Aminopyrimidine derivative as well as preparation method and application thereof

Abstract

The invention relates to an aminopyrimidine derivative as well as a preparation method and application thereof. The aminopyrimidine derivative can be used for inhibiting LRRK2 kinase or treating Parkinson's disease (PD).

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to aminopyrimidine derivatives, their preparation methods, and applications. Background Technology

[0002] Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized primarily by the progressive degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies. Clinical manifestations include motor symptoms such as tremor, rigidity, bradykinesia, and postural instability, as well as non-motor symptoms such as sleep disturbances, olfactory disturbances, autonomic dysfunction, and cognitive and psychiatric impairments. As the disease progresses, both motor and non-motor symptoms of Parkinson's disease gradually worsen, impairing patients' daily activities and imposing a significant social and medical burden.

[0003] Leucine-Rich Repeat Kinase 2 (LRRK2) is a large, multi-domain protein containing serine and threonine kinase activities. Encoded by the PARK8 gene, LRRK2 is a large protein with multiple enzymatic activities, including a ROC (Ras of complex protein, belonging to the small G protein family) with GTPase activity and a kinase domain with kinase activity, as well as COR (C-terminal of ROC), WD40, and other domains related to protein-protein interactions.

[0004] Studies have found that LRRK2 kinase inhibitors can protect neurons from neurodegeneration induced by LRRK2 overactivation, block the accumulation of increased α-synuclein in neurons, inhibit inclusion body formation, and slow the progression of Parkinson's disease. Therefore, LRRK2 is considered a very promising target for the treatment of Parkinson's disease. Summary of the Invention

[0005] The aminopyrimidine derivatives of this invention may be compounds of formula I or II, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formulas of formula I or II are as follows:

[0006]

[0007] in,

[0008] Ring A is selected from cycloalkyl, heterocyclic, aryl, or heteroaryl groups, and optionally may be further substituted by one or more substituents;

[0009] Ar1 is selected from aryl or heteroaryl, and optionally it may be further substituted by one or more substituents;

[0010] X1 is selected from N, CR1, or C;

[0011] R1 is absent or selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents.

[0012] R, R2, R3, R4, and R5 are each independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally may be further substituted by one or more substituents.

[0013] Optionally, R1 in Formula I can be linked to a substituent on Ar1 to form a ring, or R3 in Formula II can be linked to a substituent on Ar1 to form a ring;

[0014] In some implementations... Selected from:

[0015] in,

[0016] R1 and R2 are defined as described above;

[0017] R6, R7, R8, R9, R 10 R 11 R 12 Each group is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents;

[0018] Optional, R9, R 11 And the carbon atoms it is connected to can collectively represent a carbonyl group (-CO-);

[0019] In some implementations, Ar1 is selected from

[0020] in,

[0021] R 13 R 14 R 15 R 17 R 18 R 19 R 20 R 21 R 22 R23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 "R" is independently selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally may be further substituted by one or more substituents;

[0022] Optionally, R1 can be connected with R 13 R 14 R 15 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 Or any of the substituents in "R" can be linked to form a ring;

[0023] Optionally, R3 can be connected with R 13 R 14 R 15 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 Or any of the substituents in "R" can be linked to form a ring;

[0024] When R1 is linked to a substituent on Ar1 to form a ring, or when R3 is linked to a substituent on Ar1 to form a ring, or when R1 is linked to R... 13 R 14 R 15 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 Either R or R can be connected to form a loop, or R3 and R... 13 R 14 R 15 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 When any one of "or R" is connected to form a ring, the resulting linker can be:

[0025] -L1-L2-L3-

[0026] in,

[0027] L1, L2, and L3 are independently selected from bond, -O-, -C(O)-, and -[C(R')2], respectively. n -、-[OC(R')2] n -、-[C(R')2O] n -, -OC(O)-, -C(O)O-, -NR'-, -C(O)NR'-, -NR'C(O)-,

[0028] R' is selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally may be further substituted by one or more substituents;

[0029] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0030] The linker formed above is used to link ring A or pyrimidine ring with Ar1;

[0031] In some specific embodiments, the hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl group may be further substituted with one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl group;

[0032] In some specific embodiments, the hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl are preferably hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0033] The hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl may be further selected from hydrogen, halogen The group may be substituted with one or more of the following groups: nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0034] In some specific embodiments, the compound of formula I may be selected from the compounds shown in formula I-1 or formula I-2:

[0035]

[0036] in,

[0037] R, R2, R6, R7, R8, R 14 R 15 The definitions of L1, L2, and L3 are as described above;

[0038] In some specific embodiments, L1 is selected from -O-, -OC(O)-, -C(O)O-, -NR'-, -C(O)NR'- or -NR'C(O-), preferably -O- or -NR'-;

[0039] In some specific implementations, L2 is selected from -[C(R')2] n -、-[OC(R')2] n -or-[C(R')2O] n -, preferably -[C(R')2]2-, -[OC(R')2]2-, -[C(R')2O]2-, -[C(R')2]3-, -[OC(R')2]3- or -[C(R')2O]3-, more preferably -CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-CH2- or -CH(CH3)-CH2-CH2-; wherein the carbon in the linker can be in the R or S configuration;

[0040] n is defined as described above;

[0041] In some specific embodiments, L3 is selected from -O-, -OC(O)-, -C(O)O-, -NR'-, -C(O)NR'- or -NR'C(O-), preferably -O- or -NR'-;

[0042] The definition of R' is as described above;

[0043] In some specific implementations, R 15 It is selected from alkyl, haloalkyl, hydroxyalkyl or heterocyclic groups, and optionally may be further substituted by one or more substituents;

[0044] In some specific implementations, R 15The substituent is selected from C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, or 3-10 heterocyclic groups, and optionally may be further substituted by one or more substituents; preferably, the substituent is selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 cycloalkyl, 3-10 heterocyclic, 6-10 aryl, or 5-10 heteroaryl.

[0045] In some specific implementations, R 15 Selected from

[0046] in,

[0047] R 1 The substituents are independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl, and optionally may be further substituted by one or more substituents; preferably, the substituents are selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0048] In some specific embodiments, the hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl are preferably hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl;

[0049] In some specific embodiments, the hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl may be further... It is substituted by one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl, or 5-10 membered heteroaryl.

[0050] In some specific implementations, R 15 Selected from

[0051] In some specific embodiments, R7 is selected from halogens, preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine;

[0052] In some specific implementations, R 14 Selected from halogens, C1-10 alkyl groups, or 3-10 membered cycloalkyl groups, optionally further substituted by one or more substituents; R 14 Preferably methyl, cyclopropyl, or chlorinated;

[0053] In some specific embodiments, the compound of formula I may be selected from the compounds shown in formula I-3, formula I-4 or formula I-5:

[0054]

[0055] in,

[0056] R, R2, R6, R7, R8, R9, R 10 R 19 R 20 R 21 R 23 The definitions of L1, L2, and L3 are as described above;

[0057] In some specific implementations, L1 is selected from key, -O-, or -[C(R')2]. n -, preferably bond, -O- or -C(R')2-, more preferably bond, -O- or -CH2-;

[0058] In some specific implementations, L2 is selected from -[C(R')2]n -、-[OC(R')2] n -or-[C(R')2O] n -, preferably -[C(R')2]2-, -[OC(R')2]2-, -[C(R')2O]2-, -[C(R')2]3-, -[OC(R')2]3- or -[C(R')2O]3-, more preferably -CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-CH2- or -CH(CH3)-CH2-CH2-; wherein the carbon in the linker can be in the R or S configuration;

[0059] n is defined as described above;

[0060] In some specific embodiments, L3 is selected from -C(O)NR'- or -NR'C(O)-, preferably -C(O)NCH3- or -NCH3C(O)-;

[0061] R' is defined as described above;

[0062] In some specific implementations, R7, R 10 Each is independently selected from halogens, preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine;

[0063] In some specific implementations, R 19 Selected from C1-10 alkoxy groups, optionally further substituted by one or more substituents; R 19 Preferably, it is methoxy or ethoxy;

[0064] In some specific embodiments, the compound of formula I may be selected from the compounds shown in formula I-6, formula I-6', formula I-7, formula I-7', formula I-8, or formula I-9:

[0065]

[0066] in,

[0067] R, R1, R2, R9, R 10 R 11 R 12 R 13 R 14 R 15 The definitions of “R” are as described above;

[0068] In some specific implementations, R9, R 11 Together with the carbon atom it is attached to, they represent a carbonyl group (-CO-);

[0069] In some specific implementations, R 10 R 12Each is independently selected from halogens and alkyl groups, and optionally may be further substituted by one or more substituents; R 10 R 12 The preferred elements are fluorine, chlorine, bromine, iodine, and C1-10 alkyl, with chlorine being more preferred;

[0070] In some specific implementations, R 13 Selected from alkyl groups, optionally further substituted by one or more substituents; R 13 Preferably, it is a heteroaryl-substituted alkyl group; more preferably, it is a 5-10 membered heteroaryl-substituted C1-10 alkyl group; and even more preferably, it is a C1-10 alkyl group.

[0071] In some specific implementations, R 14 Selected from alkyl groups, optionally further substituted by one or more substituents; R 14 Preferably C1-10 alkyl, more preferably methyl or ethyl;

[0072] In some specific implementations, R 15 Selected from alkyl and cycloalkyl groups, optionally further substituted by one or more substituents; R 15 Preferably, it is a cyano-substituted C1-10 alkyl group or a 3-10 membered cycloalkyl group, more preferably a cyclopropyl group or...

[0073] In some specific embodiments, the compound of formula II may be selected from the compounds shown in formula II-1 or formula II-2:

[0074]

[0075] in,

[0076] R, R4, R5, R 14 R 15 The definitions of L1, L2, and L3 are as described above;

[0077] In some specific implementations, L1 is selected from -O-, -OC(O)-, -C(O)O-, -NR'-, -C(O)NR'-, -NR'C(O)- or Preferably -O-, Or -NR'-;

[0078] In some specific implementations, L2 is selected from -[C(R')2] n -、-[OC(R')2] n -or-[C(R')2O] n-, preferably -[C(R')2]2-, -[OC(R')2]2-, -[C(R')2O]2-, -[C(R')2]3-, -[OC(R')2]3- or -[C(R')2O]3-, more preferably -CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-CH2- or -CH(CH3)-CH2-CH2-; wherein the carbon in the linker can be in the R or S configuration;

[0079] n is defined as described above;

[0080] In some specific implementations, L3 is selected from -O-, -OC(O)-, -C(O)O-, -NR'-, -C(O)NR'-, -NR'C(O)- or Preferably -O-, -C(O)NR'-, -NR'C(O)- or

[0081] The definition of R' is as described above;

[0082] In some specific embodiments, R4 is selected from halogens and alkyl groups, and optionally may be further substituted by one or more substituents; R4 is preferably fluorine, chlorine, bromine, iodine, C1-10 alkyl, and more preferably chlorine;

[0083] In some specific implementations, R 14 Selected from alkyl groups, optionally further substituted by one or more substituents; R 14 Preferably C1-10 alkyl, more preferably methyl or ethyl;

[0084] In some specific implementations, R 15 Selected from

[0085] Among them, R 1 Defined as described above;

[0086] In some specific implementations, R 15 Selected from

[0087] In some specific embodiments, the compound of formula II may be selected from the compounds shown in formula II-3 or formula II-4:

[0088]

[0089] in,

[0090] R, R4, R5, R 28 R 29 R 30 R31 R 33 The definitions of L1, L2, and L3 are as described above;

[0091] In some specific embodiments, L1 is selected from -O-, -OC(O)-, -C(O)O-, -NR'-, -C(O)NR'- or -NR'C(O)-, preferably -O-, -C(O)NR'-, -NR'C(O)- or -NR'-;

[0092] In some specific implementations, L2 is selected from -[C(R')2] n -、-[OC(R')2] n -or-[C(R')2O] n -, preferably -[C(R')2]2-, -[OC(R')2]2-, -[C(R')2O]2-, -[C(R')2]3-, -[OC(R')2]3- or -[C(R')2O]3-, more preferably -CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-CH2- or -CH(CH3)-CH2-CH2-; wherein the carbon in the linker can be in the R or S configuration;

[0093] n is defined as described above;

[0094] In some specific embodiments, L3 is selected from -O-, -OC(O)-, -C(O)O-, -NR'-, -C(O)NR'- or -NR'C(O-), preferably -O-, -C(O)NR'- or -NR'C(O-);

[0095] The definition of R' is as described above;

[0096] In some specific embodiments, R4 is selected from halogens, alkyl groups, and haloalkyl groups, and optionally may be further substituted by one or more substituents; R4 is preferably fluorine, chlorine, bromine, iodine, C1-10 alkyl or C1-10 haloalkyl, more preferably chlorine or trifluoromethyl;

[0097] In some specific implementations, R 28 R 33 Each is independently selected from alkyl groups, and optionally may be further substituted by one or more substituents; R 28 R 33 Each is preferably a C1-10 alkyl group, more preferably a methyl or ethyl group;

[0098] In some specific embodiments, the compound of formula II may be selected from the compounds shown in formula II-5 or formula II-6:

[0099]

