Indazole derivative and preparation method therefor and use thereof

Abstract

The present invention relates to an indazole derivative and a preparation method therefor and a use thereof. The indazole derivative can be used for LRRK2 kinase inhibition or for treating Parkinson's disease (PD).

Description

Indazole derivatives and their preparation methods and applications Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to indazole derivatives and preparation methods and applications thereof. Background Art

[0002] Parkinson's disease (PD) is the second most common neurodegenerative disorder. Its pathological changes primarily involve 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 balance disorders, as well as non-motor symptoms such as sleep disturbances, olfactory disturbances, autonomic dysfunction, and cognitive and psychiatric impairments. With disease progression, motor and non-motor symptoms of Parkinson's disease gradually worsen, impairing patients' daily activities while also imposing a significant social and medical burden.

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

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

[0005] The existing technologies WO2016036586A1, WO2018137618A1, WO2018137607A1, WO2018137573A1, etc. also disclose indazole derivatives for LRRK2 kinase inhibitors, but there are still many shortcomings and they need to be optimized or replaced. Summary of the Invention

[0006] The indazole derivatives of the present invention may be compounds of Formula I or Formula II, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or stereoisomers thereof, wherein the structural formula of Formula I or Formula II is as follows:

[0007] in,

[0008] Ring A, Ring B, and Ring C are each independently selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and optionally they may be further substituted by one or more substituents;

[0009] R1, R2, R3, and R4 are each independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may be further substituted with one or more substituents;

[0010] In some embodiments, ring A is selected from a cycloalkyl group or a heterocyclyl group, and the cycloalkyl group or heterocyclyl group is a spiro ring, a fused ring or a bridged ring, and optionally it may be further substituted by one or more substituents;

[0011] In some embodiments, ring A is selected from 3-10 membered cycloalkyl or 3-10 membered heterocyclyl, and the 3-10 membered cycloalkyl or 3-10 membered heterocyclyl is a spiro ring, a fused ring or a bridged ring, which may be further substituted by one or more substituents;

[0012] In some embodiments, Ring A is selected from:

[0013] in,

[0014] X1, X7, X 13 、X 18 are independently selected from N or CR 11 ;

[0015] X2, X3, X4, X5, X6, X8, X9, X 10 、X 11 、X 12 、X 14 、X 15 、X 16 、X 17 、X 19 、X 20 、X 21 、X 22 are independently selected from -O-, -C(O)-, -C(R 12 )2-or-N(R 13 )-;

[0016] n1, n2, n3, n4, n5, n6, n7, n8 are each independently selected from 0, 1 or 2;

[0017] n9 and n10 are independently selected from 1, 2 or 3;

[0018] R5, R6, R7, R8, R9, R 10 、R 11 、R12 、R 13 are each independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted with one or more substituents;

[0019] In some embodiments, Ring A is selected from:

[0020] in,

[0021] X2, X3, X4, X5, X6, X8, X9, X 10 、X 11 、X 12 、X 14 、X 15 、X 16 、X 17 、X 19 、X 20 、X 21 、X 22 ,n1,n2,n3,n4,n5,n6,n7,n8,n9,n10,R5,R6,R7,R8,R9,R 10 、R 11 、R 12 、R 13 is defined as described herein;

[0022] In some embodiments, n1, n2, n3, and n4 are all 1;

[0023] In some embodiments, n1, n2, and n4 are 1, and n3 is 2;

[0024] In some embodiments, n1, n2, and n3 are 1, and n4 is 2;

[0025] In some embodiments, n1 and n4 are 2, and n2 and n3 are 1;

[0026] In some embodiments, n2 and n3 are 2, and n1 and n4 are 1;

[0027] In some embodiments, n1, n2, and n4 are 2, and n3 is 1;

[0028] In some embodiments, n2, n3, and n4 are 2, and n1 is 1;

[0029] In some embodiments, n1 and n2 are 2, and n3 and n4 are 1;

[0030] In some embodiments, n1, n2, n3, and n4 are all 2;

[0031] In some embodiments, n5, n6, n7, and n8 are all 1;

[0032] In some embodiments, n5 and n8 are 1, and n6 and n7 are 0;

[0033] In some embodiments, n5 and n6 are 2, and n7 and n8 are 1;

[0034] In some embodiments, n5 and n7 are 2, and n6 and n8 are 1;

[0035] In some embodiments, n9 is 1;

[0036] In some embodiments, n9 is 2;

[0037] In some embodiments, n10 is 1;

[0038] In some embodiments, n10 is 2;

[0039] In some embodiments, n10 is 3;

[0040] In some embodiments, if the carbon atom connected to the substituent R5 is a chiral carbon, the chirality of the carbon atom can be R or S;

[0041] In some embodiments, if the carbon atom connected to the substituent R6 is a chiral carbon, the chirality of the carbon atom can be R or S;

[0042] In some embodiments, if the carbon atom connected to the substituent R7 is a chiral carbon, the chirality of the carbon atom can be R or S;

[0043] In some embodiments, if the carbon atom connected to the substituent R8 is a chiral carbon, the chirality of the carbon atom can be R or S;

[0044] In some embodiments, if the carbon atom connected to the substituent R9 is a chiral carbon, the chirality of the carbon atom can be R or S;

[0045] In some embodiments, the substituent R 11 If the carbon atom to which it is attached is a chiral carbon, the chirality of the carbon atom can be R or S;

[0046] In some embodiments, -C(R 12 )2- in the two substituents R 12 Can be the same or different, when the two substituents R 12 When the carbon atom to which it is connected has chirality, the chirality of the carbon atom can be R or S;

[0047] In some embodiments, n1, n2, n3, n4, n5, n6, n7 and / or n8 are 2, wherein the repeating units X2, X3, X5, X6, X8, X9, X 11 and / or X 12 Can be the same or different;

[0048] In some embodiments, when n9 and / or n10 are 2 or 3, the repeating unit X defined therein is 17 and / or X 22 Can be the same or different;

[0049] In some embodiments, Ring A is selected from:

[0050] In some embodiments, Ring A is selected from:

[0051] In some embodiments, Ring B is selected from aryl or heteroaryl, which may optionally be further substituted with one or more substituents;

[0052] In some embodiments, ring B is selected from 6-10 membered aryl or 5-10 membered heteroaryl, and the 3-10 membered cycloalkyl or 3-10 membered heterocyclyl is a spiro ring, a fused ring or a bridged ring, which may be further substituted by one or more substituents;

[0053] In some embodiments, Ring B is selected from:

[0054] in,

[0055] R 14 、R 15 、R 16 、R 17 are each independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted with one or more substituents;

[0056] In some embodiments, Ring B is selected from:

[0057] In some embodiments, Ring C is selected from:

[0058] in,

[0059] R 18 、R 19 、R20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 are each independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted with one or more substituents;

[0060] In some embodiments, Ring C is selected from cycloalkyl or heterocyclyl, which may be further substituted with one or more substituents;

[0061] In some embodiments, ring C is selected from 3-10 membered cycloalkyl or 3-10 membered heterocyclyl, which may be further substituted with one or more substituents;

[0062] In some embodiments, Ring C is selected from:

[0063] In some embodiments, the hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl groups may be further substituted with one or more substituents selected from hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl groups;

[0064] In some embodiments, the hydrogen, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl is preferably hydrogen, halogen, nitro, hydroxyl, thiol, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0065] In some embodiments, the hydrogen, halogen, nitro, hydroxyl, thiol, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl may be further replaced by substituted by one or more substituents 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 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0066] In some embodiments, R2 is selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted with one or more substituents;

[0067] In some embodiments, R2 is selected from hydrogen, halogen, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, which may be further substituted with one or more substituents;

[0068] In some embodiments, R2 is selected from hydrogen, chloro or methyl;

[0069] In some embodiments, R 11 、R 12 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted with one or more substituents;

[0070] In some embodiments, R 11 、R 12 are independently selected from hydrogen, halogen, hydroxy, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, which may be further substituted with one or more substituents;

[0071] In some embodiments, R 13is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted by one or more substituents;

[0072] In some embodiments, R 13 is selected from hydrogen, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, which may be further substituted by one or more substituents;

[0073] In some embodiments, R 13 is selected from alkyl, which may optionally be further substituted with one or more alkoxy groups;

[0074] In some embodiments, R 13 is selected from C1-10 alkyl, which may optionally be further substituted by one or more C1-10 alkoxy groups;

[0075] In some embodiments, R 14 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted by one or more substituents;

[0076] In some embodiments, R 14 is selected from hydrogen, halogen, hydroxy, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, which may be further substituted by one or more substituents;

[0077] In some embodiments, R 22 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted by one or more substituents;

[0078] In some embodiments, R 22 is selected from hydrogen, halogen, hydroxy, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, which may be further substituted by one or more substituents;

[0079] In some embodiments, R 23is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted by one or more substituents;

[0080] In some embodiments, R 23 is selected from hydrogen, halogen, hydroxy, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, C1-10 alkoxy, C1-10 hydroxyalkoxy, C1-10 haloalkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, which may be further substituted by one or more substituents;

[0081] In some embodiments, R 26 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted by one or more substituents;

[0082] In some embodiments, R 26 is selected from hydrogen, C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxyalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, which may be further substituted by one or more substituents;

[0083] In some embodiments, the present invention further provides a compound of Formula I-1 or Formula II-1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formula of Formula I-1 or Formula II-1 is as follows:

[0084] in,

[0085] Ring A, Ring C, R1, R2, R3, R4, R 14 、R 15 The definition of is as above;

[0086] In some embodiments, the present invention further provides a compound of Formula I-2 or Formula II-2 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formula of Formula I-2 or Formula II-2 is as follows:

[0087] in,

[0088] Ring A, R1, R2, R3, R4, R 14 、R 15 、R 18 、R 19 、R 20 、R 21 、R22 、R 23 、R 24 、R 25 The definition of is as above;

[0089] In some embodiments, the present invention further provides a compound of Formula I-3 or Formula II-3 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formula of Formula I-3 or Formula II-3 is as follows:

[0090] in,

[0091] R1, R2, R3, R4, R5, R6, R 14 、R 15 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 , X8, X9, X 11 、X 12 , n5, n6, n7, n8 are defined as above;

[0092] In some embodiments, R5 is H;

[0093] In some embodiments, R6 is H;

[0094] In some embodiments, if the carbon atom connected to the substituent R5 is a chiral carbon, the chirality of the carbon atom can be R or S;

[0095] In some embodiments, if the carbon atom connected to the substituent R6 is a chiral carbon, the chirality of the carbon atom can be R or S;

[0096] In some embodiments, R 22 is H or hydroxyalkyl; preferably C1-10 hydroxyalkyl; more preferably hydroxymethyl;

[0097] In some embodiments, R 23 is H;

[0098] In some embodiments, the substituent R 22 If the carbon atom to which it is attached is a chiral carbon, the chirality of the carbon atom can be R or S;

[0099] In some embodiments, the compound may be further specifically:

[0100] In the present invention, the substituents in “optionally which may be further substituted by one or more substituents” are selected from hydrogen, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, 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 heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl.

[0101] The present invention also relates to a pharmaceutical composition comprising the indazole derivative of the present invention;

[0102] The present invention also relates to a pharmaceutical composition comprising a compound of Formula I or Formula II of the present invention or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof;

[0103] In some embodiments, optionally, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier;

[0104] The present invention also relates to the use of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof as an LRRK2 kinase inhibitor or for the preparation of a medicament for inhibiting LRRK2 kinase;

[0105] The present invention also relates to the use of a compound of Formula I or Formula II or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof for treating Parkinson's disease (PD) or for preparing a medicament for treating Parkinson's disease (PD).

[0106] Detailed Description of the Invention

[0107] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described, as these 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 be limiting, as the scope of the present invention is limited only by the appended claims.

[0108] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety. To the extent that definitions in this section are contrary to or inconsistent with definitions listed in patents, applications, and other publications incorporated by reference herein, the definitions in this section shall prevail over the definitions incorporated by reference herein.

[0109] In the present invention, "alkyl" refers to a saturated aliphatic hydrocarbon group, which may 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 various branched-chain isomers thereof;

[0110] In the present invention, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic 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"), further 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, cycloheptatrienyl, cyclooctyl, and the like;

[0111] In the present invention, "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing the specified number of ring atoms and including at least one heteroatom selected from N, O and S as a ring member of the cycloalkyl ring. The heterocyclyl group may contain 3 to 20 ring atoms ("3-20 membered heterocyclyl"), preferably 3 to 12 ring atoms ("3-12 membered heterocyclyl"), further preferably 3 to 10 ring atoms ("3-10 membered heterocyclyl"), more preferably 3 to 8 ring atoms ("3-8 membered heterocyclyl"), and most preferably 3 to 6 ring atoms ("3-6 membered heterocyclyl"). Non-limiting examples of heterocyclyl groups include oxiranyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, and the like;

[0112] As used herein, "aryl" refers to an optionally substituted monocyclic, biaryl, or fused bicyclic or polycyclic ring system having the well-known characteristics of aromaticity, wherein at least one ring contains a completely conjugated π-electron system. Typically, an aryl group contains 6 to 20 carbon atoms ("6-20 membered aryl") as ring members, preferably 6 to 14 carbon atoms ("6-14 membered aryl") or more preferably 6 to 10 carbon atoms ("6-10 membered aryl"). Fused aryl groups can include an aryl ring fused to another aryl ring or an aryl ring fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring. The point of attachment to the base molecule on such a fused aryl ring system can 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, anthracenyl, phenanthrenyl, indanyl, indenyl, benzo[d][1,3]dioxole, and tetrahydronaphthyl;

[0113] In the present invention, " heteroaryl " refers to monocyclic, heterobiaryl or fused bicyclic or polycyclic ring system with well-known aromaticity feature, and it contains the ring atoms of specified number and comprises at least one heteroatom selected from N, O and S as the ring members in aromatic ring.Heteroatomic inclusion allows the aromaticity of 5-ring and 6-ring.Usually, heteroaryl contains 5-20 ring atoms (" 5-20 yuan heteroaryl "), preferably 5-14 ring atoms (" 5-14 yuan heteroaryl "), and more preferably 5-10 ring atoms (" 5-10 yuan heteroaryl ").Heteroaryl ring is connected to base molecule by the ring atoms of heteroaryl ring, thus keeps aromaticity.Therefore, 6 yuan heteroaryl rings can be connected to base molecule by ring C atom, and 5 yuan heteroaryl rings can be connected to base molecule by 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, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naphthyridine, and carbazole;

[0114] In the present invention, "ester group" refers to a group formed by esterifying a carboxyl group (-COOH) and a hydroxyl group (-OH) together, with the OH group removed and the H group removed. For example, the ester group can be wherein Ra and Rb may be alkyl groups, which may 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;

[0115] In the present invention, "acyl" refers to the atomic group remaining after removing the hydroxyl group from an organic acid, and has the general formula Rb-CO-, wherein Rb is defined as 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;

[0116] In the present invention, "aldehyde group" refers to -C(O)H;

[0117] In the present invention, "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above; cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, etc. are similarly defined;

[0118] In the present invention, "amide group" refers to Wherein Rc can be H or alkyl;

[0119] In the present invention, "acylamino group" refers to wherein Rb and Rc are as defined above;

[0120] In the present invention, "amino group" refers to wherein Rc may be H or an alkyl group, and at least one Rc is not H; the alkyl-substituted amino group in the present invention may be the above-mentioned amine group;

[0121] In the present invention, "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above;

[0122] In the present invention, "haloalkoxy" refers to an alkoxy group substituted by one or more halogen groups, wherein the alkoxy group is as defined above;

[0123] As used herein, "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above;

[0124] As used herein, "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups, wherein the alkoxy group is as defined above;

[0125] In the present invention, "hydroxyl" refers to -OH;

[0126] In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodine;

[0127] In the present invention, "amino" refers to -NH2;

[0128] In the present invention, "cyano" refers to -CN;

[0129] In the present invention, "nitro" refers to -NO2;

[0130] In the present invention, the groups defined above may be optionally substituted or unsubstituted. When substituted, they may be substituted by one or more of the following groups:

[0131] hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl; optionally, they may be further substituted.

