Polysubstituted aryl compound, composition thereof and use thereof

Abstract

A polysubstituted aryl compound as shown in formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and a use of the polysubstituted aryl compound or the stereoisomer thereof or the pharmaceutically acceptable salt thereof as an NMT (N-myristoyltransferase) inhibitor in the prevention or treatment of NMT-related diseases.

Description

Polysubstituted aryl compounds, compositions thereof, and uses thereof

[0001] Cross-reference to Related Applications

[0002] This application claims priority to and the benefit of the following patent applications for invention, the contents of which are hereby incorporated by reference in their entirety:

[0003] Chinese Patent Application No. 202410755048.7, filed on June 12, 2024, with the

[0004] Chinese Patent Application No. 202411165548.1, filed on August 23, 2024, with the

[0005] Chinese Patent Application No. 202411339696.0, filed on September 25, 2024, with the

[0006] Chinese Patent Application No. 202411740508.5, filed on November 29, 2024, with the

[0007] Chinese Patent Application No. 202510383680.8, filed on March 28, 2025, with the TECHNICAL FIELD

[0008] The present disclosure relates to a novel polysubstituted aryl compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containing them and their use as NMT inhibitors in the prevention or treatment of diseases associated with NMT. BACKGROUND

[0009] N-myristoylation is a modification process that irreversibly transfers myristic acid from myristoyl-CoA to the N-terminal glycine of target proteins. In eukaryotes, N-myristoylation can occur in about 0.5-3% of proteins, can promote specific protein-protein and protein-lipid interactions, cause changes in protein conformation, and thus regulate protein function. N-myristoylation plays an important role in the processes of signal transduction, immune regulation and tumor occurrence and development in organisms.

[0010] N-myristoyltransferase (NMT) is a class of enzymes that catalyze the N-myristoylation of proteins. In humans, there are two subtypes of NMT, NMT1 and NMT2, both containing relatively conserved catalytic binding domains. Recent studies have shown that NMT participates in cancer development by influencing biological functions such as the signaling of the proto-oncogene tyrosine protein kinase Src, mitochondrial and lysosomal metabolic mechanisms, endoplasmic reticulum stress, and lipid recoding. Upregulation of NMT expression and excessive activation of its function are considered closely related to tumor development, progression, and poor prognosis. Simultaneously, research indicates that inhibiting NMT may have therapeutic effects on tumors. Therefore, there is an urgent need for a new class of NMT inhibitors to prevent or treat NMT-related diseases, such as cancer. Summary of the Invention

[0011] This disclosure provides a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0012] in:

[0013] Ring A is selected from 5-6 membered heteroaryl or 5-10 membered heterocyclic group;

[0014] R 1 R 2 Each is independently selected from non-existent, halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, C6-C 10 aryl or 5-10-membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 1b replace;

[0015] R 3 Selected from one or more R 2b The following groups are substituted: C1-C 10 Alkyl, (C1-C 10 Alkylene) r -C(=O)NR e R f (C1-C) 10 Alkylene) r -S(=O)2-C1-C 10 Alkyl, (C1-C 10 Alkylene) r -S(=O)(=NH)-C1-C 10 Alkyl, C2-C10 alkenyl, C2-C 10 alkynyl, (C1-C 10 alkylene) r -C3-C 10 cycloalkyl, (C1-C 10 alkylene) r -C5-C 10 cycloalkenyl, (C1-C 10 alkylene) r -4-10 membered heterocyclyl, (C1-C 10 alkylene) r -C6-C 10 aryl, (C1-C 10 alkylene) r -5-10 membered heteroaryl, C(=O)-4-10 membered heterocyclyl, C(=O)-C1-C 10 alkyl, O-C1-C 10 alkyl, O-C3-C 10 cycloalkyl, or P(=O)(C1-C 10 alkyl)2, each r is independently selected from 0 or 1, R e , R f are each independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl, or R e , R f together with the N atom to which they are attached form a 4-7 membered heterocyclyl;

[0016] L 1 is selected from L a -L b -L c , said L a , L b are each independently selected from a bond, C1-C4 alkylene, C3-C6 cycloalkylene, or 4-7 membered heteroalkylene, said C1-C4 alkylene, C3-C6 cycloalkylene, or 4-7 membered heteroalkylene being optionally substituted with one or more R 3b , L c is selected from -NH-, -O-, -S-, -S(=O)-, -SO2-, -C(=O)-, -NHSO2-, or -NH(C=O)-;

[0017] Z 1 , Z 2 , Z 3 , Z 4 are each independently selected from N or CR 9 , said R 9 is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl;

[0018] Ring B is selected from C6-C 10 aryl, C3-C 10 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocyclyl;

[0019] y is selected from 0, 1, 2, 3, 4, 5, or 6;

[0020] each R x is each independently selected from halogen, =0, CN, OH, NH2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, said OH, NH2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R 4b ;

[0021] R 6 is selected from or 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl is optionally substituted with one or more R 6b ;

[0022] each R 7 , R 8 is each independently selected from H, C1-C6alkyl, or C3-C6cycloalkyl, or R 7 , R 8 and the carbon atom to which they are attached together form a C3-C6cycloalkyl;

[0023] each R 10 , R 11 is each independently selected from H, C1-C6alkyl, or C3-C6cycloalkyl, or R 10 , R 11 and the carbon atom to which they are attached together form a C3-C6cycloalkyl;

[0024] q is selected from 0 or 1;

[0025] R 12 , R 13 , R 14 is each independently selected from H, C1-C6alkyl, C3-C6cycloalkyl, or C(=O)-C1-C6alkyl, or R 12 , R 13 and the nitrogen atom to which they are attached together form a 4-7 membered heterocyclyl, said C1-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, or C(=O)-C1-C6alkyl is optionally substituted with one or more R 7b ;

[0026] each R 1b , R 2b , R 3b , R 4b , R 6b is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C(=O)-C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2, said C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2 being optionally substituted with one or more R c ;

[0027] each R 7b is independently selected from deuterium, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2;

[0028] each R c is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2.

[0029] In some embodiments, y is selected from 0, 1, 2, 3, or 4.

[0030] In some embodiments, y is selected from 0, 1, or 2.

[0031] In some embodiments, the compound of Formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds of Formula (I’):

[0032] wherein, ring A, R 1 , R 2 , R 3 , L 1 , Z 1 , Z 2 , Z 3 , Z 4 , ring B, R 6 are as defined above for Formula (I), R 4 and R 5 are each independently selected from absent, or R 4 and R 5 are each independently R x .

[0033] In some embodiments, the compound represented by formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (I') or its stereoisomer or a pharmaceutically acceptable salt thereof:

[0034] in:

[0035] Ring A is selected from 5-6 membered heteroaryl or 5-10 membered heterocyclic group;

[0036] R 1 R 2 Each is independently selected from non-existent, halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, C6-C 10 aryl or 5-10-membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 1b replace;

[0037] R 3 Selected from one or more R 2b The following groups are substituted: C1-C 10 Alkyl, (C1-C 10 Alkylene) r -C(=O)NR e R f (C1-C) 10 Alkylene) r -S(=O)2-C1-C 10 Alkyl, (C1-C 10 Alkylene) r -S(=O)(=NH)-C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, (C1-C 10 Alkylene) r -C3-C 10 cycloalkyl, (C1-C 10 Alkylene) r -C5-C 10 Cycloalkenyl, (C1-C 10 Alkylene) r -4-10 membered heterocyclic group, (C1-C 10 Alkylene) r -C6-C 10 Aryl, (C1-C 10Alkylene) r -5-10 heteroaryl, C(=O)-4-10 heterocyclic, C(=O)-C1-C 10 Alkyl, O-C1-C 10 Alkyl, O-C3-C 10 cycloalkyl or P(=O)(C1-C 10 Alkyl group 2, each r is independently selected from 0 or 1, R e R f Each is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, or R e R f Together with the N atoms they are attached to, they form 4-7 membered heterocyclic groups;

[0038] L 1 Selected from L a -L b -L c The L a L b Each is independently selected from chemical bonds, C1-C4 alkylene groups, C3-C6 cycloalkylene groups, or 4-7-membered heterocyclic groups, wherein the C1-C4 alkylene groups, C3-C6 cycloalkylene groups, or 4-7-membered heterocyclic groups are optionally separated by one or more R groups. 3b Replace, L c Selected from -NH-, -O-, -S-, -S(=O)-, -SO2-, -C(=O)-, -NHSO2- or -NH(C=O)-;

[0039] Z 1 Z 2 Z 3 Z 4 Each is independently selected from N or CR 9 The R 9 Selected from H, halogens, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups;

[0040] Ring B is selected from C6-C 10 Aryl, C3-C 10 Cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocyclic;

[0041] R 4 and R 5 Each is independently selected from the following: non-existent, halogen, =O, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, C6-C 10aryl or 5-10-membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 4b replace;

[0042] R 6 Selected from Or a 4-7 membered nitrogen heterocyclic group, wherein the 4-7 membered nitrogen heterocyclic group is optionally surrounded by one or more R 6b replace;

[0043] R 7 R 8 Each is independently selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, or R 7 R 8 And the carbon atoms they are connected to together form C3-C6 cycloalkyl groups;

[0044] R 10 R 11 Each is independently selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, or R 10 R 11 And the carbon atoms they are connected to together form C3-C6 cycloalkyl groups;

[0045] q is selected from 0 or 1;

[0046] R 12 R 13 Each is independently selected from H, C1-C6 alkyl or C3-C6 cycloalkyl, or R 12 R 13 Together with the nitrogen atoms attached to them, they form a 4-7 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R 7b replace;

[0047] Each R 1b R 2b R 3b R 4b R 6b Independently selected from halogens, CN, OH, NH2, C1-C6 alkyl, C(=O)-C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, O(C1-C4 alkyl), NH(C1-C4 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, O(C1-C4 alkyl), NH(C1-C4 alkyl)2 or N(C1-C4 alkyl)2 is optionally mixed with one or more R c replace;

[0048] each R 7b is independently selected from deuterium, halogen, CN, OH, NH2, C1-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4alkyl), NH(C1-C4alkyl), or N(C1-C4alkyl)2;

[0049] each R c is independently selected from halogen, CN, OH, NH2, C1-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4alkyl), NH(C1-C4alkyl), or N(C1-C4alkyl)2.

[0050] In some embodiments, R 3 is selected from the following groups optionally substituted with one or more R 2b C1-C 10 alkyl, (C1-C 10 alkylene) r -C(=O)NR e R f , (C1-C 10 alkylene) r -S(=O)2-C1-C 10 alkyl, (C1-C 10 alkylene) r -S(=O)(=NH)-C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, (C1-C 10 alkylene) r -C3-C 10 cycloalkyl, (C1-C 10 alkylene) r -C5-C 10 cycloalkenyl, (C1-C 10 alkylene) r -4-10 membered heterocyclyl, (C1-C 10 alkylene) r -C6-C 10 aryl, or (C1-C 10 alkylene) r -5-10 membered heteroaryl, each r is independently selected from 0 or 1, R e , R f are each independently selected from C1-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl, or R e , R f together with the N atom to which they are attached form a 4-7 membered heterocyclyl.

[0051] In some embodiments, R3 Selected from one or more R 2b The following groups are substituted: C1-C 10 Alkyl, (C1-C 10 Alkylene) r -C(=O)NR e R f (C1-C) 10 Alkylene) r -S(=O)2-C1-C 10 Alkyl, (C1-C 10 Alkylene) r -S(=O)(=NH)-C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, (C1-C 10 Alkylene) r -C3-C 10 cycloalkyl, (C1-C 10 Alkylene) r -C5-C 10 Cycloalkenyl, (C1-C 10 Alkylene) r -4-10 membered heterocyclic group, (C1-C 10 Alkylene) r -C6-C 10 Aryl, (C1-C 10 Alkylene) r -5-10 heteroaryl, C(=O)-4-10 heterocyclic, C(=O)-C1-C 10 Alkyl, O-C1-C 10 Alkyl or O-C3-C 10 Cycloalkyl groups, each r independently selected from 0 or 1, R e R f Each is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, or R e R f Together with the N atoms they are attached to, they form 4-7 membered heterocyclic groups.

[0052] In some implementation schemes, each R 1b R 2b R 3b R 4b R 6bindependently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2, said C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2 being optionally substituted with one or more R c each R c independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2.

[0053] In some embodiments, R 12 , R 13 each independently selected from H, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 12 , R 13 and the nitrogen atom to which they are attached together form a 4-7 membered heterocyclyl.

[0054] In some embodiments, ring A is selected from 5-membered heteroaryl or 8-membered heterocyclyl. In some embodiments, ring A is selected from 5-membered heteroaryl containing 2 N atoms or 8-membered heterocycloalkenyl containing 2 N atoms.

[0055] In some embodiments, ring A is selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, or

[0056] In some embodiments, ring A is selected from pyrazolyl or

[0057] In some embodiments, R 1 , R 2 each independently selected from absent, halogen, =0, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl, said OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl being optionally substituted with one or more R 1b .

[0058] In some embodiments, R 1 , R 2 each independently selected from absent or C1-C4 alkyl.

[0059] In some embodiments, R 1 , R 2 are each selected from methyl.

[0060] In some embodiments, ring A is selected from pyrazolyl and R1 and R 2 All are selected from methyl groups; or ring A is selected from... And R 1 and R 2 None of them exist. In some implementation schemes, Selected from 1,5-dimethyl-1H-pyrazolyl, 3,4-dimethyl-1H-pyrazolyl or

[0061] In some implementation schemes, R 3 Selected from one or more R 2b The following groups are substituted: C1-C6 alkyl, (C1-C6 alkylene) r -S(=O)(=NH)-C1-C6 alkyl, (C1-C6 alkylene) r -C3-C 10 Cycloalkyl, (C1-C6 alkylene) r -4-7 membered heterocyclic groups, (C1-C6 alkylene groups) r -5-10-membered heteroaryl, C(=O)-4-7-membered heterocyclic, C(=O)-C1-C6 alkyl, O-C1-C6 alkyl, O-C3-C 10 Cycloalkyl or P(=O)(C1-C6 alkyl)2, each r independently selected from 0 or 1.

[0062] In some implementation schemes, R 3 Selected from one or more R 2b The following groups are substituted: C1-C6 alkyl, (C1-C2 alkylene) r -S(=O)(=NH)-C1-C6 alkyl, (C1-C2 alkylene) r -C3-C8 cycloalkyl, (C1-C2 alkylene) r -4-7 membered heterocyclic alkyl groups, (C1-C2 alkylene groups) r -5-6-membered heteroaryl, C(=O)-4-7-membered heterocyclic alkyl, C(=O)-C1-C6 alkyl, O-C1-C6 alkyl, O-C3-C8 cycloalkyl or P(=O)(C1-C6 alkyl)2, each r independently selected from 0 or 1.

[0063] In some implementation schemes, R 3 Selected from one or more R 2b The following groups are substituted: C1-C6 alkyl, (C1-C2 alkylene) r -C(=O)NR e R f (C1-C2 alkylene) r -S(=O)(=NH)-C1-C6 alkyl, (C1-C2 alkylene)r -C3-C8cycloalkyl, (C1-C2alkylene) r -4-7 membered heterocycloalkyl, (C1-C2alkylene) r -5-6 membered heteroaryl, C(=O)-4-7 membered heterocycloalkyl, C(=O)-C1-C6alkyl, O-C1-C6alkyl, O-C3-C8cycloalkyl, or P(=O)(C1-C6alkyl)2, each r is independently selected from 0 or 1, and R e , R f together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocyclyl.

[0064] In some embodiments, R 3 is selected from the following groups optionally substituted with one or more R 2b -C1-C6alkyl, (C1-C6alkylene) r -S(=O)(=NH)-C1-C6alkyl, (C1-C6alkylene) r -C3-C6cycloalkyl, (C1-C6alkylene) r -4-7 membered heterocyclyl, or (C1-C6alkylene) r -5-10 membered heteroaryl, each r is independently selected from 0 or 1.

[0065] In some embodiments, R 3 is selected from the following groups optionally substituted with one or more R 2b -C1-C6alkyl, (C1-C2alkylene) r -C3-C8cycloalkyl, C(=O)-4-7 membered heterocycloalkyl, or C(=O)-C1-C6alkyl, each r is independently selected from 0 or 1.

[0066] In some embodiments, R 3 is selected from the following groups optionally substituted with one or more R 2b -C1-C6alkyl, (C1-C2alkylene) r -C3-C8cycloalkyl, C(=O)-4-7 membered heterocycloalkyl, or C(=O)-C1-C6alkyl, each r is independently selected from 0 or 1, and each R 2b is independently selected from halogen (e.g., F), OH, O(C1-C4alkyl), or C1-C6alkyl optionally substituted with one or more halogen (e.g., F).

[0067] In some embodiments, R 3 is selected from the following groups optionally substituted with one or more R 2b -C1-C6alkyl, (C1-C2alkylene) rC3-C8cycloalkyl or C(=0)-Ci-C6alkyl, each r is independently selected from 0 or 1, and each R 2b is independently selected from halogen (e.g., F), OH, 0(Ci-C4alkyl), or Ci-C6alkyl optionally substituted with one or more halogen (e.g., F).

[0068] In some embodiments, each R 2b is independently selected from halogen, CN, OH, NH2, Ci-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 0(Ci-C4alkyl), NH(Ci-C4alkyl), or N(Ci-C4alkyl)2.

[0069] In some embodiments, each R 2b is independently selected from halogen, CN, OH, NH2, Ci-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 0(Ci-C4alkyl), NH(Ci-C4alkyl), or N(Ci-C4alkyl)2, said Ci-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 0(Ci-C4alkyl), NH(Ci-C4alkyl), or N(Ci-C4alkyl)2optionally substituted with one or more halogen (e.g., F).

[0070] In some embodiments, each R 2b is independently selected from halogen, OH, NH2, Ci-C6alkyl, C3-C6cycloalkyl, or 0(Ci-C4alkyl), said Ci-C6alkyl optionally substituted with one or more halogen (e.g., F).

[0071] In some embodiments, each R 2b is independently selected from halogen, CN, OH, Ci-C6alkyl, or 0(Ci-C4alkyl), said Ci-C6alkyl or 0(Ci-C4alkyl) optionally substituted with one or more R c .

[0072] In some embodiments, each R 2b is independently selected from halogen, CN, OH, Ci-C6alkyl, or 0(Ci-C4alkyl), said Ci-C6alkyl optionally substituted with one or more halogen (e.g., F).

[0073] In some embodiments, each R 2b is independently selected from OH or Ci-C6alkyl.

[0074] In some embodiments, R 3 is selected from

[0075] In some embodiments, R 3 is selected from In some embodiments, R 3 is selected from

[0076] In some embodiments, R 3 is selected from

[0077] In some embodiments, L 1 is selected from L a -L b -L c , said L a and L b are each independently selected from a chemical bond, C1-C4 alkylene or C3-C6 cycloalkylene, said C1-C4 alkylene or C3-C6 cycloalkylene being optionally substituted with one or more R 3b , L c is selected from -O- or -NH(C=O)-.

[0078] In some embodiments, L 1 is selected from L a -L b -L c , said L a and L b are each independently selected from a chemical bond or C3-C6 cycloalkylene, and the other of said L a and L b is selected from C1-C2 alkylene, said C1-C2 alkylene being optionally substituted with one or more R 3b , L c is selected from -O- or -NH(C=O)-, each R 3b is independently selected from halogen, e.g. F.

[0079] In some embodiments, L 1 is selected from L a -L b -L c , said L a and L b are each independently selected from a chemical bond or C3 cycloalkylene, and the other of said L a and L b is selected from C1-C2 alkylene, said C1-C2 alkylene being optionally substituted with one or more R 3b , L c is selected from -O- or -NH(C=O)-, each R 3b is independently selected from halogen, e.g. F.

[0080] each R is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2. 3b each R is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2.

[0081] each R is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2. 3b each R is independently selected from halogen.

[0082] each R is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2. 1 is selected from -CH2CH2O-, each R is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2. 1 is selected from -CH2CH2O-.

[0083] each R is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2. 1 , Z 2 , Z 3 , Z 4 each R is independently selected from CR 9 , the R 9 is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl.

[0084] each R is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2. 9 is selected from H or halogen.

[0085] each R is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2. 1 , Z 2 , Z 3 , Z 4 each R is independently selected from C-H or C-F.

[0086] each R is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2. 1 is selected from C-H or C-F, Z 2 is C-F, Z 3 is C-H, and Z 4 is C-H. In some embodiments, Z 1 is C-F, Z 2 is C-F, Z 3 is C-H, and Z 4 is C-H. In some embodiments, Z 1 is selected from C-H, Z 2 is C-F, Z 3 is C-H, and Z 4 is C-H.

[0087] In some embodiments, ring B is selected from C6-C 10 aryl, 5-14 membered heteroaryl, or 4-14 membered heterocyclyl.

[0088] In some embodiments, ring B is selected from C6-C 10 aryl, 6-14 membered heteroaryl, or 6-14 membered heterocyclyl. In some embodiments, ring B is selected from C6-C 10 aryl, 6-14 membered heteroaryl, or 6-14 membered heterocyclyl, each of which contains 1, 2, or 3 N atoms. In some embodiments, ring B is selected from C6 aryl, C 10 aryl, 6-14 membered heteroaryl, or 6-14 membered heterocyclyl, each of which contains 1 or 2 N atoms.

[0089] In some embodiments, ring B is selected from is covalently attached to R 6 .

[0090] In some embodiments, ring B is selected from is covalently attached to R 6 .

[0091] In some embodiments, ring B is selected from is covalently attached to R 6 .

[0092] In some embodiments, each R x is each independently selected from halogen, =0, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl, said OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl optionally substituted with one or more R 4b .

[0093] In some embodiments, each R x is each independently selected from halogen, =0, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl, said OH, NH2, or C1-C6 alkyl optionally substituted with one or more R 4b .

[0094] In some embodiments, each R x is each independently selected from =0, CN, OH, C1-C6 alkyl, or C3-C6 cycloalkyl, said OH or C1-C6 alkyl optionally substituted with one or more R 4b .

[0095] In some embodiments, each R x is each independently selected from =0, CN, OH, C1-C6 alkyl, or C3-C6 cycloalkyl, said OH or C1-C6 alkyl optionally substituted with one or more R 4b is each independently selected from =0, CN, OH, C1-C6 alkyl, or C3-C6 cycloalkyl, said OH or C1-C6 alkyl optionally substituted with one or more R 4b is each independently selected from =0, CN, OH, C1-C6 alkyl, or C3-C6 cycloalkyl, said OH or C1-C6 alkyl optionally substituted with one or more R

[0096] In some embodiments, R 4 and R 5 is each independently selected from =0, CN, OH, C1-C6 alkyl, or C3-C6 cycloalkyl, said OH or C1-C6 alkyl optionally substituted with one or more R 4b .

[0097] In some embodiments, R 4 and R 5 is each independently selected from =0, CN, OH, C1-C6 alkyl, or C3-C6 cycloalkyl, said OH or C1-C6 alkyl optionally substituted with one or more R 4b .

[0098] In some embodiments, R 4 and R 5 is each independently selected from =0, CN, OH, C1-C6 alkyl, or C3-C6 cycloalkyl, said OH or C1-C6 alkyl optionally substituted with one or more R 4b .

[0099] In some embodiments, R 4 and R 5 is each independently selected from =0, CN, OH, C1-C6 alkyl, or C3-C6 cycloalkyl, said OH or C1-C6 alkyl optionally substituted with one or more R 4b .

[0100] In some embodiments, R 4 and R 5 is each independently selected from =0, CN, OH, C1-C6 alkyl, or C3-C6 cycloalkyl, said OH or C1-C6 alkyl optionally substituted with one or more R 4b . 4b is each independently selected from =0, CN, OH, C1-C6 alkyl, or C3-C6 cycloalkyl, said OH or C1-C6 alkyl optionally substituted with one or more R

[0101] In some embodiments, R 4 and R 5 each independently is selected from absent, =0, CN, OH, or C3-C6cycloalkyl, said OH or C3-C6cycloalkyl optionally substituted with one or more R 4b .

[0102] In some embodiments, each R 4b is independently selected from halogen, CN, OH, NH2, C(=0)-Ci-C6alkyl, Ci-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl, said C(=0)-Ci-C6alkyl, Ci-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl optionally substituted with one or more R c , each R c is independently selected from halogen, CN, OH, NH2, Ci-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 0(Ci-C4alkyl), NH(Ci-C4alkyl), or N(Ci-C4alkyl)2.

[0103] In some embodiments, each R 4b is independently selected from halogen, CN, OH, NH2, C(=0)-Ci-C6alkyl, Ci-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl, said C(=0)-Ci-C6alkyl or Ci-C6alkyl optionally substituted with one or more OH.

[0104] In some embodiments, each R 4b is independently selected from halogen, OH, C(=0)-Ci-C6alkyl, Ci-C6alkyl, or C3-C6cycloalkyl, said C(=0)-Ci-C6alkyl or Ci-C6alkyl optionally substituted with one or more OH.

[0105] In some embodiments, each R 4b is independently selected from halogen, CN, OH, NH2, Ci-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl.

[0106] In some embodiments, each R 4b is independently selected from Ci-C6alkyl or 4-7 membered heterocyclyl.

[0107] In some embodiments, each R 4b is independently selected from 4-7 membered heterocyclyl.

[0108] In some embodiments, each R x is each independently selected from =0, CN, cyclopropyl, cyclobutyloxy, methoxy, OH, methyl, halogen, oxetanyl, methylamino, dimethylamino, CF3, or CF2H.

[0109] In some embodiments, each R x is each independently selected from =0, CN, cyclopropyl, cyclobutyloxy, methoxy, OH, methyl, CF3,

[0110] In some embodiments, R 4 and R 5 are each independently selected from absent, =0, CN, cyclopropyl, cyclobutyloxy, methoxy, OH, methyl, methylamino, dimethylamino, CF3, or CF2H.

[0111] In some embodiments, R 4 and R 5 are each independently selected from absent, =0, CN, cyclopropyl, cyclobutyloxy, methoxy, OH, methyl, methylamino or dimethylamino.

[0112] In some embodiments, R 4 and R 5 are each independently selected from absent, =0, CN, cyclopropyl, cyclobutyloxy, methoxy, methyl, CF3,

[0113] In some embodiments, R 4 and R 5 are each independently selected from absent, =0, CN, cyclopropyl, cyclobutyloxy, methoxy, OH, methyl,

[0114] In some embodiments, R 4 and R 5 are each independently selected from absent, =0, CN, cyclopropyl, or cyclobutyloxy.

[0115] In some embodiments, R 7 , R 8 are each selected from H, or R 7 , R 8 and the carbon atom to which they are attached collectively form a cyclopropyl group.

[0116] In some embodiments, R 6 is selected from wherein R 7 , R 8each independently selected from H, C1, C2, C3, or C4alkyl, C3, C4, C5, or C6cycloalkyl, or C(=0)-C1-C2alkyl, or R 7 , R 8 and the carbon atom to which they are attached collectively form a cyclopropyl group; q is selected from 0; 12 , R 13 each independently selected from H, C1, C2, C3, or C4alkyl, C3, C4, C5, or C6cycloalkyl, or C(=0)-C1-C2alkyl, or R 12 , R 13 and the nitrogen atom to which they are attached collectively form a 4-, 5-, 6-, or 7-membered heterocyclyl group, said alkyl, cycloalkyl, heterocyclyl, or C(=0)-C1-C2alkyl being optionally substituted with one or more R 7b each R 7b is independently selected from deuterium, halogen, CN, OH, NH2, or C1-C6alkyl, or, said each R 7b is independently selected from deuterium, halogen (e.g., F), or OH.

[0117] In some embodiments, R 6 is selected from wherein R 7 , R 8 , R 10 , R 11 and R 14 are each H, and q is 1.

[0118] In some embodiments, q is selected from 0.

[0119] In some embodiments, R 12 , R 13 each independently selected from H, C1-C6alkyl, C3-C6cycloalkyl, or C(=0)-C1-C6alkyl, or R 12 , R 13 and the nitrogen atom to which they are attached collectively form a 4-7 membered heterocyclyl group, said C1-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, or C(=0)-C1-C6alkyl being optionally substituted with one or more R 7b each R 7b is independently selected from deuterium, halogen, CN, OH, NH2, or C1-C6alkyl; or, said each R 7b is independently selected from deuterium, halogen, or OH.

[0120] In some embodiments, R 12 , R 13 each independently selected from H, C1, C2, C3, or C4alkyl, C3, C4, C5, or C6cycloalkyl, or C(=0)-C1-C2alkyl, or R 12 , R 13and the nitrogen atom to which they are attached together form a 4-, 5-, 6-, or 7- membered heterocyclyl, said alkyl, cycloalkyl, heterocyclyl, or C(=0)-Ci-C2alkyl is optionally substituted with one or more R 7b each R 7b is independently selected from deuterium, halogen, CN, OH, NH2, or Ci-C6alkyl; or, each R 7b is independently selected from deuterium, halogen (e.g., F), or OH.

[0121] In some embodiments, R 12 , R 13 are each independently selected from H, Ci, C2, or C3alkyl, or C3or C4cycloalkyl, said alkyl optionally substituted with one or more deuterium.

[0122] In some embodiments, R 12 , R 13 are each independently selected from H, Ci-C6alkyl, or C3-C6cycloalkyl, or R 12 , R 13 and the nitrogen atom to which they are attached together form a 4-7 membered heterocyclyl, said Ci-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl is optionally substituted with one or more R 7b each R 7b is independently selected from deuterium, halogen, CN, OH, NH2, or Ci-C6alkyl.

[0123] In some embodiments, R 12 , R 13 are each independently selected from H, Ci-C6alkyl, or C3-C6cycloalkyl, said Ci-C6alkyl or C3-C6cycloalkyl is optionally substituted with one or more R 7b each R 7b is independently selected from deuterium, halogen, CN, OH, NH2, or Ci-C6alkyl.

[0124] In some embodiments, R 12 , R 13 are each independently selected from H, methyl, ethyl optionally substituted with one or more halogen, cyclopropyl, cyclobutyl, isopropyl, CD3, acetyl optionally substituted with one or more OH, or R 12 , R 13 and the nitrogen atom to which they are attached together form a pyrrolidinyl.

[0125] In some embodiments, R 12 , R 13 are each independently selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, CD3, or R 12 , R 13together with the nitrogen atom to which they are attached form a pyrrolidinyl group.

[0126] In some embodiments, R 12 , R 13 are each independently selected from H, methyl, cyclopropyl, cyclobutyl, isopropyl, or CD3.

[0127] In some embodiments, R 12 , R 13 are each independently selected from H, methyl, or cyclopropyl.

[0128] In some embodiments, R 14 is selected from H or C1-C6 alkyl, preferably H.

[0129] In some embodiments, R 6 is selected from or a 4-, 5-, 6-, or 7-membered heterocyclyl containing 1 or 2 nitrogen atoms, wherein R 6 is when R 7 , R 8 , R 10 , R 11 , and R 14 are each H; R 6 is when R 7 and R 8 are each selected from H, or R 7 and R 8 together with the carbon atom to which they are attached form a cyclopropyl group; R 12 , R 13 are each independently selected from H, C1, C2, C3, or C4 alkyl, C3, C4, C5, or C6 cycloalkyl, or C(=O)-C1-C2 alkyl, or R 12 , R 13 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocyclyl group, said alkyl, cycloalkyl, heterocyclyl, or C(=O)-C1-C2 alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen (e.g., F), and OH.

[0130] In some embodiments, R 6 is selected from

[0131] In some embodiments, R 6 is selected from In some embodiments, R 6 is selected from

[0132] In some embodiments, R 6 is selected from

[0133] In some embodiments, R 6 is selected from

[0134] In some embodiments, R 6 is selected from

[0135] In some embodiments, R 6 is selected from

[0136] In some embodiments, the structural unit is selected from

[0137] In some embodiments, the structural unit is selected from

[0138] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds of Formula (la), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0139] wherein R 1 , R 2 , R 3 , R x , y, R 6 , R 9 , L 1 and ring B are as defined in any one of the above.

[0140] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds of Formula (lb), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0141] wherein R 1 , R 2 , R 3 , R x , y, R 6 , R9 , L 1 and ring B is as defined in any one of the preceding items.

[0142] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds of Formula (I’a), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0143] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , L 1 and ring B is as defined in any one of the preceding items.

[0144] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds of Formula (I’b), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0145] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , L 1 and ring B is as defined in any one of the preceding items.

[0146] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0147] The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (I), (I’), (Ia), (Ib), (I’a), or (I’b), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0148] In another aspect, the present disclosure relates to the use of a compound represented by Formula (I), (I'), (Ia), (Ib), (I'a) or (I'b), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or treating a NMT (N-myristoyl transferase)-related disease.

[0149] In another aspect, the present disclosure relates to the use of a compound represented by Formula (I), (I'), (Ia), (Ib), (I'a) or (I'b), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating a NMT (N-myristoyl transferase)-related disease.

[0150] In another aspect, the present disclosure relates to the use of a compound represented by Formula (I), (I'), (Ia), (Ib), (I'a) or (I'b), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating a NMT (N-myristoyl transferase)-related disease.

[0151] In another aspect, the present disclosure relates to the use of a compound represented by Formula (I), (I'), (Ia), (Ib), (I'a) or (I'b), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating a NMT (N-myristoyl transferase)-related disease.

[0152] In another aspect, the present disclosure relates to the use of a compound represented by Formula (I), (I'), (Ia), (Ib), (I'a) or (I'b), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating a NMT (N-myristoyl transferase)-related disease.

[0153] In some embodiments, the NMT (N-myristoyl transferase)-related disease is selected from a tumor.

[0154] In the present disclosure, the term "NMT (N-myristoyl transferase)-related disease" is used interchangeably with "NMT (N-myristoyl transferase)-mediated disease".

[0155] The compound of Formula (I), (I'), (Ia), (Ib), (I'a) or (I'b), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of the present disclosure is a novel class of NMT inhibitors, which has good anti-tumor cell proliferation activity and / or membrane permeability.

[0156] Definitions and explanations

[0157] Unless otherwise indicated, the terms used in the present disclosure have the following meanings, the definitions of the groups and terms recited in the present disclosure, including the definitions as examples, exemplary definitions, preferred definitions, the definitions recited in the tables, the definitions of the specific compounds in the examples, etc., can be combined and incorporated with each other arbitrarily. A particular term should not be considered indefinite or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0158] Herein represents a point of attachment.

[0159] The term "tautomer" refers to isomers of a functional group that result from the rapid movement of an atom in a molecule to two positions. The compounds of the present disclosure can exhibit tautomerism. Compounds that tautomerize can exist in two or more interconvertible forms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of the compounds.

[0160] The term "stereoisomer" refers to isomers that have the same molecular formula but different spatial arrangement of atoms. Stereoisomers include enantiomers (mirror images of the other that are non-superimposable), and diastereomers (isomers that are not mirror images of each other, but that have non-identical spatial arrangements of atoms).

[0161] The compounds of the present disclosure can have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and therefore the compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The particular geometric or stereoisomeric form can be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic mixtures or other mixtures thereof, such as those that contain both (R)- and (S)-enantiomers in no-identical amounts, and the like. Additional asymmetric carbon, sulfur, nitrogen, or phosphorus atoms or asymmetric double bonds can be present in a substituent such as an alkyl group, and all that are

[0162] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0163] The terms “optional” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, “optionally” substituted with one or more halogens means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0164] When any variable (e.g., R) a R b When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is surrounded by two R... b Replaced, then each R b Each has its own independent options.

[0165] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a bond.

[0166] When one of the variables is selected as a chemical bond or does not exist, it means that the two groups it is connected to are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0167] Unless otherwise specified, the linking direction of the linking groups mentioned in this article is arbitrary. For example, when structural unit L... 1 -L 2 -L 3 L in 2 When selected from "-NHC(=O)-", L 2 You can connect L in a left-to-right direction. 1 L 3 Composing "L" 1 -NHC(=O)-L 3 ", or you can connect L from right to left 1 L 3 Composing "L" 1 -C(=O)NH-L3 ”.

[0168] When a chemical bond is crossed to two atoms on a ring, it means that the chemical bond can be bonded to any atom on the ring. For example, the structural unit represents that the chemical bond can be bonded to any one position on the benzene ring.

[0169] C m -C n means an integer number of carbon atoms in the range m-n. For example, "C1-C 10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0170] The term "alkyl" refers to a hydrocarbon group of formula C n H 2n+1 The term "C1-C 10 alkyl" refers to a straight chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, and the like; the term "C1-C6alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, and specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like. The term "C1-C4alkyl" refers to a straight chain or branched saturated alkyl group having 1, 2, 3, or 4 carbon atoms. The "C1-C 10 alkyl" can include the range of "C1-C6alkyl" or "C1-C4alkyl", and the like, which "C1-C6alkyl" can further include "C1-C4alkyl".

[0171] The term "alkylene" refers to a straight chain or branched saturated divalent hydrocarbon group. The term "C1-C 10"Alkylene" refers to a straight-chained or branched saturated divalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The term "Ci-C6-alkylene" refers to a straight-chained or branched saturated divalent hydrocarbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms. The term "Ci-C4-alkylene" refers to a straight-chained or branched saturated divalent hydrocarbon radical having 1, 2, 3, or 4 carbon atoms.

[0172] The term "alkenyl" refers to a straight-chained or branched unsaturated aliphatic hydrocarbon radical consisting of carbon and hydrogen atoms and having at least one double bond. The term "C2-C 10 "Alkenyl" can be understood as meaning a straight-chained or branched unsaturated hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, "C2-C 10 "Alkenyl" can contain "C2-C6-alkenyl", "C2-C4-alkenyl", C2 or C3 alkenyl. It is to be understood that, in the case where the alkenyl group contains more than one double bond, the double bonds can be separated from one another or conjugated. Particular examples of the alkenyl group include, but are not limited to, ethenyl, allyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1 -methylprop-2-enyl, 2-methylprop-1 -enyl, (E)-1 -methylprop-1 -enyl, or (Z)-1 -methylprop-1 -enyl, and the like.

[0173] The term "alkynyl" refers to a straight-chained or branched unsaturated aliphatic hydrocarbon radical consisting of carbon and hydrogen atoms and having at least one triple bond. The term "C2-C 10 "Alkynyl" can be understood as meaning a straight-chained or branched unsaturated hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. "C2-C 10 "Alkynyl" can contain "C2-C6-alkynyl", "C2-C4-alkynyl", C2 or C3 alkynyl. Particular examples of the alkynyl group include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 3), but-1-ynyl, but-2-ynyl, or but-3-ynyl.

