediate A8, A16-1 was used to replace A4-1 to obtain intermediate A16 (90 mg, crude). LCMS: (ESI, m / z): 205.2 [M+H] + .

[0296] Synthesis of compound 1 of example 1

[0297] Step 1: Synthesis of compound 1-1

[0298] Under nitrogen protection, to the solution of compound A4 (150 mg, 0.33 mmol, 1 equiv) in N,N dimethylformamide (5 mL) was added N,N-diisopropylethylamine (170 mg, 1.32 mmol, 4.0 equiv), 3-(chloromethyl)pyridazine hydrochloride (82 mg, 0.5 mmol, 1.5 equiv) respectively. The reaction was carried out at room temperature for 48 h, and the desired product was found in liquid chromatography-mass spectrometry. The reaction solution was poured into water (10 mL). The system was extracted with ethyl acetate (2*20 mL), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The obtained residue was directly purified by column (methanol / dichloromethane = 5%) to obtain yellow solid compound 1-1 (90 mg, 70%). LCMS (ESI, m / z): 391.2 [M+H] + .

[0299] Step 2: Synthesis of compound 1

[0300] In a 10 mL vial was placed 4-isobutyl-2-(methylamino)-6-((1S,6R)-5-(pyridazin-3- ylmethyl)-2,5-diazabicyclo[4.2.0]oct-2-yl)benzonitrile (35 mg, 0.089 mmol, 1 equiv), toluene (2 mL), and then was added tri-n-butyltin chloride (146 mg, 0.448 mmol, 5 equiv), sodium azide (29 mg, 0.448 mmol, 5 equiv) respectively, then reacted at 140 °C for 48 hours, liquid chromatography-mass spectrometry monitoring, after the reaction was completed, the obtained residue was concentrated under reduced pressure. The obtained residue was directly purified by column (methanol / dichloromethane = 10%) to obtain (30 mg) of yellow solid crude product. The crude product was purified by preparative high performance liquid chromatography, purification conditions: (column specifications: Sunfire C18 5um, 19mm*250mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 milliliters per minute; elution gradient: 28% B to 38% B for 17 minutes; detection wavelength: UV 254nm / 214nm; retention time (minutes): 7.8-9.1), to obtain compound 1 (3.63 mg, 4.6%). LCMS (ESI, m / z): 434.2 [M+H] + .

[0301] 1 H NMR (400 MHz, DMSO-d6) δ 9.14-9.10 (m, 1H), 7.73-7.63 (m, 2H), 6.25 (s, 1H), 6.21 (s, 1H), 3.82 (d, J = 14.0 Hz, 1H), 3.65 (d, J = 13.6 Hz, 1H), 3.45-3.40 (m, 1H), 3.13-3.08 (m, 1H), 3.04-2.97 (m, 1H), 2.71 (s, 3H), 2.62-2.57 (m, 1H), 2.38 (d, J = 6.8 Hz, 2H), 2.34-2.21 (m, 2H), 2.18-2.09 (m, 1H), 1.90-1.81 (m, 1H), 1.69-1.61 (m, 1H), 1.58-1.47 (m, 2H), 0.89 (d, J = 6.4 Hz, 6H).

[0302] Synthesis of compound 2 of example 2

[0303] Step 1: Synthesis of compound 2-2

[0304] A8 (135 mg, 0.66 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (3 mL) under nitrogen protection, and 2,6-difluoro-4-isobutylbenzonitrile (155 mg, 0.79 mmol, 1.2 equiv), N,N-diisopropyl ethylamine (256 mg, 1.98 mmol, 3.0 equiv), potassium carbonate (274 mg, 1.98 mmol, 3.0 equiv) were added into the sealed tube. The reaction was stirred at 100 °C for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mL x 2). The organic phase was combined and washed with saturated brine (10 mL x 4), dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography, dichloromethane / methanol (5%), to obtain compound 2-2 (119 mg, 47%) as yellow oil. LCMS: (ESI, m / z): 380.2 [M+H]+.

[0305] Step 2: Synthesis of compound 2

[0306] 2-2 (100 mg, 0.26 mmol, 1.0 equiv) was dissolved in toluene (2 mL) under nitrogen protection, and sodium azide (137 mg, 2.11 mmol, 8.0 equiv), tri-n-butyltin chloride (686 mg, 2.11 mmol, 8.0 equiv) were added into the sealed tube. The reaction was stirred at 140 °C for 36 hours. After the reaction was completed, the reaction solution was concentrated, and TLC, dichloromethane / methanol (10%), was used to prepare the crude product. The crude product was purified by preparative high performance liquid chromatography, and the purification conditions were as follows: column specifications: Sunfire C18, 19*250mm, 10um; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 20 milliliters per minute; elution gradient: 26% B to 31% B in 17 minutes; detection wavelength: UV 254nm / 214nm; retention time (minutes): 7.3-9.7, to obtain compound 2 (31.90 mg, 29%). LCMS: (ESI, m / z): 423.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.13 - 9.11 (m, 1H), 7.69 - 7.63 (m, 2H), 6.80 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 3.81 - 3.65 (m, 2H), 3.61 - 3.57 (m, 1H), 3.17 - 3.12 (m, 1H), 2.92 - 2.87 (m, 1H), 2.63 - 2.59 (m, 1H), 2.52 - 2.47 (m, 2H), 2.30 - 2.25 (m, 1H), 2.16 - 2.11 (m, 1H), 1.97 - 1.79 (m, 3H), 1.64 - 1.52 (m, 2H), 0.89 (d, J = 4.0 Hz, 6H).

[0307] Synthesis of Example 3 compound 3

[0308] Synthesized according to the preparation method of Reference Compound 2, using compound A9 instead of A8 to give compound 3 (17.02 mg, 18%). LCMS (ESI, m / z): 493.2 [M+H] + .

[0309] 1 H NMR (400 MHz, MeOD) δ 8.246 - 8.227 (m, 1H), 7.734 (d, J = 6.8 Hz, 1H), 6.857 - 6.814 (m, 1H), 3.742 (d, J = 15.6 Hz, 1H), 3.344 - 3.306 (m, 3H), 2.835 - 2.696 (m, 3H), 2.601 - 2.538 (m, 2H), 2.446 - 2.411 (m, 1H), 2.167 - 2.109 (m, 1H), 1.958 - 1.856 (m, 1H), 1.414 (s, 6H), 0.899 (d, J = 6.4 Hz, 6H), 0.854 (d, J = 6.4 Hz, 3H).

[0310] Synthesis of Example 4 compound 4

[0311] Step 1: Synthesis of compound 4-1

[0312] Synthesized according to the preparation method of Reference Compound 2, using compound A2 instead of A8 to give compound 4-1 (90 mg, 38%) as yellow oil. LCMS (ESI, m / z): 465.1 [M+H] + .

[0313] Step 2: Synthesis of compound 4-2

[0314] To a solution of 4-1 (90 mg, 0.19 mmol, 1 equiv) in anhydrous tetrahydrofuran (3 mL) was added lithium aluminum hydride (11 mg, 0.29 mmol, 1.5 equiv) at 0 °C under nitrogen protection. The reaction was allowed to react at 0 °C for 1 h, and the desired product was found in the liquid chromatography-mass spectrometry. The reaction was quenched by adding sodium sulfate decahydrate at 0 °C. Filtration, and concentration to dryness. The resulting residue was directly purified by column (methanol / dichloromethane = 5%) to give compound 4-2 (40 mg, 48%) as yellow oil. LCMS (ESI, m / z): 437.1 [M+H] + .

[0315] Step 3: Synthesis of compound 4

[0316] Synthesis by referring to the preparation method of compound 1, using compound 4-2 to replace 1-1, to give compound 4 (4.42 mg, 10%). LCMS (ESI, m / z): 480.2 [M+H] + .

[0317] 1 H NMR (400 MHz, MeOD) d 8.31 (s, 1H), 7.70-7.64 (m, 2H), 7.31 (d, J = 6.8 Hz, 1H), 6.79 (s, 1H), 6.75 (d, J = 10.0 Hz, 1H), 4.84 (s, 2H), 4.45 (d, J = 16.4 Hz, 1H), 4.01 (s, 1H), 2.93-2.85 (m, 4H), 2.70-2.61 (m, 2H), 2.55-2.50 (m, 3H), 1.94-1.91 (m, 1H), 1.02 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.4 Hz, 6H).

[0318] Example 5 Synthesis of compound 5

[0319] Step 1: Synthesis of compound 5-2

[0320] To a solution of ethyl imidazo[l,2-b]pyridazine-2-carboxylate (400 mg, 2.09 mmol, 1 equiv) in anhydrous tetrahydrofuran (15 mL) was added lithium aluminum hydride (160 mg, 4.18 mmol, 2 equiv) at 0 °C under nitrogen protection. The reaction was allowed to react at room temperature for 2 h, and the desired product was found in the liquid chromatography-mass spectrometry. The reaction was quenched by adding sodium sulfate decahydrate at 0 °C. Filtration, and concentration to dryness. The resulting residue was directly purified by column (methanol / dichloromethane = 9%) to give compound 5-2 (150 mg, 50%) as white solid. LCMS: (ESI, m / z): 150.1 [M+H] + .

[0321] Step 2: Synthesis of compound 5-3

[0322] To a solution of 5-2 (90 mg, 0.6 mmol, 1 equiv) in anhydrous dichloromethane (5 mL) was added Dess-Martin Oxidizing Reagent (384 mg, 0.9 mmol, 1.5 equiv) at room temperature under nitrogen protection. The reaction was stirred at room temperature for 2 h. The desired product was found in LCMS. The reaction mixture was directly purified by preparative thin layer chromatography (methanol / dichloromethane = 1 / 15) to give compound 5-3 (30 mg, 33%) as a white solid. LCMS: (ESI, m / z): 148.0 [M+H] + .

