Dihydropyrimidine-2,4(1H,3H)-dione-containing polycyclic derivative, pharmaceutical composition thereof, method of preparation thereof, and uses thereof

Abstract

This disclosure relates to dihydropyrimidine-2,4(1H,3H)-dione-containing polycyclic compounds or pharmaceutically acceptable salts thereof and compositions thereof that effectively reduce or regulate the expression level of broad-space zinc finger motif (WIZ) proteins and / or induce the expression of fetal hemoglobin (HbF), as well as methods for preparing them and their use in the treatment of subjects requiring them.

Description

[Technical Field]

[0001] This disclosure relates to the field of medicinal chemistry, and more particularly to polycyclic compounds containing dihydropyrimidine-2,4(1H,3H)-dione or pharmaceutically acceptable salts thereof and compositions thereof, which effectively reduce or regulate the expression levels of broad-space zinc finger motif (WIZ) proteins and / or induce the expression of fetal hemoglobin (HbF), as well as methods for their preparation and their use in the treatment of subjects requiring them. [Background technology]

[0002] Sickle cell disease (SCD) is caused by the pathological formation of sickle hemoglobin tetramers, which consist of two α-globin chains and two abnormal β-globin chains (HbS), where adenine is replaced by thymine in the β-globin gene (HBB), and the glutamic acid residue at position 6 is replaced by valine (Rees DC et al., Lancet, 2010, 376:2018-2031). Polymerization of deoxyHbS leads to malformations of red blood cells, attacks of vascular occlusive pain, hemolytic anemia, peripheral organ failure, and premature death, resulting in a high economic burden and a reduced quality of life (Martin B et al., Social burden of sickle cell disease in the UK, 17th Annual Meeting of the Society for Sickle Cell and Thalassemia (ASCAT), October 20-22, 2022). Elevated HbF levels in adult red blood cells significantly improve symptoms in patients with sickle cell disease (SCD) and some patients with β-Mediterranean anemia (Grevet JD et al., Science 2018, 361:285-290). Hydroxyureas are approved drugs that are thought to derive their benefits by promoting HbF production. However, data on the long-term benefits of hydroxyureas for all SCD patients, particularly regarding the prevention of chronic SCD complications, remain limited (Nevitt SJ et al., Cochrane Library Central Database, 2017, 4:CD002202). Therefore, SCD patients urgently need new treatment schemes to improve their quality of life and reduce long-term healthcare costs (Piel FB et al., N Engl JMed 2017, 376:1561-1573).

[0003] G9a methyltransferase is known to regulate HbF production by inhibiting the transcription of the fetal γ-globin gene (Krivega et al., Blood, 2015). WIZ has been reported to induce gene inhibition by retaining histone H3 lysine 9 methyltransferase G9a and GLP on chromatin and inducing the deposition of H3K9me1 and H3K9me2 (Bian C et al., Elife 2015, 4:e05606), which may promote the silencing of the γ-globin gene. WIZ is known to be a novel substrate for several CRBN-based molecular adhesive degraders (including immunomodulatory (IMiD) drugs and CC-122) (Yu HH et al., bioRxiv 2019 (doi:https: / / doi.org / 10.1101 / 595389), Hagner PR et al., Blood, 2015, 126:779-789). These compounds recruit WIZ to the Cul4 / DDB1 / RBX1 / CRBN E3 ligase complex, inducing WIZ ubiquitination, followed by proteasome degradation via a mechanism commonly present in IMiD substrates (Sievers, QL et al., Science 2018, 362, eaat0572). Therefore, restoring γ-globin synthesis and HbF production through WIZ degradation by molecular adhesives is a promising therapeutic strategy for treating sickle cell disease (SCD) and β-Mediterranean anemia. [Overview of the project] [Problems that the invention aims to solve]

[0004] The objective of this invention is to provide novel compounds that can reduce / regulate the expression level of WIZ protein. [Means for solving the problem]

[0005] In a first embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, Equation (I): [ka] Here, X1 and X2 are each independently a bond, -(CH2) n -, -CH(R 1 )(CH2) n -, -C(O)-, and -S(O)2-, and are selected from the group consisting of Ring A is independently selected from the group consisting of a C6-C 10 aryl group, a monocyclic 5- or 6-membered heteroaryl group, a bicyclic 9- or 10-membered heteroaryl group, and a tricyclic 12-, 13-, or 14-membered heteroaryl group, where each said heteroaryl group has, as ring members, 1, 2, or 3 heteroatoms independently selected from O, S, and N, and where said aryl group and heteroaryl group are optionally substituted by the same or different 1 to 6 substituents R 2 Ring B is independently selected from the group consisting of a C3-C8 cycloalkyl group, a 4- to 10-membered monocyclic or bicyclic heterocyclic group, a C6-C 10 aryl group, and a 5- to 10-membered heteroaryl group, where each said heterocyclic group and heteroaryl group has, as ring members, 1, 2, or 3 heteroatoms independently selected from O, S, and N, and where said cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are optionally substituted by the same or different 1 to 6 substituents R 3 Ring C is <00XXX00>

Chemical formula

[0006] In another preferred embodiment, the compound has the structure shown in formula (Ia), Equation (Ia): [ka] Here, X1 and X2 are independently bonded, -(CH2) n -, -CH(R 1 )(CH2) n Selected from the group consisting of -, -C(O)- and -S(O)2-, Ring A is C6-C 10 The group is independently selected from the group consisting of aryl groups, monocyclic 5-membered or 6-membered heteroaryl groups, bicyclic 9-membered or 10-membered heteroaryl groups, and tricyclic 12-membered, 13-membered, or 14-membered heteroaryl groups, where each heteroaryl group independently has one, two, or three heteroatoms selected from O, S, and N as ring members, where the aryl group and heteroaryl group have one to six identical or different substituents R 2 It can be arbitrarily replaced by, Ring B is a C3-C8 cycloalkyl group, a 4-10 member monocyclic or bicyclic heterocyclic group, or a C6-C 10 The group is independently selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, where the heterocyclic group and heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from O, S, and N as ring members, where the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each have 1 to 6 identical or different substituents R 3 It can be arbitrarily replaced by, Ring C is, [ka] , C6-C 10 Aryl group condensation C5-C7 cycloalkyl, C6-C 10 Heteroaryl group condensation C5-C7 cycloalkyl, C6-C 10 Aryl group condensation 5-7 membered heterocyclic group and C6-C 10A heterocyclic group is independently selected from the group consisting of a heteroaryl group condensation and a 5-7 membered heterocyclic group, where the heterocyclic group and the heteroaryl group have 1, 2, or 3 heteroatoms independently selected from O, S, and N as ring members, where the C6-C 10 Aryl group condensation C5-C7 cycloalkyl, C6-C 10 Heteroaryl group condensation C5-C7 cycloalkyl, C6-C 10 Aryl group condensation 5-7 membered heterocyclic group and C6-C 10 The heteroaryl group condensation 5-7 membered heterocyclic group has 1-6 identical or different substituents R 4 It can be arbitrarily replaced by, Ring D consists of a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, and a C6-C 10 A group independently selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, wherein the heterocyclic group and the heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from O, S, and N as ring members, and wherein the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each have 1 to 6 identical or different substituents R 5 It can be arbitrarily replaced by, Ring E consists of a C3-C8 cycloalkyl group, a 3-8 membered heterocyclic group, and a C6-C 10 A group independently selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, wherein the heterocyclic group and the heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from O, S, and N as ring members, and wherein the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each have 1 to 6 identical or different substituents R 6 It can be arbitrarily replaced by, Here, n is 0, 1, 2, or 3. -(CH2) n The H in - can be optionally substituted with deuterium, C1-C6 alkyl groups, and halogens. Each R 1 It is independently selected from the group consisting of H, deuterium, C1-C6 alkyl groups, and halogens. Each R 2This is independently selected from the group consisting of hydrogen, halogen, hydroxyl group, nitro group, cyano group, C1-C6 alkyl group, and C1-C6 haloalkyl group. Each R 3 and R 5 This is independently selected from the group consisting of hydrogen, halogen, hydroxyl group, nitro group, cyano group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C2-C6 alkenyloxy group, C2-C6 alkynyloxy group, C2-C6 alkanoyl group, C2-C6 alkyl ester, C1-C6 thioalkyl group, C1-C6 haloalkyl group, C1-C6 haloalkoxy group, hydroxy C1-C6 alkyl group, C3-C7 cycloalkyl group, and 3-8 membered heterocyclic groups, where the cycloalkyl group and heterocyclic group are optionally substituted with halogen, CN, and -OMe. R 4 and R 6 Each of these is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy group, C1-C6 haloalkoxy group, -CN, and -OH.

[0007] In another preferred embodiment, X1 is -CH2- or -CD2-. In another preferred embodiment, X2 is -CH2- or -CD2-.

[0008] In another preferred embodiment, the compound has the structure shown in formula (I-1), Equation (I-1): [ka] Here, X1, X2, ring A, ring B, ring D, and ring E are as defined above.

[0009] In another preferred embodiment, the present invention provides compounds represented by formula (I'), (I''), or (I'''), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, Equation (I'): [ka] Equation (I''): [ka] Equation (I'''): [ka] Here, R m This is independently selected from the group consisting of halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, -CN, and -OH. Here, [ka] teeth, [ka] One of the hydrogen atoms in CH is R m This indicates that it will be replaced by, X'1 is -(CH2) m -, -CH(R n1’ )(CH2) m -, -C(O)- or -S(O)2-, Ring B' is a C3-C8 cycloalkyl group, a 4-10 member monocyclic or bicyclic heterocyclic group, or a C6-C 10 Independently selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, where the heterocyclic group and the heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from O, S, and N as ring members. R n1 , R n2 and R n1’ These are, independently, halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, -CN, -OH, C3-C8 cycloalkyl groups, 4-10 membered monocyclic or bicyclic heterocyclic groups, and C6-C 10Selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, where the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally substituted with the same or different 1-6 substituents selected from the group consisting of halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, -CN, -OH, C3-C8 cycloalkyl groups, and 4-10 membered monocyclic or bicyclic heterocyclic groups. -(CH2) m The H in - can be optionally substituted with deuterium, C1-C6 alkyl groups, and halogens. m is 0, 1, 2, or 3.

[0010] In another preferred embodiment, X'1 is -(CH2)- or -(CD2)-. In another preferred embodiment, ring B' is selected from the group consisting of 4- to 6-membered monocyclic heterocyclic groups, preferably ring B' is selected from the group consisting of piperadinyl groups and piperidinyl groups. In another preferred embodiment, R n1 , R n2 and R n1’ Each of these groups is independently selected from the group consisting of a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0011] In another preferred embodiment, the compound has the structure shown in formula (I''''), Equation (I''''): [ka] Here, ring A' is C6-C 10Independently selected from the group consisting of an aryl group, a monocyclic 5- or 6-member heteroaryl group, a bicyclic 9- or 10-member heteroaryl group, and a tricyclic 12-, 13-, or 14-member heteroaryl group, wherein each said heteroaryl group independently has 1, 2, or 3 heteroatoms selected from O, S, and N as ring members, and wherein said aryl group and heteroaryl group are optionally substituted by the same or different 1 to 6 substituents R 2 ’; Each R 2 ’ is independently selected from the group consisting of hydrogen, halogen, hydroxy group, nitro group, cyano group, C1-C6 alkyl group, and C1-C6 haloalkyl group; X’’1 is -(CH2) m -, -CH(R n3 )(CH2) m -, -C(O)- or -S(O)2-; R n3 is independently selected from the group consisting of a C3-C8 cycloalkyl group, a 4- to 10-member monocyclic or bicyclic heterocyclic group, a C6-C 10 aryl group, and a 5- to 10-member heteroaryl group, wherein said alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are optionally substituted by the same or different 1 to 6 substituents selected from the group consisting of halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, -CN, and -OH; R n4 is halogen, C1-C6 alkyl group, C1-C6 alkoxy group, -CN, -OH, C3-C8 cycloalkyl group, 4- to 10-member monocyclic or bicyclic heterocyclic group, C6-C 10Independently selected from the group consisting of an aryl group and a 5- to 10-member heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are halogen, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, -CN, -OH, C3-C8 cycloalkyl group, optionally substituted by the same or different 1 to 6 substituents selected from the group consisting of a 4- to 10-member monocyclic or bicyclic heterocyclic group, g1 and g2 are each independently 0, 1 or 2.

[0012] In another preferred embodiment, ring A' is the same as the definition of ring A. In another preferred embodiment, wherein ring A is a 9-member heteroaryl group, and preferably, ring A is

Chemical formula

Chemical formula

[0013] In another preferred embodiment, ring A is

Chemical formula

[0014] In another preferred embodiment, ring A is [ka] Selected from the group consisting of, Here, [ka] These are, [ka] One of the hydrogen atoms in CH is R 2 This refers to being independently replaced by [another element]. Here, each R 2 This is independently selected from the group consisting of hydrogen, halogen, hydroxyl group, nitro group, cyano group, C1-C6 alkyl group, and C1-C6 haloalkyl group.

[0015] In another preferred embodiment, ring B is [ka] and [ka] Selected from the group consisting of, Y6 was independently selected from the group consisting of CH and N. Z1 and Z2 are each independently selected from the group consisting of CH and N. Each R 3 This is independently selected from the group consisting of hydrogen, halogen, hydroxyl group, nitro group, cyano group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C2-C6 alkenyloxy group, C2-C6 alkynyloxy group, C2-C6 alkanoyl group, C2-C6 alkyl ester, C1-C6 thioalkyl group, C1-C6 haloalkyl group, C1-C6 haloalkoxy group, hydroxy C1-C6 alkyl group, C3-C7 cycloalkyl group, and 3-8 membered heterocyclic groups, where the cycloalkyl group and heterocyclic group are optionally substituted with halogen, CN, and -OMe. p is 0, 1, 2, 3, or 4.

[0016] In another preferred embodiment, ring B is [ka] and [ka] It is selected from the group consisting of the following. In another preferred embodiment, ring B is [ka] , and [ka] It is selected from the group consisting of the following.

[0017] In another preferred embodiment, the compound has a structure represented by a chemical formula selected from the following formulas: Formula (II-1): [ka] Formula (II-2): [ka] Formula (II-3): [ka] Here, each X2 is bonded, -(CH2) n -, -CH(R 1 )(CH2) n Independently selected from the group consisting of -, -C(O)- and -S(O)2-, Y6 was independently selected from the group consisting of CH and N. p is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. R 1 , R 2 , R 3 Rings D and E are as defined above.

[0018] In another preferred embodiment, the compound has the structure shown in formula (III), Formula (III): [ka] Here, R 2 , R 3 X2, p, Y6, ring D, and ring E are as defined above.

[0019] In another preferred embodiment, the compound has the structure shown in formula (IV), Formula (IV): [ka] Here, R 2 , R 3 X2, Y6, ring D, and ring E are as defined above.

[0020] In another preferred embodiment, the compound has a structure represented by a chemical formula selected from the following formulas: Formula (IV-1): [ka] Formula (IV-2): [ka] Here, R 2 , R 3 X2, Y6, ring D, and ring E are as defined above.

[0021] In another preferred embodiment, the compound has a structure represented by a chemical formula selected from the following formulas: Formula (V-1): [ka] Formula (V-2): [ka] Formula (V-3): [ka] Formula (V-4): [ka] Here, R 2 , R 3 X2, Y6, ring D, and ring E are as defined above.

[0022] In another preferred embodiment, ring D is selected from the group consisting of C3-C7 cycloalkyl groups (preferably C3-C6 cycloalkyl groups) and 4-8 membered heterocyclic groups (preferably 4-7 membered heterocyclic groups), where the cycloalkyl group and heterocyclic group are each of the same or different substituents R 5 It can be arbitrarily replaced by, Preferably, ring D is [ka] Selected from the group consisting of, Here, each R 5 This group is independently selected from the group consisting of hydrogen, halogen, hydroxyl group, nitro group, cyano group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C2-C6 alkenyloxy group, C2-C6 alkynyloxy group, C2-C6 alkanoyl group, C2-C6 alkyl ester, C1-C6 thioalkyl group, C1-C6 haloalkyl group, C1-C6 haloalkoxy group, hydroxy C1-C6 alkyl group, C3-C7 cycloalkyl group, and 3-8 membered heterocyclic groups, where the cycloalkyl group and heterocyclic group are optionally substituted with halogen, CN, and -OMe, or two non-adjacent carbon atoms R 5 These, together with the non-adjacent carbon atoms to which they are bonded, form a bridging ring structure. Y7 was independently selected from the group consisting of CH and N. q is 0, 1, 2, or 3. More preferably, ring D is [ka] Selected from the group consisting of, Comfortable, each R 5 This is independently selected from the group consisting of hydrogen, halogen, hydroxyl group, nitro group, cyano group, C1-C3 alkyl group, C3-C7 cycloalkyl group, and C1-C3 haloalkyl group.

[0023] In another preferred embodiment, the compound has a structure represented by a chemical formula selected from the following formulas: Equation (VI-1): [ka] Equation (VI-2): [ka] Equation (VI-3): [ka] Formula (VI-4):

Chem.

[0024] In another preferred embodiment, the compound has a structure represented by a chemical formula selected from the following formulas, Formula (VII-1):

Chem.

Chem.

[0025] In another preferred embodiment, the compound has a structure represented by a chemical formula selected from the following formulas, Formula (VIII-1):

Chem.

Chem.

[0026] In another preferred embodiment, ring E is a C3-C6 cycloalkyl group, a 4- to 6-membered heterocyclic group, a C6-C 10Selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, where the heterocyclic group and heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from O, S, and N as ring members, where the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each have 1 to 6 identical or different substituents R 6 It can be arbitrarily replaced by, Here, each R 6 This includes hydrogen, halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, C2-C6 alkynyl groups, C2-C6 alkynyloxy groups, -CN, -OH, C3-C8 cycloalkyl groups, 3-8 membered heterocyclic groups, and C5-C 10 It is independently selected from the group consisting of heteroaryl groups.

[0027] In another preferred embodiment, ring E is [ka] Here, m1 = 0, 1, 2, 3, 4, In another preferred embodiment, ring E is [ka] And here, [ka] These are, [ka] One of the hydrogen atoms in CH is R 6 This indicates that it can be independently replaced by [another element].

[0028] In another preferred embodiment, ring E is [ka] And here, if W5, W6, W7, W8, and W9 appear, then CH, CD, N, O, S, and N(R)6 ) and CR 6 is independently selected from the group consisting of In another preferred embodiment, ring E is a 5- to 9-member heteroaryl group, wherein said heteroaryl group has, as ring members, 1, 2 or 3 heteroatoms each independently selected from O, S and N, wherein said heteroaryl group is optionally substituted by 1 to 3 substituents R 6 wherein each R is independently selected from the group consisting of hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, -CN, -OH, a C3-C8 cycloalkyl group and a 3- to 8-member heterocyclic group. 6 is independently selected from the group consisting of hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, -CN, -OH, a C3-C8 cycloalkyl group and a 3- to 8-member heterocyclic group.

[0029] In another preferred embodiment, ring E is a 5-member heteroaryl group having two nitrogen atoms, wherein said heteroaryl group is optionally substituted by 1 to 3 substituents R 6 wherein each R is independently selected from the group consisting of hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, -CN, -OH, a C3-C8 cycloalkyl group and a 3- to 8-member heterocyclic group. 6 is independently selected from the group consisting of hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, -CN, -OH, a C3-C8 cycloalkyl group and a 3- to 8-member heterocyclic group.

[0030] In another preferred embodiment, ring E is

Chemical formula

[0031] In another preferred embodiment, ring E is selected from the group consisting of a C3-C6 cycloalkyl group, a 4-6 membered heterocyclic group, a thiazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyridadinyl group, a pyrazyl group, and an indazolyl group, wherein the cycloalkyl group, heterocyclic group, thiazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyridadinyl group, a pyrazyl group, and an indazolyl group are each of the same or different 1 to 6 substituents R 6 It can be arbitrarily replaced by, Here, each R 6 This includes hydrogen, halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, C2-C6 alkynyl groups, C2-C6 alkynyloxy groups, -CN, -OH, C3-C8 cycloalkyl groups, 3-8 membered heterocyclic groups, and C5-C 10 It is independently selected from the group consisting of heteroaryl groups.

[0032] In another preferred embodiment, ring E is [ka] Selected from the group consisting of, Here, each R 6 This is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy group, C1-C6 haloalkoxy group, -CN, -OH, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclic groups.

[0033] e is 0, 1, 2, 3, 4, or 5. More preferably, ring E is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, [ka] Selected from.

[0034] In another preferred embodiment, R 6 When each of these appears, it is independently selected from the group consisting of F, Cl, Br, methyl group, ethyl group, isopropyl group, cyclopropyl group, -CF3, and -CHF2. In another preferred embodiment, R 2 These are F, Cl, Br, Me, -CF3, and -CHF2.

[0035] In another preferred embodiment, R 2 These are F, Cl, and Br. In another preferred embodiment, X2 is a bond or -CH2-. In another preferred embodiment, R 3 These are methyl, ethyl, and cyclopropyl groups.

[0036] In another preferred embodiment, each R 5 These are hydrogen, halogen, C1-C6 alkyl, C3-C7 cycloalkyl, and C1-C6 haloalkyl, preferably each R 5 These are hydrogen, F, Cl, Br, methyl group, and ethyl group. q is 0, 1, 2, or 3. Here, if q is 2 or greater, then two R 5 These atoms, together with the atoms to which they are bonded, can optionally form a carbocyclic or heterocyclic ring. In another preferred embodiment, Y6 is CH or N.

[0037] In another preferred embodiment, the compound is selected from the group consisting of the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0038] In another preferred embodiment, the compound is selected from the group consisting of the following: [ka] [ka] [ka]

[0039] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

[0040] In another preferred embodiment, the pharmaceutical composition is a tablet, capsule, granule, syrup, suspension, solution, dispersant, sustained-release formulation for oral or parenteral administration, intravenous injection formulation, subcutaneous injection formulation, inhalation formulation, transdermal formulation, rectal or vaginal suppository.

[0041] In a third aspect, the present invention provides uses for any compound according to the first aspect of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof in the preparation of drugs for treating diseases or conditions affected by WIZ proteolysis.

[0042] In another preferred embodiment, the present invention provides compounds according to the first aspect of the present invention or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof for treating diseases or conditions affected by the reactivation or increase of fetal hemoglobin expression in subjects requiring such treatment.

[0043] In a fourth aspect, the present invention provides a method for inhibiting, reducing, or eliminating the activity or expression of WIZ protein in the body of a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In another preferred embodiment, the disease or condition includes sickle cell anemia and β-Mediterranean anemia. [Modes for carrying out the invention]

[0044] term In this invention, unless otherwise specified, terms used have the general meanings known to those skilled in the art. As used herein, the term “alkyl group” refers to a branched or linear saturated aliphatic hydrocarbon group. In one embodiment, an alkyl group contains 1 to about 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more commonly 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, an alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, an alkyl group is C1-C2, C1-C3, or C1-C6. The specified ranges as used herein indicate that alkyl groups having members of each of the said ranges are considered distinct classes. For example, as used herein, the term C1-C6 alkyl group refers to a linear or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, meaning that each alkyl group is described as a distinct class. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. In one embodiment, the alkyl group is optionally substituted as described herein.