[0100] in,

[0101] R, R4, R5, R 17 R 19 R 20 R 21 The definitions of L1, L2, and L3 are as described above;

[0102] In some specific embodiments, L1 is selected from -O-, -OC(O)-, -C(O)O-, -NR'-, -C(O)NR'- or -NR'C(O)-, preferably -O-, -C(O)NR'-, -NR'C(O)- or -NR'-;

[0103] In some specific implementations, L2 is selected from -[C(R')2] n -、-[OC(R')2] n -or-[C(R')2O] n -, preferably -[C(R')2]2-, -[OC(R')2]2-, -[C(R')2O]2-, -[C(R')2]3-, -[OC(R')2]3- or -[C(R')2O]3-, more preferably -CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-CH2- or -CH(CH3)-CH2-CH2-; wherein the carbon in the linker can be in the R or S configuration;

[0104] n is defined as described above;

[0105] In some specific embodiments, L3 is selected from -O-, -OC(O)-, -C(O)O-, -NR'-, -C(O)NR'- or -NR'C(O-), preferably -O-, -C(O)NR'- or -NR'C(O-);

[0106] The definition of R' is as described above;

[0107] In some specific embodiments, R4 is selected from halogens, alkyl groups, and haloalkyl groups, and optionally may be further substituted by one or more substituents; R4 is preferably fluorine, chlorine, bromine, iodine, C1-10 alkyl or C1-10 haloalkyl, more preferably chlorine or trifluoromethyl;

[0108] In some specific implementations, R 19 Selected from alkyl or alkoxy groups, optionally further substituted by one or more substituents; R 19 Preferably, it is a C1-10 alkyl or C1-10 alkoxy compound, more preferably methyl, ethyl, methoxy, or ethoxy compound;

[0109] In some specific embodiments, formula I or formula II may be further specifically as follows:

[0110]

[0111]

[0112] In this invention, the substituents in "optionally may be further substituted by one or more substituents" are selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl, preferably hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, C1-10 acyl, C1-10 acylamino, C1-10 ester, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, 6-10 membered aryl or 5-10 membered heteroaryl.

[0113] The present invention also relates to a pharmaceutical composition comprising the aminopyrimidine derivative of the present invention;

[0114] The present invention also relates to a pharmaceutical composition comprising a compound of formula I or II of the present invention or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer;

[0115] In some specific embodiments, the pharmaceutical composition may optionally also include a pharmaceutically acceptable carrier;

[0116] The present invention also relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer thereof, for use as an LRRK2 kinase inhibitor, or for use in the preparation of a drug that inhibits LRRK2 kinase.

[0117] The present invention also relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate, a tautomer, or a stereoisomer thereof for the treatment of Parkinson's disease (PD), or for the preparation of a medicament for the treatment of Parkinson's disease (PD).

[0118] Detailed description of the invention

[0119] Before further describing the invention, it should be understood that the invention is not limited to the specific embodiments described, as they may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to constitute limitation, as the scope of the invention is limited only by the appended claims.

[0120] Unless otherwise stated, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents, applications, publications, and other publications referenced herein are incorporated herein by reference in their entirety. If any definition in this section contradicts or is inconsistent with the definitions listed in the patents, applications, and other publications incorporated herein, the definition in this section shall prevail over the definition incorporated herein.

[0121] In this invention, "alkyl" refers to a saturated aliphatic hydrocarbon group, which can be a C1-20 alkyl group, preferably a C1-10 alkyl group, more preferably a C1-6 alkyl group, and most preferably a C1-3 alkyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc.

[0122] In this invention, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl group may contain 3 to 20 ring carbon atoms ("3-20 membered cycloalkyl"), preferably 3 to 12 ring carbon atoms ("3-12 membered cycloalkyl"), more preferably 3 to 10 ring carbon atoms ("3-10 membered cycloalkyl"), more preferably 3 to 8 ring carbon atoms ("3-8 membered cycloalkyl"), and most preferably 3 to 6 ring carbon atoms ("3-6 membered cycloalkyl"). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.

[0123] In this invention, "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing a specified number of ring atoms and including at least one heteroatom selected from N, O, and S as a ring member of a cycloalkyl ring. The heterocyclic group may contain 3 to 20 ring atoms ("3-20 membered heterocyclic group"), preferably 3 to 12 ring atoms ("3-12 membered heterocyclic group"), more preferably 3 to 10 ring atoms ("3-10 membered heterocyclic group"), more preferably 3 to 8 ring atoms ("3-8 membered heterocyclic group"), and most preferably 3 to 6 ring atoms ("3-6 membered heterocyclic group"). Non-limiting examples of heterocyclic groups include ethylene oxide, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydropyranyl, tetrahydrothiaranyl, piperidinyl, etc.

[0124] In this invention, "aryl" refers to a substituted monocyclic, biaryl, or fused bicyclic or polycyclic ring system having well-known aromatic characteristics, wherein at least one ring contains a fully conjugated π-electron system. Typically, aryl groups contain 6-20 carbon atoms ("6-20-membered aryl") as ring members, preferably 6-14 carbon atoms ("6-14-membered aryl") or more preferably 6-10 carbon atoms ("6-10-membered aryl"). Fused aryl groups may include aryl rings fused to another aryl ring, or aryl rings fused to saturated or partially unsaturated carbon rings or heterocycles. The connection point to the base molecule on such a fused aryl ring system may be a C atom of the aromatic portion of the ring system or a C or N atom of the non-aromatic portion. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracene, phenanthrene, indanyl, indenyl, benzo[d][1,3]dioxane, and tetrahydronaphthyl;

[0125] In this invention, "heteroaryl" refers to a monocyclic, heteroaryl, or fused bicyclic or polycyclic ring system with well-known aromatic characteristics, containing a specified number of ring atoms and including at least one heteroatom selected from N, O, and S as a ring member in the aromatic ring. The inclusion of heteroatoms allows for the aromaticity of both 5-membered and 6-membered rings. Typically, heteroaryl contains 5-20 ring atoms ("5-20-membered heteroaryl"), preferably 5-14 ring atoms ("5-14-membered heteroaryl"), and more preferably 5-10 ring atoms ("5-10-membered heteroaryl"). The heteroaryl ring is linked to the base molecule through the ring atoms of the heteroaryl ring, thereby maintaining aromaticity. Thus, a 6-membered heteroaryl ring can be linked to the base molecule through a ring C atom, while a 5-membered heteroaryl ring can be linked to the base molecule through a ring C or N atom. Examples of unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naphthidine, and carbazole;

[0126] In this invention, "ester group" refers to a group formed by the esterification of a carboxyl group (-COOH) and a hydroxyl group (-OH), where the OH group is removed from the carboxyl group and the H group is removed from the hydroxyl group. For example, an ester group can be... Ra and Rb can be alkyl groups, and can be selected from C1-20 ester groups, preferably C1-10 ester groups, further preferably C2-8 ester groups, more preferably C2-6 ester groups, and most preferably C2-3 ester groups;

[0127] In this invention, "acyl" refers to the atomic group remaining after removing the hydroxyl group from an organic acid, with the general formula Rb-CO-, where Rb is defined as described above, and the acyl group can be selected from C1-20 acyl groups, preferably C1-10 acyl groups, further preferably C1-8 acyl groups, more preferably C1-6 acyl groups, and most preferably C1-3 acyl groups;

[0128] In this invention, "aldehyde group" refers to -C(O)H;

[0129] In this invention, "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above; cycloalkyloxy, heterocyclic oxy, aryloxy, heteroaryloxy, etc. are defined similarly;

[0130] In this invention, "amide group" refers to Rc can be H or an alkyl group;

[0131] In this invention, "acylamine group" refers to Where Rb and Rc are defined as above;

[0132] In this invention, "amine group" refers to Rc can be H or alkyl, and at least one Rc is not H; the alkyl-substituted amino group in this invention can be the above-mentioned amino group;

[0133] In this invention, "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above;

[0134] In this invention, "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above;

[0135] In this invention, "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above;

[0136] In this invention, "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxyl groups, wherein the alkoxy group is as defined above;

[0137] In this invention, "hydroxyl group" refers to -OH;

[0138] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine;

[0139] In this invention, "amino" refers to -NH2;

[0140] In this invention, "cyano" refers to -CN;

[0141] In this invention, "nitro" refers to -NO2;

[0142] In this invention, the groups defined above can be optionally substituted or unsubstituted, and when substituted, they can be replaced by one or more of the following groups:

[0143] Hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclic, aryl or heteroaryl; optionally, it may be further substituted.

[0144] In this invention, any isotopically labeled derivatives of the compounds of this invention or their pharmaceutically acceptable salts are covered by this invention. Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. They can be labeled with isotopes. 2 H(D), 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, etc. are used instead. Unless otherwise stated, when a position is specifically designated as deuterium (D), the position shall be understood as having a deuterium abundance of at least 3,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0145] In this invention, the term "multiple" can specifically refer to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0146] In this invention, the following abbreviations / terms are used:

[0147] TsOH: p-Toluenesulfonic acid

[0148] EA: Ethyl acetate

[0149] prep-HPLC: Preparative liquid chromatography

[0150] THF: Tetrahydrofuran

[0151] Tos: p-Toluenesulfonyl group

[0152] TFA: Trifluoroacetic acid

[0153] RuPhos Pd G3: Methanosyl(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)

[0154] RuPhos: 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl

[0155] LCMS: Liquid chromatography-mass spectrometry

[0156] DMF: N,N-dimethylformamide

[0157] NCS: n-Chlorosilicate

[0158] DIAD: Diisopropyl azodicarbonate

[0159] DCM: Dichloromethane

[0160] PPh3: Triphenylphosphine

[0161] NH4Cl: Ammonium chloride

[0162] t-BuONa: Sodium tert-butoxide

[0163] NaH: Sodium hydride

[0164] TEA: Triethylamine

[0165] TCFH:N,N,N',N'-Tetramethylchloromethylammonium hexafluorophosphate

[0166] DMAP: 4-Dimethylpyridine

[0167] Pd(dppf)Cl2.CH2Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex

[0168] i-PrOH: Isopropanol

[0169] liHMDS: Lithium hexamethyldisilamide

[0170] dioxane: 1,4-dioxane

[0171] L-proline: L-proline

[0172] Et3N: Triethylamine

[0173] DMA: N,N-dimethylacetamide

[0174] XPHOS: 2-Dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl

[0175] Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[0176] Cs2CO3: Cesium carbonate Detailed Implementation

[0177] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0178] Example 1

[0179]

[0180] Compound 1a (50 mg, 0.272 mmol), compound 1b (75.90 mg, 0.327 mmol), and TsOH (23.42 mg, 0.136 mmol) were dissolved in 1,4-dioxane (3 mL) and reacted at 100 °C for 3 h. The reaction was then cooled to room temperature, and purified water (5 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL), separated, and the organic phase was dried with anhydrous sodium sulfate. The crude product was obtained by rotary evaporation and purified by prep-HPLC to give compound 1 (20.93 mg, yield 20.26%).

[0181] MS m / z(ESI): 380.47 [M+H] +

[0182] 1 HNMR(400MHz,Chloroform-d)δ7.67(s,1H),7.61(s,2H),6.20(s,1H),3.37(s,2H),3.21(dt,J=7.0,3.4Hz,1H),2.08(s,6H),1.32(s,5H),1.25(s,5H).

[0183] Example 2

[0184]

[0185] Step 1: Synthesis of compound 2b

[0186] Compound 2a (2.279 mmol, 350 mg) was added to a 100 mL single-necked flask, dissolved in 10 mL of THF, and 176.45 mg (4.558 mmol) of sodium hydride was added in three portions. The mixture was reacted at 0 °C for 15 min, followed by the addition of p-toluenesulfonyl chloride (2.735 mmol, 521.41 mg) and the reaction was carried out at room temperature for 30 min. The reaction was monitored by TLC until it was complete. The reaction was quenched by adding 25 mL of saturated ammonium chloride solution, and then extracted three times with 25 mL of ethyl acetate. The organic phase was dried under stirring with anhydrous sodium sulfate and concentrated to give compound 2b (501.11 mg, yield 71.45%).

[0187] MS m / z(ESI): 307 [M+H] +

[0188] Step 2: Synthesis of compound 2d

[0189] Compound 2c (1.979 mmol, 420 mg) was dissolved in 15 mL of methanol in a single-necked flask, followed by the addition of 40 mg of palladium on carbon. The mixture was purged three times with hydrogen gas and reacted under a hydrogen atmosphere for 16 h. The reaction was monitored by TLC, indicating that the starting material had completely reacted. The palladium on carbon was removed by filtration, and the solution was concentrated to give a red solid compound 2d (351.76 mg, yield 97.53%).