[0323] Step 3: Synthesis of compound 5-4

[0324] To a solution of A16 (50 mg, 0.2 mmol, 1 equiv) and 5-3 (30 mg, 0.2 mmol, 1 equiv) in 1.2-dichloroethane (1.5 mL) and anhydrous tetrahydrofuran (1.5 mL) was added sodium triacetoxyborohydride (106 mg, 0.5 mmol, 2.5 equiv) at 50 °C under nitrogen protection after the reaction was cooled to room temperature. The reaction was stirred at room temperature for 16 h. The desired product was found in LCMS. The reaction mixture was poured into water (20 mL). The system was extracted with dichloromethane (2*20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to dryness. The obtained residue was directly purified by preparative thin layer chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 5-4 (30 mg, 36%) as a yellow solid.

[0325] LCMS: (ESI, m / z): 419.1 [M+H] + .

[0326] Step 4: Synthesis of compound 5

[0327] In a 10 mL vial, add 5-4 (30 mg, 0.072 mmol, 1 equiv), toluene (2 mL), add tri-n-butyltin chloride (120 mg, 0.36 mmol, 5 equiv), sodium azide (24 mg, 0.36 mmol, 5 equiv) respectively, then react at 140 °C for 48 hours, monitor by LCMS, after the reaction is completed, the obtained residue is concentrated under reduced pressure. The obtained residue is directly purified by column (methanol / dichloromethane = 10%) to obtain (25 mg) yellow solid crude product. Purify the crude product by preparative high performance liquid chromatography, purification conditions: (column specifications: Sunfire C18 5um, 19mm*250mm; mobile phase A: water (10mmol / L ammonium bicarbonate / water), mobile phase B: acetonitrile; flow rate: 20 milliliters per minute; elution gradient: 28% B to 38% B for 17 minutes; detection wavelength: UV 254nm / 214nm; retention time (minutes): 8.6-10.4), to obtain compound 5 (4.06 mg, 12%). LCMS: (ESI, m / z): 462.2 [M+H] + .

[0328] 1 H NMR (400 MHz, DMSO-d6) δ 8.46-8.44 (m, 1H), 8.12 (s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.19-7.15 (m, 1H), 6.64 (d, J = 9.2 Hz, 1H), 6.55 (s, 1H), 3.64 (d, J = 13.6 Hz, 1H), 3.60-3.57 (m, 1H), 3.53 (d, J = 14.0 Hz, 1H), 3.17 (s, 1H), 2.89-2.86 (m, 1H), 2.59-2.56 (m, 1H), 2.44 (d, J = 7.2 Hz, 2H), 2.40-2.35 (m, 1H), 2.12-2.06 (m, 1H), 1.97-1.76 (m, 3H), 1.66-1.49 (m, 2H), 0.88 (d, J = 6.4 Hz, 6H).

[0329] Synthesis of compound 6

[0330] Synthesized according to the synthesis method of reference compound 1, using intermediate A5 instead of A4, to obtain compound 6 (1.51 mg, yield 7.56%). LCMS: (ESI, m / z): 435.3 [M+H] + .

[0331] 1H NMR (400 MHz, CD3OD) δ 9.06 (d, J = 4.0 Hz, 1H), 8.49 (s, 0.48HCOOH), 7.81 (d, J = 7.2 Hz, 1H), 7.70-7.67 (m, 1H), 6.53 (d, J = 16.0 Hz, 2H), 3.81 (d, J = 14.0 Hz, 1H), 3.73-3.68 (m, 5H), 3.18-3.13 (m, 1H), 3.08-3.02 (m, 1H), 2.69-2.64 (m, 1H), 2.48 (d, J = 7.2 Hz, 2H), 2.30-2.25 (m, 1H), 2.23-2.17 (m, 1H), 2.04-1.97 (m, 1H), 1.95-1.86 (m, 2H), 1.62-1.58 (m, 2H), 0.93 (d, J = 6.4 Hz, 6H).

[0332] Synthesis of compound 7

[0333] Synthesized according to the synthetic procedure of Reference Compound 1, using intermediate A6 in place of A4, to give compound 7 (1.07 mg, yield 5.83%). LCMS: (ESI, m / z): 484.3 [M+H] + .

[0334] 1 H NMR (400 MHz, CD3OD) δ 9.08 (d, J = 4.0 Hz, 1H), 8.47 (s, 1.21HCOOH), 7.88 (d, J = 9.6 Hz, 1H), 7.73-7.70 (m, 1H), 6.37 (d, J = 15.6 Hz, 2H), 6.03-5.73 (m, 1H), 3.89 (d, J = 14.0 Hz, 1H), 3.76 (d, J = 14.0 Hz, 1H), 3.67-3.63 (m, 1H), 3.57-3.43 (m, 3H), 3.15-3.09 (m, 2H), 2.76-2.71 (m, 1H), 2.43 (d, J = 7.2 Hz, 2H), 2.37-2.31 (m, 1H), 2.21-2.10 (m, 1H), 1.92-1.85 (m, 2H), 1.69-1.61 (m, 2H), 0.92 (d, J = 6.4 Hz, 6H).

[0335] Synthesis of compound 8

[0336] Step 1: Synthesis of compound 8-1

[0337] Synthesized using intermediate A7 instead of A4, referring to the synthetic method of Compound 1 to give Compound 8-1 (70.0 mg, yield 73.68%) as yellow oil. LCMS: (ESI, m / z): 440.1 [M+H] + .

[0338] Step 2: Synthesis of compound 8-2

[0339] To a solution of compound 8-1 (70.0 mg, 0.159 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) was added 1-methyl-1H-pyrazol-4-amine (15.5 mg, 0.159 mmol, 1.0 equiv), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl-2-yl) palladium(II) acetate (13.3 mg, 0.0159 mmol, 0.1 equiv) and cesium carbonate (155.4 mg, 0.477 mmol, 3.0 equiv) at room temperature. The reaction mixture was heated to 110 °C and stirred for 16 h under nitrogen protection. After the reaction was completed, the reaction mixture was added to ice water (20 mL) to quench and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography, methanol / methylene chloride (0-10%) to give compound 8-2 (65.0 mg, yield 89.56%) as yellow oil. LCMS: (ESI, m / z): 457.5 [M+H] + .

[0340] Step 3: Synthesis of compound 8

[0341] Synthesized using intermediate 8-2 instead of 1-5, referring to the synthetic method of Compound 1 to give compound 8 (12.54 mg, yield 17.63%). LCMS: (ESI, m / z): 500.3 [M+H] + .

[0342] 1H NMR (400 MHz, CD3OD) δ 9.10-9.08 (m, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.75-7.71 (m, 1H), 7.52 (s, 1H), 7.35 (s, 1H), 6.42 (d, J = 22.8 Hz, 2H), 3.94 (d, J = 14.0 Hz, 1H), 3.86 (s, 3H), 3.79 (d, J = 14.0 Hz, 1H), 3.70-3.65 (m, 1H), 3.28-3.25 (m, 1H), 3.21-3.26 (m, 1H), 2.83-2.77 (m, 1H), 2.57-2.52 (m, 1H), 2.44-2.40 (m, 1H), 2.35 (d, J = 7.2 Hz, 2H), 2.21-2.15 (m, 1H), 1.92-1.87 (m, 1H), 1.82-1.76 (m, 1H), 1.72-1.68 (m, 2H), 0.88 (d, J = 6.4 Hz, 6H).

[0343] Synthesis of compound 9 of example 9

[0344] Step 1: Synthesis of compound 9-1

[0345] To a solution of compound A11 (120.0 mg, 0.507 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) was added A4-2 (136.0 mg, 0.507 mmol, 1.0 equiv), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl-2-yl) palladium(II) (43.0 mg, 0.0507 mmol, 0.1 equiv), cesium carbonate (496.0 mg, 1.52 mmol, 3.0 equiv) at room temperature. The reaction mixture was heated to 90 °C and stirred for 3 h under nitrogen protection. After the reaction was completed, the reaction mixture was added to ice water (20 mL) to quench and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography, methanol / methylene chloride (0-10%) to give compound 9-1 (63.0 mg, yield 29.36%) as a yellow solid. LCMS: (ESI, m / z): 423.4 [M+H] + .

[0346] Step 2: Synthesis of compound 9

[0347] Synthesized according to the synthetic method of Compound 1, using compound 9-1 instead of compound 1-2, to give compound 9 (10.75 mg, yield 15.49%). LCMS: (ESI, m / z): 466.3 [M+H] + .

[0348] 1 H NMR (400 MHz, CD3OD) δ 6.42 (s, 1H), 6.38 (s, 1H), 4.02 (d, J = 14.0 Hz, 1H), 3.28 (s, 3H), 3.20 (d, J = 14.0 Hz, 1H), 2.94-2.91 (m, 3H), 2.88-2.80 (m, 4H), 2.66-2.58 (m, 2H), 2.48-2.41 (m, 3H), 1.95-1.89 (m, 1H), 1.69-1.64 (m, 2H), 1.59-1.56 (m, 2H), 1.06 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.4 Hz, 6H).

[0349] Synthesis of compound 10

[0350] Synthesized according to the synthetic method of Compound 2, using intermediate A12 instead of A8, to give compound 10 (10.09 mg, 22.99%). LCMS: (ESI, m / z): 485.3 [M+H] + .

[0351] 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.03HCOOH), 6.85 (d, J = 10.0 Hz, 1H), 6.81 (s, 1H), 4.99 (s, 1H), 3.89 (d, J = 13.6 Hz, 1H), 3.81–3.75 (m, 1H), 3.67–3.61 (m, 1H), 3.53–3.40 (m, 2H), 3.08 (d, J = 13.6 Hz, 1H), 2.82–2.76 (m, 2H), 2.71–2.67 (m, 1H), 2.57–2.52 (m, 3H), 2.36–2.33 (m, 2H), 2.11–2.07 (m, 1H), 1.94–1.87 (m, 1H), 1.62–1.55 (m, 2H), 1.38 (d, J = 5.2 Hz, 2H), 0.90–0.86 (m, 9H).

[0352] Synthesis of compound 11

[0353] Synthesized by referring to the synthetic method of compound 2, using intermediate A13 instead of A8, to give compound 11 (20.63 mg, 23.61%). LCMS: (ESI, m / z): 511.3 [M+H] + .