[0132] In the present invention, any isotope-labeled derivatives of the compounds of the present invention or their pharmaceutically acceptable salts are covered by the present invention. Atoms that can be isotopically labeled include but are not limited to hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, etc. They can be isotopically labeled. 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 Unless otherwise indicated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% deuterium incorporation).

[0133] In the present invention, the term "plurality" may specifically refer to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0134] In this invention, the following abbreviations / terms are used:

[0135] Boc: tert-butyloxycarbonyl

[0136] TFA: trifluoroacetic acid

[0137] TLC: Thin layer chromatography

[0138] DMSO: dimethyl sulfoxide

[0139] EA: ethyl acetate

[0140] THF: Tetrahydrofuran

[0141] LDA: lithium diisopropylamide

[0142] PE: Petroleum ether

[0143] LCMS: Liquid chromatography-mass spectrometry

[0144] DCM: dichloromethane

[0145] ACN: acetonitrile

[0146] THP:

[0147] Cbz: benzyloxycarbonyl

[0148] TsOH: p-Toluenesulfonic acid

[0149] BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine)

[0150] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium

[0151] RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl

[0152] RuPhos Pd G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate

[0153] RuPhos Pd G2: [2'-(Amino)[1,1'-biphenyl]-2-yl][[2',6'-bis(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]palladium chloride

[0154] HPLC: High Performance Liquid Chromatography

[0155] t-BuXPhos: Di-tert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine

[0156] DIEA: N,N-diisopropylethylamine

[0157] DMAP: 4-dimethylaminopyridine

[0158] LiHMDS: lithium hexamethyldisilazide

[0159] Tf: trifluoromethanesulfonyl

[0160] FA: Formic acid

[0161] XPhos Pd G3: methanesulfonate (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II)

[0162] TESCl: triethylchlorosilane

[0163] Selectfluor:1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) DETAILED DESCRIPTION

[0164] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0165] Example 1

[0166] Step 1: Synthesis of compound 1c

[0167] 4,6-Dichloro-2-methylpyrimidine (1 g, 6.135 mmol) was weighed and dissolved in 10 mL of isopropanol. (S)-morpholin-2-ylmethanol (0.72 g, 6.135 mmol) and triethylamine (1.86 g, 18.405 mmol) were added and placed in a microwave reactor. The reaction temperature was set to 100°C and the reaction time was 2 hours. After the reaction was completed, TLC monitoring was performed to confirm the reaction was complete. 50 mL of water was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 1c (1.2 g, 5.616 mmol) in a yield of 92%.

[0168] MS m / z(ESI):244[M+H] +

[0169] Step 2: Synthesis of compound 1e

[0170] Compound 1d (500 mg, 2.369 mmol) was added to compound 1e (577.30 mg, 2.369 mmol), DMSO (20 mL), and CS2CO3 (2315.60 mg, 7.107 mmol), and the mixture was stirred and dissolved. The mixture was heated at 100°C for 3 h, then returned to room temperature and purified water (30 mL) was added. A flocculent product formed, which was filtered through celite and rinsed with EA (30 mL). The organic phase was separated and dried over anhydrous sodium sulfate. The solvent was then evaporated to dryness to obtain a crude product. Purification by reverse phase purification (CH3CN / H2O) afforded 1e (213 mg) in a yield of 21.49%.

[0171] MS m / z(ESI):419.9[M+H] +

[0172] Step 3: Synthesis of compound 1g

[0173] 1f (200 mg, 0.888 mmol) was dissolved in 2 mL of THF and cooled to -78 ° C under nitrogen protection. 1 mol / L LDA in tetrahydrofuran (1.8 mL) was added. After stirring at -78 ° C for 15 minutes, N-phenylbis(trifluoromethanesulfonyl)imide (634 mg, 1.776 mmol) dissolved in 2 mL of THF was added. The reaction was continued from -78 ° C to room temperature for 1 hour. The reaction was monitored by TLC. After completion of the reaction, 5 mL of saturated NH4Cl was added for quenching. The product was extracted with 20 mL of EA. The organic phase was washed with saturated NaCl and dried over anhydrous Na2SO4. The product was concentrated under reduced pressure and purified by flash column chromatography (EA / PE=0-10%) to give 240 mg of compound 1g in a yield of 75.6%.

[0174] MS m / z(ESI):358[M+H] +

[0175] Step 4: Synthesis of compound 1h

[0176] Compound 1g (100 mg, 0.28 mmol), bis-pinacol boronate (142 mg, 0.560 mmol), potassium acetate (82 mg, 0.840 mmol), and Pd(dppf)Cl2.CH2Cl2 (23 mg, 0.028 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted overnight at 90°C under nitrogen. Completion of the reaction was monitored by TLC. After dilution with 5 mL of EA, the mixture was filtered and concentrated. Flash column chromatography (EA / PE = 0-10%) afforded 60 mg of compound 1h in a 64.0% yield.

[0177] MS m / z(ESI):336[M+H] +

[0178] Step 5: Synthesis of compound 1i

[0179] Compound 1e (60 mg, 0.143 mmol), compound 1h (60 mg, 0.179 mmol), sodium carbonate (45 mg, 0.429 mmol), and Pd(dppf)Cl2.CH2Cl2 (12 mg, 0.014 mmol) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL). The mixture was reacted at 100°C overnight under nitrogen. LCMS confirmed the completion of the reaction. The mixture was diluted with 5 mL of DCM, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Flash column chromatography (EA / PE = 30-50%) afforded 50 mg of compound 1i in a 64.0% yield.

[0180] MS m / z(ESI):547[M+H] +

[0181] Step 6: Synthesis of trifluoroacetate salt of compound 1

[0182] Compound 1i (30 mg, 0.055 mmol) was weighed and dissolved in 1 mL of methanol. 5% Pd / C (6 mg, 0.055 mmol) was added, followed by the addition of 1 drop of concentrated hydrochloric acid. The mixture was degassed with hydrogen and stirred at room temperature for 2 hours. After completion of the reaction, TLC monitoring indicated complete reaction of the starting material. The reaction solution was filtered through Celite and concentrated. Purification was performed using preparative liquid chromatography (0.01% TFA / ACN) to afford compound 1 (bis-TFA salt) (5 mg, 0.011 mmol) in a yield of 20.31%.

[0183] MS m / z(ESI):449[M+H] +

[0184] 1 H NMR(400MHz,DMSO-d6)δ9.07(s,2H),8.87(s,1H),8.33(s,1H),7.62(s,1H),6.99(s ,1H),4.58(q,J=6.9Hz,1H),4.31(d,J=50.8Hz,2H),3.96(dd,J=11.5,3.3Hz,1H),3. 53–3.44(m,4H),3.19(d,J=11.9Hz,4H),3.04–2.93(m,3H),2.76(dd,J=15.6,7.4Hz ,1H),2.59(s,3H),2.44(s,3H),2.35(p,J=6.1Hz,2H),1.56(dd,J=25.1,8.5Hz,4H).

[0185] Example 2

[0186] Step 1: Synthesis of compound 2b

[0187] 2a (2.75 g, 7.950 mmol) was weighed and dissolved in 20 mL of isopropanol. Morpholine (0.83 g, 9.540 mmol) and triethylamine (2.41 g, 23.850 mmol) were added, and the mixture was heated to 100°C for 3 hours. LCMS monitored the reaction completion, and 100 mL of ethyl acetate was added. The mixture was washed with purified water, and the organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound 2b (2.4 g, 7.800 mmol) in a yield of 98.0%.

[0188] MS m / z(ESI):306[M+H] +

[0189] Step 2: Synthesis of compound 2c

[0190] 6-Bromo-5-methyl-1H-indazole (1.5 g, 7.107 mmol), 3,4-dihydro-2H-pyran (1.2 g, 14.214 mmol), and p-toluenesulfonic acid (0.27 g, 1.421 mmol) were dissolved in tetrahydrofuran and reacted at 60°C for 1 hour. The reaction was monitored by LCMS, and the product was concentrated and purified by flash column chromatography (EA / PE = 0-5%) to afford 1.8 g of compound 2c in an 85.8% yield.

[0191] MS m / z(ESI):296[M+H] +

[0192] Step 3: Synthesis of compound 2d

[0193] 2c (300 mg, 1.016 mmol) was dissolved in 5 mL of THF and cooled to -78°C under nitrogen. 1.6 M n-butyllithium (1 mL) was added and allowed to react at -78°C for half an hour. 2-Oxaspiro[3.3]heptan-6-one (123 mg, 1.099 mmol) dissolved in 1 mL of THF was added and the mixture was allowed to warm to room temperature for 1 hour. The reaction was monitored by TLC. Saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 200 mg of compound 2d was obtained by flash column chromatography.

[0194] MS m / z(ESI):329[M+H] +

[0195] Step 4: Synthesis of compound 2e

[0196] 2d (100 mg) was dissolved in trifluoroacetic acid (2 mL), and triethylsilane (2 mL) was added. The mixture was stirred at room temperature for 1 hour. LCMS monitored the reaction completion, and the solvent was removed by vacuum concentration. The mixture was extracted with dichloromethane and washed with saturated sodium bicarbonate. This afforded crude compound 2e (80 mg).

[0197] MS m / z(ESI):229[M+H] +

[0198] Step 5: Synthesis of trifluoroacetate salt of compound 2

[0199] 2e (50 mg, 0.219 mmol), 2b (67 mg, 0.219 mmol), cuprous iodide (4.17 mg, 0.022 mmol), potassium phosphate (100.87 mg, 0.438 mmol), methyl [(1S, 2S) -2- (methylamino) cyclohexyl] amine (3.12 mg, 0.022 mmol), and dimethyl sulfoxide (2 mL) were weighed and reacted at 120 ° C. under nitrogen for 2 h. The reaction was monitored by TLC. 20 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by preparative liquid separation (0.01% TFA / ACN) to give the trifluoroacetate salt of compound 2 (4.52 mg, 0.011 mmol) in a yield of 45%.

[0200] MS m / z(ESI):406[M+H] +

[0201] 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),8.32(s,1H),7.59(s,1H),6.99(s,1H),6.66(s,1H),5.33(t,J=4.9Hz,1H),4.77( s,2H),4.56(dd,J=14.2,7.2Hz,3H),3.75–3.62(m,6H),2.56(s,3H),2.31(d,J=3.7Hz,3H),2.01(q,J=7.1,6.6Hz,4H).

[0202] Example 3

[0203] Synthesis of compound 3e:

[0204] 3a (2100 mg, 9.321 mmol) was dissolved in tetrahydrofuran (40 mL) and then cooled to -65°C in a dry ice bath. 1M LiHMDS in tetrahydrofuran (23.3 mL, 23.3 mmol) was then added dropwise. The mixture was stirred for 30 min, followed by the addition of TESCl (2810 mg, 18.644 mmol). The mixture was naturally warmed to room temperature and stirred for 2 hours. The mixture was then cooled in a dry ice ethanol bath. Saturated aqueous ammonium chloride (200 mL) was added to the reaction solution to quench the reaction. The mixture was then extracted with ethyl acetate (200 mL x 2). The organic phases were combined and washed sequentially with water (200 mL) and saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate for 1 hour, filtered, and concentrated under reduced pressure to afford 7000 mg of compound 3b, which was directly used in the next step.

[0205] MS m / z(ESI):362[M+23] +

[0206] Compound 3b (3165 mg) obtained in the previous step was dissolved in acetonitrile (40 mL), then cooled to 0°C in an ice-water bath. Selectfluor (3632 mg, 10.252 mmol) was added and stirred for 10 min. Saturated brine (400 mL) and ethyl acetate (400 mL) were added to the reaction solution, shaken well, and the layers were separated. The aqueous phase was extracted with ethyl acetate (200 ml × 2). The organic phases were combined and dried over anhydrous sodium sulfate for 1 hour, filtered through a pad of silica gel, and concentrated under reduced pressure to obtain 6300 mg of compound 3c, which was directly used in the next reaction.

[0207] MS m / z(ESI):188[M-56+1] +

[0208] Compound 3c (6300 mg) obtained in the previous step was dissolved in methanol (30 mL), then cooled to 0°C in an ice-water bath. Sodium borohydride (2626 mg, 77.692 mmol) was added and stirred for 30 min. Saturated aqueous ammonium chloride (200 mL) was added to the reaction solution to quench the reaction. The mixture was then extracted with ethyl acetate (200 mL × 3). The organic phase was washed sequentially with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate for 1 hour, filtered through a pad of silica gel, and concentrated under reduced pressure to afford 5400 mg of compound 3d, which was used directly in the next reaction.

[0209] Compound 3d (5400 mg) obtained in the previous step was dissolved in 4M HCl / ethyl acetate solution (100 mL) under ice-water bath and stirred for 3 h. The reaction solution was concentrated under reduced pressure and dried in vacuo. A 10:1 mixture of petroleum ether and ethyl acetate (100 mL) was then added to the residue. The mixture was stirred for 1 h, allowed to stand, and the solvent was then decanted. Fresh 10:1 mixture of petroleum ether and ethyl acetate (100 mL) was added to the residue and stirred for 1 h. The solvent was then decanted and dried in vacuo. Ether (100 mL) was then added to the residue, stirred at room temperature for 16 h, allowed to stand, and the solvent was then decanted. The mixture was then dried in vacuo to afford 1700 mg of compound 3e.

[0210] MS m / z(ESI):146[M+1] +

[0211] Synthesis of compound 3:

[0212] Compound 3f (150 mg, 0.338 mmol), compound 3g (230 mg, 1.584 mmol), sodium tert-butoxide (250 mg, 2.601 mmol), RuPhos (63 mg, 0.135 mmol), and dioxane (16 mL) were added to a microwave vial and evacuated for 5 min. RuPhos Pd G3 (57 mg, 0.068 mmol) was then added and stirred in a microwave at 120°C for 4 hours. Saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (50 mL) were added, shaken, separated, and the aqueous phase was extracted with ethyl acetate (50 mL). The organic layers were combined and washed with water (50 mL) and saturated sodium chloride (50 mL) in that order, dried over anhydrous sodium sulfate for 1 hour, filtered, and concentrated under reduced pressure. The mixture was then slurried with a PE:EA=5:1 mixed solvent (25 ml) for 2 hours, filtered, and the filter cake was passed through a reverse phase high performance chromatography column (eluent: acetonitrile: water = 0-100%) to obtain 32.79 mg of compound 3, with a yield of 19.09%.

[0213] MS m / z(ESI):508[M+1] + 、254[M / 2+1] +

[0214] 1 H NMR(400MHz,Chloroform-d)δ8.64(s,1H),8.03(s,1H),7.50(s,1H),6.97(s,1H),4.72(t,J=6.6Hz,2H),4.21–4.08(m,1H),3.88(s,5H),3.50(d, J=9.5Hz,1H),3.37(d,J=9.8Hz,1H),3.07(dd,J=16.7,7.9Hz,2H),2.96(dd,J=9.8,7.2Hz,2H),2.61(s,3H),2.46(s,3H),1.84(d,J=14.6Hz,1H).

[0215] Example 4

[0216] Step 1: Synthesis of compound 4b

[0217] Compound 4a (5.0 g, 22.2 mmol) was dissolved in dichloromethane (50 mL), and hydrochloric acid / 1,4-dioxane (50 mL, 4 M) was added. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to obtain compound 4b (4.1 g crude product, yield: 100%).

[0218] Step 2: Synthesis of compound 4c

[0219] Compound 4b (4.0 g) was dissolved in dichloromethane (50 mL), and triethylamine (7.7 g) and benzyl chloroformate (5.0 g) were added at 0°C. The mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the reaction solution was diluted with water and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to afford compound 4c (1.9 g).

[0220] 1 H NMR (400MHz, CDCl3) δ7.37-7.30(m,5H),5.17-5.09(m,2H),3.77-3.71(m, 2H),3.34-3.25(m,2H),2.94(s,2H),2.51-2.45(m,2H),2.22-2.14(m,2H).