[0190] MS m / z(ESI): 183 [M+H] +

[0191] Step 3: Synthesis of compound 2e

[0192] Compound 2b (300 mg, 0.975 mmol) and compound 2d (195.41 mg, 1.072 mmol) were added to a microwave reaction flask and dissolved in 8 mL of 1,4-dioxane. Then, RuPhos Pd G3 (81.63 mg, 0.097 mmol), RuPhos (90.98 mg, 0.195 mmol), and cesium carbonate (635.23 mg, 1.950 mmol) were added. After purging with nitrogen, the mixture was reacted in a microwave reactor at 100 °C for 1 h. The reaction was complete as monitored by LCMS. After cooling, 20 mL of purified water was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound 2e (360 mg, yield 81%). MS m / z (ESI): 454 [M+H] +

[0193] Step 4: Synthesis of compound 2f

[0194] Compound 2e (100 mg, 0.220 mmol) was added to a reaction vessel and dissolved in phosphorus oxychloride (3 mL). The mixture was heated under reflux for 1 h, and the product was observed by LCMS. After cooling, crushed ice was added to quench the reaction. The pH was adjusted to 7–8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL * 2), and the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated to obtain the crude product 2f (90 mg, 95% yield).

[0195] MS m / z(ESI): 436 [M+H] +

[0196] Step 5: Synthesis of 2g of compound

[0197] The crude product of compound 2f (90 mg) was added to 5 mL of potassium hydroxide solution and heated under reflux for 1 h. The reaction was monitored by LCMS and the reaction proceeded to completion. After cooling, the pH of the reaction solution was adjusted to 5-6 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 2 g (55 mg, yield 98%) of compound 2.

[0198] MS m / z(ESI): 282 [M+H] +

[0199] Step 6: Synthesis of trifluoroacetate of compound 2

[0200] 2 g (20 mg, 0.071 mmol) of compound 2 was dissolved in 1 mL of DMF, and NCS (9.49 mg, 0.071 mmol) was added. The mixture was stirred at room temperature for 10 min. The reaction was monitored by LCMS until complete. The reaction was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL * 2), dried over anhydrous sodium sulfate in the organic layer, concentrated, and then lyophilized to obtain trifluoroacetate of compound 2 (7.62 mg, yield 34%).

[0201] MS m / z(ESI): 316 [M+H] +

[0202] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.17(s,1H),7.29(s,1H),2.17(s,3H),1.96(s,6H).

[0203] Example 3

[0204]

[0205] Step 1: Synthesis of compound 3c

[0206] Compound 3a (1.0 g, 5.072 mmol), compound 3b (0.54 g, 6.087 mmol), and N-methylimidazole (2.022 mL, 25.361 mmol) were dissolved in DCM (20 mL). TCFH N,N,N',N'-tetramethylchloromethamine hexafluorophosphate (2.13 g, 7.608 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 20 min. The reaction was confirmed to be complete by LCMS. The reaction was then quenched directly with purified water (20 mL), followed by extraction with 20 mL of DCM. After separation, the organic phase was washed twice with purified water. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness before column chromatography to obtain compound 3c (0.436 g, yield: 32.04%).

[0207] MS M / Z (ESI): 269 [M+H] +

[0208] Step 2: Synthesis of compound 3e

[0209] Compound 3c (300 mg, 1.118 mmol), compound 3d (171.73 mg, 1.118 mmol), and PPh3 (439.97 mg, 1.667 mmol) were dissolved in THF (9 mL). The mixture was cooled to 0 °C and DIAD (0.554 mL, 2.796 mmol) was slowly added dropwise under nitrogen protection. After the addition was complete, the mixture was allowed to react at room temperature for 1 h. The reaction was then confirmed to be complete by LCMS. The reaction was quenched with purified water (20 mL), and the reaction mixture was extracted with ethyl acetate (20 mL). After separation, the organic phases were washed with purified water (20 mL x 2), combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain a yellow oily substance 3e (320 mg, yield: 70.86%).

[0210] Step 3: Synthesis of compound 3f

[0211] Compound 3e (320 mg, 0.792 mmol) was dissolved in a mixed solvent of EtOH (5 mL) and purified water (1 mL), and then iron powder (442.49 mg, 7.924 mmol) and NH4Cl (423.87 mg, 7.924 mmol) were added. The mixture was reacted at 90 °C for 1 h, and then filtered directly. The filter cake was washed with ethanol (20 mL) and evaporated to dryness to obtain solid 3f (541 mg), which was directly used in the next step of the reaction.

[0212] Step 4: Synthesis of 3g of compound

[0213] Compound 3f (541 mg, 0.724 mmol) and t-BuONa (416.78 mg, 4.341 mmol) were dissolved in 1,4-dioxane (10 mL). Then, under nitrogen protection, RuPhos (33.77 mg, 0.072 mmol) and RuPhos Pd G3 (60.49 mg, 0.072 mmol) were added. The mixture was reacted at 90 °C for 30 min and then filtered directly. The filter cake was washed with dioxane (10 mL). After the filtrate was evaporated to dryness, 5 mL of ethyl acetate and 15 mL of petroleum ether were added, and the mixture was stirred and filtered to obtain 3 g (107 mg) of compound.

[0214] Step 5: Synthesis of Compound 3

[0215] Compound 3 g (65 mg, 0.193 mmol) and NCS (20.58 mg, 0.154 mmol) were dissolved in THF (4 mL), stirred at 65 °C for 5 h, and then quenched directly with 10 mL of purified water. Then, ethyl acetate (20 mL * 3) was added for extraction. After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound 3 (10 mg, yield: 13.34%).

[0216] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.16(d,J=2.1Hz,1H),7.45(s,1H),7.18(dd,J=8.4,2.1Hz,1H),7.10(d,J=8.3Hz,1 H),3.89(s,3H),3.85(t,J=5.7Hz,2H),3.51–3.47(m,1H),3.42(t,J=5.1Hz,1H),2.91(s,3H),2.32(q,J=8.6,7.9Hz,2H).

[0217] Example 4

[0218]

[0219] Step 1: Synthesis of compound 4b

[0220] At 0°C, concentrated sulfuric acid (18 mL) and concentrated nitric acid (18 mL) were added dropwise to compound 4a (3.6 g, 21.7 mmol) successively. The reaction mixture was stirred at 0°C for 1 h, and the reaction was confirmed to be complete by LCMS. The reaction mixture was then added dropwise to ice water (20 mL), extracted with dichloromethane (20 mL * 3), the organic phases were combined, dried, filtered, evaporated to dryness, purified by column chromatography, and evaporated to dryness again to give compound 4b (3.3 g, yield 72%).

[0221] MS m / z (ESI): 212 [M+H] +

[0222] 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=0.8Hz,1H),8.12(d,J=9.2Hz,1H),7.87(dd,J=9.2,1.2Hz,1H),4.14(s,3H).

[0223] Step 2: Synthesis of compound 4d

[0224] NaH (990 mg, 24.77 mmol) was added to DMF (18 mL). At 0 °C, a DMF solution of 4b (2.6 g, 13.76 mmol) was added dropwise to the above system. After stirring at 0 °C for 1 h, 4c (3.48 g, 16.51 mmol) was added in portions. The reaction was carried out at 25 °C for 16 h under nitrogen protection, and the reaction was confirmed to be complete by LC-MS. The reaction was then quenched with a saturated ammonium chloride aqueous solution (10 mL). The mixture was diluted with purified water (30 mL), extracted with ethyl acetate (30 mL x 2), and the organic phases were combined. The mixture was washed three times with saturated brine (30 mL), dried, filtered, evaporated to dryness, and purified by column chromatography to give compound 4d (2.3 g yellow solid, 46% yield).

[0225] MS m / z (ESI): 365 [M+H] +

[0226] 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),7.93(d,J=9.2Hz,1H),7.36(dd,J=9.2,0.8Hz,1H),6.79(d,J=8.4 Hz,1H),4.60(m,2H),4.06(s,3H),3.83-3.72(m,1H),1.89(m,2H),1.32(s,9H),1.10(d,J=6.4Hz,1H).

[0227] Step 3: Synthesis of compound 4f

[0228] Compound 4d (1.2 g, 3.29 mmol) was added in portions to a 4 M hydrochloric acid / ethyl acetate (12 mL) solution. The reaction was carried out at 25 °C for 0.5 h, and the reaction was confirmed to be complete by LC-MS. The reaction solution was then filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filter cake was evaporated to dryness to give compound 4f (980 mg yellow solid, 95% yield).

[0229] MS m / z (ESI): 265 [M+H] +

[0230] 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.06(s,2H),7.95(d,J=9.2Hz,1H),7.38(d,J=9.2Hz,1H) ,4.88-4.71(m,2H),4.08(s,3H),3.50(d,J=6.0Hz,1H),2.20(m,1H),2.01(m,1H),1.30(s,9H).

[0231] Step 4: Synthesis of 4g of compound

[0232] Compound 4f (1.0 g, 3.33 mmol) was added to dichloromethane (10 mL). Triethylamine (1.85 mL, 13.3 mmol) and 4e (2,4,5-trichloropyrimidine) (732 mg, 4.0 mmol) were added dropwise to the system at 0 °C. The reaction was carried out under nitrogen protection at 25 °C for 3 h, and the reaction was monitored by LC-MS. The reaction solution was then diluted with purified water (30 mL), extracted with dichloromethane (20 mL x 2), and the organic phases were combined. The mixture was washed three times with saturated brine (40 mL), dried, filtered, evaporated to dryness, and purified by column chromatography to give compound 4 g (450 mg yellow solid, yield 33%).

[0233] MS m / z (ESI): 411 [M+H] +

[0234] 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=1.2Hz,1H),8.10(s,1H),7.91(d,J=9.2Hz,1H),7.66(d,J=8.4Hz,1H),7.32 (dd,J=9.2,0.8Hz,1H),4.73-4.59(m,2H),4.53-4.41(m,1H),4.05(s,3H),2.14(m,2H),1.26(d,J=6.8Hz,3H).

[0235] Step 5: Synthesis of Compound 4

[0236] 4 g (410 mg, 1.0 mmol) of compound was dissolved in ethanol / water (12 mL / 4 mL). Ammonium chloride (1.06 g, 20.0 mmol) and iron powder (560 mg, 10.0 mmol) were added to the system at 0 °C. The reaction was carried out at 90 °C for 16 h under nitrogen protection, and the reaction was monitored by LC-MS. The reaction solution was filtered, and the filter cake was rinsed with dichloromethane (10 mL). The filtrate was diluted with water (10 mL) and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed three times with saturated brine (20 mL), dried, filtered, evaporated to dryness, and purified by column chromatography to give compound 4 (450 mg, yield 33%).

[0237] MS m / z (ESI): 345 [M+H] +

[0238] 1H NMR(400MHz, DMSO-d6)δ8.73(s,1H),8.16(d,J=0.8Hz,1H),7.86(s,2H),7.18-7.09(m,2H),6.89(d,J=6.4Hz,1H),4 .84(s,1H),4.45(d,J=10.4Hz,1H),3.98(s,3H),3.79-3.69(m,1H),1.79(dd,J=15.6,9.2Hz,1H),1.24-1.22(m,3H).

[0239] Example 5

[0240]

[0241] Step 1: Synthesis of compound 5c

[0242] Compound 5a (1200 mg, 7.429 mmol) was dissolved in DMF (20 mL), and compound 5b (3150.34 mg, 14.858 mmol) and cesium carbonate (4840.71 mg, 14.857 mmol) were added. The mixture was reacted at 80 °C for 3 h. Then, 80 mL of purified water was added, and the mixture was extracted with EA (40 mL * 3). The organic phase was washed with saturated brine (50 mL), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain compound 5c (1500 mg, yield 82.20%).

[0243] MS m / z (ESI): 246.1 [M+H] +

[0244] Step 2: Synthesis of compound 5d

[0245] Compound 5c (200 mg, 0.814 mmol) was dissolved in water (10 mL), and KOH (2283.68 mg, 40.700 mmol) was added. The mixture was then microwaved at 140 °C for 12 h. The reaction was monitored by LCMS until complete. The mixture was then diluted with 30 mL of water, and the pH was adjusted to 1–2 with 1 M HCl aqueous solution. The mixture was extracted with ethyl acetate (30 mL * 5), and the organic phase was washed with saturated brine (20 mL). The organic phases were then combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid product 5d (180 mg, yield 97.30%).

[0246] MS M / Z (ESI): 228.1 [M+H] +

[0247] Step 3: Synthesis of compound 5f

[0248] Compound 5d (180 mg, 0.792 mmol) was dissolved in DMF (5 mL), followed by the addition of compound 5e (297.00 mg, 2.377 mmol) and cesium carbonate (1290.55 mg, 3.961 mmol). The mixture was reacted in a closed system at 80 °C for 2 h. Then, 20 mL of purified water was added to the reaction solution, followed by extraction with ethyl acetate (10 mL x 3). The mixture was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 5f (200 mg, yield 93.07%).

[0249] MS M / Z (ESI): 272.1 [M+H] +

[0250] Step 4: Synthesis of compound 5h

[0251] Compound 5g (71.39mg, 0.332mmol), compound 5f (90mg, 0.332mmol), and PPh3 (130.53mg, 0.498mmol) were dissolved in anhydrous THF (10mL). Under nitrogen protection, a THF solution of DIAD (134.27mg, 0.664mmol) (2mL) was added at 0℃, and the reaction was carried out at room temperature for 2h. The reaction was monitored by LCMS until complete. Then, 30mL of purified water was added, and the mixture was extracted with EA (20mL*3). The extract was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 5h (210mg).