[0174] The term "cycloalkyl" refers to a fully saturated carbon ring radical which exists as a monocyclic, fused ring, bridged ring, or spiro ring, etc. Unless otherwise indicated, the carbon ring is typically a 3- to 20-membered ring. The term "C3-C 12"Cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring carbon atoms. Specific examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc. The term "C3-C" is used in this context. 12 "Cycloalkyl" can contain "C5-C 12 cycloalkyl, C3-C 10 The range includes "cycloalkyl" and "C3-C6 cycloalkyl". The term "C5-C6 cycloalkyl" is also included. 12 "Cycloalkyl" refers to a cycloalkyl group having 5, 6, 7, 8, 9, 10, 11, or 12 ring carbon atoms. The term "C3-C" is also used. 10 "Cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in the ring. The term "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, or 6 carbon atoms in the ring.

[0175] The term "cycloalkylene" refers to a divalent cycloalkyl group. The term "C3-C6 cycloalkylene" refers to a divalent cycloalkyl group having 3, 4, 5, or 6 ring carbon atoms.

[0176] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbocyclic group having at least one carbon-carbon double bond and existing in the form of a monocyclic, fused, bridged, or spirocyclic ring. The term "C5-C..." 10 "Cycloalkenyl" refers to cycloalkenyl groups with 5, 6, 7, 8, 9, or 10 carbon atoms in the ring. Specific examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl.

[0177] The term "heterocyclyl" refers to a monocyclic, fused, spiro, or bridged ring radical that is completely saturated or partially saturated (not an aromatic heteroaromatic overall) having 1, 2, 3, 4, or 5 (e.g., 1, 2, or 3, or 1-2) heteroatoms or heteroatom groups (i.e., groups of atoms that contain heteroatoms) in its ring atom count, including, but not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=0)2-, -S(=0)-, -P(=0)2-, -P(=0)-, -NH-, -S(=0)(=NH)-, -C(=0)NH-, or -NHC(=0)NH-, etc., and which fused, spiro, or bridged ring can be bicyclic, tricyclic, tetracyclic, or pentacyclic. The term "4-14 membered heterocyclyl" refers to a heterocyclyl having a ring atom count of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, and having 1, 2, 3, 4, or 5 ring atoms independently selected from the heteroatoms or heteroatom groups described above. The term "4-10 membered heterocyclyl" refers to a heterocyclyl having a ring atom count of 4, 5, 6, 7, 8, 9, or 10, and having 1, 2, 3, 4, or 5 ring atoms independently selected from the heteroatoms or heteroatom groups described above. "4-14 membered heterocyclyl" can include "4-10 membered heterocyclyl," "5-10 membered heterocyclyl," and "4-7 membered heterocyclyl." "4-10 membered heterocyclyl" can include "4-7 membered heterocyclyl." The term "4-7 membered heterocyclyl" refers to a heterocyclyl having a ring atom count of 4, 5, 6, or 7, and having 1, 2, 3, 4, or 5 ring atoms independently selected from the heteroatoms or heteroatom groups described above. The term "4-7 membered nitrogen heterocyclyl" refers to a heterocyclyl having a ring atom count of 4, 5, 6, or 7, and having at least 1 nitrogen atom in its ring atom count. The term "4-7 membered monoheterocyclyl" refers to a 4-7 membered heterocyclyl in monocylic form. Specific examples of 4-membered heterocyclyls include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyls include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-lH-pyrrolyl; specific examples of 6-membered heterocyclyls include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[l,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyls include, but are not limited to, diazepanyl. The heterocyclyl can also be a bicyclic radical, where specific examples of 5,5 membered bicyclic radicals include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(lH)-yl; specific examples of 5,6 membered bicyclic radicals include, but are not limited to, hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[l,5-a]pyrazinyl.Optionally, the heterocyclyl group can be a benzo-fused ring group of the above 4-7 membered heterocyclyl groups, and specific examples include, but are not limited to, dihydroisoquinolyl and the like. Although some polycyclic heterocyclyl groups in the present disclosure contain a benzene ring or a heteroaromatic ring partially, the heterocyclyl group as a whole is still non-aromatic.

[0178] The term "heterocyclyl" refers to a monovalent heterocyclic ring radical. The term "4-7 membered heterocyclyl" refers to a heterocyclic ring radical having 4, 5, 6, or 7 ring atoms, and having 1, 2, 3, 4, or 5 ring atoms independently selected from the above-mentioned heteroatoms or heteroatom groups.

[0179] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic ring system having a completely conjugated pi-electron system. The aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 10 The term "aryl" can be understood as an aryl group having 6 to 10 carbon atoms. For example, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 The term "aryl" can be understood as an aryl group having 6 to 10 carbon atoms. For example, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C

[0180] The term "5-14 membered heteroaryl" refers to a monocyclic or fused polycyclic system having aromaticity, containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, and which contains 1, 2, 3, 4, 5, 6, 7, or 8, preferably 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, and S. The term "5-10 membered heteroaryl" refers to a monocyclic or bicyclic aromatic ring system having 5, 6, 7, 8, 9, or 10 ring atoms, e.g. 5 or 6 or 9 or 10 ring atoms, and which contains 1, 2, 3, 4, or 5, e.g. 1, 2, or 3 heteroatoms independently selected from N, O, and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, or thiadiazolyl and the like as well as their benzo derivatives, e.g. benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl and the like as well as their benzo derivatives, e.g. quinolinyl, quinazolinyl or isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like as well as their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, or phenoxazinyl and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1, 2, or 3, e.g. 1-2 heteroatoms independently selected from N, O, and S.

[0181] The term "halo" or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0182] The term "hydroxy" refers to an -OH group.

[0183] The term "cyano" refers to a -CN group.

[0184] The term "mercapto" refers to an -SH group.

[0185] The term "amino" refers to an -NH2 group.

[0186] The term "nitro" refers to a -NO2 group.

[0187] The term "therapeutically effective amount" means an amount of a compound of the disclosure that (i) treats the particular disease, condition, or disorder, (ii) eliminates or ameliorates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner by a consideration of the factors.

[0188] The term "prevent" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing the disease or disease state from occurring in an individual (e.g., a mammal), particularly when such individual (e.g., a mammal) is predisposed to the disease state, but has not yet been diagnosed as having it.

[0189] The term "individual" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds and fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "individual" are used interchangeably.

[0190] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0191] The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of acids or bases, including salts of compounds with inorganic acids or organic acids, and salts of compounds with inorganic bases or organic bases.

[0192] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the disclosure, or stereoisomers or salts thereof, with a pharmaceutically acceptable carrier. The objective of a pharmaceutical composition is to facilitate administration of a compound of the disclosure to an organism.

[0193] The term "pharmaceutically acceptable excipient" means an excipient that does not stimulate an undesirable response in an organism, and does not substantially interfere with the biological activity and / or property of the active compound. Suitable excipients are well known to those skilled in the art, e.g., carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0194] The words "comprise" or "comprising" and variations such as "comprises" or "comprising", when used in this document, can be understood to express the inclusion of a feature or group of features that are described, but not to the exclusion of other features that are not described or that are even mutually exclusive.

[0195] The present disclosure also includes isotopically-labeled compounds of the present disclosure, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, and the like.

[0196] Certain isotopically-labeled compounds of the present disclosure (for example, those 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to assess substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent in a procedure of synthesis of a compound disclosed in the schemes and / or examples below.

[0197] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds disclosed herein with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0198] Typical routes of administration of the disclosed compound or its stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous or intravenous administration.

[0199] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

[0200] In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0201] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, or flavoring agents.

[0202] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0203] In all methods of administration of the compounds of formula (I), (I'), (Ia), (Ib), (I'a) or (I'b) described herein, the daily dose is from 0.01 mg / kg to 200 mg / kg body weight, preferably from 0.05 mg / kg to 50 mg / kg body weight, more preferably from 0.1 mg / kg to 30 mg / kg body weight, in the form of single or separate doses.

[0204] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0205] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments. Example

[0206] The present disclosure is described in detail below with reference to embodiments, but this does not imply any adverse limitation thereof. The present disclosure has been described in detail herein, including specific embodiments thereof. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope thereof. All reagents used in this disclosure are commercially available and can be used without further purification.

[0207] Unless otherwise stated, the proportions of mixed solvents are volume-based.

[0208] Unless otherwise stated, % refers to weight percentage (wt%).

[0209] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0210] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻¹⁰. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., with tetramethylsilane (TMS) as the internal standard; "IC 50 "Half-inhibition concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0211] The eluent or mobile phase can be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent. For example, "0-10% methanol / dichloromethane" indicates that the volume ratio of methanol to dichloromethane in the mixed eluent or mobile phase is 0:100 to 10:100.

[0212] The following abbreviations are used in this disclosure:

[0213] Example 1: 6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-3-((methylamino)methyl)imidazo[1,2-a]pyridine-8-carboxynitrile (Compound 1)

[0214] Step 1: Synthesis of 1-(4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H- pyrazol-3-yl)-2,2-dimethylpropan-1-one (Intermediate 1-2)

[0215] Under nitrogen atmosphere, Intermediate 1-1 (740 mg, prepared in WO2024052685 literature procedure), 6-bromo-2,3-difluorophenol (1.35 g) and cyanomethylidene tri-n- butylphosphonium (1.58 g) were dissolved in toluene (20 mL), the resulting mixture was heated at 110 °C for 16 h. The reaction mixture was directly purified by silica gel column chromatography (ethyl acetate / petroleum ether, 0-100%) to give the title compound (989 mg).

[0216] LC-MS: m / z (ESI): 415.2 [M+H] +

[0217] Step 2: Synthesis of 1-(4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H- pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Intermediate 1-3)

[0218] Under nitrogen atmosphere, Intermediate 1-1 (740 mg, prepared in WO2024052685 literature procedure), 6-bromo-2,3-difluorophenol (1.35 g) and cyanomethylidene tri-n- butylphosphonium (1.58 g) were dissolved in toluene (20 mL), the resulting mixture was heated at 110 °C for 16 h. The reaction mixture was directly purified by silica gel column chromatography (ethyl acetate / petroleum ether, 0-100%) to give the title compound (989 mg).

[0219] LC-MS: m / z (ESI): 415.2 [M+H] +

[0220] Step 3: Synthesis of 1-(4-(2-(2,3-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Intermediate 1-4)

[0221] Under nitrogen atmosphere, Intermediate 1-1 (740 mg, prepared in WO2024052685 literature procedure), 6-bromo-2,3-difluorophenol (1.35 g) and cyanomethylidene tri-n- butylphosphonium (1.58 g) were dissolved in toluene (20 mL), the resulting mixture was heated at 110 °C for 16 h. The reaction mixture was directly purified by silica gel column chromatography (ethyl acetate / petroleum ether, 0-100%) to give the title compound (989 mg).

[0222] LC-MS: m / z (ESI): 415.2 [M+H] +

[0223] Step 4: Synthesis of 6-bromo-8-iodoimidazo[l,2-a]pyridine-3-carbaldehyde (Intermediate 1-6)

[0224] Phosphorus oxychloride (4.75 g) was added dropwise to a solution of DMF (40 mL) at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 1 h. Then intermediate 1-5 (1 g) was added to the reaction at 0 °C, and the reaction was heated to 100 °C for 5 h under nitrogen atmosphere. After that, the reaction was cooled to room temperature and quenched with water (100 mL), and the pH was adjusted to 9 with 1 M NaOH, and solid precipitated. The solid was filtered, and the filter cake was concentrated under reduced pressure to give the title compound (3.5 g).

[0225] LCMS (m / z): 350.7 [M+H] +

[0226] Step 5: Synthesis of l-(6-bromo-8-iodoimidazo[l,2-a]pyridin-3-yl)-N- methylmethanamine (Intermediate 1-7)

[0227] Intermediate 1-6 (2 g) and methylamine hydrochloride (577 mg) were dissolved in methanol (40 mL), and sodium cyanoborohydride (716 mg) was added under nitrogen atmosphere. The reaction was warmed to 35 °C for 16 h. After that, the reaction was diluted with ethyl acetate (50 mL) and washed with water (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by flash silica gel column (12 g) with eluent of 0-30% ethyl acetate / petroleum ether at gradient @ 60 mL / min to give the title compound (800 mg). 20 g flash silica gel column, eluent of 0-30% ethyl acetate / petroleum ether at gradient @ 60 mL / min.

[0228] LCMS (m / z): 367.9 [M+H] +

[0229] Step 6: Synthesis of tert-butyl ((6-bromo-8-iodoimidazo[l,2-a]pyridin-3- yl)methyl)(methyl)carbamate (Intermediate 1-8)

[0230] Intermediate 1-7 (0.8 g) was dissolved in dichloromethane (8 mL), and di-tert- butyl dicarbonate (715 mg) and triethylamine (663 mg) were added under nitrogen atmosphere. The reaction was stirred at 25 °C for 16 h. After that, the reaction was purified by flash silica gel column (12 g) with eluent of 0-20% tetrahydrofuran / petroleum ether at gradient @ 60 mL / min to give the title compound (700 mg). 12 g flash silica gel column, eluent of 0-30% ethyl acetate / petroleum ether at gradient @ 60 mL / min.

[0231] MS m / z (ESI): 467.8 [M+H] +

[0232] Step 7: Synthesis of tert-butyl ((6-bromo-8-cyanoimidazo[l,2-a]pyridin-3- yl)methyl)(methyl)carbamate (Intermediate 1-9)

[0233] Intermediate 1-8 (200 mg) and potassium ferrocyanide trihydrate (453 mg) were dissolved in dioxane (1.5 mL) and water (0.5 mL), and (dtbpf)PdCl2(28 mg) and allylpalladium chloride (15 mg) were added under a nitrogen atmosphere. The reaction solution was stirred at 100 °C for 16 hours. After that, the reaction solution was diluted with ethyl acetate (30 mL), and washed with water (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column (eluent 0-60% tetrahydrofuran / petroleum ether, gradient @ 60 mL / min) to give the title compound (80 mg). 12g Flash silica gel column, eluent 0-60% tetrahydrofuran / petroleum ether, gradient @ 60 mL / min.

[0234] MS m / z (ESI): 367.0 [M+H] +

[0235] Step 8: Synthesis of tert-butyl ((8-cyano-6-(3,4-difluoro-2-(2-(3-(l-hydroxy-2,2- dimethylpropyl)-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)imidazo[l,2-a]pyridin-3- yl)methyl)(methyl)carbamate (Intermediate 1-10)

[0236] Intermediate 1-4 (25 mg) and Intermediate 1-9 (23.6 mg) were dissolved in dioxane (0.6 mL) and water (0.2 mL), and l,l-bis(diphenylphosphino)ferrocenedichloropalladium (4 mg) and potassium carbonate (22 mg) were added under a nitrogen atmosphere. The reaction solution was stirred at 90 °C for 3 hours. After that, the reaction solution was diluted with ethyl acetate (30 mL), and washed with water (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (33 mg).

[0237] LC-MS: m / z (ESI): 623.4 [M+H] +

[0238] Step 9: Synthesis of 6-(3,4-difluoro-2-(2-(3-(l-hydroxy-2,2-dimethylpropyl)-l,5- dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)-3-((methylamino)methyl)imidazo[l,2-a]pyridine- 8-carbonitrile (Compound 1)

[0239] Intermediate 1-10 (33 mg) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL), and the reaction solution was stirred at 25 °C for 1 h. After that, the reaction solution was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: ACSSH-CPC18 150*40 mm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 25%-65%, 9 min) to give the title compound (8 mg).

[0240] LC-MS: m / z (ESI): 523.2 [M+H] +

[0241] 1 HNMR (400MHz, DMSO-d6) δ = 8.87 (s, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 7.43-7.31 (m, 2H), 4.62-4.60 (m, 1H), 4.06 (s, 3H), 4.02-3.96 (m, 1H), 3.93-3.89 (m, 1H), 3.54 (s, 3H), 2.83-2.76 (m, 1H), 2.66-2.59 (m, 1H), 2.25 (s, 3H), 1.91 (s, 3H), 0.73 (s, 9H).

[0242] Example 2, 1-(4-(2-(6-(8-cyclopropyl-3-((methylamino)methyl)imidazo[1,2- a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl)-2,2- dimethylpropan-1-ol (Compound 2)

[0243] Step 1: Synthesis of tert-butyl ((6-bromo-8-cyclopropylimidazo[1,2-a]pyridin-3- yl)methyl)(methyl)carbamate (Intermediate 2-1)

[0244] Intermediate 1-8 (200 mg) and cyclopropylboronic acid (110 mg) were dissolved in dioxane (1.2 mL) and water (0.4 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (31 mg) and cesium carbonate (419 mg) were added under nitrogen atmosphere. The reaction solution was stirred at 110 °C for 16 h. After that, the reaction solution was diluted with ethyl acetate (30 mL) and washed with water (15 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by flash silica gel column (20 g) to give the title compound (80 mg). 20 g flash silica gel column, eluent 0-60% tetrahydrofuran / petroleum ether, gradient @ 60 mL / min) to give the title compound (80 mg).

[0245] MS m / z (ESI): 381.9 [M+H] +

[0246] Step 2: Synthesis of tert-butyl ((8-cyclopropyl-6-(3,4-difluoro-2-(2-(3-(1- hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2- a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 2-2)

[0247] Intermediate 2-1 (24 mg) and Intermediate 1-4 (25 mg) were dissolved in dioxane (0.5 mL) and water (0.2 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (4 mg) and potassium carbonate (22 mg) were added under nitrogen atmosphere. The reaction was stirred at 90 °C for 3 hours. The reaction was then diluted with ethyl acetate (30 mL) and washed with water (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give the title compound (35 mg) after filtration.

[0248] MS m / z (ESI): 638.5 [M+H] +

[0249] Step 3: Synthesis of 1-(4-(2-(6-(8-cyclopropyl-3-((methylamino)methyl)imidazo[1,2- a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl]-1,5-dimethyl-1H-pyrazol-3-yl)-2,2- dimethylpropan-1-ol (Compound 2)

[0250] Intermediate 2-2 (34 mg) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL), and the reaction was stirred at 25 °C for 1 hour. The reaction was then directly concentrated to dryness under reduced pressure, and the residue was purified by high performance liquid chromatography (column: ACSSH-CP 150 x 40 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 10% - 50%, 9 min) to give the title compound (2.1 mg).

[0251] LC-MS: m / z (ESI): 538.1 [M+H] + .

[0252] 1H NMR (400 MHz, DMSO-d6) d = 8.37 (s, 1H), 8.24 (s, 1H), 7.48 (s, 1H), 7.33-7.24 (m, 2H), 6.95 (s, 1H), 4.70-4.55 (m, 1H), 4.07 (s, 1H), 4.02 (s, 2H), 3.95-3.86 (m, 1H), 3.86-3.80 (m, 1H), 3.54 (s, 3H), 2.86-2.74 (m, 1H), 2.66-2.57 (m, 1H), 2.33-2.30 (m, 1H), 2.27 (s, 3H), 1.84 (s, 3H), 1.10-1.01 (m, 4H), 0.76 (s, 9H).

[0253] Example 3, 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)pyrazolo[1,5- a]pyridin-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 3)

[0254] Step 1: Synthesis of 5-bromopyrazolo[1,5-a]pyridine-3-carbaldehyde (Intermediate 3-2)

[0255] Intermediate 3-1 (1 g) was dissolved in N,N-dimethylformamide (10 mL), and phosphorus oxychloride (2.33 g) was added at 0 °C under nitrogen atmosphere. The reaction solution was stirred at 25 °C for 16 hours. Then the reaction solution was adjusted to pH 10 with 1M sodium hydroxide, extracted with dichloromethane (20 mL x 3), and then washed with water (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (1.1 g).

[0256] MS m / z (ESI): 224.9 [M+H] +

[0257] Step 2: Synthesis of 1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-N-methylmethanamine (Intermediate 3-3)

[0258] Intermediate 3-2 (600 mg) and methylamine hydrochloride (270 mg) were dissolved in methanol (10 mL), and sodium cyanoborohydride (335 mg) was added. The reaction solution was stirred at 35 °C for 16 hours. Then the reaction solution was diluted with ethyl acetate (50 mL), washed with water (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (200 mg).

[0259] 1H NMR (400 MHz, CDC13) δ = 8.29 (d, J = 7.4 Hz, 1H), 7.88 (s, 1H), 7.67 (d, J = 1.5 Hz, 1H), 6.83 (dd, J = 2.0, 7.4 Hz, 1H), 3.65 (s, 2H), 2.22 (s, 3H)

[0260] Step 3: Synthesis of tert-butyl ((5-bromopyrazolo[l,5-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 3-4)

[0261] Intermediate 3-3 (0.1 g) was dissolved in dichloromethane (1 mL), di-tert-butyl dicarbonate (272.7 mg) and triethylamine (126 mg) were added under nitrogen atmosphere, the reaction was stirred at 25 °C for 48 h. The reaction was then purified by flash silica gel column (eluent 0-60% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min) to give the title compound (30 mg). 4g Flash silica gel column, eluent 0-60% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min) purification gave the title compound (30 mg).

[0262] MS m / z (ESI): 340.1 [M+H] +

[0263] Step 4: Synthesis of tert-butyl ((5-(3,4-difluoro-2-(2-(3-(l-hydroxy-2,2-dimethylpropyl)- 1,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)pyrazolo[l,5-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 3-5)

[0264] Intermediate 3-4 (30 mg) and Intermediate 1-4 (41.5 mg) were dissolved in dioxane (1 mL) and water (0.4 mL), palladium (6.4 mg) and potassium carbonate (36 mg) were added under nitrogen atmosphere, the reaction was stirred at 90 °C for 3 h. The reaction was then diluted with ethyl acetate (30 mL) and washed with water (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the title compound (40 mg).

[0265] MS m / z (ESI): 598.4 [M+H] +

[0266] Step 5: Synthesis of l-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)pyrazolo[l,5- a]pyridin-5-yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)-2,2-dimethylpropan- 1-ol (Compound 3)

[0267] Intermediate 3-5 (34 mg) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL), the reaction was stirred at 25 °C for 1 h. The reaction was then directly concentrated to dryness under reduced pressure, the residue was purified by high performance liquid chromatography (column: ACSSH-CP 150x40 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 10% - 50%, 9 min) to give the title compound (2.1 mg).

[0268] LC-MS: m / z (ESI): 498.1 [M+H] + .

[0269] 1 H NMR (400 MHz, DMSO-d6) d = 8.65 (d, J = 7.1 Hz, 1H), 8.36 (s, 1H), 8.12 - 8.02 (m, 1H), 7.96 - 7.85 (m, 1H), 7.40 - 7.25 (m, 2H), 7.04 (d, J = 7.1 Hz, 1H), 4.11 (s, 3H), 3.99 - 3.92 (m, 2H), 3.87 - 3.83 (m, 2H), 3.50 (s, 3H), 2.82 - 2.77 (m, 1H), 2.71 - 2.61 (m, 1H), 2.48 - 2.37 (m, 2H), 1.87 (s, 3H), 0.77 (s, 9H).

[0270] Example 4, 1-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 4)

[0271] Step 1: Synthesis of 1-(6-bromoquinolin-4-yl)-N-(2,4-dimethoxybenzyl)-N- methylmethanamine (Intermediate 4-2)

[0272] Intermediate 4-1 (400 mg) was dissolved in dichloromethane (12 mL), 2,4- dimethoxy-N-methylbenzylamine (MeNHDMB) (614 mg) and sodium cyanoborohydride (213 mg) were added. The reaction was stirred at 25 °C for 16 h. The reaction was then diluted with water (10 mL) and extracted with dichloromethane (15 mL) three times. The organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash silica gel column (flash silica gel column, eluent 0-40% tetrahydrofuran / petroleum ether, gradient @ 60 mL / min) to give the title compound (388 mg). 20g flash silica gel column, eluent 0-40% tetrahydrofuran / petroleum ether, gradient @ 60 mL / min).

[0273] MS m / z (ESI): 401.0 / 403.0 [M+H] + .

[0274] Step 2: Synthesis of l-(6-bromoquinolin-4-yl)-N-methylmethanamine trifluoroacetate (Intermediate 4-3)

[0275] A solution of Intermediate 4-2 (388 mg) in trifluoroacetic acid (3 mL) was heated to 80 °C and stirred for 16 h. After that, it was cooled and concentrated under reduced pressure to give the title compound (242 mg).

[0276] MS m / z (ESI): 251.1 / 253.1 [M+H] +

[0277] Step 3: Synthesis of tert-butyl ((6-bromoquinolin-4-yl)methyl)(methyl)carbamate (Intermediate 4-4)

[0278] Boc20 (252 mg) and triethylamine (292 mg) were added to a solution of Intermediate 4-3 (242 mg) in dichloromethane (7 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction was concentrated to dryness under reduced pressure, and the residue was purified by flash silica gel column (12 g) with eluent of 0-30% tetrahydrofuran / petroleum ether at 50 mL / min to give the title compound (190 mg). 12g flash silica gel column, eluent 0-30% tetrahydrofuran / petroleum ether, gradient @ 50 mL / min.

[0279] MS m / z (ESI): 351.1 / 353.1 [M+H] +

[0280] Step 4: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(l-hydroxy-2,2-dimethylpropyl)- 1,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)quinolin-4-yl)methyl)(methyl)carbamate (Intermediate 4-5)

[0281] Intermediate 1-4 (55 mg) and Intermediate 4-4 (41 mg) were dissolved in dioxane (1.5 mL) and water (0.5 mL), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (4.3 mg) and potassium carbonate (49 mg) were added under nitrogen atmosphere. The reaction was stirred at 100 °C for 2 h. After that, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (71 mg).

[0282] LC-MS: m / z (ESI): 609.4 [M+H] +

[0283] Step 5: Synthesis of 1-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 4)

[0284] Intermediate 4-5 (71 mg) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL), and the reaction was stirred at 20 °C for 1 h. The reaction was then directly concentrated to dryness under reduced pressure, and the residue was purified by high performance liquid chromatography (column: C18 150*30 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 25%-65%, 9 min) to give the title compound (12.4 mg).

[0285] LC-MS: m / z (ESI): 509.2 [M+H] +

[0286] 1 H NMR (400 MHz, DMSO-d6) d = 8.88-8.86 (m, 1H), 8.26-8.24 (m, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 4.3 Hz, 1H), 7.43-7.36 (m, 1H), 7.36-7.26 (m, 1H), 4.21 (s, 2H), 4.03 (s, 1H), 3.91-3.87 (m, 1H), 3.83-3.79 (m, 1H), 3.50 (s, 3H), 2.81-2.69 (m, 1H), 2.61-2.53 (m, 1H), 2.40 (s, 3H), 1.77 (s, 3H), 0.72 (s, 9H).

[0287] Example 5, 1-(4-(2-(6-(3-((cyclopropylamino)methyl)imidazo[1,2-a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 5)

[0288] Step 1: Synthesis of N-((6-bromoimidazo[1,2-a]pyridin-3-yl)methyl)cyclopropanamine (Intermediate 5-2)

[0289] Cyclopropylamine (507 mg) and compound 5-1 (1.0 g) were dissolved in a mixed solvent of methanol (10 mL) and dichloromethane (10 mL), stirred at room temperature 20 °C for 1 hour, then sodium cyanoborohydride (942 mg) was added, and the reaction solution was stirred at 20 °C for 16 hours. Then the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by flash silica gel column (eluent 0-10% methanol / dichloromethane, gradient @ 50 mL / min) to give the title compound (650 mg). 20 g Flash silica gel column, eluent 0-10% methanol / dichloromethane, gradient @ 50 mL / min.

[0290] LC-MS: m / z (ESI): 266.0 / 268.0 [M+H] +

[0291] Step 2: Synthesis of tert-butyl ((6-bromoimidazo[l,2-a]pyridin-3-yl)methyl)(cyclopropyl)carbamate (intermediate 5-3)

[0292] Intermediate 5-2 (200 mg) was dissolved in dichloromethane (2 mL), Boc2O (246 mg) and triethylamine (314 μL) were added to the system, and the reaction solution was stirred at 25 °C for 16 hours. Then the filtrate was concentrated after filtration, and the residue was purified by silica gel column chromatography to give the title compound (190 mg).

[0293] LC-MS: m / z (ESI): 366.1 / 368.1 [M+H] + .

[0294] Step 3: Synthesis of tert-butyl cyclopropyl((6-(3,4-difluoro-2-(2-(3-(l-hydroxy-2,2-dimethylpropyl)-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)imidazo[l,2-a]pyridin-3-yl)methyl)carbamate (intermediate 5-4)

[0295] Intermediate 5-3 (50 mg) and intermediate 1-4 (52 mg) were dissolved in dioxane (1 mL) and water (0.33 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (5.6 mg) and potassium carbonate (38 mg) were added under nitrogen atmosphere, and the reaction solution was stirred at 90 °C for 2 hours. Then the reaction solution was diluted with water (3 mL) and extracted with ethyl acetate (1 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated to give the title compound (70 mg).

[0296] LCMS m / z (ESI): 624.4 [M+H] +

[0297] Step 4: Synthesis of l-(4-(2-(6-(3-((cyclopropylamino)methyl)imidazo[l,2- a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)-2,2- dimethylpropan-l-ol (Compound 5)

[0298] Intermediate 5-4 (50 mg) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL), and the reaction solution was stirred at 25 °C for 4 h. After that, the reaction solution was directly concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (column: Welch Xtimate C18 150*30 mm*5 μm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 45%-65%, 11 min) to give the title compound (3.9 mg).

[0299] LC-MS: m / z (ESI): 524.2 [M+H] + .

[0300] 1 H NMR (400 MHz, DMSO-d6) d 8.51 (s, 1H), 7.59-7.50 (m, 2H), 7.41-7.25 (m, 3H), 4.64 (d, J = 5.3 Hz, 1H), 4.14-4.05 (m, 3H), 4.02-3.74 (m, 2H), 3.53 (s, 3H), 2.88-2.71 (m, 1H), 2.69-2.56 (m, 1H), 2.13-2.03 (m, 1H), 1.83 (s, 3H), 0.76 (s, 9H), 0.41-0.06 (m, 4H).

[0301] Example 6, l-(4-(2-(2,3-difluoro-6-(2-(piperazin-l-yl)pyridin-4-yl)phenoxy)ethyl)- 1,5-dimethyl-lH-pyrazol-3-yl)-2,2-dimethylpropan-l-ol (Compound 6)

[0302] Step 1: Synthesis of tert-butyl 4-(4-bromopyridin-2-yl)piperazine-l-carboxylate (Intermediate 6-1)

[0303] To a solution of 4-bromo-2-fluoropyridine (1 g) in DMF (10 mL) was added potassium carbonate (1.57 g) and tert-butyl piperazine-l-carboxylate (1.06 g) at room temperature, and the reaction solution was stirred at 70 °C for 16 h. After that, the reaction solution was diluted with water (3 mL) and extracted with ethyl acetate (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.6 g).

[0304] MS m / z (ESI): 342.1 / 344.1 [M+H] +

[0305] Step 2: Synthesis of tert-butyl 4-(4-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2- dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)pyridin-2-yl)piperazine- 1-carboxylate (Intermediate 6-2)

[0306] Intermediate 6-1 (35 mg) and Intermediate 1-4 (47 mg) were dissolved in dioxane (1 mL) and water (0.33 mL), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (4 mg) and potassium carbonate (28 mg) were added under nitrogen atmosphere, the reaction was stirred at 90 °C for 2 hours. The reaction was then diluted with water (3 mL) and extracted with ethyl acetate (1 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the title compound (50 mg).

[0307] MS m / z (ESI): 600.4 [M+H] +

[0308] Step 3: Synthesis of 1-(4-(2-(2,3-difluoro-6-(2-(piperazin-1-yl)pyridin-4-yl)phenoxy)ethyl)- 1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 6)

[0309] Intermediate 6-2 (50 mg) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL), the reaction was stirred at 25 °C for 1 hour. The reaction was then directly concentrated to dryness under reduced pressure, the residue was purified by high performance liquid chromatography (column: Boston Prime CI 8 150*30 mm*5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 25%-45%, 22 min) to give the title compound (8.6 mg).

[0310] LC-MS: m / z (ESI): 500.2 [M+H] + .

[0311] 1H NMR (400 MHz, DMSO-d6) d = 8.15 (d, J = 5.1 Hz, 1H), 7.30-7.23 (m, 2H), 6.90 (s, 1H), 6.79 (d, J = 5.1 Hz, 1H), 4.10 (s, 1H), 3.96-3.78 (m, 2H), 3.60-3.55 (m, 4H), 2.96 (s, 3H), 2.80-2.76 (m, 1H), 2.69-2.57 (m, 1H), 1.95 (s, 3H), 0.82 (s, 9H).

[0312] Example 7, 1-(4-(2-(6-(8-cyclobutoxy-3-((methylamino)methyl)imidazo[1,2- a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2- dimethylpropan-1-ol (Compound 7)

[0313] Step 1: Synthesis of tert-butyl ((6-bromo-8-cyclobutoxyimidazo[1,2-a]pyridin-3- yl)methyl)(methyl)carbamate (Intermediate 7-1)

[0314] Intermediate 1-8 (150 mg) and cyclobutanol (232 mg) were dissolved in toluene (3 mL), and 3,4,7,8-tetramethyl-1,10-phenanthroline (30.4 mg), cuprous iodide (12.3 mg) and cesium carbonate (157 mg) were added under nitrogen atmosphere. The reaction was stirred at 100 °C for 5 hours. After that, the reaction was diluted with ethyl acetate (30 mL) and washed with water (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (4 g) with eluent 0-45% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min) to give the title compound (100 mg). 4g Flash silica gel column, eluent 0-45% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min.

[0315] MS m / z (ESI): 411.9 [M+H] +

[0316] Step 2: Synthesis of tert-butyl ((8-cyclobutoxy-6-(3,4-difluoro-2-(2-(3-(1- hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[1,2- a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 7-2)

[0317] Intermediate 7-1 (30 mg) and intermediate 1-4 (33.9 mg) were dissolved in dioxane (0.4 mL) and water (0.1 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (5.3 mg) and potassium carbonate (30 mg) were added under nitrogen atmosphere. The reaction solution was stirred at 90 °C for 3 hours. After that, the reaction solution was diluted with ethyl acetate (30 mL) and washed with water (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the title compound (30 mg).

[0318] MS m / z (ESI): 668.5 [M+H] +

[0319] Step 3: Synthesis of 1-(4-(2-(6-(8-cyclobutoxy-3-((methylamino)methyl)imidazo[1,2- a]pyridin-6-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2- dimethylpropan-1-ol (Compound 7)

[0320] Intermediate 7-2 (30 mg) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL), and the reaction solution was stirred at 25 °C for 1 hour. After that, the reaction solution was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: ACSSH-CP 150 x 40 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 13%-53%, 9 min) to give the title compound (5 mg).

[0321] LC-MS: m / z (ESI): 568.2 [M+H] + .

[0322] 1 H NMR (400 MHz, DMSO-d6) d = 8.18 (s, 1H), 7.44 (s, 1H), 7.36-7.25 (m, 2H), 6.64 (s, 1H), 4.96-4.90 (m, 1H), 4.07-4.03 (m, 3H), 3.97-3.88 (m, 1H), 3.86-3.78 (m, 1H), 3.53 (s, 3H), 3.18-3.16 (m, 1H), 2.85-2.76 (m, 1H), 2.67-2.63 (m, 1H), 2.29 (s, 3H), 2.20-2.13 (m, 2H), 1.83 (s, 3H), 1.73-1.64 (m, 1H), 1.58-1.54 (m, 1H), 1.36-1.21 (m, 1H), 0.99-0.84 (m, 2H), 0.76 (s, 9H).

[0323] Example 8, 1-(4-(2-(2,3-difluoro-6-(3-(1-(methylamino)cyclopropyl)imidazo[1,2- a]pyridin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 8)

[0324] Step 1: Synthesis of ethyl 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)cyclopropane-1- carboxylate (Intermediate 8-2)

[0325] Intermediate 8-1 (5 g) was dissolved in DMF (100 mL) at 0 °C under nitrogen atmosphere, NaH (1.41 g, 60% active content) was added, the reaction was stirred at 0 °C for 30 min, 1,2-dibromoethane (4.98 g) was added. The reaction was stirred at 25 °C for 16 h under nitrogen atmosphere. After that, the mixture was poured into 100 mL ice water under nitrogen atmosphere, extracted with ethyl acetate (30 mL x 3), the organic phase was combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, then separated by silica gel column chromatography (ethyl acetate / petroleum ether, 0-37%) to give the title compound (4.2 g).

[0326] LC-MS: m / z (ESI): 308.9 [M+H] +

[0327] Step 2: Synthesis of 1-(6-bromoimidazo[1,2-a]pyridin-3-yl)cyclopropane-1-carboxylic acid (Intermediate 8-3)

[0328] Intermediate 8-2 (3.7 g) was dissolved in methanol (30 mL) and water (10 mL), lithium hydroxide (859.84 mg) was added, the reaction was stirred at 25 °C for 2 h. After that, the methanol was removed by concentration under reduced pressure, the pH was adjusted to about 7 with aqueous citric acid solution, filtered and dried to give the title compound (1.1 g).

[0329] 1 H NMR (400 MHz, DMSO-d6) d = 8.50 (s, 1H), 7.56 (d, J = 9.5 Hz, 1H), 7.51-7.47 (m, 1H), 7.37 (d, J = 9.5 Hz, 1H), 1.62 (d, J = 3.5 Hz, 2H), 1.24 (q, J = 3.4 Hz, 2H)

[0330] Step 3: Synthesis of tert-butyl (1-(6-bromoimidazo[1,2-a]pyridin-3-yl)cyclopropyl)carbamate (Intermediate 8-4)

[0331] Intermediate 8-3 (1.1 g) was dissolved in tert-butanol (10 mL) under nitrogen atmosphere, to which was added diphenylphosphoryl azide (DPPA) (1.62 g) and triethylamine (818.68 μί), and the reaction was stirred at 80 °C for 16 h. The mixture was poured into 10 mL of water, extracted with ethyl acetate (3 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (tetrahydrofuran / petroleum ether, 0-28%) to give the title compound (0.5 g).

[0332] LC-MS: m / z (ESI): 351.9 [M+H] +

[0333] Step 4: Synthesis of tert-butyl (l-(6-bromoimidazo[l,2-a]pyridin-3- yl)cyclopropyl)(methyl)carbamate (Intermediate 8-5)

[0334] Intermediate 8-4 (200 mg) was dissolved in tetrahydrofuran (2 mL) under nitrogen atmosphere, to which was added NaH (45.42 mg, 60% active content), and the reaction was stirred at 0 °C for 15 min, to which was added iodomethane (80.6 mg). The reaction was stirred at 25 °C for 16 h under nitrogen atmosphere. The mixture was poured into 10 mL of water, extracted with ethyl acetate (3 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (ethyl acetate / petroleum ether, 0-24%) to give the title compound (100 mg).