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 6.99 (d, J = 10.4 Hz, 1H), 6.93 (s, 1H), 4.90 - 4.83 (m, 1H), 4.57 - 4.32 (m, 4H), 4.13 (s, 1H), 4.01 - 3.73 (m, 3H), 3.09 - 2.87 (m, 5H), 2.65 (d, J = 13.6 Hz, 1H), 2.54 (d, J = 7.2 Hz, 2H), 2.35 (m, 1H), 1.96 - 1.89 (m, 1H), 1.73 (d, J = 4.4 Hz, 2H), 1.54 (s, 2H), 1.07 (s, 3H), 0.90 (d, J = 6.4 Hz, 6H).

[0355] Synthesis of compound 12

[0356] Synthesized by referring to the synthetic method of compound 8, using intermediate A11 instead of A7 to give compound 12-1, then using 3,3-difluorocyclobutylamine instead of 1-methyl-1H-pyrazol-4-amine, synthesized by referring to the synthetic method of compound 8 to give compound 12 (8.81 mg, yield 23.17%). LCMS: (ESI, m / z): 542.3 [M+H] + .

[0357] 1 H NMR (400 MHz, CD3OD) δ 6.49 (s, 1H), 6.27 (s, 1H), 4.02 (d, J = 14.0 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.28 (s, 3H), 3.20 (d, J = 14.0 Hz, 1H), 3.07 - 3.01 (m, 2H), 2.91 - 2.87 (m, 3H), 2.84 - 2.78 (m, 1H), 2.65 - 2.58 (m, 2H), 2.48 - 2.39 (m, 5H), 1.93 - 1.87 (m, 1H), 1.68 - 1.66 (m, 2H), 1.58 - 1.53 (m, 2H), 1.06 (d, J = 5.6 Hz, 3H), 0.94 (d, J = 6.4 Hz, 6H).

[0358] Synthesis of compound 13

[0359] Compound 13-1 was synthesized by replacing cyclopropylamine with 1 -methyl- 1H- pyrazol-4-amine, referring to the preparation method of intermediate Al, and then replacing 9-1 with intermediate 13-1, referring to the synthetic method of compound 9, to obtain compound 13 (11.23 mg, yield 18.72%). LCMS: (ESI, m / z): 532.4 [M+H] + .

[0360] 1 H NMR (400 MHz, CD3OD) δ 7.56 (s, 1H), 7.38 (s, 1H), 6.52 (d, J = 9.2 Hz, 2H), 4.07 (d, J = 14.0 Hz, 1H), 3.88 (s, 3H), 3.28 (s, 3H), 3.24 (d, J = 14.0 Hz, 1H), 2.95-2.86 (m, 4H), 2.70-2.64 (m, 2H), 2.54-2.48 (m, 1H), 2.38 (d, J = 7.2 Hz, 2H), 1.86-1.79 (m, 1H), 1.72-1.63 (m, 2H), 1.60-1.54 (m, 2H), 1.10 (d, J = 5.6 Hz, 3H), 0.89 (d, J = 6.4 Hz, 6H).

[0361] Synthesis of compound 14

[0362] Synthesis, referring to the synthetic method of compound 9, replacing A4-2 with intermediate Al, to obtain compound 14 (1.48 mg, yield 2.25%). LCMS: (ESI, m / z): 492.4 [M+H] + .

[0363] 1 H NMR (400 MHz, CD3OD) δ 6.84 (s, 1H), 6.48 (s, 1H), 4.05 (d, J = 14.4 Hz, 1H), 3.28 (s, 2H), 3.21 (d, J = 13.6 Hz, 1H), 2.93-2.83 (m, 4H), 2.66-2.63 (m, 2H), 2.49-2.46 (m, 4H), 1.94-1.91 (m, 1H), 1.68-1.64 (m, 3H), 1.57-1.56 (m, 2H), 1.09 (d, J = 5.6 Hz, 3H), 0.95 (d, J = 6.4 Hz, 6H), 0.80-0.77 (m, 2H), 0.48-0.44 (s, 2H).

[0364] Synthesis of compound 15

[0365] Step 1 : Synthesis of compound 15-1

[0366] Synthesized by referring to the synthesis method of compound 9, using intermediate A2 to replace A11, to obtain compound 15-1 (48.0 mg, yield 36.50%) as a yellow solid. LCMS: (ESI, m / z): 476.7 [M+H] + .

[0367] Step 2: Synthesis of compound 15

[0368] Synthesized by referring to the synthesis method of compound 4, using compound 15-1 to replace 4-1, to obtain compound 15 (4.18 mg, yield 10.90%). LCMS: (ESI, m / z): 491.3 [M+H] + .

[0369] 1 H NMR (400 MHz, CD3OD) δ 7.81-7.72 (m, 2H), 7.43 (d, J = 6.8 Hz, 1H), 6.44 (d, J = 8.0 Hz, 2H), 4.89 (s, 3H), 4.51-4.45 (m, 1H), 3.25-3.19 (m, 2H), 3.13-3.03 (m, 4H), 2.90-2.87 (m, 1H), 2.84 (s, 3H), 2.48 (d, J = 7.2 Hz, 2H), 1.96-1.89 (m, 1H), 1.39-1.30 (m, 3H), 0.94 (d, J = 6.4 Hz, 6H).

[0370] Example 16 Synthesis of compound 16

[0371] Synthesized by referring to the synthesis method of compound 15, using intermediate A6-1 to replace 9-1, to obtain compound 16 (10.18 mg, yield 25.32%). LCMS: (ESI, m / z): 541.4 [M+H] + .

[0372] 1H NMR (400 MHz, CD3OD) δ 7.77-7.71 (m, 2H), 7.41 (d, J = 6.8 Hz, 1H), 6.55 (d, J = 21.2 Hz, 2H), 6.08-5.79 (m, 1H), 4.88 (s, 3H), 4.37-4.31 (m, 1H), 3.66-3.58 (m, 2H), 3.20-3.13 (m, 2H), 3.08-3.01 (m, 3H), 2.94-2.82 (m, 2H), 2.49 (d, J = 7.2 Hz, 2H), 1.95-1.89 (m, 1H), 1.31-1.26 (m, 3H), 0.94 (d, J = 6.4 Hz, 6H).

[0373] Synthesis of compound 17

[0374] Synthesized according to the synthetic method of reference compound 15, using intermediate 13-1 instead of 9-1, to give compound 17 (10.88 mg, yield 15.41%). LCMS: (ESI, m / z): 557.3 [M+H] + .

[0375] 1 H NMR (400 MHz, CD3OD) δ 7.77-7.71 (m, 2H), 7.41 (d, J = 6.8 Hz, 1H), 6.55 (d, J = 21.2 Hz, 2H), 6.08-5.79 (m, 1H), 4.88 (s, 3H), 4.37-4.31 (m, 1H), 3.66-3.58 (m, 2H), 3.20-3.13 (m, 2H), 3.08-3.01 (m, 3H), 2.94-2.82 (m, 2H), 2.49 (d, J = 7.2 Hz, 2H), 1.95-1.89 (m, 1H), 1.31-1.26 (m, 3H), 0.94 (d, J = 6.4 Hz, 6H).

[0376] Synthesis of compound 18

[0377] Step 1: Synthesis of compound 18-1

[0378] To a solution of compound A3 (60.0 mg, 0.21 mmol, 1.0 equiv) in super dry acetonitrile (5 mL) was added intermediate A15 (84.3 mg, 0.21 mmol, 1.0 equiv), potassium carbonate (87.2 mg, 0.63 mmol, 3.0 equiv) and potassium iodide (35.0 mg, 0.21 mmol, 1.0 equiv) at room temperature. The reaction mixture was protected with nitrogen and stirred at 70 °C for 2 hours. After the reaction was completed, the reaction mixture was added to ice water (20 mL) to quench and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography, methanol / methylene chloride (0-10%) to give the product 18-1 (110.0 mg, yield 94.46%) as a yellow solid. LCMS: (ESI, m / z): 554.4 [M+H] + .

[0379] Step 2: Synthesis of compound 18

[0380] Synthesized according to the synthetic method of compound 15, using compound 18-1 instead of compound 15-1 to give compound 18 (15.26 mg, yield 23.51%). LCMS: (ESI, m / z): 569.5 [M+H] + .

[0381] 1 H NMR (400 MHz, CD3OD) d 7.72-7.66 (m, 2H), 7.54 (s, 1H), 7.37 (s, 1H), 7.32 (d, J = 6.8 Hz, 1H), 6.47 (d, J = 14.4 Hz, 2H), 4.84 (s, 2H), 4.17-4.06 (m, 2H), 3.87 (s, 3H), 3.70-3.67 (m, 1H), 3.42-3.39 (m, 2H), 2.89-2.79 (m, 2H), 2.58-2.56 (m, 1H), 2.36 (d, J = 7.2 Hz, 2H), 2.31-2.24 (m, 1H), 2.00-1.96 (m, 1H), 1.83-1.74 (m, 3H), 0.89 (d, J = 6.8 Hz, 6H).

[0382] Example 19 Synthesis of compound 19

[0383] Synthesized according to the synthetic method of compound 18, using intermediate A1 instead of A15 to give compound 19 (5.34 mg, yield 6.71%). LCMS: (ESI, m / z): 517.5 [M+H] + .

[0384] 1 H NMR (400 MHz, CD3OD) δ 7.71-7.63 (m, 2H), 7.34 (d, J = 6.8 Hz, 1H), 6.82 (s, 1H), 6.49 (s, 1H), 4.84 (s, 2H), 4.47 (d, J = 16.4 Hz, 1H), 3.97 (d, J = 16.8 Hz, 1H), 2.98-2.94 (m, 4H), 2.84-2.79 (m, 1H), 2.74-2.69 (m, 1H), 2.64-2.60 (m, 1H), 2.49-2.42 (m, 3H), 1.96-1.89 (m, 1H), 1.09 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.4 Hz, 6H), 0.78-0.74 (m, 2H), 0.46-0.42 (m, 2H).

[0385] Synthesis of compound 20

[0386] Synthesized according to the synthetic method of compound 10, using intermediate 2-1 to replace 5-1, to obtain compound 20 (31.46 mg, yield 25.89%). LCMS: (ESI, m / z): 455.2 [M+H] + .