[0221] Step 3: Synthesis of compound 4d

[0222] Compound 4c (1.9 g) was dissolved in toluene (40 mL), and ethylene glycol (18 g, 29.3 mmol) and TsOH (252 mg, 1.46 mmol) were added. The mixture was reacted at 110°C overnight. After completion of the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 4d (1.2 g).

[0223] 1 H NMR (400MHz, CDCl3) δ7.36-7.29(m,5H),5.13(s,2H),3.88(s,4H),3.64-3.61 (m,2H),3.35-3.33(m,2H),2.74(s,2H),2.09-2.06(m,2H),1.76-1.72(m,2H).

[0224] Step 4: Synthesis of compound 4e

[0225] Compound 4d (1.2 g) was dissolved in methanol (20 mL), and palladium on carbon (120 mg, 0.1 wt%) was added. The mixture was reacted at room temperature for 16 h under a hydrogen atmosphere. After the reaction, the reaction solution was filtered and the filtrate was dried to give compound 4e (665 mg).

[0226] MS m / z(ESI):170[M+H] +

[0227] 1H NMR (400MHz, CDCl3) δ3.90(s,4H),2.94-2.89(m,2H),2.77-2.74(m,2H),2.67-2.64(m,2H),2.42(s,1H),2.06-2.00(m,2H),1.59-1.54(m,2H).

[0228] Step 5: Synthesis of compound 4g

[0229] Compound 4f (785 mg, 2.66 mmol) was dissolved in 1,4-dioxane (30 mL), and compound 4e (630 mg, 3.72 mmol), sodium tert-butoxide (767 mg, 7.98 mmol), BINAP (331 mg, 0.532 mmol), and Pd2(dba)3 (243 mg, 0.266 mmol) were added. The mixture was reacted at 100°C for 16 h. After completion of the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to afford compound 4g (770 mg, 75% yield).

[0230] MS m / z(ESI):384[M+H] +

[0231] 1 H NMR(400MHz, CDCl3)δ7.85(s,1H),7.44(s,1H),7.03(s,1H),5.65-5.62(m,1H),4.05-4.01(m,1H),3.98-3.91(m,4H),3.77-3.70(m,1H),3.13 -3.08(m,2H),3.05-2.99(m,2H),2.83-2.78(m,2H),2.62-2.53(m,1H) ,2.40(s,3H),2.15-2.02(m,5H),1.89-1.84(m,2H),1.78-1.70(m,2H).

[0232] Step 6: Synthesis of compound 4h

[0233] Compound 4g (780 mg, 2.03 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and diluted with water. After adjusting the pH to 7 with saturated sodium bicarbonate aqueous solution, the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to afford compound 4h (539 mg, yield: 100%).

[0234] MS m / z(ESI):256[M+H] +

[0235] 1 H NMR(400MHz, CDCl3)δ7.91(s,1H),7.49(s,1H),6.97(s,1H),3.26-3.24(m,2H),3.15 -3.12(m,2H),3.09-3.05(m,2H),2.63-2.61(m,2H),2.43(s,3H),2.38-2.29(m,2H).

[0236] Step 7: Synthesis of compound 4j

[0237] Compound 4h (480 mg, 1.89 mmol) was dissolved in 1,4-dioxane (50 mL), and compound 1c (459 mg, 1.89 mmol), sodium tert-butoxide (542 mg, 5.64 mmol), BINAP (235 mg, 0.38 mmol), and Pd2(dba)3 (173 mg, 0.19 mmol) were added. The mixture was reacted at 100°C for 16 h. After completion of the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified by column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to afford compound 4j (70 mg, yield: 8%).

[0238] MS m / z(ESI):463[M+H] +

[0239] Step 8: Synthesis of compound 4

[0240] Compound 4j (70 mg, 0.15 mmol) was dissolved in tetrahydrofuran (5 mL). Methylmagnesium bromide (0.25 mL, 0.75 mmol, 3 M in 2-methyl-THF) was added at 0°C and allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was prepared using reverse phase to afford compound 4 (4.1 mg, 5% yield).

[0241] MS m / z(ESI):479[M+H] +

[0242] 1H NMR (400MHz, CD3OD) δ8.54(s,1H),8.09(s,1H),7.55(s,1H),7.00(s,1H),4.57(s,2H),4. 40(d,J=12.8Hz,1H),4.28(d,J=13.2Hz,1H),4.05-4.01(m,1H),3.65-3.61(m,3H),3.58- 3.57(m,1H),3.28(s,1H),3.12-3.03(m,1H),2.99-2.96(m,2H),2.94-2.87(m,2H),2.83- 2.81(m,1H),2.55(s,3H),2.48(s,3H),2.05-2.02(m,2H),1.81-1.78(m,2H),1.31(s,3H).

[0243] Example 5

[0244] Synthesis of compound 5

[0245] Compound 1e (30 mg, 0.072 mmol) and 2-oxa-6-azaspiro[3.3]heptane (11 mg, 0.108 mmol) were dissolved in 1,4-dioxane (2 mL), and then RuPhos (8 mg, 0.014 mmol), RuPhos Pd G3 (6 mg, 0.007 mmol), and sodium tert-butoxide (21 mg, 0.216 mmol) were added. The reaction was allowed to react at 100°C for 3 hours. LCMS monitoring of the reaction was performed. After cooling, the reaction solution was filtered, and 10 mL of ethyl acetate was added to the filtrate, followed by washing with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated. Purification on a silica gel plate gave compound 5 (18 mg, 54% yield).

[0246] MS m / z(ESI):437[M+H] +

[0247] 1 H NMR (400MHz, DMSO-d6) δ8.25(1H),7.92(1H),7.5(1H),7.0(1H),4.9(1H),4.8(4H),4.23(5H),3.5-3.62(4H),2.63(3H),2.3(3H).

[0248] Example 6

[0249] Synthesis of trifluoroacetate salt of compound 6

[0250] Compound 1e (100 mg, 0.239 mmol) and (3aR, 5r, 6aS)-octahydrocyclopenta[1,2-c]pyrrol-5-ol (46 mg, 0.359 mmol) were dissolved in 1,4-dioxane (5 mL), and then RuPhos (46 mg, 0.096 mmol), RuPhos Pd G3 (11 mg, 0.048 mmol), and cesium carbonate (234 mg, 0.717 mmol) were added. The mixture was reacted at 100°C for 3 hours. LCMS monitoring of the reaction was performed. After cooling, the reaction solution was filtered, and 30 mL of ethyl acetate was added to the filtrate, followed by washing with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated. Preparative liquid separation (0.01% TFA / ACN / H2O) gave compound 6 trifluoroacetate (7 mg, 6% yield).

[0251] MS m / z(ESI):465[M+H] +

[0252] 1 H NMR(400MHz,DMSO-d6)δ8.80(1H),8.51(1H),8.27(1H),7.61(1H),6.97(1H),4.56(1H),4.31-4 .46(3H),3.42-3.52(5H),3.22(2H),2.97-3.09(3H),2.52(3H),2.42(3H),2.06(2H),1.53(3H).

[0253] Examples 7 and 8

[0254] Step 1: Synthesis of compounds 7b and 8b

[0255] Compound 7a (578.70 mg, 2.5 mmol) and 1c (731.07 mg, 3.000 mmol) were dissolved in 15 mL of DMSO and stirred thoroughly. Cs2CO3 (2443.65 mg, 7.500 mmol) was added and heated to 110°C. The reaction was allowed to react overnight, and completion was monitored by LCMS. The reaction system was poured into 200 mL of water and extracted with EA (80 mL x 2). The mixture was dried over anhydrous sodium sulfate and concentrated. Normal phase liquid chromatography (PE:EA = 1:1) afforded a mixture of 7b and 8b (650 mg).

[0256] Step 2: Synthesis of compounds 7 and 8

[0257] A mixture of 7b and 8b (200 mg, 0.456 mmol) and 7c (0.084 mL, 0.684 mmol) were dissolved in 6 mL of dioxane. CS2CO3 (445.61 mg, 1.368 mmol) was added and stirred. Under nitrogen, RuPhos Pd G3 (38.17 mg, 0.011 mmol) and RuPhos (42.55 mg, 0.091 mmol) were added. The nitrogen atmosphere was replaced three times with stirring. The reaction was heated to 115°C in a microwave oven for 1.5 h. The reaction was monitored by LCMS. The reaction system was poured into 50 mL of water and extracted with ethyl acetate (30 mL × 3). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by normal phase liquid chromatography (PE:EA = 0-100%) to obtain approximately 80 mg of the crude product. The product was separated and purified by HPLC (H2O / CH3CN) to give compound 7 (6 mg, yield 2%) and compound 8 (8.73 mg, yield 5%).

[0258] MS m / z(ESI):486[M+H] +

[0259] Examples 9 and 10

[0260] Step 1: Synthesis of compound 9b

[0261] Compound 9a (0.743 mL, 6 mmol) and [(2S)-1,4-oxazinan-2-yl]methanol (843.48 mg, 7.200 mmol) were dissolved in 40 mL of i-PrOH (40 mL). After stirring, DIEA (2.975 mL, 18.000 mmol) was added and the mixture was heated to 85°C. The solution initially became turbid white, but after heating to 85°C for 0.5 h, it gradually became clear. After 6 h of reaction, LCMS confirmed the reaction was complete. The solution was concentrated to remove the i-PrOH, diluted with EA (50 mL), and then diluted with water (100 mL). The solution was extracted with EA (40 mL x 3), dried over anhydrous sodium sulfate, concentrated, and purified by normal phase liquid chromatography (PE:EA = 5%-40%) to afford compound 9b (1500 mg, 5.423 mmol, 90.38% yield).

[0262] MS m / z(ESI):261[M+H] +

[0263] Step 2: Synthesis of compounds 9d and 10d

[0264] Compounds 9c (0.191 mL, 1.500 mmol) and 9b (389.54 mg, 1.5 mmol) were dissolved in 10 mL of DMSO and stirred thoroughly. Cs2CO3 (1466.19 mg, 4.500 mmol) was added and heated to 110°C. The mixture was allowed to react overnight, and the reaction was monitored for completion by LCMS. The reaction mixture was poured into 200 mL of water and extracted with EA (80 mL x 2). The mixture was dried over anhydrous sodium sulfate and concentrated. Normal phase liquid chromatography (PE:EA = 1:1) afforded a mixture of compounds 9d and 10d (260 mg).

[0265] MS m / z(ESI):435[M+H] +

[0266] Step 3: Synthesis of compounds 9 and 10

[0267] A mixture of compounds 9d and 10d (140 mg, 0.322 mmol) and 2-oxa-7-azaspiro[3.5]nonane (0.059 mL, 0.484 mmol) were dissolved in toluene (7 mL). CS2CO3 (105.03 mg, 0.322 mmol) was added and stirred evenly. Under nitrogen protection, RuPhos Pd G2 (250.39 mg, 0.322 mmol) and RuPhos (60.17 mg, 0.129 mmol) were added. The nitrogen atmosphere was replaced three times with stirring. The mixture was heated in a microwave oven to 110°C for 1.5 h. The reaction was complete when monitored by LCMS. The reaction solution was poured into 50 mL of water and extracted with ethyl acetate (40 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The product was separated and purified by normal phase liquid chromatography to obtain about 35 mg of a crude product. The product was separated and purified by preparative liquid chromatography to obtain compound 9 (10 mg, yield 5.7%) and compound 10 (9.78 mg, yield 6%).

[0268] MS m / z(ESI):481[M+H] +

[0269] Example 11

[0270] Synthesis of trifluoroacetate salt of compound 11

[0271] Compound 1e (100 mg, 0.239 mmol), 2-methyloctahydropyrrolo[4,3-c]pyrrole (211 mg, 1.673 mmol), palladium acetate (10 mg), dicyclohexyl{2-[2,4,6-tri(propan-2-yl)phenyl]phenyl}phosphine (10 mg), and cesium carbonate (203 mg, 0.478 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 110 °C for 1 h under nitrogen protection. The reaction was monitored for completion by LCMS. DCM (10 mL) was added for dilution, followed by filtration and concentration under reduced pressure. The product was separated by FLASH column (EA / PE (0.1% TEA) = 50-70%) to give 20 mg of crude product. HPLC (ACN / H2O 0-70%) gave 10 mg of yellow crude product, which was then purified by TLC (MeOH / DCM) to give 4.59 mg of compound 11 trifluoroacetate salt, in a yield of 3.3%.

[0272] MS m / z(ESI):464[M+H] +

[0273] Example 12

[0274] Step 1: Synthesis of compound 12c:

[0275] Compound 12a (900 mg, 6.041 mmol) was dissolved in isopropanol (30 mL), followed by the addition of compound 12b (954 mg, 6.211 mmol) and triethylamine (3668 mg, 36.249 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated to dryness under reduced pressure, and then water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 3) and dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, filtered, and concentrated under reduced pressure. The residue was slurried in a 5:1 PE:EA mixed solvent (50 mL) for 16 hours, filtered, and dried under vacuum to obtain 1200 mg of compound 12c, in a yield of 86.49%.

[0276] Step 2: Synthesis of compound 12e:

[0277] 12d (660 mg, 3.127 mmol), 12c (600 mg, 2.613 mmol), and K2CO3 (1805 mg, 13.060 mmol) were suspended in DMSO (10 mL), then heated to 100°C in an oil bath and stirred for 16 hours. Saturated aqueous ammonium chloride (100 mL) and ethyl acetate (200 mL) were added to the reaction solution, and the layers were shaken to separate. The aqueous phase was extracted once with ethyl acetate (50 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous sodium sulfate for 1 hour, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography to afford 330 mg of compound 12e in a yield of 31.24%.

[0278] Step 3: Synthesis of compound 12:

[0279] 12e (120 mg, 0.297 mmol), 12f (67 mg, 0.448 mmol), sodium tert-butoxide (143 mg, 1.488 mmol), RuPhos (55 mg, 0.118 mmol), and dioxane (12 mL) were added to a microwave vial and evacuated for 5 min. RuPhos Pd G3 (50 mg, 0.060 mmol) was then added and stirred in a microwave at 120°C for 4 h. Saturated aqueous ammonium chloride (50 mL) and ethyl acetate (100 mL) were then added to the reaction solution, shaken and separated, and the aqueous phase was extracted with ethyl acetate (50 mL). The organic layers were combined and washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate for 1 h, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (eluent: acetonitrile:water, 60%) to obtain 27.44 mg of compound 12, in a yield of 20.12%.

[0280] MS m / z(ESI):437[M+1] +

[0281] 1 H NMR (400MHz, DMSO-d6) δ8.56(d,J=0.9Hz,1H),8.34(s,1H),8.25(d,J=0.8Hz,1 H),7.57(d,J=1.0Hz,1H),7.13(d,J=1.1Hz,1H),4.84(t,J=5.4Hz,1H),4.28(d ,J=51.7Hz,2H),4.01–3.81(m,3H),3.59–3.37(m,6H),3.12(dd,J=9.5,6.3Hz, 2H),3.07–2.96(m,3H),2.91(s,2H),2.77(dd,J=12.9,9.8Hz,1H),2.35(s,3H).

[0282] Example 13

[0283] Step 1: Synthesis of compound 13c

[0284] Compound 13a (306 mg, 1.358 mmol) was dissolved in dioxane (10 mL). Under nitrogen, compound 13b (393 mg, 1.331 mmol), p-toluenesulfonylhydrazide (248.17 mg, 1.630 mmol), lithium tert-butoxide (217.32 mg, 2.716 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhos (129.50 mg, 0.272 mmol), and Pd2(dba)3 (124.38 mg, 0.136 mmol) were added. The reaction was continued at 100°C for 2 h. After concentration, the product was added with water and extracted with EA. The product was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (EA / PE = 0-20%) to afford compound 13c (260 mg, 45.19% yield).

[0285] MS m / z(ESI):284.0[M+H-86-56] +

[0286] Step 2: Synthesis of compound 13d

[0287] Compound 13c (250 mg, 0.590 mmol) was dissolved in methanol (10 mL), and TFA (100 mg, 0.024 mmol), platinum dioxide (10 mg, 0.044 mmol), and 5% palladium on carbon (20 mg, 0.590 mmol) were added. The system was purged with hydrogen three times, and the reaction was allowed to proceed overnight under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered through celite, and the filtrate was concentrated to afford compound 13d (220 mg, 87.58% yield).