[0335] LC-MS: m / z (ESI): 366.10 [M+H] +

[0336] Step 5: Synthesis of tert-butyl (l-(6-(3,4-difluoro-2-(2-(3-(l-hydroxy-2,2- dimethylpropyl)-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)imidazo[l,2- a]pyridin-3-yl)cyclopropyl)(methyl)carbamate (Intermediate 8-6)

[0337] Intermediate 8-5 (60 mg) and Intermediate 1-4 (76.07 mg) were dissolved in dioxane (1.5 mL) and water (0.5 mL), to which was added l,l-bis(diphenylphosphino) ferrocene palladium chloride (6.69 mg) and potassium carbonate (45.28 mg) under nitrogen atmosphere, and the reaction was stirred at 90 °C for 2 h. The reaction was then diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (80 mg).

[0338] MS m / z (ESI): 624.4 [M+H] +

[0339] Step 6: Synthesis of l-(4-(2-(2,3-difluoro-6-(3-(l-(methylamino)cyclopropyl)imidazo[l,2- a]pyridin-6-yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)-2,2-dimethylpropan-l-ol (Compound 8)

[0340] Intermediate 8-6 (80 mg) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL), the reaction was stirred at 25 °C for 1 h. The reaction was then directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: C18 150*40 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 10%-50%, 9 min) to give the title compound (14.3 mg).

[0341] LC-MS: m / z (ESI): 524.2 [M+H] +

[0342] 1 H NMR (400 MHz, DMSO-d6) d = 8.69 (s, 1H), 7.58 (d, J = 9.4 Hz, 1H), 7.46 (s, 1H), 7.41-7.27 (m, 3H), 4.78-4.48 (m, 1H), 4.07 (s, 1H), 3.97-3.93 (m, 1H), 3.89-3.79 (m, 1H), 3.53 (s, 3H), 2.84-2.87 (m, 1H), 2.70-2.57 (m, 1H), 2.09 (s, 3H), 1.83 (s, 3H), 1.02-0.94 (m, 2H), 0.91-0.83 (m, 2H), 0.74 (s, 9H)

[0343] Example 9, l-(3-(2-(2,3-difluoro-6-(3-(methylamino)methyl)imidazo[l,2-a]pyridin-6- yl)phenoxy)ethyl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl)-2,2-dimethylpropan-l-ol (Compound 9)

[0344] Step 1: Synthesis of N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazole-2- carboxamide (Intermediate 9-2)

[0345] Intermediate 9-1 (10 g) was added to a 250 mL reaction flask, followed by dichloromethane (100 mL), and then dimethylhydroxylamine hydrochloride (7.7 g), TEA (23.3 g), HOBT (9.9 g), and EDCI (10.0 g). The reaction was carried out at 25 °C for 12 h. The reaction solution was then poured into water (300 mL) and extracted with dichloromethane (250 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 20:1) to give the title compound (10.45 g).

[0346] LC-MS: m / z (ESI): 196.2 [M+H] + .

[0347] Step 2: Synthesis of 1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-2,2-dimethylprop-1-one (intermediate 9-3)

[0348] Intermediate 9-2 (10.45 g) was added to a 500 mL reaction flask, and tetrahydrofuran (120 mL) was added and stirred to dissolve. The mixture was then cooled to -78 °C under a nitrogen atmosphere, and tert-butyllithium (85 mL, 1.3 M n-pentane solution) was added. The system was reacted at -78 °C for 2 h. The reaction was then quenched with saturated ammonium chloride solution (100 mL), and the reaction solution was extracted three times with EA (200 mL). The organic phases were combined, concentrated to dryness under reduced pressure, and the residue was subjected to rapid column chromatography (petroleum ether / ethyl acetate = 0–50%) to give the title compound (5.6 g).

[0349] LC-MS: m / z (ESI): 193.3 [M+H] + .

[0350] Step 3: Synthesis of 1-(3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-2,2-dimethylpropane-1-one (intermediate 9-4)

[0351] Intermediate 9-3 (4 g) was added to a 250 mL reaction flask, and ACN (200 mL) was added and stirred to dissolve. Then, NBS (4.45 g) reaction solution was added and the reaction was carried out at 25 °C for 2 h. The reaction solution was then concentrated and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the title compound (5.23 g).

[0352] LC-MS: m / z (ESI): 271.2 [M+H] + .

[0353] Step 4: Synthesis of 2,2-dimethyl-1-(3-vinyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)prop-1-one (intermediate 9-5)

[0354] Intermediate 9-4 (4.6 g) was put into a 250 mL reaction flask, DMF (50 mL) was added, stirred and dissolved, and tributylvinyl tin (10.8 g) and tetrakis triphenylphosphine palladium (2 g) were added. The reaction was placed at 110 °C for 16 h. After that, the reaction solution was poured into water (150 mL), and extracted with ethyl acetate (100 mL) for 3 times. The organic phase was combined, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain the title compound (3.8 g).

[0355] LC-MS: m / z (ESI): 219.4 [M+H] + .

[0356] Step 5: Synthesis of 2-(2-pivaloyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)acetaldehyde (Intermediate 9-6)

[0357] Intermediate 9-5 (3.7 g) was put into a 250 mL reaction flask, acetonitrile (40 mL) was added, then PhI(OAc)2(6.02 g) was added, the system was cooled to -40 °C, and then 5% H2SO4(3 mL) was added dropwise. The reaction was carried out at -40 °C for 2 h. After that, the reaction solution was poured into water (100 mL), and extracted with EA (100 mL) for 3 times. The organic phase was combined, concentrated to dryness under reduced pressure to obtain the title compound (5.8 g).

[0358] LC-MS: m / z (ESI): 235.2 [M+H] + .

[0359] Step 6: Synthesis of 1-(3-(2-hydroxyethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)-2,2-dimethylpropan-1-one (Intermediate 9-7)

[0360] Intermediate 9-6 (2 g) was put into a 100 mL reaction flask, IPA (20 mL) was added, then NaBH 4( 262 mg) was added. The reaction was carried out at 0 °C for 1 h. After that, the reaction solution was poured into saturated ammonium chloride (100 mL), and extracted with EA (100 mL) for 3 times. The organic phase was combined, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 0-50%) to obtain the title compound (437 mg).

[0361] LC-MS: m / z (ESI): 237.2 [M+H] + .

[0362] Step 7: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(2-(2-oxoacetyl-5,6-dihydro-4H- pyrrolo[l,2-b]pyrazol-3-yl)ethoxy)phenyl)imidazo[l,2-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 9-9)

[0363] Intermediate 9-7 (200 mg) was charged into a 100 mL reaction vial, toluene (5 mL) was added, then Intermediate 9-8 (364 mg), CMBP (410 mg) was added, and the reaction was stirred at 110 °C for 12 h under nitrogen atmosphere. The reaction mixture was directly concentrated to dryness under reduced pressure, and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 0-70%) to give the title compound (190 mg).

[0364] LC-MS: m / z (ESI): 608.2 [M+H] + .

[0365] Step 8: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(l-hydroxy-2,2-dimethylpropyl)-5,6- dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)ethoxy)phenyl)imidazo[l,2-a]pyridin-3-yl)methyl)(methyl) carbamate (Intermediate 9-10)

[0366] Intermediate 9-9 (190 mg) was charged into a 50 mL reaction vial, MeOH (5 mL) was added, NaBH4 (100 mg) was added, and the reaction was stirred at 25 °C for 1 h. The reaction mixture was poured into saturated ammonium chloride (20 mL) and extracted with EA (15 mL) for 3 times. The organic phase was combined and concentrated to dryness under reduced pressure to give the title compound (213 mg).

[0367] LC-MS: m / z (ESI): 610.2 [M+H] +

[0368] Step 9: Synthesis of l-(3-(2-(2,3-difluoro-6-(3-((methylamino)methyl)imidazo[l,2-a]pyridin-6- yl)phenoxy)ethyl)-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-2-yl)-2,2-dimethylpropan-l-ol (Compound 9)

[0369] Intermediate 9-10 (160 mg) was charged into a 25 mL reaction vial, DCM and TFA (5 mL, 10:1) was added, the system was stirred at room temperature for 1 h. After the reaction solution was concentrated, it was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40%-80%, elution 10 min) to give the title compound (35.41 mg).

[0370] LC-MS: m / z (ESI): 532.3 [M+Na] + .

[0371] 1 H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 7.61 (s, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.37-7.30 (m, 3H), 4.20 (s, 2H), 4.18-4.07 (m, 2H), 4.08-4.03 (m, 2H), 3.78-3.71 (m, 1H), 3.62-3.56 (m, 1H), 2.79-2.63 (m, 2H), 2.48-2.42 (m, 2H), 2.40 (s, 3H), 2.25-2.20 (m, 2H), 0.78 (s, 9H).

[0372] Example 10, 6-(3,4-difluoro-2-{2-[3-(1-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H- pyrazol-4-yl]ethoxy}phenyl)-2-methyl-4-[(methylamino)methyl]-1,2-dihydroisoquinolin-1- one (Compound 10)

[0373] Step 1: Synthesis of 6-bromo-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Intermediate 10-2)

[0374] Phosphorus oxychloride (386 mg) was dissolved in DMF (2 mL) at 0 °C under nitrogen atmosphere, the reaction was stirred at 0 °C for 30 min, and then intermediate 10-1 (200 mg) was added. The reaction was stirred at 100 °C under nitrogen atmosphere for 5 h. After the mixture was poured into 50 mL ice water, stirred for 0.5 h, filtered, and the filter cake was concentrated to give the title compound (220 mg).

[0375] LC-MS: m / z (ESI): 266.0 / 268.0 [M+H] +

[0376] Step 2: Synthesis of 6-bromo-2-methyl-4-((methylamino)methyl)isoquinolin- 1(2H)-one (Intermediate 10-3)

[0377] To a solution of Intermediate 10-2 (170 mg) and methylamine hydrochloride (86 mg) in methanol (4 mL) was added triethylamine (178 μί) and sodium cyanoborohydride (80 mg) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then concentrated to dryness under reduced pressure to give the title compound (179 mg).

[0378] Step 3: Synthesis of tert-butyl ((6-bromo-2-methyl-l-oxo-l,2-dihydroisoquinolin-4- yl)methyl)(methyl)carbamate (Intermediate 10-4)

[0379] To a solution of Intermediate 10-3 (179 mg) in methanol (4 mL) was added dichloromethane (5 mL), Boc20 (264 mg) and triethylamine (422 μί) under nitrogen atmosphere. The reaction mixture was stirred at 20 °C for 16 h. The mixture was then concentrated to dryness under reduced pressure and purified by column chromatography on silica gel (tetrahydrofuran / petroleum ether, 0-60%) to give the title compound (160 mg).

[0380] LC-MS: m / z (ESI): 381.1 [M+H] +

[0381] Step 4: Synthesis of tert-butyl methyl((2-methyl-l-oxo-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2-dihydroisoquinolin-4-yl)methyl)carbamate (Intermediate 10-5)

[0382] To a solution of Intermediate 10-4 (150 mg) and bis(pinacolato)diboron (150 mg) in dioxane (3 mL) was added potassium acetate (77 mg) and l,l'-bis(diphenylphosphino) ferrocene palladium chloride (31 mg) under nitrogen atmosphere. The reaction was stirred at 80 °C for 2 h to give the title compound (160 mg).

[0383] LC-MS: m / z (ESI): 429.3 [M+H] + .

[0384] Step 5: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(l-hydroxy-2,2-dimethylpropyl)- l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)-2-methyl-l-oxo-l,2-dihydroisoquinolin-4- yl)methyl)(methyl)carbamate (Intermediate 10-6)

[0385] A solution of intermediate 10-5 (160 mg) in dioxane (3 mL) and intermediate 1-3 (200 mg) in water (0.7 mL) was added 1,1-bis(tert-butylphosphine)ferrocenepalladium chloride (31 mg) and potassium carbonate (108 mg) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (tetrahydrofuran / petroleum ether, 0-80%) to give the title compound (160 mg).

[0386] MS m / z (ESI): 639.3 [M+H] +

[0387] Step 6: Synthesis of 6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5- dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-2-methyl-4-((methylamino)methyl)isoquinolin- 1(2H)-one (Compound 10)

[0388] A solution of intermediate 10-6 (160 mg) in dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL) was stirred at 25 °C for 3 h. The reaction mixture was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: C18 150*40 mm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 47%-47%, 9 min) to give the title compound (22.4 mg).

[0389] LC-MS: m / z (ESI): 539.4 [M+H] +

[0390] 1 H NMR (400 MHz, DMSO-d6) d = 8.28 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J = 6.9 Hz, 2H), 4.71 - 4.48 (m, 1H), 4.05 (s, 1H), 3.92 - 3.79 (m, 2H), 3.77 (s, 2H), 3.55 (s, 3H), 3.53 (s, 3H), 2.80 - 2.70 (m, 1H), 2.63 - 2.54 (m, 2H), 2.33 (s, 3H), 1.84 (s, 3H), 0.76 (s, 9H)

[0391] Example 11, 1-(4-(2-(2,3-difluoro-6-(8-((methylamino)methyl)naphthalen-2-yl)phenoxy)ethyl)- 1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 11)

[0392] Step 1: Synthesis of 7-bromo-N-methyl-1-naphthalenamide (Intermediate 11-2)

[0393] Intermediate 11-1 (900 mg) was dissolved in DMF (15 mL), to which HATU (1.62 g, 4.30 mmol), DIEA (1.39 g, 1.87 mL) and methylamine hydrochloride (290.43 mg) were added. The reaction was stirred at 20 °C for 16 h. The reaction was then extracted with ethyl acetate (40 mL) and water (40 mL), and the organic phase was separated. The organic phase was washed with saturated brine three times (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by flash column chromatography on silica gel (40 g, 0~1% methanol / dichloromethane, gradient @ 40 mL / min) to give the title compound (850 mg). 12g Flash column chromatography on silica gel, eluent 0~1% methanol / dichloromethane, gradient @ 40 mL / min.

[0394] LC-MS: m / z (ESI): 263.8 / 265.8 [M+H] +

[0395] Step 2: Synthesis of 1-(7-bromonaphthalen-1-yl)-N-methylmethanamine (Intermediate 11-3)

[0396] Intermediate 11-2 (700 mg) was dissolved in tetrahydrofuran (15 mL), to which borane tetrahydrofuran solution (1 M, 13.25 mL) was added under a nitrogen atmosphere. The reaction was stirred at 60 °C for 16 h. The reaction was then cooled in an ice water bath, and methanol 20 mL was slowly added dropwise to quench the reaction under a nitrogen atmosphere. 3 mL of 2 M aqueous hydrochloric acid solution was then added, and the mixture was heated to 60 °C and stirred for 2 h. The solvent was removed by concentration under reduced pressure, and the residue was purified by flash column chromatography on silica gel (40 g, 0~10% methanol / dichloromethane, gradient @ 60 mL / min) to give the title compound (540 mg). 12g Flash column chromatography on silica gel, eluent 0~10% methanol / dichloromethane, gradient @ 60 mL / min.

[0397] LC-MS: m / z (ESI): 250.1 / 252.1 [M+H] +

[0398] Step 3: Synthesis of tert-butyl ((7-bromonaphthalen-1-yl)methyl)(methyl)carbamate (Intermediate 11-4)

[0399] Intermediate 11-3 (540 mg) was dissolved in dichloromethane (10 mL), to which Boc20 (565.4 mg) and triethylamine (602.2 μί) were added, and the reaction was stirred at 25 °C for 16 h. After that, the reaction was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluent: 0-6% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min) to give the title compound (500 mg). 12g Flash column chromatography on silica gel (eluent: 0-35% ethyl acetate / petroleum ether, gradient @ 40 mL / min) was used to purify the residue to give the title compound (50 mg).

[0400] LC-MS: m / z (ESI): 293.8 [M-56+H] +

[0401] Step 4: Synthesis of tert-butyl methyl ((7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl)methyl)carbamate (Intermediate 11-5)

[0402] Intermediate 11-4 (200 mg) was dissolved in dioxane (2 mL), to which B2Pin2 (435.0 mg), l,l-bis(diphenylphosphino)ferrocene palladium chloride (23.3 mg) and potassium acetate (112.1 mg) were added under a nitrogen atmosphere. The reaction was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction was used directly in the next step.

[0403] LC-MS: m / z (ESI): 398.1 [M+H] + .

[0404] Step 5: Synthesis of tert-butyl ((7-(3,4-difluoro-2-(2-(3-(l-hydroxy-2,2-dimethylpropyl)- 1,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)naphthalen-l-yl)methyl)(methyl)carbamate (Intermediate 11-6)

[0405] Intermediate 11-5 (40 mg) and Intermediate 1-3 (42.0 mg) were dissolved in dioxane (0.6 mL) and water (0.2 mL), to which l,l-bis(diphenylphosphino)ferrocene palladium chloride (4.1 mg) and potassium carbonate (27.8 mg) were added under a nitrogen atmosphere, and the reaction was stirred at 90 °C for 1 h under a nitrogen atmosphere. After that, the reaction was quenched with water (2 mL), and extracted with ethyl acetate (2 mL x 3). The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel (eluent: 0-35% ethyl acetate / petroleum ether, gradient @ 40 mL / min) to give the title compound (50 mg). 4g Flash column chromatography on silica gel (eluent: 0-35% ethyl acetate / petroleum ether, gradient @ 40 mL / min) was used to purify the residue to give the title compound (50 mg).

[0406] MS m / z (ESI): 608.4 [M+H]+

[0407] Step 6: Synthesis of 1-(4-(2-(2,3-difluoro-6-(8-((methylamino)methyl)naphthalen-2- yl)phenoxy)ethyl)-1,5-dimethyl-1 H-pyrazol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 11)

[0408] Intermediate 11-6 (40 mg) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL), the reaction was stirred at 25 °C for 1 h. The reaction was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: C18 150*40 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 25%-65%, 9 min) to give the title compound (9.4 mg).

[0409] LC-MS: m / z (ESI): 508.3 [M+H] + .

[0410] 1 H NMR (400 MHz, DMSO-d6) d = 8.25 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.61 - 7.47 (m, 2H), 7.43 - 7.25 (m, 2H), 4.22 (s, 2H), 4.04 (s, 1H), 3.93 - 3.69 (m, 2H), 3.50 (s, 3H), 2.82 - 2.68 (m, 1H), 2.63 - 2.55 (m, 1H), 2.42 (s, 3H), 1.76 (s, 3H), 0.74 (s, 9H).

[0411] Example 12, Synthesis of 1-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)isoquinolin-6- yl)phenoxy)ethyl)-1,5-dimethyl-1 H-pyrazol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 12)

[0412] Step 1 : Synthesis of 1-(6-bromoisoquinolin-4-yl)-N-methylmethanamine (Intermediate 12-2)

[0413] To a mixture of intermediate 12-1 (110 mg), methylamine hydrochloride (62.92 mg) in methanol (2 mL) was added triethylamine (141.46 mg) and sodium cyanoborohydride (58.57 mg) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent and the residue was directly purified by column chromatography on silica gel (MeOH / DCM, 0-8%) to give the title compound (90 mg).

[0414] LC-MS: m / z (ESI): 251.0 [M+H] +

[0415] Step 2: Synthesis of tert-butyl ((6-bromoisoquinolin-4-yl)methyl)(methyl)carbamate (intermediate 12-3)

[0416] To a mixture of intermediate 12-2 (20 mg) in dichloromethane (0.5 mL) was added triethylamine (24.18 mg) and di-tert-butyl dicarbonate (34.76 mg) at room temperature. The resulting mixture was stirred at room temperature (25 °C) for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent to give the title compound (27 mg).

[0417] LC-MS: m / z (ESI): 350.8 / 352.8 [M+H] +

[0418] Step 3: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)- 1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)isoquinolin-4-yl)methyl)(methyl)carbamate (intermediate 12-4)

[0419] To a mixture of intermediate 1-4 (30 mg) and intermediate 12-3 (22.69 mg) in dioxane (0.5 mL) and water (0.1 mL) was added 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (4.73 mg) and potassium carbonate (17.86 mg) under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was extracted with ethyl acetate (10 mL x 3) after adding water (10 mL). The organic phase was combined and concentrated under reduced pressure to remove the solvent to give the title compound (39 mg).

[0420] LC-MS: m / z (ESI): 609.4 [M+H] +

[0421] Step 4: Synthesis of l-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)isoquinolin-6- yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)-2,2-dimethylpropan-l-ol (Compound 12)

[0422] Intermediate 12-4 (39 mg) was dissolved in hydrochloric acid dioxane (2 M, 0.5 mL) at room temperature, and the reaction was stirred at 25 °C for 1 h. The reaction was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: ACSSH-CL C18 150*40 mm; mobile phase: [A: water (0.08% ammonium bicarbonate), B: acetonitrile]; B%: 40%-80%, 9 min) to give the title compound (3.2 mg).

[0423] LC-MS: m / z (ESI): 509.1 [M+H] +

[0424] 1 H NMR (400 MHz, CD3OD) d = 9.16 (s, 1H), 8.40 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.32-7.24 (m, 1H), 7.14-7.03 (m, 1H), 4.13-4.08 (m, 3H), 3.92-3.75 (m, 2H), 3.44 (s, 3H), 2.79-2.66 (m, 1H), 2.63-2.51 (m, 1H), 2.43 (s, 3H), 1.78 (s, 3H), 0.68 (s, 9H)

[0425] Example 13, (4-(2-(2,3-difluoro-6-(4-(methylamino)methyl)quinolin-6-yl)phenoxy)ethyl)- 1,5-dimethyl-lH-pyrazol-3-yl)(pyrrolidin-l-yl)methanone (Compound 13)

[0426] Step 1: Synthesis of (l,5-dimethyl-lH-pyrazol-3-yl)(pyrrolidin-l-yl)methanone (Intermediate 13-2)

[0427] Intermediate 13-1 (5.0 g), pyrrolidine (3.8 g) were dissolved in DCM (100 mL), HATU (17.7 g) and DIEA (30 mL) were added, and the reaction was stirred at 25 °C for 12 h. The reaction was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to give the title compound (5.5 g).

[0428] LC-MS: m / z (ESI): 194.3 [M+H] + .

[0429] Step 2: Synthesis of (4-bromo-l,5-dimethyl-lH-pyrazol-3-yl)(pyrrolidin-l- yl)methanone (Intermediate 13-3)

[0430] Intermediate 13-2 (5.0 g) was dissolved in acetonitrile (50 mL), NBS (6.9 g) was added under ice-bath, the reaction was stirred at 25 °C for 12 h under nitrogen atmosphere. Then the reaction was concentrated, the residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to give the title compound (2.9 g).

[0431] LC-MS: m / z (ESI): 272.2 [M+H] + .

[0432] Step 3: Synthesis of (l,5-dimethyl-4-vinyl-lH-pyrazol-3-yl)(pyrrolidin-l- yl)methanone (Intermediate 13-4)

[0433] Intermediate 13-3 (2.9 g) and tributyl(vinyl)tin (6.8 g) were dissolved in DMF (30 mL), then Pd(PPh3)4 (1.23 g) was added, the reaction was stirred at 110 °C for 12 h under nitrogen atmosphere. Then the reaction was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1) to give the title compound (1 g).

[0434] LC-MS: m / z (ESI): 220.2 [M+H] + .

[0435] Step 4: Synthesis of (4-(2-hydroxyethyl)-l,5-dimethyl-lH-pyrazol-3-yl)(pyrrolidin- 1-yl)methanone (Intermediate 13-5)

[0436] Intermediate 13-4 (850 mg) was put into a 100 mL reaction flask, 1,4-dioxane (10 mL) was added and stirred to dissolve, then 9-BBN (19 mL, 0.5 mol tetrahydrofuran solution) was added. The reaction was stirred at 100 °C for 12 h. Then the reaction was cooled to 0 °C, 6N NaOH (1.7 mL) and 30% H2O2 (1.3 mL) were added. The reaction was heated to 50 °C for 2 h. Then the reaction was poured into saturated sodium thiosulfate solution (10 mL), extracted with ethyl acetate (100 mL), the organic phase was concentrated to dryness under reduced pressure, the residue was purified by reverse phase column chromatography (H2O:ACN = 3:1) to give the title compound (400 mg).

[0437] LC-MS: m / z (ESI): 238.2 [M+H] + .

[0438] Step 5: Synthesis of tert-butyl ((6-(3,4-difluoro-2-hydroxyphenyl)quinolin-4- yl)methyl)(methyl)carbamate (Intermediate 13-6)

[0439] Intermediate 4-4 (200 mg) was put into a 100 mL reaction bottle, stirred and dissolved in 1,4-dioxane (5 mL), and water (1 mL), 2-hydroxy-3,4-difluorobenzeneboronic acid (150 mg), K2CO3 (236 mg) and Pd(dppf)Cl2 (44 mg) were added to the system. The reaction solution was reacted at 100 °C for 12 h, and then the reaction solution was poured into water (50 mL) and extracted with EA (100 mL). The organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 3:1) to give the title compound (180 mg).

[0440] LC-MS: m / z (ESI): 401.2 [M+H] + .

[0441] Step 6: Synthesis of tert-butyl ((6-(2-(1,5-dimethyl-3-(pyrrolidine-1-carbonyl)-1H- pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)quinolin-4-yl)methyl)(methyl)carbamate (Intermediate 13-7)

[0442] Intermediate 13-6 (100 mg) was put into a 100 mL reaction bottle, stirred and dissolved in toluene (3 mL), and Intermediate 13-5 (120 mg) and CMBP (300 mg) were added. The system was heated to 110 °C and reacted for 12 h. Then the reaction solution was poured into saturated sodium thiosulfate and extracted with ethyl acetate (100 mL). The organic phase was concentrated to dryness under reduced pressure to give the crude title compound (160 mg).

[0443] LC-MS: m / z (ESI): 620.3 [M+H] + .

[0444] Step 11: Synthesis of (4-(2-(2,3-difluoro-6-(4-(methylamino)methyl)quinolin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)(pyrrolidin-1-yl)methanone (Compound 13)

[0445] Intermediate 13-7 (160 mg) was charged into a 25 mL reaction vial, DCM and TFA (5 mL, 10:1) was added, the mixture was stirred at room temperature for 1 h. Then the reaction solution was directly concentrated and purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40%-80%, elution 10 min) to give the title compound (35.28 mg).

[0446] LC-MS: m / z (ESI): 520.2 [M+H] + .

[0447] 1 H NMR (400 MHz, DMSO-d6): δ 8.95 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.84-7.75 (m, 1H), 7.61 (d, J = 4.4 Hz, 1H), 7.41-7.30 (m, 2H), 4.47 (s, 2H), 4.01-3.97 (m, 2H), 3.61 (s, 3H), 3.55-3.50 (m, 2H), 3.34-3.31 (m, 2H), 2.82-2.79 (m, 2H), 2.57 (s, 3H), 1.87 (s, 3H), 1.76-1.65 (m, 4H).

[0448] Example 14, Synthesis of (4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6- yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)(1-methylcyclobutyl)methanol (Compound 14)

[0449] Step 1: Synthesis of 3-bromo-4-iodo-1,5-dimethyl-1H-pyrazole (Intermediate 14-1)

[0450] Under argon atmosphere, 3-bromo-1,5-dimethyl-1H-pyrazole (10.8 g), NIS (21 g) were dissolved in acetonitrile (60 mL), the resulting mixture was stirred at 60 °C for 16 h. Then the reaction solution was concentrated under reduced pressure to remove the solvent, saturated sodium thiosulfate solution (50 mL) was added after extraction with ethyl acetate (100 mL x 3), the combined organic phase was concentrated under reduced pressure to remove the solvent, the residue was directly purified by silica gel column chromatography (THF / PE, 0-50%) to give the title compound (17.3 g).

[0451] LC-MS: m / z (ESI): 301.2 [M+H] +

[0452] Step 2: Synthesis of 3-bromo-l,5-dimethyl-4-vinyl-lH-pyrazole (Intermediate 14-2)

[0453] A mixture of Intermediate 14-1 (17.3 g), potassium vinyltrifluoroborate (15.5 g), tetrakis(triphenylphosphine)palladium (3.3 g), (dppf)PdCl2(2.1 g), potassium carbonate (15.9 g), 1,4-dioxane (100 mL) and water (15 mL) was heated to 80 °C under argon atmosphere and stirred for 16 h. The reaction mixture was then concentrated under reduced pressure to remove the solvent and the residue was directly purified by silica gel column chromatography (THF / PE, 0-50%) to give the title compound (12.7 g).

[0454] LC-MS: m / z (ESI): 201.3 [M+H] +

[0455] Step 3: Synthesis of 2-(3-bromo-l,5-dimethyl-4-vinyl-lH-pyrazol-4-yl)acetaldehyde (Intermediate 14-3)

[0456] To a mixture of Intermediate 14-2 (12.7 g), iodobenzene diacetate (22 g) and acetonitrile (125 mL) was added dropwise 5% dilute sulfuric acid (11.5 mL) at -30 °C under argon atmosphere. After the addition, the resulting mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to remove the solvent and the residue was directly purified by silica gel column chromatography (THF / PE, 0-100%) to give the title compound (8.88 g).

[0457] LC-MS: m / z (ESI): 217.2 [M+H] +

[0458] Step 4: Synthesis of 2-(3-bromo-l,5-dimethyl-4-vinyl-lH-pyrazol-4-yl)ethan-l-ol (Intermediate 14-4)

[0459] To a mixture of Intermediate 14-3 (8.88 g) dissolved in ethanol (100 mL) was added sodium borohydride (1.5 g) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to remove the solvent and water (50 mL) was added followed by extraction with ethyl acetate (100 mL x 3). The combined organic phase was concentrated under reduced pressure to remove the solvent and the residue was directly purified by silica gel column chromatography (THF / PE, 0-100%) to give the title compound (8.27 g).

[0460] LC-MS: m / z (ESI): 219.2 [M+H] +

[0461] Step 5: Synthesis of 3-bromo-l,5-dimethyl-4-(2-((triisopropylsilyl)oxy)ethyl)- lH-pyrazole (Intermediate 14-5)

[0462] To a mixture of Intermediate 14-4 (8.27 g) and imidazole (3.9 g) in dichloromethane (100 mL) was added triisopropylsilyl chloride (TIPSC1) (14.7 g) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was then concentrated under reduced pressure to remove the solvent, and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-40%) to give the title compound (12.2 g).

[0463] LC-MS: m / z (ESI): 375.4 [M+H] +

[0464] Step 6: Synthesis of N-methoxy-N,l-dimethylcyclobutane-l-carboxamide (Intermediate 14-6)

[0465] To a mixture of l-methylcyclobutane-l-carboxylic acid (2 g), N,0-dimethylhydroxylamine hydrochloride (3.4 g), HATU (8 g) and DMF (10 mL) was added DIEA (18 mL) at room temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. Water (50 mL) was then added and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was concentrated under reduced pressure to remove the solvent, and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-40%) to give the title compound (2.4 g).

[0466] LC-MS: m / z (ESI): 158.4 [M+H] +

[0467] Step 7: Synthesis of (4-(2-hydroxyethyl)-l,5-dimethyl-lH-pyrazol-3-yl)(l- methylcyclobutyl)methanone (Intermediate 14-7)

[0468] To a mixture of Intermediate 14-5 (220 mg) and anhydrous diethyl ether (2 mL) was added tert-butyllithium (1.3 M in n-pentane, 0.9 mL) at -78 °C under argon atmosphere. The resulting mixture was stirred at -78 °C for 15 min. Intermediate 14-6 (0.2 mL) was then added, and the resulting mixture was allowed to warm to room temperature naturally and stirred for 2 h. TBAF (1 M in tetrahydrofuran, 2.5 mL) was then added to the reaction, and the resulting mixture was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure, and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-100%) to give the title compound (92 mg).

[0469] LC-MS: m / z (ESI): 237.4 [M+H] +

[0470] Step 8: Synthesis of (4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-l,5-dimethyl-lH- pyrazol-3-yl)(l-methylcyclobutyl)methanone (Intermediate 14-8)

[0471] A mixture of Intermediate 14-7 (185 mg), cyano methylene tri-n-butyl phosphonium (0.379 mL), 6-bromo-2,3-difluorophenol (0.326 mL) and toluene (3 mL) was stirred at 110 °C for 16 h under argon atmosphere. The mixture was then directly purified by silica gel column chromatography (THF / PE, 0-30%) to give the title compound (153 mg).

[0472] LC-MS: m / z (ESI): 427.2 [M+H] +

[0473] Step 9: Synthesis of tert-butyl methyl((6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-4- yl)methyl)carbamate (Intermediate 14-9)

[0474] A mixture of Intermediate 4-4 (30 mg) and pinacol diboronic acid (32.53 mg) was dissolved in dioxane (0.5 mL) under nitrogen atmosphere. Palladium (Pd) catalyst, l,l'-bis(diphenylphosphino)ferrocene chloride (3.49 mg) and potassium acetate (25.15 mg) were added under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 1 h. The mixture was then directly purified by silica gel column chromatography (THF / PE, 0-15%) to give the title compound (34 mg).

[0475] LC-MS: m / z (ESI): 399.3 [M+H] +

[0476] Step 10: Synthesis of tert-butyl ((6-(2-(2-(l,5-dimethyl-3-(l- methylcyclobutanecarbonyl)-lH-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)quinolin-4- yl)methyl)(methyl)carbamate (Intermediate 14-10)

[0477] Intermediate 14-9 (14 mg) and intermediate 14-8 (14 mg) were dissolved in dioxane (0.8 mL) and water (0.2 mL) under nitrogen atmosphere, 1,1-bis(diphenylphosphino)ferrocene palladium chloride (2.57 mg) and potassium carbonate (14.57 mg) were added under nitrogen atmosphere, the reaction was stirred at 90 °C for 3 h. The mixture was then directly purified by silica gel column chromatography (THF / PE, 0-40%) to give the title compound (10 mg).

[0478] LC-MS: m / z (ESI): 619.2 [M+H] +

[0479] Step 11: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(hydroxy(l- methylcyclobutyl)methyl)-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)quinolin-4- yl)methyl)(methyl)carbamate (Intermediate 14-11)

[0480] To a mixture of intermediate 14-10 (10 mg) dissolved in methanol (0.5 mL) was added lithium borohydride (2 M in tetrahydrofuran, 80.81 μί) at 0 °C under nitrogen atmosphere, the resulting mixture was stirred at room temperature for 1 h. The reaction was then concentrated under reduced pressure to remove the solvent, water (0.5 mL) was added and the solvent was removed under reduced pressure to give the title compound (10 mg).

[0481] LC-MS: m / z (ESI): 619.2 [M+H] +

[0482] Step 12: Synthesis of (4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6- yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)(l-methylcyclobutyl)methanol (Compound 14)

[0483] Intermediate 14-11 (10 mg) was dissolved in 2 N hydrochloric acid in dioxane (0.5 mL) at room temperature, the reaction was stirred at 25 °C for 1 h. The reaction was then directly concentrated under reduced pressure to dryness and purified by high performance liquid chromatography (column: ACS SH-CK C18 150*40 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 18%-58%, 9 min) to give the title compound (2.1 mg).

[0484] LC-MS: m / z (ESI): 619.2 [M+H] +

[0485] 1H NMR (400 MHz, DMSO-d6) d = 8.87 (d, J = 4.4 Hz, 1H), 8.24 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.43 - 7.27 (m, 2H), 4.19 - 4.16 (m, 3H), 3.94 - 3.78 (m, 2H), 3.49 (s, 3H), 2.79 - 2.69 (m, 1H), 2.64 - 2.53 (m, 1H), 2.38 (s, 3H), 2.14 - 1.98 (m, 2H), 1.75 (s, 3H), 1.74 - 1.66 (m, 1H), 1.62 - 1.48 (m, 1H), 1.43 - 1.33 (m, 1H), 1.30 (s, 1H), 0.88 (s, 3H).

[0486] Step 13: S-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6-yl)phenoxy)ethyl)- 1,5-dimethyl-1H-pyrazol-3-yl)(1-methylcyclobutyl)methanol and R-(4-(2-(2,3-difluoro-6-(4- ((methylamino)methyl)quinolin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)(1- methylcyclobutyl)methanol (Compound 14-P1 and Compound 14-P2)

[0487] Compound 14 (20 mg) was prepared by supercritical fluid chromatography (column: Daicel ChiralPak IG (250*30 mm, 10 pm); mobile phase: A: carbon dioxide; B: methanol (0.1% ammonia water); B%: 60%; flow rate: 80 ml / min) to give Compound 14-P1 (6.6 mg) and Compound 14-P2 (5.8 mg).

[0488] The two isomers were analyzed by the chromatographic method:

[0489] Compound 14-P1:

[0490] Under the above chromatographic conditions, the retention time of Compound 14-P1 was 1.325 min.

[0491] MS m / z (ESI): 521.4 [M+H] +

[0492] 1H NMR (400 MHz, Methanol-d4) δ = 8.87 (d, J = 4.5 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.92 (dd, J = 1.8, 8.7 Hz, 1H), 7.62 (d, J = 4.5 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.21 - 7.13 (m, 1H), 4.31 (d, J = 8.3 Hz, 3H), 3.98 - 3.83 (m, 2H), 3.55 (s, 3H), 2.84 - 2.75 (m, 1H), 2.71 - 2.62 (m, 1H), 2.56 (s, 3H), 2.17 - 2.04 (m, 2H), 1.85 (s, 3H), 1.83 - 1.73 (m, 1H), 1.64 - 1.53 (m, 1H), 1.46 - 1.38 (m, 1H), 1.35 - 1.30 (m, 1H), 0.92 (s, 3H).

[0493] Compound 14-P2:

[0494] The retention time of compound 14-P2 is 1.839 min under the above chromatographic conditions.

[0495] MS m / z (ESI): 521.4 [M+H] +

[0496] 1 H NMR (400 MHz, Methanol-d4) δ = 8.87 (d, J = 4.5 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.92 (dd, J = 1.8, 8.7 Hz, 1H), 7.62 (d, J = 4.5 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.21 - 7.12 (m, 1H), 4.31 (d, J = 8.1 Hz, 3H), 3.98 - 3.91 (m, 1H), 3.90 - 3.83 (m, 1H), 3.55 (s, 3H), 2.82 - 2.75 (m, 1H), 2.71 - 2.62 (m, 1H), 2.56 (s, 3H), 2.17 - 2.04 (m, 2H), 1.85 (s, 3H), 1.83 - 1.73 (m, 1H), 1.64 - 1.53 (m, 1H), 1.47 - 1.38 (m, 1H), 1.34 - 1.31 (m, 1H), 0.92 (s, 3H).

[0497] Example 15. Synthesis of l-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6- yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)-3,3,3-trifluoro-2,2-dimethylpropan-l-ol (Compound 15)

[0498] Step 1. Synthesis of 3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropanamide (Intermediate 15-1)

[0499] To a mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (1 g), N,O-dimethylhydroxylamine hydrochloride (0.75 g), HATU (2.9 g) and DMF (5 mL) was added DIEA (8 mL) at room temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. After which water (30 mL) was added and extracted with ethyl acetate (50 mL x 3), the combined organic phase was concentrated under reduced pressure to remove the solvent and the residue was directly purified by silica gel column chromatography (THF / PE, 0-40%) to give the title compound (866 mg).