[0252] MS M / Z (ESI): 470.1 [M+H] +

[0253] Step 5: Synthesis of Compound 5

[0254] Compound 5h (200 mg, 0.427 mmol) was dissolved in ethanol (20 mL), and an aqueous solution of iron powder (238.48 mg, 4.271 mmol) and ammonium chloride (228.45 mg, 4.271 mmol) (4 mL) was added. The mixture was reacted at 95 °C for 16 h, then filtered, the filtrate was concentrated, and the crude product was obtained by silica gel column chromatography. The crude product was then prepared by pre-HPLC to obtain compound 5 (21.55 mg, yield 12.43%).

[0255] MS M / Z (ESI): 402.1 [M+H] +

[0256] 1H NMR (400MHz, DMSO-d6) δ9.29(s,1H),9.15(s,1H),7.69(d,J=2.2Hz,1H),7.36(d,J=2.3Hz,1H),4.51(s,2H),4.26(td,J=11.3,5.6Hz,2 H),3.95(dd,J=11.2,4.4Hz,2H),3.46(ddd,J=13.6,11.8,2.0Hz,2H),3.30(s,1H),2.27(s,3H),2.05–1.94(m,2H),1.78–1.71(m,2H).

[0257] Example 6

[0258]

[0259] Step 1: Synthesis of compound 6c

[0260] Compound 6a (1380 mg, 8.065 mmol) was dissolved in THF (30 mL), and compound 6b (1356.85 mg, 16.130 mmol) and TsOH (277.76 mg, 1.613 mmol) were added. The mixture was reacted at 80 °C for 12 h. The reaction was monitored by TLC until it was complete. The mixture was then cooled, concentrated under vacuum, and purified by silica gel column chromatography to obtain compound 6c (yellow solid product, 1.8 g, yield 87.45%).

[0261] MS M / Z (ESI): 278.1 [M+23] +

[0262] Step 2: Synthesis of compound 6e

[0263] Compound 6c (500 mg, 1.959 mmol) was dissolved in DMF (5 mL), and N-methylimidazole (0.781 mL, 9.795 mmol) and N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (1099.32 mg, 3.918 mmol) were added. After stirring at room temperature for 15 min, compound 6d (345.37 mg, 3.918 mmol) was added, and the mixture was stirred at room temperature for 12 h. Then, 30 mL of purified water was added, followed by extraction with EA (20 mL * 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain compound 6e (500 mg, yield 78.44%).

[0264] MS M / Z (ESI): 326.2 [M+H] +

[0265] Step 3: Synthesis of 6g of compound

[0266] Compound 6e (500 mg, 1.537 mmol) was dissolved in isopropanol (10 mL), and then TEA (1.068 mL, 7.684 mmol) and compound 6f (338.24 mg, 1.844 mmol) were added. The mixture was stirred at room temperature for 1 h, then concentrated and purified by silica gel column chromatography to give compound 6 g (224 mg, yield 30.86%).

[0267] MS M / Z (ESI): 472.1 [M+H] +

[0268] Step 4: Synthesis of compound 6h

[0269] 6 g (224 mg, 0.474 mmol) of compound was dissolved in 4 M HCl / MeOH (7 mL), stirred at room temperature for 2 h, and the reaction was monitored by TLC until complete. The solution was then concentrated to give compound 6 h (yellow solid, 180 mg, yield 97.77%).

[0270] MS M / Z (ESI): 388.0 [M+H] +

[0271] Step 5: Synthesis of compound 6J

[0272] Compound 6h (180 mg, 0.481 mmol) was dissolved in DMF (6 mL), followed by the addition of cesium carbonate (653.07 mg, 2.004 mmol) and compound 6I (283.33 mg, 1.336 mmol). The reaction was carried out at 80 °C for 16 h, and the reaction was monitored by LCMS to ensure complete reaction. Purified water (30 mL) was added to the reaction solution, followed by extraction with EA (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This crude product was then purified by pre-HPLC to obtain compound 6J (70 mg, yield 30.81%).

[0273] MS M / Z (ESI): 472.1 [M+H] +

[0274] Step 6: Synthesis of compound 6k

[0275] Compound 6J (70 mg, 0.148 mmol) was dissolved in ethanol (5 mL), and iron powder (82.76 mg, 1.482 mmol), purified water (1 mL), and ammonium chloride (79.27 mg, 1.482 mmol) were added. The mixture was reacted at 90 °C for 3 h. The reaction was monitored by LCMS until it was complete. The mixture was then cooled to room temperature, filtered, and concentrated to obtain crude compound 6K (50 mg), which was then directly used for the next reaction.

[0276] Step 7: Synthesis of Compound 6

[0277] Compound 6k (50 mg, 0.113 mmol) was dissolved in DMF (5 mL), and RuPhos Pd G3 (10 mg, 0.012 mmol), RuPhos (10.55 mg, 0.023 mmol), and sodium tert-butoxide (21.72 mg, 0.226 mmol) were added. The mixture was reacted at 80 °C for 4 h under nitrogen protection. After filtration, compound 6 (6.85 mg, yield 14.93%) was purified by pre-HPLC.

[0278] MS M / Z (ESI): 406.1 [M+H] +

[0279] 1 H NMR(400MHz,Chloroform-d)δ7.79(d,J=13.5Hz,1H),6.21(d,J=41.4Hz,1H),4.30(dt,J=13.3,8.4Hz,1H),4.12(dd,J=9.9,5.8Hz,1H),4.03(d,J=11 .6Hz,2H),3.63(dt,J=54.6,4.4Hz,1H),3.47–3.35(m,3H),3.30–3.18(m, 2H),2.95(s,2H),2.87–2.64(m,3H),2.29–2.07(m,5H),1.80–1.69(m,2H).

[0280] Example 7

[0281]

[0282] Step 1: Synthesis of compound 7c

[0283] Compound 7b (458.77 mg, 3.301 mmol) and compound 7a (500 mg, 2.201 mmol) were dissolved in DMF (6 mL), and cesium carbonate (2150.91 mg, 6.602 mmol) was added. The mixture was reacted at 80 °C for 14 h, and then 40 mL of purified water was added. The mixture was extracted with EA (20 mL * 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain compound 7c (pale yellow oil, 400 mg, yield 63.71%).

[0284] MS M / Z (ESI): 286.1 [M+H] + .

[0285] Step 2: Synthesis of compound 7e

[0286] Compound 7c (300 mg, 1.052 mmol) was dissolved in THF (6 mL), and PPh3 (413.71 mg, 1.577 mmol) was added. Under nitrogen protection, a THF solution (2 mL) of DIAD (425.26 mg, 2.103 mmol) was added at 0 °C. After stirring at room temperature for 1 h, a THF solution (4 mL) of compound 7d (248.72 mg, 1.157 mmol) was added, and the reaction was carried out at room temperature for 2 h. Then, 30 mL of purified water was added, followed by extraction with 20 mL of EA. After separation, the aqueous phase was extracted twice more with EA (20 mL * 2), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give compound 7e (460 mg, yield 90.70%). MS M / Z (ESI): 483.1 [M+H] + .

[0287] Step 3: Synthesis of Compound 7

[0288] Compound 7e (230 mg, 0.477 mmol) was dissolved in ethanol (20 mL), and an aqueous solution of iron powder (133.14 mg, 2.384 mmol) and ammonium chloride (127.54 mg, 2.384 mmol) (4 mL) was added. The mixture was reacted at 95 °C for 4 h, then filtered, purified by pre-HPLC, and lyophilized to obtain compound 7 (yellow solid, 21.64 mg, yield 10.36%).

[0289] MS M / Z (ESI): 416.1 [M+H] + .

[0290] 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),9.14(s,1H),7.70(d,J=2.3Hz,1H),7.36(d,J=2.3Hz,1H),4.41–4.36(m,2H),4.31–4.24(m,1H),3.9 5(d,J=11.2Hz,2H),3.49–3.41(m,3H),3.30(s,1H),2.26(s,3H),2.04–1.91(m,2H),1.75(dd,J=14.0,10.4Hz,2H),1.32(d,J=6.8Hz,2H).

[0291] Example 8

[0292]

[0293] Step 1: Synthesis of compound 8c

[0294] Compounds 8a (500 mg, 2.536 mmol), 8b (271.29 mg, 3.043 mmol), and N-methylimidazole (1.011 mL, 12.681 mmol) were dissolved in DMF (20 mL). TCFH N,N,N',N'-tetramethylchloromethanemid hexafluorophosphate (1067.39 mg, 3.804 mmol) was added in portions under ice bath conditions. The reaction mixture was reacted at room temperature for 20 min. The reaction solution was quenched with purified water (20 mL), followed by the addition of DCM (20 mL). After separation, the organic phase was washed with purified water (20 mL x 2), and the aqueous phases were combined. The mixture was extracted with DCM (30 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness before column chromatography to obtain compound 8c (453 mg, yield 66.61%). MS M / Z (ESI): 269.3 [M+H] +

[0295] Step 2: Synthesis of compound 8e

[0296] Compound 8c (300 mg, 1.118 mmol), compound 8d (171.73 mg, 1.118 mmol), and PPh3 (439.97 mg, 1.667 mmol) were dissolved in THF (9 mL). The solution was then cooled to 0 °C and, under nitrogen protection, 1 mL of a THF solution containing DIAD (0.554 mL, 2.796 mmol) was slowly added dropwise. After the addition was complete, the solution was a clear, yellow liquid. The reaction was allowed to proceed at room temperature for 1 h. The reaction was then quenched with purified water (20 mL) and diluted with ethyl acetate (20 mL). After separation, the organic phase was washed with purified water (20 mL x 2), the aqueous phases were combined, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain compound 8e (320 mg, yield 70.86%).

[0297] MS M / Z (ESI): 404.8 [M+H] +

[0298] The third step involves the synthesis of compound 8f.

[0299] Compound 8e (320 mg, 0.792 mmol) was dissolved in a mixed solvent of EtOH (5 mL) and H2O (1 mL), and iron powder (442.49 mg, 7.924 mmol) and NH4Cl (423.87 mg, 7.924 mmol) were added. The mixture was reacted at 90 °C for 1 h, filtered directly, and the filter cake was washed with ethanol (10 mL * 2). The mixture was then evaporated to dryness, and the residue was added to toluene (15 mL) and evaporated to dryness to obtain crude solid compound 8f (541 mg).

[0300] Step 4: Synthesis of 8g of compound

[0301] Compound 8f (541 mg, 0.724 mmol) and t-BuONa (416.78 mg, 4.341 mmol) were dissolved in dioxane solvent (10 mL). Under nitrogen protection, RuPhos (33.77 mg, 0.072 mmol) and RuPhos Pd G3 (60.49 mg, 0.072 mmol) were added, and the mixture was reacted at 90 °C for 30 min. The mixture was filtered, and the filter cake was washed with dioxane (20 mL * 2), evaporated to dryness, and then ethyl acetate (5 mL) was added. After ultrasonic dispersion, 15 mL of petroleum ether was added, followed by ultrasonication. The solid was uniformly dispersed and filtered to obtain 8 g (107 mg, yield 43.83%) of an orange-yellow solid. MS M / Z (ESI): 338.3 [M+H] +

[0302] Step 5: Synthesis of Compound 8

[0303] Compound 8 g (65 mg, 0.193 mmol) and N-chlorosuccinimide (32.58 mg, 0.244 mmol) were dissolved in THF (4 mL). The mixture was heated to 65 °C and stirred for 5 h. The reaction was monitored by LCMS until it was complete. The reaction solution was cooled to room temperature, and purified water (10 mL) was added to quench the reaction. Then, ethyl acetate (20 mL * 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a brick-red solid compound 8 (10 mg, yield 13.34%).

[0304] MS M / Z (ESI): 372.8 [M+H] +

[0305] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.16(d,J=2.1Hz,1H),7.45(s,1H),7.18(dd,J=8.4,2.1Hz,1H),7.10(d,J=8.3Hz,1 H),3.89(s,3H),3.85(t,J=5.7Hz,2H),3.51–3.47(m,1H),3.42(t,J=5.1Hz,1H),2.91(s,3H),2.32(q,J=8.6,7.9Hz,2H).

[0306] Example 9

[0307]

[0308] Synthesis of compound 9b (Step 1)

[0309] Compound 9a (200 mg, 1.136 mmol), di-tert-butyl dicarbonate (520.6 mg, 2.384 mmol), DMAP (13.88 mg, 0.114 mmol), and TEA (344.93 mg, 3.409 mmol) were dissolved in THF (10 mL) and stirred at 65 °C for 2 h. 1.0 eq of di-tert-butyl dicarbonate (247.88 mg, 1.136 mmol) was added, and stirring was continued at 65 °C for 3 h. The reaction was monitored by LCMS until complete. The solvent was evaporated, and ethyl acetate (15 mL) and purified water (15 mL) were added. After separation, the aqueous phase was extracted with ethyl acetate (15 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a pale yellow oily substance 9b (452 ​​mg), which was directly used in the next reaction.

[0310] MS M / Z (ESI): 376.1 [M+H] +

[0311] The second step involves the synthesis of compound 9d.