[0288] MS m / z(ESI):286.0[M+H-86-56] +

[0289] Step 3: Synthesis of compound 13e

[0290] Compound 13d (250 mg, 0.587 mmol) was dissolved in HCl / EA (4 mL) and allowed to react overnight at room temperature. LCMS monitored the reaction completion and the mixture was concentrated to afford compound 13e (163 mg, yield 99.96%).

[0291] MS m / z(ESI):242.0[M+H] +

[0292] Step 4: Synthesis of compound 13g

[0293] Compound 13e (190 mg, 0.684 mmol) was dissolved in methanol (6 ml). After the solution was clarified, compound 13f (246.43 mg, 3.420 mmol) was added. After stirring for 30 min, sodium cyanoborohydride (128.94 mg, 2.052 mmol) was added and the mixture was allowed to react at room temperature overnight. After concentration to remove the methanol, 20 ml of water was added, and the mixture was extracted with EA (15 ml x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 13g (200 mg, yield 98.33%).

[0294] MS m / z(ESI):298.0[M+H] +

[0295] Step 5: Synthesis of compound 13

[0296] Compound 13g (160 mg, 0.538 mmol) was dissolved in toluene (10 mL), and compound 13h (104.88 mg, 0.430 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (38.26 mg, 0.269 mmol), CuI (51.23 mg, 0.269 mmol), and K3PO4 (228.39 mg, 1.076 mmol) were added. Under nitrogen protection, microwave reaction was carried out at 120°C for 3 h. After concentration, the crude product was purified by silica gel column chromatography (EA / PE = 0-100%) to give compound 13 (28 mg, yield 10.01%).

[0297] MS m / z(ESI):505.0[M+H] +

[0298] Example 14

[0299] Step 1: Synthesis of compound 14c

[0300] Compound 14a (200 mg) was dissolved in DCM (10 mL), and DIEA (822.57 mg, 6.364 mmol) was added to dissolve the mixture. Compound 14b (166.04 mg, 0.954 mmol) and DMAP (7.78 mg, 0.064 mmol) were then added. The mixture was reacted at room temperature for 3 h. Purification by silica gel column chromatography (EA / PE = 0-50%) afforded compound 14c (138 mg, 67.90% yield).

[0301] MS m / z(ESI):320.2[M+H] +

[0302] Step 2: Synthesis of compound 14d

[0303] Borane tetrahydrofuran complex (1566 μL, 1.566 mmol) was added dropwise to a THF solution (10 ml) of compound 14c (100 mg, 0.313 mmol) under ice-cooling. The mixture was allowed to react at room temperature for 1 h. The reaction was quenched by dropwise addition of 1N aqueous hydrochloric acid. After concentration, the mixture was purified by silica gel column chromatography (1% TEA in MeOH:DCM = 0-20%) to afford compound 14d (95 mg, 99.35% yield).

[0304] MS m / z(ESI):306.2[M+H] +

[0305] Step 3: Synthesis of compound 14

[0306] Compound 14d (100 mg, 0.327 mmol) was dissolved in DMSO (10 ml). Under nitrogen protection, compound 14e (109.75 mg, 0.327 mmol), CuI (31.18 mg, 0.164 mmol), and K3PO4 (139.02 mg, 0.655 mmol) were added. Finally, (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (23.29 mg, 0.164 mmol) was added. Under nitrogen protection, the mixture was reacted in a microwave oven at 130°C for 4 h. The mixture was separated and purified by preparative liquid phase separation (ACN / water = 10%-100%) to give compound 14 (28.40 mg, yield 16.07%).

[0307] MS m / z(ESI):513.2[M+H] +

[0308] Example 15

[0309] Step 1: Synthesis of compound 15c

[0310] Compound 15a (90 mg) was dissolved in methanol (10 ml), and compound 15b (106.08 mg, 1.432 mmol) was added. After stirring at room temperature for 30 min, sodium cyanoborohydride (53.99 mg, 0.859 mmol) was added and allowed to react at room temperature for 3 h. The reaction solution was concentrated, added with water (20 ml), and extracted with EA (10 ml x 3). The combined organic phases were washed with saturated brine (15 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 0-80%) to obtain compound 15c (80 mg, yield 93.29%).

[0311] MS m / z(ESI):300.2[M+H] +

[0312] Step 2: Synthesis of compound 15

[0313] Compound 15c (60 mg, 0.200 mmol) was dissolved in DMSO (6 ml). Compound 15d (73.88 mg, 0.220 mmol), CuI (19.08 mg, 0.100 mmol), K3PO4 (85.07 mg, 0.401 mmol), and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (15.801 μL, 0.100 mmol) were added under nitrogen. The reaction was microwaved at 130°C for 5 h under nitrogen. Water (20 ml) was added, and the mixture was extracted with EA (15 ml x 3). The combined organic phases were washed with 15 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative liquid separation (ACN / water = 10%-100%) afforded compound 15 (7.14 mg, 6.69% yield).

[0314] MS m / z(ESI):507.3[M+H] +

[0315] Example 16

[0316] Step 1: Synthesis of compound 16c

[0317] Compound 16a (500 mg, 2.509 mmol) was dissolved in DMF (10 ml). NaH (180.68 mg, 7.528 mmol) was added under ice-cooling. After stirring at room temperature for 15 min, compound 16b (858.42 mg, 5.019 mmol) was added and allowed to react overnight at room temperature. 50 ml of water was added, and the mixture was extracted with EA (30 ml x 3). The mixture was washed with saturated brine (25 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (EA / PE = 0-10%) to afford compound 16c (560 mg, 77.12% yield).

[0318] MS m / z(ESI):312.1[M+Na] +

[0319] Step 2: Synthesis of compound 16d

[0320] Compound 16c (560 mg, 1.935 mmol) was dissolved in EA (5 mL), and HCl / EA (5 mL) (4 M) was added. The mixture was reacted at room temperature for 30 min. After concentration, propylene oxide (10 mL) was added to remove HCl. After reaction at room temperature for 2 h, the mixture was concentrated to give compound 16d (360 mg, yield 98.29%).

[0321] Step 3: Synthesis of compound 16f

[0322] Compound 16d (90.49 mg, 0.478 mmol) was dissolved in dioxane (10 ml). Compound 16e (100 mg, 0.239 mmol), RuPhos 95% (44.62 mg, 0.096 mmol), RuPhos Pd G3 95% (39.89 mg, 0.048 mmol), and sodium tert-butoxide (114.87 mg, 1.195 mmol) were added under nitrogen. The mixture was reacted at 80°C overnight under nitrogen. After concentration, the product was directly purified by silica gel column chromatography (EA / PE = 0-50%) to afford product 16f (60 mg, 47.66% yield).

[0323] MS m / z(ESI):527.2[M+H]

[0324] Step 4: Synthesis of compound 16

[0325] Compound 16f (50 mg, 0.095 mmol) was dissolved in methanol (10 ml), and glacial acetic acid (100 μL, 1.745 mmol) and 20% palladium hydroxide on carbon (10 mg, 0.071 mmol) were added. After hydrogen was purged three times, the mixture was reacted at 45°C under a hydrogen balloon overnight. After filtration, the mixture was purified by preparative chromatography (ACN / water = 10%-100%) to afford compound 16 (4.91 mg, 11.85% yield).

[0326] MS m / z(ESI):437.3[M+H]

[0327] 1 H NMR (400MHz, Chloroform-d) δ8.35 (s, 1H), 7.93 (d, J = 0.7Hz, 1H), 7.36 (s, 1H) ),6.89(s,1H),4.24(s,2H),4.04–3.96(m,1H),3.78(s,1H),3.74–3.68(m,1 H),3.67–3.60(m,3H),3.53(d,J=9.1Hz,2H),3.10(dd,J=29.7,10.8Hz,3H), 2.90(d,J=11.9Hz,1H),2.60(s,3H),2.29(s,3H),1.73(s,2H),1.18(s,2H).

[0328] Examples 17 and 18

[0329] Step 1: Synthesis of compound 17b

[0330] Compound 17a (520 mg, 2.137 mmol) was dissolved in EA (5 mL), and HCl / EA (4 M, 5 mL) was added. The mixture was reacted at room temperature for 1 h, and concentrated to give compound 17b (383 mg).

[0331] Step 2: Synthesis of compounds 17 and 18

[0332] Compound 17b (85.90 mg, 0.478 mmol) was dissolved in dioxane (10 mL). Under nitrogen, compound 17c (100 mg, 0.239 mmol), RuPhos 95% (22.31 mg, 0.048 mmol), RuPhos Pd G3 95% (19.95 mg, 0.024 mmol), and sodium tert-butoxide (114.87 mg, 1.195 mmol) were added. The mixture was reacted at 110°C overnight under nitrogen. Water (30 mL) was added, and the mixture was extracted with EA (15 mL x 3). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative liquid phase separation (ACN / water = 10%-100%) afforded two compounds: compound 17 (19.84 mg, 16.41% yield) and compound 18 (12.77 mg, 10.56% yield).

[0333] MS m / z(ESI):481.3[M+H] +

[0334] Compound 17:

[0335] 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),8.17(d,J=0.7Hz,1H),7.48(d,J=1.0Hz,1H),6.95(s,1H),4.90(d,J=31 .2Hz,2H),4.35(s,2H),4.24(s,1H),3.95(dd,J=11.4,3.2Hz,1H),3.82(dd,J=9.2,4.7Hz,1H),3.60(dd,J=9. 2,2.5Hz,1H),3.57–3.43(m,6H),3.29(d,J=11.0Hz,1H),3.21(d,J=9.9Hz,1H),3.04–2.96(m,1H),2.75(dd,J =12.8,10.1Hz,1H),2.52(s,3H),2.39–2.33(m,3H),2.22–2.15(m,2H),2.12–2.04(m,1H),1.95–1.88(m,1H).

[0336] Compound 18:

[0337] 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),8.17(s,1H),7.49(d,J=1.0Hz,1H),6. 95(s,1H),4.94(s,2H),4.42–4.18(m,3H),3.91(ddd,J=35.4,10.5,3.7Hz, 2H),3.60–3.42(m,8H),3.26(dt,J=6.8,2.6Hz,1H),2.99(td,J=12.5,3.6H z,1H),2.75(dd,J=13.0,10.0Hz,1H),2.42–2.33(m,3H),2.16–1.93(m,4H).

[0338] Example 19

[0339] Step 1: Synthesis of compound 19b

[0340] Compound 19a (150 mg, 0.753 mmol) was dissolved in DMF (5 mL). NaH (90.34 mg, 3.764 mmol) was added at 0°C and stirred at room temperature for 15 min. Methyl iodide (0.094 mL, 1.506 mmol) was then added and the mixture was reacted at room temperature for 2 h. 20 mL of water was added and the mixture was extracted with EA (10 mL × 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound 19b, which was used directly in the next step.

[0341] Step 2: Synthesis of compound 3

[0342] Compound 19b was dissolved in EA (3 mL), HCl / EA (3 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction was completed after monitoring by LCMS. After concentration, compound 19c (80 mg) was obtained.

[0343] Step 3: Synthesis of Compound 19

[0344] Compound 19c (71.54 mg, 0.478 mmol) was dissolved in DMF (10 mL). Compound 19d (100 mg, 0.239 mmol), sodium tert-butoxide (114.87 mg, 1.195 mmol), RuPhos 95% (44.62 mg, 0.096 mmol), and RuPhos Pd G3 95% (39.89 mg, 0.048 mmol) were added under nitrogen. The mixture was microwaved at 80°C for 1 h under nitrogen. After filtration, the product was purified by preparative liquid chromatography (acetonitrile / water = 0-100%) to afford compound 19 (13.55 mg, 11.95% yield).

[0345] MS m / z(ESI):451.2[M+H] +

[0346] 1 H NMR(400MHz,DMSO-d6)δ8.37(s,1H),8.21(s,1H),7.54(s,1H),6.95(s,1H) ,4.86(t,J=5.5Hz,1H),4.29(d,J=38.1Hz,2H),3.98–3.90(m,1H),3.60–3. 44(m,7H),3.29(s,3H),3.15–3.10(m,2H),2.99(td,J=12.6,3.5Hz,1H),2. 75(dd,J=13.0,9.8Hz,1H),2.53(s,3H),2.32(s,3H),1.79(p,J=1.2Hz,2H)

[0347] Example 20

[0348] Step 1: Synthesis of compound 20c

[0349] Compound 20a (500 mg, 2.369 mmol) was added to compound 20b (577.30 mg, 2.369 mmol), DMSO (20 mL), and CS2CO3 (2315.60 mg, 7.107 mmol), and the mixture was stirred and dissolved. The mixture was heated to 100°C for 3 h, then returned to room temperature and purified water (30 mL) was added. A flocculent product formed, which was filtered through celite and rinsed with EA (30 mL). The organic phase was separated and dried over anhydrous sodium sulfate. The solvent was then evaporated to dryness to obtain a crude product, which was purified by preparative HPLC to afford compound 20c (213 mg, 21.49% yield).

[0350] MS m / z(ESI):419.9[M+H] +

[0351] Step 2: Synthesis of compound 20

[0352] Compound 20c (60 mg, 0.143 mmol) and compound 20d (20.25 mg, 0.143 mmol) were added to a 40 mL screw-capped reaction flask. Dioxane (3 mL) and CS2CO3 (139.78 mg, 0.429 mmol) were added and stirred for 5 min. BINAP (17.81 mg, 0.029 mmol) and Pa2(dba)3 (13.09 mg, 0.014 mmol) were added and dissolved. N2 was purged for 2 min, and the reaction flask was sealed. The temperature was raised to 110°C in an oil bath and the reaction was stirred overnight. The temperature was cooled to room temperature, filtered, and the filtrate was spin-dried to obtain a residue. EA (10 mL) and purified water (5 mL) were added and the mixture was separated. The organic phase was dried by spin-drying, DMSO (2 mL) was added, and the product was separated and purified by preparative liquid chromatography (0.01% TFA / H2O:ACN 95%-5%). The product was dried by spin-drying, DMSO (2 mL) was added, and the product was purified again under the same preparative liquid chromatography conditions. The product was lyophilized to obtain compound 20 (3.82 mg, yield 3.77%).

[0353] MS m / z(ESI):479.27[M+H] +

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 7.65 (s, 1H), 7.37–7.02 (m, 3H), 4.63 (q, J = 7.0 Hz, 3H), 3.21 (t, J = 7.7 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 2.78 (s, 2H), 2.61 (d, J = 3.1 Hz, 2H), 2.48 (s, 3H), 1.93 (dd, J = 12.5, 7.8 Hz, 2H), 1.78–1.68 (m, 2H), 1.59 (s, 3H), 1.57 (s, 3H), 1.30 (d, J = 3.6 Hz, 3H). Example 21

[0355] Step 1: Synthesis of compound 20c

[0356] Compound 20a (50 mg, 0.237 mmol) was added to compound 20b (85.33 mg, 0.237 mmol), DMSO (10 mL), and CS2CO3 (231.56 mg, 0.711 mmol), and the mixture was stirred and dissolved. The mixture was heated to 100°C for 2 h, then returned to room temperature and purified water (30 mL) was added. A flocculent product formed, which was filtered through celite and rinsed with EA (30 mL). The organic phase was separated and dried over anhydrous sodium sulfate. The solvent was then evaporated to dryness to obtain a crude product, which was then purified by preparative HPLC to afford compound 20c (47 mg, 44.75% yield).

[0357] MS m / z(ESI):444.35[M+H] +

[0358] Step 2: Synthesis of compound 21

[0359] Compound 20c (100 mg, 0.226 mmol) was added to a reaction flask, followed by compound 20d (86.23 mg, 0.678 mmol) and 1,4-dioxane (5 mL). The mixture was stirred and dissolved. CS2CO3 (220.91 mg, 0.678 mmol), RuPhos 95% (21.09 mg, 0.045 mmol), and RuPhos Pd G3 95% (37.85 mg, 0.045 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 min. The sealed system was heated to 110°C in an oil bath and allowed to react overnight. The mixture was allowed to return to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added, followed by separation. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the mixture, and the mixture was purified by reverse phase preparative high performance liquid chromatography (NH4HCO3 / aqueous ammonia) to obtain compound 21 (13.04 mg, yield 11.81%).