[0500] LC-MS: m / z (ESI): 200.2 [M+H] +

[0501] Step 2. Synthesis of 3,3,3-trifluoro-l-(4-(2-hydroxyethyl)-l,5-dimethyl-lH-pyrazol-3-yl)- 2,2-dimethylpropan-l-one (Intermediate 15-2)

[0502] To a mixture of Intermediate 14-5 (220 mg) and anhydrous diethyl ether (2 mL) was added tert-butyllithium (1.3 M in n-pentane, 0.9 mL) at -78 °C under argon atmosphere. The resulting mixture was stirred at -78 °C for 15 min. After which Intermediate 15-1 (0.25 mL) was added and the resulting mixture was allowed to warm to room temperature naturally and stirred for 2 h. After which TBAF (1 M in tetrahydrofuran, 2.5 mL) was added to the reaction and the resulting mixture was stirred at room temperature for 2 h. After which the solvent was removed by concentration under reduced pressure and the residue was directly purified by silica gel column chromatography (THF / PE, 0-100%) to give the title compound (113 mg).

[0503] LC-MS: m / z (ESI): 279.4 [M+H] +

[0504] Step 3. Synthesis of l-(4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3- yl)-3,3,3-trifluoro-2,2-dimethylpropan-l-one (Intermediate 15-3)

[0505] A mixture of intermediate 15-2 (113 mg), cyano methylene tri-n-butyl phosphonium (CMBP) (0.2 mL), 6-bromo-2,3-difluorophenol (0.17 mL) and toluene (1.5 mL) was stirred at 110 °C for 16 h under argon atmosphere. The mixture was then directly purified by silica gel column chromatography (THF / PE, 0-30%) to give the title compound (115 mg).

[0506] LC-MS: m / z (ESI): 469.2 [M+H] +

[0507] Step 4: Synthesis of tert-butyl ((6-(2-(2-(1,5-dimethyl-3-(3,3,3-trifluoro-2,2- dimethylpropionyl)-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)quinolin-4- yl)methyl)(methyl)carbamate (intermediate 15-4)

[0508] To a mixture of intermediate 15-3 (35 mg), intermediate 14-9 (20 mg), potassium carbonate (20 mg), dioxane (1 mL) and water (0.2 mL) was added PdCl2(dppf) (4 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was directly purified by silica gel column chromatography (THF / PE, 0-30%) to give the title compound (20 mg).

[0509] LC-MS: m / z (ESI): 661.2 [M+H] +

[0510] Step 5: Synthesis of tert-butyl ((6-(2-(2-(1,5-dimethyl-3-(3,3,3-trifluoro-1- hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)quinolin- 4-yl)methyl)(methyl)carbamate (intermediate 15-5)

[0511] To a mixture of intermediate 15-4 (20 mg) and anhydrous methanol (2 mL) was added lithium borohydride (2 M in tetrahydrofuran, 0.15 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. To the resulting mixture was then added water (0.5 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The solvent was then removed under reduced pressure to give the title compound (20 mg).

[0512] LC-MS: m / z (ESI): 663.1 [M+H] +

[0513] Step 6: Synthesis of l-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6- yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)-3,3,3-trifluoro-2,2-dimethylpropan-l- ol (Compound 15)

[0514] To intermediate 15-5 (20 mg) was added hydrochloric acid (2 M in dioxane, 2 mL) at room temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated to remove the solvent and purified directly by high performance liquid chromatography (column: C18 150 x 30 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 28%-68%, 9 min) to give the title compound (5.4 mg).

[0515] LC-MS: m / z (ESI): 563.1 [M+H] +

[0516] 1 H NMR (400 MHz, DMSO-d6) d = 8.88 (d, J = 4.0 Hz, 1H), 8.24 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 3.7 Hz, 1H), 7.45 - 7.29 (m, 2H), 4.58 (s, 1H), 4.17 (s, 2H), 3.90 - 3.79 (m, 2H), 3.54 (s, 3H), 2.75 - 2.66 (m, 1H), 2.64 - 2.54 (m, 1H), 2.38 (s, 3H), 1.78 (s, 3H), 1.13 (s, 3H), 0.79 (s, 3H)

[0517] Example 16, Synthesis of l-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6- yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)-3-fluoro-2,2-dimethylpropan-l-ol (Compound 16)

[0518] Step 1: Synthesis of 3-fluoro-N-methoxy-N,2,2-trimethylpropanamide (Intermediate 16-1)

[0519] To a mixture of 3-fluoro-2,2-dimethylpropanoic acid (1 g), N,0-dimethylhydroxylamine hydrochloride (0.7 g), HATU (2.7 g) and DMF (5 mL) was added DIEA (7 mL) at room temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. After which water (30 mL) was added and extracted with ethyl acetate (50 mL x 3), the combined organic phase was concentrated under reduced pressure to remove the solvent and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-40%) to give the title compound (1 g).

[0520] LC-MS: m / z (ESI): 164.3 [M+H] +

[0521] Step 2: Synthesis of 3-fluoro-1-(4-(2-hydroxyethyl)-1,5-dimethyl-1H-pyrazol-3-yl)- 2,2-dimethylpropan-1-one (Intermediate 16-2)

[0522] To a mixture of Intermediate 14-5 (220 mg) and anhydrous diethyl ether (2 mL) was added tert-butyllithium (1.3 M in n-pentane, 0.9 mL) at -78 °C under argon atmosphere. The resulting mixture was stirred at -78 °C for 15 min. After which Intermediate 16-1 (0.25 mL) was added and the resulting mixture was allowed to warm to room temperature and stirred for 2 h. After which TBAF (1 M in tetrahydrofuran, 2.5 mL) was added to the reaction and the resulting mixture was stirred at room temperature for 2 h. After which the solvent was removed under reduced pressure and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-100%) to give the title compound (105 mg).

[0523] LC-MS: m / z (ESI): 243.4 [M+H] +

[0524] Step 3: Synthesis of (4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H- pyrazol-3-yl)-3-fluoro-2,2-dimethylpropan-1-one (Intermediate 16-3)

[0525] A mixture of Intermediate 16-2 (113 mg), cyano methylene tri-n-butyl phosphonium (0.2 mL), 6-bromo-2,3-difluorophenol (0.17 mL) and toluene (1.5 mL) was stirred at 110 °C for 16 h under argon atmosphere. After which the mixture was directly purified by column chromatography on silica gel (THF / PE, 0-30%) to give the title compound (126 mg).

[0526] LC-MS: m / z (ESI): 433.3 [M+H] +

[0527] Step 4: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(3-fluoro-2,2-dimethyl- propionyl)-1,5-dimethyl-1 H-pyrazol-4-yl)ethoxy)phenyl)quinolin-4-yl)methyl)(methyl) carbamate (Intermediate 16-4)

[0528] To a mixture of Intermediate 16-3 (33 mg), Intermediate 14-9 (20 mg), potassium carbonate (20 mg), dioxane (1 mL) and water (0.2 mL) was added PdCl2(dppf) (4 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-30%) to give the title compound (18 mg).

[0529] LC-MS: m / z (ESI): 625.2 [M+H] +

[0530] Step 5: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(3-fluoro-1 -hydroxy-2,2- dimethylpropyl)-1,5-dimethyl-1 H-pyrazol-4-yl)ethoxy)phenyl)quinolin-4-yl)methyl)(methyl) carbamate (Intermediate 16-5)

[0531] To a mixture of Intermediate 16-4 (18 mg) and anhydrous methanol (2 mL) was added lithium borohydride (2 M in tetrahydrofuran, 0.15 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. To the resulting mixture was then added water (0.5 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The solvent was then removed under reduced pressure to give the title compound (18 mg).

[0532] LC-MS: m / z (ESI): 627.1 [M+H] +

[0533] Step 6: Synthesis of 1-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6-yl)phenoxy) ethyl)-1,5-dimethyl-1 H-pyrazol-3-yl)-3-fluoro-2,2-dimethylpropan-1 -ol (Compound 16)

[0534] To intermediate 16-5 (18 mg) was added hydrochloric acid (2 M in dioxane, 2 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated to remove the solvent and directly purified by high performance liquid chromatography (column: C18 150 x 30 mm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 6% - 46%, 9 min) to give the title compound (2.8 mg).

[0535] LC-MS: m / z (ESI): 527.1 [M+H] +

[0536] 1 H NMR (400 MHz, DMSO-d6) d = 8.87 (d, J = 4.3 Hz, 1H), 8.25 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 4.3 Hz, 1H), 7.47 - 7.27 (m, 2H), 4.99 - 4.81 (m, 1H), 4.30 - 4.27 (m, 1H), 4.19 - 4.14 (m, 3H), 4.08 - 4.03 (m, 1H), 3.90 - 3.79 (m, 2H), 3.53 (s, 3H), 2.75 - 2.67 (m, 1H), 2.63 - 2.53 (m, 1H), 2.38 (s, 3H), 1.77 (s, 3H), 0.79 (s, 3H), 0.70 (s, 3H)

[0537] Example 17, 1-(4-(2-(2,3-difluoro-6-(2-methoxy-4-((methylamino)methyl)quinolin-6- yl)phenoxy)ethyl)-1,5-dimethyl-1 H-pyrazol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 17)

[0538] Step 1 : Synthesis of 4-bromo-N-(4-bromophenyl)-3-oxobutanamide (Intermediate 17-2)

[0539] Intermediate 17-1 (100 mg) and tribromopyridinium salt (196.8 mg) were added into ethyl acetate (20 mL) and stirred at 25 °C for 16 h. The reaction solution was then diluted with water (40 mL) and extracted with ethyl acetate (30 mL*3), the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (130.8 mg)

[0540] LC-MS: m / z (ESI): 333.9 [M+H] +

[0541] Step 2: Synthesis of 6-bromo-4-(bromomethyl)quinolin-2(lH)-one (Intermediate 17-3)

[0542] Intermediate 17-2 (130 mg) was added to concentrated sulfuric acid (4 mL) and the reaction was stirred at 90 °C for 1 h. After that, the reaction was cooled to room temperature and ice (10 g) was added to the reaction mixture. The mixture was stirred for 0.5 h. Filtration and drying of the filter cake gave the title compound (268 mg).

[0543] LC-MS: m / z (ESI): 315.8 / 317.8 / 319.8 [M+H] +

[0544] Step 3: Synthesis of 6-bromo-4-(((2,4-dimethoxybenzyl)(methyl)amino)methyl)quinolin- 2(lH)-one (Intermediate 17-4)

[0545] 1-(2,4-dimethoxyphenyl)-N-methylmethanamine (70.3 mg) was added to a solution of Intermediate 17-3 (123 mg) and triethylamine (117.8 mg) in DMSO (1.97 mL) and the reaction was stirred at 25 °C for 1 h. After that, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash silica gel column (0-10% methanol / dichloromethane) to give the title compound (160 mg).

[0546] LC-MS: m / z (ESI): 417.0 / 419.0 [M+H] +

[0547] Step 4: Synthesis of 6-bromo-4-((methylamino)methyl)quinolin-2(lH)-one (Intermediate 17-5)

[0548] A solution of Intermediate 17-4 (160 mg) in trifluoroacetic acid (2 mL) was heated to 70 °C and stirred for 16 h. After that, the reaction was directly concentrated to dryness under reduced pressure to give the title compound (102.4 mg).

[0549] LC-MS: m / z (ESI): 267.0 / 269.0 [M+H] +

[0550] Step 5: Synthesis of tert-butyl ((6-bromo-2-oxo-l,2-dihydroquinolin-4-yl)methyl)(methyl)carbamate (Intermediate 17-6)

[0551] To a solution of intermediate 17-5 (102 mg) in DCM (0.7 mL) was added triethylamine (319 μί) and Boc20 (125 mg), the reaction was stirred at 25 °C for 1 h. The reaction was then diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography on silica gel (eluent: 0-10% tetrahydrofuran / petroleum ether, gradient @ 45 mL / min) to give the title compound (31.6 mg). 4g Flash column chromatography on silica gel (eluent: 0-10% tetrahydrofuran / petroleum ether, gradient @ 45 mL / min) to give the title compound (31.6 mg).

[0552] LC-MS: m / z (ESI): 367.0 / 369.0 [M+H] + .

[0553] Step 6: Synthesis of tert-butyl ((6-bromo-2-methoxyquinolin-4-yl)methyl)(methyl)carbamate (intermediate 17-7)

[0554] Trimethyl oxonium tetrafluoroborate (13.7 mg) was added to a solution of intermediate 17-6 (31 mg) in dichloromethane (4 mL), the reaction was stirred at 25 °C for 16 h. The reaction was then diluted with water (1 mL), triethylamine (51.2 mg, 70.59 μί) and Boc20 (110.5 mg) were added, 10 min later the reaction was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated to dryness under reduced pressure, the residue was purified by flash column chromatography on silica gel (eluent: 0-10% tetrahydrofuran / petroleum ether, gradient @ 45 mL / min) to give the title compound (8 mg). 4g Flash column chromatography on silica gel (eluent: 0-10% tetrahydrofuran / petroleum ether, gradient @ 45 mL / min) to give the title compound (31.6 mg).

[0555] LC-MS: m / z (ESI): 367.0 / 369.0 [M+H] +

[0556] Step 7: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)- 1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-2-methoxyquinolin-4-yl)methyl)(methyl)carbamate (intermediate 17-8)

[0557] To a mixture of intermediate 17-7 (8 mg), intermediate 1-4 (19.5 mg), potassium carbonate (8.7 mg), dioxane (1 mL) and water (0.3 mL) was added (dppf)PdCl2(0.77 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 1 h. Then the reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure to give the title compound (13.4 mg).

[0558] LC-MS: m / z (ESI): 639.3 [M+H] +

[0559] Step 8: Synthesis of 1-(4-(2-(2,3-difluoro-6-(2-methoxy-4-((methylamino)methyl)quinolin-6- yl)phenoxy)ethyl)-1,5-dimethyl-1 H-pyrazol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 17)

[0560] To a solution of intermediate 17-8 (13.4 mg) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. Then the mixture was concentrated to remove the solvent and directly purified by high performance liquid chromatography (column: Boston Prime C18 150*30mm*5um; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 60%-80%, 10 min) to give the title compound (6.6 mg).

[0561] LC-MS: m / z (ESI): 539.1 [M+H] +

[0562] 1 H NMR (400 MHz, CD3OD) d = 8.01 (s, 1H), 7.86-7.81 (m, 1H), 7.77-7.72 (m, 1H), 7.30-7.26 (m, 1H), 7.17-7.07 (m, 1H), 7.03 (s, 1H), 4.19 (s, 1H), 4.17 (s, 2H), 4.07 (s, 3H), 3.95-3.74 (m, 2H), 3.55 (s, 3H), 2.82-2.76 (m, 1H), 2.69-2.60 (m, 1H), 2.54 (s, 3H), 1.81 (s, 3H), 0.78 (s, 9H)

[0563] Example 18, 1-(4-(2-(2,3-difluoro-6-(2-methyl-4-((methylamino)methyl)quinolin-6- yl)phenoxy)ethyl)-1,5-dimethyl-1 H-pyrazol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 18)

[0564] Step 1 : Synthesis of 6-bromo-N,2-dimethylquinoline-4-carboxamide (Intermediate 18-2)

[0565] Intermediate 18-1 (500 mg) and methylamine hydrochloride (228 mg) were dissolved in dichloromethane (5 mL) under nitrogen atmosphere, DIEA (728 mg) and HATU (850 mg) were added successively, the reaction was stirred at 20 °C for 2 h. Then the mixture was concentrated under reduced pressure, and the title compound (730 mg) was obtained by silica gel column chromatography (tetrahydrofuran / petroleum ether, 0-60%).

[0566] LC-MS: m / z (ESI): 279.0 / 281.0 [M+H] +

[0567] Step 2: Synthesis of 1-(6-bromo-2-methylquinoline-4-yl)-N-methylmethanamine (Intermediate 18-3)

[0568] Intermediate 18-2 (620 mg) was dissolved in tetrahydrofuran (6 mL), 10 M borane- dimethyl sulfide solution (1 mL) was added dropwise at 0 °C under nitrogen atmosphere, the reaction was stirred at 70 °C for 5 h. Then the reaction was quenched by dropwise addition of methanol (10 mL) under ice-water bath, and the title compound (620 mg) was obtained by concentration under reduced pressure.

[0569] LC-MS: m / z (ESI): 265.1 / 267.1 [M+H] +

[0570] Step 3: Synthesis of tert-butyl ((6-bromo-2-methylquinoline-4-yl)methyl)(methyl)carbamate (Intermediate 18-4)

[0571] Intermediate 18-3 (620 mg) was dissolved in dichloromethane (6 mL) under nitrogen atmosphere, Boc20 (1 g) and triethylamine (978 μί) were added, the reaction was stirred at 20 °C for 5 h. Then the mixture was concentrated under reduced pressure, and the title compound (30 mg) was obtained by silica gel column chromatography (tetrahydrofuran / petroleum ether, 0-60%).

[0572] LC-MS: m / z (ESI): 365.0 / 367.0 [M+H] +

[0573] Step 4: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2- dimethylpropyl)-1,5-dimethyl-1 H-pyrazol-4-yl)ethoxy)phenyl)-2-methylquinolin-4- yl)methyl)(methyl)carbamate (Intermediate 18-5)

[0574] Intermediate 18-4 (26 mg) and Intermediate 1-4 (33 mg) were dissolved in dioxane (1.2 mL) and water (300 μί) under nitrogen atmosphere, to which potassium carbonate (29 mg) and 1,1 -bis(diphenylphosphino)ferrocene palladium chloride (6 mg) were added, and the reaction was stirred at 90 °C for 2 h. After which it was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / pet. ether, 0-100%) to give the title compound (18 mg).

[0575] LC-MS: m / z (ESI): 655.2 [M+Na] + .

[0576] Step 6: Synthesis of 1-(4-(2-(2,3-difluoro-6-(2-methyl-4-((methylamino)methyl)quinolin-6- yl)phenoxy)ethyl)-1,5-dimethyl-1 H-pyrazol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 18)

[0577] Intermediate 18-5 (18 mg) was dissolved in dichloromethane (500 μί), to which 2M hydrochloric acid / dioxane solution (127 μί) was added, and the reaction was stirred at 25 °C for 3 h. After which the reaction was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (Column: C18 150*30mm*5μιη; Mobile Phase: [A: Water (0.05% ammonia water + 10mM ammonium bicarbonate), B: Acetonitrile]; B%: 39%-79%, 9min, 100%, 2min) to give the title compound (1.9 mg).

[0578] LC-MS: m / z (ESI): 523.4 [M+H] + .

[0579] 1H NMR (400 MHz, DMSO-d6) d = 8.19 (d, J = 1.5 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.45 (s, 1H), 7.41 - 7.26 (m, 2H), 4.65 - 4.55 (m, 1H), 4.12 (s, 2H), 4.02 (d, J = 5.3 Hz, 1H), 3.91 - 3.74 (m, 2H), 3.51 (s, 3H), 2.79 - 2.69 (m, 1H), 2.65 (s, 3H), 2.58 - 2.53 (m, 1H), 2.37 (s, 3H), 1.77 (s, 3H), 0.73 (s, 9H)

[0580] Example 19, 1-(4-(2-(2,3-difluoro-6-(4-(methylamino)methyl)quinolin-6-yl)phenoxy)ethyl)- 1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (Compound 19)

[0581] Step 1: Synthesis of tert-butyl (6-(2-(2-(1,5-dimethyl-3-neopentanoyl-1H-pyrazol-4-yl)ethoxy)- 3,4-difluorophenyl)quinolin-4-yl)methyl)carbamate (Intermediate 19-1)

[0582] Intermediate 13-6 (160 mg) was put into a 100 mL reaction bottle, and toluene (3 mL) was added to stir and dissolve. Then compound 1-1 (180 mg) and CMBP (482 mg) were added. The reaction liquid was reacted at 110 °C for 12 h. After that, the reaction liquid was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain the title compound (200 mg).

[0583] LC-MS: m / z (ESI): 607.4 [M+H] + .

[0584] Step 2: Synthesis of 1-(4-(2-(2,3-difluoro-6-(4-(methylamino)methyl)quinolin-6-yl)phenoxy)ethyl)- 1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (Compound 19)

[0585] Intermediate 19-1 (200 mg) was charged into a 25 mL reaction vial, DCM and TFA (5 mL, 5:1) was added, the mixture was stirred at room temperature for 1 h. The reaction was monitored by LC-MS. The reaction mixture was concentrated and purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40%-80%, elution 10 min) to give the title compound (13.18 mg).

[0586] LC-MS: m / z (ESI): 507.4 [M+H] + .

[0587] 1 H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J = 4.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.80-7.74 (m, 1H), 7.57 (d, J = 4.4 Hz, 1H), 7.39-7.26 (m, 2H), 4.28 (s, 2H), 3.93 (t, J = 6.4 Hz, 2H), 3.66 (s, 3H), 2.82 (t, J = 6.8 Hz, 2H), 2.45 (s, 3H), 1.86 (s, 3H), 1.20 (s, 9H).

[0588] Example 20, 1-(6-(2-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)quinolin-4-yl)-N-methylmethanamine (Compound 20)

[0589] Step 1: Synthesis of 1,5-dimethyl-3-neopentyl-4-(2-((triisopropylsilyl)oxy)ethyl)-1H- pyrazole (Intermediate 20-1)

[0590] Intermediate 14-5 (220 mg), potassium 2,2-dimethylpropyltrifluoroborate (310 mg), cataCXium A Pd G3 (42 mg), cesium carbonate (570 mg), dimesityl sulfide (2 mL) and water (0.3 mL) were heated to 120 °C under argon atmosphere for 16 h. The mixture was directly purified by silica gel column chromatography (THF / PE, 0-40%) to give the title compound (100 mg).

[0591] LC-MS: m / z (ESI): 367.5 [M+H] +

[0592] Step 2: Synthesis of 2-(l,5-dimethyl-3-neopentyl-lH-pyrazol-4-yl)ethan-l-ol (Intermediate 20-2)

[0593] To a mixture of Intermediate 20-1 in DCM (2 mL) was added TBAF (1 M in tetrahydrofuran, 1 mL) at room temperature. The mixture was stirred at room temperature for 2 h. Then the solvent was removed by concentration under reduced pressure. The residue was directly purified by column chromatography on silica gel (THF / PE, 0-100%) to give the title compound (68 mg).

[0594] LC-MS: m / z (ESI): 211.4 [M+H] +

[0595] Step 3: Synthesis of 4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-l,5-dimethyl-3- neopentyl-lH-pyrazole (Intermediate 20-3)

[0596] A mixture of Intermediate 20-2 (68 mg), cyano methylene tri-n-butyl phosphonium (0.156 mL), 6-bromo-2,3-difluorophenol (0.135 mL) and toluene (1 mL) was stirred at 110 °C for 16 h under argon atmosphere. Then the mixture was directly purified by column chromatography on silica gel (THF / PE, 0-30%) to give the title compound (29 mg).

[0597] LC-MS: m / z (ESI): 401.2 [M+H] +

[0598] Step 4: Synthesis of ((6-(2-(2-(l,5-dimethyl-3-neopentyl-lH-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)quinolin-4-yl)methyl)(methyl)carbamic acid tert-butyl ester (Intermediate 20-4)

[0599] A mixture of Intermediate 14-9 (30 mg) and Intermediate 20-3 (29 mg) in dioxane (0.8 mL) and water (0.2 mL) was stirred at 90 °C for 1 h under nitrogen atmosphere with the presence of l,l'-bis(diphenylphosphino)ferrocene palladium chloride (3 mg) and potassium carbonate (21 mg). Then the reaction was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (THF / PE = 0-20%) to give the title compound (30 mg).

[0600] MS m / z (ESI): 593.2 [M+H] +

[0601] Step 5: Synthesis of l-(6-(2-(2-(l,5-dimethyl-3-neopentyl-lH-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)quinolin-4-yl)-N-methylmethanamine (Compound 20)

[0602] Intermediate 20-4 (30 mg) was dissolved in 2M hydrochloric acid in dioxane (2 mL) and the reaction was stirred at 25 °C for 2 h. The reaction was then directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: C18 150 x 30 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 28%-68%, 9 min) to give the title compound (0.8 mg).

[0603] LC-MS: m / z (ESI): 493.4 [M+H] + .

[0604] 1 H NMR (400 MHz, DMSO-d6) d = 8.94 (d, J = 4.5 Hz, 1H), 8.19 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 4.5 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.23 - 7.13 (m, 1H), 4.52 (s, 2H), 3.86 (t, J = 7.2 Hz, 2H), 3.53 (s, 3H), 2.73 (s, 3H), 2.66 (t, J = 7.2 Hz, 2H), 2.14 (s, 2H), 1.89 (s, 3H), 0.74 (s, 9H)

[0605] Example 21, Synthesis of bicyclo[l.l.l]pentan-l-yl (4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6-yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)methanol (Compound 21)

[0606] Step 1: Synthesis of N-methoxy-N-methylbicyclo[l.l.l]pentane-l-carboxamide (Intermediate 21-1)

[0607] To a mixture of bicyclo[l.l.l]pentane-l-carboxylic acid (260 mg), N,0- dimethylhydroxylamine hydrochloride (450 mg), HATU (1.06 g) and DMF (3 mL) was added DIEA (3 mL) at room temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. After which water (30 mL) was added and extracted with ethyl acetate (50 mL x 3), the combined organic phase was concentrated under reduced pressure to remove the solvent and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-40%) to give the title compound (311 mg).

[0608] LC-MS: m / z (ESI): 156.2 [M+H] +

[0609] Step 2: Synthesis of bicyclo[l.l.l]pentan-l-yl(4-(2-hydroxyethyl)-l,5-dimethyl- lH-pyrazol-3-yl)methanone (Intermediate 21-2)

[0610] To a mixture of Intermediate 14-5 (220 mg) and anhydrous diethyl ether (2 mL) was added tert-butyllithium (1.3 M in n-pentane, 0.9 mL) at -78 °C under argon atmosphere. The resulting mixture was stirred at -78 °C for 15 min. To which was added Intermediate 21-1 (165 mg), the resulting mixture was allowed to warm to room temperature naturally and stirred for 2 h. After which TBAF (1 M in tetrahydrofuran, 2.5 mL) was added to the reaction, the resulting mixture was stirred at room temperature for 2 h. After which the solvent was removed under reduced pressure, the residue was directly purified by column chromatography on silica gel (THF / PE, 0-100%) to give the title compound (102 mg).

[0611] LC-MS: m / z (ESI): 235.3 [M+H] +

[0612] Step 3: Synthesis of bicyclo[l.l.l]pentan-l-yl(4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)- 1,5-dimethyl-lH-pyrazol-3-yl)methanone (Intermediate 21-3)

[0613] A mixture of Intermediate 21-2 (102 mg), cyanomethylidene tri-n-butylphosphonium (0.2 mL), 6-bromo-2,3-difluorophenol (0.18 mL) and toluene (1.5 mL) was stirred at 110 °C for 16 h under argon atmosphere. After which the mixture was directly purified by column chromatography on silica gel (THF / PE, 0-30%) to give the title compound (82 mg).

[0614] LC-MS: m / z (ESI): 425.2 [M+H] +

[0615] Step 4: Synthesis of tert-butyl ((6-(2-(2-(3-(bicyclo[l.l.l]pentan-l- carbonyl)-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)quinolin-4- yl)methyl)(methyl)carbamate (Intermediate 21-4)

[0616] To a mixture of Intermediate 21-3 (32 mg), Intermediate 14-9 (20 mg), potassium carbonate (20 mg), dioxane (1 mL) and water (0.2 mL) was added PdCl2(dppf) (4 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-30%) to give the title compound (20 mg).

[0617] LC-MS: m / z (ESI): 617.2 [M+H] +

[0618] Step 5: Synthesis of tert-butyl ((6-(2-(2-(3-(bicyclo[l.l.l]pentan-l- yl(hydroxymethyl)-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)quinolin- 4-yl)methyl)(methyl)carbamate (Intermediate 21-5)

[0619] To a mixture of Intermediate 21-4 (20 mg) and anhydrous methanol (2 mL) was added lithium borohydride (2 M in tetrahydrofuran, 0.15 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. To the resulting mixture was then added water (0.5 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The solvent was then removed under reduced pressure to give the title compound (20 mg).

[0620] LC-MS: m / z (ESI): 619.1 [M+H] +

[0621] Step 6: Synthesis of bicyclo[l.l.l]pentan-l-yl(4-(2-(2,3-difluoro-6-(4-((methylamino) methyl)quinolin-6-yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)methanol (Compound 21)

[0622] To intermediate 21-5 (20 mg) was added hydrochloric acid (2 M in dioxane, 2 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated to remove the solvent and directly purified by high performance liquid chromatography (column: C18 150 x 30 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 25% - 65%, 9 min) to give the title compound (1.7 mg).

[0623] LC-MS: m / z (ESI): 519.1 [M+H] +

[0624] 1 H NMR (400 MHz, CD3OD) d = 8.90 (d, J = 4.5 Hz, 1H), 8.19 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 4.5 Hz, 1H), 7.36 - 7.30 (m, 1H), 7.21 - 7.12 (m, 1H), 4.47 - 4.34 (m, 3H), 4.07 - 3.99 (m, 1H), 3.93 - 3.85 (m, 1H), 3.44 (s, 3H), 2.79 - 2.71 (m, 1H), 2.68 - 2.59 (m, 4H), 2.35 (s, 1H), 1.84 (s, 3H), 1.56 - 1.51 (m, 3H), 1.49 - 1.44 (m, 3H)

[0625] Example 22, 1-(4-(2-(6-(4-((cyclobutylamino)methyl)quinolin-6-yl)-2,3- difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 22)

[0626] Step 1: Synthesis of N-((6-bromoquinolin-4-yl)methyl)cyclobutane-1,1-diamine (Intermediate 22-2)

[0627] Intermediate 22-1 (1.20 g) was charged into a 100 mL reaction flask, EtOH (10 mL) was added, followed by cyclobutylamine (0.54 g), sodium cyanoborohydride (0.96 g) and tetraisopropyl titanate (4.35 g). The reaction was carried out at 25 °C for 5 h, after which the reaction liquid was poured into water and extracted with ethyl acetate (150 mL). The organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA = 2:1) to give the title compound (964 mg).

[0628] LC-MS: m / z (ESI): 291.2 [M+H] + .

[0629] Step 2: Synthesis of tert-butyl cyclobutyl(6-bromoquinolin-4-yl)methyl)carbamate (Intermediate 22-3)

[0630] Intermediate 22-2 (964 mg) was put into a 100 mL reaction bottle, DCM (10 mL) was added, then TEA (1.00 g), Boc20 (2.17 g) were added, the reaction liquid was stirred at 25 °C for 2 h, then the reaction liquid was poured into water, extracted with ethyl acetate (100 mL), the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the title compound (490 mg).

[0631] LC-MS: m / z (ESI): 391.2 [M+H] + .

[0632] Step 3: Synthesis of tert-butyl cyclobutyl(6-(3,4-difluoro-2-hydroxyphenyl)quinolin-4- yl)methyl)carbamate (Intermediate 22-4)

[0633] Intermediate 22-3 (440 mg) was put into a 100 mL reaction bottle, 1,4-dioxane (10 mL) was added and stirred to dissolve, and water (2 mL), 2-hydroxy-3,4-difluorobenzoic acid (720 mg), potassium carbonate (1.14 g) and Xphos Pd G2 (294 mg) were added to the system. The reaction liquid was stirred at 100 °C for 12 h, then the reaction liquid was poured into water (100 mL), extracted with EA (100 mL), the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 3:1) to give the title compound (220 mg).

[0634] LC-MS: m / z (ESI): 441.2 [M+H] + .

[0635] Step 4: Synthesis of tert-butyl cyclobutyl(6-(2-(2-(1,5-dimethyl-3-neopentanoyl-1H-pyrazol-4- yl)ethoxy)-3,4-difluorophenyl)quinolin-4-yl)methyl)carbamate (Intermediate 22-5)

[0636] Intermediate 22-4 (100 mg) was put into a 100 mL reaction bottle, toluene (3 mL) was added and stirred to dissolve. Then compound 1-1 (103 mg) and CMBP (277 mg) were added. The reaction liquid was reacted at 110 °C for 12 h. Then the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 3:1) to give the title compound (80 mg).

[0637] LC-MS: m / z (ESI): 647.4 [M+H] + .

[0638] Step 5: Synthesis of tert-butyl cyclobutyl(6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2- dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)quinolin-4-yl)methyl) carbamate (Intermediate 22-6)

[0639] Intermediate 22-5 (80 mg) was put into a 50 mL single-necked reaction flask, MeOH (2 mL) was added, NaBH4 (22.80 mg, 0.60 mmol) was added, and the reaction was stirred at 25 °C for 1 h. After that, the reaction solution was poured into saturated ammonium chloride (20 mL) and extracted with EA (15 mL) three times. The organic phases were combined and concentrated to dryness under reduced pressure to give the title compound (84 mg).

[0640] LC-MS: m / z (ESI): 649.2 [M+H] + .

[0641] Step 6: Synthesis of 1-(4-(2-(6-(4-((cyclobutylamino)methyl)quinolin-6-yl)-2,3- difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 22)

[0642] Intermediate 22-6 (84 mg) was put into a 25 mL reaction flask, DCM and TFA (3 mL, 5:1) were added, and the reaction was stirred at room temperature for 1 h. After that, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography (chromatography column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40%-80%, elution for 10 min) to give the title compound (17.07 mg).

[0643] LC-MS: m / z (ESI): 571.2 [M+Na] + .

[0644] 1H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.59 (d, J = 4.4 Hz, 1H), 7.43 - 7.30 (m, 2H), 4.60 (s, 1H), 4.26 (s, 2H), 4.04 (s, 1H), 3.94 - 3.86 (m, 1H), 3.84 - 3.81 (m, 1H), 3.50 (s, 3H), 2.81 - 2.52 (m, 2H), 2.18 - 2.10 (m, 2H), 1.93 - 1.80 (m, 2H), 1.77 (s, 3H), 1.70 - 1.55 (m, 2H), 0.73 (s, 9H).

[0645] Example 23, l-(6-(2-(2-(3-cyclopropyl-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)quinolin-4-yl)-N-methylmethanamine (Compound 23)

[0646] Step 1: Synthesis of 3-cyclopropyl-l,5-dimethyl-4-(2-((triisopropylsilyl)oxy)ethyl)-lH- pyrazole (Intermediate 23-1)

[0647] Intermediate 14-5 (0.50 g) was charged into a 100 mL reaction vial, stirred to dissolve in Xylenes (5 mL), and water (1 mL), cyclopropylboronic acid (345 mg), cesium carbonate (1.31 g), and cataCXium A Pd G3 (95 mg) were added to the system, which was heated to 130 °C for 12 h under argon atmosphere. After that, the reaction solution was poured into water (100 mL), extracted with EA (100 mL), and the organic phase was separated and concentrated to dryness under reduced pressure. The residue was purified by reverse phase column (80-100% ACN) to give the title compound (300 mg).

[0648] LC-MS: m / z (ESI): 337.4 [M+H] + .

[0649] Step 2: Synthesis of 2-(3-cyclopropyl-l,5-dimethyl-lH-pyrazol-4-yl)ethan-l-ol (Intermediate 23-2)

[0650] Intermediate 23-1 (0.30 g) was put into a 100 mL reaction bottle, TBAF (5 mL, 1M THF solution) solution was added, and the mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction solution was poured into saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (100 mL), and the organic phase was separated and concentrated to dryness under reduced pressure. The residue was purified by reverse phase column (ACN:H2O = 1:3) to give the title compound (60 mg).

[0651] LC-MS: m / z (ESI): 181.2 [M+H] + .

[0652] Step 3: Synthesis of tert-butyl (6-(2-(2-(3-cyclopropyl-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)quinolin-4-yl)methyl)carbamate (Intermediate 23-3)

[0653] Intermediate 23-2 (60 mg) was put into a 100 mL reaction bottle, and toluene (2 mL) was added and stirred to dissolve. Then intermediate 13-6 (132 mg) and CMBP (398 mg) were added. The reaction was stirred at 110 °C for 12 h. After the reaction was completed, the organic phase was concentrated to dryness under reduced pressure to give the title compound (100 mg).

[0654] LC-MS: m / z (ESI): 563.2 [M+H] + .

[0655] Step 4: Synthesis of l-(6-(2-(2-(3-cyclopropyl-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)quinolin-4-yl)-N-methylmethanamine (Compound 23)

[0656] Intermediate 23-3 (100 mg) was put into a 25 mL reaction bottle, and a mixed solution of DCM and TFA (3 mL, 5: 1) was added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40%-80%, elution for 10 min) to give the title compound (11.83 mg).

[0657] LC-MS: m / z (ESI): 463.2 [M+H] + .

[0658] 1H NMR (400 MHz, CD3OD): δ 8.91 (d, J = 4.4 Hz, 1H), 8.16 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.90-7.85 (m, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.36-7.28 (m, 1H), 7.19-7.09 (m, 1H), 4.50 (s, 2H), 3.91 (t, J = 7.2 Hz, 2H), 3.42 (s, 3H), 2.74-2.66 (m, 5H), 1.82 (s, 3H), 1.41-1.30 (m, 1H), 0.56-0.46 (m, 4H).

[0659] Example 24, 1-(4-(2-(2,3-difluoro-6-(6-((methylamino)methyl)imidazo[2,1- a]isoquinolin-8-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1- ol (Compound 24)

[0660] Step 1: Synthesis of 6-bromo-4-iodoisoquinoline-1-amine (Intermediate 24-2)

[0661] Intermediate 24-1 (2.5 g) was dissolved in DMF (20 mL), and NIS (3.78 g) was added under nitrogen atmosphere. The reaction was stirred at 25 °C for 3 h. Then the reaction was slowly added into ice water (50 mL), filtered, and the filter cake was dried to give the title compound (3 g).

[0662] LCMS (m / z): 349.0 [M+H] +

[0663] Step 2: Synthesis of 8-bromo-6-iodoimidazo[2,1-a]isoquinoline (Intermediate 24-3)

[0664] Intermediate 24-2 (1.2 g) and 2-chloroacetaldehyde (809.8 mg) were dissolved in ethanol (8 mL) and water (2 mL), and sodium bicarbonate (433 mg) was added under nitrogen atmosphere. The reaction was heated to 90 °C for 2 h. Then the reaction was diluted with dichloromethane (50 mL), washed with water (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column (12 g) with the eluent of 0-60% ethyl acetate / petroleum ether at 60 mL / min to give the title compound (600 mg). 12 g flash silica gel column, eluent of 0-60% ethyl acetate / petroleum ether, gradient @ 60 mL / min.