[0387] 1 H NMR (400 MHz, CD3OD) δ 6.96-6.92 (m, 2H), 4.45 (d, J = 16.0 Hz, 1H), 4.06 (d, J = 16.0 Hz, 1H), 3.48-3.36 (m, 3H), 3.19-3.16 (m, 4H), 3.13-3.11 (m, 2H), 2.97-2.88 (m, 1H), 2.59 (d, J = 7.2 Hz, 2H), 1.99-1.92 (m, 1H), 1.78-1.74 (m, 2H), 1.62-1.59 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H), 0.96 (d, J = 6.4 Hz, 6H).

[0388] Synthesis of compound 21

[0389] Synthesized according to the synthetic method of compound 9, using intermediate A8 to replace A11, to obtain compound 21 (2.48 mg, yield 7.21%). LCMS: (ESI, m / z): 434.4 [M+H] + .

[0390] 1H NMR (400 MHz, CD3OD) δ 9.10-9.09 (m, 1H), 7.96-7.93 (m, 1H), 7.75-7.72 (m, 1H), 6.37 (d, J = 10.4 Hz, 2H), 3.97 (d, J = 14.0 Hz, 1H), 3.79 (d, J = 14.0 Hz, 1H), 3.69-3.64 (m, 1H), 3.24-3.18 (m, 1H), 2.87-2.81 (m, 4H), 2.63-2.58 (m, 1H), 2.49-2.43 (m, 3H), 2.22-2.16 (m, 1H), 1.93-1.84 (m, 2H), 1.74-1.71 (m, 2H), 1.36-1.29 (m, 1H), 0.93 (d, J = 6.4 Hz, 6H).

[0391] Synthesis of compound 22

[0392] Intermediate 22-1 was synthesized according to the procedure for the preparation of Intermediate Al, and compound 22 was synthesized according to the procedure for the synthesis of compound 9, using Intermediate A16 instead of Al l, to give compound 22 (10.45 mg, yield 11.67%).

[0393] LCMS: (ESI, m / z): 510.2 [M+H] + .

[0394] 1 H NMR (400 MHz, CD3OD) δ 9.11-9.10 (m, 1H), 7.97-7.95 (m, 1H), 7.76-7.73 (m, 1H), 6.46 (s, 1H), 6.26 (s, 1H), 4.00 (d, J = 14.0 Hz, 1H), 3.92-3.90 (m, 1H), 3.82 (d, J = 14.0 Hz, 1H), 3.67 (d, J = 6.8 Hz, 1H), 3.33 (s, 1H), 3.26-3.20 (m, 1H), 3.13-3.01 (m, 2H), 2.87-2.83 (m, 1H), 2.68-2.63 (m, 1H), 2.54-2.37 (m, 5H), 2.24-2.18 (m, 1H), 1.92-1.85 (m, 2H), 1.75-1.73 (m, 2H), 0.92 (d, J = 6.4 Hz, 6H).

[0395] Synthesis of compound 23

[0396] Intermediate 23-1 was synthesized by referring to the preparation method of Intermediate A5-1, by referring to the synthesis method of compound 9, using Intermediate A16 instead of A11 to obtain compound 23 (44.55 mg, yield 49.49%).

[0397] LCMS: (ESI, m / z): 485.3 [M+H] + .

[0398] 1 H NMR (400 MHz, CD3OD) δ 9.09 - 9.70 (m, 1H), 7.83 - 7.81 (m, 1H), 7.72 - 7.69 (m, 1H), 6.66 (d, J = 8.0 Hz, 2H), 6.09 - 5.79 (m, 1H), 4.26 - 4.11 (m, 2H), 3.87 (d, J = 14.4 Hz, 1H), 3.77 (d, J = 14.0 Hz, 1H), 3.70 - 3.65 (m, 1H), 3.26 - 3.21 (m, 1H), 3.08 - 3.02 (m, 1H), 2.73 - 2.69 (m, 1H), 2.52 (d, J = 6.4 Hz, 2H), 2.38 - 2.23 (m, 2H), 2.03 - 1.88 (m, 3H), 1.67 - 1.61 (m, 2H), 0.93 (d, J = 6.8 Hz, 6H).

[0399] Synthesis of compound 24 of example 24

[0400] Intermediate 24-1 was synthesized by referring to the preparation method of Intermediate A1, by referring to the synthesis method of compound 9, using Intermediate A16 instead of A11 to obtain compound 24 (44.55 mg, yield 49.49%).

[0401] LCMS: (ESI, m / z): 510.2 [M+H] + .

[0402] 1H NMR (400 MHz, CD3OD) δ 9.10 - 9.08 (m, 1H), 7.82 - 7.80 (m, 1H), 7.73 - 7.69 (m, 1H), 6.64 (s, 1H), 6.56 (s, 1H), 3.90 - 3.77 (m, 3H), 3.28 - 3.26 (m, 1H), 3.16 - 3.12 (m, 3H), 3.05 - 2.93 (m, 2H), 2.73 - 2.68 (m, 1H), 2.48 (d, J = 7.2 Hz, 2H), 2.39 (s, 1H), 2.32 - 2.17 (m, 3H), 1.92 - 1.77 (m, 3H), 1.63 - 1.53 (m, 2H), 0.92 (d, J = 6.4 Hz, 6H).

[0403] Synthesis of compound 25

[0404] Intermediate 25-1 was synthesized according to the procedure for the preparation of Intermediate Al, synthesized according to the procedure for the synthesis of compound 9, using Intermediate Al 6 instead of Al l, to give compound 25 (31.69 mg, yield 36.20%).

[0405] LCMS: (ESI, m / z): 490.4 [M+H] + .

[0406] 1 H NMR (400 MHz, CD3OD) δ 9.09 - 9.07 (m, 1H), 7.83 - 7.80 (m, 1H), 7.72 - 7.69 (m, 1H), 6.77 (d, J = 4.4 Hz, 2H), 3.86 - 3.75 (m, 3H), 3.47 - 3.43 (m, 4H), 3.24 - 3.21 (m, 1H), 3.18 - 3.13 (m, 1H), 2.93 - 2.88 (m, 2H), 2.76 - 2.71 (m, 3H), 2.50 (d, J = 7.2 Hz, 2H), 2.34 - 2.27 (m, 2H), 1.92 - 1.83 (m, 3H), 1.64 - 1.59 (m, 2H), 0.92 (d, J = 6.8 Hz, 6H).

[0407] Synthesis of compound 26

[0408] Synthesized according to the procedure for the synthesis of compound 2, using Intermediate A8 instead of Al l, to give compound 26 (26.22 mg, yield 47.07%). LCMS: (ESI, m / z): 423.2 [M+H] + .

[0409] 1 H NMR (400 MHz, DMSO-d6) δ 9.13-9.11 (m, 1H), 7.69-7.63 (m, 2H), 6.78 (d, J = 10.4 Hz, 1H), 6.69 (s, 1H), 3.79 (d, J = 13.6 Hz, 1H), 3.66 (d, J = 14.0 Hz, 1H), 3.61-3.52 (m, 1H), 3.16-3.12 (m, 1H), 2.91-2.87 (m, 1H), 2.63-2.59 (m, 1H), 2.47 (s, 2H), 2.29-2.25 (m, 1H), 2.15-2.11 (m, 1H), 1.96-1.79 (m, 3H), 1.64-1.52 (m, 2H), 0.88 (d, J = 6.8 Hz, 6H).

[0410] Synthesis of compound 27

[0411] Intermediate 27-1 was synthesized according to the procedure for the preparation of Intermediate Al, synthesized according to the procedure for the synthesis of compound 9, using Intermediate A8 instead of Al l, to give compound 27 (14.45 mg, yield 10.96%).

[0412] LCMS: (ESI, m / z): 484.2 [M+H] + .

[0413] 1 H NMR (400 MHz, DMSO-d6) δ 9.13-9.11 (m, 1H), 7.69-7.63 (m, 2H), 6.78 (d, J = 10.4 Hz, 1H), 6.69 (s, 1H), 3.79 (d, J = 13.6 Hz, 1H), 3.66 (d, J = 14.0 Hz, 1H), 3.61-3.52 (m, 1H), 3.16-3.12 (m, 1H), 2.91-2.87 (m, 1H), 2.63-2.59 (m, 1H), 2.47 (s, 2H), 2.29-2.25 (m, 1H), 2.15-2.11 (m, 1H), 1.96-1.79 (m, 3H), 1.64-1.52 (m, 2H), 0.88 (d, J = 6.8 Hz, 6H).

[0414] Synthesis of compound 28

[0415] Intermediate 28-1 was synthesized by referring to the preparation method of Intermediate A1, by referring to the synthesis method of compound 9, using Intermediate A8 to replace A11, to give compound 28 (0.44 mg, yield 0.80%).

[0416] LCMS: (ESI, m / z): 460.3 [M+H] + .

[0417] 1 H NMR (400 MHz, Methanol-d4) δ 9.07 - 9.06 (m, 1H), 7.86 - 7.83 (m, 1H), 7.71 (d, J = 4.4 Hz, 1H), 6.66 (s, 1H), 6.29 (s, 1H), 4.59 - 4.55 (m, 1H), 3.84 (d, J = 13.6 Hz, 1H), 3.73 (d, J = 14.4 Hz, 1H), 3.67 - 3.65 (m, 1H), 3.08 - 3.02 (m, 1H), 2.72 - 2.65 (m, 1H), 2.42 (d, J = 7.6 Hz, 2H), 2.38 - 2.36 (m, 1H), 2.31 - 2.25 (m, 1H), 2.12 - 2.07 (m, 1H), 1.91 - 1.85 (m, 2H), 1.64 - 1.57 (m, 3H), 0.93 (d, J = 6.4 Hz, 6H), 0.69 - 0.66 (m, 2H), 0.36 - 0.33 (m, 2H).

[0418] Synthesis of compound 29

[0419] Intermediate 29-1 was synthesized by referring to the preparation method of Intermediate A1, by referring to the synthesis method of compound 9, using Intermediate A8 to replace A11, to give compound 29 (12.79 mg, yield 16.75%).

[0420] LCMS: (ESI, m / z): 510.3 [M+H] + .