[0045] As used herein, the term “alkenyl group” refers to a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, where these double bonds may be located in stable sites on the chain. Non-limiting examples include C2-C6 alkenyl groups (e.g., C2, C3, C4, C5, C6) and C2-C4 alkenyl groups. As used herein, the designations represent alkenyl groups having each member of the range as a distinct class, as described in the alkyl group portion herein. Examples of alkenyl groups include, but are not limited to, vinyl groups, propenyl groups, and butadienyl groups (including 1,2-butadienyl and 1,3-butadienyl groups). In one embodiment, the alkenyl group may be optionally substituted as described herein.

[0046] As used herein, the term “alkynyl group” refers to a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, where these triple bonds can be located at any stable site on the chain, such as C2-C6 alkynyls (e.g., C2, C3, C4, C5, C6). As used herein, the specified range represents an alkynyl group having each member of the range as a separate class, as described in the alkyl portion herein. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl groups. In one embodiment, the alkynyl group may be optionally substituted as described herein.

[0047] As used herein, the term “alkoxy group” refers to an alkyl group having a specified number of carbon atoms, covalently bonded via an oxygen crosslink (-O-), as defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy, and 3-methylpentoxy groups. Similarly, “alkylthio group” or “thioalkyl group” refers to an alkyl group having a specified number of carbon atoms, covalently bonded via a sulfur crosslink (-S-), as defined above. Examples of thioalkyl groups include, but are not limited to, CH3-S-, CH3CH2-S-, and CH3-S-CH2-. In one embodiment, the alkoxy group may be optionally substituted as described herein.

[0048] As used herein, the term “alkenyloxy group” refers to an alkenyl group having a specified number of carbon atoms covalently bonded to a substituent via an oxygen bridge (-O-), as defined above. As used herein, the term “alkynyloxy group” refers to an alkynyl group having a specified number of carbon atoms covalently bonded to a substituent via an oxygen bridge (-O-), as defined above.

[0049] As used herein, the term “alkanoyl group” refers to an alkyl group having a specified number of carbon atoms, covalently bonded via a carbonyl (C=O) bridge, as defined above. The carbonyl carbon is included in the number of carbon atoms; i.e., a C2 alkanoyl group is a CH3(C=O) group. In one embodiment, the alkanoyl group may be optionally substituted as described herein. As used herein, the term "alkyl ester" refers to an alkyl group having a specified number of carbon atoms, wherein the alkyl group is covalently bonded via an ester bond. The direction of the ester bond can be any direction, for example, a -O(C=O) alkyl group or a -(C=O)O alkyl group. Examples of alkyl esters include, but are not limited to, -O(C=O)CH3, -O(C=O)CH2CH3, -(C=O)OCH3, and -(C=O)OCH2CH3.

[0050] As used herein, the term "cycloalkyl group" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic structure (including fused, bridging, and spirocyclic systems). The term "cycloalkyl group" includes cycloalkenyls (i.e., cyclic groups having at least one double bond). As used herein, C3-C8 cycloalkyl groups consist of 3 to 8 cyclic carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 cyclic carbon atoms). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and partially unsaturated groups such as cyclopentenyl and cyclohexenyl.

[0051] As used herein, the terms "amide" or "carboxamide" refer to -C(O)NR c R d This refers to R c and R d Each of these is independently selected from hydrogen, alkyl (e.g., C1-C6 alkyl), alkenyl (e.g., C2-C6 alkenyl group), alkynyl (e.g., C2-C6 alkynyl group), -C0-C4 alkyl (C3-C7 cycloalkyl), -C0-C4 alkyl (C3-C7 heterocyclic alkyl), -C0-C4 alkyl (aryl), and -C0-C4 alkyl (heteroaryl), or R c and R d These, together with the nitrogen atoms to which they are bonded, form a C3-C7 heterocyclic structure. In one embodiment, R c and R d Each base can be independently substituted as described herein.

[0052] As used herein, the term "haloalkyl group" refers to branched and linear alkyl groups substituted with one or more halogen atoms, the number of which can reach the maximum permissible value. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, monomethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl groups.

[0053] As used herein, the term “haloalkoxy group” refers to a haloalkyl group, as defined herein, bonded via oxygen crosslinking (oxygen in an alcohol group). As used herein, the terms "halo" or "halogen" refer independently to one of fluorine, chlorine, bromine, and iodine.

[0054] As used herein, the term “aryl group” refers to an aromatic group that contains only carbon atoms in the aromatic ring. In one embodiment, the aryl group consists of 1 to 3 single or fused rings and 6 to about 10 ring atoms (i.e., C6-C6). 10The aryl group includes, for example, 6, 7, 8, 9, or 10 ring atoms, and does not contain heteroatoms as ring members. In particular, such aryl groups may be further substituted with carbon atoms or non-carbon atoms or groups. Such substitutions may include condensation with a 5- to 7-membered saturated cyclic group, which optionally includes one or two heteroatoms independently selected from N, O, and S, forming, for example, a 3,4-methylenedioxyphenyl group. Examples of aryl groups include phenyl groups, naphthyl groups (including 1-naphthyl and 2-naphthyl groups), fluorenyl groups, and anthracene groups. In one embodiment, the aryl group is a side chain. An example of a side chain ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described herein.

[0055] As used herein, the term “heterocyclic group” refers to a saturated or partially unsaturated monocyclic or bicyclic group consisting of 4, 5, 6, 7, 8, 9, or 10 ring atoms (i.e., containing one or more double and / or triple bonds in the ring but not aromatic), where at least one ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon, where one or more ring atoms are optionally and independently substituted by one or more of the above substituents. In one embodiment, the sole heteroatom is oxygen. The heterocyclic group may be a monocyclic group having 4 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, and S), or a bicyclic group having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, and S), such as the [4,5], [5,5], [5,6], or [6,6] systems. In one embodiment, the sole heteroatom is sulfur.Examples of heterocyclic groups include pyrrolidinyl group, dihydrofuranyl group, tetrahydrothienyl group, tetrahydropyranyl group, dihydropyranyl group, tetrahydrothiopyranyl group, piperidino group, piperidonyl group, morpholino, thiomorpholino, thioxanyl group, piperazinyl group, homopiperazinyl group, azetidinyl group, oxetanyl group, thietanyl group, homopiperidinyl group, oxepanyl group, thiepanyl group, oxazepinyl group, diazepinyl group, thiazepinyl group, 2-pyrrolinyl group, 3-pyrrolinyl group, indlinyl group, 2H-pyranyl group, 4H-pyranyl group, dioxanyl group, 1,3-dioxolanyl group, pyrazolinyl group, dithianyl group, dithiolanyl group, dihydropyranyl group, and dihydrothienyl This includes, but is not limited to, the following groups: dihydrofuranyl group, dihydroisoquinolinyl group, tetrahydroisoquinolinyl group, pyrazolidinylimidazolinyl group, imidazolidinyl group, 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexanyl group, 3-azabicyclo[4.1.0]heptanyl group, azabicyclo[2.2.2]hexanyl group, 3H-indolyl group, quinolidinyl group, N-pyridylurea derivatives, and pyrrolopyrimidines. Spirocyclic structures are also included in this definition. Here, examples of heterocyclic groups in which one or two ring carbon atoms are substituted with oxo (=O) groups include pyrimidinonyl groups and 1,1-dioxothiomorpholinyl groups. Heterocyclic groups in this specification may be optionally and independently substituted with one or more substituents described herein.

[0056] As used herein, the term “heteroaryl group” can refer to a stable monocyclic aromatic ring containing 1 to 3 heteroatoms selected from N, O, and S, or in a particular embodiment, 1 to 2 heteroatoms, with the remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5 to 7-membered aromatic ring, the aromatic ring containing 1 to 3 heteroatoms selected from N, O, and S, or in a particular embodiment, 1 to 2 heteroatoms, with the remaining ring atoms being carbon. The 5 to 10-membered heteroaryl groups described herein may contain 5, 6, 7, 8, 9, or 10 ring atoms. In one embodiment, the sole heteroatom is nitrogen. In one embodiment, the sole heteroatom is oxygen. In one embodiment, the sole heteroatom is sulfur. Monocyclic heteroaryl groups typically contain 5 to 7 ring atoms. In a particular embodiment, a bicyclic heteroaryl group is a 9 to 10-membered heteroaryl group, i.e., a group containing 9 or 10 ring atoms, where one 5 to 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring. If the total number of S atoms and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent. In one embodiment, the total number of S atoms and O atoms in a heteroaryl group does not exceed 2. In another embodiment, the total number of S atoms and O atoms in an aromatic heterocyclic formula does not exceed 1.Examples of heteroaryl groups include pyridinyl (e.g., 2-pyridinyl group, 2-hydroxypyridinyl group, 3-pyridinyl group, 3-hydroxypyridinyl group, 4-pyridinyl group, 4-hydroxypyridinyl group), imidazolyl group, imidazopyridinyl group, pyrimidinyl (e.g., 4-hydroxypyridinyl group), pyrazolyl group, triazolyl group, pyrazinyl group, tetrazolyl group, furyl group, thienyl group, isoxazolyl group, thiazolyl group, oxadiazolyl group, oxazolyl group, isothiazolyl group, pyrrolyl group, quinolinyl group, isoquinolinyl group, and tetrahydr This includes, but is not limited to, the heteroaryl group, indolyl group, benzimidazolyl group, benzofuranyl group, synnolinyl group, indazolyl group, indolidinyl group, phthalazinyl group, pyridadinyl group, triazinyl group, isoindolyl group, pteridinyl group, prinyl group, oxadiazolyl group, triazolyl group, thiadiazolyl group, thiadiazolyl group, flazanyl group, benzoflazanyl group, benzothiophenyl group, benzothiazolyl group, benzoxazolyl group, quinazolinyl group, quinoxalinyl group, naphthilidinyl group, tetrahydrofuranyl group, and phlopyridinyl group. The heteroaryl group may be optionally and independently substituted with one or more substituents described herein.

[0057] As used herein, the term “substitution” means that, under conditions not exceeding the normal valence state of the specified atom, one or more hydrogen atoms on a specified atom or group are substituted by a portion selected from the indicated group. Unless otherwise specified, any heteroatom with a lower valence state is assumed to have enough hydrogen atoms to compensate for that valence state.

[0058] When a ring system is substituted by a substituent, this means that the substituent is bonded to one aromatic or non-aromatic ring system and substitutes for one of the available hydrogen atoms on the ring system. Specifically, [ka] teeth, [ka] If any one of the hydrogen atoms in the CH ring is R 2 Replaced by, i.e. [ka] teeth, [ka] It has a chemical formula selected from the group consisting of R, where R 2 This is as defined above.

[0059] Active ingredients As used herein, “compound of the present invention” means the compound represented by Formula I, and further includes pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. The compounds of the present invention can form salts, which are also included within the scope of the present invention. Unless otherwise specified, it should be understood that the compounds of the present invention include salts thereof. As used herein, the term “salt” refers to salts formed in the form of an acid or base from inorganic or organic acids and bases. Furthermore, if the compounds of the present invention contain a base fragment (including, but not limited to, pyridine or imidazole) or an acid fragment (including, but not limited to, a carboxylic acid), amphoteric ions that can form “internal salts” are also included within the scope of the term “salt.” Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, but other salts are also useful and can be used, for example, in separation or purification steps in the preparation process. The compounds of the present invention can form salts, for example, by reacting compound I with a certain amount (e.g., an equal amount) of acid or base and precipitating in a medium or by freeze-drying in an aqueous solution.

[0060] The compounds of the present invention comprise basic fragments containing, but not limited to, amines, pyridines, or imidazole rings, and these compounds can form salts with organic or inorganic acids. Typical acids that can form salts include acetic acid (e.g., trihaloacetic acid such as acetic acid or trifluoroacetic acid), adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, disulfuric acid, boric acid, butyric acid, citric acid, camphoric acid, camphor sulfonic acid, cyclopentanepropionic acid, diethylene glycolic acid, dodecyl sulfate, ethanesulfonic acid, fumaric acid, gluconic acid, glycerophosphate, hemisulfuric acid, heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and hydroxyethanesulfonic acid. This includes (e.g., 2-hydroxyethanesulfonic acid), lactic acid, maleic acid, methanesulfonic acid, naphthalenesulfonic acid (e.g., 2-naphthalenesulfonic acid), nicotinic acid, nitric acid, oxalic acid, pectinic acid, persulfate, phenylpropionic acid (e.g., 3-phenylpropionic acid), phosphoric acid, picric acid, neopentanoic acid, propionic acid, salicylic acid, succinic acid, sulfuric acid (e.g., formed with sulfuric acid), sulfonic acid, tartaric acid, thiocyanic acid, toluenesulfonic acid (e.g., toluenesulfonic acid), dodecanoic acid, etc.

[0061] Some compounds of the present invention may include acidic fragments containing but not limited to carboxylic acids, and these fragments can form salts with various organic or inorganic bases. Typical salts formed with bases include ammonium salts, alkali metal salts (e.g., sodium salts, lithium salts, and potassium salts), alkaline earth metal salts (e.g., calcium salts, and magnesium salts), salts formed with organic bases (e.g., organic amines) such as benzylamine, dicyclohexylamine, hydravamin (salt formed with N,N-bis(dehydroabietin)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, and tert-butylamine, as well as salts formed with amino acids (e.g., arginine, lysine, etc.). Nitrogen-containing basic groups can form quaternary ammonium salts with halides such as low molecular weight alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and hexadecyl groups), and aralkyl halides (e.g., bromides of benzyl and phenyl groups).

[0062] Prodrugs and solvates of the compounds of the present invention are also included within the scope of the present invention. The term "prodrug" as used herein refers to a compound produced by a metabolic or chemical transformation through a chemical process, used to prepare the compounds, salts, or solvates of the present invention for the treatment of related diseases. The compounds of the present invention include solvates such as hydrates. The compounds, salts, or solvates of the present invention can exist in tautomer forms, such as amides and iminoethers. All of these tautomers are included within the scope of the present invention.

[0063] All stereoisomers of the compounds (e.g., chiral carbon atoms that may exist due to various substitutions), including their enantiomer and diastereomer forms, are all within the scope of protection of this invention. Independent stereoisomers of this invention may not coexist with other isomers (e.g., as pure or substantially pure optical isomers with specific activity), or they may be mixtures (e.g., racemic compounds), or they may be mixtures formed with all other stereoisomers or parts thereof. Chiral centers in this invention have two configurations: S configuration or R configuration, as defined by the International Union of Pure and Applied Chemistry (IUPAC), established in 1974. Racemic compound forms can be separated by physical methods such as fractional crystallization, or by derivatization to diastereomers followed by separation crystallization, or by chiral column chromatography. Single optical isomers can be obtained from racemic compounds by appropriate methods, including but not limited to conventional methods such as precipitation using optically active salts followed by recrystallization.

[0064] When a stereocenter is labeled "*R" or "*S", this means that the absolute stereochemical properties of that stereocenter have not yet been determined (even if the bond diagram exhibits stereospecificity), but it is essentially a single configuration. In other words, "*R" can be an absolute R configuration or an absolute S configuration. Similarly, "*S" can be an absolute R configuration or an absolute S configuration. "*R" or "*S" is randomly assigned to this type of molecule. A stereocenter labeled "*R" can be the same as or different from another stereocenter labeled "*S" in a single configuration. A stereocenter labeled "*R" can be the same as or different from another stereocenter labeled "*R" in a single configuration. A stereocenter labeled "*S" can be another single configuration, the same as or different from another stereocenter labeled "*S".

[0065] For example, compound 102-B [ka] The absolute stereochemistry of is undetermined, and [ka] Compound 102-a has one of the structural formulas. [ka] The absolute stereochemistry of is undetermined, and [ka] Compound 102-a' has one of the following structural formulas (excluding the absolute stereochemistry of compound 102-B), and has one of the following structural formulas. [ka] The absolute stereochemistry of is determined to be cis isomer, and [ka] Compound 102-B' has one of the structural formulas. [ka] The absolute stereochemistry of is determined to be that of a trans isomer, and [ka] It has one of the following structural formulas.

[0066] In the present invention, the weight content of the compounds obtained sequentially by preparation, separation, and purification is 90% or more, for example, 95% or more and 99% or more ("extremely pure" compounds), and is as described herein. Furthermore, the "extremely pure" compounds of the present invention are also part of the present invention. All configuration isomers of the compounds of the present invention, whether in the form of mixtures, pure products, or highly pure products, are all within the scope of the present invention. The definition of the compounds of the present invention includes cis (Z) and trans (E) olefin isomers, as well as carbocyclic and heterocyclic cis and trans isomers.

[0067] Throughout this specification, groups and substituents can be selected to provide stable fragments and compounds. The definitions of specific functional groups and chemical terms are described in detail. In this invention, chemical elements are defined in accordance with the definitions in the Periodic Table of Elements (CAS edition) and the Handbook of Chemistry and Physics (75th edition). Definitions of specific functional groups are also provided. Furthermore, the fundamental principles of organic chemistry, specific functional groups, and reactivity are further introduced from the book "Organic Chemistry," written by Thomas Sorrell, published by University Science Books, Sausalito, 1999, which is incorporated herein by reference in its entirety.

[0068] Some compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. The present invention encompasses all compounds, including their cis and trans isomers, R-type and S-type enantiomers, diastereomers, (D)-type isomers, (L)-type isomers, racemic mixtures, and other mixtures. Furthermore, the chiral carbon atom may be represented as a substituent such as an alkyl group. All isomers and mixtures thereof are included in the present invention.

[0069] According to the present invention, a mixture of isomers may contain different proportions of isomers. For example, a mixture containing only two isomers may have combinations of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all of these proportions of isomers are within the scope of the present invention. Similar proportions readily understood by those skilled in the art, and proportions of more complex isomer mixtures, are also within the scope of the present invention.

[0070] The present invention also includes isotope-labeled compounds, which are equivalent to the original compounds as described herein. However, in practice, it is common for one or more atoms to be substituted with atoms of different atomic weights or mass numbers. The isotopes of the compounds that can be listed in the present invention are, 2 H, 3 H,13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 This invention includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. Compounds, enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates containing isotopes or other isotopic atoms are all within the scope of this invention. Some isotope-labeled compounds in this invention are, for example, radioisotopes. 3 H and 14 It also includes isotope-labeled compounds such as C, and can be used in experiments concerning the tissue distribution of drugs and substrates. Tritium ( 3 H) and carbon-14 ( 14 C) is relatively easy to prepare and detect. Furthermore, deuterium (i.e., 2 Heavier isotopes such as H) exhibit better metabolic stability and may be preferable in certain cases because they offer advantages in specific therapies, such as extended half-life or reduced in vivo dose. Isotope-labeled compounds can be prepared by conventional methods, i.e., by replacing non-isotope reagents that can be prepared using the disclosure scheme shown in the available examples with readily available isotope-labeled reagents.

[0071] When designing the synthesis of the compounds of the present invention, they can be prepared by asymmetric synthesis or derivatized with a chiral auxiliary agent. The resulting diastereomer mixture can be separated and the chiral auxiliary agent removed to obtain a pure enantiomer. Furthermore, if the molecule contains a basic functional group (e.g., an amino acid) or an acidic functional group (e.g., a carboxyl group), a diastereomer can be formed with a suitable optically active acid or base salt, and the pure enantiomer can be obtained by separating it using conventional methods (e.g., crystallization or chromatography).

[0072] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to extend their scope of application. In general, regardless of whether the term “substitution” appears before or after the term “any,” all general formulas containing substituents in the compounds of the present invention refer to the substitution of a hydrogen atom with a specific structural substituent. When multiple positions in a particular structure are substituted by multiple specific substituents, each substituent position may be identical or different. As used herein, the term “substitution” includes all substitutions that enable the substitution of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromaticcyclic and non-aromatic organic compounds. In the present invention, valence states such as heteroatom nitrogen may be supplemented by hydrogen substituents or any of the above-mentioned permissible organic compounds. Furthermore, the present invention is not intended to be limited to substituted organic compounds. The present invention considers that combinations of substituents and variable groups may be beneficial in the form of stable compounds for the treatment of diseases (e.g., infectious diseases or proliferative diseases). In this specification, the term "stable" refers to a stable compound that achieves the above objective by maintaining the integrity of its compound structure for a sufficiently long period of time, preferably for a sufficiently long period of time. Metabolites of the compound of this application and pharmaceutically acceptable salts thereof, as well as prodrugs of the compound of this application and pharmaceutically acceptable salts thereof in vivo, are also included in the claims.

[0073] Preparation method The methods for preparing the compounds of formula (I) of the present invention will be described in more detail below, but these specific methods are not limiting to the present invention. The compounds of the present invention can be easily prepared by any combination of the various synthesis methods described herein or known in the art, and such combinations can be easily achieved by those skilled in the art.

[0074] Pharmaceutical composition and administration method The pharmaceutical compositions of the present invention are used, for example, to prevent and / or treat diseases or conditions affected by WIZ protein degradation, such as sickle cell disease, β-Mediterranean anemia, anemia, or related hemoglobin disorders. Compounds of formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When used in combination, the compounds of formula (I) can be administered simultaneously or sequentially without altering the original drug administration plan. When used in combination with one or more other drugs, drug combinations including one or more known drugs and compounds of formula (I) are preferred. Drug combinations also include administering compounds of formula (I) and one or more known drugs within an overlapping period. When compound (I) is used in combination with one or more other drugs, the dosage of compound (I) or the known drug can be lower than the dosage when used alone.

[0075] The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to) injections, tablets, capsules, aerosols, suppositories, films, pills, topical applications, controlled-release formulations, sustained-release formulations, or nano-formulations. The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier, and the dosage is a safe and effective dose. Here, "safe and effective dose" refers to a dose of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, each dose of the pharmaceutical composition of the present invention contains 1 to 2000 mg of the compound, preferably 1 to 1000 mg of the compound. Preferably, "one formulation" is a capsule or a tablet.

[0076] "Pharmacochemically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that each component of the composition can be blended with each other in relation to the compounds of the present invention and among them without significantly reducing the potency of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0077] The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and typical methods of administration include (but are not limited to) oral, intratumor, rectal, injection (intravenous, intramuscular, or subcutaneous), and topical administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with components such as (a) fillers or compatibilizers such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants such as glycerin; (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) dissolution retarders such as paraffin; (f) absorption enhancers such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include a buffering agent.

[0078] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coating and shell materials (enteric coatings and other materials known in the art). They may contain opacifiers. The release of the active compound or compound of the composition can be delayed in a specific part of the gastrointestinal tract. Examples of embedding components are polymers and waxes. If necessary, the active compound can form microcapsules with one or more of the above excipients.

[0079] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, sesame seed oil, and sesame oil or combinations thereof.

[0080] In addition to these inert diluents, the composition may also include additives such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances. In addition to the active compound, the suspension may include suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or a combination thereof. Compositions for intramuscular injection may include physiologically acceptable sterile aqueous or aqueous solutions, dispersants, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersants. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and any suitable mixtures thereof.

[0081] Topical dosage forms of the compounds of the present invention include ointments, powders, patch preparations, aerosols, and inhalants. Under sterile conditions, the active ingredient is mixed with a physiologically acceptable carrier and any preservative, buffer, or propellant (if necessary).

[0082] The compounds of the present invention can be administered alone or in combination with any other pharmaceutically acceptable compounds. When the aforementioned pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., human) in need of treatment, where the dose is the effective amount of the drug. For a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dose must take into account factors such as the route of administration and the patient's health condition, all of which are within the scope of a skilled physician's expertise.