[0312] Compound 9b (500 mg, 1.329 mmol), compound 9c (438.68 mg, 1.993 mmol), and K3PO4 (846.22 mg, 3.987 mmol) were dissolved in a mixed solvent of 1,4-dioxane (8 mL) and H2O (1.5 mL). Under nitrogen protection, Pd(dppf)Cl2.CH2Cl2 (108.52 mg, 0.133 mmol) was added, and the mixture was microwaved at 100 °C for 3 h. The reaction was monitored by LCMS until complete. The reaction solution was quenched with purified water (30 mL), and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Then, ethyl acetate (5 mL) was added to dissolve the solid, followed by the addition of petroleum ether (50 mL). The solid precipitated, was filtered, and the filtrate was subjected to column chromatography to obtain compound 9d (323 mg, yield 84%).

[0313] MS M / Z (ESI): 290.2 [M+H] +

[0314] The third step involves the synthesis of compound 9g.

[0315] Compound 9f (238.71 mg, 1.090 mmol) was dissolved in i-PrOH (3 mL) and cooled to 0 °C. TEA (0.152 mL, 1.090 mmol) was added, followed by i-PrOH solution of compound 9e (200 mg, 1.090 mmol) (1 mL). The mixture was stirred at 35 °C for 3 h. The reaction was monitored by LC-MS until complete. The reaction mixture was directly added to purified water (10 mL), followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 9 g (240 mg, yield 77.41%) of a white solid. MS M / Z (ESI): 285 [M+2] +

[0316] The fourth step is the synthesis of compound 9h.

[0317] Compound 9 g (162.51 mg, 0.570 mmol), compound 9d (150 mg, 0.518 mmol), K2CO3 (143.3 mg, 1.037 mmol), and potassium iodide (8.61 mg, 0.052 mmol) were added to DMF (5 mL) and reacted at 80 °C for 1 h. The reaction was quenched by adding purified water (20 mL) to the reaction solution, and then extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated with silica gel, and column chromatography was performed to give a yellow solid 9 h (113 mg, yield 40.58%).

[0318] MS M / Z (ESI): 457.9 [M+H] +

[0319] Step 5: Synthesis of Compound 9

[0320] Compound 9h (113 mg, 0.247 mmol) was added to a mixed solvent of DCM (4 mL) and TFA (1.5 mL) and reacted at room temperature for 2 h. The reaction was monitored by LCMS until it was complete, and the solution was directly evaporated to dryness to give compound 9 (6.0 mg, yield 6.8%).

[0321] MS M / Z (ESI): 357.8 [M+H] +

[0322] 1H NMR(400MHz, Methanol-d4)δ7.99(s,1H),7.72(dd,J=7.0,2.4Hz,1H),7.43(ddd,J=7.1,5.5,2.0Hz,2H),7.32 (dd,J=7.2,2.1Hz,1H),4.54(t,J=6.0Hz,2H),3.71(td,J=9.8,4.7Hz,3H),3.56(s,4H),2.36(q,J=5.9Hz,2H).

[0323] Example 10

[0324]

[0325] Synthesis of compound 10c in step one

[0326] Compound 10a (600 mg, 2.351 mmol) was dissolved in DMF (10 mL), and N-methylimidazole (0.937 mL, 11.754 mmol) and TCFH N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (1319.19 mg, 4.702 mmol) were added. After stirring for 15 min, compound 10b (528.30 mg, 2.351 mmol) was added. The reaction was carried out at room temperature for 2 h. The reaction was monitored by LCMS until complete. 40 mL of purified water was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain compound 10c (900 mg, yield 93.05%).

[0327] MS M / Z(ESI): 434.2 [M+23] +

[0328] The second step involves the synthesis of compound 10d.

[0329] Compound 10c (900 mg, 2.187 mmol) was dissolved in 4 M hydrochloric acid / 1,4-dioxane solution (20 mL), stirred at room temperature for 14 h, and the reaction was monitored by LCMS until complete. After concentration, crude hydrochloride of compound 10d was obtained and used directly in the next step (981.51 mg).

[0330] MS M / Z(ESI): 228.1 [M+H] +

[0331] The third step involves the synthesis of compound 10f.

[0332] The hydrochloride salt of compound 10d (981.51 mg, 2.916 mmol) was dissolved in isopropanol (10 mL), and TEA (2950.65 mg, 29.160 mmol) and compound 10e (534.84 mg, 2.916 mmol) were added. After reacting at room temperature for 1 h, the reaction was monitored by LCMS until complete. The solution was concentrated and purified by silica gel column chromatography to give compound 10f (600 mg, yield 54.99%). MS M / Z (ESI): 374.0 [M+H] +

[0333] The fourth step involves the synthesis of compound 10h.

[0334] Compound 10f (580 mg, 1.550 mmol) and compound 10g (307.29 mg, 1.705 mmol) were dissolved in DMF (10 mL), and cesium carbonate (1010.08 mg, 3.100 mmol) was added. The mixture was sealed and reacted at 100 °C for 12 h. The reaction was monitored by LCMS until complete. The reaction was quenched with 60 mL of purified water, extracted with ethyl acetate (30 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to obtain compound 10h (197 mg, yield 27.73%).

[0335] MS M / Z(ESI): 458.1 [M+H] +

[0336] Step 5: Synthesis of compound 10i

[0337] Compound 10h (197 mg, 0.430 mmol) was dissolved in ethanol (10 mL), and iron powder (240.03 mg, 4.298 mmol) was added. Ammonium chloride (229.93 mg, 4.298 mmol) was dissolved in water (2 mL) and then added to the ethanol solution of compound 10h. The reaction was carried out at 95 °C for 4 h. The reaction was monitored by LCMS until it was complete. The mixture was filtered and concentrated to obtain compound 10i (180 mg, yield 97.77%).

[0338] MS M / Z(ESI): 428.1 [M+H] +

[0339] Step 6: Synthesis of Compound 10

[0340] Compound 10i (180 mg, 0.420 mmol) was dissolved in DMF (10 mL), and RuPhos (39.22 mg, 0.084 mmol), sodium tert-butoxide (80.77 mg, 0.840 mmol), and RuPhos Pd G3 (35.19 mg, 0.042 mmol) were added. The mixture was reacted in a microwave at 110 °C for 2 h under nitrogen protection. The reaction was monitored by LCMS until complete. The mixture was filtered and purified to obtain compound 10 (15.69 mg, yield 9.53%).

[0341] MS M / Z(ESI): 392.1 [M+H] + .

[0342] 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),7.78(d,J=30.0Hz,1H),7.17–6.86(m,1H),4.35(td,J=13.1,12.5,8.1Hz,2H),3.94(d,J=11.6Hz,2H),3.4 9–3.39(m,3H),3.31(s,1H),3.17(dd,J=13.5,7.0Hz,1H),2.85(s,3H), 2.26(d,J=32.7Hz,3H),1.95(qt,J=12.3,6.2Hz,2H),1.84–1.67(m,2H).

[0343] Example 11

[0344]

[0345] Synthesis of compound 11c in step one

[0346] Compound 11a (3 g, 15.627 mmol) and compound 11b (3.64 g, 17.190 mmol) were dissolved in DMF (20 mL), and cesium carbonate (10.18 g, 31.255 mmol) was added. The mixture was reacted at 100 °C for 3 h. The reaction was monitored by LCMS until complete. The reaction was quenched with 100 mL of purified water, extracted with ethyl acetate (50 mL * 3), and the organic phases were combined. The mixture was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain compound 11c (3 g, yield 69.53%).

[0347] MS M / Z(ESI): 276.0 [M+H] +

[0348] The second step involves the synthesis of compound 11d.

[0349] Compound 11c (3 g, 10.866 mmol) was dissolved in purified water (80 mL), and KOH (6.10 g, 108.660 mmol) was added. The mixture was reacted at 140 °C for 4 h. The reaction was monitored by LC-MS until complete. The reaction was quenched with 200 mL of purified water, extracted with DCM:MeOH (10:1) (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 11d (1550 mg, yield 66.91%). MS M / Z (ESI): 214.1 [M+H] +

[0350] The third step involves the synthesis of compound 11f.

[0351] Compound 11e (1817.19 mg, 14.541 mmol) and compound 11d (1550 mg, 7.271 mmol) were dissolved in DMF (25 mL), and cesium carbonate (4737.76 mg, 14.541 mmol) was added. The mixture was reacted at 100 °C for 2 h. The reaction was monitored by LCMS until complete. 100 mL of purified water was added, and the mixture was extracted with vinyl acetate (50 mL * 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 11f (1500 mg, yield 80.20%).

[0352] MS M / Z(ESI): 258.1 [M+H] +

[0353] The fourth step is the synthesis of compound 11h.

[0354] Compound 11f (1500 mg, 5.831 mmol) was dissolved in THF (30 mL), and compound 16 g (980.99 mg, 11.662 mmol) and p-toluenesulfonic acid (110.91 mg, 0.583 mmol) were added. The reaction was carried out at 80 °C for 3 h. The reaction was monitored by LCMS until it was complete. After concentration to remove THF, 50 mL of purified water was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography to obtain compound 11h (1570 mg, yield 78.88%).

[0355] MS M / Z(ESI): 364.1 [M+H] +

[0356] Step 5: Synthesis of compound 11i

[0357] Compound 11h (1200 mg, 3.515 mmol) was added to a three-necked flask and dissolved in THF (25 mL). The mixture was cooled to -60 °C under nitrogen protection, and then liHMDS (1 M THF) (14.061 mL, 14.061 mmol) was added. After stirring for 1 h, a THF solution of hexachloroethane (1664.31 mg, 7.031 mmol) (5 mL) was added. The mixture was kept at this temperature for 30 min and then slowly heated to room temperature. After reacting for 14 h, the reaction was monitored by LCMS until complete. The reaction was quenched with 10 mL of saturated ammonium chloride aqueous solution, diluted with 50 mL of purified water, extracted with ethyl acetate (40 mL * 3), washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a brown oily compound 11i (800 mg, yield 60.56%).

[0358] MS M / Z (ESI): 398.1 [M+Na] +

[0359] Step 6: Synthesis of compound 11j

[0360] Compound 11i (300 mg, 0.798 mmol) was dissolved in methanol (10 mL), and p-toluenesulfonic acid (15.18 mg, 0.080 mmol) was added. The reaction was carried out at room temperature for 3 h. The reaction was monitored by LCMS until complete. The solution was concentrated, and the reaction was quenched with 20 mL of purified water. The solution was extracted with ethyl acetate (20 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily compound 11j (244 mg, yield 103.07%). MS M / Z (ESI): 292.1 [M+H] +

[0361] Step 7: Synthesis of compound 11l

[0362] Compound 11k (145.96 mg, 0.679 mmol) and compound 11j (220 mg, 0.754 mmol) were dissolved in THF (10 mL). After purging the system with nitrogen three times, the temperature was lowered to 0 °C, and a THF solution of DIAD (305.02 mg, 1.508 mmol) (2 mL) was added. The reaction was carried out at room temperature for 2 h, and the reaction was monitored by LCMS to ensure complete reaction. The reaction was quenched by adding 50 mL of purified water, extracted with ethyl acetate (30 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 700 mg of crude product. The crude product was used to prepare and purify again, and concentrated to obtain compound 11l (149 mg, yield 40.42%).

[0363] MS M / Z(ESI): 488.0 [M+H] +

[0364] Step 8: Synthesis of Compound 11

[0365] Compound 11i (140 mg, 0.286 mmol) was dissolved in EtOH (10 mL), and purified water (1 mL), iron powder (159.96 mg, 2.865 mmol), and ammonium chloride solid (153.23 mg, 2.865 mmol) were added. The mixture was reacted at 50 °C for 2 h, then at 80 °C for 2 h, and then at 90 °C for 5 h. The reaction was monitored by LCMS until it was complete. The mixture was filtered and purified to obtain compound 11 (28.97 mg, yield 23.99%).

[0366] MS M / Z(ESI): 422.0 [M+H] +

[0367] 1 H NMR (400MHz, DMSO-d6) δ9.52(s,1H),9.21(s,1H),7.75(d,J=2.3Hz,1H),7.42(d,J=2.2Hz,1H),4.56(t,J=3.3Hz,2H),4.46(tt,J=11.3,4.2 Hz,1H),4.30(s,2H),3.96(dd,J=11.1,4.4Hz,2H),3.48(td,J=11.9,2.0Hz,2H),2.00(qd,J=12.2,4.6Hz,2H),1.81(dd,J=13.1,4.1Hz,2H).

[0368] Example 12

[0369]

[0370] The first step is the synthesis of compound 12c.

[0371] Compound 12a (300 mg, 0.798 mmol), compound 12b (137.14 mg, 1.597 mmol), tricyclohexylphosphine (44.77 mg, 0.160 mmol), and K3PO4 (338.88 mg, 1.597 mmol) were dissolved in dioxane (10 mL), and Pd(dppf)Cl2 (58.41 mg, 0.080 mmol) was added. The mixture was reacted at 100 °C for 14 h under nitrogen protection. The reaction was monitored by LCMS until complete. The mixture was concentrated and purified by silica gel column chromatography to obtain compound 12c (280 mg, yield 91.99%).

[0372] MS M / Z(ESI): 298.2 [M-83] +

[0373] The second step involves the synthesis of compound 12d.