[0421] 1H NMR (400 MHz, Methanol-d4) δ 9.11 - 9.09 (m, 1H), 7.97 - 7.94 (m, 1H), 7.76 - 7.73 (m, 1H), 6.45 (s, 1H), 6.25 (s, 1H), 3.99 (d, J = 14.0 Hz, 1H), 3.93 - 3.88 (m, 1H), 3.81 (d, J = 14.0 Hz, 1H), 3.69 - 3.64 (m, 1H), 3.37 - 3.34 (m, 1H), 3.25 - 3.20 (m, 1H), 3.08 - 3.01 (m, 2H), 2.87 - 2.81 (m, 3.5 Hz, 1H), 2.66 - 2.61 (m, 1H), 2.52 - 2.44 (m, 5H), 2.25 - 2.17 (m, 1H), 1.91 - 1.83 (m, 2H), 1.77 - 1.71 (m, 2H), 0.92 (d, J = 6.8 Hz, 6H).

[0422] Synthesis of compound 30

[0423] Intermediate 30-1 was synthesized according to the procedure for the preparation of Intermediate Al, synthesized according to the procedure for the synthesis of compound 9, using Intermediate A8 instead of Al l, to give compound 30 (12.35 mg, yield 17.33%).

[0424] LCMS: (ESI, m / z): 496.2 [M+H] + .

[0425] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 - 9.10 (m, 1H), 7.65 (d, J = 3.2 Hz, 2H), 6.52 (s, 1H), 6.24 (s, 1H), 3.76 - 3.61 (m, 7H), 3.09 - 3.05 (m, 1H), 2.98 - 2.93 (m, 1H), 2.55 (d, J = 4.4 Hz, 1H), 2.42 (d, J = 7.2 Hz, 2H), 2.12 - 2.03 (m, 2H), 1.88 - 1.66 (m, 3H), 1.47 (s, 2H), 0.89 (d, J = 6.4 Hz, 6H).

[0426] Synthesis of compound 31

[0427] Intermediate 31-1 was synthesized according to the procedure for the preparation of Intermediate Al, synthesized according to the procedure for the synthesis of compound 9, using Intermediate A8 instead of Al l, to give compound 31 (12.30 mg, yield 17.38%).

[0428] LCMS: (ESI, m / z): 467.2 [M+H] + .

[0429] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 - 9.10 (m, 1H), 7.65 (d, J = 3.2 Hz, 2H), 6.59 (s, 1H), 6.51 (s, 1H), 3.71 - 3.60 (m, 3H), 3.12 - 2.98 (m, 6H), 2.57 - 2.54 (m, 1H), 2.43 (d, J = 7.2 Hz, 2H), 2.29 - 2.22 (m, 2H), 2.11 - 2.04 (m, 2H), 1.88 - 1.85 (m, 1H), 1.70 - 1.65 (m, 2H), 1.48 - 1.41 (m, 2H), 0.90 - 0.88 (m, 6H).

[0430] Synthesis of compound 32

[0431] Intermediate 32-1 was synthesized according to the procedure for the preparation of Intermediate Al, synthesized according to the procedure for the synthesis of compound 9, using Intermediate A8 instead of Al l, to give compound 32 (25.14 mg, yield 30.58%).

[0432] LCMS: (ESI, m / z): 491.4 [M+H] + .

[0433] 1 H NMR (400 MHz, DMSO-d6) δ 9.15 - 9.08 (m, 1H), 8.16 (s, 1H), 7.67 - 7.61 (m, 2H), 6.59 (s, 1H), 6.53 (s, 1H), 5.00 - 4.92 (m, 1H), 3.81 - 3.71 (m, 2H), 3.67 - 3.62 (m, 3H), 3.55 - 3.46 (m, 2H), 3.14 - 3.07 (m, 1H), 2.93 - 2.85 (m, 1H), 2.62 - 2.54 (m, 1H), 2.46 (d, J = 7.2 Hz, 2H), 2.20 - 2.04 (m, 3H), 1.91 - 1.75 (m, 4H), 1.57 - 1.49 (m, 2H), 0.89 (d, J = 6.4 Hz, 6H).

[0434] Synthesis of compound 33

[0435] Intermediate 33-1 was synthesized by referring to the preparation method of Intermediate A1, and by referring to the synthetic method of Compound 9, using Intermediate A8 to replace A11 to obtain Compound 33 (7.23 mg, yield 5.36%).

[0436] LCMS: (ESI, m / z): 500.3 [M+H] + .

[0437] 1 H NMR (400 MHz, CD3OD) δ 9.09 - 9.08 (m, 1H), 8.44 (s, 0.58HCOOH), 7.92 (d, J = 7.2 Hz, 1H), 7.75 - 7.71 (m, 1H), 7.52 (s, 1H), 7.35 (s, 1H), 6.43 (d, J = 22.8 Hz, 2H), 3.94 (d, J = 14.0 Hz, 1H), 3.86 (s, 3H), 3.79 (d, J = 14.0 Hz, 1H), 3.72 - 3.63 (m, 1H), 3.29 - 3.24 (m, 1H), 3.22 - 3.15 (m, 1H), 2.86 - 2.72 (m, 1H), 2.58 - 2.52 (m, 1H), 2.47 - 2.38 (m, 1H), 2.35 (d, J = 7.2 Hz, 2H), 2.24 - 2.12 (m, 1H), 1.93 - 1.87 (m, 1H), 1.74 - 1.67 (m, 1H), 1.75 - 1.67 (m, 2H), 0.88 (d, J = 6.4 Hz, 6H).

[0438] Synthesis of Compound 34

[0439] First Step: Synthesis of Compound 34-1

[0440] To a solution of compound A8 hydrochloride (150 mg, 0.62 mmol, 1.0 equiv) in dimethyl sulfoxide (5 mL) was added 2-bromo-6-fluoro-4-isobutylbenzonitrile (160 mg, 0.62 mmol, 1 equiv), N,N-diisopropylethylamine (242 mg, 1.87 mmol, 3 equiv) at room temperature. The reaction mixture was heated to 120 °C and stirred for 3 hours under nitrogen protection. After the reaction was completed, the reaction mixture was added to ice water (20 mL) to quench and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography, methanol / methylene chloride (0-10%) to obtain compound 34-1 (68 mg, yield 24.78%) as a yellow solid.

[0441] LCMS:(ESI,m / z):441.9[M+2] + .

[0442] Step 2: Synthesis of compound 34-2

[0443] To a 1,4-dioxane (5 mL) solution of compound 34-1 (68 mg, 0.154 mmol, 1.0 equiv), tetrakis(triphenylphosphine)palladium (18 mg, 0.015 mmol, 0.1 equiv) and (tributyltin)methanol (100 mg, 0.309 mmol, 2 equiv) were added at room temperature. The reaction mixture was heated to 130 °C under nitrogen protection and stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography in methanol / dichloromethane (0–10%) to give compound 34-2 (32 mg, 52.93% yield) as a yellow solid.

[0444] LCMS:(ESI,m / z):392.2[M+H] + .

[0445] Step 3: Synthesis of compound 34-3

[0446] To a solution of compound 34-2 (32 mg, 0.082 mmol, 1.0 equiv) in dichloromethane (5 mL), Dys-Martin oxidant (70 mg, 0.16 mmol, 2 equiv) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was complete, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography in methanol / dichloromethane (0–10%) to give the product compound 34-3 (20 mg, yield 62.82%) as a yellow solid.

[0447] LCMS:(ESI,m / z):390.1[M+H] + .

[0448] Step 4: Synthesis of compound 34-4

[0449] To a solution of compound 34-3 (20 mg, 0.051 mmol, 1.0 equiv) in dichloromethane (5 mL), diethylaminotrifluoride (6 mg, 0.154 mmol, 3 equiv) was added at room temperature. The reaction mixture was stirred at 30 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography in methanol / dichloromethane (0–10%) to give the product compound 34-4 (17 mg, yield 80.46%) as a yellow solid.

[0450] LCMS:(ESI,m / z):412.2[M+H] + ,RT(min):1.365.

[0451] Step 5: Synthesis of Compound 34

[0452] Under nitrogen protection, sodium azide (14 mg, 0.206 mmol, 5 equiv) and tri-n-butyltin azide (67.3 mg, 0.206 mmol, 5 equiv) were added to a xylene (2 mL) solution of compound 34-4 (17 mg, 0.041 mmol, 1.0 equiv) in a microwave tube. The reaction mixture was heated to 140 °C and stirred for 3 days. After the reaction was completed, the reaction solution was filtered through a potassium fluoride solid washing filter. The solid was washed with ethyl acetate, and the filtrate was concentrated. The resulting residue was directly purified by column chromatography using methanol / dichloromethane (0-10%) to obtain a yellow crude solid. The crude product was purified by preparative high-performance liquid chromatography (HPLC) under the following conditions: (Column specifications: Pursuit XRs 10C18 10um, 21.2mm*250mm; Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile; Flow rate: 20 mL / min; Elution gradient: 29-31% B for 25 min; Detection wavelength: UV 254nm / 214nm; Retention time (min): 9.8–11.2), yielding a white solid compound 34 (4.95 mg, yield 26.36%).

[0453] LCMS:(ESI,m / z):455.2[M+H] + .

[0454] 1H NMR (400MHz, CD3OD) δ9.11(d,J=3.6Hz,1H),7.81(d,J=7.2Hz,1H),7.74–7.71(m,1H),7.27(s,1 H),7.14(s,1H),6.53(t,J=55.2Hz,1H),3.99(d,J=14.4Hz,1H),3.90(d,J=14.4Hz,1H),3.78–3 .74(m,1H),3.38–3.36(m,1H),3.12–3.07(m,1H),2.79–2.71(m,1H),2.59(d,J=7.2Hz,2H),2.5 1–2.43(m,1H),2.39–2.35(m,1H),2.02–1.88(m,3H),1.77–1.61(m,2H),0.94(d,J=6.4Hz,6H).

[0455] Biological testing evaluation

[0456] Test Example 1 uses the AT2R binding experiment to determine the affinity of the test compound for the AT2 receptor.