[0083] The present invention further provides a method for preparing a pharmaceutical composition, the method comprising the step of mixing a pharmaceutically acceptable carrier with a compound of formula (I) of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0084] The main advantages of this invention are as follows: 1. The compounds described in the present invention have a novel structure. 2. The compounds described in the present invention can effectively reduce or regulate the expression level of broad-space zinc finger structure domain (WIZ) proteins and / or induce the expression of fetal hemoglobin (HbF). 3. The compounds described in the present invention have low clearance, good oral exposure, and high oral bioavailability.

[0085] The present invention will be further described below with reference to specific examples. It should be understood that these examples are intended solely to illustrate the present invention and not to limit its scope. The specific conditions of the unspecified experimental methods described in the following examples are generally carried out under conventional conditions or according to the manufacturer's recommendations. Unless otherwise specified, percentages and quantities are by weight. [Examples]

[0086] Method for preparing the compound of the present invention The compounds of the present invention can be prepared by reactions and techniques known in the art, as well as by the methods described herein. Those skilled in the art will know that the methods for preparing the compounds of the present invention described herein are not limiting, and the steps in the methods are interchangeable and do not affect the structure of the final product. Preferably, the compounds described in the present invention can be prepared according to schemes 1 to 3.

[0087] Scheme 1 [ka] As shown in Figure 1, the compound of formula (II(1-2)) of the present invention can be prepared using conventional organic synthesis methods and commercially available raw materials.

[0088] General Stage 1: The starting material of A-1 is halogenated in ACN, DMF, or DCM solvent under NBS, NIS, or Br2 conditions, and then the intermediate is oxidized under MnO2 or other oxidizing reagent conditions. After obtaining the aldehyde intermediate, the piperazine derivative is coupled with the aldehyde in the presence of NaBH(AcO)3 and under AcOH catalysis to produce compound A-2.

[0089] General Stage 2: Compound A-2 is subjected to a Buchwald-Hartwig reaction under palladium catalysis or an Ullmann reaction under copper catalysis in a solvent (e.g., dioxane, DMF, or DMSO) to produce compound A-3. The yield of the cross-coupling reaction varies depending on the substrate and catalyst.

[0090] General Stage 3: The protecting group of compound A-3 can be removed with HCl / dioxane, TFA, or TFA and TfOH to obtain the deprotected compound A-4.

[0091] General Stage 4: The compounds of formula II(1-2) can be synthesized by reducing compound A-4 with a suitable aldehyde or ketone in the presence of a reducing agent (e.g., NaBH3CN) and AcOH. Alternatively, the compounds of formula II(1-2) can be synthesized by alkylating compound A-4 with a suitable alkyl halide, methanesulfonate, toluenesulfonate, or trifluoromethanesulfonate in the presence of an amine or carbonate base and a polar solvent (e.g., DIPEA or K2CO3 and DMF). Here, W3, Y2, Y1, ring D, and ring E are as defined in the claims.

[0092] Scheme 2 [ka] As shown in Figure 2, the compound of formula II(1-2) of the present invention can be prepared using conventional organic synthesis methods and commercially available raw materials.

[0093] General Stage 5: Compound B-2 is prepared by the Suzuki reaction and halogenation reaction. Under appropriate temperature and N2 protection, compound B-1 is reacted with a boric acid derivative in an organic solvent (e.g., THF, toluene, DMF, dioxane, etc.) in the presence of a palladium catalyst, ligand, and base (e.g., t-BuOK, Cs2CO3, NaH). The yield depends on the substrate, palladium, and ligand. To obtain compound B-2, the halogenation reaction is carried out under NBS, NIS, or Br2 conditions.

[0094] Following the second stage, proceed to general stage 2. To prepare compound B-3, compound B-2 is subjected to a Buchwald-Hartwig reaction or a Ullmann reaction under a copper catalyst in a solvent (e.g., dioxane, DMF, or DMSO) under palladium catalysis.

[0095] General Stage 6: The Boc group in compound B-3 can be removed by HCl / dioxane or other conditions (e.g., TFA).

[0096] General Stage 7: The compounds of formula II(1-2) can be synthesized by the reductive amination or alkylation reaction described in scheme 1, after which the protecting group is removed using TFA / TFOH, where W3, Y2, Y1, ring D and ring E are as defined in the claims.

[0097] Scheme 3 [ka] As shown in Figure 3, the compound of formula II-3 of the present invention can be prepared using conventional organic synthesis methods and commercially available raw materials.

[0098] General Stage 8: The amino group of commercially available 5-bromobenzo[d]isoxazole-3-amine is reacted with acrylonitrile under basic conditions (e.g., Cs2CO3). The cyano intermediate is then hydrolyzed with H2SO4 to produce amide C-2.

[0099] General Stage 9: Brominated C-2 can be substituted by the Suzuki reaction. To prepare compound C-3, the brominated compound and the boranyl group derivative are reacted in the presence of a palladium catalyst (e.g., Ruphos Pd G3), a solvent (e.g., DMF or dioxane), and a base (e.g., Cs2CO3).

[0100] General stage 10: In the presence of an amine or carbonate base (e.g., Cs2CO3) and a polar solvent (e.g., acetonitrile), the primary amide and amino groups of C-3 are cyclized with a carbonyl group equivalent to form a dihydrouracil moiety such as 1,1'-carbonyldiimidazole (CDI). The protecting group (e.g., Boc) can be removed at room temperature under acidic conditions to obtain the free amine C-4.

[0101] General Stage 11: C-4 can be converted to formula II-3 by reduction amination with a suitable aldehyde in the presence of a borohydride reagent (e.g., NaBH3CN), or by alkylation with a suitable alkyl halide, methanesulfonate, toluenesulfonate, or trifluoromethanesulfonate in the presence of an amine or carbonate base and a polar solvent (e.g., DIPEA or K2CO3 and DMF).

[0102] chemistry The following describes several methods for preparing the compounds of the present invention. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used directly without further purification. In the following specification, CAN refers to acetonitrile, AcOH refers to acetic acid, Boc refers to the tert-butoxycarbonyl group, Bn refers to the benzyl group, BH3 refers to borane, t-BuOK refers to potassium tert-butoxide, BINAP refers to 1,1'-binaphthyl-2,2'-diphenylmethylphosphine, calcd. refers to calculation, Cbz refers to the benzyloxycarbonyl group, col. refers to column, conc refers to concentrated, CDI refers to 1,1'-carbonyldiimidazole, DCM refers to dichloromethane, and DIEA or DIPEA refers to N,N-diiso Propylethylamine is used, DMF is dimethylformamide, DMP is des-martinperioden, DMSO is dimethyl sulfoxide, DPPP is 1,3-bis(diphenylphosphino)propane, Et3N is triethylamine, siRNA or EA is ethyl acetate, ee is enantiomer excess, ESI is electrospray ionization, FA is formic acid, HATU is 2-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate, Hex is hexane, and HNMR is... 1¹H refers to NMR, HCl refers to hydrochloric acid, HPLC refers to high-performance liquid chromatography, IPA refers to isopropanol, LC-MS or LCMS refers to liquid chromatography-mass spectrometry, LDA refers to lithium diisopropylamino, LAH refers to lithium aluminum hydride, Ms refers to sulfonyl group, NIS refers to N-iodosuccinimide, NBS refers to N-bromosuccinimide, and NaBH3CN is sodium borocyanohydride. PdCl2(dppf) refers to [1,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II), PdCl2(dba)3 refers to tris(dibenzylideneacetone)dipalladium(O), t R or Rt refers to the retention time. (s) (s) or (s) refers to a solid, sat. refers to saturated, SFC refers to supercritical fluid chromatography, SOCl2 refers to thionyl chloride, TBAF refers to tetrabutylammonium fluoride, TBS refers to tert-butyldimethylsilyl group, TEA refers to triethylamine, T3P refers to n-propylphosphonic anhydride, THF refers to tetrahydrofuran, TFA refers to trifluoroacetic acid, T or Temp refers to temperature, TMS refers to trimethylsilyl group, TsCl refers to 4-toluenesulfonyl chloride, Tf2O refers to trifluoromethanesulfonic anhydride, TfOH refers to trifluoromethanesulfonic acid, K2CO3 refers to potassium carbonate, RuPhosPd G3 refers to the RuPhos-G3-palladium ring, methanesulfonate (2-dicyclohexylphosphinol-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), and W refers to the wavelength.

[0103] Preparation of intermediates Preparation of intermediate INT-1: (S)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate potassium [ka]

[0104] Step 1: Synthesis of (((3S)-4-(tert-butoxycarbonyl)-3-methylpiperazine-1-ium-1-yl)methyl)trifluoroborate Under a nitrogen gas atmosphere, a mixture of potassium methyltrifluoroborate bromide (3.00 g, 14.9 mmol) and tert-butyl(2S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (3.14 g, 15.7 mmol) in tetrahydrofuran (30 mL) is stirred at 70°C for 18 hours. The mixture is concentrated under reduced pressure to obtain the crude product ((3S)-4-(tert-butoxycarbonyl)-3-methylpiperazine-1-ium-1-yl)methyl)trifluoroborate (6.14 g, crude product) (white solid), which can be used in the next step without further purification.

[0105] Step 2: Synthesis of potassium (S)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate Add K2CO3 (4.13 g, 29.9 mmol) to an acetone solution (90 mL) of (((3S)-4-(tert-butoxycarbonyl)-3-methylpiperazine-1-ium-1-yl)methyl)trifluoroborate (6.14 g, crude product). Stir the mixture at 25°C for 12 hours. Filter the mixture and wash the filter cake with acetone (50 mL). Then dry the filter cake to obtain a white solid (S)-((4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl)methyl)trifluoroborate potassium (7.5 g, crude product). 1H NMR(400MHz,DMSO-d6)δ 3.98-3.86(m,1H),3.57-3.48(m,1H),2.92-2.83(m,1H),2.79(d,J=11.6Hz,1H),2.69(d,J=11.6H z,1H),1.73-1.66(m,1H),1.56-1.45(m,1H),1.37(s,9H),1.23-1.14(m,2H),1.10(d,J=6.8Hz,3H)

[0106] Preparation of intermediates INT-2 and INT-3: (S)-1-(5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0107] Step 1: Synthesis of (S)-2-methyl-4-(pyrazolo[1,5-a]pyridine-5-ylmethyl)piperazine-1-carboxylate tert-butyl ester A mixture of 5-bromopyrazolo[1,5-a]pyridine (500 mg, 2.54 mmol), [(3S)-4-tert-butoxycarbonyl-3-methylpiperazin-1-yl]methyltrifluoroborane potassium (2.44 g, 7.61 mmol), Cs2CO3 (2.48 g, 7.61 mmol), toluene (5 mL), and water (1 mL) was added to a microwave test tube, then purged with nitrogen gas for 5 minutes, and treated with RuPhos Pd G3 (212 mg, 254 μmol). The mixture was again purged with nitrogen gas for 5 minutes, and then stirred at 100°C for 1 hour under microwave irradiation. The mixture was concentrated under reduced pressure and purified by high-performance silica gel chromatography (ISCO®, 12g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient elution, 20 mL / min) to obtain (S)-2-methyl-4-(pyrazolo[1,5-a]pyridine-5-ylmethyl)piperazine-1-carboxylate tert-butyl ester (900 mg, yield 75.1%, purity 70%) as a white solid. f= 0.3 (petroleum ether:ethyl acetate = 3:1). 1 1H NMR (400MHz, CDCl3)δ 8.41(d,J=7.2Hz,1H),7.93(d,J=2.0Hz,1H),7.42(s,1H),6.84(dd,J=1.2,7.2 Hz,1H),6.45(d,J=1.6Hz,1H),4.20(s,1H),3.83(d,J=12.8Hz,1H),3.58-3.35( m,2H),3.18-3.06(m,1H),2.78(d,J=11.2Hz,1H),2.59(d,J=12.0Hz,1H),2.18 (dd,J=4.0,11.2Hz,1H),2.11-2.01(m,1H),1.46(s,9H),1.25(d,J=6.8Hz,3H).

[0108] Step 2: Synthesis of (S)-4-((3-iodopyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (2S)-2-methyl-4-(pyrazolo[1,5-a]pyridine-5-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.21 mmol) ACN solution (5 mL) is mixed with NIS (327 mg, 1.45 mmol). The mixture is stirred at 25°C for 30 minutes. The mixture is concentrated under reduced pressure to obtain the residue, which is purified by high-performance silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient elution, 30 mL / min) to obtain (S)-4-((3-iodopyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (367 mg, yield 66.4%) as a white solid. f = 0.6 (petroleum ether:ethyl acetate = 3:1). 1H NMR(400MHz,DMSO-d6)δ 8.69(d,J=7.2Hz,1H),8.08(s,1H),7.40(s,1H),6.93(d,J=7.2Hz,1H),4.14-4.06(m,1H),3.74-3.68(m,1H),3.67-3.62(m,1H) ,3.48-3.44(m,1H),3.11-2.99(m,1H),2.84-2.77(m,1H),2.64-2.59(m,1H),2.12-2.01(m,2H),1.40(s,9H),1.23-1.19(m,3H).

[0109] Step 3: Synthesis of (S)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester To a solution of (S)-4-((3-iodopyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (267 mg, 585 μmol) and 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (164 mg, 702 μmol) in dioxane (4 mL), CuI (22.3 mg, 117 μmol), Cs2CO3 (381 mg, 1.17 mmol), and (1S,2S)-cyclohexane-1,2-diamine (13.4 mg, 117 μmol) are added. The mixture is stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure and purified by high-performance silica gel chromatography (ISCO®, 4g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient elution, 15 mL / min) to obtain compound (S)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, yield 60.8%) as a colorless oil. f = 0.5 (ethyl acetate / petroleum ether = 0:1). 1H NMR(400MHz,CDCl3)δ 8.34(d,J=7.2Hz,1H),7.88(s,1H),7.43(d,J=8.8Hz,2H),7.19(s,1H),6. 93-6.77(m,3H),4.99(s,2H),4.26-4.17(m,1H),3.86-3.76(m,6H),3.57- 3.37(m,2H),3.17-3.07(m,1H),2.94(t,J=6.8Hz,2H),2.81-2.69(m,1H), 2.59(d,J=11.2Hz,1H),2.24-2.07(m,2H),1.46(s,9H),1.28-1.25(m,3H).

[0110] Step 4: Synthesis of (S)-3-(4-methoxybenzyl)-1-(5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride A mixture of (S)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (1.40 g, 2.49 mmol) and HCl / dioxane (4 M, 15 mL, 24.1 eq) is stirred at 20°C for 2 hours. The mixture is concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (conditions: 15% to 45% B phase (A phase: water (neutral), B phase: MeCN, flow rate: 30 mL / min)) and directly freeze-dried to obtain compound (S)-3-(4-methoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (1.2 g, 2.40 mmol, HCl salt) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.61(d,J=7.2Hz,1H),8.05(s,1H),7.41(s,1H),7.25(d,J=8.4Hz,2H),6.93-6.85(m,3H),4.83(s,2H),3.79(t,J=6.8Hz,2H),3.74(s, 3H),3.56(s,2H),3.24-3.18(m,2H),3.01-2.93(m,3H),2.89-2.79(m,2H),2.41-2.30(m,1H),2.19-2.08(m,1H),1.19(d,J=6.4Hz,3H).

[0111] Step 5: Synthesis of (S)-1-(5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A solution of (S)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (200 mg, 0.355 mmol) in TFA (3 mL) and TfOH (1 mL) is stirred at 25°C for 12 hours. The pH of the mixture was adjusted to 7-8 with a saturated NaHCO3 solution, and then concentrated under vacuum. Subsequently, it was purified by reverse-phase HPLC (conditions: 20-50% B phase (A phase: water (neutral), B phase: MeCN, 20 mL / min)), and then directly freeze-dried to obtain compound (S)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (80 mg, yield 65.7%, purity 70%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.47(s,1H),8.60(d,J=7.2Hz,1H),8.02(s,1H),7.49(s,1H),6.89(d,J=7.2Hz,1H),3.81-3.71(m,2H),3.5 6(s,2H),3.21-3.09(m,2H),2.95-2.75(m,6H),2.37-2.26(m,1H),2.14-2.05(m,1H),1.17(d,J=6.4Hz,3H).

[0112] Alternative synthesis method for INT-2-2: (S)-2-methyl-4-(pyrazolo[1,5-a]pyridine-5-ylmethyl)piperazine-1-carboxylate tert-butyl ester [ka]

[0113] Step 1: Synthesis of (2S)-2-methyl-4-(pyrazolo[1,5-a]pyridine-5-carbonyl)piperazine-1-carboxylate tert-butyl ester To a solution of pyrazolo[1,5-a]pyridine-5-carboxylic acid (2 g, 12.33 mmol) in DCM (30 mL), DIEA (3.19 g, 24.67 mmol) and HATU (5.16 g, 13.57 mmol) are added. The mixture is stirred at 25°C for 0.5 hours. Then, tert-butyl(2S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.47 g, 12.33 mmol) is added, and the mixture is stirred at 25°C for 1.5 hours. The mixture is poured into water (30 mL) and extracted with DCM (30 mL x 2). The combined organic extract is washed with saline solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance silica gel chromatography (ISCO®, 20g SepaFlash® silica flash column, eluent 0-80% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to obtain compound (2S)-2-methyl-4-(pyrazolo[1,5-a]pyridine-5-carbonyl)piperazine-1-carboxylic acid tert-butyl ester (4.47 g, crude product) as a yellow oily substance. f = 0.4 (petroleum ether / ethyl acetate = 1:1). 1H NMR(400MHz,CDCl3)δ 8.52(d,J=7.2Hz,1H),8.02(d,J=2.4Hz,1H),7.63(s,1H),6.79(dd,J=1.2,7.2Hz,1H),6.63(d,J=1.2Hz,1H),4.65-4. 22(m,2H),4.03-3.84(m,1H),3.68-3.33(m,1H),3.24-3.05(m,2H),2.88-2.86(m,1H),1.47(s,9H),1.24-1.01(m,3H). LCMS(ESI + ):m / z 345.4[M+H] + . .

[0114] Step 2: Synthesis of (2S)-2-methyl-4-(pyrazolo[1,5-a]pyridine-5-ylmethyl)piperazine-1-carboxylate tert-butyl ester At 0°C, dissolve (2S)-2-methyl-4-(pyrazolo[1,5-a]pyridine-5-carbonyl)piperazine-1-carboxylate tert-butyl ester (2g, 5.81 mmol) in THF (10 mL) and BH 3· Add THF (1M, 40.65 mL). Then stir the mixture at 75°C for 12 hours. Cool the reaction mixture to 0°C, then quench the reaction by adding methanol (10 mL) dropwise under N2 protection. Subsequently, heat the mixture to 60°C and hold for 2 hours, then cool to 25°C and concentrate under reduced pressure to obtain the residue. Purify the crude product by high-performance silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to obtain compound (2S)-2-methyl-4-(pyrazolo[1,5-a]pyridine-5-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (1.17 g, yield 61.0%) as a colorless oil. f = 0.3 (petroleum ether / ethyl acetate = 3:1). 11H NMR (400MHz, CDCl3)δ 8.41(d,J=7.2Hz,1H),7.93(d,J=2.0Hz,1H),7.42(s,1H),6.84(dd,J=1.6,7.2 Hz,1H),6.45(d,J=1.6Hz,1H),4.27-4.15(m,1H),3.87-3.77(m,1H),3.56-3.48 (m,1H),3.43-3.35(m,1H),3.18-3.07(m,1H),2.82-2.73(m,1H),2.63-2.56(m ,1H),2.21-2.14(m,1H),2.10-2.05(m,1H),1.46(s,9H),1.25(d,J=7.2Hz,3H). LCMS(ESI + ):m / z 331.5[M+H] + .

[0115] Preparation of intermediate INT-5: (S)-1-(2-fluoro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0116] Step 1: Synthesis of (1-aminopyridine-1-ium-4-yl)methanol; 2,4-dinitrophenol salt At 0°C, O-(2,4-dinitrophenyl)hydroxylamine (219 g, 1.10 mol) is added to a solution of 4-pyridinemethanol (120 g, 1.10 mol) in DCM (1600 mL). The mixture is stirred at 25°C for 12 hours. The mixture is concentrated under reduced pressure to obtain the crude product, which can be used in the next step without further purification. The compound (1-aminopyridine-1-ium-4-yl)methanol; 2,4-dinitrophenol salt (339 g, crude product) is obtained as a yellow solid.

[0117] Step 2: Synthesis of 2,2-difluorovinyl 4-methylbenzenesulfonate At -78°C, add n-butyllithium (2.5M, 19.7 mmol, 7.87 mL) dropwise to a solution of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (2.50 g, 9.83 mmol) in THF (30 mL) and continue for 10 minutes. After the addition is complete, stir the mixture at the same temperature for 30 minutes, then add THF (5 mL) and water (5 mL) dropwise at -78°C. Quench the reaction at 0°C by adding saturated NH4Cl (40 mL), then extract with EA (30 mL x 3). The combined organic layers were washed with saline solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was then purified by high-performance silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient elution, 35 mL / min) to obtain compound 2,2-difluorovinyl 4-methylbenzenesulfonate (1.80 g, yield 84.7%) as a colorless oil. f = 0.43 (petroleum ether:ethyl acetate = 3:1). 1 H NMR(400MHz, CDCl3)δ 7.82(d,J=8.4Hz,2H),7.39(d,J=8.4Hz,2H),6.08(dd,J=4.0,14.4Hz,1H),2.48(s,3H).

[0118] Step 3: Synthesis of (2-fluoropyrazolo[1,5-a]pyridine-5-yl)methanol At 0°C, add K2CO3 (22.4g, 162 mmol) and 2,2-difluorovinyl 4-methylbenzenesulfonate (7.60g, 32.4 mmol) to a 200 mL solution of dioxane containing (1-aminopyridine-1-ium-4-yl)methanol; 2,4-dinitrophenol salt. Stir the mixture at 60°C for 12 hours. Under the same conditions, perform the experiment in two batches as described above. Combine the results of the two batches of experiments. The mixture is poured into water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic extract is washed with saline solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by high-performance silica gel chromatography (ISCO®, 120g SepaFlash® silica flash column, eluent 0-100% ethyl acetate / petroleum ether gradient elution, 100 mL / min) to obtain the compound (2-fluoropyrazolo[1,5-a]pyridine-5-yl)methanol (3.8 g, yield 35.3%) as a yellow solid. f = 0.4 (petroleum ether:ethyl acetate = 1:1). 1 H NMR(400MHz, CDCl3)δ 8.22(d,J=7.2Hz,1H),7.39(s,1H),6.73(dd,J=1.6,7.2Hz,1H),5.97(d,J=5.6Hz,1H),4.72(d,J=3.2Hz,2H),1.98(br.s.,1H).

[0119] Step 4: Synthesis of 2-fluoropyrazolo[1,5-a]pyridine-5-carbaldehyde Add MnO2 (75.8 g, 830 mmol) to a solution of (2-fluoropyrazolo[1,5-a]pyridine-5-yl)methanol (13.8 g, 83.1 mmol) in DCM (150 mL). Stir the mixture at 25°C for 12 hours. The mixture is filtered and concentrated under reduced pressure to obtain the crude product. Compound 2-fluoropyrazolo[1,5-a]pyridine-5-carbaldehyde (12.48 g, crude product) is obtained as a white solid. 1 H NMR(400MHz, CDCl3)δ 10.14-9.85(m,1H),8.36(d,J=7.2Hz,1H),7.96(s,1H),7.29-7.26(m,1H),6.35(d,J=5.6Hz,1H).