[0374] Compound 12c (280 mg, 0.734 mmol) was dissolved in methanol (10 mL), and p-toluenesulfonic acid (13.96 mg, 0.073 mmol) was added. After reacting at room temperature for 12 h, the reaction was monitored by LCMS until it was complete. The solution was concentrated and purified by silica gel column chromatography to give the product, a yellow solid compound 12d (145 mg, yield 66.44%).

[0375] MS M / Z(ESI): 298.2 [M+H] +

[0376] The third step involves the synthesis of compound 12f.

[0377] Compound 12e (104.87 mg, 0.488 mmol), compound 12d (145 mg, 0.488 mmol), and PPh3 (191.88 mg, 0.732 mmol) were dissolved in THF (10 mL). After purging the system three times with nitrogen, a THF solution of DIAD (197.24 mg, 0.975 mmol) (2 mL) was added at 0 °C. The reaction was allowed to proceed for 3 h at room temperature. The reaction was monitored by LC-MS until complete. The solution was concentrated and purified by silica gel column chromatography to give compound 12f (130 mg, yield 53.92%). MS M / Z (ESI): 494.1 [M+H] +

[0378] Step 4: Synthesis of Compound 12

[0379] Compound 12f (120 mg, 0.243 mmol) was dissolved in EtOH (10 mL), and iron powder (135.55 mg, 2.428 mmol), ammonium chloride (129.85 mg, 2.428 mmol), and purified water (1 mL) were added. The mixture was reacted at 95 °C for 12 h. The reaction was monitored by LC-MS until complete. The solution was filtered, concentrated, and compound 12 (5.06 mg, yield 4.87%) was obtained. MS M / Z (ESI): 428.1 [M+H] +

[0380] 1H NMR(400MHz, DMSO-d6)δ9.15(s,1H),9.01(s,1H),7.70(d,J=2.2Hz,1H),7.36(d,J=2.2Hz,1H),4.61–4.43(m,3H),4.25(s,2H), 3.98(d,J=9.3Hz,2H),3.48(d,J=11.6Hz,2H),2.03(t,J=15.2Hz,2H),1.82–1.65(m,3H),1.04–0.93(m,2H),0.77–0.66(m,2H).

[0381] Example 13

[0382]

[0383] The first step is the synthesis of compound 13c.

[0384] Compound 13a (1000 mg, 6.190 mmol) and compound 13b (1000 mg, 6.535 mmol) were dissolved in DMF (12 mL), and cesium carbonate (4033.92 mg, 12.381 mmol) was added. The mixture was reacted at 100 °C for 14 h under a sealed container. The reaction was monitored by LCMS until complete. 60 mL of purified water was added, and the mixture was extracted with ethyl acetate (30 mL * 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography to obtain compound 13c (770 mg, yield 53.24%).

[0385] MS M / Z(ESI): 234.1 [M+H] +

[0386] The second step involves the synthesis of compound 13d.

[0387] Compound 13c (770 mg, 3.296 mmol) was suspended in purified water (25 mL), and KOH (3698.77 mg, 65.92 mmol) was added. The reaction was carried out at 140 °C for 3 h. The reaction was monitored by LC-MS until complete. The pH was adjusted to 1 with HCl (1 N) aqueous solution, extracted with ethyl acetate (30 mL * 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oily compound 13d (300 mg, yield 42.29%). MS M / Z (ESI): 216.2 [M+H] +

[0388] The third step involves the synthesis of compound 13f.

[0389] Compound 13e (348.41 mg, 2.788 mmol) was dissolved in DMF (5 mL), and compound 13d (300 mg, 1.394 mmol) and cesium carbonate (908.38 mg, 2.788 mmol) were added. The mixture was reacted at 100 °C for 2 h. After the reaction was monitored by LCMS to ensure completion, 20 mL of purified water was added, and the mixture was extracted with ethyl acetate (15 mL * 3). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to give compound 13f (180 mg, yield 42.88%). MS M / Z (ESI): 260.2 [M + H] +

[0390] The fourth step is the synthesis of compound 13h.

[0391] Compound 13f (149.29 mg, 0.576 mmol), compound 13g (180 mg, 0.837 mmol), and PPh3 (273.16 mg, 1.041 mmol) were dissolved in THF (10 mL). After purging the system with nitrogen three times, the mixture was cooled to 0 °C, and a THF (2 mL) solution of DIAD (280.78 mg, 1.389 mmol) was added. The mixture was reacted at room temperature for 3 h, and the reaction was monitored by LCMS until it was complete. The mixture was then concentrated and purified by silica gel column chromatography to obtain the crude product. The crude product was further prepared to obtain compound 13h (80 mg, yield 30.51%).

[0392] Step 5: Synthesis of Compound 13

[0393] Compound 13h (80 mg, 0.175 mmol) was dissolved in ethanol (10 mL), and purified water (1 mL), iron powder (97.90 mg, 1.753 mmol), and ammonium chloride (93.78 mg, 1.753 mmol) were added. The mixture was reacted at 95 °C for 14 h. The reaction was monitored by LC-MS until complete. The mixture was filtered and purified to obtain compound 13 (13.5 mg, yield 19.75%). MS M / Z (ESI): 390.1 [M+H] +

[0394] 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),9.15(s,1H),7.68(d,J=2.3Hz,1H),7.34(d,J=2.3Hz,1 H), 4.62 (s, 1H), 4.52 (d, J = 3.3Hz, 2H), 4.33 (s, 2H), 3.80 (s, 2H), 2.26 (s, 3H), 1.11 (s, 6H).

[0395] Example 14

[0396]

[0397] The first step is the synthesis of compound 14c.

[0398] Compound 14a (500 mg, 3.095 mmol) and compound 14b (566.10 mg, 4.643 mmol) were dissolved in DMF (5 mL), and pyridine (1224.16 mg, 15.476 mmol) and copper acetate (281.09 mg, 1.548 mmol) were added. After reacting with air at 95 °C for 14 h, 30 mL of purified water was added, and the mixture was extracted with ethyl acetate (25 mL * 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography to obtain compound 14c (300 mg, yield 40.79%).

[0399] ESI-MS: 238.0 [M+H] +

[0400] The second step involves the synthesis of compound 14d.

[0401] Compound 14c (500 mg, 2.104 mmol) was dissolved in purified water (10 mL), and NaOH (1683.22 mg, 42.080 mmol) was added. The mixture was sealed and reacted at 140 °C for 12 h. The reaction was monitored by LCMS until it was complete. The pH was adjusted to 1-2 with 1 N HCl, and the mixture was extracted with EA (30 mL * 3). The mixture was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 14d (200 mg, yield 43.36%).

[0402] ESI-MS: 220.1 [M+H] +

[0403] The third step involves the synthesis of compound 14f.

[0404] Compound 14e (207.06 mg, 0.821 mmol) and compound 14d (180 mg, 0.821 mmol) were dissolved in DMF (10 mL), potassium carbonate (340.46 mg, 2.464 mmol) was added, and the mixture was stirred at 100 °C for 1 h. 60 mL of purified water was added, and the mixture was extracted with EA (30 mL * 3). The mixture was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 14f (251 mg, yield 78.29%).

[0405] ESI-MS: 291.2 [M+H-100] +

[0406] Step 4: Synthesis of the salt of compound 14g

[0407] Compound 14f (251 mg, 0.643 mmol) was dissolved in DCM (10 mL), TFA (2.5 mL) was added, and the mixture was stirred at room temperature for 2 h. After concentration, 14 g of crude product (260 mg) was obtained and used directly in the next reaction.

[0408] Step 5: Synthesis of compound 14i

[0409] Compound 14h (218.65 mg, 1.192 mmol) and compound 14g (241 mg, 0.596 mmol) were dissolved in i-PrOH (10 mL), and DIEA (770.37 mg, 5.960 mmol) was added. The mixture was stirred at room temperature for 1 h, concentrated, and then purified by silica gel column chromatography to obtain compound 14i (110 mg, yield 42.21%).

[0410] ESI-MS: 436.9 [M+H] +

[0411] Step 6: Synthesis of Compound 14

[0412] Compound 14i (100 mg, 0.229 mmol) was dissolved in ethanol (10 mL), and iron powder (127.70 mg, 2.287 mmol), ammonium chloride (122.32 mg, 2.287 mmol), and purified water (1 mL) were added. The mixture was reacted at 105 °C for 14 h, filtered, and the filtrate was concentrated to give a white solid compound 14 (25.6 mg, yield 30.19%). ESI-MS: 371.0 [M+H] +

[0413] 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),7.84(s,1H),7.52–7.45(m,4H),7.32(tt,J=6.3,2.2Hz,1H),6.90(d,J=7.5Hz,1H),4.4 0–4.27(m,2H),3.92(d,J=6.4Hz,1H),2.26(s,3H),1.80–1.70(m,1H),1.65(dd,J=13.8,10.7Hz,1H),1.26(d,J=7.1Hz,3H).

[0414] Example 15

[0415]

[0416] The first step is the synthesis of compound 15c.

[0417] Compound 15a (1 g, 6.190 mmol) was dissolved in DMF (30 mL), and cesium carbonate (9.17 g, 28.157 mmol) and compound 15b (3 g, 14.079 mmol) were added. The reaction was carried out at 100 °C for 12 h. After the reaction was monitored by LCMS to be complete, 120 mL of purified water was added, and the mixture was extracted with ethyl acetate (60 mL * 3). The extract was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography to give compound 15c (180 mg, yield 4.35%). MS M / Z (ESI): 294.0 [M + H] +

[0418] The second step involves the synthesis of compound 15d.

[0419] Compound 15c (180 mg, 0.613 mmol) was dissolved in purified water (10 mL), and NaOH (490.26 mg, 12.257 mmol) was added. The reaction was carried out at 140 °C for 4 h. The reaction was monitored by LCMS until it was complete. The pH was adjusted to 1-2 with HCl (1N), extracted with ethyl acetate (20 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 15d (150 mg, yield 88.92%).

[0420] MS M / Z(ESI): 276.0 [M+H] +

[0421] The third step involves the synthesis of compound 15f.

[0422] Compound 15e (148.50 mg, 0.785 mmol) and compound 15d (180 mg, 0.654 mmol) were dissolved in THF (8 mL), and PPh3 (257.26 mg, 0.981 mmol) was added. Under nitrogen protection, a THF solution of DIAD (396.66 mg, 1.962 mmol) was added dropwise at 0 °C. After reacting at room temperature for 3 h, the reaction was monitored by LCMS until complete. 50 mL of purified water was added, and the mixture was extracted with ethyl acetate (15 mL * 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 15f, which was used directly in the next step. MS M / Z (ESI): 347.1 [M-100+H] +

[0423] The fourth step involves the synthesis of 15g of compound.

[0424] Compound 15f (500 mg, 1.12 mmol) was dissolved in EA (10 mL), and 4 M HCl / EA (5 mL) solvent was added. The mixture was stirred at room temperature for 1 h, and the reaction was monitored by LCMS until complete. 15 mL of purified water was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution, and then extracted with EA (20 mL x 3). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated to give 15 g (200 mg, yield 51.56%) of the compound. MS M / Z (ESI): 347.1 [M+H] +

[0425] Step 5: Synthesis of compound 15i

[0426] Compound 15h (150 mg, 0.818 mmol) was dissolved in DCM (10 mL), and TEA (277.51 mg, 2.742 mmol) and compound 15g (190 mg, 0.548 mmol) were added. The mixture was reacted at room temperature for 14 h. The reaction was monitored by LC-MS until complete, and the solution was directly concentrated and purified by silica gel column chromatography to give compound 15i (180 mg, yield 66.52%). MS M / Z (ESI): 493.0 [M+H] +

[0427] Step 6: Synthesis of Compound 15

[0428] Compound 15i (200 mg, 0.405 mmol) was dissolved in isopropanol (9 mL), and iron powder (226.37 mg, 4.054 mmol), ammonium chloride (216.84 mg, 4.054 mmol), and purified water (1 mL) were added. The mixture was reacted at 95 °C for 14 h. The reaction was monitored by LC-MS until complete. The mixture was filtered to obtain compound 15 (20.74 mg, yield 11.98%). MS M / Z (ESI): 427.0 [M+H] +

[0429] 1 H NMR (400MHz, DMSO-d6) δ7.75 (s, 1H), 4.40 (tt, J = 10.8, 3.7Hz, 1H), 4.32–4. 21(m,1H),4.16(t,J=11.1Hz,1H),3.84–3.73(m,1H),3.34(t,J=13.8Hz,2H ),3.21–3.10(m,2H),2.46–2.29(m,2H),2.12(s,4H),2.04(d,J=10.9Hz,1H ),1.78–1.66(m,1H),1.57(dd,J=15.6,10.5Hz,1H),1.20(d,J=7.1Hz,3H).