[0360] MS m / z(ESI):490.62[M+H] +

[0361] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.25(s,1H),7.61(s,1H),6.98(s,1H),4.58(t,J=6.5Hz,2H),4.49(t,J=6.0Hz,2H),4.40( s,4H),3.68(d,J=5.6Hz,4H),3.46(q,J=6.2Hz,1H),2.85(s,4H),2.35(d,J=6.3Hz,6H),2.00(q,J=5.6,4.6Hz,4H),1.24(s,4H).

[0362] Example 22

[0363] Step 1: Synthesis of compound 22c

[0364] Compound 22a (1.0 g, 5.044 mmol) and compound 22b (1.09 g, 15.132 mmol) were added to a reaction flask, followed by MeOH (10 mL) and AcOH (1.0 mL). The mixture was stirred for 30 min, followed by sodium cyanoborohydride (0.95 g, 15.132 mmol). The mixture was stirred for 3 h, dried by spin drying, and extracted with EA (40 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and purified by preparative liquid chromatography (PE / EA (0%-100%)) to afford compound 22c (1.4 g, 92.77% yield).

[0365] MS m / z(ESI):255.33[M+H] +

[0366] Step 2: Synthesis of compound 22d

[0367] Compound 22c (1.4 g, 5.505 mmol) was added to DCM (10 mL) and TFA (10 mL). The mixture was stirred at room temperature for 1 h. Purified water (15 mL) and DCM (10 mL×2) were added to the system. The liquids were separated and the aqueous phase was lyophilized to obtain compound 22d (728 mg, yield 49.30%).

[0368] Step 3: Synthesis of Compound 22

[0369] Compound 22d (331.79 mg) was added to a reaction flask, followed by compound 22e (300 mg, 0.717 mmol) and 1,4-dioxane (15 mL). The mixture was stirred to dissolve. CS2CO3 (701.02 mg, 2.152 mmol), RuPhos 95% (66.94 mg, 0.143 mmol), and RuPhos Pd G3 95% (120.11 mg, 0.143 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 min. The mixture was sealed and heated to 110°C in an oil bath for 2 h. The mixture was then allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / aqueous ammonia), and lyophilized to obtain the product, which was further purified by reverse phase preparative HPLC (0.01% TFA in H2O / ACN) to obtain compound 22 (23.80 mg, yield 5.48%).

[0370] 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.30(s,1H),8.24(s,1H),7.59(s,1H),6.96(s,1H), 4.85–4.73(m,2H),4.69–4.50(m,4H),4.30(d,J=57.1Hz,3H),4.08–3.91(m,3H),3.53–3. 44(m,4H),3.00(td,J=12.6,3.6Hz,1H),2.76(dd,J=13.0,9.8Hz,1H),2.36(s,3H),2.27( d,J=18.2Hz,2H),1.99(p,J=7.1,6.6Hz,1H),1.52(d,J=7.0Hz,1H),1.24(d,J=3.4Hz,3H).

[0371] Example 23

[0372] Synthesis of compound 23

[0373] Compound 23a (50 mg, 0.120 mmol) was added to a reaction flask, followed by compound 23b (50.64 mg, 0.359 mmol) and 1,4-dioxane (5 mL). The mixture was stirred and dissolved. CS2CO3 (117.30 mg, 0.360 mmol), RuPhos 95% (11.20 mg, 0.024 mmol), and RuPhos Pd G3 95% (20.10 mg, 0.024 mmol) were added. The mixture was thoroughly purged with nitrogen for 2 min. The sealed system was heated to 110°C in an oil bath and allowed to react overnight. The mixture was allowed to return to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative high performance liquid chromatography (NH 4 HCO 3 / ammonia solution), and lyophilized to obtain compound 23 (3.68 mg, yield 6.43%).

[0374] MS m / z(ESI):479.60[M+H] +

[0375] 1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.25(s,1H),7.61(s,1H),6.97(s,1H) ,4.85(s,1H),3.95(dd,J=11.3,3.3Hz,1H),3.79(t,J=7.1Hz,2H),3.57–3.5 0(m,4H),3.45(td,J=6.8,3.0Hz,3H),2.92(t,J=5.5Hz,4H),2.54(s,3H),2 .36(s,3H),1.80(t,J=7.1Hz,2H),1.77–1.68(m,4H),1.24(d,J=3.5Hz,3H).

[0376] Example 24

[0377] Synthesis of compound 24

[0378] Compound 24a (120 mg, 0.287 mmol) was added to a reaction flask, followed by compound 24b (144.79 mg, 0.861 mmol) and 1,4-dioxane (10 mL). The mixture was stirred to dissolve. CS2CO3 (280.41 mg, 0.861 mmol), RuPhos 95% (26.77 mg, 0.057 mmol), and RuPhos Pd G3 95% (48.04 mg, 0.057 mmol) were then added. The mixture was purged thoroughly with nitrogen for 2 min. The sealed system was heated in an oil bath at 110°C overnight. The reaction was allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the mixture, and the mixture was purified by reverse phase preparative high performance liquid chromatography (NH4HCO3 / aqueous ammonia) and lyophilized to obtain compound 24 (19.45 mg, yield 13.41%).

[0379] MS m / z(ESI):506.62[M+H] +

[0380] 1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.27(s,1H),7.62(s,1H),6.98(s,1H),4.86(t ,J=5.4Hz,1H),3.95(d,J=10.1Hz,1H),3.57–3.43(m,3H),3.30(s,3H),3.21(d,J=12 .3Hz,2H),3.00(t,J=11.4Hz,1H),2.86(t,J=12.1Hz,2H),2.70(s,3H),2.54(s,3H) ,2.40(s,3H),2.30(t,J=8.0Hz,3H),2.17–2.07(m,2H),2.01(dt,J=13.1,7.2Hz,3H)

[0381] Example 25

[0382] Synthesis of compound 25

[0383] Compound 25a (66 mg, 0.152 mmol) was added to a reaction flask, followed by compound 25b (64.38 mg, 0.456 mmol) and 1,4-dioxane (5 mL). The mixture was stirred to dissolve. CS2CO3 (148.55 mg, 0.456 mmol), RuPhos 95% (14.18 mg, 0.030 mmol), and RuPhos Pd G3 95% (25.45 mg, 0.030 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 minutes. The mixture was sealed and heated to 110°C in an oil bath for 3 hours. The mixture was then allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia water: H2O / ACN, 10%-100%) and lyophilized to obtain compound 25 (8.24 mg, yield 10.96%).

[0384] MS m / z(ESI):495.60[M+H] +

[0385] 1H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.27(s,1H),7.62(s,1H),6.85(s,1H),4.87(t,J=5.4Hz,1H),4.01(s,3H),3.97–3.93(m,1H),3.78(t ,J=7.1Hz,2H),3.58–3.43(m,8H),3.09–2.98(m,2H),2.90(t,J=5.6Hz,4H),2.36(s,3H),1.78(t,J=7.1Hz,2H),1.71(td,J=5.3,2.3Hz,4H)

[0386] Example 26

[0387] Synthesis of compound 26

[0388] Compound 26a (42 mg, 0.100 mmol) was added to a reaction flask, followed by compound 26b (34.09 mg, 0.301 mmol) and 1,4-dioxane (5 mL). The mixture was stirred and dissolved. CS2CO3 (98.14 mg, 0.301 mmol), RuPhos 95% (9.37 mg, 0.020 mmol), and RuPhos Pd G3 95% (16.82 mg, 0.020 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 min. The sealed system was heated to 110°C in an oil bath and allowed to react overnight. The reaction mixture was then allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative high performance liquid chromatography and lyophilized to obtain compound 26 (15.28 mg, yield 27.07%).

[0389] MS m / z(ESI):451.24[M+H] +

[0390] 1 H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.47(s,1H),7.07(s,1H),4.15–4.04(m,3H),3.79(q,J=11.7,10.0Hz, 4H),3.62(dd,J=10.6,7.0Hz,4H),3.52(s,2H),3.29(s,2H),3.17(s,2H),2.87(s,3H),2.76(s,2H),2.52(s,3H).

[0391] Example 27

[0392] Synthesis of trifluoroacetate salt of compound 27

[0393] Compound 27a (42 mg, 0.100 mmol) was added to a reaction flask, followed by compound 27b (38.31 mg, 0.301 mmol) and 1,4-dioxane (5 mL). The mixture was stirred to dissolve. CS2CO3 (98.14 mg, 0.301 mmol), RuPhos 95% (9.37 mg, 0.020 mmol), and RuPhos Pd G3 95% (16.82 mg, 0.020 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 min. The sealed system was placed in an oil bath and heated to 110°C. The reaction was allowed to proceed overnight. The mixture was then allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative liquid chromatography (TFA / ACN) and lyophilized to obtain trifluoroacetic acid salt of compound 27 (15.20 mg, yield: 26.27%).

[0394] MS m / z(ESI):465.25[M+H] +

[0395] 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),8.19(s,1H),7.51(s,1H),6.96(s,1H),4.29(d,J= 36.0Hz,2H),3.95(dd,J=11.5,3.3Hz,1H),3.81(td,J=7.0,1.8Hz,3H),3.55–3.49(m,3H ),3.48–3.44(m,2H),3.39(t,J=6.9Hz,2H),3.28(q,J=9.2Hz,2H),3.00(td,J=12.5,3.6 Hz,1H),2.80–2.72(m,1H),2.52(s,3H),2.39(s,3H),1.98(dqd,J=11.1,7.3,3.7Hz,4H)

[0396] Example 28

[0397] Synthesis of compound 28

[0398] Compound 28a (42 mg, 0.100 mmol) was added to a reaction flask, followed by compound 28b (34.09 mg, 0.301 mmol) and 1,4-dioxane (5 mL). The mixture was stirred to dissolve. CS2CO3 (98.14 mg, 0.301 mmol), RuPhos 95% (9.37 mg, 0.020 mmol), and RuPhos Pd G3 95% (16.82 mg, 0.020 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 minutes. The mixture was sealed in an oil bath and heated to 110°C. The reaction was allowed to proceed overnight. The mixture was then allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the residue, and the residue was purified by reverse-phase preparative high performance liquid chromatography (TFA / ACN) and lyophilized to obtain compound 28 (4.73 mg, yield 8.34%).

[0399] MS m / z(ESI):451.24[M+H] +

[0400] 1 H NMR(400MHz,Chloroform-d)δ8.52(s,1H),8.02(d,J=0.8Hz,1H),7.47(s,1H),6.96(s,1H),4.30(t,J=14.7Hz,2H),4.11– 4.03(m,3H),3.82–3.76(m,1H),3.75–3.62(m,5H),3.27–3.08(m,5H),3.05–2.92(m,3H),2.62(s,3H),2.47–2.40(m,3H).

[0401] Example 29

[0402] Step 1: Synthesis of compound 29c

[0403] Compound 29a (2.25 g, 9.987 mmol) was added to a reaction flask under nitrogen, followed by THF (80 mL). The mixture was stirred until clear. The mixture was replaced by vacuum three times, cooled to -78°C with liquid nitrogen, and stirred for 5 min. LiHMDS (1 M) (20 mL) was added, stirred for 30 min, and a solution of compound 29b (3.92 g, 10.986 mmol) in THF (20 mL) was added. The reaction system was allowed to warm to room temperature and stirred overnight. Saturated aqueous ammonium chloride (10 mL) was added to the reaction system at 0°C, followed by EA (30 mL x 2). The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and purified on a silica gel column (PE / EA 0%-100%) to afford compound 29c (3.42 g, 95.83% yield).

[0404] MS m / z(ESI):358.34[M+H] +

[0405] Step 2: Synthesis of compound 29e

[0406] Compound 29c (2.2 g, 6.157 mmol) was added to a reaction flask, followed by 1,4-dioxane (35 mL). Compound 29d (1.88 g, 7.388 mmol) was added and stirred to dissolve. Pd(dppf)Cl2.CH2Cl2 (0.50 g, 0.616 mmol) and KOAc (1.81 g, 18.470 mmol) were then added. The system was maintained under a N2 purge. The flask was sealed under N2. The oil bath was heated to 110°C and the reaction was allowed to proceed overnight. The mixture was returned to room temperature, and purified water (30 mL) and EA (50 mL x 2) were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was then purified on a silica gel column (PE / EA 0%-100%) to afford compound 29e (3.4 g).

[0407] MS m / z(ESI):336.25[M+H] +

[0408] Step 3: Synthesis of compound 29h

[0409] Compound 29f (1.5 g, 5.082 mmol) was added to a reaction flask, followed by 1,4-dioxane (35 mL). Compound 29e (2.04 g, 6.098 mmol) was stirred and dissolved. Pd(dppf)Cl2.CH2Cl2 (0.41 g, 0.508 mmol) and Na2CO3 (1.08 g, 10.163 mmol) were then added. Purified water (1 mL) was added, and the system was maintained under a nitrogen purge. The flask was sealed under nitrogen. The oil bath was heated to 110°C and the reaction was allowed to proceed overnight. The mixture was returned to room temperature, and purified water (30 mL) and EA (50 mL x 2) were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried to dryness to afford the crude product. The crude product was then purified on a silica gel column (PE / EA 0%-100%) to afford compound 29h (600 mg, 27.88% yield).

[0410] MS m / z(ESI):424.56[M+H] +

[0411] Step 4: Synthesis of compound 29i

[0412] Compound 29h (410 mg, 0.968 mmol) was added to a reaction flask, followed by MeOH (15 mL) and FA (0.1 mL) and stirred to dissolve. 5% Pd / C (50 mg) was added, and the atmosphere was replaced with hydrogen five times. The reaction was allowed to proceed at 50°C overnight. The mixture was returned to room temperature, filtered, and the filter cake was rinsed with MeOH (20 mL). The filtrate was then dried to afford the crude product of compound 29i (304 mg).

[0413] MS m / z(ESI):426.57[M+H] +

[0414] Step 5: Synthesis of compound 29j

[0415] Compound 29i (304 mg, 0.714 mmol) was added with dioxane (10 mL) and HCl / dioxane (4 M) (10 mL). The mixture was stirred at room temperature for 2 h. Purified water (15 mL) and EA (10 mL × 2) were added. The layers were separated and the aqueous phase was lyophilized to give compound 29j (244 mg, yield: 97.39%).

[0416] MS m / z(ESI):242.16[M+H] +

[0417] Step 6: Synthesis of compound 29l

[0418] Compound 29j (96.5 mg, 0.400 mmol) and compound 29k (86.44 mg, 1.200 mmol) were added to a reaction flask, and MeOH (10 mL) and AcOH (0.1 mL) were added. The mixture was stirred for 30 min, and sodium cyanoborohydride (75.38 mg, 1.200 mmol) was added. The reaction was stirred for 3 h. Preparative high performance liquid chromatography (water / ACN 0%-100%) was used to obtain compound 29l (80 mg, yield: 67.27%).

[0419] MS m / z(ESI):298.12[M+H] +

[0420] Step 7: Synthesis of compound 29

[0421] Compound 29l (60 mg, 0.202 mmol) was added to a reaction flask, followed by dioxane (10 mL) and stirring to dissolve. Compound 29m (49.16 mg, 0.202 mmol), cuprous iodide (38.42 mg, 0.202 mmol), (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (ligand) (28.70 mg, 0.202 mmol), and K3PO4 (128.47 mg, 0.605 mmol) were then added. Stirring was continued under nitrogen, and the flask was sealed and heated in an oil bath to 110°C for 3 h. The reaction mixture was cooled to room temperature, and 30 mL of purified water was added. The solid was filtered off, and extraction was then performed with EA (30 mL x 2). The organic phase solvent was dried, MeOH (5 mL) was added to dissolve the clear solution, and the product was purified by reverse phase preparative high performance liquid chromatography (NH4HCO3 / ammonia water: H2O / ACN 0%-100%) and lyophilized to obtain compound 29 (2.51 mg, yield: 2.47%).