[0120] Step 5: Synthesis of (S)-4-((2-fluoropyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester Add AcOH (6.85 g, 114 mmol, 6.53 mL) to a solution of 2-fluoropyrazolo[1,5-a]pyridine-5-carbaldehyde (12.48 g, 76.0 mmol) and tert-butyl(2S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (18.3 g, 91.2 mmol) in MeOH (150 mL). Stir the mixture at 50 °C for 12 hours. Then add NaBH3CN (9.56 g, 152 mmol) to the mixture and stir at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by high-performance silica gel chromatography (ISCO®, 120g SepaFlash® silica gel high-performance chromatography column, eluent 0-50% ethyl acetate / petroleum ether gradient elution, 100 mL / min) to obtain compound (S)-4-((2-fluoropyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (25.0 g, yield 94.4%) as a colorless oil. f = 0.3 (petroleum ether / ethyl acetate = 3:1). 1 H NMR(400MHz,CDCl3)δ 8.25-8.18(m,1H),7.30(s,1H),6.84(dd,J=1.6,7.2Hz,1H),5.93(d,J=5.2Hz,1H),4.26-4.16(m,1H),3.88-3.78(m,1H),3.55-3.33(m, 2H),3.20-3.06(m,1H),2.82-2.70(m,1H),2.63-2.52(m,1H),2.24-2.14(m,1H),2.08-2.05(m,1H),1.46(s,9H),1.25(d,J=6.8Hz,3H).

[0121] Step 6: Synthesis of (S)-4-((3-bromo-2-fluoropyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (S)-4-((2-fluoropyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (4.42 g, 12.7 mmol) is dissolved in DCM (50 mL) and NBS (2.71 g, 15.2 mmol) is added. The mixture is stirred at 25 °C for 1 hour. The mixture is diluted with DCM (20 mL), washed sequentially with H2O (5 mL x 2) and saline solution (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Compound (S)-4-((3-bromo-2-fluoropyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (4.9 g, yield 90.4%) is obtained as a white solid. f = 0.5 (petroleum ether:ethyl acetate = 3:1). 1 H NMR(400MHz,CDCl3)δ 8.20(d,J=7.2Hz,1H),7.32(s,1H),6.92(d,J=7.2Hz,1H),4.33-4.18(m,1H),3.91-3.81(m,1H),3.61-3.53(m,1H),3.47-3.39(m,1 H),3.21-3.08(m,1H),2.85-2.73(m,1H),2.65-2.55(m,1H),2.27-2.18(m,1H),2.16-2.07(m,1H),1.47(s,9H),1.29-1.26(m,3H).

[0122] Step 7: Synthesis of (S)-4-((2-fluoro-3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (S)-4-((3-bromo-2-fluoropyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (4.85 g, 11.4 mmol) and 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (3.19 g, 13.6 mmol) are dissolved in dioxane (50 mL) and CuI (1.08 g, 5.68 mmol), Cs2CO3 (7.40 g, 22.70 mmol), trans-(1S,2S)-cyclohexane-1,2-diamine (648 mg, 5.68 mmol), and 4AMS (7.40 g) are added. The mixture is stirred at 80°C for 12 hours. The mixture is filtered and concentrated under reduced pressure to obtain the crude product. The residue was purified by high-speed silica gel chromatography (ISCO®, 80g SepaFlash® silica flash column, eluent 0-80% ethyl acetate / petroleum ether gradient elution, 45 mL / min) to obtain compound (S)-4-((2-fluoro-3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (1.95 g, yield 29.6%) as a white solid. f = 0.2 (petroleum ether:ethyl acetate = 1:1). 1 H NMR(400MHz,CDCl3)δ 8.19-8.14(m,1H),7.42(d,J=8.8Hz,2H),7.10(s,1H),6.92(dd,J=1.6,7.2Hz,1H),6.87-6.79(m ,2H),5.03-4.92(m,2H),4.25-4.17(m,1H),3.87-3.81(m,1H),3.79(s,3H),3.75(t,J=6.8Hz,2H ),3.56-3.50(m,1H),3.40-3.33(m,1H),3.17-3.06(m,1H),2.93(t,J=6.7Hz,2H),2.79-2.71(m, 1H),2.60-2.51(m,1H),2.20-2.14(m,1H),2.13-2.06(m,1H),1.46(s,9H),1.23(d,J=7.2Hz,3H). LCMS(ESI + ):m / z 581.4[M+H]+

[0123] Step 8: Synthesis of (S)-1-(2-fluoro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (S)-4-((2-fluoro-3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (1.40 g, 2.41 mmol) is dissolved in DCM (2 mL) and HCl / dioxane (2 mL) is added. The mixture is stirred at 25 °C for 1 hour. The mixture is concentrated under reduced pressure to obtain the crude product. Compound (S)-1-(2-fluoro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.25 g, crude product, hydrochloride salt) is obtained as a yellow solid. The crude product can be used in the next step without further purification. LCMS (ESI + ):m / z 481.3[M+H] + .

[0124] Preparation of intermediate INT-6: 3-bromo-1-ethyl-4-fluoro-1H-pyrazole [ka]

[0125] Step 1: Synthesis of 4-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (INT-6-2) A solution of 4-fluoro-1H-pyrazole (2.0 g, 23.2 mmol) in THF (20 mL) is cooled to 0°C, and sodium hydride (828 mg, 34.8 mmol) is added. The mixture is stirred at 0°C for 30 minutes, and then dimethylaminosulfonyl chloride (4.3 g, 34.8 mmol, dissolved in 10 mL of THF) is added. The reaction mixture is stirred at room temperature for 2 hours. The reaction is quenched with H2O (100 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by high-performance silica gel chromatography (ISCO®, 25g SepaFlash® silica flash column, eluent 0-15% petroleum ether / ethyl acetate, 45 mL / min) to obtain compound 4-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (4.0 g, yield 88%) as a white solid. LCMS (ESI + ): m / z 194.2[M+H] + .

[0126] Step 2: Synthesis of 3-bromo-4-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (INT-6-3) A solution of 4-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (4.0 g, 21 mmol) in THF (50 mL) is cooled to -78°C. n-butyllithium (2.5 N, 9.2 mL, 23 mmol) is added dropwise. The mixture is stirred at -78°C for 1 hour. Then 1,2-dibromo-1,1,2,2-tetrachloroethane (7.5 g, 23 mmol, dissolved in 30 mL of THF) is added. The reaction mixture is stirred at -78°C for 2 hours. The reaction is quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by high-performance silica gel chromatography (ISCO®, 50g SepaFlash® silica flash column, eluent 0-15% petroleum ether / ethyl acetate, 60 mL / min) to obtain compound 3-bromo-4-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (5.0 g, yield 89%) as a white solid. LCMS (ESI + ):m / z 272.1[M+H] + .

[0127] Step 3: Synthesis of 3-bromo-4-fluoro-1H-pyrazole (INT-6-4) A mixture of 3-bromo-4-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (620 mg, 2.3 mmol) and TFA (1 mL) in DCM (5 mL) is stirred at 50°C for 1 hour. The reaction is quenched with saturated NaHCO3 aqueous solution (20 mL), and extracted with EA (15 mL x 2). The combined organic extract is washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a white solid (330 mg, yield 88%). This solid can be used in the next step without further purification. LCMS (ESI + ):m / z 165.1[M+H] + .

[0128] Step 4: Synthesis of 3-bromo-1-ethyl-4-fluoro-1H-pyrazole (INT-6) At 0°C, add sodium hydride (540 mg, 13.5 mmol) to a solution of 3-bromo-4-fluoro-1H-pyrazole (1.5 g, 9.0 mmol) in THF (20 mL). Stir the mixture at 0°C for 30 minutes. Then add iodoethane (2.1 g, 13.5 mmol, dissolved in 10 mL of THF). Stir the reaction mixture at room temperature for 2 hours. Quench the reaction with H₂O (100 mL) and extract with ethyl acetate (EA) (50 mL x 2). The combined organic extracts were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by high-performance silica gel chromatography (ISCO®, 25g SepaFlash® silica flash column, eluent 0-15% petroleum ether / ethyl acetate, 40 mL / min) to obtain compound 3-bromo-1-ethyl-4-fluoro-1H-pyrazole (1.4 g, yield 78%) as a colorless oil. LCMS (ESI + ): m / z 193.1[M+H] + .

[0129] Example 1: Preparation of Compound 1: (S)-4-(4-((4-((3-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)-3-fluorobenzonitrile [ka]

[0130] Step 1: Synthesis of 4-(4-(dimethoxymethyl)piperidine-1-yl)-3-fluorobenzonitrile To a solution of 4-(dimethoxymethyl)piperidine (500 mg, 3.14 mmol) in DMF (10 mL), K2CO3 (1.08 g, 7.85 mmol) and 3,4-difluorobenzonitrile (480 mg, 3.45 mmol) are added. The mixture is stirred at 120 °C for 12 hours. The mixture is concentrated under reduced pressure to obtain the crude product. The residue is purified by high-performance silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient elution, 35 mL / min) to obtain 4-(4-(dimethoxymethyl)piperidine-1-yl)-3-fluorobenzonitrile (700 mg, yield 80.1%) as a white solid. f = 0.5 (ethyl acetate / petroleum ether = 5:1). 1 H NMR(400MHz,DMSO-d6)δ 7.71-7.64(m,1H),7.57-7.52(m,1H),7.12(t,J=8.8Hz,1H),4.10(d,J=6.4Hz,1H),3.56(d,J=12.4H) z,2H),3.27(s,6H),2.76(t,J=12.4Hz,2H),1.74-1.69(m,2H),1.42-1.34(m,2H),1.15-1.09(m,1H).

[0131] Step 2: Synthesis of 3-fluoro-4-(4-formyl-1-piperidinyl)benzonitrile Add FA (1 mL) to a solution of 4-(4-(dimethoxymethyl)piperidine-1-yl)-3-fluorobenzonitrile (100 mg, 359 μmol, 1 eq) in H2O (0.3 mL). Stir the mixture at 50°C for 2 hours. Concentrate the mixture under reduced pressure to obtain 3-fluoro-4-(4-formyl-1-piperidinyl)benzonitrile (80 mg, crude product) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ 9.72(s,1H),7.36(d,J=8.4Hz,1H),7.29(d,J=2.0Hz,1H),6.93(t,J=8.8Hz,1H),3.5 4(m,2H),3.03-2.87(m,2H),2.54-2.38(m,1H),2.13-2.00(m,2H),1.91-1.78(m,2H).

[0132] Step 3: Synthesis of (S)-3-fluoro-4-(4-((4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)benzonitrile (S)-3-(4-methoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (94.5 mg, 189 μmol, HCl salt) was added to TEA (34.9 mg, 344 μmol) in a 2 mL solution of MeOH, and the mixture was stirred at 20°C for 30 minutes. Then, 3-fluoro-4-(4-formyl-1-piperidinyl)benzonitrile (40.0 mg, 172 μmol) and AcOH (36.2 mg, 603 μmol) were added. The mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to 20°C, and NaBH3CN (21.7 mg, 344 μmol) was added. The mixture was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure. The residue is purified by preparative TLC (DCM:MeOH=10:1) to obtain (S)-3-fluoro-4-(4-(4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)benzonitrile (40 mg, yield 15.7%, purity 46%) as a pale yellow oily substance. f =0.66(DCM / MeOH=10:1). LCMS(ESI + ):m / z 679.6[M+H] + .

[0133] Step 4: Synthesis of Compound 1: (S)-4-(4-((4-((3-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)-3-fluorobenzonitrile (S)-3-fluoro-4-[4-(4-(3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl]piperidine-1-yl]benzonitrile (40.0 mg, 58.9 μmol) in a TFA (0.5 mL) solution to which TfOH (0.5 mL) is added. The mixture is stirred at 20°C for 3 hours. The pH of the mixture is adjusted to 7-8 with an aqueous NaHCO3 solution. The resulting mixture is diluted with ethyl acetate (15 mL) and washed with water (15 mL). After phase separation, the aqueous layer is extracted with ethyl acetate (15 mL x 2). The combined organic extract is dried over anhydrous Na2SO4, filtered, and vacuum concentrated. The crude product was purified by reverse-phase HPLC (conditions: 40% to 60% of mobile phase B (mobile phase A: water (neutral), mobile phase B: MeCN, flow rate: 20 mL / min)) to obtain (S)-4-[4-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl]piperidine-1-yl)-3-fluorobenzonitrile (4.38 mg, 7.74 μmol, yield 13.13%, purity 98.708%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.47(s,1H),8.58(d,J=7.2Hz,1H),8.01(s,1H),7.67(d,J=13.6Hz,1H),7.54(d,J=8.0H z,1H),7.45(s,1H),7.11(t,J=8.8Hz,1H),6.89(d,J=7.2Hz,1H),3.77(t,J=6.8Hz,2H),3 .43-3.42(m,2H),2.81-2.75(m,5H),2.59-2.56(m,1H),2.48-2.30(m,2H),2.27-2.13(m, 2H),2.03-1.83(m,4H),1.74-1.62(m,2H),1.36-1.09(m,4H),0.98-0.93(m,3H),LCMS(ESI + ):m / z 559.2[M+H] + .

[0134] Example 2: Preparation of Compound 2: (S)-1-(5-((4-((4-(4-fluorophenyl)cyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0135] Step 1: Synthesis of 4-(4-fluorophenyl)cyclohexane-3-ene-1-carboxylate ethyl To a solution of 1-fluoro-4-iodobenzene (1 g, 4.50 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxabolhexacyclopentan-2-yl)cyclohexane-3-en-1-carboxylate ethyl (1.26 g, 4.50 mmol) in dioxane (10 mL) and water (2 mL), Pd(PPh3)4 (521 mg, 450 μmol) and K2CO3 (1.87 g, 13.5 mmol) are added. The mixture is stirred at 80°C for 16 hours under an N2 atmosphere. The mixture is diluted with ethyl acetate (20 mL) and washed with water (20 mL). After layer separation, the aqueous layer is extracted with ethyl acetate (20 mL x 2). The combined organic extract is dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (ISCO®, 12g SepaFlash® silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient elution, 25 mL / min) to obtain ethyl 4-(4-fluorophenyl)cyclohexane-3-ene-1-carboxylate (790 mg, yield 70.6%) as a yellow oil. f = 0.55 (petroleum ether:ethyl acetate = 10:1). 1 H NMR(400MHz,CDCl3)δ 7.36-7.28(m,2H),6.99(t,J=8.8Hz,2H),6.04(m,1H),4.17(q,J=7.2Hz,2H),2.66-2.56 (m,1H),2.55-2.38(m,4H),2.24-2.14(m,1H),1.91-1.76(m,1H),1.28(t,J=7.2Hz,3H).

[0136] Step 2: Synthesis of ethyl 4-(4-fluorophenyl)cyclohexane-1-carboxylate To a solution of ethyl 4-(4-fluorophenyl)cyclohexane-3-ene-1-carboxylate (790 mg, 3.18 mmol) in ethyl acetate (10 mL), wet Pd / C (339 mg, 318 μmol, 10% w / w) is added. The mixture is stirred at 20°C under an H2 atmosphere (15 psi) for 17 hours. The mixture is filtered through a diatomaceous earth pad and concentrated under reduced pressure. The residue is purified by high-performance silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient elution, 20 mL / min) to obtain ethyl 4-(4-fluorophenyl)cyclohexane-1-carboxylate (680 mg, yield 85.4%) as a colorless oil. f = 0.47 (petroleum ether:ethyl acetate = 10:1). 1 H NMR(400MHz,CDCl3)δ 7.19-7.10(m,2H),7.02-6.91(m,2H),4.23-4.11(m,2H),2.69(s,1H),2.59-2.44(m,1H),2.31-2.18(m,2H) ),2.10(d,J=11.2Hz,1H),2.02-1.91(m,1H),1.82-1.71(m,2H),1.64(d,J=8.8Hz,2H),1.33-1.26(m,3H).

[0137] Step 3: Synthesis of 4-(4-fluorophenyl)cyclohexane-1-carboxylic acid Add NaOMe (5.4M, 2.52mL) to a solution of ethyl 4-(4-fluorophenyl)cyclohexanecarboxylate (680 mg, 2.72 mmol) in MeOH (5 mL). Stir the mixture at 50°C for 16 hours. Remove the MeOH by concentrating the mixture under reduced pressure. Dilute the residue with water (10 mL) and adjust the pH to 4-5 with 1N HCl aqueous solution. Dilute the resulting mixture with ethyl acetate (20 mL) and wash with water (20 mL). After layering, extract the aqueous layer with ethyl acetate (20 mL x 2). Dry the combined organic extract over Na2SO4, filter, and concentrate under reduced pressure to obtain 4-(4-fluorophenyl)cyclohexanecarboxylic acid (650 mg, crude product) as a yellow solid.

[0138] Step 4: Synthesis of (4-(4-fluorophenyl)cyclohexyl)methanol Under an N2 atmosphere at 0°C, LiAlH4 (1M, 4.39mL) is added dropwise to a solution of 4-(4-fluorophenyl)cyclohexanecarboxylic acid (650 mg, 2.92 mmol) in THF (6 mL). The mixture is stirred at 20°C for 1 hour. The mixture is quenched at 0°C by adding water (200 μL). Then, potassium sodium tartrate aqueous solution (10 mL) is added to the resulting mixture and stirred for 30 minutes. The mixture is diluted with ethyl acetate (20 mL) and washed with water (20 mL). After layering, the aqueous layer is extracted with ethyl acetate (20 mL x 2). The combined organic extract is dried over Na2SO4, filtered, and vacuum concentrated to obtain (4-(4-fluorophenyl)cyclohexyl)methanol (400 mg, crude product) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.20-7.12(m,2H),6.97(t,J=8.8Hz,2H),3.52(d,J=6.0Hz,2H),2.55-2.42(m,1H),1.95-1.91(m,4H),1.57-1.38(m,4H),1.19-1.06(m,2H).

[0139] Step 5: Synthesis of 4-(4-fluorophenyl)cyclohexanecarbaldehyde To a solution of (4-(4-fluorophenyl)cyclohexyl)methanol (130 mg, 624.19 μmol) in DCM (2 mL), phosphorus pentachloride (PCC) (201.82 mg, 936.28 μmol) is added. The mixture is stirred at 20°C for 2 hours. The mixture is filtered through a diatomaceous earth pad and then concentrated under vacuum to obtain 4-(4-fluorophenyl)cyclohexanecarbaldehyde (100 mg, crude product) as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ 9.68(s,1H),7.19-7.13(m,2H),7.04-6.95(m,2H),2.55-2.44(m,1H),2. 35-2.26(m,1H),2.15-2.10(m,2H),2.03-2.00(m,2H),1.50-1.40(m,4H).

[0140] Step 6: Synthesis of (S)-1-(5-((4-((4-fluorophenyl)cyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (S)-3-(4-methoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (70.0 mg, 140.3 μmol, HCl salt) is dissolved in MeOH (2 mL) and TEA (28.4 mg, 281 μmol) is added, and the mixture is stirred at 20°C for 10 minutes. Then 4-(4-fluorophenyl)cyclohexanecarbaldehyde (57.9 mg, 281 μmol) and AcOH (29.5 mg, 491 μmol) are added. The mixture is stirred at 50°C for 2 hours. The reaction mixture is cooled to 20°C and NaBH3CN (17.6 mg, 280.6 μmol) is added. The mixture is stirred at 20°C for 14 hours. The mixture is concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=15:1) to obtain (S)-1-(5-((4-((4-(4-fluorophenyl)cyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (40 mg, yield 30.1%, purity 69%) as a yellow oily substance. f =0.43(DCM / MeOH=15:1). LCMS(ESI + ):m / z 653.6[M+H] + .

[0141] Step 7: Synthesis of Compound 2: (S)-1-(5-((4-((4-(4-fluorophenyl)cyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(5-((4-((4-(4-(4-fluorophenyl)cyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (40.0 mg, 61.27 μmol) is dissolved in TFA (0.5 mL) and TfOH (0.5 mL, 5.65 mmol) is added. The mixture is stirred at 20°C for 2 hours. The pH of the mixture is adjusted to 7-8 with saturated NaHCO3 solution. The resulting mixture is diluted with ethyl acetate (20 mL) and washed with water (20 mL). After phase separation, the aqueous layer is extracted with ethyl acetate (20 mL x 2). The combined organic extract is dried over anhydrous Na2SO4, filtered, and vacuum concentrated. The residue was purified by preparative HPLC (chromatographic column: Kromasil 100-5-C18 30×150 mm, mobile phase A: water (0.01% FA), mobile phase B: acetonitrile, 25 mL / min, gradient conditions from 10% B to 40%) to obtain (S)-1-(5-((4-((4-(4-(4-fluorophenyl)cyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.8 mg, yield 5.08%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.45(br.s,1H),8.58(d,J=7.2Hz,1H),8.01(s,1H),7.45(s,1H),7.32-7.18(m, 2H),7.15-7.01(m,2H),6.94-6.83(m,1H),3.85-3.69(m,2H),3.46-3.45(m,2H), 2.86-2.73(m,4H),2.70-2.65(m,1H),2.42-2.30(m,2H),2.28-2.18(m,2H),2.04 -1.91(m,3H),1.84-1.70(m,3H),1.58-1.33(m,4H),1.06-0.87(m,5H),LCMS(ESI + ):m / z 533.4[M+H] + .

[0142] Example 3: Preparation of Compound 3: (S)-1-(5-((4-((1-(4-fluorophenyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0143] Step 1: Synthesis of 4-(dimethoxymethyl)-1-(4-fluorophenyl)piperidine The reaction mixture of 1-fluoro-4-iodobenzene (1.00 g, 4.50 mmol), 4-(dimethoxymethyl)piperidine (1.43 g, 9.01 mmol), K2CO3 (1.25 g, 9.01 mmol), and L-proline (622 mg, 5.41 mmol) in DMSO (20 mL) was purged with a nitrogen gas stream for 3 minutes, and then CuI (257 mg, 1.35 mmol) was added. The resulting mixture was heated at 100 °C for 12 hours. The pH of the mixture was adjusted to 6-7 by adding saturated NaHCO3 aqueous solution, and then extracted with ethyl acetate (30 mL x 2). The combined organic extract was washed with saline solution (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance silica gel chromatography (ISCO®, 12g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient elution, 30 mL / min) to obtain 4-(dimethoxymethyl)-1-(4-fluorophenyl)piperidine (550 mg, yield 48.2%) as a colorless oil. f = 0.69 (ethyl acetate / petroleum ether = 5:1). 1 H NMR(400MHz,CDCl3)δ 7.01-6.86(m,4H),4.13-4.07(m,1H),3.57(d,J=12.0Hz,2H),3.38(s,6H),2. 62(t,J=11.6Hz,2H),1.90-1.82(m,2H),1.77-1.67(m,1H),1.53-1.43(m,2H).

[0144] Step 2: Synthesis of 1-(4-fluorophenyl)piperidine-4-carbaldehyde 4-(dimethoxymethyl)-1-(4-fluorophenyl)piperidine (0.1 g, 394.77 μmol) is added to a mixture of HCOOH (0.75 mL) and H2O (0.25 mL), and the mixture is then stirred at 50°C for 1 hour. The reaction mixture is concentrated under reduced pressure to obtain 1-(4-fluorophenyl)piperidine-4-carbaldehyde (90 mg, crude product, FA) as a yellow oily substance. LC-MS (ESI) + ):m / z 208.2[M+H] + .