[0430] Example 16

[0431]

[0432] Synthesis of compound 16b in step one

[0433] Compound 16a (5000 mg, 25.361 mmol) and silver sulfate (4500 mg, 14.432 mmol) were added to a 100 mL three-necked flask, followed by 100 mL of sulfuric acid. The mixture was stirred until dissolved, and then bromine (1.562 mL, 30.411 mmol) was added. The mixture was stirred at room temperature for 2 h in the dark. The reaction solution was added dropwise to an ice-water mixture (1000 mL), filtered, and the filter cake was washed with water. The filtrate was then extracted with dichloromethane (300 mL x 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 15 mL of dichloromethane was added to the residue. The mixture was then frozen (-20 °C) for 1 week, filtered, and dried under vacuum to give a brownish-red solid, 16b (3300 mg, yield 47.14%). MSM / Z(ESI):258[M-18+1] +

[0434] The second step involves the synthesis of compound 16d.

[0435] Compound 16b (1500 mg, 5.434 mmol) was dissolved in DMF (20 mL), then N-methylimidazole (2231 mg, 27.171 mmol), TCFH N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (3049 mg, 10.867 mmol), and then compound 16c (2231 mg, 27.171 mol) were added. After stirring at room temperature for 2 h, the reaction was monitored by LCMS to ensure complete reaction. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the mixture was shaken well. The aqueous layer was washed successively with saturated sodium bicarbonate aqueous solution (100 mL), saturated saline solution (100 mL), 10% sodium dihydrogen phosphate (100 mL), and saturated saline solution (100 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude yellow solid 16d (2193 mg), which was directly added to the next reaction.

[0436] MS M / Z(ESI): 304 [M-100+1] +

[0437] The third step involves the synthesis of compound 16e.

[0438] Compound 16d (2700 mg, 6.680 mmol) was dissolved in ethyl acetate (50 mL) under an ice-water bath, and then 4 M ethyl hydrochloride solution (50 mL) was added. The mixture was stirred at 0 °C for 5 h, and the reaction was monitored by LCMS until complete. The reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL), and dried under vacuum to obtain a pale yellow solid 16e (2100 mg), which was directly added to the next reaction.

[0439] MS M / Z(ESI): 304[M+1] +

[0440] The fourth step is the synthesis of compound 16f.

[0441] Compound 16e (2100 mg, 6.166 mmol), CuI (235 mg, 1.234 mmol), L-proline (284 mg, 2.467 mmol), and K2CO3 (3817 mg, 27.619 mmol) were suspended in DMSO (20 mL). The mixture was stirred at 90 °C for 5 h. The reaction was monitored by LCMS until complete. Saturated ammonium chloride aqueous solution (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL * 5). The aqueous phase was adjusted to pH 3 with HCl aqueous solution (1 M) and then extracted with dichloromethane (100 mL * 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude brown solid 16f (1000 mg), which was directly added to the next reaction.

[0442] MS M / Z(ESI): 224[M+1] +

[0443] Step 5: Synthesis of compound 16h

[0444] Compound 16f (200 mg, 0.896 mmol), compound 16g (235 mg, 1.341 mmol), and PPh3 (540 mg, 2.061 mmol) were dissolved in tetrahydrofuran (20 mL), cooled to 0 °C in an ice-water bath, and then DIAD (417 mg, 2.061 mmol) was added. The mixture was then allowed to warm naturally to room temperature and stirred for 12 h. The reaction was monitored by LCMS to ensure complete reaction.

[0445] Compound 16f (800 mg, 3.584 mmol), compound 16g (942 mg, 5.376 mmol), and PPh3 (2350 mg, 8.961 mmol) were dissolved in tetrahydrofuran (80 mL), then cooled to 0 °C in an ice-water bath, and then DIAD (1812 mg, 8.961 mmol) was added. The mixture was then allowed to warm naturally to room temperature and stirred for 14 h. The reaction was monitored by LCMS to ensure complete reaction.

[0446] Combine the above reaction solutions, add purified water (100 mL) and ethyl acetate (100 mL), shake well, separate the layers, extract the aqueous layer once more with ethyl acetate (50 mL), wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, pass the residue through a silica gel column to obtain 3000 mg of crude yellow solid (containing phosphine oxychloride) after 16 hours, and directly add it to the next reaction.

[0447] Step 6: Synthesis of compound 16i

[0448] The crude product from 16h was dissolved in ethyl acetate (20mL), and 4M ethyl hydrochloride solution (20mL) was added under ice-water bath. The mixture was then naturally heated to room temperature and stirred for 14h. The reaction was monitored by LCMS until complete. The mixture was filtered and dried under vacuum to obtain 550mg of the pale yellow solid crude product 16i, which was directly added to the next step of the reaction.

[0449] MS M / Z(ESI): 281[M+1] +

[0450] Step 7: Synthesis of compound 16k

[0451] Compound 16i (290 mg, 0.916 mmol) was dissolved in isopropanol (10 mL), and triethylamine (556 mg, 5.495 mmol) and 16j (176 mg, 0.960 mmol) were added. The mixture was stirred at room temperature for 72 h, and the reaction was monitored by LCMS until complete. The mixture was concentrated under reduced pressure, and then ethyl acetate (50 mL) and purified water (50 mL) were added to the reaction solution. The mixture was shaken well, and the aqueous phase was extracted with ethyl acetate (30 mL * 2). The organic layers were combined and washed successively with purified water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to give a pale yellow solid 16k (370 mg, yield 95.49%).

[0452] MS M / Z(ESI): 397[M+1] +

[0453] Step 8: Synthesis of compound 16l

[0454] Compound 16k (350 mg, 0.819 mmol) was dissolved in ethanol (20 mL) and water (4 mL). Iron powder (431 mg, 7.718 mmol) and ammonium chloride (413 mg, 7.721 mmol) were added. The mixture was heated in an oil bath to 90 °C and stirred for 3 h. The reaction was monitored by LCMS until complete. The reaction solution was concentrated under reduced pressure. The residue was added to ethyl acetate (100 mL) and purified water (100 mL), shaken well, and separated into layers. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 330 mg of crude gray solid 16k, which was directly used in the next reaction.

[0455] MS M / Z(ESI): 427[M+1] +

[0456] Step 9: Synthesis of Compound 16

[0457] Compound 16 (190 mg, 0.478 mmol) was dissolved in THF (15 mL), and then sodium tert-butoxide (138 mg, 1.436 mmol), 2-(di-tert-butylphosphine)biphenyl (28 mg, 0.094 mmol), and palladium acetate (11 mg, 0.049 mmol) were added sequentially. After degassing for 5 minutes, the mixture was stirred in an oil bath at 70 °C for 18 h under argon protection. The reaction was monitored by LCMS until complete. Saturated ammonium chloride aqueous solution (100 mL) and ethyl acetate (100 mL * 2) were added to the reaction solution for extraction. The mixture was washed with purified water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 90 mg of crude product. Then, compound 16 (37.48 mg, yield 41.81%) was obtained by high performance liquid chromatography.

[0458] MS M / Z(ESI): 361[M+1] +

[0459] 1 H NMR (400MHz, DMSO-d6) δ7.93(s,1H),7.86(s,1H),7.30(d,J=9.1Hz,1H),7.18(d,J=9.1Hz,1H),6.90(s, 1H), 4.82 (d, J = 12.1Hz, 1H), 4.34 (s, 1H), 4.03 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 1.15 (d, J = 7.2Hz, 3H).

[0460] Example 17

[0461]

[0462] The first step is the synthesis of compound 17c.

[0463] Compound 17a (900 mg, 6.564 mmol), compound 17b (1265 mg, 7.220 mmol), and PPh3 (4304 mg, 16.410 mmol) were dissolved in tetrahydrofuran (40 mL), cooled to 0 °C in an ice-water bath, and then DIAD (3318 mg, 16.410 mmol) was added. The mixture was then heated to room temperature and stirred for 14 h. The reaction was monitored by LCMS until complete. The reaction was quenched by adding purified water (100 mL) to the reaction solution. The mixture was extracted with ethyl acetate (100 mL * 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give colorless solid 17c (1100 mg, yield 56.94%).

[0464] The second step involves the synthesis of compound 17e.

[0465] Compound 17c (800 mg, 2.718 mmol), compound 17d (1959 mg, 13.590 mmol), and Na2CO3 (2880 mg, 27.180 mmol) were suspended in EtOH (15 mL). The mixture was sealed in an oil bath and stirred at 100 °C for 72 h. The reaction was monitored by LCMS until complete. The mixture was concentrated under reduced pressure. Then, purified water (100 mL) and ethyl acetate (100 mL) were added to the residue and the mixture was shaken well. The aqueous phase was extracted once again with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a colorless and transparent solid 17e (720 mg, yield 82.68%).

[0466] MS M / Z(ESI): 321[M+1] +

[0467] The third step involves the synthesis of compound 17f.

[0468] Compound 17e (720 mg, 2.247 mmol) was dissolved in EA (10 mL), and then 4 M hydrogen chloride / ethyl acetate solution (10 mL) was added. After stirring at room temperature for 12 h, the reaction was monitored by LCMS until it was complete. The solution was concentrated under reduced pressure to obtain 600 mg of pale yellow solid 17f, which was directly added to the next reaction.

[0469] MS M / Z(ESI): 321[M+1] +

[0470] The fourth step involves the synthesis of compound 17h.

[0471] Compound 17f (600 mg, 2.337 mmol) was dissolved in isopropanol (20 mL), then Et3N (3.248 mL, 23.370 mmol) was added, and the mixture was stirred for 5 min. Then 2,4,5-trichloropyrimidine (429 mg, 2.337 mmol) was added, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure. Then ethyl acetate (100 mL) and purified water (100 mL) were added to the residue, and the mixture was shaken well. The layers were separated, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the residue was passed through a silica gel column to give a pale yellow solid 17h (560 mg, yield 65.25%).

[0472] MS M / Z(ESI): 367[M+1] +

[0473] Step 5: Synthesis of Compound 17

[0474] Compound 17h (120 mg, 0.327 mmol) was dissolved in THF (10 mL), and then sodium tert-butoxide (126 mg, 1.307 mmol), 2-(di-tert-butylphosphine)biphenyl (49 mg, 0.163 mmol), and palladium acetate (18 mg, 0.082 mmol) were added sequentially. After degassing for 5 min, the mixture was stirred in an oil bath at 78 °C for 14 h under argon protection. The reaction was monitored by LCMS until complete. The reaction solution was filtered, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a crude product. The crude product was further slurried in a PE:EA = 5:1 mixed solvent (5 mL) for 16 h, filtered, and freeze-dried to obtain compound 17 (11.47 mg, yield 10.08%).

[0475] MS M / Z(ESI): 331[M+1] +

[0476] 1 H NMR (400MHz, DMSO-d6) δ9.51(s,1H),7.89(s,1H),7.29(t,J=8.0Hz,1H),7.13(d,J=8.3Hz,1H),6.89(d,J=7.7Hz,1H),6.67(d, J=6.4Hz,1H),4.70(d,J=13.1Hz,1H),4.21(q,J=7.1Hz,1H),4.05(dd,J=13.1,7.4Hz,1H),3.87(s,3H),1.15(d,J=7.3Hz,3H).

[0477] Example 18

[0478]

[0479] The first step is the synthesis of compound 18c.

[0480] Compound 18a (900 mg, 6.564 mmol), compound 18b (1150 mg, 6.564 mmol), and PPh3 (4304 mg, 16.410 mmol) were dissolved in tetrahydrofuran (40 mL), cooled to 0 °C in an ice-water bath, and then DIAD (3.253 mL, 16.410 mmol) was added. The mixture was then naturally heated to room temperature and stirred for 14 h. The reaction was monitored by LCMS until complete. Purified water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 2). The extract was then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1800 mg of colorless oily compound 18c, which was directly added to the next reaction.

[0481] The second step involves the synthesis of compound 18e.

[0482] Compound 18c (1300 mg, 9.481 mmol), compound 18d (3183 mg, 22.084 mmol), Na2CO3 (4681 mg, 44.168 mmol), and DIEA (685 mg, 5.300 mmol) were suspended in DMA (15 mL). The mixture was sealed in an oil bath and stirred at 130 °C for 14 h. The reaction was monitored by LCMS until complete. The reaction solution was concentrated under reduced pressure. Then, purified water (100 mL) and ethyl acetate (100 mL) were added to the residue and shaken well. The aqueous phase was extracted once again with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 18e (380 mg, yield 13.62%).

[0483] MS M / Z(ESI): 321[M+1] +

[0484] The third step involves the synthesis of compound 18f.

[0485] Compound 18e (300 mg, 0.936 mmol) was dissolved in EA (10 mL), and then 4 M ethyl hydrochloride (5 mL) was added. The mixture was stirred at room temperature for 2 h, and the reaction was monitored by LCMS until complete. The mixture was concentrated under reduced pressure and then slurried with ethyl acetate (30 mL) for 2 h. After filtration, the mixture was dried under vacuum to obtain a crude white solid 18f (290 mg), which was used directly in the next step.

[0486] MS M / Z(ESI): 221[M+1] +

[0487] The fourth step involves the synthesis of compound 18 hours later.

[0488] Compound 18f (250 mg, 0.974 mmol) was dissolved in isopropanol (20 mL), Et3N (1.353 mL, 9.738 mmol) was added, and the mixture was stirred for 5 min. Then, 18 g (178.61 mg, 0.974 mmol) was added, and the mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS until complete, and the mixture was concentrated under reduced pressure. Purified water (100 mL) and ethyl acetate (100 mL) were added to the residue, and the mixture was shaken well. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a pale yellow solid 18 h (160 mg, yield 44.74%).