[0422] MS m / z(ESI):505.28[M+H] +

[0423] 1H NMR (400MHz, DMSO-d6) δ8.92(d,J=45.2Hz,1H),8.30(d,J=0.8Hz,1H),7.56(d,J=18.5Hz,1H),6.98(s,1H),4.87(dt,J=11. 0,5.5Hz,1H),4.57(q,J=5.9Hz,2H),4.37(q,J=5.6Hz,2H),4.26(s,1H),3.95(dd,J=11.0,3.5Hz,1H),3.65(p,J=7.4,6.8Hz ,1H),3.53(td,J=8.7,4.9Hz,2H),3.45(dt,J=13.4,9.3Hz,3H),3.24(d,J=6.2Hz,3H),3.00(td,J=12.5,3.6Hz,1H),2.82– 2.72(m,1H),2.53(s,3H),2.45–2.38(m,3H),2.07–1.83(m,4H),1.59(dd,J=20.4,7.6Hz,2H),1.43(td,J=14.0,8.0Hz,2H).

[0424] Example 30

[0425] Synthesis of compound 30

[0426] Compound 30a (42 mg, 0.100 mmol) was added to a reaction flask, followed by compound 30b (42.54 mg, 0.301 mmol) and 1,4-dioxane (5 mL). The mixture was stirred to dissolve. CS2CO3 (98.14 mg, 0.301 mmol), RuPhos 95% (9.37 mg, 0.020 mmol), and RuPhos Pd G3 95% (16.82 mg, 0.020 mmol) were then added. A nitrogen purge was performed for 2 min. The sealed system was placed in an oil bath and heated to 110°C. The reaction was allowed to proceed overnight. The reaction was then allowed to return to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the mixture, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia:H2O / ACN, 10%-100%) and lyophilized to obtain compound 30 (3.94 mg, yield: 8.20%).

[0427] MS m / z(ESI):479.27[M+H] +

[0428] 1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.25(d,J=0.8Hz,1H),7.60(s,1H),6.98(s,1H),5.32 (t,J=4.8Hz,1H),4.86(t,J=5.5Hz,1H),4.30(d,J=37.9Hz,2H),3.93(s,1H),3.77(t,J=6. 7Hz,2H),3.57–3.43(m,4H),3.29(s,1H),3.01(d,J=12.3Hz,3H),2.91(d,J=12.1Hz,2H),2 .79–2.73(m,1H),2.53(s,3H),2.36(s,3H),1.99(p,J=7.1,6.6Hz,4H),1.93–1.88(m,2H).

[0429] Example 31

[0430] Synthesis of compound 31

[0431] Compound 31a (42 mg, 0.100 mmol) was added to a reaction flask, followed by compound 31b (29.86 mg, 0.301 mmol) and 1,4-dioxane (5 mL). The mixture was stirred and dissolved. CS2CO3 (98.14 mg, 0.301 mmol), RuPhos 95% (9.37 mg, 0.020 mmol), and RuPhos Pd G3 95% (16.82 mg, 0.020 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 min. The mixture was sealed in an oil bath and heated to 110°C for 2 h. The reaction was then allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the mixture, and the mixture was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia:H2O / ACN, 10%-100%) and lyophilized to obtain compound 31 (13.53 mg, yield: 30.87%).

[0432] MS m / z(ESI):436.22[M+H] +

[0433] 1H NMR (400MHz, DMSO-d6) δ8.68 (s, 1H), 8.28 (d, J = 0.8Hz, 1H), 7.64 (s, 1H), 6.99 ( s,1H),4.86(t,J=5.4Hz,1H),4.63(d,J=6.0Hz,2H),4.30(d,J=44.1Hz,2H),4.0 0–3.93(m,1H),3.58–3.50(m,2H),3.49–3.38(m,6H),3.11–2.97(m,2H),2.76( dd,J=12.9,9.9Hz,1H),2.53(s,3H),2.40(s,3H),1.99(dt,J=13.2,6.9Hz,1H).

[0434] Example 32

[0435] Synthesis of compound 32

[0436] Compound 32a (22 mg, 0.050 mmol) was added to a reaction flask, followed by compound 32b (21.24 mg, 0.150 mmol) and THF (5 mL). The mixture was stirred and dissolved. Sodium tert-butoxide (14.42 mg, 0.150 mmol) and XPhos Pd G3 (8.46 mg, 0.010 mmol) were added and the mixture was purged with nitrogen for 2 min. The sealed system was placed in an oil bath, heated to 80°C, and reacted for 2 h. Purified water (15 mL) and EA (35 mL x 2) were added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the residue, and the residue was purified by reverse-phase preparative HPLC (NH4HCO3 / ammonia:H2O / ACN, 10%-100%) and lyophilized to obtain compound 32 (7.06 mg, yield: 28.21%).

[0437] MS m / z(ESI):499.21[M+H] +

[0438] 1H NMR (400MHz, DMSO-d6) δ8.60(s,1H),8.32(s,1H),7.95(s,1H),6.99(s,1H),4.86(t,J=5.4Hz,1H),4.26(s,2H),4.00–3.91(m,1H),3.79(t, J=7.1Hz,2H),3.60–3.41(m,6H),3.03(d,J=18.2Hz,5H),2.77(t,J=11.5Hz,1H),2.54(s,3H),1.80(t,J=7.1Hz,2H),1.74(d,J=3.6Hz,4H).

[0439] Example 33

[0440] Synthesis of compound 33

[0441] Compound 33a (4 mg, 0.101 mmol) was added to a reaction flask, followed by compound 33b (34.39 mg, 0.304 mmol) and 1,4-dioxane (5 mL). The mixture was stirred and dissolved. Sodium tert-butoxide (29.21 mg, 0.304 mmol), RuPhos 95% (9.46 mg, 0.020 mmol), and RuPhos Pd G3 95% (16.97 mg, 0.020 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 minutes. The sealed system was placed in an oil bath and heated to 110°C. The reaction was allowed to proceed overnight, then returned to room temperature. Purified water (15 mL) and EA (35 mL x 2) were added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (15 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia water: H2O / ACN, 10%-100%) and lyophilized to obtain compound 33 (12.14 mg, yield: 25.68%).

[0442] MS m / z(ESI):467.23[M+H] +

[0443] 1H NMR (400MHz, DMSO-d6) δ8.17(d,J=0.7Hz,1H),8.13(s,1H),7.49(d,J=1.0Hz,1H),6.83(s,1H),4.85(t,J=5.5Hz,1H),4.20(s,2H),3 .93(d,J=39.7Hz,7H),3.55–3.40(m,10H),3.01(t,J=11.2Hz,1H),2.81–2.74(m,1H),2.41–2.36(m,3H),1.99(p,J=6.8,6.1Hz,1H).

[0444] Example 34

[0445] Synthesis of compound 34

[0446] Compound 34a (44 mg, 0.101 mmol) was added to a reaction flask, followed by compound 34b (34.39 mg, 0.304 mmol) and 1,4-dioxane (5 mL). The mixture was stirred to dissolve. Sodium tert-butoxide (29.21 mg, 0.304 mmol), RuPhos 95% (9.46 mg, 0.020 mmol), and RuPhos Pd G3 95% (16.97 mg, 0.020 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 minutes. The sealed system was placed in an oil bath and heated to 110°C. The reaction was allowed to proceed overnight. The mixture was then allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (15 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia water: H2O / ACN, 10%-100%) and lyophilized to obtain compound 34 (6.24 mg, yield: 13.24%).

[0447] MS m / z(ESI):467.23[M+H] +

[0448] 1H NMR (400MHz, DMSO-d6) δ8.35(s,1H),8.26(s,1H),7.58(s,1H),6.85(s,1H),4.86(t,J=5.5Hz,1H),4.20(s,2H),4.01(s,3H),3.95–3.90(m,2H),3 .54–3.42(m,7H),3.11(dd,J=9.4,5.9Hz,2H),3.05(dd,J=9.5,2.3Hz,2H ),2.92(s,2H),2.79(t,J=11.8Hz,1H),2.37(s,3H),2.00(q,J=7.2Hz,1H)

[0449] Example 35

[0450] Synthesis of compound 35

[0451] Compound 35a (42 mg, 0.100 mmol) was added to a reaction flask, followed by compound 35b (29.86 mg, 0.301 mmol) and 1,4-dioxane (5 mL). The mixture was stirred to dissolve. CS2CO3 (98.14 mg, 0.301 mmol), RuPhos 95% (9.37 mg, 0.020 mmol), and RuPhos Pd G3 95% (16.82 mg, 0.020 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 minutes. The sealed system was placed in an oil bath and heated to 110°C. The reaction was allowed to proceed overnight. The mixture was then allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (5 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia water: H2O / ACN, 10%-100%) and lyophilized to obtain compound 35 (22.08 mg, yield: 50.38%).

[0452] MS m / z(ESI):437.22[M+H] +

[0453] 1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),8.18(s,1H),7.51(s,1H),6.94(s,1H),4.86 (t,J=5.4Hz,1H),4.60(s,1H),4.39–4.14(m,4H),3.95(dd,J=11.5,3.2Hz,1H),3 .88(dd,J=7.5,1.7Hz,1H),3.57–3.38(m,6H),3.04–2.95(m,1H),2.75(dd,J=12. 9,9.9Hz,1H),2.49(s,3H),2.31(s,3H),2.02–1.97(m,1H),1.89(d,J=9.7Hz,1H).

[0454] Example 36

[0455] Step 1: Synthesis of compound 36c

[0456] Compound 36a (295 mg, 0.999 mmol) was added to a reaction flask, followed by compound 36b (339.27 mg, 2.998 mmol) and 1,4-dioxane (30 mL). The mixture was stirred to dissolve. CS2CO3 (976.86 mg, 2.998 mmol), RuPhos 95% (93.27 mg, 0.200 mmol), and RuPhos Pd G3 95% (167.37 mg, 0.200 mmol) were then added. The mixture was thoroughly purged with nitrogen for 2 minutes. The sealed system was placed in an oil bath and heated to 110°C. The reaction was allowed to proceed overnight. The mixture was then allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (15 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative HPLC (H 2 O / ACN, 10%-100%) and lyophilized to obtain compound 36c (195 mg, yield 59.59%).

[0457] MS m / z(ESI):328.43[M+H] +

[0458] Step 2: Synthesis of compound 36d

[0459] Compound 36c (195 mg, 0.596 mmol) was added with HCl / EA (4 M) (5 mL), and the reaction was stirred at room temperature for 2 h. Purified water (15 mL) and EA (10 mL×2) were added, and the layers were separated. The aqueous phase was lyophilized to obtain compound 36d (172 mg).

[0460] MS m / z(ESI):244.14[M+H]+

[0461] Step 3: Synthesis of compound 36

[0462] Compound 36d (36 mg, 0.148 mmol) was added to a reaction flask, followed by dioxane (5 mL) and stirring to dissolve. Compound 36e (33.54 mg, 0.148 mmol), cuprous iodide (28.18 mg, 0.148 mmol), (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (ligand) (21.05 mg, 0.148 mmol), and K3PO4 (94.22 mg, 0.444 mmol) were then added. Stirring was continued under nitrogen, and the flask was sealed and heated in an oil bath. The temperature was raised to 110°C and the reaction was allowed to proceed overnight. The system was cooled to room temperature and filtered. 30 mL of purified water was added to the filtrate, and the solid was filtered off. Extraction was then performed with EA (30 mL x 2). The organic phase was dried by rotary evaporation, MeOH (5 mL) was added to dissolve the clear phase, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia water: H2O / ACN, 0%-100%) and lyophilized to give compound 36 (5.58 mg, yield: 8.70%).

[0463] MS m / z(ESI):434.22[M+H] +

[0464] 1 H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.26(s,1H),8.20(s,1H),7.58(s,1H), 6.92(s,1H),5.32(dd,J=5.5,4.1Hz,1H),4.15(s,1H),3.94(d,J=1.7Hz,1H) ,3.83(s,1H),3.53(dd,J=8.9,4.3Hz,2H),3.12(d,J=6.0Hz,2H),3.07(dd,J =9.7,2.2Hz,2H),2.94(s,2H),2.54(s,3H),2.38(s,3H),2.02–1.97(m,2H).

[0465] Example 37

[0466] Synthesis of compound 37

[0467] Compound 37a (88 mg, 0.201 mmol) was added to a reaction flask, followed by compound 37b (68.10 mg, 0.602 mmol) and 1,4-dioxane (15 mL). The mixture was stirred to dissolve. Sodium tert-butoxide (57.83 mg, 0.602 mmol), RuPhos 95% (18.72 mg, 0.040 mmol), and RuPhos Pd G3 95% (33.59 mg, 0.040 mmol) were then added. A nitrogen purge was performed for 2 minutes. The mixture was placed in a sealed container and microwave-heated to 110°C for 3 hours. The mixture was allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (15 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia water: H2O / ACN, 10%-100%) and lyophilized to obtain compound 37 (2.73 mg, yield: 2.89%).

[0468] MS m / z(ESI):471.96[M+H] +

[0469] 1 H NMR (400MHz, DMSO-d6) δ8.36(s,1H),8.23(s,1H),7.84(s,1H),6.96(s,1H),4.86(t,J=5.5Hz,1H),4.28(d,J=47.3Hz,2H),3.9 5(d,J=10.9Hz,1H),3.89(t,J=6.3Hz,2H),3.62(t,J=9.4Hz,2H),3.57–3.39(m,9H),3.02(d,J=12.2Hz,1H),2.79–2.73(m,1H).

[0470] Example 38

[0471] Synthesis of compound 38

[0472] Compound 37a (88 mg, 0.201 mmol) was added to a reaction flask, followed by compound 37b (68.10 mg, 0.602 mmol) and 1,4-dioxane (15 mL). The mixture was stirred to dissolve. Sodium tert-butoxide (57.83 mg, 0.602 mmol), RuPhos 95% (18.72 mg, 0.040 mmol), and RuPhos Pd G3 95% (33.59 mg, 0.040 mmol) were then added. A nitrogen purge was performed for 2 minutes. The mixture was placed in a sealed container and microwave-heated to 110°C for 3 hours. The mixture was allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain an oil. MeOH (15 mL) was added to dissolve the residue, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia water: H2O / ACN, 10%-100%) and lyophilized to obtain compound 38 (4.94 mg, yield: 5.22%).

[0473] MS m / z(ESI):471.96[M+H] +

[0474] 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.31(d,J=0.8Hz,1H),7.92(s,1H),6.99(s,1H),4.86(t,J=5.5Hz,1H),4.30(d,J=42.6Hz,2H),3.98–3.90(m,3 H),3.57–3.50(m,4H),3.49–3.43(m,2H),3.25(d,J=3.6Hz,4H),3.02(d,J =11.0Hz, 1H), 2.96 (d, J = 9.4Hz, 2H), 2.77 (t, J = 11.5Hz, 1H), 2.53 (s, 3H).

[0475] Example 39

[0476] Synthesis of compound 39

[0477] Compound 39a (88 mg) was added to a reaction flask, followed by compound 39b (68.10 mg, 0.602 mmol) and 1,4-dioxane (15 mL). The mixture was stirred to dissolve. Sodium tert-butoxide (57.83 mg, 0.602 mmol), RuPhos 95% (18.72 mg, 0.040 mmol), and RuPhos Pd G3 95% (33.59 mg, 0.040 mmol) were then added. The mixture was purged thoroughly with nitrogen for 2 minutes. The mixture was placed in a sealed container and microwave-heated to 110°C for 3 hours. The mixture was allowed to cool to room temperature, and purified water (15 mL) and EA (35 mL x 2) were added. The mixture was separated. The organic phase was dried over anhydrous sodium sulfate and then spin-dried to obtain an oil. MeOH (15 mL) was added to dissolve the mixture, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia:H2O / ACN, 10%-100%) and lyophilized to obtain compound 39 (10.12 mg, yield: 11.53%).