[0145] Step 3: Synthesis of (S)-1-(5-((4-((1-(4-fluorophenyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione To a 2 mL solution of 1-(4-fluorophenyl)piperidine-4-carbaldehyde (71.06 mg, 280.56 μmol, 2 eq, FA) and (S)-3-(4-methoxybenzyl)-1-(5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (70.0 mg, 140 μmol, HCl), TEA (56.8 mg, 561 μmol) is added to adjust the pH to 7-8. The mixture is stirred for 0.5 hours, then AcOH (42.1 mg, 701 μmol) is added and the mixture is stirred at 25°C for 5.5 hours. Subsequently, NaBH3CN (26.5 mg, 421 μmol) is added to the mixture and the mixture is stirred at 25°C for 2 hours. The mixture is concentrated under reduced pressure to obtain the crude product. The crude product is purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain (S)-1-(5-((4-((1-(4-fluorophenyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (88.0 mg, crude product) as a yellow oily substance. LCMS (ESI +):m / z 654.6[M+H] + .

[0146] Step 4: Synthesis of Compound 3: (S)-1-(5-((4-((1-(4-fluorophenyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(5-((4-((1-(4-fluorophenyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (88.0 mg, 135 μmol) is added to a mixture of TFA (0.5 mL) and TfOH (0.5 mL). The mixture is stirred at 25°C for 0.5 hours. The pH of the mixture is adjusted to 7-8 with saturated NaHCO3 aqueous solution. The resulting mixture is diluted with ethyl acetate (5 mL) and washed with water (3 mL). After phase separation, the aqueous layer is extracted with ethyl acetate (5 mL x 2). The combined organic extract is dried over anhydrous Na2SO4, filtered, and vacuum concentrated. The residue was purified by preparative HPLC (chromatographic column: 100-5-C18 30×150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions: from 1% B to 40%) to obtain (S)-1-(5-((4-((1-(4-fluorophenyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (15.0 mg, yield 20.9%) as a white solid. 11H NMR (400MHz, DMSO-d6)δ 10.47(br.s,1H),8.58(d,J=6.8Hz,1H),8.01(s,1H),7.51-7.38(m,1H),7.05- 6.98(m,2H),6.96-6.86(m,3H),3.86-3.68(m,2H),3.53-3.51(m,2H),2.85-2. 72(m,5H),2.69-2.66(m,1H),2.37-2.31(m,2H),2.26-2.09(m,4H),1.99-1.81 (m,4H),1.74-1.49(m,2H),1.29-1.06(m,2H),0.95(d,J=5.6Hz,3H),LCMS(ESI + ):m / z 534.2[M+H] + .

[0147] Example 4: Preparation of Compound 4: (S)-6-(4-((4-((3-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile [ka]

[0148] Step 1: Synthesis of (S)-4-[[4-[[3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl]methyl]-2-methylpiperazine-1-yl]methyl]piperidine-1-carboxylate tert-butyl ester (S)-3-(4-methoxybenzyl)-1-(5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (585 mg, 1.17 mmol, HCl) is added to DCE (4 mL) and MeOH (4 mL). The mixture is stirred at 25°C for 5 minutes. Then 4-formylpiperidine-1-carboxylate tert-butyl ester (250 mg, 1.17 mmol) and AcOH (246 mg, 4.10 mmol) are added to the mixture. The mixture is stirred at 50°C for 12 hours. Then NaBH3CN (147 mg, 2.34 mmol) is added to the mixture at 25°C. The mixture is stirred at 25°C for 1 hour. The mixture is poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic extract is washed with saline solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This is purified by high-performance silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent 0-10% methanol / dichloromethane gradient elution, 20 mL / min) to obtain compound (S)-4-((4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (400 mg, yield 51.7%) as a white solid. f = 0.43 (dichloromethane:methanol = 10:1). 1H NMR(400MHz,CDCl3)δ 8.35(d,J=7.2Hz,1H),7.90(s,1H),7.43(d,J=8.6Hz,2H),7.24(s,1H),6.89-6.77 (m,3H),4.21-4.06(m,2H),3.80-3.77(m,3H),3.59-3.53(m,2H),3.51-3.46(m,4H) ,3.15-3.06(m,5H),3.00-2.94(m,2H),2.83-2.76(m,3H),2.72-2.68(m,1H),2.40- 2.33 (m, 2H), 1.93-1.77 (m, 3H), 1.72-1.66 (m, 1H), 1.45 (s, 9H), 1.26-1.16 (m, 4H).

[0149] Step 2: Synthesis of (S)-3-(4-methoxybenzyl)-1-(5-((3-methyl-4-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-4-((4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-carboxylate tert-butyl ester (400 mg, 606 μmol) is mixed with DCM (3 mL) and HCl / dioxane (3 mL) and stirred at 25°C for 1 hour. The mixture is concentrated under reduced pressure and used in the next step without further purification. Compound (S)-3-(4-methoxybenzyl)-1-(5-((3-methyl-4-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (360 mg, HCl, crude product) is obtained as a white solid. LCMS (ESI + ):m / z 560.4[M+H] + .

[0150] Step 3: Synthesis of (S)-6-(4-((4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (S)-3-(4-methoxybenzyl)-1-(5-((3-methyl-4-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (50 mg, 83.9 μmol, HCl) and 6-chloropyridine-3-nitrile (17.4 mg, 126 μmol) are dissolved in DMF (1 mL) and K2CO3 (46.4 mg, 335 μmol) is added. The mixture is stirred at 100 °C for 12 hours. The mixture was concentrated under reduced pressure and purified by high-performance silica gel chromatography (ISCO®, 4g SepaFlash® silica flash column, eluent 0-10% methanol / dichloromethane gradient elution, 20 mL / min) to obtain compound (S)-6-(4-((4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (29.0 mg, yield 40.2%) as a colorless oil. f =0.4 (Dichloromethane:Methanol = 10:1)LCMS(ESI + ):m / z 662.4[M+H] + .

[0151] Step 4: Synthesis of Compound 4: (S)-6-(4-((4-((3-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (S)-6-(4-((4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (29.0 mg, 43.8 μmol) is mixed with TFA (1 mL) and TfOH (1 mL) and stirred at 25°C for 12 hours. The pH of the mixture is adjusted to 7-8 with saturated NaHCO3 aqueous solution and then extracted with ethyl acetate (5 mL x 3). The organic layer was washed with saline solution (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. It was then purified by reverse-phase HPLC (conditions: 10% to 50% B phase (A phase: water (mobile phase A), B phase: acetonitrile, flow rate: 20 mL / min)) and directly freeze-dried to obtain compound (S)-6-(4-((4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (5.17 mg, yield 21.8%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.44(br.s.,1H),8.57(d,J=7.2Hz,1H),8.44(d,J=2.4Hz,1H),8.01(s,1H),7.79(dd,J=2.4,9. 2Hz,1H),7.44(s,1H),6.94-6.85(m,2H),4.47-4.33(m,2H),3.79-3.75(m,2H),3.01-2.85(m,3H) ,2.82-2.75(m,3H),2.70-2.52(m,3H),2.48-2.43(m,1H),2.37-2.30(m,1H),2.25-2.14(m,2H),1 .99-1.90(m,2H),1.88-1.76(m,2H),1.72-1.63(m,1H),1.11-0.96(m,2H),0.93(d,J=6.2Hz,3H). LCMS(ESI + ):m / z 542.3[M+H] + .

[0152] Example 5: Preparation of Compound 5: (S)-1-(5-((4-((1-(3-fluoro-4-methoxyphenyl)azetidine-3-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0153] Step 1: Synthesis of 1-(3-fluoro-4-methoxyphenyl)azetidine-3-carboxylate methyl ester A mixture of 4-bromo-2-fluoro-1-methoxybenzene (1.00 g, 4.88 mmol), methylazetidine-3-carboxylic acid ester (739 mg, 4.88 mmol, hydrochloride), XPhos (233 mg, 488 μmol), and Cs2CO3 (4.77 g, 14.6 mmol) in dioxane (10 mL) is degassed and purged three times with nitrogen gas. Then, Pd2(dba)3 (223.32 mg, 243.87 μmol) is added to the mixture, and the mixture is stirred at 100°C for 12 hours under an N2 atmosphere. H2O (20 mL) is added to the mixture, and it is extracted with DCM (30 mL x 3). The organic layer is dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by high-speed silica gel chromatography (ISCO®, 20g SepaFlash® silica flash column, eluent 0-50% ethyl acetate:petroleum ether, 100 mL / min) to obtain the compound methyl 1-(3-fluoro-4-methoxyphenyl)azetidine-3-carboxylic acid ester (700 mg, yield 60.0%). f =0.3 (petroleum ether / ethyl acetate = 4:1) is obtained as a yellow oily substance. LCMS (ESI + ):m / z 241.2[M+H] +

[0154] Step 2: Synthesis of 1-(3-fluoro-4-methoxyphenyl)azetidine-3-carbaldehyde At -78°C, add diisobutylaluminum (1.5 M, 1.25 mL, 1.88 mmol) dropwise to a solution of methyl 1-(3-fluoro-4-methoxyphenyl)azetidine-3-carboxylic acid (300 mg, 1.25 mmol) in DCM (15 mL). Stir the mixture at -78°C for 0.5 hours. Quench the mixture at 0°C with 50% Rochelle salt aqueous solution (10 mL). Stir the mixture at 25°C for 3 hours. Pour the mixture into water (10 mL) and extract with dichloromethane (DCM) (20 mL x 2). Wash the combined organic extract with saline solution (20 mL), dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain the crude product, which can be used in the next step without further purification. Compound 1-(3-fluoro-4-methoxyphenyl)azetidine-3-carbaldehyde (260 mg, 99.1% yield) is obtained as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 9.94(d,J=2.4Hz,1H),6.95-6.79(m,1H),6.32-6.23(m,1H),6.20-6.14(m,1H),4.04-3.95(m,4H),3.83(s,3H),3.48-3.44(m,1H).

[0155] Step 3: Synthesis of Compound 5: (S)-1-(5-((4-((1-(3-fluoro-4-methoxyphenyl)azetidine-3-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of (S)-1-(5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (16.37 mg, 47.80 μmol) in MeOH (3 mL), TEA (9.67 mg, 95.59 μmol, 13.31 μL) was added, and the mixture was stirred at 20°C for 10 minutes. Then, 1-(3-fluoro-4-methoxyphenyl)azetidine-3-carbaldehyde (10 mg, 47.80 μmol) and AcOH (5.74 mg, 95.59 μmol) were added. The mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to 20°C, and NaBH3CN (10.51 mg, 167.29 μmol) was added. The mixture was stirred at 20°C for 2 hours. The mixture is concentrated under reduced pressure to obtain the residue. The residue is purified by preparative HPLC (chromatography column: Kromasil 100-5-C18 30×150 mm, mobile phase A: water (0.01% TFA), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions: from 30% B to 70%). The pure trace is freeze-dried to obtain the compound, which is then redissolved in a solution of ACN (5 mL) and HCl (0.5%, 5 mL), and freeze-dried again to obtain the target product. Compound (S)-1-(5-((4-((1-(3-fluoro-4-methoxyphenyl)azetidine-3-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (4.62 mg, yield 16.90%, hydrochloride salt) is obtained as a white solid. 1H NMR(400MHz,DMSO-d6)δ 10.53(br.s.,1H),8.74(d,J=6.8Hz,1H),8.12(s,1H),7.98(s,1H),7.27(d,J=5.6Hz ,1H),7.10-6.93(m,1H),6.52-6.38(m,1H),6.36-6.22(m,1H),4.53-4.33(m,2H),4. 04-3.96(m,2H),3.84-3.78(m,4H),3.75-3.71(m,9H),3.35-3.29(m,1H),3.27-3.19 (m,1H),2.89-2.76(m,2H),2.63-2.54(m,1H),2.49-2.40(m,1H),1.45-1.33(m,3H). LCMS(ESI + ):m / z 536.2[M+H] + .

[0156] Example 6: Preparation of Compound 6: (S)-1-(5-((4-((1-(4-chloro-3-fluorophenyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0157] Step 1: Synthesis of 1-(4-chloro-3-fluorophenyl)-4-(dimethoxymethyl)piperidine To a solution of 4-bromo-1-chloro-2-fluorobenzene (395 mg, 1.88 mmol) in toluene (5 mL), 4-(dimethoxymethyl)piperidine (300 mg, 1.88 mmol), BINAP (117 mg, 188 μmol), Pd2(dba)3 (86.27 mg, 94.21 μmol), and t-BuONa (543 mg, 5.65 mmol) were added. The mixture was stirred at 100 °C for 12 hours under N2. The mixture was concentrated under reduced pressure, and the residue was purified by high-performance silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent 0-40% ethyl acetate / petroleum ether gradient elution, 30 mL / min) to obtain compound 1-(4-chloro-3-fluorophenyl)-4-(dimethoxymethyl)piperidine (400 mg, yield 73.8%) as a yellow oil. f = 0.5 (petroleum ether:ethyl acetate = 5:1). 1 H NMR(400MHz,CDCl3)δ 7.19(t,J=8.8Hz,1H),6.71-6.60(m,2H),4.07(d,J=7.2Hz,1H),3.71-3.62(m,2H), 3.37(s,6H),2.73-2.63(m,2H),1.87-1.80(m,2H),1.58(s,1H),1.44-1.36(m,2H).

[0158] Steps 2-4: Synthesis of compound 6: (S)-1-(5-((4-((1-(4-chloro-3-fluorophenyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Compound 3 is prepared using 1-(4-chloro-3-fluorophenyl)-4-(dimethoxymethyl)piperidine as a starting material, according to the synthesis steps of compound 3. Compound (S)-1-(5-((4-((1-(4-chloro-3-fluorophenyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (8.09 mg, yield 49.0%) is obtained as a white solid. 1H NMR(400MHz,DMSO-d6)δ 10.44(br.s.,1H),8.56(d,J=7.2Hz,1H),8.00(s,1H),7.43(s,1H),7.33-7.24(m,1H ),6.94-6.85(m,2H),6.77-6.71(m,1H),3.78-3.68(m,4H),2.77(t,J=6.4Hz,3H),2.7 1-2.53(m,5H),2.47-2.43(m,1H),2.38-2.32(m,1H),2.25-2.12(m,2H),1.98-1.89(m ,2H),1.85-1.78(m,1H),1.69-1.60(m,2H),1.27-0.99(m,3H),0.93(d,J=6.0Hz,3H). LCMS(ESI + ):m / z 568.3[M+H] + .

[0159] Example 7: The following compounds in Table 1 are prepared by the method of Compound 4. Table 1 [Table 1]

[0160] Example 8: Preparation of Compound 9: 1-(5-(((S)-4-(((1R,4S)-4-cyclopropylcyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0161] Step 1: Synthesis of (1R,4R)-4-formylcyclohexane-1-carboxylate methyl ester Add PCC (938.7 mg, 4.35 mmol) to a solution of methyl(1R,4R)-4-(hydroxymethyl)cyclohexane-1-carboxylate methyl ester (500 mg, 2.90 mmol) in DCM (5 mL). Stir the mixture at 25°C for 1 hour. Filter the mixture and concentrate under reduced pressure to obtain the crude product. Purify the residue by high-performance silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent 0-40% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to obtain methyl(1R,4R)-4-formylcyclohexane-1-carboxylate methyl ester (380 mg, yield 76.9%) as a white solid. f = 0.5 (petroleum ether:ethyl acetate = 4:1). 1 H NMR (400MHz, CDCl3) δ 9.64(s,1H),3.68(s,3H),2.34-2.20(m,2H),2.16-2.02(m,4H),1.57-1.42(m,2H),1.38-1.23(m,2H).

[0162] Step 2: Synthesis of (1R,4R)-4-vinylcyclohexane-1-carboxylate methyl ester Under an N2 atmosphere at 0°C, t-BuOK (1M, 17.6 mL) is added to a THF (30 mL) solution of methyltriphenylphosphonium bromide (6.30 g, 17.6 mmol). The mixture is stirred at 0°C for 1 hour. Then, a THF (20 mL) solution of (1R,4R)-4-formylcyclohexane-1-carboxylic acid ester (2 g, 11.7 mmol) is slowly added. The reaction mixture is heated to 20°C and stirred for 12 hours. The mixture is diluted with siRNA (20 mL) and washed with water (20 mL). After layering, the aqueous layer is extracted with siRNA (20 mL, secondary). The combined organic extracts are dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by high-performance silica gel chromatography (ISCO®, 20g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient elution, 20 mL / min) to obtain (1R,4R)-4-vinylcyclohexane-1-carboxylate methyl ester (660 mg, yield 33.4%) as a colorless liquid. f = 0.6 (petroleum ether:ethyl acetate = 4:1). 1 H NMR(400MHz,CDCl3)δ 5.82-5.70(m,1H),5.02-4.88(m,2H),3.69-3.64(m,3H),2.31-2.20(m,1H), 2.05-1.91(m,3H),1.91-1.79(m,2H),1.52-1.41(m,2H),1.19-1.05(m,2H).

[0163] Step 3: Synthesis of (1R,4R)-4-cyclopropylcyclohexane-1-carboxylate methyl ester Under a nitrogen atmosphere at 0°C, ZnEt2 (1M, 10.7 mL) is added dropwise to a 15 mL solution of (1R,4R)-4-vinylcyclohexane-1-carboxylate methyl ester (600.0 mg, 3.57 mmol) in DCM. Then chloroiodomethane (3.77 g, 21.40 mmol, 1.55 mL) is added dropwise. The mixture is stirred at 0°C for 2 hours. The reaction is quenched by adding 15 mL of saturated NH4Cl aqueous solution. The resulting mixture is diluted with DCM (20 mL) and washed with water (20 mL). After phase separation, the aqueous layer is extracted with DCM (20 mL). The combined organic extract is dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (1R,4R)-4-cyclopropylcyclohexane-1-carboxylate methyl ester (610 mg, crude product) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 3.68-3.62(m,3H),2.30-2.19(m,1H),2.01-1.94(m,2H),1.93-1.84(m,2H),1.41-1.2 8(m,2H),1.17-1.03(m,2H),0.51-0.41(m,2H),0.40-0.34(m,2H),0.08-0.01(m,2H).

[0164] Step 4: Synthesis of methyl((1R,4R)-4-cyclopropylcyclohexyl)methanol Under a nitrogen atmosphere at 0°C, LiAlH4 (1M, 5.02 mL) is added dropwise to a solution of (1R,4R)-4-cyclopropylcyclohexane-1-carboxylate methyl ester (610 mg, 3.35 mmol) in THF (8 mL). The mixture is stirred at 20°C for 2 hours. The mixture is quenched by adding an aqueous solution of Na2SO4.10H2O (10 mL) and stirred for 30 minutes. The mixture is diluted with HCl (20 mL) and washed with water (20 mL). After layering, the aqueous layer is extracted with HCl (20 mL x 2). The combined organic extract is dried over Na2SO4, filtered, and vacuum concentrated to obtain (1R,4R)-4-cyclopropylcyclohexyl)methanol (420 mg, crude product) as a colorless oil. 1H NMR(400MHz,CDCl3)δ 3.46-3.41(m,2H),1.89-1.77(m,4H),1.55-1.51(m,1H),1.16-1.03(m,2H),0.93-0.82(m,2H),0.51-0.33(m,4H),0.08-0.01(m,2H)

[0165] Step 5: Synthesis of (1R,4R)-4-cyclopropylcyclohexane-1-carbaldehyde PCC (157.2 mg, 729.3 μmol) is added to a solution of ((1R,4R)-4-cyclopropylcyclohexyl)methanol (75 mg, 486.2 μmol) in DCM (2 mL). The mixture is stirred at 20°C for 2 hours. The mixture is filtered through a diatomaceous earth pad and then concentrated under vacuum to obtain (1R,4R)-4-cyclopropylcyclohexane-1-carbaldehyde (50 mg, crude product) as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ 9.61(s,1H),2.25-2.13(m,1H),2.04-1.90(m,4H),1.31-1.07(m,5H),0.50-0.42(m,1H),0.41-0.33(m,2H),0.09-0.02(m,2H)

[0166] Step 6: Synthesis of Compound 9: 1-(5-(((S)-4-(((1R,4S)-4-cyclopropylcyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (30 mg, 79.2 μmol, HCl) is dissolved in MeOH (0.5 mL) and DMF (0.5 mL). TEA (16.03 mg, 158.4 μmol, 22.04 μL) is added to the solution and the mixture is stirred at 20°C for 10 minutes. Then (1R,4R)-4-cyclopropylcyclohexane-1-carbaldehyde (18.1 mg, 118.78 μmol) and AcOH (16.6 mg, 277.2 μmol, 15.9 μL) are added. The mixture is stirred at 50°C for 2 hours. The reaction mixture is cooled to 20°C and NaBH3CN (9.95 mg, 158.4 μmol) is added. The mixture is stirred at 20°C for 16 hours. The mixture is concentrated under reduced pressure. The crude product is purified by reverse-phase HPLC (conditions: 40%-70% B phase (A phase: water (neutral), B phase: acetonitrile, flow rate: 20 mL / min)) and directly freeze-dried. The crude product is then purified again by preparative TLC to obtain 1-(5-(((S)-4-(((1R,4S)-4-cyclopropylcyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.96 mg, yield 7.8%, purity 100%) as a white solid. f = 0.45 (dichloromethane:methanol = 10:1). 1 H NMR(400MHz,DMSO-d6)δ 10.50(s,1H),8.61(d,J=7.2Hz,1H),8.05(s,1H),7.48(s,1H),6.92(d,J=7.2Hz,1H),3.80( t,J=6.8Hz,2H),3.61(s,2H),2.83-2.80(m,2H),2.22-2.11(m,2H),2.00-1.86(m,4H),1.84- 1.74(m,3H),1.71-1.64(m,1H),1.56-1.41(m,3H),1.25-1.19(m,1H),1.17-1.03(m,3H),1. 01-0.92(m,3H),0.92-0.86(m,1H),0.52-0.45(m,2H),0.39-0.34(m,2H),0.08-0.04(m,2H).

[0167] Example 9: The following compounds in Table 2 are prepared by the method of Compound 6. Table 2 [Table 2-1] [Table 2-2] [Table 2-3]

[0168] Example 10: Preparation of Compound 16: (S)-6-(4-((4-((3-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile [ka]

[0169] Step 1: Synthesis of 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanenitrile At 25°C, add prop-2-enonitrile (2.07g, 39.0mmol) and Cs2CO3 (19.9g, 61.0mmol) to a solution of 5-bromo-1,2-benzoxazole-3-amine (10.0g, 46.9mmol) in ACN (100mL). Stir the mixture at 80°C for 12 hours. Dilute the mixture with ethyl acetate (50mL) and wash with water (100mL). After layer separation, extract the aqueous layer with ethyl acetate (50mL x 2). The combined organic extracts were dried over Na2SO4, filtered, and vacuum concentrated, then purified by high-performance silica gel chromatography (ISCO®, 120g SepaFlash® silica flash column, EA:PE gradient of 0-50% eluent, 100mL / min) to obtain compound 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanenitrile (8.5g, yield 31.9%) as a white solid.f = 0.5 (PE:Â=3:1). 1 H NMR(400MHz,CDCl3)δ 7.66(d,J=1.6Hz,1H),7.61(dd,J=1.6,8.8Hz,1H),7.33(d,J=8.8Hz,1H),4.84-4.77(m,1H),3.76(q,J=6.4Hz,2H),2.90(t,J=6.4Hz,2H).