[0665] LCMS (m / z): 373.0 [M+H] +

[0666] Step 3: Synthesis of methyl 8-bromoimidazo[2,1-a]isoquinoline-6-carboxylate (Intermediate 24-4)

[0667] Intermediate 24-3 (0.7 g) was dissolved in methanol (10 mL), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (137.33 mg) and triethylamine (569.72 mg) were added under nitrogen atmosphere, the reaction solution was stirred at 60 °C for 16 h under carbon monoxide atmosphere. The reaction solution was concentrated to dryness under reduced pressure, the residue was purified by flash column chromatography (silica gel, eluent: tetrahydrofuran / petroleum ether = 0 / 60, gradient @ 60 mL / min) to give the title compound (400 mg). 12g Flash column chromatography (silica gel, eluent: tetrahydrofuran / petroleum ether = 0 / 60, gradient @ 60 mL / min) purification gave the title compound (400 mg).

[0668] MS m / z (ESI): 304.8 [M+H] +

[0669] Step 4: Synthesis of (8-bromoimidazo[2,1-a]isoquinolin-6-yl)methanol (Intermediate 24-5)

[0670] DIBAL-H (1 M, 2.95 mL) was added to a mixture of Intermediate 24-4 (300 mg) in dichloromethane (5 mL) at -78 °C under argon atmosphere, the reaction solution was stirred at -78 °C for 3 h. Ice water (30 mL) was added to the reaction solution, which was diluted with dichloromethane (50 mL), washed with water (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, eluent: tetrahydrofuran / petroleum ether = 0 / 100, gradient @ 60 mL / min) to give the title compound (90 mg). 12g Flash column chromatography (silica gel, eluent: tetrahydrofuran / petroleum ether = 0 / 100, gradient @ 60 mL / min) purification gave the title compound (90 mg).

[0671] MS m / z (ESI): 277.0 [M+H] +

[0672] Step 5: Synthesis of 8-bromoimidazo[2,1-a]isoquinoline-6-carbaldehyde (Intermediate 24-6)

[0673] Intermediate 24-5 (80 mg) was dissolved in dichloromethane (2 mL), DMP (183.67 mg) was added under nitrogen atmosphere, the reaction solution was stirred at 25 °C for 3 h. The reaction solution was then purified by flash column chromatography (silica gel, eluent: tetrahydrofuran / petroleum ether = 0 / 70, gradient @ 60 mL / min) to give the title compound (75 mg). 12g Flash column chromatography (silica gel, eluent: tetrahydrofuran / petroleum ether = 0 / 70, gradient @ 60 mL / min) purification gave the title compound (75 mg).

[0674] MS m / z (ESI): 275.0 [M+H] +

[0675] Step 6: Synthesis of tert-butyl ((8-bromoimidazo[2,1-a]isoquinolin-6- yl)methyl)(methyl)carbamate (Intermediate 24-8)

[0676] Intermediate 24-6 (75 mg) was dissolved in methanol (2 mL) and dichloromethane (1 mL), and then NaBH3CN (34.27 mg) and triethylamine (82.76 mg) were added under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then purified by flash silica gel column (12 g) with eluent of 0-8% methanol / dichloromethane, gradient @ 60 mL / min to give the title compound (79 mg). 12 g The reaction mixture was then purified by flash silica gel column (12 g) with eluent of 0-80% tetrahydrofuran / petroleum ether, gradient @ 60 mL / min to give the title compound (40 mg).

[0677] LC-MS: m / z (ESI): 289.9 [M+H] +

[0678] Step 7: Synthesis of tert-butyl ((8-bromoimidazo[2,1-a]isoquinolin-6- yl)methyl)(methyl)carbamate (Intermediate 24-8)

[0679] Intermediate 24-7 (70 mg) was dissolved in dichloromethane (1 mL), and then Boc2O (78.97 mg) and triethylamine (73.24 mg) were added under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was then purified by flash silica gel column (12 g) with eluent of 0-80% tetrahydrofuran / petroleum ether, gradient @ 60 mL / min to give the title compound (40 mg). 12 g The reaction mixture was then purified by flash silica gel column (12 g) with eluent of 0-80% tetrahydrofuran / petroleum ether, gradient @ 60 mL / min to give the title compound (40 mg).

[0680] LC-MS: m / z (ESI): 389.8, 391.8 [M+H] +

[0681] Step 8: Synthesis of tert-butyl ((8-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2- dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)imidazo[2,1-a]isoquinolin- 6-yl)methyl)(methyl)carbamate (Intermediate 24-9)

[0682] Intermediate 24-8 (16.81 mg) and intermediate 1-4 (20 mg) were dissolved in dioxane (0.5 mL) and water (0.2 mL), Pd-118 (2.81 mg) and potassium carbonate (11.91 mg) were added under nitrogen atmosphere, the reaction was stirred at 90 °C for 3 h. After that, the reaction was diluted with ethyl acetate (30 mL) and washed with water (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness to give the title compound (30 mg).

[0683] LC-MS: m / z (ESI): 648.4 [M+H] +

[0684] Step 9: Synthesis of 1-(4-(2-(2,3-difluoro-6-(6-((methylamino)methyl)imidazo[2,1- a]isoquinolin-8-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 24)

[0685] Intermediate 24-9 (30 mg) was dissolved in hydrochloric acid dioxane (2 M, 0.5 mL), the reaction was stirred at 25 °C for 1 h. After that, the reaction was directly concentrated to dryness under reduced pressure, the residue was purified by high performance liquid chromatography (column: ACSSH-CD C18 150*40 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 20%-40%, 9 min) to give the title compound (8 mg).

[0686] LC-MS: m / z (ESI): 548.1 [M+H] +

[0687] 1 H NMR (400 MHz, DMSO-d6) d = 8.53 (d, J = 8.3 Hz, 1H), 8.44 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.57 (s, 1H), 7.45 - 7.30 (m, 2H), 4.72 - 4.53 (m, 1H), 4.16 (s, 2H), 4.03 (s, 1H), 3.95 - 3.77 (m, 2H), 3.50 (s, 3H), 2.82 - 2.72 (m, 1H), 2.63 - 2.55 (m, 1H), 2.47 (s, 3H), 1.82 (s, 3H), 0.72 (s, 9H)

[0688] Example 25: Synthesis of 1-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinoline-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-cyclobutane-1-ol (compound 25)

[0689] Step 1: Synthesis of 2-(3-(1-(methoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethane-1-ol (intermediate 25-1)

[0690] Under an argon atmosphere and at -78°C, a 1.3M, 1.8mL solution of tert-butyllithium in n-pentane was added to a mixture of intermediate 14-5 (440mg) and anhydrous diethyl ether (4mL). The resulting mixture was stirred at -78°C for 15min. Cyclobutanone (410mg) was then added, and the mixture was allowed to rise to room temperature and stirred for 2h. Bromomethyl ether (MOMBr) (730mg) was then added, and the mixture was stirred at room temperature for 2h. Finally, a 1M, 5mL solution of TBAF in tetrahydrofuran was added, and the mixture was stirred at room temperature for 2h. The solvent was then removed by concentration under reduced pressure, and the residue was directly purified by silica gel column chromatography (THF / PE, 0-100%) to give the title compound (17mg).

[0691] LC-MS: m / z (ESI): 255.3 [M+H] +

[0692] Step 2: Synthesis of 4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-3-(1-(methoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazole (intermediate 25-2)

[0693] Under an argon atmosphere, a mixture of intermediate 25-1 (17 mg), cyanomethylenetri-n-butylphosphine (49 mg), 6-bromo-2,3-difluorophenol (42 mg), and toluene (1 mL) was stirred at 110 °C for 16 h. The mixture was then directly purified by silica gel column chromatography (THF / PE, 0-30%) to give the title compound (16 mg).

[0694] LC-MS: m / z (ESI): 445.2 [M+H] +

[0695] Step 3: Synthesis of ((6-(3,4-difluoro-2-(2-(3-(1-(methoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)quinoline-4-yl)methyl)(methyl)tert-butyl carbamate (intermediate 25-3)

[0696] Intermediate 25-2 (10 mg) and intermediate 14-9 (8.94 mg) were dissolved in dioxane (0.4 mL) and water (0.1 mL), and 1,1-bis(tert-butylphosphine)ferrocenepalladium chloride (1.46 mg) and potassium carbonate (6.21 mg) were added under a nitrogen atmosphere. The reaction solution was stirred at 90 °C for 3 h. After that, the reaction solution was diluted with ethyl acetate (30 mL) and washed with water (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (20 mg).

[0697] LC-MS: m / z (ESI): 637.4 [M+H] +

[0698] Step 4: Synthesis of 1-(4-(2-(2,3-difluoro-6-(4-((methylamino)methyl)quinolin-6-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)cyclobutan-1-ol (Compound 25)

[0699] Intermediate 25-3 (20 mg) was dissolved in 2M HC1 / dioxane solution (0.5 mL), and the reaction solution was stirred at 25 °C for 1 h. After that, the reaction solution was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: ACSSH-CK C18 150*40 mm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 42%-82%, 9 min) to obtain the title compound (1.1 mg).

[0700] LC-MS: m / z (ESI): 493.1 [M+H] +

[0701] 1 H NMR (400 MHz, DMSO-d6) d = 8.87 (d, J = 4.2 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 4.0 Hz, 1H), 7.42 - 7.23 (m, 2H), 5.17 (s, 1H), 4.17 (s, 2H), 3.90 (t, J = 7.5 Hz, 2H), 3.50 (s, 3H), 2.38 (s, 3H), 2.04 - 1.97 (m, 2H), 1.74 (s, 3H), 1.62 - 1.56 (m, 1H), 1.37 - 1.31 (m, 1H), 1.20 - 1.14 (m, 4H)

[0702] Example 26. Synthesis of 6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethyl- propyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-4-((methylamino)- methyl)quinolin-2(1H)-one (Compound 26)

[0703] Step 1: Synthesis of tert-butyl ((6-bromo-1-methyl-2-oxo-1,2-dihydroquinolin-4- yl)methyl)(methyl)carbamate (Intermediate 26-1)

[0704] To a mixture of Intermediate 17-6 (50 mg) and anhydrous N,N-dimethylformamide (1 mL) was added sodium hydride (16 mg) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 0.5 h. Then iodomethane (29 mg) was added to the resulting mixture, which was stirred at room temperature for 1 h. After the addition of water (5 mL), the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and concentrated under reduced pressure to remove the solvent. The residue was directly purified by column chromatography on silica gel (THF / PE, 0-35%) to give the title compound (30 mg).

[0705] LC-MS: m / z (ESI): 380.9 [M+H] +

[0706] Step 2: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethyl- propyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-2-oxo-1,2- dihydroquinolin-4-yl)methyl)(methyl)carbamate (Intermediate 26-2)

[0707] To a mixture of Intermediate 26-1 (25 mg), Intermediate 1-4 (31 mg), potassium carbonate (18 mg), dioxane (1 mL) and water (0.2 mL) was added PdCl2(dppf) (5 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. After the addition of water (5 mL), the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and concentrated under reduced pressure to remove the solvent to give the title compound (40 mg).

[0708] LC-MS: m / z (ESI): 639.1 [M+H] +

[0709] Step 3: Synthesis of 6-(3,4-difluoro-2-(2-(3-(1-hydroxy-2,2-dimethylpropyl)-1,5- dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-4-((methylamino)methyl)quinolin- 2(1H)-one (Compound 26)

[0710] To intermediate 26-2 (40 mg) was added HC1 / dioxane solution (2 M, 2 mL) at room temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated to remove the solvent and directly purified by high performance liquid chromatography (column: C18 150 x 30 mm; mobile phase: [A: water (10 mM ammonium bicarbonate + 0.05% ammonia water), B: acetonitrile]; B%: 18% - 58%, 9 min) to afford the title compound (1.2 mg).

[0711] LC-MS: m / z (ESI): 539.1 [M+H] +

[0712] 1 H NMR (400 MHz, DMSO-d6) d = 7.97 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.36 - 7.25 (m, 2H), 6.68 (s, 1H), 4.58 (d, J = 4.5 Hz, 1H), 4.00 (d, J = 4.4 Hz, 1H), 3.92 (s, 2H), 3.86 - 3.78 (m, 1H), 3.77 - 3.68 (m, 1H), 3.64 (s, 3H), 3.54 (s, 3H), 2.78 - 2.71 (m, 1H), 2.63 - 2.54 (m, 1H), 2.35 (s, 3H), 1.88 (s, 3H), 0.71 (s, 9H)

[0713] Example 27, Synthesis of N-((6-(2-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4-yl)ethoxy)- 3,4-difluorophenyl)quinolin-4-yl)methyl)methane-d3-amine (Compound 27)

[0714] Step 1: Synthesis of N-((6-bromoquinolin-4-yl)methyl)methane-d3-amine (Intermediate 27-1)

[0715] To a mixture of compound 4-1 (1 g), deuterated methylamine hydrochloride (896.4 mg) in methanol (10 mL) and dichloromethane (10 mL) was added triethylamine (1.29 g) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 10 min, then sodium cyanoborohydride (532.4 mg) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water directly for the next step. The title compound was used as theoretical amount (1.08 g).

[0716] LC-MS: m / z (ESI): 254.0, 256.0 [M+H] +

[0717] Step 2: Synthesis of tert-butyl ((6-bromoquinolin-4-yl)methyl)(methyl-d3)carbamate (Intermediate 27-2)

[0718] To a mixture of Intermediate 27-1 (1.08 g) in methanol (10 mL) was added triethylamine (1.29 g) and di-tert-butyl dicarbonate (1.39 g) at room temperature. The resulting mixture was stirred at room temperature (25 °C) for 6 h. The reaction was concentrated under reduced pressure to remove the solvent. Water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (THF / PE, 0-20%) to give the title compound (712.1 mg).

[0719] LC-MS: m / z (ESI): 354.0, 356.0 [M+H] +

[0720] Step 3: Synthesis of tert-butyl (methyl-d3)((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinolin-4-yl)methyl)carbamate (Intermediate 27-3)

[0721] To a mixture of Intermediate 27-2 (200 mg) and bis(pinacolato)diboron (286.7 mg) in dioxane (6 mL) was added 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (41.3 mg) and potassium acetate (166.2 mg) under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 1 h. The reaction was concentrated under reduced pressure to remove the solvent. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (THF / PE, 0-20%) to give the title compound (247 mg).

[0722] LC-MS: m / z (ESI): 402.1 [M+H] +

[0723] Step 4: Synthesis of tert-butyl ((6-(2-(2-(l,5-dimethyl-3-neopentyl-lH-pyrazol-4- yl)ethoxy)-3,4-difluorophenyl)quinolin-4-yl)methyl)(methyl-d3)carbamate (Intermediate 27-4)

[0724] Intermediate 27-3 (45 mg) and Intermediate 20-3 (45 mg) were dissolved in dioxane (1 mL) and water (0.3 mL) under nitrogen atmosphere. PdCl2(dtbpf) (7.3 mg) and potassium carbonate (31 mg) were added under nitrogen atmosphere. The reaction was stirred at 90 °C for 1 h. The reaction was concentrated under reduced pressure to remove the solvent. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was combined and concentrated under reduced pressure to remove the solvent to give the title compound (66 mg).

[0725] LC-MS: m / z (ESI): 596.3 [M+H] +

[0726] Step 5: Synthesis of N-((6-(2-(2-(l,5-dimethyl-3-neopentyl-lH-pyrazol-4- yl)ethoxy)-3,4-difluorophenyl)quinolin-4-yl)methyl)methane-d3-amine (Compound 27)

[0727] To Intermediate 27-4 (66 mg) was added HCl in dioxane (2 M, 4 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was concentrated to remove the solvent. The residue was purified by high performance liquid chromatography (column: 55-Boston Prime C18 150 x 30 mm, 5 pm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 40% - 80%, 9 min) to give the title compound (16.8 mg).

[0728] LC-MS: m / z (ESI): 496.4 [M+H]+

[0729] 1 H NMR (400 MHz, DMSO-d6) d = 8.86 (d, J = 4.5 Hz, 1H), 8.24 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.39 - 7.33 (m, 2H), 4.15 (s, 2H), 3.75 (t, J = 8.0 Hz, 2H), 3.50 (s, 3H), 2.55 - 2.53 (m, 2H), 2.01 (s, 2H), 1.83 (s, 3H), 0.67 (s, 9H).

[0730] Example 28, Synthesis of l-(4-(2-(2,3-difluoro-6-(4-(((methyl-d3)amino)methyl)quinolin-6-yl)phenoxy)ethyl)- 1,5-dimethyl- lH-pyrazol-3-yl)-3-fluoro-2,2-dimethylpropan- 1 -ol (Compound 28)

[0731] Step 1: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(3-fluoro-2,2-dimethylpropanoyl)- 1,5-dimethyl- lH-pyrazol-4-yl)ethoxy)phenyl)quinolin-4-yl)methyl)(methyl-d3)carbamate (Intermediate 28-1)

[0732] To a mixture of Intermediate 16-3 (60 mg), Intermediate 27-3 (56 mg), potassium carbonate (38 mg), dioxane (1 mL) and water (0.2 mL) was added Pd-118 (9 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvents, and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-30%) to give the title compound (70 mg).

[0733] LC-MS: m / z (ESI): 628.1 [M+H] +

[0734] Step 2: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(3-fluoro- 1 -hydroxy-2,2-dimethylpropyl)- 1,5-dimethyl- lH-pyrazol-4-yl)ethoxy)phenyl)quinolin-4- yl)methyl)(methyl-d3)carbamate (Intermediate 28-2)

[0735] To a mixture of Intermediate 28-1 (70 mg) and anhydrous methanol (2 mL) was added lithium borohydride tetrahydrofuran solution (2 M, 0.6 mL) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. To the resulting mixture was then added water (0.5 mL), and the resulting mixture was stirred at room temperature for 0.5 h. The solvent was then removed under reduced pressure to give the title compound (70 mg).

[0736] LC-MS: m / z (ESI): 652.2 [M+Na] +

[0737] Step 3: Synthesis of l-(4-(2-(2,3-difluoro-6-(4-(((methyl-d3)amino)methyl)quinolin-6-yl)phenoxy)ethyl)- 1,5-dimethyl- lH-pyrazol-3-yl)-3-fluoro-2,2-dimethylpropan- 1 -ol (Compound 28)

[0738] To intermediate 28-2 (70 mg) was added HC1 in dioxane (2 M, 2 mL) at room temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated to remove the solvent and directly purified by high performance liquid chromatography (column: C18 150 x 40 mm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate], B: acetonitrile]; B%: 37% - 77%, 9 min) to give the title compound (10.8 mg).

[0739] LC-MS: m / z (ESI): 530.3 [M+H] +

[0740] 1 H NMR (400 MHz, DMSO-d6) d = 8.87 (d, J = 4.3 Hz, 1H), 8.24 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.45 - 7.27 (m, 2H), 4.89 (s, 1H), 4.32 - 4.27 (m, 1H), 4.20 - 4.12 (m, 3H), 4.04 (d, J = 8.8 Hz, 1H), 3.93 - 3.77 (m, 2H), 3.52 (s, 3H), 2.76 - 2.68 (m, 1H), 2.62 - 2.56 (m, 1H), 1.77 (s, 3H), 0.78 (s, 3H), 0.70 (s, 3H)

[0741] Example 29, Synthesis of (4-(2-(2,3-difluoro-6-(4-(((methyl-d3)amino)methyl)quinolin-6-yl)phenoxy)ethyl)- 1,5-dimethyl- 1 H-pyrazol-3-yl)( 1 -methylcyclobutyl)methanol (Compound 29)

[0742] Step 1: Synthesis of tert-butyl ((6-(2-(2-(l,5-dimethyl-3-(l-methylcyclobutan- 1 -carbonyl)- 1 H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)quinolin-4- yl)methyl)(methyl-d3)carbamate (Intermediate 29-1)

[0743] To a mixture of intermediate 14-8 (60 mg), intermediate 27-3 (56 mg), potassium carbonate (38 mg), dioxane (1 mL) and water (0.2 mL) was added Pd-118 (9 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-30%) to give the title compound (70 mg).

[0744] LC-MS: m / z (ESI): 622.1 [M+H] +

[0745] Step 2: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(hydroxy(l- methylcyclobutyl)methyl)-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)quinolin-4- yl)methyl)(methyl-d3)carbamate (intermediate 29-2)

[0746] To a mixture of intermediate 29-1 (70 mg) and anhydrous methanol (2 mL) was added lithium borohydride in tetrahydrofuran (2 M, 0.6 mL) at 0 °C under argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. To the resulting mixture was then added water (0.5 mL), and the resulting mixture was stirred at room temperature for 0.5 h. The solvent was then removed by concentration under reduced pressure to give the title compound (70 mg).

[0747] LC-MS: m / z (ESI): 624.3 [M+H] +

[0748] Step 3: Synthesis of (4-(2-(2,3-difluoro-6-(4-(((methyl-d3)amino)methyl)quinolin-6- yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)(l-methylcyclobutyl)methanol (Compound 29)

[0749] To intermediate 29-2 (70 mg) was added HCl in dioxane (2 M, 2 mL) at room temperature under argon atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated to remove the solvent and directly purified by high performance liquid chromatography (column: C18 150 x 40 mm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 40%-80%, 9 min) to give the title compound (5.9 mg).

[0750] LC-MS: m / z (ESI): 524.3 [M+H] +

[0751] 1H NMR (400 MHz, DMSO-d6) d = 8.87 (d, J = 4.4 Hz, 1H), 8.25 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.89-7.82 (m, 1H), 7.56 (d, J = 4.3 Hz, 1H), 7.44-7.25 (m, 2H), 4.74 (s, 1H), 4.19 (s, 1H), 4.16 (s, 2H), 3.94-3.76 (m, 2H), 3.49 (s, 3H), 2.79-2.70 (m, 1H), 2.68-2.53 (m, 1H), 2.13-1.99 (m, 2H), 1.75 (s, 3H), 1.74-1.67 (m, 1H), 1.59-1.49 (m, 1H), 1.41-1.34 (m, 1H), 1.29-1.21 (m, 1H), 0.88 (s, 3H)

[0752] Example 30, 1-(7-cyclopropyl-5-(2-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4- yl)ethoxy)-3,4-difluorophenol)pyrazolo[1,5-a]pyridin-3-yl)-N-methylmethanamine (Compound 30)

[0753] Step 1: Synthesis of 5-bromo-7-iodopyrazolo[1,5-a]pyridine (Intermediate 30-2)

[0754] Compound 30-1 (5 g, 25.5 mmol) was put into a 100 mL reaction bottle, THF (50 mL) was added, the reaction solution was cooled to -40 °C, then lithium salt of magnesium dichloride (2,2,6,6-tetramethylpiperidine) (TMPMgCl·LiCl, 38 mL, 1 mol / L THF solution) was added dropwise. The reaction solution was reacted at -40 °C for 2 h, then I2 (9.72 g, 38.3 mmol) was added, the reaction solution was reacted at -40 °C for 1 h. The reaction solution was quenched with saturated ammonium chloride, extracted with EA (100 mL) for 3 times. The organic phase was combined and concentrated to dryness under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 0-60%) to give the title compound (6.5 g).

[0755] LC-MS: m / z (ESI): 324.8 [M+H] +

[0756] Step 2: Synthesis of 5-bromo-7-cyclopropylpyrazolo[1,5-a]pyridine (Intermediate 30-3)

[0757] Into a 100 mL reaction flask, intermediate 30-2 (5.68 g, 17.6 mmol) was added, stirred to dissolve in 1,4-dioxane (50 mL), and then water (10 mL), cyclopropylboronic acid (2.28 g, 26.51 mmol), K2CO3(7.30 g, 52.9 mmol) and Pd(dppf)Cl2(1.29 g, 1.76 mmol) were added. The reaction was stirred at 100 °C for 12 h. The reaction was poured into water (200 mL), extracted with EA (200 mL), and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to give the title compound (3.25 g).

[0758] LC-MS: m / z (ESI): 239.3 [M+H] +

[0759] Step 3: Synthesis of 5-bromo-7-cyclopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (intermediate 30-4)

[0760] Into a 50 mL single-necked reaction flask, intermediate 30-3 (2.87 g, 12.2 mmol) was added, followed by DMF (30 mL), and then POCl3(2.79 g, 18.2 mmol). The reaction was stirred at 25 °C for 2 h. Subsequently, the reaction was poured into water (100 mL), extracted with EA (100 mL), and the organic phase was combined and concentrated to dryness under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 0-70%) to give the title compound (440 mg).

[0761] LC-MS: m / z (ESI): 265.0 [M+H] +

[0762] Step 4: Synthesis of 1-(5-bromo-7-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-N- methylmethanamine (intermediate 30-5)

[0763] Into a 50 mL single-necked reaction flask, intermediate 30-4 (440 mg, 1.67 mmol) was added, followed by MeOH (10 mL), and then methylamine hydrochloride (1.12 g, 16.6 mmol) and sodium borohydride in acetic acid (1.18 g, 5.57 mmol). The reaction was stirred at 25 °C for 12 h. The reaction was used directly in the next step.

[0764] LC-MS: m / z (ESI): 280.0 [M+H] +

[0765] Step 5: Synthesis of tert-butyl (5-bromo-7-cyclopropylpyrazolo[l,5-a]pyridin-3- yl)methyl)(methyl)carbamate (Intermediate 30-6)

[0766] To the reaction solution of Intermediate 30-5 was added TEA (1.67 g, 16.5 mmol) followed by Boc20 (3.62 g, 16.6 mmol) and the reaction was stirred at 25 °C for 2 h. The reaction was poured into water (100 mL) and extracted with EA (100 mL). The organic phase was combined and concentrated to dryness under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 0-40%) to give the title compound (363 mg).

[0767] LC-MS: m / z (ESI): 382.2 [M+H] +

[0768] Step 6: Synthesis of tert-butyl (7-cyclopropyl-5-(3,4-difluoro-2- hydroxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)methyl)carbamate (Intermediate 30-7)

[0769] Intermediate 30-6 (363 mg, 0.96 mmol) was added to a 100 mL reaction flask, stirred to dissolve in 1,4-dioxane (5 mL), and to the system was added water (1 mL), 2-hydroxy-3,4-difluorobenzenboronic acid (250 mg, 1.44 mmol), K2CO3(397 mg, 2.88 mmol) and Pd(dppf)Cl2(73 mg, 0.01 mmol). The reaction was stirred at 100 °C for 12 h. The reaction was poured into water (50 mL) and extracted with EA (50 mL). The organic phase was combined and concentrated to dryness under reduced pressure. The residue was purified by silica gel column (PE:EA = 1:1) to give the title compound (260 mg).

[0770] LC-MS: m / z (ESI): 430.2 [M+H] +

[0771] Step 7: Synthesis of tert-butyl (7-cyclopropyl-5-(2-(2-(l,5-dimethyl-3-neopentyl- lH-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)pyrazolo[l,5-a]pyridin-3-yl)methyl)carbamate (Intermediate 30-8)

[0772] Intermediate 30-7 (120 mg, 0.28 mmol) was charged into a 50 mL single necked reaction flask, toluene (2 mL) was added, then intermediate 20-2 (94 mg, 0.45 mmol) and CMBP (360 mg, 1.49 mmol) were added, the reaction was stirred at 110 °C for 12 h under nitrogen atmosphere. The reaction was concentrated to dryness under reduced pressure, to give the title compound (150 mg).

[0773] LC-MS: m / z (ESI): 622.5 [M+H] +

[0774] Step 8: Synthesis of 1-(7-cyclopropyl-5-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4- yl)ethoxy)-3,4-difluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylmethanamine (Compound 30)

[0775] Intermediate 30-8 (150 mg, 0.24 mmol) was charged into a 25 mL reaction flask, a mixture of DCM and TFA (5 mL, 10:1) was added, the system was stirred at room temperature for 1 h. The reaction was concentrated to dryness under reduced pressure, the residue was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40%-80%, elution for 10 min) to give Compound 30 (7.78 mg, formate salt form).

[0776] LC-MS: m / z (ESI): 522.4 [M+H] + .

[0777] 1 H NMR (400 MHz, CD3OD): δ 8.53 (s, 1H), 8.21 (s, 1H), 7.70 (s, 1H), 7.27-7.23 (m, 1H), 7.17-7.09 (m, 1H), 6.81 (s, 1H), 4.41 (s, 2H), 3.93-3.85 (m, 2H), 3.56 (s, 3H), 2.75-2.66 (m, 6H), 2.16 (s, 2H), 1.99 (s, 3H), 1.28-1.22 (m, 2H), 0.95-0.92 (m, 2H), 0.76 (s, 9H).

[0778] Example 31, 1-(5-(2-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)-7-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-methylmethanamine (Compound 31)

[0779] Step 1: Synthesis of 5-bromo-7-chloropyrazolo[1,5-a]pyridine (Intermediate 31-1)

[0780] Compound 30-1 (5.00 g, 25.5 mmol) was placed into a 250 mL reaction flask, THF (50 mL) was added, the system was cooled to -40 °C, then TMPMgCl.LiCl (38 mL, 1 mol / L THF solution) was added dropwise. The reaction liquid was reacted at -40 °C for 1 h, then hexachloroethane (8.65 g, 36.5 mmol) was added, and the reaction liquid was reacted at -40 °C for 1 h. The reaction liquid was quenched with saturated ammonium chloride, extracted with EA (100 mL) for 3 times, the organic phases were combined, concentrated to dryness under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 0-60%) to give the title compound (4.3 g).

[0781] LC-MS: m / z (ESI): 231.0 [M+H] + .

[0782] Step 2: Synthesis of 5-bromo-7-methoxypyrazolo[1,5-a]pyridine (Intermediate 31-2)

[0783] Intermediate 31-1 (4.1 g, 17.8 mmol) was placed into a 100 mL reaction flask, MeOH (40 mL) was added, then sodium methoxide (2.89 g, 53.5 mmol) was added. The reaction liquid was reacted at 50 °C for 12 h, the reaction liquid was poured into water, extracted with ethyl acetate (200 mL), the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 3:1) to give the title compound (4 g).

[0784] LC-MS: m / z (ESI): 227.0 [M+H] + .

[0785] Step 3: Synthesis of 5-bromo-7-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde (Intermediate 31-3)

[0786] Intermediate 31-2 (3.40 g, 15.0 mmol) was placed into a 100 mL single-mouth reaction flask, DMF (30 mL) was added, then POCl3 (2.79 g, 18.2 mmol) was added, and the reaction liquid was reacted at 25 °C for 2 h. The reaction liquid was poured into water (100 mL), extracted with EA (100 mL), the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 0-60%) to give the title compound (2.9 g).

[0787] LC-MS: m / z (ESI): 255.0 [M+H]+ .

[0788] Step 4: Synthesis of tert-butyl (5-bromo-7-methoxypyrazolo[1,5-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 31-5)

[0789] Into a 100 mL single necked flask, Intermediate 31-3 (2.9 g, 11.42 mmol) was taken, MeOH (10 mL) was added, followed by the addition of methylamine hydrochloride (7.74 g, 115 mmol) and sodium borohydride in acetic acid (12.16 g, 57.4 mmol) and the reaction mass was allowed to react at 25 °C for 12 h. The reaction mass was used as such for the next step.

[0790] LC-MS: m / z (ESI): 270.2 [M+H] + .

[0791] Step 5: Synthesis of tert-butyl (5-bromo-7-methoxypyrazolo[1,5-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 31-5)

[0792] To the reaction mass of Intermediate 31-4, TEA (11.6 g, 115 mmol) was added, followed by the addition of Boc20 (25.0 g, 115 mmol) and the reaction mass was allowed to react at 25 °C for 2 h. The reaction mass was poured into water (100 mL) and extracted with EA (100 mL). The organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 0-30%) to afford the title compound (2.1 g).

[0793] LC-MS: m / z (ESI): 370.2 [M+H] +

[0794] Step 6: Synthesis of tert-butyl (5-(3,4-difluoro-2-hydroxyphenyl)-7-methoxypyrazolo[1,5-a]pyridin-3-yl)methyl)carbamate (Intermediate 31-6)

[0795] Into a 100 mL flask, Intermediate 31-5 (1.60 g, 4.34 mmol) was taken, 1,4-dioxane (20 mL) was added and stirred to dissolve, to this, water (4 mL), 2-hydroxy-3,4-difluorobenzenboronic acid (1.13 g, 6.49 mmol), K2CO3 (1.80 g, 13.0 mmol) and Pd(dppf)Cl2 (0.31 g, 0.42 mmol) were added. The reaction mass was allowed to react at 100 °C for 12 h. The reaction mass was poured into water (100 mL) and extracted with EA (100 mL). The organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA = 1:1) to afford the title compound (900 mg).

[0796] LC-MS: m / z (ESI): 420.2 [M+H] +

[0797] Step 7: Synthesis of tert-butyl (5-(2-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4- yl)ethoxy)-3,4-difluorophenyl)-7-methoxypyrazolo[1,5-a]pyridin-3-yl)methyl)carbamate (Intermediate 31-7)

[0798] Into a 50 mL single necked reaction flask was placed Intermediate 31-6 (400 mg, 0.95 mmol), toluene (2 mL), then Intermediate 20-2 (300 mg, 1.43 mmol), CMBP (1.14 g, 4.73 mmol), the reaction was stirred at 110 °C for 12 h under nitrogen atmosphere. The reaction was concentrated to dryness under reduced pressure, the residue was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 µm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40%-80% over 10 min) to give the title compound (30 mg).

[0799] LC-MS: m / z (ESI): 612.4 [M+H] +

[0800] Step 8: Synthesis of 1-(5-(2-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)-7-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-methylmethanamine (Compound 31)

[0801] Into a 25 mL reaction flask was placed Intermediate 31-7 (30 mg, 0.05 mmol), a mixture of DCM and TFA (2 mL, 5:1), the system was stirred at room temperature for 1 h. The reaction was concentrated to dryness under reduced pressure, the residue was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 µm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40%-80% over 10 min) to give the title compound (15.87 mg, hydrochloride form).

[0802] LC-MS: m / z (ESI): 512.3 [M+H] + .

[0803] 1H NMR (400 MHz, DMSO-d6): δ 8.83 (s, 2H), 8.17 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.41-7.31 (m, 2H), 6.56 (d, J = 1.2 Hz, 1H), 4.36-4.30 (m, 2H), 4.09 (s, 3H), 3.91-3.83 (m, 2H), 3.52 (s, 3H), 2.68-2.60 (m, 2H), 2.56-2.52 (m, 3H), 2.09 (s, 2H), 1.89 (s, 3H), 0.73 (s, 9H).

[0804] Example 32, l-(6-(2-(2-(3,4-dimethyl-l-neopentyl-lH-pyrazol-5-yl)ethoxy)-3,4- difluorophenyl)quinolin-4-yl)-N-methylmethanamine (Compound 32)

[0805] Step 1: Synthesis of 3,4-dimethyl-l-neopentyl-lH-pyrazole (Intermediate 32-2)

[0806] Cyanomethylene tri-n-butylphosphonium (20.09 g, 83.22 mmol) was added dropwise to a solution of compound 32-1 (5 g, 52.01 mmol) and 2,2-dimethylpropane-l-ol (4.58 g, 52.01 mmol) in toluene (100 mL) under nitrogen atmosphere. The reaction was stirred at 60 °C for 16 h. The reaction was then concentrated under reduced pressure to remove the solvent and the residue was purified by column chromatography on silica gel (tetrahydrofuran / n-hexane, 0-3%) to give the title compound (3.45 g).

[0807] LC-MS: m / z (ESI): 167.1 [M+H] +

[0808] Step 2: Synthesis of 5-iodo-3,4-dimethyl-l-neopentyl-lH-pyrazole (Intermediate 32-3)

[0809] N-iodosuccinimide (18.06 g, 80.26 mmol) was added to a solution of Intermediate 32-2 (3.34 g, 20.06 mmol) in DMF (70 mL) and the reaction was stirred at 80 °C for 16 h. The reaction was then quenched with saturated sodium thiosulfate solution (100 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and concentrated under reduced pressure to remove the solvent. The residue was then purified by column chromatography on silica gel (tetrahydrofuran / n-hexane, 0-4%) to give the title compound (2.96 g).

[0810] LC-MS: m / z (ESI): 292.9 [M+H] +

[0811] Step 3: Synthesis of 3,4-dimethyl-l-neopentyl-5-vinyl-lH-pyrazole (Intermediate 32-4)

[0812] Intermediate 32-3 (3.36 g, 11.50 mmol) and potassium vinyltrifluoroborate (3.08 g, 23.00 mmol) were dissolved in a mixture solvent of dioxane (60 mL) and water (10 mL), and potassium carbonate (3.18 g, 23.00 mmol), tetrakis(triphenylphosphine)palladium (664 mg, 575 μmol) and l,l'-bis(diphenylphosphino)ferrocene palladium dichloride (420 mg, 575 μmol) were added successively. The reaction was heated to 80 °C under nitrogen atmosphere and stirred for 16 h. Then water (50 mL) was added to the reaction, which was extracted with ethyl acetate (20 mL x 3). The organic phase was combined and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (THF / PE, 0-4%) to give the title compound (2.00 g).

[0813] LC-MS: m / z (ESI): 193.1 [M+H] +

[0814] Step 4: Synthesis of 5-(2-(9-borabicyclo[3.3.1]nonane-9-yl)ethyl)-3,4-dimethyl-l- neopentyl-lH-pyrazole (Intermediate 32-5)

[0815] 9-borabicyclo[3.3.1]nonane (9-BBN) (4.16 mL, 0.5 M in tetrahydrofuran, 2.08 mmol) was added dropwise to a solution of Intermediate 32-4 (100 mg, 520 μmol) in THF under nitrogen atmosphere. The reaction was stirred at 65 °C for 16 h. Then the reaction was quenched with ethanol (1 mL) and used directly in the next step.

[0816] Step 5: Synthesis of 2-(3,4-dimethyl-l-neopentyl-lH-pyrazol-5-yl)ethan-l-ol (Intermediate 32-6)

[0817] To a mixture of Intermediate 32-5 (163 mg, 518 μmol) in tetrahydrofuran (4 mL) and water (0.5 mL) was added 35% hydrogen peroxide (96.22 μL, 3.11 mmol) and sodium hydroxide solution (6 M, 172 μL, 1.04 mmol). The reaction was stirred at 50 °C for 2 h. Then the reaction was directly concentrated under reduced pressure to remove the solvent to give the title compound (109 mg).

[0818] LC-MS: m / z (ESI): 211.1 [M+H] +

[0819] Step 6: Synthesis of 5-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-3,4-dimethyl-1- neopentyl-1H-pyrazole (Intermediate 32-7)

[0820] Cyanomethylene tri-n-butylphosphonium (250.17 mg, 1.04 mmol) was added dropwise to a solution of Intermediate 32-6 (109 mg, 518 μmol) and 6-bromo-2,3- difluorophenol (162.47 mg, 777 μmol) in toluene (4 mL) under nitrogen atmosphere. The reaction was stirred at 100 °C for 2 h. The reaction was then concentrated under reduced pressure to remove the solvent and the residue was purified by column chromatography on silica gel (tetrahydrofuran / n-hexane, 0-4%) to give the title compound (170 mg).