[0478] MS m / z(ESI):437.22[M+H] +

[0479] 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.89(d,J=2.1Hz,1H),7.60(d,J=8.8Hz,1 H),6.94(s,1H),6.67(dd,J=8.8,2.1Hz,1H),4.86(t,J=5.5Hz,1H),4.28(d,J=3 6.8Hz,2H),3.99–3.89(m,3H),3.61–3.37(m,9H),3.23(dd,J=10.2,8.3Hz,3H) ,2.99(td,J=12.5,3.6Hz,1H),2.74(dd,J=12.9,9.9Hz,1H),2.61–2.51(m,3H).

[0480] Example 40

[0481] Synthesis of compound 40

[0482] Compound 40a (48 mg, 0.197 mmol) was added to a reaction flask, followed by dioxane (10 mL) and stirring to dissolve. Compound 40b (53.21 mg, 0.197 mmol), cuprous iodide (37.57 mg, 0.197 mmol), (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (ligand) (28.06 mg, 0.197 mmol), and K3PO4 (125.62 mg, 0.592 mmol) were then added. Stirring was continued under nitrogen, and the flask was sealed and heated in an oil bath to 110°C overnight. The reaction was allowed to cool to room temperature, and 30 mL of purified water was added. The solid was filtered off, and extraction was then performed with EA (30 mL x 2). The organic phase was dried by rotary evaporation, MeOH (5 mL) was added to dissolve the clear solution, and the residue was purified by reverse phase preparative HPLC (NH4HCO3 / ammonia: H2O / can, 0%-100%) and lyophilized to obtain compound 40 (9.69 mg, yield: 10.31%).

[0483] MS m / z(ESI):477.25[M+H] +

[0484] 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H),8.23(s,1H),7.58(s,1H),6.93(s,1H),4.88(t,J= 5.5Hz,1H),4.28(s,2H),3.94(t,J=7.9Hz,3H),3.54(t,J=6.5Hz,5H),3.15(t,J=4.7Hz, 2H),3.09–3.04(m,2H),2.98(d,J=17.4Hz,3H),2.77(t,J=11.4Hz,1H),2.38(s,3H),2.0 7(q,J=5.1,3.7Hz,1H),2.02–1.96(m,1H),1.14(q,J=3.1Hz,2H),1.07(d,J=7.9Hz,2H).

[0485] Example 41

[0486] Step 1: Synthesis of compound 41c

[0487] In a 50 mL single-necked flask, compound 41a (588 mg, 3.607 mmol) and DMF (5 mL) were added and magnetically stirred. Compound 41b (362 mg, 3.607 mmol) and potassium carbonate (848 mg, 6.136 mmol) were added under nitrogen protection. The reaction was stirred at room temperature for 1.5 h. The reaction was completed as monitored by LCMS. Water (30 mL) was added and stirred to dissolve. The mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and washed with water (15 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain 0.68 g of compound 41c.

[0488] Step 2: Synthesis of compound 41e

[0489] In a 50 mL single-necked flask, compound 41c (680.1 mg, 3.000 mmol) was added, and DMF (6 mL) was magnetically stirred. Compound 41d (0.383 mL, 3.000 mmol) and cesium carbonate (1954.1 mg, 5.997 mmol) were added. Under nitrogen protection, the temperature was raised to 100°C for 5 h. Samples were taken for LCMS monitoring to confirm the completion of the reaction. The temperature was cooled to room temperature, and water (30 mL) was added. The mixture was stirred and slurried at room temperature for 30 min. The mixture was filtered and washed with water (5 mL). Preparative liquid separation (acetonitrile:water (0.01% TFA) = (10%-30%-50%-80%)) was performed to obtain 166 mg of compound 41e.

[0490] Step 3: Synthesis of Compound 41

[0491] In a 50 mL single-necked flask, compound 41e (166 mg, 0.414 mmol) and 1,4-dioxane (5 mL) were added and magnetically stirred to dissolve. Compound 41f (360 mg) was added, followed by sodium tert-butoxide (695 mg, 7.232 mmol), RuPhos (112 mg, 0.240 mmol), and RuPhos Pd G3 (202 mg, 0.242 mmol). The mixture was evacuated and replaced with nitrogen three times under nitrogen protection. The temperature was raised to 100 °C for 3 h. Heating was stopped, and the temperature was cooled to room temperature. Preparative liquid separation (water (0.01% TFA):acetonitrile) was performed to obtain 19.8 mg of compound 41.

[0492] 1HNMR(400MHz,DMSO-d6)8.99(s,1H),8.43(s,1H),8.27(s,1H),7.58(s,1H),7.10(s,1H),3.85-3.95(m,4H),3.2 9-3.55(m,4H),3.05-3.25(m,4H),2.93-2.96(m,4H),2.82(s,3H),2.52(s,3H),2.38(s,3H),2.25-2.29(m,2H).

[0493] Example 42

[0494] Step 1: Synthesis of compound 42c

[0495] In a 50 mL single-necked flask, compound 42a (507.7 mg, 3.115 mmol), compound 42b (319.2 mg, 3.156 mmol), and DMF (5 mL) were added and magnetically stirred to obtain a clear solution. Potassium carbonate (902.3 mg, 6.529 mmol) was added and stirred at room temperature for 1 h. The reaction was completed after LCMS monitoring. Water (30 mL) and dichloromethane (20 mL × 2) were added for extraction. The organic phases were combined, washed with water (15 mL), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 1.52 g of compound 42c.

[0496] Step 2: Synthesis of compound 42e

[0497] In a 50 mL single-necked flask, compound 42c (300.0 mg, 1.318 mmol) was added and magnetically stirred with DMF (5 mL). Compound 42d (278.09 mg, 1.318 mmol) was added and stirred to dissolve. Cesium carbonate (888.3 mg, 2.726 mmol) was added and the mixture was protected by nitrogen. The temperature was raised to 100°C and the reaction was allowed to react overnight. The reaction was monitored by LCMS to determine completion. The mixture was cooled to room temperature, filtered, and subjected to preparative liquid separation to afford compound 42e (250 mg, 47.1% yield).

[0498] Step 3: Synthesis of Compound 42

[0499] In a 50 mL single-necked flask, compound 42e (90 mg, 0.224 mmol), compound 42f (51.2 mg, 0.452 mmol), RuPhos (37.1 mg, 0.080 mmol), RuPhos Pd G3 (55.2 mg, 0.066 mmol), sodium tert-butoxide (83 mg, 0.864 mmol), and 1,4-dioxane (2 mL) were added. The mixture was evacuated and replaced with nitrogen three times under nitrogen protection. The temperature was raised to 100°C and the reaction was allowed to react overnight. The reaction was monitored by LCMS to be complete. The mixture was filtered through a filter, purified by preparative liquid chromatography, concentrated, and lyophilized to obtain 7.05 mg of compound 42.

[0500] 1 HNMR(400MHz,DMSO-d6)8.18(s,1H),7.90(s,1H),7.45(s,1H),6.62(d,J=2.0H Z ,1H),3.49-3.86(m,2H),3.15-3.48(m,12H),2.50(s,3H),2.45-2.47(m,2H),2.34(s,3H),1.37(s,3H).

[0501] Examples 43 and 44

[0502] Step 1: Synthesis of compound 43b

[0503] 43a (200 mg, 1.427 mmol) was dissolved in 2 mL of THF and cooled to -78°C under nitrogen. 1 M LDA (2.8 mL, 1 M in THF, 2.8 mmol) was added. After reacting at -78°C for 15 minutes, N-phenylbis(trifluoromethanesulfonyl)imide (1019 mg, 2.853 mmol) dissolved in 2 mL of THF was added. The mixture was warmed from -78°C to room temperature and the reaction was continued for 1 hour. The reaction was detected by TLC. After completion of the reaction, 5 mL of saturated NH4Cl was added for quenching. The mixture was extracted with 20 mL of EA and 2 × 5 mL of saturated NaCl solution. The organic phase was washed and dried over anhydrous Na2SO4 and concentrated under reduced pressure. 170 mg of compound 43b was obtained by flash column chromatography (EA / PE = 0-15%). The yield was 44%.

[0504] MS m / z(ESI):273[M+H] +

[0505] Step 2: Synthesis of compound 43c

[0506] Compound 43b (100 mg), bis-pinacol boronate (142 mg, 0.560 mmol), potassium acetate (82 mg, 0.840 mmol), and Pd(dppf)Cl2.CH2Cl2 (23 mg, 0.028 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 90°C overnight under nitrogen. The reaction was monitored by TLC. After dilution with 5 mL of EA, the mixture was filtered, concentrated, and purified by flash column chromatography (EA / PE = 0-10%) to afford 60 mg of compound 43c, in a 64.0% yield.

[0507] MS m / z(ESI):251[M+H] +

[0508] Step 3: Synthesis of compound 43d

[0509] Compound 43c (60 mg, 0.239 mmol), compound 2c (70 mg, 0.239 mmol), sodium carbonate (45 mg, 0.429 mmol), and Pd(dppf)Cl2.CH2Cl2 (12 mg, 0.014 mmol) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL). The mixture was reacted at 100°C overnight under nitrogen. The reaction was monitored by LCMS. After dilution with 5 mL of DCM, the mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Flash column chromatography (EA / PE = 30-50%) afforded 60 mg of compound 43d in a 74.0% yield.

[0510] MS m / z(ESI):339[M+H] +

[0511] Step 4: Synthesis of compound 43e

[0512] Compound 43d (60 mg, 0.176 mmol) was weighed and dissolved in 5 mL of methanol. Pd / C (5 mg) was then added and allowed to react overnight under a hydrogen atmosphere. Completion of the reaction was monitored by LCMS. The reaction solution was filtered through Celite and concentrated to obtain 55 mg of crude compound 43e.

[0513] MS m / z(ESI):341[M+H] +

[0514] Step 5: Synthesis of compound 43f

[0515] Compound 43e (55 mg) was weighed, 2 mL of acetic acid was added, and the mixture was stirred at room temperature for 2 hours. LCMS monitored the reaction completion, and the reaction was quenched with water. The pH was adjusted to 7-8 with sodium bicarbonate, and the mixture was extracted with dichloromethane. The mixture was concentrated and purified by column chromatography to afford compound 43f (20 mg, 0.781 mmol).

[0516] MS m / z(ESI):257[M+H] +

[0517] Step 6: Synthesis of trifluoroacetate salt of compound 43 and trifluoroacetate salt of compound 44

[0518] To the reaction mixture 43f (10 mg), 1c (12 mg), CuI (4 mg, 0.021 mmol), K3PO4 (18 mg, 0.083 mmol), and methyl[(1S,2S)-2-(methylamino)cyclohexyl]amine (3 mg, 0.021 mmol) was added 2 mL of DMSO, degassed under nitrogen, and reacted at 120°C for 3 h. The reaction was monitored by TLC, quenched by the addition of 20 mL of water, and extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. Purification by preparative liquid separation (0.01% TFA / ACN) afforded compound 43 trifluoroacetate (1.75 mg) and compound 44 trifluoroacetate (1.2 mg).

[0519] Compound 43 trifluoroacetate:

[0520] MS m / z(ESI):464.0[M+H] +

[0521] 1 H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.31(s,1H),7.61(s,1H),7.25(s,1H),7.13(s,1H ),6.99(d,J=9.0Hz,2H),4.56(q,J=7.0Hz,3H),4.47(s,2H),4.28(s,2H),3.96(dd,J=11 .3,3.4Hz,2H),3.01(d,J=3.5Hz,2H),2.82–2.74(m,2H),2.53(s,3H),2.43(s,3H),2.2 3(d,J=12.8Hz,2H),2.05–1.98(m,2H),1.82–1.76(m,2H),1.63(td,J=13.1,3.4Hz,3H).

[0522] Examples 45 and 46

[0523] Compounds 45a (77 mg, 0.174 mmol) and 45b (49.05 mg, 0.347 mmol) were dissolved in 3 mL of 1,4-dioxane. RuPhos (16.21 mg, 0.035 mmol) and CS2CO3 (169.76 mg, 0.521 mmol) were added and stirred until homogeneous. RuPhos Pd G3 (14.54 mg, 0.017 mmol) was then added. The nitrogen atmosphere was replaced three times with stirring. The mixture was microwave-heated at 120°C for 1 h to yield the product, indicating complete reaction of the starting materials. The reaction system was poured into 20 mL of water to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3), washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column (DCM:MeOH = 0-30%) to afford the crude product as a pale yellow solid. The residue was separated and purified by preparative HPLC (0.01% TFA CH3CN / H2O) to give trifluoroacetic acid salt of compound 45 (6 mg, yield 5%) and trifluoroacetic acid salt of compound 46 (4 mg, yield 3%).

[0524] MS m / z(ESI):504[M+H] +

[0525] Trifluoroacetate salt of compound 45:

[0526] 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.46(s,1H),8.28(s,1H),7.60(s,1H),7.11(s,2H),4.71(t,4H),4.40(s,1H),4.27(s,1H),3 .41(q,6H),3.17(d,2H),2.99(d,2H),2.77(q,1H),2.55(s,3H),2.42(s,3H),2.34(d,1H),1.89(q,2H),1.65(s,2H),1.52(s,3H).

[0527] Trifluoroacetate salt of compound 46:

[0528] 1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.82(s,1H),7.54(s,1H),7.39(s,1H),7.12(s,2H),4.71(t,4H),4.40(s,1H),4.27(s,1H),3 .41(q,6H),3.17(d,2H),2.99(d,2H),2.77(q,1H),2.55(s,3H),2.42(s,3H),2.34(d,1H),1.89(q,2H),1.65(s,2H),1.52(s,3H).

[0529] Example 47

[0530] Step 1: Synthesis of compound 47c

[0531] Compound 47a (300 mg, 1.840 mmol) was dissolved in isopropanol (5 ml), followed by the addition of compound 47b (245 mg, 1.896 mmol) and triethylamine (550 mg, 5.435 mmol). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. Water (100 mL) and ethyl acetate (100 mL) were then added to the residue, shaken well, and the layers separated. The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate for 1 h, filtered, and concentrated under reduced pressure to afford 470 mg of compound 47c in a yield of 99.85%.

[0532] MS m / z(ESI):256[M+1] +

[0533] Step 2: Synthesis of compound 47e

[0534] Compound 47d (495 mg, 2.345 mmol), 47c (400 mg, 1.564 mmol), and K2CO3 (1297 mg, 9.384 mmol) were suspended in DMSO (10 mL), then heated to 110°C in an oil bath and stirred for 72 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, shaken well, and the layers separated. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate for 1 hour, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (eluent: acetonitrile and water, 65-100%) to afford 250 mg of compound 47e, in a yield of 37.14%.

[0535] Step 3: Synthesis of Compound 47

[0536] 47e (120 mg, 0.279 mmol), 47f (92 mg, 0.615 mmol), sodium tert-butoxide (161 mg, 1.675 mmol), RuPhos (94 mg, 0.112 mmol) and dioxane (18 mL) were added to a microwave vial and evacuated for 5 min. RuPhos Pd G3 (94 mg, 0.112 mmol) was then added and stirred in a microwave at 120 °C for 3 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then slurried with a 5:1 mixed solvent of PE:EA for 2 h, filtered, and the filter cake was dissolved with dichloromethane and concentrated to dryness. The residue was purified by HPLC (eluent: acetonitrile:water, 75%), concentrated under reduced pressure, and freeze-dried to obtain 69.21 mg of compound 47, with a yield of 50.97%.

[0537] MS m / z(ESI):463[M+1] +

[0538] 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),8.19(s,1H),7.54(s,1H),6.62(s,1H),4.38(s,1H),3.91(dd,J=8.6,6.8Hz,2H),3.91–3.60(m,1H) ,3.50(dd,J=8.9,4.2Hz,2H),3.15–2.98(m,4H),2.91(s,2H),2.35(s,3H),2.32–2.14(m,1H),2.01–1.71(m,2H),1.13(d,J=8.6Hz,6H).

[0539] Example 48

[0540] Step 1: Synthesis of compound 48c

[0541] Compound 48a (300 mg, 2.014 mmol) was dissolved in isopropanol (5 mL), followed by the addition of 48b (270 mg, 2.090 mmol) and triethylamine (611 mg, 6.041 mmol). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. Water (100 mL) and ethyl acetate (100 mL) were then added to the residue, shaken well, and the layers separated. The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate for 1 h, filtered, and concentrated under reduced pressure to afford 400 mg of compound 48c in a yield of 82.13%.