[0170] Step 2: Synthesis of 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide Add H2SO4 (4 mL) to a TFA (20 mL) solution of 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanenitrile (7.00 g, 26.3 mmol). Stir the mixture at 25°C for 3 hours. Pour the mixture into water (40 mL) and extract with ethyl acetate (40 mL x 2). Dilute the mixture with ethyl acetate (40 mL) and extract with Na2CO3. (S) The solution is based to pH 9-10 and then filtered. The filter cake is washed with saline solution (30 mL), redissolved in a solution of CAN (30 mL) and water (15 mL), and freeze-dried to obtain the crude product. Compound 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide (22.0 g, crude product) is obtained as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.24(d,J=1.6Hz,1H),7.77(dd,J=1.6,8.8Hz,1H),7.57(d,J=8.8Hz,1H),7.49(br.s.,1 H),7.22(t,J=5.6Hz,1H),6.98(br.s.,1H),3.54(q,J=6.8Hz,2H),2.55(t,J=6.8Hz,2H)

[0171] Step 3: Synthesis of (S)-4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester A mixture of 3-((5-bromobenzo[d]isoxazole-3-yl)amino)propanamide (3.00 g, 10.6 mmol), [(3S)-4-tert-butoxycarbonyl-3-methylpiperazine-1-yl]methylpotassium-trifluoroborane (3.38 g, 10.6 mmol), RuPhos Pd G3 (883 mg, 1.06 mmol), and Cs2CO3 (6.88 g, 21.1 mmol) in toluene (30 mL) and water (6 mL) is degassed and purged three times with nitrogen gas, then stirred at 100°C for 12 hours under a nitrogen gas atmosphere. The mixture is poured into water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with saline solution (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by high-performance silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, methanol / dichloromethane gradient elution with 0-30% eluent, 40 mL / min) to obtain compound (S)-4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (880 mg, yield 20.0%) as a yellow oil. f = 0.2 (dichloromethane:methanol = 10:1). 1 1H NMR (400MHz, CDCl3)δ 7.50(dd,J=1.2,8.8Hz,1H),7.45-7.40(m,1H),7.34(d,J=8.8Hz,1H),5.68(br .s.,1H),5.44(br.s.,1H),5.15-5.08(m,1H),4.23-4.16(m,1H),3.84-3.72(m ,3H),3.60-3.44(m,2H),3.16-3.05(m,1H),2.77-2.68(m,3H),2.60-2.53(m,1 H),2.17-2.12(m,1H),2.04-1.97(m,1H),1.48-1.44(m,9H),1.25-1.21(m,3H).

[0172] Step 4: Synthesis of (S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester At 0°C, add NaH (402 mg, 10.1 mmol, 60% purity) to a THF (8 mL) solution containing (S)-4-((3-((3-amino-3-oxopropyl)amino)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (840 mg, 2.01 mmol). Stir the mixture at 0°C for 0.5 hours. At 0°C, add CDI (489 mg, 3.02 mmol) to the above solution. Stir the mixture at 25°C for 1.5 hours. Dilute the mixture with ethyl acetate (20 mL), quench with 2 M AcOH (5 mL), and extract with ethyl acetate (20 mL x 2). The combined organic extracts were washed with saline solution (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by high-performance silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent 0-10% methanol / dichloromethane gradient elution, flow rate 25 mL / min) to obtain compound (S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (410 mg, yield 38.6%) as a yellow oil. f = 0.4 (Dichloromethane:Methanol = 10:1). 1 H NMR(400MHz,CDCl3)δ 7.75(s,1H),7.63(d,J=8.8Hz,1H),7.50(d,J=8.8Hz,1H),4.24-4.22(m, 1H),3.91(dd,J=6.8,13.4Hz,2H),3.85-3.76(m,1H),3.75-3.67(m,2H), 3.65-3.48(m,2H),3.15-3.06(m,1H),2.95-2.89(m,2H),2.78-2.72(m,1 H),2.61-2.55(m,1H),2.18-2.13(m,1H),1.45(s,9H),1.24-1.23(m,3H).

[0173] Step 5: Synthesis of (S)-1-(5-((3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Add hydrochloric acid / dioxane (2 mL) to a solution of (S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-6-fluorobenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (410 mg, 924 μmol) in DCM (2 mL). Stir the mixture at 25°C for 1 hour. Concentrate the mixture under reduced pressure to obtain the crude product, which can be used in the next step without further purification. Compound (S)-1-(5-((3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (351 mg, hydrochloride, crude product) is obtained as a white solid. LCMS (ESI + ):m / z 344.2[M+H] + .

[0174] Step 6: Synthesis of Compound 16: (S)-6-(4-((4-((3-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (S)-1-(5-((3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (50 mg, 145.61 μmol) is mixed with Et3N (36.84 mg, 364.03 μmol) in a 1 mL solution of DMF. Then, 6-(4-formylpiperidine-1-yl)nicotinonitrile (31.34 mg, 145.61 μmol) and AcOH (30.6 mg, 510 μmol) are added to the solution. The mixture is stirred at 50°C for 12 hours. Then, the mixture is stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure and purified by reverse-phase HPLC (conditions: 10% to 40% B phase (A phase: water (FA), B phase: MeCN, flow rate: 20 mL / min)), and then directly freeze-dried to obtain compound (S)-6-(4-((4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (4.7 mg, yield 6.0%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.91(br.s.,1H),8.44(d,J=2.4Hz,1H),7.79(dd,J=2.4,9.2Hz,1H),7.72(s,1H),7.69-7.65 (m,1H),7.61-7.56(m,1H),6.90(d,J=9.2Hz,1H),4.46-4.34(m,2H),4.07(t,J=6.8Hz,2H),3.5 6-3.49(m,2H),2.99-2.86(m,2H),2.83-2.76(m,3H),2.63-2.54(m,2H),2.35-2.26(m,1H),2.2 0-2.10(m,2H),1.96-1.74(m,5H),1.71-1.64(m,1H),1.11-0.93(m,2H),0.90(d,J=6.4Hz,3H). LCMS(ESI + ):m / z 543.2[M+H] + .

[0175] Example 11: Preparation of Compound 17: (S)-6-(4-((4-((3-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)benzofuran-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile [ka]

[0176] Step 1: Synthesis of (S)-4-(benzofuran-5-ylmethyl)-2-methylpiperazine-1-carboxylate tert-butyl ester Add acetic acid (822 mg, 13.7 mmol, 783.4 μL) to a methanol (30 mL) solution of benzofuran-5-carbaldehyde (2.00 g, 13.7 mmol) and (S)-2-methylpiperazine-1-carboxylate tert-butyl ester (2.74 g, 13.7 mmol). Stir the mixture at 50°C for 2 hours. Then cool the mixture to 20°C and add NaBH3CN (1.72 g, 27.4 mmol). Stir the mixture at 20°C for 16 hours. Concentrate the mixture to remove the solvent. Dilute the residue with siRNA (30 mL) and wash with water (30 mL). After layering, extract the aqueous layer with siRNA (30 mL x 2). Dry the combined organic extract over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by high-speed silica gel chromatography (ISCO®, 20g SepaFlash® silica flash column, 0-20% ethyl:PE gradient elution, 40 mL / min) to obtain (S)-4-(benzofuran-5-ylmethyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (2.30 g, yield 43.2%) as a colorless oil. f = 0.55 (PE:τ=5:1). 1H NMR(400MHz,CDCl3)δ 7.61(d,J=2.0Hz,1H),7.55-7.51(m,1H),7.44(d,J=8.4Hz,1H),7.29(dd,J=1.6,8.4Hz ,1H),6.74(dd,J=0.8,2.4Hz,1H),4.24-4.15(m,1H),3.85-3.72(m,1H),3.64-3.56(m, 1H),3.52-3.45(m,1H),3.18-3.05(m,1H),2.77(d,J=11.2Hz,1H),2.61(d,J=11.2Hz,1 H),2.14(dd,J=4.0,11.2Hz,1H),2.04-1.96(m,1H),1.45(s,9H),1.24(d,J=6.8Hz,3H).

[0177] Step 2: Synthesis of (S)-4-((3-bromobenzofuran-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester Add bromine (Br2) (1.16 g, 7.26 mmol) to a solution of (S)-4-(benzofuran-5-ylmethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (1.20 g, 3.63 mmol) in DCM (15 mL). Stir the mixture at 20°C for 1.5 hours. Dilute the reaction with water (30 mL). Extract the resulting mixture with DCM (30 mL x 2). Dry the combined organic extract over Na2SO4, filter, and concentrate under reduced pressure. Dissolve the crude residue in THF (15 mL) and add a solution of KOH (407.6 mg, 7.26 mmol) in MeOH (4 mL). Stir the mixture at 20°C for 1 hour. Dilute the mixture with siRNA (30 mL) and wash with water (30 mL). After layering, extract the aqueous layer with siRNA (30 mL x 2). The combined organic extracts are dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by high-performance silica gel chromatography (ISCO®, 12g SepaFlash® silica flash column, 0-20% ethyl acetate / petroleum ether gradient eluent, 25 mL / min) to obtain (S)-4-((3-bromobenzofuran-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (370 mg, yield 18.9%) as a colorless oil. f =0.4 (PE:SiO=5:1). LCMS(ESI + ):m / z 411.1[M+H] + .

[0178] Step 3: Synthesis of (S)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzofuran-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester To a solution of 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (254 mg, 1.08 mmol) and (S)-4-((3-bromobenzofuran-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (370 mg, 904 μmol) in dioxane (5 mL), CuI (86.1 mg, 452 μmol), K3PO4 (384 mg, 1.81 mmol), and (1S,2S)-cyclohexane-1,2-diamine (51.6 mg, 452 μmol) were added. The mixture was microwave-stirred at 120 °C for 8 hours. The mixture was filtered and then concentrated under vacuum. The residue was analyzed using high-speed silica gel chromatography (ISCO®, 4g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient elution, 20 mL / min) [thin-layer chromatography (acidic silica gel, petroleum ether:ethyl acetate = 1:1), R f Purified by [=0.5], (S)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzofuran-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (250 mg, yield 49.2%) is obtained as a yellow oil. f =0.5 (PE:Â=1:1). LCMS(ESI + ):m / z 563.2[M+H] +

[0179] Step 4: Synthesis of (S)-3-(4-methoxybenzyl)-1-(5-((3-methylpiperazine-1-yl)methyl)benzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of (S)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzofuran-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (250 mg, 444.3 μmol) and HCl / dioxane (4 M, 3 mL) is stirred at 20°C for 2 hours. The mixture is concentrated under reduced pressure to obtain (S)-3-(4-methoxybenzyl)-1-(5-((3-methylpiperazine-1-yl)methyl)benzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (220 mg, crude product, HCl salt) as a yellow oily substance, which can be used in the next step without further purification. LCMS (ESI + ):m / z 463.2[M+H] +

[0180] Step 5: Synthesis of 6-(4-(dimethoxymethyl)piperidine-1-yl)nicotinonitrile To a solution of 6-chloronicotinonitrile (435 mg, 3.14 mmol) in DMF (5 mL), add K2CO3 (868 mg, 6.28 mmol) and 4-(dimethoxymethyl)piperidine (500 mg, 3.14 mmol). Stir the mixture at 80°C for 2 hours. Dilute the mixture with  (30 mL) and wash with saline solution (30 mL x 3). Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by high-performance silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, EA / PE gradient of 0-20% eluent, 30 mL / min) to obtain 6-(4-(dimethoxymethyl)piperidine-1-yl)nicotinonitrile (800 mg, yield 97.5%) as a white solid. f =0.27(PE:EtOAc=5:1). LCMS(ESI + ):m / z 262.3[M+H] +

[0181] Step 6: Synthesis of 6-(4-formylpiperidine-1-yl)nicotinonitrile Add FA (2.44 g, 53.0 mmol, 2 mL) to a solution of 6-(4-(dimethoxymethyl)piperidine-1-yl)nicotinonitrile (200 mg, 765.4 μmol) in H2O (0.7 mL). Stir the mixture at 50°C for 2 hours. Concentrate the mixture under reduced pressure to obtain 6-(4-formylpiperidine-1-yl)nicotinonitrile (160 mg, crude product) as a yellow oily substance. f = 0.38 (PE:SiO=2:1). 1 H NMR(400MHz,CDCl3)δ 9.71(s,1H),8.40(d,J=2.0Hz,1H),7.61(dd,J=2.4,9.2Hz,1H),6.62(d,J=9.2Hz,1H),4.3 0-4.20(m,2H),3.29-3.20(m,2H),2.67-2.53(m,1H),2.07-1.98(m,2H),1.75-1.66(m,2H).

[0182] Step 7: Synthesis of (S)-6-(4-((4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzofuran-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (S)-3-(4-methoxybenzyl)-1-(5-((3-methylpiperazine-1-yl)methyl)benzofuran-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg, 151 μmol) in MeOH (1 mL) is mixed with TEA (30.6 mg, 302.7 μmol, 42.13 μL) and the mixture is stirred at 20°C for 30 minutes. Then 6-(4-formylpiperidine-1-yl)nicotinonitrile (48.9 mg, 227.0 μmol) and AcOH (31.8 mg, 529.7 μmol, 30.3 μL) are added. The mixture is stirred at 50°C for 2 hours. The reaction mixture is cooled to 20°C and NaBH3CN (28.5 mg, 454.0 μmol) is added. The mixture is stirred at 20°C for 1 hour. The mixture is concentrated under reduced pressure. The residue was purified by high-speed silica gel chromatography (ISCO®, 4g SepaFlash® silica flash column, eluent 0-10% methanol / dichloromethane, 20 mL / min) to obtain (S)-6-(4-((4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzofuran-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (150 mg, yield 74.9%) as a colorless oil. f = 0.4 (Dichloromethane:Methanol = 10:1). LCMS (ESI + ):m / z 662.3[M+H] +

[0183] Step 8: Synthesis of Compound 17: (S)-6-(4-((4-((3-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)benzofuran-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (S)-6-(4-((4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzofuran-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (150 mg, 227 μmol) is dissolved in TFA (0.5 mL) and TfOH (848 mg, 5.65 mmol, 0.5 mL) is added. The mixture is stirred at 20 °C for 1.5 hours. The mixture is adjusted to pH = 7-8 with saturated NaHCO3 aqueous solution. The resulting mixture is diluted with ELISA (20 mL) and washed with water (20 mL). After phase separation, the aqueous layer is extracted with ELISA (20 mL x 2). The combined organic extract is dried over anhydrous Na2SO4, filtered, and vacuum concentrated. The residue is purified by preparative TLC. The crude product was purified by preparative HPLC (chromatographic column: Kromasil 100-5-C18 30×150 mm, mobile phase A: water (0.01% FA), mobile phase B: acetonitrile, 25 mL / min, gradient conditions from 10% B to 50%) to obtain (S)-6-(4-((4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzofuran-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-yl)nicotinonitrile (5.72 mg, yield 4.55%) as a white solid. f = 0.52 (dichloromethane:methanol = 10:1). 1H NMR(400MHz,DMSO-d6)δ 10.55(br.s,1H),8.44(d,J=2.4Hz,1H),8.11(s,1H),7.79(dd,J=2.4,9.2Hz,1H),7.54(d,J=8.4Hz,1H),7 .49(s,1H),7.30(dd,J=1.2,8.4Hz,1H),6.90(d,J=9.2Hz,1H),4.45-4.36(m,2H),3.84(t,J=6.8Hz,2H),3 .53-3.52(m,2H),2.99-2.86(m,3H),2.84-2.76(m,3H),2.66-2.55(m,2H),2.47-2.30(m,2H),2.25-2.10( m,2H),1.99-1.88(m,2H),1.87-1.82(m,1H),1.72-1.62(m,1H),1.11-0.94(m,2H),0.92(d,J=6.0Hz,3H). LCMS(ESI + ):m / z 542.5[M+H] +

[0184] Example 12: Preparation of Compound 20: (S)-1-(6-fluoro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0185] Step 1: Synthesis of 5-bromo-2,4-difluorobenzonitrile Add CuCN (330 mg, 3.68 mmol) to a solution of 1,5-dibromo-2,4-difluorobenzene (1.0 g, 3.68 mmol) in DMF (10 mL). Stir the mixture at 130 °C for 12 hours. Pour the mixture into water (20 mL) and extract with ethyl acetate (20 mL x 2). Wash the combined organic extract with saline solution (20 mL), dry over anhydrous Na₂SO₄, filter, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by high-performance silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient elution, 30 mL / min) to obtain compound 5-bromo-2,4-difluorobenzonitrile (220 mg, yield 27.4%) as a white solid. f = 0.6 (petroleum ether:ethyl acetate = 5:1). 1 H NMR (400MHz, CDCl3) δ 7.92-7.83(m, 1H), 7.12-7.03(m, 1H).

[0186] Step 2: Synthesis of 5-bromo-6-fluorobenzo[d]isoxazole-3-amine At 0°C, add t-BuOK (1.0M, 41.3mL, 41.3 mmol) to a solution of ethanehydroxamic acid (3.10 g, 41.3 mmol) in DMF (30 mL). Then, add 5-bromo-2,4-difluorobenzonitrile (3.00 g, 13.8 mmol) dissolved in DMF (5 mL) to the above mixture. Stir the mixture at 80°C for 12 hours. Pour the mixture into water (40 mL) and extract with ethyl acetate (40 mL x 2). The combined organic extracts were washed with saline solution (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by high-performance silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, eluent 0-50% dichloromethane / petroleum ether gradient elution, 50 mL / min) to obtain compound 5-bromo-6-fluorobenzo[d]isoxazole-3-amine (3.50 g, yield 55.1%) as a white solid. f = 0.3 (petroleum ether: dichloromethane = 1:1).1 H NMR (400MHz, CDCl3) δ 7.78 (d, J = 6.4 Hz, 1H), 7.22 (d, J = 8 Hz, 1H), 6.90 (d, J = 10.4 Hz, 2H).

[0187] Step 3: Synthesis of 3-((5-bromo-6-fluorobenzo[d]isoxazole-3-yl)amino)propanenitrile At 25°C, 5-bromo-6-fluorobenzo[d]isoxazole-3-amine (1.7 g, 7.36 mmol) is added to a 35 mL ACN solution with prop-2-enonitrile (430 mg, 8.10 mmol) and Cs2CO3 (3.12 g, 9.57 mmol). The mixture is stirred at 80°C for 3 hours. The mixture is concentrated under reduced pressure and purified by high-performance silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent 0-80% ethyl acetate / petroleum ether gradient elution, 30 mL / min) to obtain compound 3-((5-bromo-6-fluorobenzo[d]isoxazole-3-yl)amino)propanenitrile (870 mg, yield 41.6%) as a colorless oil. f = 0.3 (ethyl acetate / petroleum ether = 1:1). 1 H NMR(400MHz, CDCl3)δ 7.73(d,J=6.4Hz,1H),7.22(d,J=8.0Hz,1H),4.95-4.85(m,1H),3.79-3.70(m,2H),2.93-2.85(m,2H).

[0188] Step 4: Synthesis of 3-((5-bromo-6-fluorobenzo[d]isoxazole-3-yl)amino)propanamide Add H2SO4 (4.49 g, 45.8 mmol) to a TFA (8 mL) solution of 3-((5-bromo-6-fluorobenzo[d]isoxazole-3-yl)amino)propanenitrile (850 mg, 2.99 mmol). Stir the mixture at 25°C for 6 hours. Adjust the pH of the mixture to 7-8 with saturated NaHCO3 solution and extract with ethyl acetate (20 mL x 3). The organic layer was washed with saline solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was then purified by high-performance silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 0-10% methanol / dichloromethane gradient elution, 20 mL / min) to obtain compound 3-((5-bromo-6-fluorobenzo[d]isoxazole-3-yl)amino)propanamide (125 mg, yield 13.3%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.70(d,J=6.4Hz,1H),7.18(d,J=8.0Hz,1H),5.56-5.45(m,1H),5.41-5.30(m,1H),5.23-5.13(m,1H),3.71-3.65(m,2H),2.71-2.63(m,2H).

[0189] Step 5: Synthesis of (S)-4-((3-((3-amino-3-oxopropyl)amino)-6-fluorobenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester A solution of 3-((5-bromo-6-fluorobenzo[d]isoxazole-3-yl)amino)propanamide (300 mg, 993 μmol), [(3S)-4-tert-butoxycarbonyl-3-methylpiperazine-1-yl]methyltrifluoroboranonium potassium (954 mg, 2.98 mmol), and Cs2CO3 (971 mg, 2.98 mmol) in toluene (4 mL) and H2O (0.8 mL) was added to a microwave test tube, purged with N2 for 5 minutes, and then treated with RuPhos Pd G3 (83.1 mg, 99.3 μmol). The mixture was again purged with N2 for 5 minutes, and then stirred at 100°C for 1 hour under microwave irradiation. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic extracts were washed with saline solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by high-performance silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, 0-10% methanol / dichloromethane gradient elution, 20 mL / min) to obtain compound (S)-4-((3-((3-amino-3-oxopropyl)amino)-6-fluorobenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (180 mg, yield 89.7%) as a yellow oil. f = 0.5 (Dichloromethane / Methanol = 10:1). 1 H NMR(400MHz,CDCl3)δ 7.71(d,J=6.4Hz,1H),7.18(d,J=8.0Hz,1H),5.59-5.49(m,1H),5.43-5.34(m,1H),5.24-5.14(m,1H),4.24-4.16(m,1H),3. 76-3.68(m,4H),3.00-2.88(m,2H),2.82-2.75(m,1H),2.72-2.65(m,4H),2.63-2.57(m,1H),1.46(s,9H),1.25-1.22(m,3H).

[0190] Step 6: Synthesis of (S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-6-fluorobenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester At 0°C, add NaH (50.5 mg, 1.26 mmol, 60% purity) to a solution of (S)-4-((3-((3-amino-3-oxopropyl)amino)-6-fluorobenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (110 mg, 253 μmol) in THF (3 mL). Stir the mixture at 0°C for 0.5 hours. Add CDI (61.4 mg, 379 μmol) to the above solution. Stir the mixture at 25°C for 1.5 hours. Pour the mixture into 2 M AcOH (5 mL) and extract with ethyl acetate (5 mL x 2). The combined organic extracts were washed with saline solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was then purified by high-performance silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent 0-10% methanol / dichloromethane ether gradient elution, 20 mL / min) to obtain compound (S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-6-fluorobenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (80.0 mg, yield 71.2%) as a colorless oil. f = 0.4 (Dichloromethane / Methanol = 10:1). LCMS (ESI + ):m / z 462.4[M+H] + .

[0191] Step 7: Synthesis of (S)-1-(6-fluoro-5-((3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-6-fluorobenzo[d]isoxazole-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (80.0 mg, 173 μmol) is mixed in DCM (2 mL) and 4 M HCl / dioxane (2 mL) and stirred at 25°C for 1 hour. The mixture is concentrated under reduced pressure to obtain the crude product, which can be used in the next step without further purification. Compound (S)-1-(6-fluoro-5-((3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (68.0 mg, HCl, crude product) is obtained as a white solid. LCMS (ESI + ):m / z 362.3[M+H] + .