[0457] Experimental procedure:

[0458] 1. Reagent preparation

[0459] 1.1 Cell line: Tag-lite Angiotensin AT2 labeled Cell;

[0460] 1.2 Experimental buffer: 1X TLB (5mL 5X TLB + 20mL H2O);

[0461] 2. Assay for the activity of the test compound

[0462] 2.1 Prepare experimental buffer (1X TLB), 4X positive control compound and test compound working solution, and 4X Tag-lite angiotensin receptor red agonist;

[0463] 2.2 Freeze-thaw one vial of labeled-AT2R cells in a 37°C water bath until the ice is completely melted (1-2 min). Quickly transfer the frozen-thawed cells to 5 mL of 1X TLB from step 1, mix gently, and centrifuge at 200 g for 5 min.

[0464] 2.3 Discard the supernatant, resuspend the cells in 1 ml of 1X TLB and mix well, then add 1.7 ml of 1X TLB and mix well before using at room temperature;

[0465] 2.4 Add 10 μl of cells to a 384-well plate (Greiner, 784075), 200 g, RT, 3 s; add 5 μl of 4X compound to a 384-well plate; add 5 μl of 4X Tag-lite angiotensin receptor red agonist to all test wells;

[0466] 2.5 After the reaction plate was left to stand at room temperature (25°C) for 1 hour, it was centrifuged at 200g for 60 seconds using RT, and data were collected using an Envision HTRF detector.

[0467] 3. Data Analysis

[0468] 3.1% inhibition calculation:

[0469] %inhibition=100-(Signalcmpd-SignalAve_PC) / (SignalAve_VC-SignalAve_PC)×100.

[0470] 3.2 Calculation of compound IC using GraphPad nonlinear fitting formula 50 :

[0471] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0472] X: Log value of compound concentration; Y: % inhibition.

[0473] 4. Experimental Results

[0474] Table 1

[0475] Experimental results show that the compound of this invention has a good binding effect on AT2R.

[0476] Test Example 2 uses the AT1R binding experiment to determine the affinity of the test compound for the AT1 receptor.

[0477] Experimental procedure:

[0478] 1. Reagent Preparation

[0479] 1) Cell line: Tag-lite Angiotensin AT1 labeled Cell;

[0480] 2) Experimental buffer: 1X TLB (5mL 5X TLB + 20mL H2O);

[0481] 2. Determination of the inhibitory activity of the test compound

[0482] 1) Prepare experimental buffer 1X TLB, 4X positive control compound and test compound working solution, 4X Tag-lite angiotensin receptor red agonist;

[0483] 2) Freeze-thaw one vial of labeled-AT1R cells in a 37°C water bath until the ice is completely melted (1-2 min). Quickly transfer the frozen-thawed cells to 5 mL of 1X TLB from step 1, mix gently, and centrifuge at 200 g for 5 min.

[0484] 3) Discard the supernatant, resuspend the cells in 1 ml of 1X TLB and mix well, then add 1.7 ml of 1X TLB and mix well before using at room temperature;

[0485] 4) Add 10 μl of cells to a 384-well plate (Greiner, 784075), 200 g, RT, 3 s; add 5 μl of 4X compound to a 384-well plate; add 5 μl of 4X Tag-lite angiotensin receptor red agonist to all test wells;

[0486] 5) After the reaction plate was left to stand at room temperature (25°C) for 1 hour, it was centrifuged at 200g for 60 seconds using RT, and data were collected using an Envision HTRF detector.

[0487] 3. Data Analysis

[0488] 1)Z'factor=1-3*(SDMax+SDMin) / (MeanMax-MeanMin);

[0489] 2)CVMax=(SDMax / MeanMax)*100%;

[0490] 3)CVMin=(SDMin / MeanMin)*100%;

[0491] 4) S / B = Single / Background;

[0492] 5) Calculation Equation for EC 50 / IC 50 Value:

[0493] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50-X)*HillSlope))

[0494] 4. Experimental Results

[0495] Table 2

[0496] Experimental results show that the compound of this invention does not have a good binding effect on AT1R.

[0497] Test Example 3 investigated the pharmacokinetic behavior of the compound of the present invention in mice.

[0498] Experimental reagents: The compounds of this invention, prepared in-house.

[0499] Experimental plan:

[0500] Three healthy male ICR mice (SPF grade, source: Beijing Vital River Laboratory Animal Technology Co., Ltd.), weighing 18-25g, were administered the compound at a dose of 1mg / kg via intravenous injection at a volume of 5ml / kg. The compound was prepared using 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0501] Three healthy male ICR mice (SPF grade, source: Beijing Vital River Laboratory Animal Technology Co., Ltd.), weighing 18-25g, were administered the compound at a dose of 5mg / kg by gavage at a volume of 10ml / kg. The compound was prepared using 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0502] Blood samples were collected via buccal sampling at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after intravenous administration and at the same time after gavage administration. Approximately 0.05 mL of blood was collected per sample. Heparin sodium was used for anticoagulation. Blood samples were placed on ice and centrifuged within one hour to separate the plasma (centrifugation conditions: 6000 g, 3 min, 2-8 °C). The concentration of compounds in the plasma was determined by liquid chromatography-tandem mass spectrometry. Plasma samples were stored at -80 °C before analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 based on the blood drug concentration data at different time points.

[0503] Experimental results show that the compound of the present invention has low clearance rate, high plasma exposure, and good oral bioavailability in rodent ICR mice, and has good pharmacokinetic properties.

[0504] Test Example 4 investigated the pharmacokinetic behavior of the compound of the present invention in rats.

[0505] Experimental reagents: The compounds of this invention, prepared in-house.

[0506] Experimental plan:

[0507] Three healthy male SD rats (SPF grade, source: Beijing Vital River Laboratory Animal Technology Co., Ltd.), weighing 180-250g, were administered the compound at a dose of 1mg / kg via intravenous injection at a volume of 2ml / kg. The compound was prepared using 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0508] Three healthy male SD rats (SPF grade, source: Beijing Vital River Laboratory Animal Technology Co., Ltd.), weighing 180-250g, were administered the compound at a dose of 5mg / kg by gavage at a volume of 10ml / kg. The compound was prepared using 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0509] Blood samples were collected intravenously at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after intravenous administration and at the same time after gavage administration. Approximately 0.25 mL of blood was collected per sample. Heparin sodium was used for anticoagulation. Blood samples were placed on ice after collection and centrifuged within one hour to separate the plasma (centrifugation conditions: 6000 g, 3 min, 2-8℃). The concentration of compounds in the plasma was determined by liquid chromatography-tandem mass spectrometry. Plasma samples were stored at -80℃ before analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 based on the blood drug concentration data at different time points. The experimental results are as follows:

[0510] Table 3

[0511] Reference compound A0: It was prepared according to WO2023006893A1.

[0512] Experimental results show that the compound of this invention has high plasma exposure in rodent SD rats and exhibits good pharmacokinetic properties.

[0513] Test Example 5 investigated the analgesic effect of the compound of the present invention in inhibiting pain in a mouse model of selective nerve injury.

[0514] 1. Experimental reagents

[0515] Compound 21 and control compound A0.

[0516] A solution of 5% DMSO + 10% Solutol + 85% Saline was used.

[0517] 2. Experimental methods and materials

[0518] 2.1 Laboratory animals and their housing conditions

[0519] Laboratory animals: C57BL / 6 mice, weighing 18-22 grams, male, purchased from Beijing Vital River Laboratory Animal Co., Ltd.

[0520] Rearing conditions: 4 animals per cage, 12 / 12-hour light / dark cycle, temperature 22-25℃, humidity 40-70%, free access to food and water.

[0521] 2.2 Experimental Methods:

[0522] 1.1 Adaptation

[0523] After the experimental animals arrive, they are acclimatized for 3-7 days.

[0524] 1.2 Model Establishment

[0525] (1) Aseptic procedures are performed during the surgical procedure.

[0526] (2) Surgical instruments (scissors, forceps, scalpel, surgical cotton and sutures) were sterilized before the operation.

[0527] (3) Anesthetize the animal with 50mg / kg of Shutai 50 + 8mg / kg of xylazine hydrochloride injection (intraperitoneal injection, 2.5mL / kg), squeeze the animal's toes to confirm that the animal has been completely anesthetized before the operation; apply ophthalmic ointment to the animal's eyes to prevent the animal's cornea from drying out.

[0528] (4) Shave the hair in the surgical area of ​​the animal and disinfect the skin three times with iodine and 70% ethanol; start the surgery after the skin is dry.

[0529] (5) Expose the sciatic nerve and its three distal branches: the tibial nerve, the common peroneal nerve, and the sural nerve. Cut the tibial nerve and the common peroneal nerve with ophthalmic shears, while preserving the sural nerve.

[0530] (6) Suture the wound.

[0531] (7) Clean surgical instruments and sterilize them using a heat bead sterilizer.

[0532] (8) After surgery, place the animal on an electric blanket and inject 1 mL of physiological saline subcutaneously to prevent dehydration. Once the animal has fully recovered (and can move freely), return it to its cage.

[0533] 1.3 Grouping

[0534] On days 4-6 after modeling, the animals were placed in the experimental environment to acclimatize for 30 minutes per day for 3 consecutive days. On day 7 after modeling, the baseline values ​​of mechanorepain hypersensitivity were measured in the animals. Animals that did not show mechanorepain hypersensitivity (withdrawal threshold greater than 0.6g) were removed, and 72 animals that successfully developed the model (withdrawal threshold less than 0.6g) were selected and divided into 9 groups of 8 animals each.

[0535] Table 4

[0536] 1.4 Administration

[0537] Mice in each group were given the corresponding drug via intraperitoneal or oral administration at a dose of 10 mL / kg, according to the experimental protocol.

[0538] 1.5 Mechanical Hypersensitivity Test

[0539] ● On day 8 after modeling, mechanical hypersensitivity tests were performed on the left hind foot of mice at 1, 2 and 4 hours after drug administration.

[0540] ● Place the mice individually in an acrylic box with a mesh bottom to ensure the mice's feet can be tested. The mice will be allowed 15 minutes to acclimatize before the test.

[0541] ● After adaptation, test the mouse's left hind paw using the test fiber. The test fiber includes eight test intensities: 2.36 (0.02g), 2.44 (0.04g), 2.83 (0.07g), 3.22 (0.16g), 3.61 (0.4g), 3.84 (0.6g), 4.08 (1g), and 4.17 (1.4g). During testing, press the test fiber vertically against the skin and apply force to bend the fiber for 6-8 seconds, with a 5-second interval between each test. A rapid withdrawal of the paw during the test is recorded as a pain response. Withdrawal of the paw when the test fiber leaves the skin is also recorded as a pain response. If the animal moves or walks without recording a pain response, the test should be repeated.