[0821] LC-MS: m / z (ESI): 401.1 [M+H] +

[0822] Step 7: Synthesis of ((6-(2-(2-(3,4-dimethyl-1-neopentyl-1H-pyrazol-5-yl)ethoxy)-3,4- difluorophenyl)quinolin-4-yl)methyl)(methyl)amino tert-butyl ester (Intermediate 32-8)

[0823] Intermediate 32-7 (170 mg, 424 μmol) and Intermediate 14-9 (169 mg, 423 μmol) were dissolved in dioxane (5 mL) and water (1.5 mL) under nitrogen atmosphere, PdCl2(dtbpf) (13.8 mg, 21.1 μmol) and potassium carbonate (87.8 mg, 635 μmol) were added under nitrogen atmosphere, the reaction was stirred at 90 °C for 1 h. The reaction was then concentrated under reduced pressure to remove the solvent, water (15 mL) was added and extracted with ethyl acetate (10 mL x 3), the organic phases were combined and concentrated under reduced pressure to remove the solvent, the residue was purified by column chromatography on silica gel (tetrahydrofuran / n-hexane, 0-20%) to give the title compound (25.7 mg). 12g Fast silica gel column 2 in series, tetrahydrofuran / n-hexane, 0-20%) purification.

[0824] LC-MS: m / z (ESI): 593.2 [M+H] +

[0825] Step 8: Synthesis of 1-(6-(2-(2-(3,4-dimethyl-1-neopentyl-1H-pyrazol-5-yl)ethoxy)-3,4- difluorophenyl)quinolin-4-yl)-N-methylmethanamine (Compound 32)

[0826] To intermediate 32-8 (25.7 mg, 43.4 pmol) was added a solution of HCI in dioxane (2 M, 2.17 mL) at room temperature and the reaction was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure to remove the solvent and the residue was directly purified by high performance liquid chromatography (column: WePure Biotech XP tC18 150 x 40 mm, 7 pm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 49% - 89%, 9 min) to give the title compound (11 mg).

[0827] LC-MS: m / z (ESI): 493.4 [M+H] +

[0828] 1 H NMR (400 MHz, CD3OD) d = 8.86 (d, J = 4.5 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 1.8, 8.8 Hz, 1H), 7.60 (d, J = 4.4 Hz, 1H), 7.32 (ddd, J = 2.1, 6.1, 8.7 Hz, 1H), 7.21 - 7.10 (m, 1H), 4.28 (s, 2H), 3.95 (t, J = 6.8 Hz, 2H), 3.52 (s, 2H), 2.89 (t, J = 6.8 Hz, 2H), 2.55 (s, 3H), 1.99 (s, 3H), 1.62 (s, 3H), 0.74 (s, 9H).

[0829] Example 33, 1-(4-(2-(6-(4-(aminomethyl)quinolin-6-yl)-2,3-difluorophenoxy)ethyl)- 1,5-dimethyl- 1 H-pyrazol-3-yl)-3-fluoro-2,2-dimethylpropan- 1 -ol methanamine (Compound 33)

[0830] Step 1 : Synthesis of tert-butyl ((6-bromoquinolin-4-yl)methyl)carbamate (Intermediate 33-3)

[0831] Intermediate 33-1 (1 g, 3.48 mmol) and intermediate 33-2 (1.65 g, 6.97 mmol) were dissolved in a mixed solvent of dioxane (10 mL) and water (3 mL), and 1,1-bis(tert-butylphosphine)ferrocenepalladium chloride (227.13 mg, 348.49 μmol) and potassium carbonate (1.44 g, 10.45 mmol) were added under nitrogen protection. The reaction solution was stirred at 80 °C for 16 h. Then the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (190 mg) was obtained by purification on a silica gel column.

[0832] MS m / z (ESI): 338.9 [M+H] +

[0833] Step 2: Synthesis of tert-butyl ((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4- yl)methyl)carbamate (intermediate 33-4)

[0834] Intermediate 33-3 (190 mg, 563 μmol) and pinacol diboronic acid (214.62 mg, 845.17 μmol) were dissolved in dioxane (5 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (46.01 mg, 56.34 μmol) and potassium acetate (165.89 mg, 1.69 mmol) were added under nitrogen protection. The reaction solution was stirred at 90 °C for 1 h. Then the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (200 mg) was obtained.

[0835] MS m / z (ESI): 385.2 [M+H] +

[0836] Step 3: Synthesis of 1-(4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)- 3-fluoro-2,2-dimethylpropan-1-ol (intermediate 33-5)

[0837] Intermediate 16-3 (160 mg, 369 μmol) was dissolved in isopropanol (5 mL), and sodium borohydride (279.42 mg, 7.39 mmol) was added at 0 °C under nitrogen atmosphere. The reaction solution was stirred at 25 °C for 48 h. Then the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The title compound (170 mg) was obtained.

[0838] LCMS (m / z): 437.0 [M+H] +

[0839] Step 5: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(3-fluoro-1- hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)quinolin-4- yl)methyl)carbamate (Intermediate 33-6)

[0840] Intermediate 33-5 (90.62 mg, 208.18 μmol) and Intermediate 33-4 (80 mg, 208.18 μmol) were dissolved in a mixed solvent of dioxane (2 mL) and water (0.6 mL), and 1,1-bis(tert-butylphosphino)ferrocene palladium chloride (13.57 mg, 20.82 μmol) and potassium carbonate (57.54 mg, 416.37 μmol) were added under nitrogen protection. The reaction solution was stirred at 90 °C for 1 h. Then the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (120 mg).

[0841] MS m / z (ESI): 613.3 [M+H] +

[0842] 1 H NMR (400 MHz, DMSO-d6) d = 8.98 - 8.78 (m, 1H), 8.23 - 8.02 (m, 1H), 7.97 - 7.74 (m, 1H), 7.71 - 7.46 (m, 2H), 7.44 - 7.33 (m, 1H), 7.02 - 6.74 (m, 1H), 4.67 (d, J = 7.0 Hz, 1H), 4.35 - 4.02 (m, 2H), 3.93 (s, 2H), 3.58 - 3.50 (m, 2H), 2.21 - 2.16 (m, 1H), 1.40 (d, J = 13.2 Hz, 6H), 1.37 - 1.34 (m, 3H), 1.16 (s, 3H), 1.07 (s, 12H).

[0843] Step 6: Synthesis of 1-(4-(2-(6-(4-(aminomethyl)quinolin-6-yl)-2,3-difluorophenoxy)ethyl)- 1,5-dimethyl-1H-pyrazol-3-yl)-3-fluoro-2,2-dimethylpropan-1-ol (Compound 33)

[0844] Intermediate 33-6 (120 mg, 195.86 pmol) was dissolved in a solution of HCI in dioxane (2 M, 5 mL) and the reaction was stirred at 25 °C for 1 h. The reaction was then directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: 41-WePure Biotech XP tC18 150 x 40 mm, 7 pm; mobile phase: [A: water (0.05% ammonia water + 10 mM sodium bicarbonate), B: acetonitrile]; B%: 28% - 68%, 9 min) to give the title compound (17.6 mg).

[0845] LC-MS: m / z (ESI): 513.3 [M+H] + .

[0846] 1 H NMR (400 MHz, Methanol-d4) d = 8.88 (d, J = 3.8 Hz, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.67 (s, 1H), 7.39 - 7.29 (m, 1H), 7.17 (q, J = 8.7 Hz, 1H), 4.46 (s, 1H), 4.38 (s, 2H), 4.29 - 4.11 (m, 1H), 4.05 - 3.81 (m, 3H), 3.55 (s, 3H), 2.83 - 2.62 (m, 2H), 1.86 (s, 3H), 0.82 (s, 3H), 0.75 - 0.69 (m, 3H)

[0847] Example 34, Synthesis of 6-(2-(2-(1,5-dimethyl-3-neopentyl-1 H-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)-1 -methyl-4-((methylamino)methyl)quinolin-2(1 H)-one (Compound 34)

[0848] Step 1 : Synthesis of tert-butyl methyl((1 -methyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2-dihydroquinolin-4-yl)methyl)carbamate (Intermediate 34-1 )

[0849] To a mixture of Intermediate 26-1 (50 mg, 131 pmol), bis(pinacolato)diboron (66 mg, 262 pmol), potassium acetate (288 mg, 293 pmol), dioxane (1 mL) was added Pd(dppf)CI2(9 mg, 12 pmol) at room temperature under nitrogen atmosphere and the reaction was stirred at 90 °C for 2 h. The solvent was removed by concentration under reduced pressure to give the title compound (56 mg).

[0850] LC-MS: m / z (ESI): 429.3 [M+H] +

[0851] Step 2: Synthesis of tert-butyl (6-(2-(2-(l,5-dimethyl-3-neopentyl-lH-pyrazol-4- yl)ethoxy)-3,4-difluorophenyl)-l-methyl-2-oxo-l,2-dihydroquinolin-4-yl)methyl)(methyl) carbamate (Intermediate 34-2)

[0852] To a mixture of Intermediate 34-1 (43 mg, 100 pmol), Intermediate 20-3 (27 mg, 67 pmol), potassium carbonate (18 mg, 134 pmol), dioxane (1 mL), water (0.2 mL) was added Pd(dppf)Cl2(5 mg, 6.73 pmol) under nitrogen atmosphere. The reaction was stirred at 90 °C for 2 h. Then water (10 mL) was added, extracted with ethyl acetate (5 mL*3), combined organic phase, concentrated to dryness under reduced pressure to give the title compound (41 mg).

[0853] LC-MS: m / z (ESI): 623.1 [M+H] +

[0854] Step 3: Synthesis of 6-(2-(2-(l,5-dimethyl-3-neopentyl-lH-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)-l-methyl-4-((methylamino)methyl)quinolin-2(lH)-one (Compound 34)

[0855] To a mixture of Intermediate 34-2 (41 mg, 66 pmol) was added HCl in dioxane (2 M, 2 mL) under argon atmosphere. The reaction was stirred at room temperature for 1 h. Then the solvent was removed under reduced pressure, the residue was directly purified by high performance liquid chromatography (column: 41-WePure Biotech XP tC18 150*40mm, 7pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 10%-50%, 9min) to give the title compound (6.4 mg).

[0856] LC-MS: m / z (ESI): 523.4 [M+H] +

[0857] 1H NMR (400 MHz, CD3OD) 7.92 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.28 (t, J = 6.4 Hz, 1H), 7.20-7.10 (m, 1H), 6.82 (s, 1H), 4.21 (s, 2H), 3.89-3.75 (m, 5H), 3.60 (s, 3H), 2.74-2.62 (m, 5H), 2.14 (s, 2H), 2.01 (s, 3H), 0.75 (s, 9H).

[0858] Example 35, Synthesis of (6-(3,4-difluoro-2-(2-(3-(1-hydroxycyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-4-((methylamino)methyl)quinolin-2(1H)-one (Compound 35)

[0859] Step 1: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(1-(methoxymethoxy) cyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-2-oxo-1,2- dihydroquinolin-4-yl)methyl)(methyl)carbamate (Intermediate 35-1)

[0860] To a mixture of Intermediate 34-1 (56 mg, 131 µmol), Intermediate 25-2 (50 mg, 112 µmol), potassium carbonate (31 mg, 224 µmol), dioxane (1 mL), water (0.2 mL) was added Pd-118 (7 mg, 11 µmol) under nitrogen atmosphere. The reaction was stirred at 90 °C for 2 h. Then water (10 mL) was added and extracted with ethyl acetate (5 mL*3). The organic phase was combined and concentrated to dryness under reduced pressure to give the title compound (74 mg).

[0861] LC-MS: m / z (ESI): 667.4 [M+H] +

[0862] Step 2: Synthesis of (6-(3,4-difluoro-2-(2-(3-(1-(methoxymethoxyhydroxy)cyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-2-oxo-4-((methylamino)methyl)quinolin-2(1H)-one (Compound 35)

[0863] To intermediate 35-1 (70 mg, 105 pmol) was added HC1 in dioxane (2 M, 2 mL) under argon atmosphere and the resulting mixture was stirred at rt for 1 h. After that, the solvent was removed by concentration under reduced pressure and the residue was directly purified by high performance liquid chromatography (column: 41-We Pure Biotech XP tC18 150 x 40 mm, 7 pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 4% - 44%, 10 min) to give the title compound (5.7 mg).

[0864] LC-MS: m / z (ESI): 523.3 [M+H] +

[0865] 1 H NMR (400 MHz, DMSO-d6) d = 7.93 (d, J = 1.8 Hz, 1H), 7.71 (dd, J = 1.9, 8.7 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.34 - 7.25 (m, 2H), 6.69 (s, 1H), 3.93 (s, 2H), 3.84 (t, J = 7.7 Hz, 2H), 3.67 (s, 3H), 3.56 (s, 3H), 2.67 (t, J = 7.7 Hz, 2H), 2.46 - 2.43 (m, 1H), 2.37 (s, 3H), 2.35 - 2.26 (m, 3H), 2.05 - 1.95 (m, 2H), 1.87 (s, 3H), 1.66 - 1.55 (m, 1H), 1.41 - 1.29 (m, 1H).

[0866] Example 36, 1-(6-(2-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4-yl)ethoxy)-4- fluorophenyl)quinolin-4-yl)-N-methylmethanamine

[0867] Step 1: Synthesis of 4-(2-(2-bromo-5-fluorophenoxy)ethyl)-1,5-dimethyl-3- neopentyl-1H-pyrazole (Intermediate 36-1)

[0868] A mixture of intermediate 20-2 (80 mg, 0.38 mmol), 2-bromo-5-fluorophenol (360 mg, 1.89 mmol), CMBP (277 mg, 1.15 mmol) and toluene (2 mL) was heated to 120 °C under argon atmosphere for 5 h. The solvent was removed by concentration under reduced pressure and the resulting concentrate was directly purified by silica gel column chromatography (THF / PE, 0-40%) to give the title compound (85 mg).

[0869] LC-MS: m / z (ESI): 383.4 [M+H]+ .

[0870] Step 2: Synthesis of tert-butyl ((6-(2-(2-(l,5-dimethyl-3-neopentyl-lH-pyrazol-4- yl)ethoxy)-4-fluorophenyl)quinolin-4-yl)methyl)(methyl)carbamate (Intermediate 36-2)

[0871] A mixture of Intermediate 36-1 (85 mg, 0.22 mmol), Intermediate 14-9 (106 mg, 0.27 mmol), Pd(dppf)Cl2(17 mg, 0.02 mmol), potassium carbonate (158 mg, 0.68 mmol), 1,4-dioxane (2 mL) and water (0.3 mL) was heated to 100 °C and stirred for 1 h at room temperature. The solvent was removed by concentration under reduced pressure, and the residue was directly purified by column chromatography on silica gel (THF / PE, 0-60%) to give the title compound (75 mg).

[0872] LC-MS: m / z (ESI): 575.6 [M+H] +

[0873] Step 3: Synthesis of l-(6-(2-(2-(l,5-dimethyl-3-neopentyl-lH-pyrazol-4-yl)ethoxy)-4- fluorophenyl)quinolin-4-yl)-N-methylmethanamine (Compound 36)

[0874] Intermediate 36-2 (75 mg, 0.13 mmol) was added into a 25 mL reaction vial, and a mixed solvent of DCM and TFA (2 mL, volume ratio 5: 1) was added. The system was stirred at room temperature for 1 h. Then, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative liquid chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40%-80%, elution for 10 min) to give the title compound (26.57 mg).

[0875] LC-MS: m / z (ESI): 475.3 [M+H] + .

[0876] 1H NMR (400 MHz, DMSO-d6): δ 8.86 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.83-7.78 (m, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.50-7.44 (m, 1H), 7.08-7.03 (m, 1H), 6.94-6.88 (m, 1H), 4.25 (s, 2H), 4.04-3.99 (m, 2H), 3.55 (s, 3H), 2.74-2.67 (m, 2H), 2.44 (s, 3H), 2.14 (s, 2H), 1.92 (s, 3H), 0.80 (s, 9H).

[0877] Example 37, (6-(2-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)quinolin-4-yl)methanamine (Compound 37)

[0878] Step 1: Synthesis of tert-butyl (6-(2-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4- yl)ethoxy)-3,4-difluorophenyl)quinolin-4-yl)methyl)carbamate (Intermediate 37-1)

[0879] Intermediate 20-3 (90 mg, 234 μmol) and Intermediate 33-4 (94 mg, 234 μmol) were dissolved in dioxane (0.8 mL) and water (0.2 mL), 1,1-bis(tert-butylphosphine) ferrocenepalladium chloride (7.63 mg, 11.7 μmol) and potassium carbonate (65 mg, 468 μmol) were added under nitrogen atmosphere, and the reaction was stirred at 90 °C for 1 h. Then the reaction was diluted with water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (130 mg).

[0880] MS m / z (ESI): 579.4 [M+H] +

[0881] Step 2: Synthesis of (6-(2-(2-(1,5-dimethyl-3-neopentyl-1H-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)quinolin-4-yl)methanamine (Compound 37)

[0882] Intermediate 37-1 (130 mg, 224 pmol) was dissolved in HC1 / dioxane (2 M, 5 mL) and the reaction was stirred at 25 °C for 2 h. The reaction was then concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: 41-WePure Biotech XP tC18 150 x 40 mm, 7 pm; mobile phase: [A: water (0.05% ammonia water + 10 mM sodium bicarbonate), B: acetonitrile]; B%: 37% - 77%, 9 min) to give the title compound (15.5 mg).

[0883] LC-MS: m / z (ESI): 479.3 [M+H] + .

[0884] 1 H NMR (400 MHz, CD3OD) d = 8.88 (d, J = 4.0 Hz, 1H), 8.15 (s, 1H), 8.11-7.85 (m, 2H), 7.67 (d, J = 3.4 Hz, 1H), 7.32 (t, J = 6.4 Hz, 1H), 7.16 (q, J = 8.7 Hz, 1H), 4.35 (s, 2H), 3.83 (t, J = 7.0 Hz, 2H), 3.54 (s, 3H), 2.64 (t, J = 7.1 Hz, 2H), 2.14 (s, 2H), 1.88 (s, 3H), 0.73 (s, 9H)

[0885] Example 38, 1-(4-(2-(6-(7-cyclopropyl-3-((methylamino)methyl)pyrazolo[1,5- a]pyridin-5-yl)-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)cyclobutan-1- ol (Compound 38)

[0886] Step 1: Synthesis of tert-butyl (7-cyclopropyl-5-(3,4-difluoro-2-(2-(3-(1- (methoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)pyrazolo[1,5- a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 38-1)

[0887] Intermediate 25-2 (29.61 mg, 116 pmol) and Intermediate 30-7 (50 mg, 116 pmol) were dissolved in toluene (1 mL) and under a nitrogen atmosphere, cyanomethylene tri-n-butylphosphonium (56.67 mg, 232 pmol) was added and the reaction was stirred at 100 °C for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash silica gel column chromatography (eluent: DCM / MeOH, 99:1 to 97:3) to give the title compound (50 mg). 12g Flash column chromatography, eluent: 0-40% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min) purification afforded the title compound (45 mg).

[0888] LC-MS: m / z (ESI): 666.6 [M+H] +

[0889] Step 2: Synthesis of 1-(4-(2-(2,3-difluoro-6-(7-methoxy-3-((methylamino)methyl)pyrazolo[1,5- a]pyridin-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)cyclobutan-1-ol (Compound 39)

[0890] Intermediate 38-1 (45 mg, 68 μmol) was dissolved in HCl in dioxane (2 M, 1 mL) and the reaction was stirred at 25 °C for 1 h. The reaction was then directly concentrated to dryness under reduced pressure and the residue was purified by high performance liquid chromatography (column: Biotech-XP C18 150*40 mm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 22%-62%, 9 min) to afford the title compound (6.2 mg).

[0891] LC-MS: m / z (ESI): 522.3 [M+H] +

[0892] 1 H NMR (400 MHz, DMSO-d6) d = 8.35 (s, 1H), 8.11 (s, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.33-7.25 (m, 2H), 6.71 (d, J = 1.2 Hz, 1H), 4.10 (s, 2H), 3.92 (s, 3H), 3.54 (s, 3H), 2.75-2.66 (m, 3H), 2.42 (s, 3H), 2.39-2.31 (m, 3H), 2.04-1.98 (m, 2H), 1.84 (s, 3H), 1.67-1.55 (m, 1H), 1.44-1.34 (m, 1H), 1.19-1.12 (m, 2H), 0.99-0.93 (m, 2H).

[0893] Example 39, 1-(4-(2-(2,3-difluoro-6-(7-methoxy-3-((methylamino)methyl)pyrazolo[1,5- a]pyridin-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)cyclobutan-1-ol (Compound 39)

[0894] Step 1: Synthesis of tert-butyl ((5-(3,4-difluoro-2-(2-(3-(1-(methoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-7- methoxypyrazolo[1,5-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 39-1)

[0895] Intermediate 31-6 (50 mg, 119 μmol) and Intermediate 25-2 (30.32 mg, 119 μmol) were dissolved in toluene (1 mL), and cyanomethylidene tri-n-butylphosphonium (58.02 mg, 238 μmol) was added under nitrogen atmosphere. The reaction was stirred at 100 °C for 3 h. The solvent was removed by concentration under reduced pressure, and the residue was purified by flash silica gel column (eluent 0-60% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min) to give the title compound (45 mg). 12g Flash silica gel column, eluent 0-60% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min.

[0896] LC-MS: m / z (ESI): 656.5 [M+H] +

[0897] Step 2: Synthesis of 1-(4-(2-(2,3-difluoro-6-(7-methoxy-3-((methylamino)methyl)pyrazolo[1,5- a]pyridin-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)cyclobutan-1-ol (Compound 39)

[0898] Intermediate 39-1 (45 mg, 68 μmol) was dissolved in hydrochloric acid dioxane (2 M, 1 mL), and the reaction was stirred at 25 °C for 1 h. The reaction was then directly concentrated to dryness under reduced pressure, and the residue was purified by high performance liquid chromatography (column: Biotech-XP C18 150*40 mm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 16%-56%, 9 min) to give the title compound (7.2 mg).

[0899] LC-MS: m / z (ESI): 512.3 [M+H] +

[0900] 1H NMR (400 MHz, DMSO-d6) d = 8.34 (s, 1H), 8.05 (s, 1H), 7.53 (s, 1H), 7.40-7.25 (m, 2H), 6.47 (s, 1H), 4.09 (s, 3H), 4.06 (s, 2H), 3.96 (t, J = 7.6 Hz, 3H), 3.53 (s, 3H), 2.73 (t, J = 7.7 Hz, 2H), 2.41-2.33 (m, 5H), 2.06-1.95 (m, 2H), 1.83 (s, 3H), 1.66-1.54 (m, 1H), 1.45-1.32 (m, 1H)

[0901] Example 40, 1-(4-(2-(6-(4-((dimethylamino)methyl)quinolin-6-yl)-2,3- difluorophenoxy)ethyl)-1,5-dimethyl-1 H-pyrazol-3-yl)-2,2-dimethylpropan-1 -ol

[0902] Step 1 : Synthesis of 1-(6-bromoquinolin-4-yl)-N,N-dimethylmethanamine (Intermediate 40-1)

[0903] Intermediate 4-3 (500 mg, 1.99 mmol) was dissolved in MeOH (10 mL), aqueous formaldehyde (0.5 mL, 36-38% mass fraction), AcOH (24 mg, 0.4 mmol), NaBH3CN (375 mg, 5.97 mmol) were added. The reaction was stirred at 20 °C for 16 h under nitrogen protection. Then water (25 mL) was added to the reaction, and extracted with EtOAc (15 mL) for three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give the title compound (330 mg).

[0904] LC-MS: m / z (ESI): 265.0 [M+H] +

[0905] Step 2: Synthesis of 6-(4-((dimethylamino)methyl)quinolin-6-yl)-2,3- difluorophenol (Intermediate 40-2)

[0906] Intermediate 40-1 (300 mg, 1.13 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), (3,4-difluoro-2-hydroxyphenyl)boronic acid (236 mg, 1.36 mmol), potassium carbonate (469 mg, 3.39 mmol), Pd(dppf)Cl2(165 mg, 0.026 mmol) were added. The reaction was stirred at 90 °C for 16 h under nitrogen atmosphere. The reaction was diluted with water (25 mL) and extracted with ethyl acetate (15 mL) for 3 times. The combined organic phase was washed with saturated brine, dried over sodium sulfate, concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give the title compound (200 mg).

[0907] LC-MS: m / z (ESI): 315.2 [M+H] +

[0908] Step 3: Synthesis of 1-(4-(2-(6-(4-((dimethylamino)methyl)quinolin-6-yl)-2,3- difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-one (Intermediate 40-3)

[0909] Intermediate 40-2 (80 mg, 0.025 mmol) was dissolved in 1,4-dioxane (5 mL), Intermediate 1-1 (57 mg, 0.025 mmol), diethyl azodicarboxylate (DEAD, 110 mg, 0.063 mmol), triphenylphosphine (133 mg, 0.051 mmol) were added. The reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography on C18 (H2O / MeCN = 40 / 60) to give the title compound (30 mg).

[0910] LC-MS: m / z (ESI): 521.2 [M+H] +

[0911] Step 4: Synthesis of 1-(4-(2-(6-(4-((dimethylamino)methyl)quinolin-6-yl)-2,3- difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 40)

[0912] Intermediate 40-3 (30 mg, 57.6 μmol) was dissolved in MeOH (5 mL), cooled to 0 °C, and NaBH4(6.5 mg, 173 μmol) was added. The reaction was stirred for 1 h. The reaction was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in DMF and purified by preparative liquid chromatography (column: Prime C18, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 10%-30%, elution 13.5 min) to give the title compound (4.4 mg).

[0913] LC-MS: m / z (ESI): 544.9 [M+Na] + .

[0914] 1 H NMR (400 MHz, DMSO-d6): δ 8.87 (d, J = 4.4 Hz, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.8, 2.0 Hz, 1H), 7.51 (d, J = 4.4 Hz, 1H), 7.39-7.29 (m, 2H), 4.58 (d, J = 5.2 Hz, 1H), 4.03 (d, J = 5.1 Hz, 1H), 3.92-3.75 (m, 4H), 3.50 (s, 3H), 2.79-2.56 (m, 2H), 2.23 (s, 6H), 1.74 (s, 3H), 0.72 (s, 9H).

[0915] Example 41, 1-(4-(2-(2,3-difluoro-6-(8-((methylamino)methyl)naphthalen-2-yl)phenoxy)ethyl)- 1,5-dimethyl-1H-pyrazol-3-yl)cyclobutan-1-ol (Compound 41)

[0916] Step 1: Synthesis of tert-butyl ((7-(3,4-difluoro-2-(2-(3-(1- (methoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)naphthalen-1- yl)methyl)(methyl)carbamate (Intermediate 41-1)

[0917] Intermediate 11-5 (44.6 mg, 112 μmol) and intermediate 25-2 (25 mg, 56 μmol) were dissolved in dioxane (1 mL) and water (0.25 mL), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (2.1 mg, 2.8 μmol) and potassium carbonate (23.3 mg, 168 μmol) were added under nitrogen atmosphere. The reaction was stirred at 90 °C for 1 h under nitrogen protection. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate. After being concentrated to dryness under reduced pressure, the residue was purified by flash silica gel column (eluent 0-30% tetrahydrofuran / n-hexane, gradient @ 45 mL / min) to give the title compound (27.5 mg). 4g Flash silica gel column, eluent 0-30% tetrahydrofuran / n-hexane, gradient @ 45 mL / min.

[0918] MS m / z (ESI): 636.6 [M+H] +

[0919] Step 2: Synthesis of 1-(4-(2-(2,3-difluoro-6-(8-((methylamino)methyl)naphthalen-2- yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)cyclobutan-1-ol (Compound 41)

[0920] Intermediate 41-1 (27.5 mg, 43.3 μmol) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.33 mL), and the reaction was stirred at 25 °C for 1 h. The reaction was then directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: C18 150*40 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 13%-43%, 11 min) to give the title compound (4.1 mg).

[0921] LC-MS: m / z (ESI): 492.1 [M+H] +

[0922] 1H NMR (400 MHz, CD3OD) d = 8.52 (s, 1H), 8.07 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.73-7.66 (m, 1H), 7.66-7.57 (m, 2H), 7.32-7.28 (m, 1H), 7.18-7.07 (m, 1H), 4.59 (s, 2H), 3.96 (t, J = 6.9 Hz, 2H), 3.42 (s, 3H), 2.77 (s, 3H), 2.76-2.70 (m, 2H), 2.50-2.36 (m, 2H), 2.17-2.05 (m, 2H), 1.82-1.67 (m, 4H), 1.54-1.37 (m, 1H)

[0923] Example 42, 3-(4-(2-(6-(4-((dimethylamino)methyl)quinolin-6-yl)-2,3- difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 42)

[0924] Step 1: Synthesis of 3-(chloromethyl)-1,5-dimethyl-1H-pyrazole (Intermediate 42-2)

[0925] Compound 42-1 (9.0 g, 71.4 mmol) was put into a 250 mL reaction flask, dichloromethane (100 mL) was added and cooled to 0 °C, then SOCl2 (25.5 g, 214.3 mmol) was added to the system, 25 °C for 1 h. The reaction solution was concentrated to dryness under reduced pressure to give the title compound (10 g).

[0926] LC-MS: m / z (ESI): 145.2 [M+H] + .

[0927] Step 2: Synthesis of methyl 3-(1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropanoate (Intermediate 42-3)

[0928] Methyl isobutyrate (8.5 g, 83.3 mmol) was put into a 250 mL reaction flask, THF (100 mL) was added, and cooled to -78 °C under nitrogen protection, then LDA (48.6 mL, 2.0 M) was added, the system was reacted at -78 °C for 0.5 h, then intermediate 42-2 (4.0 g, 27.7 mmol) was added, the system was reacted at -78 °C for 2 h. Quench with saturated ammonium chloride, extract 3 times with EA (200 mL). The organic phases were combined and concentrated, and the residue was subjected to flash column chromatography (petroleum ether / ethyl acetate = 0-50%) to give the title compound (3.3 g).

[0929] LC-MS: m / z (ESI): 211.4 [M+H] + .

[0930] Step 3: Synthesis of 3-(1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Intermediate 42-4)

[0931] Intermediate 42-3 (990 mg, 4.7 mmol) was placed into a 100 mL reaction flask, THF (10 mL) was added and stirred to dissolve. It was cooled to 0 °C, then LiAlH4(535.8 mg, 14.1 mmol) was added, and reacted at 0 °C for 1 h. The reaction was quenched with water and 10% aqueous sodium hydroxide solution, filtered, and the filtrate was concentrated to give the title compound (730 mg).

[0932] LC-MS: m / z (ESI): 183.3 [M+H] + .

[0933] Step 4: Synthesis of 3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazole (Intermediate 42-5)

[0934] Intermediate 42-4 (730.0 mg, 4.0 mmol) was placed into a 100 mL reaction flask, DMF (10 mL) was added and stirred to dissolve, then tert-butyldiphenylsilyl chloride (TBDPSCl) (1.6 g, 6.0 mmol) and imidazole (544 mg, 8.0 mmol) were added. It was reacted at 25 °C for 2 h. The reaction solution was poured into water (150 mL), extracted with EA (100 mL) for 3 times. The organic phases were combined, the solvent was removed by reduced pressure concentration, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-30%) to give the title compound (1.5 g).

[0935] LC-MS: m / z (ESI): 421.4 [M+H] + .

[0936] Step 5: Synthesis of 3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-4-iodo-1,5-dimethyl-1H-pyrazole (Intermediate 42-6)

[0937] Into a 100 mL reaction vial, was placed intermediate 42-5 (1.3 g, 3.1 mmol), dissolved in acetonitrile (10 mL), followed by the addition of NIS (1.1 g, 4.6 mmol), and allowed to react at 25 °C for 2 h. The reaction was poured into water (100 mL) and extracted with EA (100 mL) three times. The organic phases were combined and concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-20%) to give the title compound (1.5 g).

[0938] LC-MS: m / z (ESI): 547.2 [M+H] + .

[0939] Step 6: Synthesis of 3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1,5- dimethyl-4-vinyl-1H-pyrazole (intermediate 42-7)

[0940] Into a 100 mL reaction vial, was placed intermediate 42-6 (1.3 g, 2.4 mmol), dissolved in toluene (20 mL), followed by the addition of tributylvinyltin (1.5 g, 4.8 mmol) and Pd(PPh3)4 (277 mg, 0.24 mmol), and allowed to react at 110 °C for 12 h. The reaction was directly concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0-20%) to give the title compound (1.1 g).

[0941] LC-MS: m / z (ESI): 447.4 [M+H] + .

[0942] Step 7: Synthesis of 2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1,5- dimethyl-1H-pyrazol-4-yl)acetaldehyde (intermediate 42-8)

[0943] Into a 100 mL reaction vial, was placed intermediate 42-7 (1.0 g, 2.2 mmol), dissolved in ACN (10 mL), followed by the addition of PhI(OAc)2 (760 mg, 2.3 mmol), and the temperature was lowered to -40 °C, followed by the dropwise addition of 5% H2SO4 (0.4 mL). The reaction was allowed to react at -40 °C for 2 h. The reaction was poured into saturated aqueous sodium bicarbonate solution (100 mL) and extracted with EA (100 mL) three times. The organic phases were combined and concentrated under reduced pressure to dryness to give the title compound (0.8 g).

[0944] LC-MS: m / z (ESI): 463.2 [M+H] + .

[0945] Step 8: Synthesis of 2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)- 1,5-dimethyl-1H-pyrazol-4-yl)ethan-1-ol (Intermediate 42-9)

[0946] Intermediate 42-8 (1.4 g, 3.0 mmol) was charged into a 100 mL reaction flask, EtOH (20 mL) was added, followed by NaBH4(228.0 mg, 6.0 mmol). The reaction was stirred at 0 °C for 1 h. The reaction was poured into saturated aqueous ammonium chloride solution (100 mL) and extracted with EA (100 mL) for 3 times. The organic phase was combined and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 0-50%) to give the title compound (600 mg).

[0947] LC-MS: m / z (ESI): 465.5 [M+H] + .

[0948] Step 9: Synthesis of 1-(6-(2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)- 1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)quinolin-4-yl)-N,N- dimethylmethanamine (Intermediate 42-10)

[0949] Intermediate 42-9 (140.0 mg, 0.3 mmol) was charged into a 100 mL reaction flask, toluene (5 mL) was added, followed by Intermediate 40-2 (95 mg, 0.3 mmol), CMBP (723 mg, 3 mmol). The reaction was stirred at 110 °C for 12 h under nitrogen atmosphere. The reaction was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 0-70%) to give the title compound (80 mg).

[0950] LC-MS: m / z (ESI): 761.6 [M+H] + .

[0951] Step 10: Synthesis of 3-(4-(2-(6-(4-((dimethylamino)methyl)quinolin-6-yl)-2,3- difluorophenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Compound 42)

[0952] Intermediate 42-10 (70.0 mg, 0.1 mmol) was charged into a 25 mL reaction vial, DMF (2 mL) was added, then CsF (76.0 mg, 0.5 mmol) was added, and the reaction was stirred at 80 °C for 12 h under nitrogen atmosphere. The reaction was filtered, and the filtrate was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 40%-80%, elution 10 min) to give the title compound (2.24 mg).

[0953] LC-MS: m / z (ESI): 523.2 [M+H] + .

[0954] 1 H NMR (400 MHz, CD3OD): δ 8.85 (d, J = 4.4 Hz, 1H), 8.35 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.88-7.82 (m, 1H), 7.58 (d, J = 4.4 Hz, 1H), 7.37-7.26 (m, 1H), 7.20-7.10 (m, 1H), 3.99 (s, 2H), 3.82 (d, J = 7.2 Hz, 1H), 3.54 (s, 3H), 3.10 (s, 2H), 2.66 (d, J = 7.2 Hz, 1H), 2.37 (s, 6H), 2.21 (s, 2H), 1.84 (s, 3H), 0.67 (s, 6H).

[0955] Example 43, Synthesis of 6-(3,4-difluoro-2-(2-(3-(1-hydroxycyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-4-((dimethylamino)methyl)-1-(2-hydroxyethyl)quinolin-2(1H)-one (Compound 43)

[0956] Step 1: Synthesis of 6-bromo-4-(((2,4-dimethoxybenzyl)(methyl)amino)methyl)-1-(2-hydroxyethyl)quinolin-2(1H)-one (Intermediate 43-1)

[0957] Intermediate 17-4 (1 g, 2.4 mmol) was dissolved in DMF (10 mL), and cesium carbonate (2.34 g, 7.19 mmol) and oxirane (4.79 mmol, 3 M in tetrahydrofuran, 1.6 mL) were added under nitrogen atmosphere. The reaction was warmed to 70 °C for 20 h. The reaction was then diluted with ethyl acetate (50 mL) and washed with water (15 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: 52-Welch Xtimate C18 150 x 30 mm, 5 µm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 65% - 95%, 10 min) to give the title compound (450 mg)

[0958] LC-MS: m / z (ESI): 461.1 / 463.1 [M+H] +

[0959] Step 2: Synthesis of 6-bromo-1-(2-hydroxyethyl)-4-((methylamino)methyl)quinolin- 2(1H)-one (Intermediate 43-2)

[0960] Intermediate 43-1 (400 mg, 867 µmol) was dissolved in TFA (5 mL) and stirred at 80 °C for 2 h. The reaction was then concentrated to dryness to give the title compound (269.8 mg).

[0961] LC-MS: m / z (ESI): 311.0 [M+H] +

[0962] Step 3: Synthesis of 6-bromo-4-((dimethylamino)methyl)-1-(2-hydroxyethyl)quinolin- 2(1H)-one (Intermediate 43-3)

[0963] Intermediate 43-2 (269.8 mg, 867.0 µmol) was dissolved in methanol (10 mL), and triethylamine (526 mg, 5.20 mmol) and 37% aqueous formaldehyde solution (1.06 g, 13 mmol) were added. The mixture was stirred at 25 °C for 10 min, and then sodium cyanoborohydride (980 mg, 15.6 mmol) was added. The reaction was stirred at 25 °C for 1 h. The reaction was then directly purified by high performance liquid chromatography (column: 56-Boston Green ODS 150 x 30 mm, 5 µm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 12% - 52%, 9 min) to give the title compound (74 mg).