[0192] Step 8: Synthesis of Compound 14: (S)-1-(6-fluoro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(6-fluoro-5-((3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (68.0 mg, 170 μmol, HCl) is mixed with Et3N (25.9 mg, 256 μmol) in DMF (2 mL) and stirred for 5 minutes. Then, 2-methylpropanal (18.5 mg, 256 μmol) and AcOH (25.7 mg, 427 μmol) are added to the mixture and stirred at 50°C for 12 hours. The mixture is cooled to 25°C and NaBH3CN (21.5 mg, 342 μmol) is added. The solution is then stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure, purified by reverse-phase HPLC (conditions: 10% to 40% B phase (A phase: water (FA), B phase: MeCN, flow rate: 20 mL / min)), and directly freeze-dried to obtain compound (S)-1-(6-fluoro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)benzo[d]isoxazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.61 mg, yield 0.85%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.93(br.s.,1H),7.87(d,J=7.2Hz,1H),7.70(d,J=9.6Hz,1H),4.12-4.01(m,2 H),3.57-3.52(m,2H),2.83-2.77(m,2H),2.76-2.65(m,1H),2.63-2.52(m,2H), 2.36-2.29(m,2H),2.24-2.17(m,1H),2.12-2.05(m,1H),1.98-1.91(m,1H),1.8 6-1.78(m,1H),1.74-1.63(m,1H),0.92(d,J=6.0Hz,3H),0.82(d,J=6.4Hz,6H). LCMS(ESI + ):m / z 418.3[M+H] + .

[0193] Example 13: The following compounds in Table 3 are prepared by the method of Compound 6 and an appropriate aldehyde reaction. Table 3 [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8]

[0194] Example 14: The following compounds in Table 4 are prepared by the method of Compound 17 and a suitable aldehyde. Table 4 [Table 4-1] [Table 4-2] [Table 4-3]

[0195] Example 15: The following compounds in Table 5 are prepared by the method of compound 20. Table 5 [Table 5-1] [Table 5-2]

[0196] Example 16: Preparation of Compound 48: (S)-1-(2-fluoro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0197] Step 1: Synthesis of (S)-1-(2-fluoro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(2-fluoro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (80.0 mg, 154 μmol, HCl) is dissolved in MeOH (2 mL) and TEA (39.1 mg, 387 μmol) is added. Then, AcOH (32.5 mg, 542 μmol) and 2-methylpropanal (11.1 mg, 155 μmol) are added to the mixture and the mixture is stirred at 50°C for 12 hours. NaBH3CN (19.5 mg, 310 μmol) is added to the mixture and the mixture is stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure and purified by high-performance silica gel chromatography (ISCO®, 12g SepaFlash® silica flash column, methanol / dichloromethane gradient elution with 0-20% eluent, 25 mL / min) to obtain compound (S)-1-(2-fluoro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (30.0 mg, yield 28.2%) as a yellow solid. f = 0.4 (Dichloromethane:Methanol = 10:1). LCMS (ESI + ):m / z 537.4[M+H] + .

[0198] Step 2: Synthesis of (S)-1-(2-fluoro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Add TfOH (0.5 mL) to a solution of (S)-1-(2-fluoro-5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (30 mg, 55.9 μmol) in TFA (1.5 mL). Stir the mixture at 25°C for 4 hours. The pH of the mixture was adjusted to 7-8 with an aqueous NaHCO3 solution, and then concentrated under vacuum. Subsequently, it was purified by reverse-phase HPLC (conditions: 25-40% B phase (A phase: water (0.01% FA), B phase: MeCN, flow rate: 20 mL / min)), and then directly freeze-dried to obtain compound (S)-1-(2-fluoro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (10.0 mg, yield 38.5%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.56(br.s.,1H),8.51(d,J=7.2Hz,1H),7.53-7.44(m,1H),6.96(dd,J =1.6,7.2Hz,1H),3.78-3.74(m,2H),3.42-3.37(m,2H),2.84-2.74(m,3 H),2.62-2.55(m,2H),2.43-2.32(m,2H),2.28-2.11(m,2H),2.02-1.84 (m,2H),1.78-1.62(m,1H),0.94(d,J=6.4Hz,3H),0.84(d,J=6.8Hz,6H). LCMS(ESI + ):m / z 417.2[M+H] + .

[0199] Example 17: The following compounds in Table 6 are prepared by the method for compound 48. Table 6 [Table 6]

[0200] Example 18: Preparation of Compound 51: (S)-1-(5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)-2-methylpyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0201] Step 1: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)pyridine At 0°C, add TEA (13.9g, 137mmol, 19.1mL) and TBSCl (20.7g, 137mmol, 16.9mL) to a 100mL solution of 4-pyridinemethanol (10.0g, 91.6mmol) in DCM. Stir the mixture at 25°C for 18 hours. Dilute the reaction mixture with DCM (200mL) and wash with water (200mL). After layering, extract the aqueous layer with DCM (200mL x 2). Dry the combined organic extract over anhydrous Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by high-performance silica gel chromatography (ISCO®, 120g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient elution, 60 mL / min) to obtain compound 4-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (10.0 g, yield 48.9%) as a pale yellow oily substance. f =0.33 (petroleum ether:ethyl acetate = 3:1). LCMS(ESI + ):m / z 224.4[M+H] + .

[0202] Step 2: Synthesis of 1-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-1-onium; 2,4-dinitrophenol salt To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (10.0 g, 44.8 mmol) in MeCN (50 mL), O-(2,4-dinitrophenyl)hydroxylamine (8.91 g, 44.8 mmol) is added. The mixture is stirred at 40°C for 16 hours. The mixture is concentrated under reduced pressure. The crude product 1-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-1-onium; 2,4-dinitrophenol salt (19 g, crude product) is obtained as a brown oily substance and can be used in the next step without further purification.

[0203] Step 3: Synthesis of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate ethyl To a solution of 1-amino-4-(((tert-butyldimethylsilyl)oxy)methyl)pyridine-1-onium;2,4-dinitrophenol salt (24.7 g, 58.5 mmol) in DMF (100 mL), add K2CO3 (12.1 g, 87.7 mmol) and buta-2-inoate (6.55 g, 58.5 mmol, 6.81 mL). Stir the mixture at 25°C for 16 hours. Dilute the mixture with siRNA (200 mL) and wash with brine (200 mL x 3). Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by high-performance silica gel chromatography (ISCO®, 120g SepaFlash® silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient elution, 80 mL / min) to obtain compound 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate ethyl (5.2 g, yield 25.5%) as a yellow oily substance. f = 0.4 (petroleum ether:ethyl acetate = 10:1). 1H NMR(400MHz,CDCl3)δ 8.21(d,J=7.2Hz,1H),7.88(s,1H),6.69(dd,J=1.6,7.2Hz,1H),4.66(s,2H),4.2 4(q,J=7.2Hz,2H),2.53(s,3H),1.28(t,J=7.2Hz,3H),0.83(s,9H),0.00(s,6H).

[0204] Step 4: Synthesis of (2-methylpyrazolo[1,5-a]pyridine-5-yl)methanol Add H2SO4 (15 mL) to a solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate ethyl (5.10 g, 14.6 mmol) in H2O (15 mL). Stir the mixture at 80°C for 18 hours. Adjust the pH of the reaction solution to 7-8 at 0°C with a 15% NaOH aqueous solution. Dilute the resulting mixture with HCl (30 mL) and wash with water (30 mL). After layering, extract the aqueous layer with HCl (30 mL x 2). Dry the combined organic extract over anhydrous Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by high-performance silica gel chromatography (ISCO®, 20g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to obtain the compound (2-methylpyrazolo[1,5-a]pyridine-5-yl)methanol (1.90 g, yield 80.1%) as a yellow solid. f = 0.3 (petroleum ether:ethyl acetate = 1:1). 1 H NMR (400MHz, CDCl3) δ 8.30(d,J=7.2Hz,1H),7.37(s,1H),6.63(d,J=7.2Hz,1H),6.24(s,1H),4.69(s,2H),2.47(s,3H).

[0205] Step 5: Synthesis of 2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde Add MnO2 (2.41 g, 27.75 mmol) to a solution of (2-methylpyrazolo[1,5-a]pyridine-5-yl)methanol (900 mg, 5.55 mmol) in DCM (10 mL). Stir the mixture at 25°C for 16 hours. Filter the mixture through a diatomaceous earth pad and concentrate under reduced pressure. The crude product 2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde (770 mg, crude product) is obtained as a yellow solid and can be used in the next step without further purification. f =0.66 (petroleum ether:ethyl acetate = 1:1)

[0206] Step 6: Synthesis of (S)-2-methyl-4-((2-methylpyrazolo[1,5-a]pyridine-5-yl)methyl)piperazine-1-carboxylate tert-butyl ester Add AcOH (289 mg, 4.81 mmol) to a methanol (10 mL) solution of 2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde (770 mg, 4.81 mmol) and tert-butyl(2S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (963 mg, 4.81 mmol). Stir the mixture at 50°C for 6 hours. Cool the reaction mixture to 25°C and add NaBH3CN (604.18 mg, 9.61 mmol, 2 eq). Stir the mixture at 25°C for 16 hours. Concentrate the mixture under reduced pressure. The residue was purified by high-performance silica gel chromatography (ISCO®, 12g SepaFlash® silica flash column, eluent 0-20% ethyl acetate / petroleum ether gradient elution, 30 mL / min) to obtain compound (S)-2-methyl-4-((2-methylpyrazolo[1,5-a]pyridine-5-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (1.10 g, yield 46.5%, purity 70%) as a colorless oil. LCMS (ESI + ):m / z 345.6[M+H] + .

[0207] Step 7: Synthesis of (S)-4-((3-iodo-2-methylpyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (S)-2-methyl-4-((2-methylpyrazolo[1,5-a]pyridine-5-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (1.10 g, 3.19 mmol) is dissolved in MeCN (10 mL) and NIS (718 mg, 3.19 mmol) is added. The mixture is stirred at 25 °C for 2 hours. The mixture is concentrated under reduced pressure. The residue is purified by high-performance silica gel chromatography (ISCO®, 12 g SepaFlash® silica gel high-performance chromatography column, eluent 0-20% ethyl acetate / petroleum ether gradient eluent, 30 mL / min) to obtain compound (S)-4-((3-iodo-2-methylpyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (1.40 g, yield 93.2%) as a pale yellow solid. f = 0.24 (petroleum ether:ethyl acetate = 5:1). 1 H NMR(400MHz,CDCl3)δ 8.28(d,J=7.2Hz,1H),7.24(s,1H),6.81(d,J=6.8Hz,1H),4.21(s,1H),3 .84(d,J=13.2Hz,1H),3.60-3.52(m,1H),3.41(d,J=13.8Hz,1H),3.20-3 .09(m,1H),2.77(d,J=10.8Hz,1H),2.59(d,J=11.2Hz,1H),2.46(s,3H), 2.22-2.15(m,1H),2.14-2.05(m,1H),1.46(s,9H),1.27(d,J=6.8Hz,3H).

[0208] Step 8: Synthesis of (S)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-methylpyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester To a solution of 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (149 mg, 638 μmol) and (S)-4-((3-iodo-2-methylpyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (300 mg, 638 μmol) in dioxane (4 mL), CuI (24.3 mg, 126 μmol), trans-1,2-diaminocyclohexane (14.6 mg, 128 μmol), and Cs2CO3 (416 mg, 1.28 mmol) were added. The mixture was microwave-stirred at 95°C for 8 hours. The mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was then purified by high-performance silica gel chromatography (ISCO®, 4g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient elution, 25 mL / min) to obtain compound (S)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-methylpyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (149 mg, yield 22.7%, purity 56%) as a yellow solid. f =0.25 (petroleum ether:ethyl acetate = 1:1). LCMS (ESI + ):m / z 577.5[M+H] + .

[0209] Step 9: Synthesis of (S)-3-(4-methoxybenzyl)-1-(2-methyl-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of (S)-4-((3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-methylpyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester (149 mg, 258 μmol) and HCl / dioxane (4 M, 3 mL) is stirred at 25°C for 2 hours. The mixture is concentrated under reduced pressure. The residue was purified by preparative HPLC (chromatography column: Kromasil 100-5-C18 30×150 mm, mobile phase A: water (0.01% formic acid), mobile phase B: acetonitrile, 25 mL / min, gradient conditions from 5%B to 45%) to obtain compound (S)-3-(4-methoxybenzyl)-1-(2-methyl-5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (44.0 mg, yield 24.6%, purity 74%, HCl) as a colorless oil. LCMS (ESI + ):m / z 477.5[M+H] + .

[0210] Step 10: Synthesis of (S)-1-(5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)-2-methylpyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (S)-3-(4-methoxybenzyl)-1-(2-methyl-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (44.0 mg, 85.8 μmol, HCl) is dissolved in MeOH (2 mL) and TEA (17.4 mg, 172 μmol) is added, and the mixture is stirred at 25°C for 30 minutes. Then 2-methylpropanal (12.4 mg, 172 μmol) and AcOH (18.0 mg, 300 μmol) are added. The mixture is stirred at 50°C for 2 hours. The reaction mixture is cooled to 25°C and NaBH3CN (10.8 mg, 172 μmol) is added. The mixture is stirred at 25°C for 2 hours. The mixture is concentrated under reduced pressure. The residue is collected by preparative TLC (DCM:MeOH=10:1, Rf Purified by (=0.7), compound (S)-1-(5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)-2-methylpyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (34.0 mg, yield 58.8%, purity 79%) is obtained as a colorless oil. f = 0.7 (Dichloromethane:Methanol = 10:1). LCMS (ESI + ):m / z 533.8[M+H] + .

[0211] Step 11: Synthesis of Compound 51: (S)-1-(5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)-2-methylpyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)-2-methylpyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (34.0 mg, 63.8 μmol) is dissolved in TFA (0.5 mL) and TfOH (848 mg, 5.65 mmol, 0.5 mL) is added. The mixture is stirred at 25°C for 2 hours. The pH of the mixture is adjusted to 7-8 with an aqueous solution of NaHCO3. The resulting mixture is diluted with water (20 mL). After phase separation, the aqueous layer is extracted with ELISA (20 mL x 2). The combined organic extract is dried over anhydrous Na2SO4, filtered, and vacuum concentrated. The residue was purified by preparative HPLC (chromatographic column: Kromasil 100-5-C18 30X150mm, mobile phase A: water (0.01% FA), mobile phase B: acetonitrile, 25 mL / min, gradient conditions from 1% B to 40%) to obtain compound (S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)-2-methylpyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione as a white solid. 1H NMR(400MHz,DMSO-d6)δ 10.43(br.s.,1H),8.50(d,J=6.8Hz,1H),7.48-7.33(m,1H),6.89-6.7 6(m,1H),3.71-3.67(m,2H),3.54-3.53(m,2H),2.88-2.76(m,3H),2.75 -2.63(m,3H),2.61-2.54(m,2H),2.45-2.30(m,2H),2.27(s,3H),2.23 -2.11(m,1H),2.04-1.78(m,1H),1.18-1.01(m,3H),0.96-0.83(m,6H). LCMS(ESI + ):m / z 413.3[M+H] + .

[0212] Example 19: Preparation of Compound 52: (S)-1-(4-chloro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0213] Step 1: Synthesis of 3-chloropyridine-4-ylaminocarboxylic acid tert-butyl ester Add BoC2O (44.6 g, 204 mmol, 46.9 mL) to a solution of 3-chloropyridine-4-amine (25.0 g, 195 mmol) in dioxane (80 mL). Stir the mixture at 25°C for 16 hours. Concentrate the mixture under reduced pressure to obtain (3-chloropyridine-4-yl)carbamate (45 g, crude product) as a yellow solid. This product can be used in the next step without further purification. LCMS (ESI) + ):m / z 173.4[M+H-56]+.

[0214] Step 2: Synthesis of N-(1-amino-3-chloropyridine-1-ium-4-yl)aminocarboxylic acid tert-butyl ester; 2,4-dinitrophenol salt To a solution of tert-butyl(3-chloropyridine-4-yl)aminocarbamate (45.0 g, 197 mmol) in MeCN (300 mL), O-(2,4-dinitrophenyl)hydroxylamine (78.4 g, 394 mmol) is added. The mixture is stirred at 50°C for 20 hours. The mixture is concentrated under reduced pressure to obtain tert-butyl N-(1-amino-3-chloropyridine-1-yl)carbamate; 2,4-dinitrophenol salt (84 g, crude product) as a brown oily substance, which can be used in the next step without further purification. f = 0.07 (petroleum ether:ethyl acetate = 10:1).

[0215] Step 3: Synthesis of 5-((tert-butoxycarbonyl)amino)-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate ethyl To a solution of N-(1-amino-3-chloropyridine-1-ium-4-yl)aminocarboxylic acid tert-butyl ester; 2,4-dinitrophenol salt (84.0 g, 196 mmol) in DMF (450 mL), add K2CO3 (81.3 g, 588 mmol) and ethyl propiolate (19.3 g, 196 mmol, 19.3 mL). Stir the mixture at 25°C for 20 hours. Dilute the mixture with toluene (500 mL) and wash with brine (500 mL x 3). Dry the organic layer over anhydrous sodium 2SO4, filter, and concentrate under reduced pressure. The residue was purified by high-speed silica gel chromatography (ISCO®, 220g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient elution, 70 mL / min) to obtain ethyl 5-((tert-butoxycarbonyl)amino)-4-chloropyrazolo[1,5-a]pyridine-3-carboxylic acid ester (31.8 g, yield 37.7%) as a yellow solid. f =0.58 (petroleum ether:ethyl acetate = 3:1). LCMS (ESI + ):m / z 340.3[M+H] + .

[0216] Step 4: Synthesis of ethyl 5-amino-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate Add TFA (30.7 g, 269.3 mmol, 20 mL) to a DCM (50 mL) solution of 5-((tert-butoxycarbonyl)amino)-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate ethyl (31.8 g, 93.6 mmol) (a mixture of 5-((tert-butoxycarbonyl)amino)-6-chloropyrazolo[1,5-a]pyridine-3-carboxylate ethyl). Stir the mixture at 25°C for 20 hours. Concentrate the mixture to remove the solvent, then adjust the pH to 7-8 with an aqueous solution of NaHCO3. Dilute the resulting mixture with ELISA (200 mL) and wash with water (200 mL). After layering, extract the aqueous layer with ELISA (100 mL x 2). Dry the combined organic extract over anhydrous Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by high-performance silica gel chromatography (ISCO®, 120g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum ether gradient, 60 mL / min) to obtain yellow solid ethyl 5-amino-6-chloropyrazolo[1,5-a]pyridine-3-carboxylate (4.63 g, yield 20.6%) and yellow solid ethyl 5-amino-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate (5.8 g, yield 25.9%). f =0.2 (petroleum ether:ethyl acetate = 3:1). LCMS(ESI + ): m / z 240.3[M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.46(s,1H),8.23(s,1H),7.31(s,1H),4.75-4.46(m,2H),4.34(q,J=7.2Hz,2H),1.39(t,J=7.2Hz,3H)

[0217] Step 5: Synthesis of 4-chloro-5-iodopyrazolo[1,5-a]pyridine-3-carboxylate ethyl Add a dropwise solution of sodium nitrite (633.4 mg, 9.18 mmol) in aqueous solution (7 mL) to a solution of ethyl 5-amino-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate (2.00 g, 8.35 mmol) in MeCN (14 mL) and 6 M HCl (41.7 mL). Stir the mixture at 0°C for 1 hour. Add a dropwise solution of KI (2.77 g, 16.7 mmol) in aqueous solution (7 mL) to the mixture. Stir the reaction mixture at 0°C for 1 hour. Adjust the pH of the reaction mixture to 7-8 with a 15% NaOH aqueous solution. Dilute the resulting mixture with HCl (30 mL) and wash with water (30 mL). After layering, extract the aqueous layer with HCl (30 mL x 2). Dry the combined organic extract over anhydrous Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by high-performance silica gel chromatography (ISCO®, 20g SepaFlash® silica flash column, eluent 0-20% ethyl acetate / petroleum ether gradient elution, 40 mL / min) to obtain ethyl 4-chloro-5-iodopyrazolo[1,5-a]pyridine-3-carboxylate (2.2 g, yield 72.2%) as a yellow solid. f =0.6 (petroleum ether:ethyl acetate = 5:1). LCMS (ESI + ):m / z 351.1[M+H] + .

[0218] Step 6: Synthesis of 4-chloro-5-iodopyrazolo[1,5-a]pyridine Add H2SO4 (9.20 g, 93.8 mmol, 5 mL) to a solution of ethyl 4-chloro-5-iodopyrazolo[1,5-a]pyridine-3-carboxylate (2.20 g, 6.28 mmol) in H2O (5 mL). Stir the mixture at 80°C for 16 hours. Adjust the pH of the reaction solution to 7-8 at 0°C with 15% NaOH aqueous solution. Dilute the resulting mixture with HCl (30 mL) and wash with water (30 mL). After phase separation, extract the aqueous layer with HCl (30 mL x 2). Dry the combined organic extract over anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain 4-chloro-5-iodopyrazolo[1,5-a]pyridine (1.5 g, crude product) as a yellow solid. 1H NMR(400MHz, CDCl3)δ 8.12(dd,J=0.8,7.2Hz,1H),7.93(d,J=2.0Hz,1H),7.08(d,J=7.2Hz,1H),6.65(dd,J=0.8,2.0Hz,1H).

[0219] Step 7: Synthesis of 4-chloro-5-iodo-3-nitropyrazolo[1,5-a]pyridine At 0°C, nitronium tetrafluoroborate (171.7 mg, 1.29 mmol) is added to a solution of 4-chloro-5-iodopyrazolo[1,5-a]pyridine (300 mg, 1.08 mmol) in MeCN (3 mL). The mixture is stirred at 0°C for 1 hour. The reaction mixture is quenched by adding ice water (20 mL). A large precipitate forms, which is filtered, and the solid is collected. The crude product is vacuum-dried to obtain 4-chloro-5-iodo-3-nitropyrazolo[1,5-a]pyridine (160 mg, crude product) as a dark green solid. LCMS (ESI + ):m / z 324.1[M+H] + .

[0220] Step 8: Synthesis of 4-chloro-5-iodopyrazolo[1,5-a]pyridine-3-amine To a solution of 4-chloro-5-iodo-3-nitropyrazolo[1,5-a]pyridine (160 mg, 495 μmol) in EtOH (4 mL) and H2O (1 mL), Fe (138 mg, 2.47 mmol) and NH4Cl (265 mg, 4.95 mmol) are added. The mixture is stirred at 80°C for 1 hour. The reaction mixture is concentrated to remove the solvent. The mixture is diluted with pharmaceutically acceptable ammonium compounds (20 mL) and washed with water (20 mL). After layering, the aqueous layer is extracted with pharmaceutically acceptable ammonium compounds (20 mL x 2). The combined organic extract is dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (conditions: 30%-60% B phase (A phase: water (neutral), B phase: acetonitrile, flow rate: 25 mL / min)) to obtain 4-chloro-5-iodopyrazolo[1,5-a]pyridine-3-amine (100 mg, yield 68.2%) as a yellow solid. LC-MS (ESI + ):m / z 294.2[M+H] + .1 H NMR(400MHz,CDCl3)δ 7.86(d,J=7.2Hz,1H),7.58(s,1H),6.82(d,J=7.2Hz,1H),3.88-3.26(m,2H)

[0221] Step 9: Synthesis of ethyl (4-chloro-5-iodopyrazolo[1,5-a]pyridine-3-yl)carbamate To a solution of 4-chloro-5-iodopyrazolo[1,5-a]pyridine-3-amine (430 mg, 1.47 mmol) in THF (5 mL), DMAP (35.8 mg, 293 μmol) and TEA (297 mg, 2.93 mmol, 408 μL) are added. Then ethyl cyanocarboxylate (218 mg, 2.20 mmol) is added. The mixture is stirred at 65°C for 16 hours. The mixture is concentrated under reduced pressure. The residue is purified by high-performance silica gel chromatography (ISCO®, 12 g SepaFlash® silica gel high-performance chromatography column, eluent 0-30% ethyl acetate / petroleum ether gradient elution, 30 mL / min) to obtain ethyl (4-chloro-5-iodopyrazolo[1,5-a]pyridine-3-yl)carbamate (459 mg, yield 80.6%) as a green solid. LCMS (ESI + ):m / z 366.2[M+H] + .