[0542] MS m / z(ESI):242[M+1] +

[0543] Step 2: Synthesis of compound 48e

[0544] Compound 48d (393 mg, 1.862 mmol), 48c (300 mg, 1.241 mmol), and K2CO3 (1030 mg, 7.452 mmol) were suspended in DMSO (6 mL), heated to 110°C in an oil bath, and stirred for 72 hours. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction mixture, shaken well, and the layers separated. The mixture was then extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by preparative HPLC (eluent: acetonitrile:water, 50-100%) and freeze-dried to afford 195 mg of compound 48e, a yield of 37.74%.

[0545] Step 3: Synthesis of Compound 48

[0546] 48e (120 mg, 0.288 mmol), 48f (96 mg, 0.642 mmol), sodium tert-butoxide (166 mg, 1.727 mmol), RuPhos (108 mg, 0.231 mmol) and dioxane (18 mL) were added to a microwave vial and evacuated for 5 min. RuPhos Pd G3 (97 mg, 0.116 mmol) was then added and stirred in a microwave at 120 °C for 3 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then, the mixture was slurried with a PE:EA=5:1 mixed solvent (20 mL) for 2 h, filtered, and the filter cake was dissolved with dichloromethane and concentrated to dryness. The residue was purified by HPLC (eluent: acetonitrile: water, 75%), concentrated under reduced pressure, and freeze-dried to obtain 74.15 mg of compound 48, with a yield of 54.48%.

[0547] MS m / z(ESI):449[M+1] + 、225[M / 2+1] +

[0548] 1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.36(s,1H),8.22(s,1H),7.55(s,1H),6.7 8(s,1H),4.39(s,1H),3.89(dd,J=8.6,6.9Hz,2H),3.91–3.60(m,1H),3.51(dd,J =8.9,4.1Hz,2H),3.10(dd,J=9.4,5.9Hz,2H),3.00(dd,J=9.4,2.3Hz,2H),2.90( s,2H),2.35(s,3H),2.35–2.18(m,1H),2.02–1.75(m,2H),1.13(d,J=6.7Hz,6H).

[0549] Example 49

[0550] Synthesis of compound 49

[0551] Compound 49b (50 mg, 0.120 mmol), compound 49a (45.61 mg, 0.359 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.024 mmol, 11.16 mg), chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl tert-butyl ether (9.76 mg, 0.012 mmol), and sodium tert-butoxide (22.97 mg, 0.239 mmol) were added to a microwave reaction bottle, and then 2 mL of dioxane and 0.2 mL of water were added. After nitrogen purging, the mixture was reacted at 100°C in a microwave reactor for 2 h. After the reaction was completed, the reaction solution was directly filtered to obtain a yellow liquid, which was purified by preparative liquid separation (acetonitrile / water = 50:50) and lyophilized to obtain compound 49 (10.00 mg, yield 17.66%).

[0552] MS m / z(ESI):465[M+H] +

[0553] 1 H-NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.26(s,1H),7.61(s,1H),6.98(s,1H),4.86(s,1H),4.40(s,4H),4.29(s,1H),3.95( d,J=11.9Hz,1H),3.64–3.39(m,4H),3.05–2.96(m,1H),2.90–2.64(m,6H),2.54(s,3H),2.36(s,3H),2.00(d,J=5.7Hz,4H).

[0554] Example 50

[0555] Synthesis of compound 50

[0556] The hydrochloride salt of compound 50a (50 mg, 0.321 mmol), compound 50b (80 mg, 0.191 mmol), tris(dibenzylideneacetone)dipalladium (58.86 mg, 0.064 mmol), XANT PHOS (74.39 mg, 0.129 mmol), and cesium carbonate (314.15 mg, 0.964 mmol) were added to a microwave reaction vial, followed by dioxane (8 ml). After nitrogen purging, the reaction was microwaved at 100°C for 1.5 h. The product was directly separated by preparative liquid chromatography and lyophilized to afford compound 50 (26.65 mg, 17.26% yield).

[0557] MS m / z(ESI):457.2[M+H] +

[0558] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.23(s,1H),7.57(s,1H),6.97(s,1H),5.32(t,J=4.9Hz,1H),4.30(d,J=41.1Hz,2H),3.95(dd,J=11.3,3.4H z,1H),3.69(dd,J=10.1,2.4Hz,2H),3.59–3.43(m,7H),3.08–2.94(m,1H ),2.76(t,J=11.5Hz,1H),2.53(s,3H),2.35(s,3H),2.00(q,J=7.2Hz,1H)

[0559] Example 51

[0560] Synthesis of compound 51

[0561] The hydrochloride salt of compound 51a (20 mg, 0.167 mmol), compound 51b (46.64 mg, 0.111 mmol), RuPhos (20.81 mg, 0.045 mmol), RuPhos Pd G3 (18.67 mg, 0.022 mmol), and cesium carbonate (108.98 mg, 0.334 mmol) were added to a microwave reaction vial. 5 mL of dioxane was added to dissolve the mixture. After nitrogen purging, the mixture was reacted at 100°C for 1 h. The reaction solution was filtered and purified by preparative liquid separation to obtain compound 51 (4.53 mg, 9.18% yield).

[0562] MS m / z(ESI):421.2[M+H] +

[0563] 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.21(s,1H),7.53(s,1H),6.96(s,1H),4.85(s,1H),4.28 (d,J=45.3Hz,2H),3.95(dd,J=11.4,3.3Hz,1H),3.54(td,J=11.0,10.0,5.1Hz,2H),3.47(t,J= 7.2Hz,4H),3.10(d,J=8.8Hz,2H),2.99(td,J=12.5,3.6Hz,1H),2.81–2.68(m,1H),2.53(s,3H ), 2.31 (s, 3H), 1.62 (dt, J = 6.6, 3.0Hz, 2H), 0.74 (q, J = 4.0Hz, 1H), 0.54 (td, J = 7.5, 4.1Hz, 1H).

[0564] Example 52

[0565] Compound 52 was prepared according to Example 183 in the specification of patent WO2017012576A1.

[0566] Experimental Example 1

[0567] ADP-Glo ​​Kinase Assay

[0568] 1. The compound was diluted with DMSO (manufacturer: Sigma, catalog number: D4540). SYSTEM) transfer 40 nL of compound into a 384-reaction plate.

[0569] 2. Prepare 2× kinase solution using 1× kinase reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij-35, 1 mM EGTA, 2 mM DTT) and transfer 2 μL of LRRK2 G2019S solution to a 384-well reaction plate.

[0570] 3. Centrifuge at 1000 rpm for 1 minute and incubate at 25°C for 10 minutes. Prepare a 2x mixture of substrate (LRRK Tide peptide: 0.1 mg / mL) and ATP in kinase reaction buffer. Add 2 μL of the substrate and ATP mixture to the reaction plate to start the reaction. Centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 120 minutes.

[0571] 4. Transfer 4 μL of ADP-Glo ​​reagent to a 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Transfer 8 μL of detection solution to a 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes.

[0572] 5. Read the luminescence signal of each well on the microplate reader in ADP-Glo ​​mode. Set the reading value of the negative control to 0% inhibition rate and the reading value of the positive control to 100% inhibition rate. Calculate the inhibition rate of each test solution, and then analyze the data using GraphPad 8 software. Use the nonlinear fitting formula to obtain the IC value of the compound. 50 (half inhibitory concentration).

[0573] Experimental Example 2 Pharmacokinetic Evaluation

[0574] 1. Purpose of the study

[0575] After a single oral gavage administration of compound 52 to SD rats, blood samples were collected at different time points. The peripheral circulating blood, lung tissue, and brain tissue of the animals were collected. The concentration of the test substance was detected by LC-MS / MS and the relevant parameters were calculated to investigate the pharmacokinetics, tissue distribution, blood-brain permeability and other properties of the test substance.

[0576] 2. Experimental Materials

[0577] SD rats (male, 6-8 weeks old, weight 175-200 g)

[0578] 3. Experimental Operation

[0579] The pharmacokinetic properties of the compounds following oral administration in rodents were tested using a standard protocol. The candidate compound was prepared as a 0.5 mg / mL suspension and administered orally to rats as a single dose. The oral vehicle consisted of 4% DMSO, 10% Solutol, and 86% saline. Male Sprague-Dawley rats were administered an oral dose of 5 mg / kg. Peripheral blood, lung tissue, and brain tissue were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.

[0580] Plasma Sample Processing: 30 μL of plasma sample was collected and protein precipitated with 300 μL of methanol containing 10 ng / mL internal standard. The mixture was vortexed for 1 minute. Samples in EP tubes were centrifuged at 14,000 rpm for 7 minutes, while samples processed in 96-well plates were centrifuged at 4,000 rpm for 10 minutes. 300 μL of the supernatant was transferred to a 96-well plate. 10 μL of the supernatant was analyzed by liquid chromatography-mass spectrometry / mass spectrometry.

[0581] Lung Sample Processing: 50 μL of lung tissue homogenate (W:V = 1:5, lung: 50% methanol) was collected and protein precipitated with 500 μL of methanol containing 10 ng / mL internal standard. The mixture was vortexed for 1 minute. Subsequently, samples in EP were centrifuged at 14,000 rpm for 7 minutes, while samples processed in 96-well plates were centrifuged at 4,000 rpm for 10 minutes. 500 μL of the supernatant was transferred to a 96-well plate. 10 μL of the supernatant was analyzed by liquid chromatography-mass spectrometry / mass spectrometry.

[0582] Brain Sample Analysis: Protein precipitation was performed by mixing 50 μL of brain homogenate (W:V = 1:5, brain: 50% methanol) with 500 μL of methanol containing 100 ng / mL internal standard. The mixture was vortexed for 1 minute. Samples in EP tubes were then centrifuged at 14,000 rpm for 7 minutes, while samples processed in 96-well plates were centrifuged at 4,000 rpm for 10 minutes. 500 μL of the supernatant was transferred to a 96-well plate. 10 μL of the supernatant was analyzed by liquid chromatography-mass spectrometry / mass spectrometry (LC-MS / MS).

[0583] 4. Data Analysis

[0584] The plasma concentration was quantitatively analyzed by LC-MS / MS analysis, and the pharmacokinetic parameters were calculated. The peak plasma concentration was 495.8 ng / mL (Cmax), the time to peak plasma concentration was 0.5 h (Tmax), and the brain exposure was 939.7 (AUC 0-last ), the brain-to-plasma exposure ratio was 0.66. The Kpuu calculated based on the exposure was 0.18.

[0585] Experimental Example 3 Pharmacokinetic Evaluation

[0586] 1. Purpose of the study

[0587] After a single oral gavage of compound 49 in SD rats, blood samples were collected at different time points. The peripheral circulating blood, lung tissue, and brain tissue of the animals were collected. The concentration of the test substance was detected by LC-MS / MS and the relevant parameters were calculated to investigate the pharmacokinetics, tissue distribution, blood-brain permeability and other properties of the test substance.

[0588] 2. Experimental Materials

[0589] SD rats (male, 6-8 weeks old, weight 175-195 g)

[0590] 3. Experimental Operation

[0591] The pharmacokinetic profile of the compound following oral administration in rodents was tested using a standard protocol. The candidate compound was prepared as a 0.63 mg / mL suspension and administered orally to rats as a single dose. The oral vehicle consisted of 4% DMSO, 10% Solutol, and 86% saline. Male Sprague-Dawley rats were administered an oral dose of 6.3 mg / kg. Peripheral blood, lung tissue, and brain tissue were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.

[0592] Plasma Sample Processing: 30 μL of plasma sample was collected and protein precipitated with 300 μL of methanol containing 10 ng / mL internal standard. The mixture was vortexed for 1 minute. Samples in EP tubes were centrifuged at 14,000 rpm for 7 minutes, while samples processed in 96-well plates were centrifuged at 4,000 rpm for 10 minutes. 290 μL of supernatant was transferred to a 96-well plate. 3 μL of supernatant was analyzed by liquid chromatography-mass spectrometry / mass spectrometry.

[0593] Lung and brain sample processing: 30 μL of tissue homogenate (W:V = 1:10, tissue: 50% methanol) was collected and protein precipitated with 300 μL of methanol containing 10 ng / mL internal standard. The mixture was vortexed for 1 minute. Samples in EP tubes were centrifuged at 14,000 rpm for 7 minutes, while samples processed in 96-well plates were centrifuged at 4,000 rpm for 10 minutes. 290 μL of supernatant was transferred to a 96-well plate. 3 μL of supernatant was analyzed by liquid chromatography-mass spectrometry / mass spectrometry.

[0594] 4. Data Analysis

[0595] The plasma concentration was quantitatively analyzed by LC-MS / MS analysis, and the pharmacokinetic parameters were calculated. The peak plasma concentration was 595.8 ng / mL (Cmax), the time to peak plasma concentration was 2 h (Tmax), and the brain exposure was 11713 (AUC 0-last ), the brain-to-plasma exposure ratio was 2.70, and the calculated Kpuu of exposure was 0.35.

Claims

1. An indazole derivative 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: in, Ring A, Ring B, and Ring C are each independently selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, and optionally they may be further substituted by one or more substituents; R1, R2, R3, and R4 are each independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl, or heteroaryl, which may be further substituted by one or more substituents.

2. The indazole derivative or pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof according to claim 1, characterized in that: The ring A is selected from: in, X1, X7, X 13 、X 18 are independently selected from N or CR 11 ; X2, X3, X4, X5, X6, X8, X9, X 10 、X 11 、X 12 、X 14 、X 15 、X 16 、X 17 、X 19 、X 20 、X 21 、X 22 are independently selected from -O-, -C(O)-, -C(R 12 )2-or-N(R 13 )-; n1, n2, n3, n4, n5, n6, n7, n8 are each independently selected from 0, 1 or 2; n9 and n10 are independently selected from 1, 2 or 3; R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 are independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted by one or more substituents.

3. The indazole derivative according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that: Ring A is selected from: in, X2, X3, X4, X5, X6, X8, X9, X 10 、X 11 、X 12 、X 14 、X 15 、X 16 、X 17 、X 19 、X 20 、X 21 、X 22 ,n1,n2,n3,n4,n5,n6,n7,n8,n9,n10,R5,R6,R7,R8,R9,R 10 、R 11 、R 12 、R 13 The definition of is as above.

4. The indazole derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that: Ring A is selected from:

5. The indazole derivative or pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof according to claim 4, characterized in that: Ring A is selected from:

6. The indazole derivative according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that: Ring B is selected from aryl or heteroaryl, which may be further substituted by one or more substituents; Preferably, Ring B is selected from: in, R 14 、R 15 、R 16 、R 17 are each independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted with one or more substituents; 7. The indazole derivative or pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof according to claim 6, characterized in that: Ring B is selected from:

8. The indazole derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, characterized in that: Ring C is selected from: in, R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 26 are independently selected from hydrogen, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, acyl, acylamino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted by one or more substituents.

9. The indazole derivative or pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof according to claim 8, characterized in that: Ring C is selected from:

10. An indazole derivative of Formula I-1 or Formula II-1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structure of Formula I-1 or Formula II-1 is as follows: in, Ring A, Ring C, R1, R2, R3, R4, R 14 、R 15 The definition of is as above.

11. An indazole derivative of Formula I-2 or Formula II-2, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formula of Formula I-2 or Formula II-2 is as follows: in, Ring A, R1, R2, R3, R4, R 14 、R 15 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 The definition of is as above.

12. An indazole derivative of Formula I-3 or Formula II-3, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the structural formula of Formula I-3 or Formula II-3 is as follows: in, R1, R2, R3, R4, R5, R6, R 14 、R 15 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 , X8, X9, X 11 、X 12 , n5, n6, n7, and n8 are defined as above.

13. The indazole derivative according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof, wherein the compound is:

14. A pharmaceutical composition comprising the indazole derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof.

15. Use of the indazole derivative according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof as an LRRK2 kinase inhibitor or for the preparation of a medicament for inhibiting LRRK2 kinase; or, for the treatment of Parkinson's disease (PD), Or used for preparing medicine for treating Parkinson's disease (PD).

Images