[0964] LC-MS: m / z (ESI): 325.1 / 327.1 [M+H]+

[0965] Step 4, Synthesis of 4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-3-(1- (ethoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazole (Intermediate 43-4)

[0966] The same as the synthesis of Intermediate 25-2, but bromomethyl methyl ether was replaced by chloromethyl ethyl ether in the route to give Intermediate 43-4.

[0967] LCMS (m / z): 461.0 [M+H] +

[0968] Step 5: Synthesis of 4-(2-(2,3-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)ethyl)-3-(1-(ethoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazole (Intermediate 43-5)

[0969] Intermediate 43-4 (100 mg, 218 µmol) and pinacol diboronic acid (110 mg, 435 µmol) were dissolved in dioxane (2 mL), and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (15.9 mg, 21.8 µmol) and potassium acetate (42.7 mg, 435 µmol) were added under nitrogen atmosphere. The reaction solution was stirred at 100 °C for 3 h. Then the reaction solution was diluted with ethyl acetate (30 mL) and washed with water (15 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column (12 g) eluting with 0-35% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min) to give the title compound (70 mg). 12g flash silica gel column, eluting with 0-35% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min).

[0970] LC-MS: m / z (ESI): 507.2 [M+H] +

[0971] Step 6: Synthesis of 4-((dimethylamino)methyl)-6-(2-(2-(3-(1- (ethoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)-1-(2-hydroxyethyl)quinolin-2(1H)-one (Intermediate 43-6)

[0972] To a mixture of intermediate 43-3 (12 mg, 37 pmol), intermediate 43-5 (56 mg, 0.11 mmol), potassium carbonate (10 mg, 74 pmol), 1,4-dioxane (1 mL), water (0.2 mL) was added Pd-118 (3 mg, 4.61 pmol) at room temperature under nitrogen atmosphere, the resulting mixture was stirred at 90 °C for 2 h. Then the mixture was added water (10 mL), extracted with ethyl acetate (5 mL*3), the organic phase was concentrated to dryness under reduced pressure to give the title compound (23 mg).

[0973] LC-MS: m / z (ESI): 625.4 [M+H] +

[0974] Step 7: Synthesis of 6-(3,4-difluoro-2-(2-(3-(1-hydroxycyclobutyl)-1,5-dimethyl-1H- pyrazol-4-yl)ethoxy)phenyl)-4-((dimethylamino)methyl)-1-(2-hydroxyethyl)quinolin- 2(1H)-one (Compound 43)

[0975] To a mixture of intermediate 43-6 (23 mg, 37 pmol) was added hydrochloric acid (2 M in dioxane, 2 mL) at room temperature under nitrogen atmosphere, the resulting mixture was stirred at room temperature for 1 h. Then the mixture was concentrated to remove the solvent and directly purified by high performance liquid chromatography (column: 41-WePure Biotech XP tC18 150*40 mm, 7 pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 16%-46%, 10 min) to give the title compound (8.4 mg).

[0976] LC-MS: m / z (ESI): 567.4 [M+H] +

[0977] 1 H NMR (400 MHz, DMSO-d6) d = 8.19-8.03 (m, 1H), 7.75-7.61 (m, 2H), 7.33-7.21 (m, 2H), 6.63 (s, 1H), 5.14 (s, 1H), 4.97 (s, 1H), 4.36 (t, J = 6.4 Hz, 2H), 3.84 (t, J = 7.4 Hz, 2H), 3.68 (s, 2H), 3.60 (s, 2H), 3.56 (s, 3H), 2.69 (t, J = 7.5 Hz, 2H), 2.35-2.28 (m, 2H), 2.22 (s, 6H), 2.00 (d, J = 10.6 Hz, 2H), 1.88-1.79 (m, 3H), 1.66-1.53 (m, 1H), 1.40-1.28 (m, 1H)

[0978] Example 44. Synthesis of l-cyclopropyl-6-(3,4-difluoro-2-(2-(3-(l- hydroxycyclobutyl)-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)-4-((methylamino)methyl)quinolin- 2(lH)-one (Compound 44)

[0979] Step 1: Synthesis of tert-butyl ((6-bromo-l-cyclopropyl-2-oxo-l,2-dihydroquinolin-4- yl)methyl)(methyl)carbamate (Intermediate 44-1)

[0980] To a mixture of Intermediate 17-6 (50 mg, 136 μmol), copper acetate (54 mg, 272 μmol), cyclopropylboronic acid (23 mg, 272 μmol), triethylamine (27 mg, 272 μmol), pyridine (22 mg, 272 μmol), 1,2-dichloroethane (1 mL) was added 4A molecular sieves (20 mg) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 16 h. After filtration, the filtrate was concentrated under reduced pressure to remove the solvent. The residue was directly purified by column chromatography on silica gel (THF / PE, 0-20%) to give the title compound (40 mg).

[0981] LC-MS: m / z (ESI): 407.0 / 409.0 [M+H] +

[0982] Step 2: Synthesis of tert-butyl ((l-cyclopropyl-2-oxo-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2-dihydroquinolin-4-yl)methyl)(methyl)carbamate (Intermediate 44-2)

[0983] To a mixture of Intermediate 44-1 (40 mg, 98 μmol), bis(pinacolato)diboron (50 mg, 196 μmol), potassium acetate (31 mg, 295 μmol), dioxane (2 mL) was added Pd(dppf)Cl2(7 mg, 9.8 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. After filtration, the filtrate was concentrated to dryness under reduced pressure to give the title compound (44 mg).

[0984] LC-MS: m / z (ESI): 455.1 [M+H] +

[0985] Step 3: Synthesis of tert-butyl ((l-cyclopropyl-6-(2-(2-(3-(l- (ethoxymethoxy)cyclobutyl)-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)-3,4- difluorophenyl)-2-oxo-l,2-dihydroquinolin-4-yl)methyl)(methyl)carbamate (Intermediate 44-3)

[0986] To a mixture of Intermediate 44-2 (40 mg, 88 pmol), Intermediate 43-4 (40 mg, 88 pmol), potassium carbonate (24 mg, 176 pmol), dioxane (1 mL), water (0.2 mL) was added Pd-118 (6 mg, 8.8 pmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. Then the mixture was added water (10 mL) and extracted with ethyl acetate (5 mL*3). The organic phase was concentrated to dryness under reduced pressure to give the title compound (62 mg).

[0987] LC-MS: m / z (ESI): 707.4 [M+H] +

[0988] Step 4: Synthesis of l-cyclopropyl-6-(3,4-difluoro-2-(2-(3-(l- hydroxycyclobutyl)-l,5-dimethyl-lH-pyrazol-4-yl)ethoxy)phenyl)-4- ((methylamino)methyl)quinolin-2(lH)-one (Compound 44)

[0989] To a mixture of Intermediate 44-3 (60 mg, 85 pmol) was added HC1 / dioxane solution (2 M, 2 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated to remove the solvent and then directly purified by high performance liquid chromatography (column: 41-WePure Biotech XP tC18 150*40 mm, 7 pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 10%-40%, 11 min) to give the title compound (10.7 mg).

[0990] LC-MS: m / z (ESI): 549.4 [M+H] +

[0991] 1H NMR (400 MHz, DMSO-d6) d = 7.95-7.82 (m, 2H), 7.69 (d, J = 7.7 Hz, 1H), 7.33-7.21 (m, 2H), 6.58 (s, 1H), 3.91 (s, 2H), 3.84 (t, J = 7.6 Hz, 2H), 3.55 (s, 3H), 3.05-2.87 (m, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.37 (s, 3H), 2.34-2.28 (m, 2H), 2.05-1.95 (m, 2H), 1.86 (s, 3H), 1.65-1.54 (m, 1H), 1.39-1.28 (m, 3H), 1.26-1.06 (m, 1H), 0.77 (s, 2H).

[0992] Example 45, 6-(3,4-difluoro-2-(2-(3-(3-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H- pyrazol-4-yl)ethoxy)phenyl)-4-((dimethylamino)methyl)-1-methylquinolin-2(1H)-one (Compound 45)

[0993] Step 1: Synthesis of 4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-3-(3-((tert- butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazole (Intermediate 45-1)

[0994] Intermediate 42-9 (0.1 g, 215.19 pmol) and 6-bromo-2,3-difluorophenol (47.2 mg, 226 pmol) were dissolved in toluene (2 ml), and cyanomethylene tri-n-butylphosphonium (105 mg, 430 pmol) was added under nitrogen atmosphere. The reaction was heated to 100 °C for 3 hr. After that, the reaction was diluted with ethyl acetate (50 mL) and washed with water (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column (12 g) with eluent 0-35% tetrahydrofuran / n-hexane, gradient @ 40 mL / min) to give the title compound (130 mg). 12 g

[0995] LCMS (m / z): 655.6 [M+H] +

[0996] Step 2: Synthesis of 3-(4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H- pyrazol-3-yl)-2,2-dimethylpropan-1-ol (Intermediate 45-2)

[0997] ​Intermediate 45-1 (40 mg, 61 μmol) was dissolved in DMF (1 mL), and cesium fluoride (716 mg, 305 μmol) was added under nitrogen atmosphere. The reaction was heated to 80 °C for 16 h. The reaction was diluted with ethyl acetate (30 mL), washed with water (10 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (25 mg).

[0998] LCMS (m / z): 419.0 [M+H] +

[0999] Step 3: Synthesis of N-(4-bromophenyl)-N-methyl-3-oxobutanamide (Intermediate 45-4)

[1000] Compound 45-3 (6 g, 32.2 mmol) was dissolved in toluene (60 mL), and 4- methylenedihydrooxazin-2-one (3.25 g, 38.7 mmol) was added under nitrogen atmosphere. The reaction was stirred at 90 °C for 6 h. The reaction was purified by flash silica gel column (80 g) with 0-60% tetrahydrofuran / petroleum ether as eluent at 70 mL / min. 80 g The title compound (6 g) was obtained by flash silica gel column (80 g) with 0-60% tetrahydrofuran / petroleum ether as eluent at 70 mL / min.

[1001] MS m / z (ESI): 271.8 [M+H] +

[1002] Step 4: Synthesis of 4-bromo-N-(4-bromophenyl)-N-methyl-3-oxobutanamide (Intermediate 45-5)

[1003] Intermediate 45-4 (1 g, 3.70 mmol) was dissolved in ethyl acetate (10 mL), and pyridinium tribromide (1.95 g, 4.07 mmol) was added under nitrogen atmosphere. The reaction was stirred at 25 °C for 16 h. The reaction was diluted with ethyl acetate (60 mL), washed with water (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by flash silica gel column (12 g) with 0-15% tetrahydrofuran / n-hexane as eluent at 60 mL / min. 12 g The title compound (700 mg) was obtained by flash silica gel column (12 g) with 0-15% tetrahydrofuran / n-hexane as eluent at 60 mL / min.

[1004] MS m / z (ESI): 350.0 [M+H] +

[1005] Step 5: Synthesis of 6-bromo-4-(bromomethyl)-1-methylquinolin-2(1H)-one (Intermediate 45-6)

[1006] Intermediate 45-5 (400 mg, 1.15 mmol) was dissolved in concentrated sulfuric acid (4 mL), and the reaction was stirred at 90 °C for 2 h. The reaction was then slowly added to ice water (50 mL), filtered, and the filter cake was washed with water (30 mL x 3) and concentrated to give the title compound (350 mg).

[1007] LC-MS: m / z (ESI): 331.9 [M+H] +

[1008] Step 6: Synthesis of 6-bromo-4-((dimethylamino)methyl)-l-methylquinolin-2(lH)-one (Intermediate 45-7)

[1009] Intermediate 45-6 (0.1 g, 302.11 μmol) and dimethylamine hydrochloride (49.2 mg, 604 μmol) were dissolved in N,N-dimethylformamide (1.5 mL), and triethylamine (91.7 mg, 906 μmol) was added under a nitrogen atmosphere. The reaction was stirred at 60 °C for 3 h. The reaction was then diluted with ethyl acetate (50 mL), washed with water (15 mL x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash silica gel column chromatography (eluent 0-50% tetrahydrofuran in n-hexane, gradient @ 40 mL / min) to give the title compound (40 mg). 12 g Flash silica gel column, eluent 0-50% tetrahydrofuran in n-hexane, gradient @ 40 mL / min.

[1010] LC-MS: m / z (ESI): 297.1 [M+H] +

[1011] Step 7: Synthesis of 4-((dimethylamino)methyl)-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinolin-2(lH)-one (Intermediate 45-8)

[1012] Intermediate 45-7 (40 mg, 135 μmol) and bis(pinacolato)diboron (68.8 mg, 271 μmol) were dissolved in dioxane (1 mL), and l,l'-bis(diphenylphosphino)ferrocene palladium chloride (9.9 mg, 13.5 μmol) and potassium acetate (39.9 mg, 406 μmol) were added under a nitrogen atmosphere. The reaction was stirred at 90 °C for 3 h. The reaction was used directly in the next step without purification.

[1013] LC-MS: m / z (ESI): 343.2 [M+H] +

[1014] Step 8: Synthesis of 6-(3,4-difluoro-2-(2-(3-(3-hydroxy-2,2-dimethylpropyl)-1,5- dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-4-((dimethylamino)methyl)-1- methylquinolin-2(1H)-one (Compound 45)

[1015] Intermediate 45-8 (20 mg) and intermediate 45-2 (25 mg) were dissolved in dioxane (0.6 mL) and water (0.2 mL), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (4.0 mg, 6.0 μmol) and potassium carbonate (24.8 mg, 180 μmol) were added under nitrogen atmosphere, the reaction was stirred at 90 °C for 3 hr. The reaction was then directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: 41-WePure Biotech XP tC18 150*40 mm; mobile phase: [A: water (0.05% ammonia water + 10 mM ammonium bicarbonate), B: acetonitrile]; B%: 41% - 71%, 11 min) to give the title compound (3.9 mg).

[1016] LC-MS: m / z (ESI): 553.4 [M+H] +

[1017] 1 H NMR (400 MHz, DMSO-d6) d = 8.12 (d, J = 1.8 Hz, 1H), 7.74-7.70 (m, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.35-7.27 (m, 2H), 6.68-6.60 (m, 1H), 4.40 (t, J = 5.6 Hz, 1H), 3.73 (t, J = 7.5 Hz, 2H), 3.67 (s, 3H), 3.61 (s, 2H), 3.54 (s, 3H), 3.00 (d, J = 5.7 Hz, 2H), 2.61 (t, J = 7.4 Hz, 2H), 2.22 (s, 6H), 2.09 (s, 2H), 1.91 (s, 3H), 0.62 (s, 6H)

[1018] Example 46, 6-(3,4-difluoro-2-(2-(3-(3-hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H- pyrazol-4-yl)ethoxy)phenyl)-1-methyl-4-((methylamino)methyl)quinolin-2(1H)-one (Compound 46)

[1019] Step 1: Synthesis of tert-butyl ((6-(3,4-difluoro-2-(2-(3-(3-hydroxy-2,2- dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-2-oxo-1,2- dihydroquinolin-4-yl)methyl)(methyl)carbamate (Intermediate 46-1)

[1020] Intermediate 34-1 (30 mg, 70 pmol) and Intermediate 45-2 (29 mg, 70 pmol) were dissolved in dioxane (2 mL) and water (0.6 mL), and 1,1-bis(tert-butylphosphine) ferrocenepalladium chloride (2.3 mg, 3.5 pmol) and potassium carbonate (20.6 mg, 210 pmol) were added under nitrogen atmosphere. The reaction was stirred at 90 °C for 1 hr. The reaction was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by flash silica gel column (eluent 0-40% tetrahydrofuran / industrial hexane, gradient @ 40 mL / min) to give the title compound (44 mg). 4g The residue was purified by flash silica gel column (eluent 0-40% tetrahydrofuran / industrial hexane, gradient @ 40 mL / min) to give the title compound (44 mg).

[1021] MS m / z (ESI): 639.4 [M+H] +

[1022] Step 2: Synthesis of 6-(3,4-difluoro-2-(2-(3-(3-hydroxy-2,2-dimethylpropyl)-1,5- dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-4-((methylamino)methyl)quinolin- 2(1H)-one (Compound 46)

[1023] Intermediate 46-1 (44 mg, 69 pmol) was dissolved in 2M hydrochloric acid in dioxane (3 mL) and stirred at 25 °C for 1 hr. The reaction was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: 40-WePure Biotech XP tC18 150 x 30 mm, 7 pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 17% - 57%, 8 min) to give the title compound (13.7 mg).

[1024] LC-MS: m / z (ESI): 539.4 [M+H] + .

[1025] 1H NMR (400 MHz, DMSO-d6) δ = 8.18 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.74-7.70 (m, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.35-7.28 (m, 2H), 6.70 (s, 1H), 3.94 (s, 2H), 3.74 (br t, J = 7.6 Hz, 2H), 3.66 (s, 3H), 3.54 (s, 3H), 3.00 (s, 2H), 2.62-2.56 (m, 2H), 2.37 (s, 3H), 2.10 (s, 2H), 1.92 (s, 3H), 0.63 (s, 6H)

[1026] Example 47, 6-(3,4-difluoro-2-(2-(3-(1-hydroxycyclobutyl)-1,5-dimethyl-1H-pyrazol-4- yl)ethoxy)phenyl)-4-(2-hydroxyethyl)-1-methylquinolin-2(1H)-one (Compound 47)

[1027] Step 1: Synthesis of 2H-pyran-2,4,6(3H,5H)-trione (Intermediate 47-2)

[1028] Compound 47-1 (5 g, 34 mmol) was added to a mixture of acetic acid (7.5 mL) and acetic anhydride (5 mL) at below 5 °C, stirred at below 10 °C for 1 hr, filtered, the filter cake was washed with toluene (5 mL x 3), dried to give the title compound (2.12 g).

[1029] 1 H NMR (400 MHz, DMSO-d6) δ = 12.5 (s, 1H), 5.23 (s, 1H), 3.68 (s, 2H)

[1030] Step 2: Synthesis of 5-ethoxy-3,5-dioxopentanoic acid (Intermediate 47-3)

[1031] Intermediate 47-2 (2.21 g, 17.2 mmol) was dissolved in anhydrous ethanol (30 mL), the reaction was stirred at 20 °C for 16 hrs, then concentrated under reduced pressure to give the title compound (3 g).

[1032] 1 H NMR (400 MHz, DMSO-d6) δ = 12.7 (s, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.69 (s, 2H), 3.57 (s, 2H), 1.19 (t, J = 7.2 Hz, 3H)

[1033] Step 3: Synthesis of ethyl 5-((4-bromophenyl)(methyl)amino)-3,5-dioxopentanoate (Intermediate 47-4)

[1034] To a solution of 4-bromo-N-methylaniline (800 mg, 4.30 mmol), DMAP (52.5 mg, 430 μmol) and Intermediate 47-3 (749 mg, 4.30 mmol) in dichloromethane (10 mL) was added N,N'-dicyclohexylcarbodiimide (DCC) (887 mg, 4.30 mmol) portionwise at ice-bath temperature. The reaction was stirred at 25 °C for 16 hr. The reaction was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by flash silica gel column (40 g) eluting with 0-20% tetrahydrofuran in n-hexane at 45 mL / min gradient to afford the title compound (1.34 g). 40g Flash silica gel column, eluent 0-20% tetrahydrofuran in n-hexane at 45 mL / min gradient.

[1035] LC-MS: m / z (ESI): 342.1 / 344.1 [M+H] +

[1036] Step 4: Synthesis of 2-(6-bromo-l-methyl-2-oxo-l,2-dihydroquinolin-4-yl)acetic acid (Intermediate 47-5)

[1037] Intermediate 47-4 (300 mg, 877 μmol) was dissolved in concentrated sulfuric acid (1 mL) and heated to 90 °C and stirred for 45 min. The cooled reaction was then slowly added to an ice-water bath, filtered and the filter cake was dried to afford the title compound (238 mg).

[1038] LC-MS: m / z (ESI): 296.0 / 298.0 [M+H] +

[1039] Step 5: Synthesis of 6-bromo-4-(2-hydroxyethyl)-l-methylquinolin-2(lH)-one (Intermediate 47-6)

[1040] To a solution of Intermediate 47-5 (238 mg, 804 μmol) in tetrahydrofuran (5 mL) was added borane dimethyl sulfide complex (10 M, 804 μL) dropwise and the reaction was stirred at 25 °C for 2 hr. Methanol (5 mL) was then slowly added to the reaction at 0 °C. The solution was then concentrated to dryness under reduced pressure to afford the title compound (227 mg).

[1041] LC-MS: m / z (ESI): 282.1 / 284.1 [M+H] +

[1042] Step 6: Synthesis of 4-(2-hydroxyethyl)-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinolin-2(lH)-one (Intermediate 47-7)

[1043] To a mixture of Intermediate 47-6 (47 mg, 167 μmol), bis(pinacolato)diboron (84.6 mg, 333 μmol), potassium acetate (49.0 mg, 500 μmol), dioxane (2 mL) was added Pd(dppf)Cl2(12 mg, 16 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 1 h. The mixture was used directly in the next step, which contained the title compound (55 mg).

[1044] LC-MS: m / z (ESI): 330.0 [M+H] +

[1045] Step 7: Synthesis of 6-(2-(2-(3-(l-(ethoxymethoxy)cyclobutyl)-l,5-dimethyl-lH- pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)-4-(2-hydroxyethyl)-l-methylquinolin-2(lH)- one (Intermediate 47-8)

[1046] To a mixture of Intermediate 47-7 (54 mg, 164 μmol), Intermediate 43-4 (75.35 mg, 164.04 μmol), potassium carbonate (68.0 mg, 492 μmol), dioxane (2 mL), water (0.5 mL) was added Pd-118 (10.7 mg, 16.4 μmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 1 h. The mixture was added water (20 mL), extracted with ethyl acetate (10 mL*3), the organic phase was concentrated to dryness under reduced pressure, the residue was purified by flash silica gel column (12 g 12 g The title compound (40 mg) was obtained by flash silica gel column purification, eluent 0~70% tetrahydrofuran / n-hexane, gradient @ 45 mL / min.

[1047] LC-MS: m / z (ESI): 582.3 [M+H] +

[1048] Step 8: Synthesis of 6-(3,4-difluoro-2-(2-(3-(l-hydroxycyclobutyl)-l,5-dimethyl-lH- pyrazol-4-yl)ethoxy)phenyl)-4-(2-hydroxyethyl)-l-methylquinolin-2(lH)-one (Compound 47)

[1049] To a solution of intermediate 47-8 (40 mg, 69 pmol) in dioxane (5 mL) was added concentrated hydrochloric acid (12 M, 115 pL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 10 min. The mixture was then concentrated to remove the solvent and directly purified by high performance liquid chromatography (column: 40-We Pure Biotech XP tC18 150 x 30 mm, 7 pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 23%-63%, 8 min) to afford the title compound (2.8 mg).

[1050] LC-MS: m / z (ESI): 546.2 [M+Na] +

[1051] 1 H NMR (400 MHz, CD3OD) d = 7.95 (d, J = 1.8 Hz, 1H), 7.73-7.69 (m, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.28-7.16 (m, 1H), 7.16-7.05 (m, 1H), 6.69 (s, 1H), 3.96-3.84 (m, 4H), 3.80 (s, 3H), 3.61 (s, 3H), 3.09 (t, J = 6.5 Hz, 2H), 2.75 (t, J = 7.1 Hz, 2H), 2.41-2.35 (m, 2H), 2.14-2.01 (m, 2H), 1.95 (s, 3H), 1.81-1.63 (m, 1H), 1.52-1.38 (m, 1H)

[1052] Example 48, 6-(3,4-difluoro-2-(2-(3-(3-fluoro-1-hydroxy-2,2-dimethylpropyl)-1,5- dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-4-((methylamino)methyl)quinolin- 2(1H)-one (Compound 48)

[1053] Step 1: Synthesis of 1-(4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-1,5-dimethyl-1H- pyrazol-3-yl)-3-fluoro-2,2-dimethylpropan-1-ol (Intermediate 48-1)

[1054] Intermediate 16-3 (100 mg, 231 μιηοΐ) was dissolved in isopropanol (IP A) (5 mL) and sodium borohydride (0.23 g, 6.1 mmol) was added under nitrogen at 0 °C. The reaction was stirred at 25 °C for 48 h. The reaction was then quenched with ice water solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the title compound (90 mg).

[1055] MS m / z (ESI): 435.1 / 437.1 [M+H] +

[1056] Step 3: Synthesis of 6-(3,4-difluoro-2-(2-(3-(3-fluoro-1-hydroxy-2,2-dimethyl- propyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-4-((methylamino)methyl) quinolin-2(1H)-one (Compound 48)

[1057] Intermediate 34-1 (88.6 mg, 207 μιηοΐ) and intermediate 48-1 (90 mg, 207 μιηοΐ) were dissolved in dioxane (2 mL) and water (0.6 mL) and 1,1-bis(tert-butylphosphine) ferrocene palladium chloride (6.74 mg, 10.3 μιηοΐ) and potassium carbonate (61 mg, 620 μιηοΐ) were added under nitrogen. The reaction was stirred at 90 °C for 1 h. The reaction was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the title compound (135 mg).

[1058] MS m / z (ESI): 657.3 [M+H] +

[1059] Step 3: Synthesis of 6-(3,4-difluoro-2-(2-(3-(3-fluoro-1-hydroxy-2,2-dimethyl- propyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-methyl-4-((methylamino)methyl) quinolin-2(1H)-one (Compound 48)

[1060] Intermediate 48-2 (135 mg, 206 μιηοΐ) was dissolved in 2 M hydrochloric acid in dioxane (5 mL) and stirred at 25 °C for 1 h. The reaction was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: 56-Boston Green ODS 150 x 30 mm, 5 μιη; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 18% - 58%, 9 min) to give the title compound (33.9 mg).

[1061] LC-MS: m / z (ESI): 557.4 [M+H] + .

[1062] 1 H NMR (400 MHz, DMSO-d6) d = 7.97 (d, J = 2.0 Hz, 1H), 7.78 - 7.74 (m, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.36 - 7.27 (m, 2H), 6.70 (s, 1H), 4.33 - 4.23 (m, 2H), 4.19 - 4.15 (m, 1H), 4.04 (d, J = 8.4 Hz, 1H), 3.96 (s, 2H), 3.87 - 3.79 (m, 1H), 3.79 - 3.72 (m, 1H), 3.66 (s, 3H), 3.57 (s, 3H), 2.77 - 2.69 (m, 1H), 2.64 - 2.57 (m, 1H), 2.38 (s, 3H), 1.89 (s, 3H), 0.81 - 0.75 (m, 3H), 0.69 (s, 3H).

[1063] Example 49, 1-(4-(2-(2,3-difluoro-6-(7-methoxy-3-((methylamino)methyl)pyrazolo[1,5- a]pyridin-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-3-fluoro-2,2-dimethylpropan- 1-ol (Compound 49)

[1064] Step 1: Synthesis of tert-butyl ((5-(3,4-difluoro-2-(2-(3-(3-fluoro-2,2-dimethylpropanoyl)- 1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-7-methoxypyrazolo[1,5-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 49-1)

[1065] Intermediate 16-2 (40 mg, 165 μmol) and Intermediate 31-6 (69 mg, 165 μmol) were dissolved in toluene (1 mL), and cyanomethylidene tri-n-butylphosphonium (80.3 mg, 330 μmol) was added under nitrogen atmosphere. The reaction was stirred at 100 °C for 3 hr. The reaction was then purified by silica gel column chromatography (eluent: 0-50% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min). 12g The title compound (80 mg) was purified by flash silica gel column chromatography (eluent: 0-50% tetrahydrofuran / petroleum ether, gradient @ 40 mL / min).

[1066] LC-MS: m / z (ESI): 644.4 [M+H] +

[1067] Step 2: Synthesis of tert-butyl ((5-(3,4-difluoro-2-(2-(3-(3-fluoro-1- hydroxy-2,2-dimethylpropyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-7- methoxypyrazolo[1,5-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 49-2)

[1068] Intermediate 49-1 (40 mg, 62 μmol) was dissolved in methanol (2 mL) at 0 °C under nitrogen atmosphere, lithium borohydride (621 μmol, 2 M, 310 μL) was added under nitrogen atmosphere, the reaction was stirred at 25 °C for 3 hr. The reaction was then quenched with ice water solution (10 mL), diluted with ethyl acetate (30 mL), washed with water (10 mL x 2), the organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (30 mg)

[1069] LC-MS: m / z (ESI): 646.4 [M+H] +

[1070] Step 3: Synthesis of 1-(4-(2-(2,3-difluoro-6-(7-methoxy-3-((methylamino)methyl)pyrazolo[1,5- a]pyridin-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-3-fluoro-2,2- dimethylpropan-1-ol (Compound 49)

[1071] Intermediate 49-2 (30 mg, 46.46 μmol) was dissolved in hydrochloric acid dioxane (2 M, 1 mL), the reaction was stirred at 25 °C for 1 hr. The reaction was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: 56-Boston Green ODS 150*30 mm; 5 μm mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 13%-53%, 9 min) to give the title compound (6.2 mg).

[1072] LC-MS: m / z (ESI): 546.2 [M+H] +

[1073] 1H NMR (400 MHz, DMSO-d6) d = 8.34 (s, 1H), 8.04 (s, 1H), 7.51 (d, J = 1.5 Hz, 1H), 7.40-7.28 (m, 2H), 6.48 (d, J = 1.2 Hz, 1H), 4.36-4.29 (m, 1H), 4.21-4.17 (m, 1H), 4.10 (s, 3H), 4.07 (d, J = 8.6 Hz, 1H), 3.99 (s, 2H), 3.95-3.91 (m, 1H), 3.89-3.85 (m, 1H), 3.53 (s, 3H), 2.81-2.75 (m, 1H), 2.70-2.65 (m, 1H), 2.48-2.44 (m, 1H), 2.38 (s, 3H), 1.85 (s, 3H), 0.81 (d, J = 1.3 Hz, 3H), 0.74 (s, 3H)

[1074] Example 50, Synthesis of 6-(3,4-difluoro-2-(2-(3-(1-hydroxycyclobutyl)-1,5-dimethyl-1H- pyrazol-4-yl)ethoxy)phenyl)-1-(2-hydroxyethyl)-4-((methylamino)methyl)quinolin-2(1H)-one (Compound 50)

[1075] Step 1: Synthesis of tert-butyl ((6-bromo-1-(2-hydroxyethyl)-2-oxo-1,2-dihydroquinolin-4- yl)methyl)(methyl)carbamate (Intermediate 50-1)

[1076] To a mixture of Intermediate 17-6 (200 mg, 545 μmol), oxirane (48 mg, 1.09 mmol), DMF (2 mL) was added cesium carbonate (533 mg, 1.62 mmol) at room temperature under nitrogen atmosphere, the resulting mixture was stirred at 70 °C for 16 h. Then the mixture was added water (20 mL), extracted with ethyl acetate (20 mL*3), the organic phase was concentrated to dryness under reduced pressure, the residue was directly purified by silica gel column chromatography (THF / PE, 0-35%) to give the title compound (120 mg).

[1077] LC-MS: m / z (ESI): 411.0 [M+H] +

[1078] Step 2: Synthesis of tert-butyl ((1-(2-hydroxyethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2-dihydroquinolin-4-yl)methyl)(methyl)carbamate (Intermediate 50-2)

[1079] To a mixture of intermediate 50-1 (60 mg, 146 pmol), bis(pinacolato)diboron (55 mg, 219 pmol), potassium acetate (29 mg, 292 pmol), dioxane (2 mL) was added Pd(dppf)Cl2(11 mg, 14.6 pmol) at room temperature under nitrogen atmosphere, the resulting mixture was stirred at 90 °C for 2 h. The mixture was used directly in the next step, which contained the title compound (66 mg).

[1080] LC-MS: m / z (ESI): 459.4 [M+H] +

[1081] Step 3: Synthesis of tert-butyl ((6-(2-(2-(3-(1-(ethoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)-1-(2-hydroxyethyl)-2-oxo-1,2-dihydroquinolin-4-yl)methyl)(methyl)carbamate (intermediate 50-3)

[1082] To a mixture of intermediate 50-2 (66 mg, 144 pmol), intermediate 43-4 (66 mg, 144 pmol), potassium carbonate (40 mg, 288 pmol), dioxane (2 mL), water (0.5 mL) was added Pd-118 (9 mg, 14.4 pmol) at room temperature under nitrogen atmosphere, the resulting mixture was stirred at 90 °C for 2 h. The mixture was added water (10 mL), extracted with ethyl acetate (5 mL*3), the organic phase was concentrated to dryness under reduced pressure to give the title compound (100 mg).

[1083] LC-MS: m / z (ESI): 711.4 [M+H] +

[1084] Step 4: Synthesis of 6-(3,4-difluoro-2-(2-(3-(1-hydroxycyclobutyl)-1,5-dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-1-(2-hydroxyethyl)-4-((methylamino)methyl)quinolin-2(1H)-one (compound 50)

[1085] To a mixture of intermediate 50-3 (100 mg, 141 pmol) was added hydrochloric acid dioxane solution (2 M, 5 mL) at room temperature under argon atmosphere, the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated to remove the solvent and purified by high performance liquid chromatography directly (column: 41-WePure Biotech XP tC18 150*40 mm, 7 pm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 16%-46%, 10 min) to give the title compound (23.4 mg).

[1086] LC-MS: m / z (ESI): 553.4 [M+H] +

[1087] 1 H NMR (400 MHz, DMSO-d6) d = 8.30 - 8.26 (m, 1H), 7.83 (s, 1H), 7.68 (s, 2H), 7.33 - 7.20 (m, 2H), 6.71 (s, 1H), 4.37 (s, 2H), 4.13 (s, 2H), 3.94 - 3.82 (m, 4H), 3.68 (t, J = 6.3 Hz, 2H), 3.51 (s, 3H), 2.64 (s, 2H), 2.51 (s, 3H), 2.27 (t, J = 8.6 Hz, 2H), 2.02 - 1.94 (m, 2H), 1.83 (s, 3H), 1.64 - 1.55 (m, 1H), 1.30 (d, J = 10.1 Hz, 1H).

[1088] Example 51. Synthesis of 1-(4-(2-(2,3-difluoro-6-(7-methoxy-3-((methylamino)methyl)pyrazolo[1,5-a]pyridin-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H-pyrazol-3-yl)-3,3-difluorocyclobutan-1-ol (Compound 51)

[1089] Step 1: Synthesis of 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3,3-difluorocyclobutan-1-ol (Intermediate 51-2)

[1090] Solution 1: Tetrahydrofuran (80 mL) solution of Intermediate 51-1 (2 g, 11.43 mmol).

[1091] Solution 2: 1.6 M n-butyllithium in n-pentane, 11.43 mL.

[1092] Solution 3: Tetrahydrofuran (70 mL) solution of 3,3-difluorocyclobutanone (1.94 g, 18.28 mmol).

[1093] Solution 1 was pumped into flow reactor 1 {FLR1, PFA, Coil Reactor, (1 / 16”) mm, 0.15 ml, -65 °C} from pump 1 {S1, P1, 15.804 mL / min}.

[1094] Solution 2 was pumped into flow reactor 1 {FLR1, PFA, Coil Reactor, (1 / 16”) mm, 0.15 ml, -65 °C} from pump 2 {S2, P2, 2.196 mL / min}.

[1095] Solution 3 was pumped into flow reactor 2 {FLR2, PFA, coil reactor, (1 / 16") mm, 0.6 ml, -65 °C} by pump 3 {S3, P3, 15.765 mL / min}.

[1096] The residence time of flow reactor 1 was {FLR1, 0.5 seconds}.

[1097] The residence time of flow reactor 2 was {FLR2, 1.07 seconds}.

[1098] The mixture was collected in a bottle (quenched with saturated ammonium chloride at 5 °C).

[1099] Pump 1 and pump 2 and pump 3 were started simultaneously. The reaction mixture was collected after 10 minutes of running.

[1100] The reaction solution was then diluted with ethyl acetate (100 mL) and washed with water (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column (40 g) to give the title compound (0.45 g). 40 g Flash silica gel column, eluent 0-35% tetrahydrofuran / n-hexane, gradient @ 40 mL / min) to give the title compound (0.45 g).

[1101] LC-MS: m / z (ESI): 203.1 [M+H] +

[1102] Step 2: Synthesis of 3-(1-(ethoxymethoxy)-3,3-difluorocyclobutyl)-1,5-dimethyl-1H- pyrazole (Intermediate 51-3)

[1103] Intermediate 51-2 (0.45 g, 2.23 mmol) was dissolved in tetrahydrofuran (15 mL), and sodium hydride (267 mg, 6.68 mmol, 60% active content) was added at 0 °C under a nitrogen atmosphere. The reaction solution was stirred at 25 °C for 0.25 hr. Then ethyl chloromethyl ether (631 mg, 6.68 mmol) was slowly added to the reaction solution. The reaction solution was warmed to 40 °C and reacted for 16 hours. The reaction solution was then quenched with ice water (30 mL) and extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (0.5 g).

[1104] LC-MS: m / z (ESI): 261.1 [M+H] +

[1105] Step 3: Synthesis of 3-(1-(ethoxymethoxy)-3,3-difluorocyclobutyl)-4-iodo-1,5-dimethyl-1H- pyrazole (Intermediate 51-4)

[1106] Intermediate 51-3 (0.5 g, 1.92 mmol) was dissolved in acetonitrile (5 mL), N-iodosuccinimide (1.08 g, 4.8 mmol) was added under nitrogen atmosphere, the reaction was stirred at 25 °C for 3 hr. The reaction was then purified by flash silica gel column (eluent 0~30% tetrahydrofuran / n-hexane, gradient @ 40 mL / min) to give the title compound (0.3 g). 12g Flash silica gel column, eluent 0~30% tetrahydrofuran / n-hexane, gradient @ 40 mL / min) purification gave the title compound (0.3 g).

[1107] LC-MS: m / z (ESI): 387.1 [M+H] +

[1108] Step 4: Synthesis of 3-(1-(ethoxymethoxy)-3,3-difluorocyclobutyl)-1,5-dimethyl-4- vinyl-1H-pyrazole (Intermediate 51-5)

[1109] To a mixture of Intermediate 51-4 (380 mg, 984 µmol), potassium vinyltrifluoroborate (264 mg, 1.97 mmol), potassium carbonate (271.99 mg, 1.97 mmol), dioxane (4 mL), water (1 mL) was added Pd(PPh3)4 (56.8 mg, 49.2 µmol) and Pd(dppf)Cl2 (36 mg, 49 µmol) at room temperature under nitrogen atmosphere, the resulting mixture was stirred at 90 °C for 3 h. The reaction was then diluted with ethyl acetate (60 mL) and washed with water (30 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, the residue was purified by flash silica gel column (eluent 0~30% tetrahydrofuran / n-hexane, gradient @ 40 mL / min) to give the title compound (220 mg). 12g Flash silica gel column, eluent 0~30% tetrahydrofuran / n-hexane, gradient @ 40 mL / min) purification gave the title compound (0.3 g).