[0542] ● The test initially uses 3.22 (0.16g). If the animal shows a pain response, the next test uses a test fiber with a lower strength; if the animal does not show a pain response, the next test uses a test fiber with a higher strength (Chaplan et al. 1994). The maximum strength of the test fiber is 4.17 (1.4g).

[0543] The test results are recorded in the table below, with x indicating a pain response and o indicating no pain response.

[0544] Table 5

[0545] ● Mechanosensitive hypersensitivity is expressed as the withdrawal threshold (PWT) in mouse behavioral tests, and is calculated using the following formula:

[0546] 50% reaction threshold (g) = (10 (Xf+kδ) ) / 10,000

[0547] Xf = Final test fiber value used in the test

[0548] k = table value (Chaplan et al. 1994, page 62)

[0549] δ = mean difference

[0550] 1.6 Key Instruments

[0551] Table 6

[0552] 1.7 Timeline

[0553] See Figure 1

[0554] 1.8 Experimental Test Indicators

[0555] Table 7

[0556] 2.3 Data Statistics

[0557] Data was collected using Excel software.

[0558] Data were analyzed using one-way or two-way ANOVA with Dunnett's multiple comparison test in Prism (Graph pad software, Inc.) software. The area under the analgesic efficacy curve (AUC) was calculated using Prism (Graph pad software, Inc.) software. First, select the XY type, enter the data, click analyze, and then select Area under curve (AUC) in XY analyses.

[0559] 3. Results

[0560] In a mouse model of selective nerve injury, the area under the curve (AUC) of each compound was calculated to show its analgesic effect in inhibiting pain in mice at 1, 2, and 4 hours after administration. 0-4h The higher the AUC value, the better the analgesic effect.

[0561] Table 8

[0562] Note: P-value (compared to the solvent control group), ***: P<0.001; **: P<0.01; ns: no statistically significant difference.

[0563] 4. Conclusion

[0564] The compounds of this invention exhibit good analgesic effects in a mouse model of selective nerve injury, inhibiting pain in mice.

[0565] Test Example 6 investigated the analgesic effect of the compound of the present invention in inhibiting pain in a rat model of chronic compression injury of the sciatic nerve.

[0566] 1. Experimental reagents

[0567] Compound 1 and control compound A0.

[0568] A solution of 5% DMSO + 10% Solutol + 85% Saline was used.

[0569] 2. Experimental Materials and Methods

[0570] 2.1 Experimental Materials

[0571] 2.1.1 Laboratory animals and their housing conditions

[0572] Laboratory animals: Sprague-Dawley rats, weighing 80-100 grams, male, purchased from Beijing Vital River Laboratory Animal Co., Ltd. Householding conditions: 4 rats / cage, 12 / 12-hour light / dark cycle, temperature 22-25℃, humidity 40-70%, free access to food and water.

[0573] 2.1.2 Key Experimental Equipment

[0574] Table 9

[0575] 2.2 Experimental Methods:

[0576] 2.2.1 Adaptation

[0577] After the experimental animals arrive, they are acclimatized for 3-7 days.

[0578] 2.2.2 Model Establishment

[0579] 1) Aseptic procedures are performed during the surgical process.

[0580] 2) Surgical instruments (scissors, forceps, scalpel, surgical cotton, sutures) were sterilized before the operation.

[0581] 3) Anesthetize the animal using Sutacetin 50 + Xylazine Hydrochloride Injection (20 mg / kg + 8 mg / kg, intraperitoneal injection). Squeeze the animal's toes to confirm that it is fully anesthetized before surgery. Apply ophthalmic ointment to the animal's eyes to prevent corneal dryness.

[0582] 4) Disinfect the surgical area on the sole of the left hind foot three times with povidone-iodine and 70% ethanol. Begin the surgery after the skin has dried.

[0583] 5) Separate the left sciatic nerve and loosely ligate it four times with 4-0 chromic catgut about 7 mm upstream of the bifurcation of the sciatic nerve, with a spacing of about 1 mm.

[0584] 6) Suture the wound.

[0585] 7) Clean surgical instruments and sterilize them using a heat bead sterilizer.

[0586] 8) After surgery, place the animal on an electric blanket and inject 5 mL of physiological saline subcutaneously to prevent dehydration. Once the animal has fully recovered (and can move freely), return it to its cage.

[0587] 2.2.3 Base value test grouping:

[0588] 1) Place the animal in the test environment for at least 30 minutes each day from the 7th to the 9th day after surgery to allow it to acclimatize.

[0589] 2) On the 10th day after surgery, all animals were tested for basic mechanical pain value (PWT). Animals that did not show mechanical pain hypersensitivity (PWT greater than 5g) were removed, and 24 animals were randomly divided into 3 groups of 8 animals each.

[0590] Table 10

[0591] 2.2.4 Weighing before administration

[0592] On the 11th day after surgery, all animals in all groups were weighed and administered medication according to their grouping information.

[0593] 2.2.5 Efficacy Test

[0594] Mechanical pain tests were performed on the animals using test fibers 1 hour and 2 hours after a single dose.

[0595] 2.2.6 Mechanical pain perception testing method:

[0596] 1) Place the rats individually in an acrylic box with a mesh bottom to ensure that the rats' feet can be tested. Allow the rats acclimatization period of 15 minutes before testing.

[0597] 2) After adaptation, test the rats' left hind paws at the center of the sole using test fibers. The test fibers included eight test intensities: 3.61 (0.4g), 3.84 (0.6g), 4.08 (1g), 4.31 (2g), 4.56 (4g), 4.74 (6g), 4.93 (8g), and 5.18 (15g). During testing, the test fiber was pressed vertically against the skin, applying force to bend the fiber for 6-8 seconds, with a 5-second interval between each test. A rapid withdrawal of the paw during the test was recorded as a pain response. Withdrawal of the paw when the test fiber left the skin was also recorded as a pain response. If the animal moved or walked without a pain response, the test should be repeated.

[0598] 3) When testing, first use 4.31 (2g). If the animal shows a pain response, use a test fiber with a lower strength for the next test; if the animal does not show a pain response, use a test fiber with a higher strength for the next test. The maximum strength of the test fiber is 5.18 (15g).

[0599] 4) The test results are recorded in the table below. Records with pain response are x, and records without pain response are o.

[0600] Table 11

[0601] Mechanical hypersensitivity to pain is expressed as the withdrawal threshold (PWT) in rat behavioral tests, and is calculated using the following formula:

[0602] 50% reaction threshold (g) = (10 (Xf+k) ) / 10,000

[0603] Xf = Final test fiber value used in the test

[0604] k = table value (Chaplan et al. 1994, page 62)

[0605] δ = mean difference (0.224)

[0606] 2.2.7 Timeline

[0607] See Figure 2

[0608] 2.2.8 Experimental test indicators:

[0609] Table 12

[0610] 2.2.9 Data Collection and Analysis:

[0611] Data was collected using Excel software.

[0612] The data was analyzed using Prism (Graph pad software, Inc.) software.

[0613] 3. Experimental Results

[0614] Table 13 Note: P-value (compared to the solvent control group), ***: P<0.001; **: P<0.01.

[0615] 4. Conclusion

[0616] The compound of this invention has a good analgesic effect in inhibiting pain in a rat model of chronic compression injury of the sciatic nerve.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein, Ring A is a 5-10 membered heteroaryl or a partially saturated 5-12 membered heterocyclyl; x2 is 0, 1, 2, 3, 4, 5 or 6; R 6 independently D, halogen, cyano, OH, oxo, C 1-6 alkyl, -O-C 1-6 alkyl, -C(O)OR 62 , -C 1-6 alkylene-C 3- 6cycloalkyl or -C 1-6 alkylene-3-6 membered heterocycloalkyl; said alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 61 ; R 61 independently D, halogen, OH, oxo, -O-C 1-6 alkyl, C 1-6 alkyl or C 1-6 haloalkyl substituted; R 62 is C 1-6 alkyl; L 1 -CH2-; R l1a R l1b -; R l1a and R l1b are independently H, D, halogen, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; or, R l1a and R l1b together form =0; M 2 is N or CR b1 ; M 1 is N or CR b2 ; R b1 and R b2 independently H, D, or C 1-6 alkyl; x3 is 0, 1, 2, 3, 4, 5, 6, 7 or 8; R 5 independently D, halogen, cyano, oxo, C 1-6 alkyl or C 3-6 cycloalkyl; or 2 R 5 by the linked groups together form a ring B, ring B is 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; said cycloalkyl and heterocycloalkyl are optionally substituted with one or more R a1 substituents; R a1 independently D, halogen, cyano, oxo, or C 1-6 alkyl; R 4 H, D, halogen, cyano, C 1-6 alkyl or C 3-6 cycloalkyl; or R 4 with 1 R 5 by the linked groups together form a ring C, ring C is a partially saturated 5-7 membered heterocyclyl; said heterocyclyl is optionally substituted by one or more R a2 substituents; R a2 independently D, halogen, cyano, oxo, or C 1-6 alkyl; R 3 is H, halogen, cyano, -L 3 -C 1-6 alkyl, -L 3 -C 2-6 alkenyl, -L 3 -C 3-6 cycloalkyl or -L 3 -3-6 membered heterocycloalkyl; said alkyl, alkenyl, cycloalkyl and heterocycloalkyl groups are optionally substituted by one or more R c1 groups; L 3 independently a bond, -O-, -NR l2 -, -O-CH2- or C 1-3 alkylene; R l2 is independently H or C 1-6 alkyl; said -CH2- and C 1-3 alkylene are optionally substituted with one or more R c2 ; R 2 H, D, halogen or C 1-6 alkyl; R 1 halo, -OH, cyano, C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; said alkyl, cycloalkyl and heterocycloalkyl groups are optionally substituted by one or more R c substituents; R c , R c1 , and R c2 are independently halogen or OH; x1 is 0, 1, 2, 3 or 4; L is a bond, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl; said heterocycloalkyl and heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; L 2 is a bond, -O-, -NR l2a -, -C(R l2b R l2b ) y1 -, -CONR l2a -, -NR l2a CO- or -NR l2a -C(R l2b R l2b ) y1 -; R l2a independently H or C 1-6 alkyl; R l2b independently H, D, halogen, or C 1-6 alkyl; y1 is 1, 2, 3 or 4; or R 2 with L 2 -L together with the group to which it is attached forms a ring D, ring D is partially saturated C 3-6 cycloalkyl, partially saturated 5-7 membered heterocyclyl or 5-6 membered heteroaryl; said cycloalkyl, heterocyclyl and heteroaryl are optionally substituted with one or more R a3 substituents; R a3 independently D, halogen, cyano, oxo, or C 1-6 alkyl; The above-mentioned heteroaryl, heterocycloalkyl and heterocyclyl independently have 1, 2, 3 or 4 heteroatoms independently selected from N, O and S.