[0489] MS M / Z(ESI): 367[M+1] +

[0490] Step 5: Synthesis of Compound 18

[0491] Compound 18h ​​(120 mg, 0.326 mmol) was dissolved in dioxane (36 mL), followed by the addition of XPHOS (124 mg, 0.262 mmol), Pd2(dba)3 (60 mg, 0.066 mmol), and Cs2CO3 (212 mg, 0.654 mmol). The mixture was degassed for 10 min, stirred in an oil bath at 78 °C for 12 h under argon protection, and then saturated ammonium chloride aqueous solution (50 mL) and ethyl acetate (50 mL) were added to the reaction solution. The mixture was shaken well, and the layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL), and the organic layers were combined. The mixture was then washed successively with purified water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by preparative high-performance liquid chromatography (HPLC) to obtain a white solid 18 (23.40 mg, yield 21.65%).

[0492] MS M / Z(ESI): 331[M+1] +

[0493] 1 H NMR (400MHz, DMSO-d6) δ9.69(s,1H),7.87(s,1H),7.63(d,J=2.5Hz,1H),7.33(d,J=9.0Hz,1H), 7.09(t,J=6.2Hz,1H),6.93(dd,J=9.1,2.3Hz,1H),4.14(s,2H),3.86(s,3H),2.05–1.86(m,2H).

[0494] Example 19

[0495]

[0496] The first step is the synthesis of compound 19c.

[0497] Compound 19a (450 mg, 1.980 mmol), compound 19b (525 mg, 2.773 mmol), and PPh3 (1298 mg, 4.951 mmol) were dissolved in tetrahydrofuran (20 mL), cooled in an ice-water bath, and then DIAD (1000 mg, 4.951 mmol) was added. The mixture was allowed to warm naturally to room temperature and stirred for 14 h. Then, purified water (100 mL) was added to the reaction solution, and ethyl acetate (100 mL * 2) was used for extraction. The mixture was then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1000 mg of crude white solid 19c, which was directly added to the next reaction.

[0498] The second step involves the synthesis of compound 19d.

[0499] The crude compound 19c was dissolved in EA (20 mL), and then 4 M HCl / EA (30 mL) solution was added. The mixture was stirred at room temperature for 12 h, concentrated under reduced pressure, and then ethyl acetate (50 mL) was added to the residue and stirred for 4 h. The mixture was filtered, the filter cake was washed with ethyl acetate, and dried under vacuum to give a white solid compound 19d (600 mg, two-step yield 90.5%).

[0500] MS M / Z(ESI): 279[M+1] +

[0501] The third step involves the synthesis of compound 19f.

[0502] Compound 19d (560 mg, 1.673 mmol) and compound 19e (506 mg, 1.840 mmol) were dissolved in isopropanol (20 mL), and then triethylamine (2.325 mL, 16.727 mmol) was added. After stirring at room temperature for 14 h, the mixture was concentrated to dryness under reduced pressure. Purified water (100 mL) and ethyl acetate (100 mL) were added to the residue, and the mixture was shaken well and separated into layers. The aqueous layer was extracted again with ethyl acetate (50 mL * 2). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless and transparent solid 19f (900 mg), which was directly added to the next reaction.

[0503] MS M / Z(ESI): 537[M+1] +

[0504] The fourth step involves the synthesis of compound 19h.

[0505] Compound 19g (398mg, 2.012mmol), compound 19f (900mg, 1.677mmol), and Na2CO3 (178mg, 1.677mmol) were dissolved in a mixed solvent of toluene (56mL), anhydrous ethanol (14mL), and purified water (3mL). The mixture was then degassed for 3 min, and Pd(dppf)Cl2.CH2Cl2 (1373mg, 1.677mmol) was added. The mixture was degassed for 5 min, and then stirred in an oil bath at 85°C for 14 h. The mixture was filtered, concentrated under reduced pressure, and purified water (100mL) and ethyl acetate (100mL) were added to the residue. The mixture was shaken well, and the layers were separated. The aqueous layer was extracted with ethyl acetate (50mL*2). The organic layers were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give a brown solid 19h (700mg, yield 86.8%).

[0506] MS M / Z(ESI): 481[M+1] +

[0507] Step 5: Synthesis of compound 19i

[0508] Compound 19h (700 mg, 1.455 mmol) was dissolved in AcOH (10 mL, 174.688 mmol) and stirred at 120 °C for 2 h. The mixture was then concentrated under reduced pressure. Ethyl acetate (100 mL) and saturated sodium bicarbonate aqueous solution (100 mL) were added to the residue, and the mixture was shaken well and separated into layers. The aqueous layer was extracted with ethyl acetate (50 mL), and the organic layer was washed with saturated brine (100 mL). The mixture was dried over anhydrous sodium sulfate, filtered through silica gel, and concentrated under reduced pressure to give a brown solid compound 19i (450 mg, yield 71.1%).

[0509] MS M / Z(ESI): 435[M+1] +

[0510] Step 6: Synthesis of compound 19j

[0511] Compound 19i (200 mg, 0.460 mmol) was dissolved in ethanol (10 mL) and purified water (1 mL), then iron powder (257 mg, 4.599 mmol) and ammonium chloride (246 mg, 4.599 mmol) were added. The mixture was heated in an oil bath to 90 °C and stirred for 6 hours. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated under reduced pressure. The residue was added to ethyl acetate (100 mL) and purified water (100 mL), shaken well, and separated into layers. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown solid crude product 19j (200 mg), which was directly used in the next reaction.

[0512] MS M / Z(ESI): 405[M+1] +

[0513] Step 7: Synthesis of compound 19k

[0514] Compound 19j (200 mg, 0.494 mmol) was dissolved in dioxane (15 mL), and the mixture was evacuated three times. Then, Cs2CO3 (322 mg, 0.988 mmol), Pd2(dba)3 (90 mg, 0.099 mmol), and XPHOS (188 mg, 0.395 mmol) were added sequentially. After degassing for 5 min, the mixture was stirred in an oil bath at 85 °C for 3 h under nitrogen protection. The mixture was filtered, and saturated ammonium chloride aqueous solution (50 mL) and ethyl acetate (50 mL) were added to the filtrate. The mixture was shaken well, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL * 2), and the organic phase was washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give a pale yellow solid 19k (70 mg, yield 38.46%).

[0515] MS M / Z(ESI): 369[M+1] +

[0516] Step 8: Synthesis of Compound 19

[0517] Compound 19k (7.5 mg, 0.020 mmol) was dissolved in THF (0.5 mL), and then NCS (2.45 mg, 0.018 mmol) was added. The mixture was heated to room temperature and stirred for 6 h. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL * 3). The organic phase was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate.

[0518] Compound 19k (15 mg, 0.041 mmol) was dissolved in THF (1 mL), and then NCS (5.44 mg, 0.041 mmol) was added. The mixture was heated to room temperature and stirred for 6 h. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL * 3). The organic phase was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate.

[0519] Compound 19k (23 mg, 0.062 mmol) was dissolved in THF (2 mL), and then NCS (8.34 mg, 0.062 mmol) was added. The mixture was heated to room temperature and stirred for 6 h. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL * 3). The organic phase was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate.

[0520] The above dried liquids were combined, filtered, concentrated under reduced pressure, and the residues were separated and purified by TLC thin-layer chromatography. Then, compound 19 (3.47 mg, yield 6.98%) was prepared by high performance liquid chromatography.

[0521] MS M / Z(ESI): 403[M+1] +

[0522] 1 H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.47(s,1H),7.31(s,1H),4.54–4.46(m,1H),4.44–4.36(m,1H),4.32–4 .10(m,1H),4.00–3.85(m,2H),3.45(t,J=11.9Hz,2H),2.23(s,3H),2.04–1.65(m,6H),1.52(d,J=7.1Hz,3H).

[0523] Experimental Example 1

[0524] 1. Reagents and consumables

[0525]

[0526]

[0527] 2. Instruments

[0528]

[0529] 3. In-Cell Western Blotting

[0530] LRRK2-G2019S pSer935-Hek 293 cells (DMEM medium, 10% FBS, 1% PS, 1 mg / ml G418 culture) were seeded into 384-well plates and cultured overnight at 37°C with 5% CO2. The next day, serially diluted compounds (0.02-3000 nM) were added and incubated at 37°C with 5% CO2 for 2 h. Cells were fixed with 8% fixative and incubated at room temperature for 20 minutes. Each well was washed twice with PBS, followed by methanol and incubation at room temperature for 10 minutes. Each well was washed twice with PBS, followed by Li-Cor blocking buffer and incubation at room temperature for 1 hour. The blocking buffer was removed, and primary antibodies (Anti-LRRK2 phospho S935 (abcam, ab133450) and GAPDH (D4C6R) Mouse mAb (CST, 97166S)) were added and incubated overnight at 4°C. Cells were washed three times with PBST (PBS + 0.05% Tween-20), followed by fluorescent secondary antibodies (IRDye 680RD & IRDye 800CW) and incubation at room temperature in the dark for 1 hour. Cells were washed three times with PBST (PBS + 0.05% Tween-20), and the plate was centrifuged upside down (1000 rpm x 1 min) and scanned using an Odyssey CLx. Based on the measured absorbance values, the inhibition rate at each concentration of the compound was calculated, and the IC50 was obtained by fitting the curve. 50 value.

[0531]

[0532]

Claims

1. A compound of Formula I or Formula II, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formula of Formula I or Formula II is as follows: wherein, Ring A is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally which can be further substituted with one or more substituents; Ar1is selected from aryl or heteroaryl, optionally which can be further substituted with one or more substituents; X1is selected from N, CR1, or C; R1is absent or selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally which can be further substituted with one or more substituents; R, R2, R3, R4, R5are each independently selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally which can be further substituted with one or more substituents; Optionally, R1in Formula I can be linked with a substituent on Ar1to form a ring, or, R3in Formula II can be linked with a substituent on Ar1to form a ring.

2. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein, selected from the group consisting of: R1, R2are defined as above; R6, R7, R8, R9, R 10 , R 11 , R 12 are each independently selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally which can be further substituted with one or more substituents; Optionally, R9, R 11 and the carbon atom to which they are attached can together represent a carbonyl group (-CO-); and / or, Ar1is selected from wherein, R 13 , R 14 , R 15 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R" are each independently selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally which can be further substituted with one or more substituents; Optionally, R1may be taken together with R 13 , R 14 , R 15 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 or any of the substituents in R” to form a ring; Optionally, R3may be linked to R 13 , R 14 , R 15 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 or any of the substituents in R” to form a ring; When R1 is linked to a substituent on Ar1 to form a ring, or when R3 is linked to a substituent on Ar1 to form a ring, or when R1 is linked to R... 13 R 14 R 15 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 Either R or R can be connected to form a loop, or R3 and R... 13 R 14 R 15 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 24 R 25 R 26 R 27 R 28 R 29 R 30 R 31 R 32 R 33 When any one of "or R" is connected to form a ring, the resulting linker can be: -L1-L2-L3- wherein, L1, L2, L3are each independently selected from the group consisting of a bond, -O-, -C(O)-, -[C(R')2]p- n - -[OC(R')2]p- n - -[C(R')2O]p- n - -OC(O)-, -C(O)O-, -NR'-, -C(O)NR'-, -NR'C(O)-, R' is selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally which can be further substituted with one or more substituents; n is selected from 0, 1, 2, 3, 4, 5, or 6.

3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the compound of Formula I is selected from a compound of Formula I-1 or Formula I-2: wherein, R, R2, R6, R7, R8, R 14 , R 15 , L1, L2, L3 are defined as above.

4. The compound of any one of claim 3, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R 15 selected from R 1 each independently is selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally which can be further substituted with one or more substituents; Preferably, R 15 selected from 5. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein, the compound of Formula I is selected from a compound of Formula I-3, Formula I-4, or Formula I-5: wherein, R, R2, R6, R7, R8, R9, R 10 , R 19 , R 20 , R 21 , R 23 , L1, L2, L3 are defined as above.

6. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the compound of Formula I is selected from a compound of Formula I-6, Formula I-6', Formula I-7, Formula I-7', Formula I-8, or Formula I-9: wherein, R, R1, R2, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R" are as defined above.

7. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein The compound of Formula II is selected from a compound of Formula II-1 or Formula II-2: wherein, R, R4, R5, R 14 , R 15 , L1, L2, L3 are defined as above.

8. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein The compound of Formula II is selected from a compound of Formula II-3 or Formula II-4: wherein, R, R4, R5, R 28 , R 29 , R 30 , R 31 , R 33 , L1, L2, L3 are defined as above.

9. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein The compound of Formula II is selected from a compound of Formula II-5 or Formula II-6: wherein, R, R4, R5, R 17 , R 19 , R 20 , R 21 , L1, L2, L3 are defined as above.

10. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, The compound of Formula I or Formula II is selected from:

11. A pharmaceutical composition comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof.

12. Use of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, for the manufacture of a medicament for inhibiting LRRK2 kinase.

13. The use of claim 12 for the manufacture of a medicament for treating Parkinson's Disease (PD).

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