[1110] LC-MS: m / z (ESI): 387.1 [M+H] +

[1111] Step 5: Synthesis of 4-(2-(9-borabicyclo[3.3.1]nonan-9-yl)ethyl)-3-(1-(ethoxymethoxy)- 3,3-difluorocyclobutyl)-1,5-dimethyl-1H-pyrazole (Intermediate 51-6)

[1112] Intermediate 51-5 (220 mg, 768 µmol) was dissolved in tetrahydrofuran (2 mL), 9-BBN (763 mg, 0.5 M in THF, 6.15 mL) was added under nitrogen atmosphere at 0 °C. The reaction was warmed to 65 °C for 16 h. The reaction was used in the next step without purification.

[1113] Step 6: Synthesis of 2-(3-(l-(ethoxymethoxy)-3,3-difluorocyclobutyl)-l,5- dimethyl-lH-pyrazol-4-yl)ethan-l-ol (Intermediate 51-7)

[1114] Intermediate 51-6 (300 mg, 735 pmol) was dissolved in ethanol (2 mL) and water (1 mL) at 0 °C under nitrogen atmosphere, sodium hydroxide (59 mg, 1.47 mmol) was added, after 15 min, hydrogen peroxide (500 mg, 4.41 mmol, 454.37 pL, 30% purity) was added to the reaction. The reaction was warmed to 25 °C for 2 hr. After that, the reaction was diluted with ethyl acetate (50 mL) and washed with saturated sodium sulfite water (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by flash silica gel column (12 g) with 0-60% tetrahydrofuran / n-hexane, gradient @ 40 mL / min) to give the title compound (220 mg). 12 g Flash silica gel column, eluent 0-60% tetrahydrofuran / n-hexane, gradient @ 40 mL / min.

[1115] LC-MS (m / z): 305.2 [M+H] +

[1116] Step 7: Synthesis of ((5-(2-(2-(3-(l-(ethoxymethoxy)-3,3-difluorocyclobutyl)-l,5- dimethyl-lH-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)-7-methoxypyrazolo[l,5- a]pyridin-3-yl)methyl)(methyl)carbamic acid tert-butyl ester (Intermediate 51-8)

[1117] Intermediate 51-7 (30 mg, 98.58 pmol) and Intermediate 31-6 (41.3 mg, 98.6 pmol) were dissolved in toluene (1 mL), cyanomethylene tri-n-butylphosphonium (48 mg, 197 pmol) was added under nitrogen atmosphere, the reaction was stirred at 100 °C for 3 hr. After that, the reaction was directly concentrated to dryness, which was used in the next step without purification.

[1118] LC-MS (m / z): 706.4 [M+H] +

[1119] Step 8: Synthesis of l-(4-(2-(2,3-difluoro-6-(7-methoxy-3-((methylamino)methyl)pyrazolo[l,5- a]pyridin-5-yl)phenoxy)ethyl)-l,5-dimethyl-lH-pyrazol-3-yl)-3,3-difluorocyclobutan-l- ol (Compound 51)

[1120] Intermediate 51-8 (50 mg, 70 μmol) was dissolved in hydrochloric acid dioxane (0.5 mL, 2M), the reaction was stirred at 25 °C for 1 hr. Then the reaction was directly concentrated to dryness under reduced pressure, purified by high performance liquid chromatography (column: 55-Boston Prime C18 150*30 mm, 5 μm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 9%-39%, 12 min) to give the title compound (3.5 mg).

[1121] LC-MS: m / z (ESI): 548.3 [M+H] +

[1122] 1 H NMR (400 MHz, DMSO-d6) d = 8.34 (s, 1H), 8.05 (s, 1H), 7.53-7.51 (m, 1H), 7.38-7.25 (m, 2H), 6.47-6.43 (m, 1H), 4.08 (s, 3H), 4.04 (s, 2H), 3.95 (t, J = 7.5 Hz, 2H), 3.53 (s, 3H), 3.14-3.04 (m, 2H), 2.77-2.55 (m, 3H), 2.38 (s, 3H), 1.83 (s, 3H), 1.60-1.34 (m, 2H)

[1123] Example 52, 1-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)-7- (trifluoromethyl)pyrazolo[1,5-a]pyridin-5-yl)phenoxy)ethyl)-1,5-dimethyl-1H- pyrazol-3-yl)cyclobutan-1-ol (Compound 52)

[1124] Step 1: Synthesis of 5-bromo-7-iodopyrazolo[1,5-a]pyridine (Intermediate 52-2)

[1125] Intermediate 52-1 (1 g, 5.08 mmol) was dissolved in THF (10 mL) at -45 °C under nitrogen atmosphere, 2,2,6,6-lithium chloride tetramethylpiperidylmagnesium complex (TMPMgCl.LiCl) (7.61 mL, 1M) was added under nitrogen atmosphere, the reaction was stirred at -45 °C for 2 hr. Then iodine (966 mg, 7.61 mmol) was added to the reaction, the reaction was stirred at 25 °C for 16 hr. Then the reaction was diluted with ethyl acetate (60 mL), washed with water (30 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by flash silica gel column chromatography (eluent: dichloromethane) to give the title compound (1.2 g). 12 g The title compound (1.5 g) was obtained by purification on a flash silica gel column, eluent 0-15% tetrahydrofuran / n-hexane, gradient @ 60 mL / min.

[1126] LC-MS (m / z): 322.8 [M+H] +

[1127] Step 2: Synthesis of 5-bromo-7-iodopyrazolo[1,5-a]pyridine-3-carbaldehyde (Intermediate 52-3)

[1128] Phosphorus oxychloride (1.78 g, 11.61 mmol) was added dropwise to a solution of DMF (15 mL) at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 1 hr. Then intermediate 52-2 (1.50 g, 4.64 mmol) was added to the reaction at 0 °C. The reaction was heated to 100 °C for 5 hrs under nitrogen atmosphere. The reaction was then cooled to room temperature and quenched with water (50 mL). The pH was adjusted to 9 with 1M NaOH. The solid was filtered and dried to give the title compound (1.4 g).

[1129] LC-MS (m / z): 350.9 / 352.9 [M+H] +

[1130] Step 3: Synthesis of 1-(5-bromo-7-iodopyrazolo[1,5-a]pyridin-3-yl)-N-methylmethanamine (Intermediate 52-4)

[1131] Intermediate 52-3 (1.40 g, 3.99 mmol) and methylamine (404 mg, 5.98 mmol) were dissolved in methanol (20 mL) and dichloromethane (10 mL), and sodium cyanoborohydride (501 mg, 7.98 mmol) was added under nitrogen atmosphere. The reaction was warmed to 35 °C for 16 hrs. The reaction was then diluted with ethyl acetate (60 mL) and washed with water (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a flash silica gel column, eluent 0-100% tetrahydrofuran / n-hexane, gradient @ 50 mL / min to give the title compound (500 mg). 12 g The title compound (500 mg) was obtained by purification on a flash silica gel column, eluent 0-100% tetrahydrofuran / n-hexane, gradient @ 50 mL / min.

[1132] LC-MS (m / z): 365.9 / 367.9 [M+H] +

[1133] Step 4: Synthesis of tert-butyl ((5-bromo-7-iodopyrazolo[1,5-a]pyridin-3- yl)methyl)(methyl)carbamate (Intermediate 52-5)

[1134] Intermediate 52-4 (500 mg, 1.37 mmol) was dissolved in dichloromethane (5 mL), di-tert-butyl dicarbonate (447 mg, 2.05 mmol) and triethylamine (415 mg, 4.10 mmol) were added under nitrogen atmosphere, the reaction was stirred at 25 °C for 16 hr. The reaction was then purified by flash silica gel column (12 g) with 0-30% tetrahydrofuran / n-hexane as eluent at gradient @ 40 mL / min to give the title compound (200 mg). 12 g The title compound was purified by flash silica gel column (12 g) with 0-30% tetrahydrofuran / n-hexane as eluent at gradient @ 40 mL / min.

[1135] LC-MS m / z (ESI): 465.9 / 467.9 [M+H] +

[1136] Step 5: Synthesis of tert-butyl ((5-bromo-7-(trifluoromethyl)pyrazolo[1,5- a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 52-6)

[1137] Intermediate 52-5 (110 mg, 236 µmol) was dissolved in N,N-dimethylformamide (2 mL), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MFSDA) (90.7 mg, 472 µmol) and cuprous iodide (90.7 mg, 472 µmol) were added under nitrogen atmosphere, the reaction was then diluted with ethyl acetate (30 mL), washed with water (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by flash silica gel column (12 g) with 0-50% tetrahydrofuran / n-hexane as eluent at gradient @ 40 mL / min to give the title compound (0.1 g). 12 g The title compound was purified by flash silica gel column (12 g) with 0-30% tetrahydrofuran / n-hexane as eluent at gradient @ 40 mL / min.

[1138] LC-MS m / z (ESI): 465.9 / 467.9 [M+H] +

[1139] Step 6: Synthesis of tert-butyl methyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7- (trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)methyl)carbamate (Intermediate 52-7)

[1140] Intermediate 52-6 (100 mg, 245 µmol) and bis(pinacolato)diboron (124 mg, 490 µmol) were dissolved in dioxane (2 mL), palladium (1,1'-bis(diphenylphosphino)ferrocene) chloride (18 mg, 25 µmol) and potassium acetate (39.9 mg, 735 µmol) were added under nitrogen atmosphere, the reaction was stirred at 90 °C for 5 hr. The reaction was used in the next step without purification.

[1141] Step 7: Synthesis of tert-butyl ((5-(2-(2-(3-(l-(ethoxymethoxy)cyclobutyl)-l,5- dimethyl-lH-pyrazol-4-yl)ethoxy)-3,4-difluorophenyl)-7- (trifluoromethyl)pyrazolo[l,5-a]pyridin-3-yl)methyl)(methyl)carbamate (Intermediate 52-8)

[1142] Intermediate 52-7 (99 mg, 218 μmol) and Intermediate 43-4 (100 mg, 218 μmol) were dissolved in dioxane (2 mL) and water (0.5 mL), and 1,1-bis(diphenylphosphino) ferrocene palladium chloride (14 mg, 22 μmol) and potassium carbonate (60 mg, 435 μmol) were added under nitrogen atmosphere. The reaction was stirred at 90 °C for 3 hr. The reaction was then diluted with ethyl acetate (50 mL) and washed with water (30 mL x 3). The organic phase was combined and dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (150 mg).

[1143] LC-MS: m / z (ESI): 708.5 [M+H] +

[1144] Step 8: Synthesis of l-(4-(2-(2,3-difluoro-6-(3-((methylamino)methyl)-7- (trifluoromethyl)pyrazolo[l,5-a]pyridin-5-yl)phenoxy)ethyl)-l,5-dimethyl-lH- pyrazol-3-yl)cyclobutan-l-ol (Compound 52)

[1145] Intermediate 52-8 (150 mg, 212 μmol) was dissolved in hydrochloric acid dioxane (2 M, 3 mL) and stirred at 25 °C for 3 hr. The reaction was directly concentrated to dryness under reduced pressure and purified by high performance liquid chromatography (column: ACSSH-CD C18 150*40 mm; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 12%-42%, 12 min) to give the title compound (27 mg).

[1146] LC-MS: m / z (ESI): 550.4 [M+H] +

[1147] 1H NMR (400 MHz, DMSO-d6) δ = 8.32-8.29 (m, 1H), 8.25 (d, J = 5.1 Hz, 2H), 7.69-7.64 (m, 1H), 7.48-7.40 (m, 1H), 7.39-7.30 (m, 1H), 4.10 (s, 2H), 4.03 (t, J = 7.8 Hz, 2H), 3.55 (s, 3H), 2.70 (t, J = 7.8 Hz, 2H), 2.45-2.39 (m, 3H), 2.38-2.30 (m, 2H), 2.06-1.95 (m, 2H), 1.88 (s, 3H), 1.67-1.56 (m, 1H), 1.44-1.32 (m, 1H)

[1148] Example 53, Synthesis of 6-(3,4-difluoro-2-(2-(3-(1-hydroxycyclobutyl)-1,5- dimethyl-1H-pyrazol-4-yl)ethoxy)phenyl)-3-fluoro-1-methyl-4-((methylamino)methyl)quinolin- 2(1H)-one (Compound 53)

[1149] Step 1: Synthesis of 1-(1,5-dimethyl-1H-pyrazol-3-yl)cyclobutan-1-ol (Intermediate 53-2)

[1150] Solution 1: Intermediate 53-1 (4.6 g, 26.28 mmol) in tetrahydrofuran (92 mL).

[1151] Solution 2: n-butyllithium in n-pentane (1.6 M in pentane, 24.64 mL).

[1152] Solution 3: Cyclobutanone (2.76 g, 39.42 mmol) in tetrahydrofuran (50 mL).

[1153] Solution 1 was pumped into flow reactor 1 {FLR1, PFA, Coil reactor, (1 / 16”) mm, 0.15 ml, -60°C} from pump 1 {S1, P1, 14.359 mL / min}.

[1154] Solution 2 was pumped into flow reactor 1 {FLR1, PFA, Coil reactor, (1 / 16”) mm, 0.15 ml, -60°C} from pump 2 {S2, P2, 3.641 mL / min}.

[1155] Solution 3 was pumped into flow reactor 2 {FLR2, PFA, Coil reactor, (1 / 16”) mm, 0.6 ml, -60°C} from pump 3 {S3, P3, 5.557 mL / min}.

[1156] Flow reactor 1 residence time is {FLR1, 0.5 sec}.

[1157] Flow reactor 2 residence time is {FLR2, 1.53 sec}.

[1158] The mixture was collected in a bottle (quenched with saturated ammonium chloride solution at 5°C).

[1159] Pump 1 and pump 2 and pump 3 were started simultaneously. The reaction mixture was collected after running for 2.5 minutes.

[1160] The reaction solution was then diluted with ethyl acetate (150 mL) and washed with water (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column (40 g) with eluent 0-35% tetrahydrofuran / n-hexane, gradient @ 60 mL / min) to give the title compound (2.2 g). 40 g flash silica gel column, eluent 0-35% tetrahydrofuran / n-hexane, gradient @ 60 mL / min) to give the title compound (2.2 g).

[1161] LC-MS: m / z (ESI): 167.1 [M+H] +

[1162] Step 2: Synthesis of 3-(1-(ethoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazole (Intermediate 53-3)

[1163] Intermediate 53-2 (1.7 g, 10.23 mmol) was dissolved in tetrahydrofuran (60 ml), and sodium hydride (1.23 mg, 30.68 mmol, 60% purity) was added at 0°C under a nitrogen atmosphere. The reaction solution was stirred at 25°C for 0.25 hr. Then ethyl chloromethyl ether (1.45 g, 15.34 mmol) was slowly added to the reaction solution. The reaction solution was stirred at 20°C for 8 hours. Then the reaction solution was quenched with ice water (30 mL) and extracted with ethyl acetate (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column (20 g) with eluent 0-20% tetrahydrofuran / n-hexane, gradient @ 60 mL / min) to give the title compound (1.7 g). 20 g flash silica gel column, eluent 0-20% tetrahydrofuran / n-hexane, gradient @ 60 mL / min) to give the title compound (1.7 g).

[1164] LC-MS: m / z (ESI): 225.2 [M+H] +

[1165] Step 3: Synthesis of 3-(1-(ethoxymethoxy)cyclobutyl)-4-iodo-1,5-dimethyl-1H-pyrazole (Intermediate 53-4)

[1166] Intermediate 53-3 (1.74 g, 7.76 mmol) was dissolved in acetonitrile (17 mL), and N-iodosuccinimide (2.62 g, 11.64 mmol) was added under a nitrogen atmosphere. The reaction was stirred at 25 °C for 3 h. The reaction was then purified by flash silica gel column (0-30% tetrahydrofuran / n-hexane, gradient @ 60 mL / min) to give the title compound (2.2 g). 40 g Flash silica gel column, eluent 0-30% tetrahydrofuran / n-hexane, gradient @ 60 mL / min) purification gave the title compound (2.2 g).

[1167] LC-MS: m / z (ESI): 351.1 [M+H] +

[1168] Step 4: Synthesis of 3-(1-(ethoxymethoxy)cyclobutyl)-1,5-dimethyl-4- ethenyl-1H-pyrazole (Intermediate 53-5)

[1169] To a mixture of Intermediate 53-4 (1 g, 2.86 mmol), potassium vinyltrifluoroborate (573.75 mg, 4.28 mmol), potassium carbonate (789.31 mg, 5.71 mmol), 1,4-dioxane (16 mL), water (4 mL) was added Pd(PPh3)4 (164.99 mg, 142.78 μmol) and Pd(dppf)Cl2 (104.47 mg, 142.78 μmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 3 h. The reaction was then diluted with ethyl acetate (60 mL) and washed with water (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column (0-30% tetrahydrofuran / n-hexane, gradient @ 40 mL / min) to give the title compound (450 mg). 12 g Flash silica gel column, eluent 0-30% tetrahydrofuran / n-hexane, gradient @ 40 mL / min) purification gave the title compound (450 mg).

[1170] LC-MS: m / z (ESI): 251.2 [M+H] +

[1171] Step 5: Synthesis of 4-(2-(9-borabicyclo[3.3.1]nonan-9-yl)ethyl)-3-(1- (ethoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazole (Intermediate 53-6)

[1172] Intermediate 53-5 (0.45 g, 1.80 mmol) was dissolved in tetrahydrofuran (5 ml) and 9-BBN (1.79 g, 0.5 M in THF, 14.38 ml) was added at 0 °C under nitrogen atmosphere. The reaction was warmed to 65 °C and stirred for 16 h. The reaction was then diluted with ethyl acetate (50 ml) and washed with water (30 ml x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (669 mg).

[1173] LCMS (m / z): 297.1 [M+H-H20] +

[1174] Step 6: Synthesis of 2-(3-(1-(ethoxymethoxy)cyclobutyl)-1,5-dimethyl-1H- pyrazol-4-yl)ethan-1-ol (Intermediate 53-7)

[1175] Intermediate 53-6 (669 mg, 1.8 mmol) was dissolved in a mixture of tetrahydrofuran (8 ml), ethanol (2 ml) and water (1 ml) at 0 °C under nitrogen atmosphere. Sodium hydroxide (143.72 mg, 3.59 mmol) was added and after 15 min, hydrogen peroxide (1.22 g, 10.78 mmol, 30% purity) was added. The reaction was warmed to 50 °C and stirred for 2 h. The reaction was then diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium sulfite solution (15 ml x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (12 g) eluting with 0-60% tetrahydrofuran in n-hexane at 40 ml / min to give the title compound (350 mg). 12 g The residue was purified by flash silica gel column chromatography (12 g) eluting with 0-60% tetrahydrofuran in n-hexane at 40 ml / min to give the title compound (350 mg).

[1176] LCMS (m / z): 269.2 [M+H] +

[1177] Step 7: Synthesis of 4-(2-(6-bromo-2,3-difluorophenoxy)ethyl)-3-(1- (ethoxymethoxy)cyclobutyl)-1,5-dimethyl-1H-pyrazole (Intermediate 53-8)

[1178] Intermediate 53-7 (0.35 g, 1.30 mmol) and 6-bromo-2,3-difluoro-phenol (286.20 mg, 1.37 mmol) were dissolved in toluene (5 ml) and cyanomethylene tri-n-butylphosphorane (CMBP) (952.24 mg, 3.91 mmol) was added under nitrogen atmosphere. The reaction was warmed to 100 °C and stirred for 3 h. The reaction was then purified by flash silica gel column chromatography (12 g) eluting with 0-60% tetrahydrofuran in n-hexane at 40 ml / min to give the title compound (350 mg). 12 g The title compound (490 mg) was obtained by purification on a flash silica gel column eluting with 0-35% tetrahydrofuran / n-hexane at 50 mL / min.

[1179] LCMS (m / z): 459.0 / 461.0 [M+H] +

[1180] Step 8: Synthesis of 4-bromo-N-(4-bromophenyl)-2-fluoro-3-oxobutanamide (Intermediate 53-9)

[1181] To a mixture of Intermediate 17-2 (500 mg, 1.49 mmol), acetonitrile (10 mL) was added 1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane tetrafluoroborate (Selectfluor) (688 mg, 1.94 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h. Then the mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (THF / PE, 0-15%) to give the title compound (350 mg).

[1182] LC-MS: m / z (ESI): 354.0 [M+H] +

[1183] Step 9: Synthesis of 6-bromo-4-(((2,4-dimethoxybenzyl)(methyl)amino)methyl)-3- fluoroquinolin-2(1H)-one (Intermediate 53-10)

[1184] To a mixture of Intermediate 53-9 (250 mg, 708.52 µmol) was added sulfuric acid (8 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 1 h. Then the mixture was slowly added into ice water (80 mL), and the liquid was removed by filtration. To a mixture of the above residue, 1-(2,4-dimethoxyphenyl)-N- methylmethanamine (169 mg, 931.44 µmol), DMF (5 mL) was added triethylamine (234 mg, 2.33 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 1 h. Then the mixture was added into water (50 mL), and extracted with ethyl acetate (20 mL*3). The organic phase was concentrated to dryness under reduced pressure to give the title compound (330 mg).

[1185] LC-MS: m / z (ESI): 435.1 [M+H] +

[1186] Step 10: Synthesis of 6-bromo-3-fluoro-4-((methylamino)methyl)quinolin-2(1H)-one (Intermediate 53-11)

[1187] To intermediate 53-10 (330 mg, 758.12 pmol) was added trifluoroacetic acid (4 mL) at room temperature under nitrogen atmosphere, the resulting mixture was stirred at 80 °C for 6 h. Then the mixture was concentrated to dryness under reduced pressure to give the title compound (216 mg).

[1188] LC-...

Claims

a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: wherein: Ring A is selected from 5-6 membered heteroaryl or 5-10 membered heterocyclyl; R 1 R 2 Each is independently selected from non-existent, halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, C6-C 10 aryl or 5-10-membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 1b replace; R 3 Selected from one or more R 2b The following groups are substituted: C1-C 10 Alkyl, (C1-C 10 Alkylene) r -C(=O)NR e R f (C1-C) 10 Alkylene) r -S(=O)2-C1-C 10 Alkyl, (C1-C 10 Alkylene) r -S(=O)(=NH)-C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, (C1-C 10 Alkylene) r -C3-C 10 cycloalkyl, (C1-C 10 Alkylene) r -C5-C 10 Cycloalkenyl, (C1-C 10 Alkylene) r -4-10 membered heterocyclic group, (C1-C 10 Alkylene) r -C6-C 10 Aryl, (C1-C 10 Alkylene) r -5-10 heteroaryl, C(=O)-4-10 heterocyclic, C(=O)-C1-C 10 Alkyl, O-C1-C 10 Alkyl, O-C3-C 10 cycloalkyl or P(=O)(C1-C 10 Alkyl group 2, each r is independently selected from 0 or 1, R e R f Each is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, or R e R f Together with the N atoms they are attached to, they form 4-7 membered heterocyclic groups; L 1 is selected from L a -L b -L c , said L a , L b is each independently selected from a bond, Ci-C4alkylene, C3-C6cycloalkylene or 4-7 membered heterocyclylene, said Ci-C4alkylene, C3-C6cycloalkylene or 4-7 membered heterocyclylene optionally substituted with one or more R 3b , L c is selected from -NH-, -O-, -S-, -S(=O)-, -SO2-, -C(=O)-, -NHSO2- or -NH(C=O)-; Z 1 , Z 2 , Z 3 , Z 4 each independently is selected from N or CR 9 , said R 9 is selected from H, halogen, CN, OH, NH2, C1-C6alkyl, C3-C6cycloalkyl or 4-7 membered heterocyclyl; Ring B is selected from C6-Ci0aryl, C3-C10cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocyclyl; 10 aryl, C3-C10cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocyclyl; 10 cycloalk y is selected from 0, 1, 2, 3, 4, 5 or 6; Each R x Each is independently selected from halogens, =O, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic groups, C6-C 10 aryl or 5-10-membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7-membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 4b replace; R 6 selected from or 4-7 membered nitrogen heterocyclyl optionally substituted with one or more R 6b substituted; each R 7 , R 8 is each independently selected from H, C1-C6alkyl, or C3-C6cycloalkyl, or R 7 , R 8 and the carbon atom to which they are attached collectively form a C3-C6cycloalkyl; each R 10 , R 11 are each independently selected from H, C1-C6alkyl, or C3-C6cycloalkyl, or R 10 , R 11 and the carbon atom to which they are attached collectively form a C3-C6cycloalkyl; q is selected from 0 or 1; R 12 , R 13 , R 14 are each independently selected from H, Ci-C6-alkyl, C3-C6-cycloalkyl or C(=0)-Ci-C6-alkyl, or R 12 , R 13 and the nitrogen atom to which they are attached together form a 4- to 7- membered heterocyclyl, said Ci-C6-alkyl, C3-C6-cycloalkyl, 4- to 7- membered heterocyclyl or C(=0)-Ci-C6-alkyl is optionally substituted by one or more R 7b ; Each R 1b R 2b R 3b R 4b R 6b Independently selected from halogens, CN, OH, NH2, C1-C6 alkyl, C(=O)-C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, O(C1-C4 alkyl), NH(C1-C4 alkyl)2, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, O(C1-C4 alkyl), NH(C1-C4 alkyl)2 or N(C1-C4 alkyl)2 is optionally mixed with one or more R c replace; Each R 7b It is independently selected from deuterium, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, O (C1-C4 alkyl), NH (C1-C4 alkyl) or N (C1-C4 alkyl)2; Each R c It is independently selected from halogens, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic groups, O (C1-C4 alkyl), NH (C1-C4 alkyl) or N (C1-C4 alkyl)2. The compound of Formula (I) according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the following compounds of Formula (la) or (lb), or a stereoisomer or a pharmaceutically acceptable salt thereof: wherein, R 1 , R 2 , R 3 , R x , y, R 6 , R 9 , L 1 and ring B are as defined in claim 1. The compound of Formula (I) according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the following compounds of Formula (I’), or a stereoisomer or a pharmaceutically acceptable salt thereof wherein, Ring A, R 1 , R 2 , R 3 , L 1 , Z 1 , Z 2 , Z 3 , Z 4 , Ring B and R 6 R 4 and R 5 are each independently absent or R x as defined in claim 1. The compound of Formula (I) according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the following compounds of Formula (I’a) or (I’b), or a stereoisomer or a pharmaceutically acceptable salt thereof: wherein R 1 , R 2 , R 3 , R 6 , R 9 , L 1 and ring B is as defined in claim 1, R 4 and R 5 are each independently absent or R x as defined in claim 1. The compound of Formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 3, wherein ring A is selected from 5-membered heteroaryl or 8-membered heterocyclyl; or, ring A is selected from 5-membered heteroaryl containing 2 N atoms or 8-membered heterocyclenyl containing 2 N atoms; or, ring A is selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl or or, ring A is selected from pyrazolyl or Alternatively, ring A is selected from pyrazolyl and R 1 and R 2 are each selected from methyl; or ring A is selected from and R 1 and R 2 are both absent. The compound of Formula (I) according to any one of claims 1-5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 are each independently selected from absent, halogen, =0, CN, OH, NH2, C1-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl, said OH, NH2, C1-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl optionally substituted with one or more R 1b ; alternatively, R 1 , R 2 are each independently selected from absent or C1-C4alkyl; alternatively, R 1 , R 2 are each selected from methyl. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein, R 3 selected from the group consisting of optionally substituted C1-C6alkyl, (C1-C6alkylene) 2b (C1-C6alkylene)C(=O)-C1-C6alkyl, (C1-C6alkylene)C(=O)-C3-C r (C1-C6alkylene)C(=O)-C1-C6alkyl, (C1-C6alkylene)C(=O)-C3-C r (C1-C6alkylene)C(=O)-C1-C6alkyl, (C1-C6alkylene)C(=O)-C3-C 10 (C1-C6alkylene)C(=O)-C1-C6alkyl, (C1-C6alkylene)C(=O)-C3-C r (C1-C6alkylene)C(=O)-C1-C6alkyl, (C1-C6alkylene)C(=O)-C3-C r (C1-C6alkylene)C(=O)-C1-C6alkyl, (C1-C6alkylene)C(=O)-C3-C 10 (C1-C6alkylene)C(=O)-C1-C6alkyl, (C1-C6alkylene)C(=O)-C3-C R 3 selected from the group consisting of optionally substituted C1-C6alkyl, (C1-C2alkylene) 2b -S(=O)(=NH)-C1-C6alkyl, (C1-C2alkylene) r -S(=O)(=NH)-C1-C6alkyl, (C1-C2alkylene) r -C3-C8cycloalkyl, (C1-C2alkylene) r -4-7 membered heterocycloalkyl, (C1-C2alkylene) r -5-6 membered heteroaryl, C(=O)-4-7 membered heterocycloalkyl, C(=O)-C1-C6alkyl, O-C1-C6alkyl, O-C3-C8cycloalkyl, or P(=O)(C1-C6alkyl)2, each r is independently selected from 0 or 1 ; or, R 3 Selected from one or more R 2b The following groups are substituted: C1-C6 alkyl, (C1-C2 alkylene) r -C3-C8 cycloalkyl, C(=O)-4-7 heterocyclic alkyl or C(=O)-C1-C6 alkyl, each r independently selected from 0 or 1; or; R 3 selected from the following groups optionally substituted with one or more R 2b C1-C6alkyl, (C1-C2alkylene) r C3-C8cycloalkyl, C(=O)-4-7 membered heterocycloalkyl, or C(=O)-C1-C6alkyl, each r is independently selected from 0 or 1, and each R 2b is independently selected from halogen (e.g., F), OH, O(C1-C4alkyl), or C1-C6alkyl optionally substituted with one or more halogen (e.g., F); or, R 3 selected from or, R 3 selected from The compound of Formula (I) according to any one of claims 1-7, or a stereoisomer or pharmaceutically acceptable salt thereof, each R 2b is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2, said C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2 being optionally substituted with one or more halogen (e.g., F); or, Each R 2b Independently selected from halogens, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or O (C1-C4 alkyl), wherein the C1-C6 alkyl group is optionally substituted with one or more halogens (e.g., F); or, Each R 2b Independently selected from halogens, CN, OH, C1-C6 alkyl or O (C1-C4 alkyl), wherein the C1-C6 alkyl is optionally substituted with one or more halogens (e.g., F); or, Each R 2b It is independently selected from OH or C1-C6 alkyl groups. The compound of Formula (I) according to any one of claims 1-8, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L 1 is selected from L a -L b -L c , said L a , L b is each independently selected from a bond, C1-C4 alkylene, or C3-C6 cycloalkylene, said C1-C4 alkylene or C3-C6 cycloalkylene optionally substituted with one or more R 3b , L c is selected from -O- or -NH(C=O)-, and each R 3b is independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, O(C1-C4 alkyl), NH(C1-C4 alkyl), or N(C1-C4 alkyl)2; or, L 1 is selected from L a -L b -L c , one of L a and L b is selected from a chemical bond or C3-C6cycloalkylene, and the other of L a and L b is selected from C1-C2alkylene optionally substituted with one or more R 3b , L c is selected from -O- or -NH(C=O)-, each R 3b is independently selected from halogen, for example F; or, L 1 is selected from L a -L b -L c , one of L a and L b is selected from a chemical bond or a C3 cycloalkylene group, and the other of L a and L b is selected from a C1-C2 alkylene group, which is optionally substituted with one or more R 3b , L c is selected from -O- or -NH(C=O)-, each R 3b is independently selected from halogen, for example F; or, L 1 selected from -CH2CH2O-, or, L 1 selected from -CH2CH2O-. The compound of Formula (I) according to any one of claims 1, 3, and 5-9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z 1 , Z 2 , Z 3 , Z 4 is each independently selected from CR 9 , said R 9 is selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl; or, Z 1 , Z 2 , Z 3 , Z 4 each is independently selected from C-H or C-F; or, Z 1 is selected from C-H or C-F, Z 2 is C-F, Z 3 and Z 4 are both C-H; or, Z 1 is C-F, Z 2 is C-F, Z 3 and Z 4 are both C-H. The compound of Formula (I) according to claim 2 or 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R 9 is independently selected from H or F; or, each R 9 is independently selected from H or F. The compound of Formula (I) according to any one of claims 1-11, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from C6-C 10 aryl, 5-14 membered heteroaryl, or 4-14 membered heterocyclyl; or Ring B is selected from C6-C 10 aryl, 6-14 membered heteroaryl, or 6-14 membered heterocyclic group, wherein the 6-14 membered heteroaryl and 6-14 membered heterocyclic group each contain 1, 2, or 3 N atoms; or... Ring B is selected from C6aryl, C 10 aryl, 6-14 membered heteroaryl, or 6-14 membered heterocyclyl, each of which contains 1 or 2 N atoms; or, Ring B is selected from the *end is connected to R 6 covalently linked; or, Ring B is selected from The * end is covalently linked to R 6 covalently linked. The compound of Formula (I) according to any one of claims 1-12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R x is each independently selected from halogen, =0, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl, said OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl optionally substituted with one or more R 4b substituents; or Each R x Each is independently selected from halogens, =O, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the OH, NH2, or C1-C6 alkyl group is optionally converted by one or more R groups. 4b Replace; or, each R is independently selected from =0, CN, OH, C1-C6alkyl, or C3-C6cycloalkyl, said OH or C1-C6alkyl optionally substituted with one or more R x each independently selected from =0, CN, OH, C1-C6alkyl, or C3-C6cycloalkyl, said OH or C1-C6alkyl optionally substituted with one or more R 4b substituents; or, each R x are each independently selected from =0, CN, OH, C1-C6alkyl or C3-C6cycloalkyl, said OH or C1-C6alkyl being optionally substituted with one or more R 4b are each independently selected from =0, CN, OH, C1-C6alkyl or C3-C6cycloalkyl, said OH or C1-C6alkyl being optionally substituted with one or more R 4b are each independently selected from C3-C6cycloalkyl (such as cyclobutyl), C1-C6alkyl (such as methyl), OH or halogen (such as F); or, each R is independently selected from =0, CN, cyclopropyl, cyclobutyloxy, methoxy, OH, methyl, halogen, oxetanyl, x each R is independently selected from =0, CN, cyclopropyl, cyclobutyloxy, methoxy, OH, methyl, halogen, oxetanyl, methylamino, dimethylamino, CF3, or CF2H; or, each R is independently selected from =0, CN, cyclopropyl, cyclobutyloxy, methoxy, methyl, x each R is independently selected from =0, CN, cyclopropyl, cyclobutyloxy, methoxy, methyl, or CF3. The compound of Formula (I) according to any one of claims 1-13, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein each R 4b is independently selected from halogen, CN, OH, NH2, C(=0)-Ci-C6alkyl, Ci-C6alkyl, C3-C6cycloalkyl, or 4-7 membered heterocyclyl, optionally substituted with one or more R c is independently selected from halogen, CN, OH, NH2, Ci-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 0(Ci-C4alkyl), NH(Ci-C4alkyl), or N(Ci-C4alkyl)2; or, c is independently selected from halogen, CN, OH, NH2, Ci-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 0(Ci-C4alkyl), NH(Ci-C4alkyl), or N(Ci-C4alkyl)2; or, Each R 4b The components are independently selected from halogens, OH, C(=O)-C1-C6 alkyl, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C(=O)-C1-C6 alkyl or C1-C6 alkyl is optionally substituted by one or more OH groups. The compound of Formula (I) according to any one of claims 1-14, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein q is selected from 0, and R 7 , R 8 are each selected from H, or R 7 , R 8 and the carbon atom to which they are attached collectively form a cyclopropyl group. The compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein q is selected from 1, and R 7 , R 8 , R 10 , R 11 are each selected from H. The compound of Formula (I) according to claim 15, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 12 and R 13 are each independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or C(=O)-C1-C6 alkyl, or R 12 , R 13 and the nitrogen atom to which they are attached together form a 4-7 membered heterocyclyl, said C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, or C(=O)-C1-C6 alkyl is optionally substituted with one or more R 7b , and each R 7b is independently selected from deuterium, halogen, CN, OH, NH2, or C1-C6 alkyl; or R 12 and R 13 are each independently selected from H, C1, C2, C3, or C4alkyl, C3, C4, C5, or C6cycloalkyl, or C(=O)-C1-C2alkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocyclyl group, said alkyl, cycloalkyl, heterocyclyl, or C(=O)-C1-C2alkyl is optionally substituted with one or more R 7b and each R 7b is independently selected from deuterium, halogen (e.g., F), or OH; or, R 12 and R 13 each independently is selected from H, C1, C2, or C3alkyl, or C3or C4cycloalkyl, said alkyl being optionally substituted with one or more deuterium; or, R 12 and R 13 each independently is selected from H, methyl, ethyl optionally substituted with one or more halogen (e.g., F), cyclopropyl, cyclobutyl, isopropyl, CD3, acetyl optionally substituted with one or more OH, or R 12 , R 13 and the nitrogen atom to which they are attached collectively form a pyrrolidinyl group. The compound of Formula (I) according to claim 16, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 14 is selected from H or C1-C6 alkyl; or, R 14 is selected from H. The compound of Formula (I) according to any one of claims 1-14, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 6 is selected from or 4, 5, 6 or 7 membered heterocyclyl containing 1 or 2 nitrogen atoms, wherein R 6 is when q is 1, and R 7 , R 8 , R 10 , R 11 , and R 14 are each H; R 6 is q is 0, and R 7 and R 8 are each independently selected from H, C1, C2, C3, or C4alkyl, C3, C4, C5, or C6cycloalkyl, or C(=O)-C1-C2alkyl, or R 7 and R 8 together with the carbon atom to which they are attached form a cyclopropyl group, R 12 and R 13 are each independently selected from H, C1, C2, C3, or C4alkyl, C3, C4, C5, or C6cycloalkyl, or C(=O)-C1-C2alkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocyclyl group, said alkyl, cycloalkyl, heterocyclyl, or C(=O)-C1-C2alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen (e.g., F), and OH; or, R 6 selected from or, R 6 selected from The compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2 and 5-19, wherein y is selected from 0, 1, 2, 3 or 4; or, y is selected from 0, 1 or 2. The compound of Formula (I) according to any one of claims 1-11, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the structural element each independently selected from the group consisting of The compound of Formula (I) according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the following compounds or a pharmaceutically acceptable salt thereof: A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Use of a compound according to any one of claims 1 to 22, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, in the manufacture of a medicament for the prevention or treatment of a NMT (N-myristoyl transferase) related disease. A method of preventing or treating a NMT (N-myristoyl transferase) related disease in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1 to 22, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23. A compound according to any one of claims 1 to 22, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for use in the prevention or treatment of a NMT (N-myristoyl transferase) related disease. Use of a compound according to any one of claims 1 to 22, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, in the prevention or treatment of a NMT (N-myristoyl transferase) related disease.

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