2. The compound as shown in formula (I) or pharmaceutically acceptable salt thereof according to claim 1, wherein, It satisfies at least one of the following conditions: (1) The halogen or halo is F, Cl or Br; preferably F; (2) the C 1-6 alkyl and -O-C 1-6 C in alkyl 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl or t-butyl, preferably methyl or ethyl; (3) the C 1-6 alkylene, C 1-3 alkylene is independently -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -C(CH3)2-, preferably -CH2- or -CH2CH2-; (4) the C 3-6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (5) the partially saturated C 3-6 Cycloalkenyl is cyclopentenyl, cyclohexenyl or cyclohexadienyl. (6) said 3-6 membered heterocycloalkyl is independently azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl or piperazinyl; preferably (7) the partially saturated 5-12 membered heterocyclyl is independently a partially saturated 5, 6, 7, 9, or 11 membered heterocyclyl; preferably N-hexa- fulyl, O-hexa-furyl, (8) 5-10 membered heteroaryl is independently 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl; preferably pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, (9) When substituted, the number of substitutions is 1, 2 or 3; (10) Ring A is a 5-membered and 6-membered heteroaryl-, a partially saturated 6-membered heterocyclyl, a partially saturated 7-membered spirocyclic heterocyclyl, a partially saturated 5-membered and 6-membered heterocyclyl, or a partially saturated 7-membered spirocyclic heterocyclyl and 6-membered heterocyclyl; (11) 2 R 5 by the linked groups together form a ring B; (12) R 4 with 1 R 5 by the linked groups together form a ring C; (13) R 2 with L 2 -L together with the group to which it is attached forms a ring D; (14) when L 2 when L is a bond, x1 is 1.

3. The compound as shown in formula (I) or pharmaceutically acceptable salt thereof according to claim 1, wherein, It satisfies at least one of the following conditions: (1) in ring A, the 5-10 membered heteroaryl is a 5-membered and 6-membered heteroaryl- or a 6-membered and 5-membered heteroaryl-, preferably wherein ring A 1 is a 5-membered heteroaryl; X 11 , X 12 , X 13 and X 14 are independently C, CH, N or NH; X 15 is O, C, CH, N or NH, preferably O, N or NH; and X 11 , X 12 , X 13 , X 14 and X 15 at least one of X is a single bond or a double bond; preferably (2) in ring A, the partially saturated 5-12 membered heterocyclyl is a partially saturated 5-membered and 6-membered heterocyclyl, preferably wherein ring A 2 is a partially saturated 5-membered heterocyclyl group; X 21 , X 22 , X 23 and X 24 are independently CH, CH2, N or NH, and at least one is N or NH, and still more preferably X 24 is independently C, CH or CH2; and still more preferably (3) in ring A, the partially saturated 5-12 membered heterocyclyl is a partially saturated 7 membered spirocyclyl and 6 membered heterocyclyl, preferably wherein ring A 2 is a partially saturated 5-membered heterocyclyl group; X 21 , X 22 and X 23 are independently CH, CH2, N or NH, and at least one is N or NH; preferably (4) in ring A, the partially saturated 5-12 membered heterocyclyl is a partially saturated 6 membered heterocyclyl, preferably 31 , X 32 and X 33 are independently C, CH, N or NH, and at least one is N or NH; preferably (5) in ring A, the partially saturated 5-12 membered heterocyclyl is a partially saturated 7 membered spirocyclyl heterocyclyl, preferably (6) x2 is 0, 1, 2 or 3; (7) R 6 independently oxo, C 1-6 alkyl, -C(O)OR 62 or -C 1-6 alkylene-3-6 membered heterocycloalkyl; said alkyl and heterocycloalkyl groups being optionally substituted with one or more R 61 preferably methyl, =O, (8) R 61 and R 62 are independently OH or methyl; (9) R l1a and R l1b are independently H; (10) L 1 is -CH2-, -CHF-, -CF2-, -CHCH3-, -CO-, or -C(cyclopropyl)-; again preferably -CH2-; (11) M 1 is N; (12) M 2 is N; (13) x3 is 0, 1, 2 or 3; (14) R 5 H or C 1-6 alkyl; preferably H or methyl; (15) in ring B, the C 3-6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl; said cycloalkyl is optionally substituted with one or more R a1 substituents; (17) in ring B, said 3-6 membered heterocycloalkyl is a 5 membered heterocycloalkyl, preferably tetrahydrofuranyl, tetrahydrothiophenyl or pyrrolidinyl; preferably The heterocycloalkyl group is optionally substituted by one or more R a1 substituents; (18) R a1 independently C 1-6 alkyl; preferably methyl; (19) For (20) R 4 is H; (21) in ring C, said partially saturated 5-7 membered heterocyclyl is a partially saturated 6-7 membered heterocyclyl; said heterocyclyl is optionally substituted with one or more R a2 substituted; preferably a side is connected to the benzene ring shown; (22) R 3 halogen, -L 3 -C 3-6 cycloalkyl or -L 3 -C 1-6 alkyl, said C 1-6 alkyl and C 3-6 cycloalkyl are optionally substituted by one or more R c1 substituents L 3 is C 1-3 alkylene; said alkylene is optionally substituted by one or more R c2 substituents; preferably R 3 is C 1-6 alkyl, cyclopropyl-CH2-, cyclobutyl-CH2-, said C 1-6 alkyl, cyclopropyl, cyclobutyl and -CH2- are optionally substituted by one, two or three F; still preferably isobutyl, (23) R 2 is H; (24) R 1 halogen, OH, C 1-6 alkyl, -O-C 1-6 alkyl or C 3-6 cycloalkyl; said alkyl and cycloalkyl groups being optionally substituted by one or more R c preferably F, methyl, CHF2, CF3, ethyl, -CH2CHF2, isopropyl, cyclopropyl, -O-methyl or OH; (25)R c , R c1 and R c2 are independently halogen; preferably F; (26) L is a bond, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; preferably a bond, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, (27) R l2a independently H; (28) R l2b independently H or halogen; preferably H or F; (29) L 2 is a bond, -O-, -NR l2a -, -C(R l2b R l2b ) y1 -, -CONR l2a -, -NR l2a CO- or -NR l2a -C(R l2b R l2b ) y1 ; preferably a bond, -O-, -NH-, -CH2-, -CF2-, -CONH-, -NHCO- or -NHCH2-; (30) R a3 independently C 1-6 alkyl; preferably methyl; (31) Ring D is partially saturated C 5-6 cycloalkyl, partially saturated 5-7 membered heterocyclyl, or 5-6 membered heteroaryl; said cycloalkyl, heterocycloalkyl, and heteroaryl are optionally substituted with one or more R a3 substituents; preferably b side is connected to the benzene ring shown; (32) Formula I at least satisfies one of the following conditions: (i) ring A is 5-membered and 6-membered heteroaryl-, a partially saturated 6-membered heterocyclyl, a partially saturated 7-membered spirocyclic heterocyclyl, a partially saturated 5-membered and 6-membered heterocyclyl, or a partially saturated 7-membered spirocyclic heterocyclyl and 6-membered heterocyclyl; (ii) 2 R 5 by the linked groups together form a ring B; (iii) R 4 with 1 R 5 by the linked groups together form a ring C; (iv) R 2 with L 2 -L together with the group to which it is attached forms a ring D; (v) x2 is 1, 2, 3, 4, 5 or 6; R 6 at least one of said alkyl, alkylene, cycloalkyl and heterocycloalkyl groups is substituted with -OH.

4. The compound as shown in formula (I) or pharmaceutically acceptable salt thereof according to claim 1, wherein, It satisfies at least one of the following conditions: (1) For (2) F, Br, cyclopropyl, -CHF2, -O-CH3, (3) For preferably 5. The compound as shown in formula (I) or pharmaceutically acceptable salt thereof according to claim 1, wherein, The compound as shown in formula (I) is a compound as shown in formula (I-1), formula (I-1.1), formula (I-2), formula (I-3), formula (I-4), formula (I-4.1), formula (I-4.1a) or formula (I-4.1b): wherein, Z is a bond or NH or NHMe or O or S, m = 0, 1, 2 or 3, n = 0, 1, 2 or 3; y is 0, 1, 2 or 3; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, L 1 , L 2 , M 1 , M 2 , A, B, C, ring D, x1, x2, or x3 are as defined in claim 1.

6. The compound as shown in formula (I) or pharmaceutically acceptable salt thereof according to claim 1, wherein, The compound as shown in the formula (I) is 7. A compound of Formula II, ###0002### Formula II wherein: M 1 , M 2 , L, L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , x1, x2 and x3 are as defined in any one of claims 1-6; Preferably, the compound of formula (II) is any one of the following structures:

8. A pharmaceutical composition comprising: (1) a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, and (2) a pharmaceutically acceptable excipient.

9. Use of a substance in the preparation of a medicament for the prevention and / or treatment of a disease, disorder or condition; The substance is a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, or a pharmaceutical composition according to claim 8; Preferably, the disease, disorder or condition is an AT2R-mediated related disease, disorder or condition; Alternatively, the disease, disorder or condition is pain; More preferably, the AT2R-mediated related disease, disorder or condition is pain.

10. Use of a substance in the preparation of an AT2R antagonist; The substance is a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6.

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