[0222] Step 10: Synthesis of ethyl (4-chloro-5-vinylpyrazolo[1,5-a]pyridine-3-yl)carbamate To a solution of potassium trifluoro(vinyl)borate (170 mg, 1.27 mmol) and ethyl (4-chloro-5-iodopyrazolo[1,5-a]pyridine-3-yl)carbamate (387 mg, 1.06 mmol) in DMF (4 mL), add Pd(dppf)Cl2 (77.5 mg, 106 μmol) and TEA (321 mg, 3.18 mmol, 442 μL). Microwave-stir the mixture at 70°C for 1 hour. Dilute the mixture with pharmaceutically acceptable solution (20 mL) and wash with saline solution (20 mL x 3). Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure. The residue was purified by reverse-phase HPLC (conditions: B phase 70%~100% (A phase: water (neutral), B phase: MeCN, flow rate: 25 mL / min)) to obtain ethyl (4-chloro-5-vinylpyrazolo[1,5-a]pyridine-3-yl)carbamate (280 mg, yield 52.8%) as a yellow solid. LCMS (ESI + ):m / z 266.3[M+H] + .

[0223] Step 11: Synthesis of ethyl (4-chloro-5-formylpyrazolo[1,5-a]pyridine-3-yl)carbamate At 0°C, osmium(VI) potassium dihydrate (19.4 mg, 52.7 μmol) is added to a solution of ethyl (4-chloro-5-vinylpyrazolo[1,5-a]pyridine-3-yl) carbamate (280 mg, 1.05 mmol) in THF (3 mL), followed by the addition of a solution of NaIO4 (451 mg, 2.11 mmol, 116.8 μL) in H2O (1 mL). The mixture is stirred at 0°C for 2 hours. The mixture is diluted with HCl (20 mL) and washed with water (20 mL). After layering, the aqueous layer is extracted with HCl (20 mL x 2). The combined organic extracts are dried over Na2SO4, filtered, and vacuum concentrated. The residue was purified by high-speed silica gel chromatography (ISCO®, 4g SepaFlash® silica flash column, eluent 0-20% ethyl acetate / petroleum ether gradient elution, 20 mL / min) to obtain ethyl (4-chloro-5-formylpyrazolo[1,5-a]pyridine-3-yl)carbamate (180 mg, yield 38.3%) as a yellow solid. f=0.35 (petroleum ether:ethyl acetate = 4:1). LCMS (ESI + ):m / z 268.0[M+H] + .

[0224] Step 12: Synthesis of (S)-4-((4-chloro-3-((ethoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester Add AcOH (40.4 mg, 673 μmol, 38.5 μL) to a solution of ethyl (4-chloro-5-formylpyrazolo[1,5-a]pyridine-3-yl)carbamate (180 mg, 673 μmol) and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (135 mg, 673 μmol) in MeOH (3 mL). Stir the mixture at 50 °C for 16 hours. Cool the reaction mixture to 25 °C and add NaBH3CN (84.5 mg, 1.34 mmol). Stir the mixture at 25 °C for 3 hours. Concentrate the mixture under reduced pressure. The residue was purified by high-speed silica gel chromatography (ISCO®, 4g SepaFlash® silica flash column, eluent 0-30% ethyl acetate / petroleum ether gradient elution, 20 mL / min) to obtain (S)-4-((4-chloro-3-((ethoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (130 mg, yield 27.8%) as a white solid. f =0.3 (petroleum ether:ethyl acetate = 3:1). LCMS(ESI + ):m / z 474.4[M+Na] + .

[0225] Step 13: Synthesis of (S)-4-((4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylate tert-butyl ester A solution of acrylamide (15.7 mg, 221.3 μmol) and (S)-4-((4-chloro-3-((ethoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (50 mg, 110.6 μmol) in t-BuOH (1 mL) is mixed with 1 M t-BuOK (121.7 μL). The mixture is stirred at 60°C for 3 hours. The mixture is concentrated under reduced pressure. The residue is purified by preparative TLC to obtain (S)-4-((4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (35 mg, yield 49.8%) as a colorless oil. R f =0.7 (petroleum ether:ethyl acetate = 1:2). LCMS (ESI + ):m / z 499.5[M+Na] + .

[0226] Step 14: Synthesis of (S)-1-(4-chloro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of (S)-4-((4-chloro-3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (35.0 mg, 73.4 μmol) and HCl / dioxane (4 M, 1 mL) is stirred at 25°C for 1 hour. The mixture is concentrated under reduced pressure to obtain (S)-1-(4-chloro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (30 mg, crude product, HCl) as a pale yellow oily substance. This product does not need to be further purified and can be used in the next step. LCMS (ESI + ):m / z 377.4[M+H] + .

[0227] Step 15: Synthesis of (S)-1-(4-chloro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of (S)-1-(4-chloro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (30.0 mg, 72.6 μmol, HCl) in MeOH (1 mL), Et3N (14.7 mg, 145 μmol, 20.2 μL) was added, and the mixture was stirred at 25°C for 30 minutes. Then, isobutyraldehyde (10.5 mg, 145 μmol, 13.3 μL) and AcOH (15.3 mg, 254 μmol, 14.5 μL) were added. The mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to 25°C, and NaBH3CN (9.12 mg, 145.2 μmol) was added. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (chromatographic column: Kromasil 100-5-C18 30×150 mm, mobile phase A: water (0.01% FA), mobile phase B: acetonitrile, 25 mL / min, gradient conditions from 1% B to 40%) to obtain (S)-1-(4-chloro-5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (5.24 mg, yield 16.7%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.48(s,1H),8.65(d,J=7.2Hz,1H),8.11(s,1H),7.05(d,J=7.2Hz,1H ),3.73-3.67(m,2H),3.59(s,2H),2.80-2.73(m,3H),2.64-2.56(m,2H) ,2.37-2.24(m,3H),2.17-2.08(m,1H),2.05-1.95(m,1H),1.89-1.81( m,1H),1.74-1.64(m,1H),0.94(d,J=6.0Hz,3H),0.83(d,J=6.4Hz,6H). LCMS(ESI + ):m / z 433.3[M+H] + .

[0228] Example 19: Preparation of Compound 53: (S)-1-(2-fluoro-5-((3-methyl-4-((1-(5-methylpyrimidine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0229] Step 1: Synthesis of 2-(4-(dimethoxymethyl)piperidine-1-yl)-5-methylpyrimidine To a solution of 4-(dimethoxymethyl)piperidine (520 mg, 3.25 mmol) in DMF (10 mL), K2CO3 (540 mg, 3.89 mmol) and 2-chloro-5-methylpyrimidine (500 mg, 3.89 mmol) are added. The mixture is stirred at 110°C for 2 hours. The reaction is quenched with water, extracted with DCM (2 × 20 mL), the organic phase is washed with saline solution, and dried over Na2SO4. The residue is purified by high-performance silica gel chromatography (ISCO®, 12 g SepaFlash® silica gel high-performance chromatography column, eluent 0-50% ethyl acetate / petroleum ether gradient elution, 35 mL / min) to obtain 2-(4-(dimethoxymethyl)piperidine-1-yl)-5-methylpyrimidine (300 mg, yield 37%) as a white solid. f =0.5 (ethyl acetate / petroleum ether = 5:1). LCMS(ESI + ):m / z 252.5[M+H] + .

[0230] Step 2: Synthesis of 1-(5-methylpyrimidine-2-yl)piperidine-4-carbaldehyde Add FA (1.5 mL) to a solution of 2-(4-(dimethoxymethyl)piperidine-1-yl)-5-methylpyrimidine (300 mg, 1.2 mmol) in H2O (0.5 mL). Stir the mixture at 50°C for 2 hours. Concentrate the mixture under reduced pressure to obtain 1-(5-methylpyrimidine-2-yl)piperidine-4-carbaldehyde (300 mg, crude product) as a pale yellow solid, which can be used in the next step without purification. LCMS (ESI + ):m / z 220.4[M+ H2O]+.

[0231] Step 3: Synthesis of (S)-1-(2-fluoro-5-((3-methyl-4-((1-(5-methylpyrimidine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione Add TEA (34.9 mg, 0.35 mmol) to a solution of (S)-1-(2-fluoro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.20 mmol, HCl) in MeOH (2 mL), and stir the mixture at 20°C for 30 minutes. Then add 1-(5-methylpyrimidine-2-yl)piperidine-4-carbaldehyde (100 mg, 0.49 mmol) and ZnCl2 (0.5 mL, 1 mmol, 2 M THF solution). Stir the mixture at 50°C for 16 hours. Cool the reaction mixture to 20°C and add NaBH3CN (21.7 mg, 0.35 mmol). Stir the mixture at 20°C for 2 hours. The mixture is concentrated under reduced pressure. The residue is purified by preparative TLC (DCM:MeOH = 10:1) to obtain (S)-1-(2-fluoro-5-((3-methyl-4-((1-(5-methylpyrimidine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (65 mg, yield 49%, purity 80%) as a pale yellow oil. f= 0.4 (Dichloromethane:Methanol = 10:1). LCMS (ESI + ):m / z 670.8[M+H] + .

[0232] Stage 4: (S)-1-(2-fluoro-5-((3-methyl-4-((1-(5-methylpyrimidine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(2-fluoro-5-((3-methyl-4-((1-(5-methylpyrimidine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (65.0 mg, 0.10 mmol) is dissolved in TFA (1 mL) and TfOH (1 mL) is added. The mixture is stirred at 20°C for 3 hours. The pH of the mixture is adjusted to 7-8 with an aqueous solution of NaHCO3. The resulting mixture is diluted with ethyl acetate (15 mL) and washed with saline solution (15 mL). After separation of layers, the aqueous layer is extracted with ethyl acetate (15 mL x 2). The combined organic extract is dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by reverse-phase HPLC (conditions: 40%-60% B phase (A phase: water (neutral), B phase: MeCN, flow rate: 20 mL / min)) to obtain (S)-1-(2-fluoro-5-((3-methyl-4-((1-(5-methylpyrimidine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (36 mg, yield 58%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 10.54(s,1H),8.51(d,J=7.2Hz,1H),7.59(d,J=9.0Hz,1H),7.48(s,1H), 7.39(d,J=11.9Hz,1H),6.96(d,J=5.5Hz,1H),3.92(s,4H),3.74(t,J=6. 6Hz,3H),3.59-3.42(m,2H),3.03-2.71(m,4H),2.63(d,J=35.0Hz,3H),2 .41-2.15(m,3H),2.07-1.60(m,5H),1.24(s,3H),0.94(d,J=6.1Hz,4H). LCMS(ESI + ):m / z 550.31[M+H] + .

[0233] Example 20: Table 7 Methods for preparing compounds and compounds 53 and 53. Table 7 Table 7-1 Table 7-2 Table 7-3 Table 7-4 Table 7-5 Table 7-6 Table 7-7 Table 7-8 Table 7-9 Table 7-10 [Table 7-11] [Table 7-12] [Table 7-13] [Table 7-14]

[0234] Example 21: Preparation of Compound 85: 3-(2-fluoro-5-(((S)-3-methyl-4-((1-(1-methyl-1H-pyrazole-3-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)piperidine-2,6-dione [ka]

[0235] Step 1: Synthesis of 4-(dimethoxymethyl)-1-(1-methyl-1H-pyrazole-3-yl)piperidine Under a nitrogen gas atmosphere, a mixture of 4-(dimethoxymethyl)piperidine (119 mg, 0.75 mmol), 3-bromo-1-methyl-1H-pyrazole (119 mg, 0.75 mmol), NaOTMS (85 mg, 0.79 mmol), and GPhos Pd G6 TES (CAS: 2489525-81-5, 37.6 mg, 0.04 mmol) in THF (20 mL) was heated at 50°C for 3 hours. The mixture was concentrated under reduced pressure to obtain the residue, which was purified by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, eluent 0-30% petroleum ether / ethyl acetate, 36 mL / min) to obtain compound 4-(dimethoxymethyl)-1-(1-methyl-1H-pyrazole-3-yl)piperidine (50 mg, yield 28%) as a colorless oil. LCMS (ESI + ): m / z 240.3[M+H] + .

[0236] Step 2: Synthesis of 1-(1-methyl-1H-pyrazole-3-yl)piperidine-4-carbaldehyde A mixture of 4-(dimethoxymethyl)-1-(1-methyl-1H-pyrazole-3-yl)piperidine (50 mg, 0.21 mmol), FA (3 mL), and H2O (1 mL) was stirred at 50°C for 1 hour. The reaction was stopped with aqueous NaHCO3 solution (20 mL) and extracted with EA (15 mL x 2). The combined organic layer was washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, eluent 0-30% petroleum ether / ethyl acetate, 36 mL / min) to obtain compound 1-(1-methyl-1H-pyrazole-3-yl)piperidine-4-carbaldehyde (25 mg, yield 63%) as a colorless oil. LCMS (ESI + ): m / z 194.3[M+H] + .

[0237] Step 3: Synthesis of 3-(2-fluoro-5-(((S)-3-methyl-4-((1-(1-methyl-1H-pyrazole-3-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione A mixture of (S)-1-(2-fluoro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (31 mg, 0.06 mmol), 1-(1-methyl-1H-pyrazole-3-yl)piperidine-4-carbaldehyde (25 mg, 0.13 mmol), and DIEA (17 mg, 0.13 mmol) in MeOH (5 mL) is stirred at room temperature for 10 minutes. ZnCl2 (0.2 mL, 0.4 mmol, 2 M THF solution) is added, and the mixture is stirred at room temperature overnight. Then NaBH3CN (8 mg, 0.13 mmol) is added, and the reaction mixture is stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the residue, which was then purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica flash column, 0-10% DCM / MeOH eluent, 36 mL / min) to obtain compound 3-(2-fluoro-5-(((S)-3-methyl-4-((1-(1-methyl-1H-pyrazole-3-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (35 mg, yield 83%) as a yellow oil. LCMS (ESI + ):m / z 658.6[M+H] + .

[0238] Step 4: Synthesis of 3-(2-fluoro-5-(((S)-3-methyl-4-((1-(1-methyl-1H-pyrazole-3-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)piperidine-2,6-dione A mixture of 3-(2-fluoro-5-(((S)-3-methyl-4-((1-(1-methyl-1H-pyrazole-3-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (35 mg, 0.05 mmol) and TfOH (2 mL) in TFA (2 mL) is stirred at 30°C for 1 hour. The reaction is stopped with aqueous NaHCO3 solution (30 mL) and extracted with EA (15 mL x 2). The combined organic layers were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was then purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica gel high-performance chromatography column, 0-10% DCM / MeOH eluent, 36 mL / min) to obtain compound 3-(2-fluoro-5-(((S)-3-methyl-4-((1-(1-methyl-1H-pyrazole-3-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)piperidine-2,6-dione (12 mg, yield 41%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.55(s,1H),8.52(d,J=7.1Hz,1H),7.49(t,J=2.2Hz,2H),6.96(dd,J=7.1,1.8H z,1H),5.99(d,J=2.1Hz,1H),3.74(d,J=4.7Hz,8H),3.04(s,2H),2.79(t,J=6.7Hz ,3H),2.73-2.62(m,3H),2.39(d,J=34.3Hz,2H),2.12(s,1H),1.91(d,J=12.9Hz,4 H),1.73(d,J=12.9Hz,1H),1.55(s,1H),1.42-1.20(m,3H),1.06(d,J=6.6Hz,2H). LCMS(ESI + ):m / z 538.5[M+H] + .

[0239] Example 22: The following compounds in Table 8 are prepared by the preparation method of compound 85 and appropriate heteroaryl fragments. Table 8 [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7]

[0240] Example 23: Preparation of Compound 98: (S)-1-(2-fluoro-5-((3-methyl-4-((4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, Compound 99: 1-(2-fluoro-5-(((S)-3-methyl-4-(((1*s,4*R)-4-(1-methyl-1H-pyrazole-3-yl)cyclo Hexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, Compound 100: 1-(2-fluoro-5-(((S)-3-methyl-4-(((1*r,4*S)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0241] Step 1: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-one A 60 mL DCM solution of 4-hydroxymethylcyclohexanone (5.0 g, 39.0 mmol) is cooled to 0°C, and imidazole (4.0 g, 58.5 mmol) and TBS-Cl (7.1 g, 46.8 mmol) are added. The reaction mixture is stirred at room temperature for 1 hour. The reaction is quenched with H2O (100 mL) and extracted with DCM (50 mL x 2). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue is purified by high-performance silica gel chromatography (ISCO®, 50 g SepaFlash® silica flash column, eluent 0-10% petroleum ether / ethyl acetate, 60 mL / min) to obtain compound 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexanone (7.0 g, yield 74%) as a colorless oil.

[0242] Step 2: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-en-1-yl(1,1,1,2,3,3,4,4-octafluoro-4l3-buta-2-yl)-l2-fluoranthulfonate A 20 mL THF solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-one (2.0 g, 8.3 mmol) is cooled to 0°C, and DBU (3.8 g, 24.9 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (3.8 g, 12.5 mmol) are added. The reaction mixture is stirred at 0°C for 3 hours. The reaction is quenched with H2O (100 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was then purified by high-performance silica gel chromatography (ISCO®, 25g SepaFlash® silica flash column, eluent 0-5% petroleum ether / ethyl acetate, 45 mL / min) to obtain compound 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-en-1-yl(1,1,1,2,3,3,4,4-octafluoro-4l3-buta-2-yl)-l2-fluoranthulfonate (2.1 g, yield 49%) as a colorless oil.

[0243] Step 3: Synthesis of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-en-1-yl)-1-methyl-1H-pyrazole A mixture of 4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-en-1-yl(1,1,1,2,3,3,4,4-octafluoro-4l3-buta-2-yl)-12-fluoranthulfonate (2.1 g, 4.0 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabolhexacyclopentan-2-yl)-1H-pyrazole (832 mg, 4.0 mmol), K2CO3 (1.7 g, 12.0 mmol), and Pd(dppf)Cl2·DCM (327 mg, 0.4 mmol) is heated at 100°C for 2 hours in a nitrogen atmosphere in 1,4-dioxane / water (10 mL, 4:1). The reaction mixture is quenched with H2O (30 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was then purified by high-performance silica gel chromatography (ISCO®, 25g SepaFlash® silica flash column, eluent 0-15% petroleum ether / ethyl acetate, 36 mL / min) to obtain compound 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-en-1-yl)-1-methyl-1H-pyrazole (550 mg, yield 49%) as a colorless oil. LCMS (ESI + ):m / z 307.4[M+H] + .

[0244] Step 4: Synthesis of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-1-methyl-1H-pyrazole Under a hydrogen gas atmosphere, a mixture of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-en-1-yl)-1-methyl-1H-pyrazole (500 mg, 1.6 mmol) and Pd / C (100 mg) in EtOH (10 mL) is stirred at room temperature for 2 hours. The mixture is filtered through a diatomaceous earth pad. The filtrate is concentrated under reduced pressure to obtain a colorless oily substance (500 mg, 99% yield), which can be used in the next step without further purification. LCMS (ESI + ):m / z 309.5[M+H] + .

[0245] Step 5: Synthesis of (4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methanol Add TBAF (1N, 8mL, 8.0 mmol) to 10 mL of THF solution of 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-1-methyl-1H-pyrazole (500 mg, 1.6 mmol). Stir the mixture at room temperature for 1 hour. Pour the reaction mixture into water (50 mL) and extract with EA (20 mL x 2). Wash the combined organic layer with saline solution, dry over Na2SO4, filter, and concentrate under reduced pressure to obtain a colorless oil (300 mg, yield 98%), which can be used in the next step without further purification. LCMS (ESI + ): m / z 195.4[M+H] + .

[0246] Step 6: Synthesis of 4-(1-methyl-1H-pyrazole-3-yl)cyclohexane-1-carbaldehyde Cool a 10 mL DCM solution of (4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methanol (310 mg, 1.6 mmol) to 0°C. Add DMP (1016 mg, 2.4 mmol). Stir the reaction mixture at room temperature for 1 hour. Pour the mixture into an aqueous NaHCO3 solution (30 mL) and extract with DCM (15 mL x 2). Wash the combined organic layers with saline solution, dry over Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Purify by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, eluent 0-30% petroleum ether / ethyl acetate, 36 mL / min) to obtain compound 4-(1-methyl-1H-pyrazole-3-yl)cyclohexane-1-carbaldehyde (280 mg, yield 91%) as a colorless oil. LCMS (ESI + ):m / z 193.3[M+H] + .

[0247] Step 7: Synthesis of (S)-1-(2-fluoro-5-((3-methyl-4-((4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of (S)-1-(2-fluoro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.42 mmol), 4-(1-methyl-1H-pyrazole-3-yl)cyclohexane-1-carbaldehyde (161 mg, 0.84 mmol), and DIEA (108 mg, 0.84 mmol) in MeOH (5 mL) is stirred at room temperature for 10 minutes. ZnCl2 (0.5 mL, 1 mmol, 2 M THF solution) is added, and the mixture is stirred at room temperature overnight. Then sodium borocyanohydride (53 mg, 0.84 mmol) is added, and the reaction mixture is stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the residue, which was purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica flash column, 0-10% DCM / MeOH eluent, 36 mL / min) to obtain compound (S)-1-(2-fluoro-5-((3-methyl-4-((4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, yield 73%) as a yellow oil. LCMS (ESI + ):m / z 657.6[M+H] + .

[0248] Step 8: Synthesis of (S)-1-(2-fluoro-5-((3-methyl-4-((4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of (S)-1-(2-fluoro-5-((3-methyl-4-((4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.30 mmol) and TfOH (3 mL) in TFA (3 mL) is stirred at 30 °C for 1 hour. The reaction mixture is quenched with aqueous NaHCO3 solution (50 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was then purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica flash column, 0-10% dichloromethane / methanol eluent, 36 mL / min) to obtain compound (S)-1-(2-fluoro-5-((3-methyl-4-((4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg, yield 43%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.55(s,1H),8.52(d,J=7.1Hz,1H),7.49(t,J=2.2Hz,2H),6.96(dd,J=7.1,1.8H z,1H),5.99(d,J=2.1Hz,1H),3.74(d,J=4.7Hz,8H),3.04(s,2H),2.79(t,J=6.7Hz ,3H),2.73-2.62(m,3H),2.39(d,J=34.3Hz,2H),2.12(s,1H),1.91(d,J=12.9Hz,4 H),1.73(d,J=12.9Hz,1H),1.55(s,1H),1.42-1.20(m,3H),1.06(d,J=6.6Hz,3H). LCMS(ESI + ):m / z 537.5[M+H] + .

[0249] Step 9: Chiral separation of compounds 99 and 100 Compound 98 (540 mg, 1.01 mmol) was separated by a preparative SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [CO2-EtOH], B: 40%, isocratic elution mode, A / B = 1 / 1, 1.0 mL / min, temperature: 35 °C, wavelength: 254 nm). Compound 99 (25 mg, 13.82%) was obtained as peak 1, a white solid, with Rt = 0.54 min. Compound 100 (230 mg, 14.47%) was obtained as peak 2, a white solid, with Rt = 0.95 min.

[0250] Example 24: The compounds in Table 9 are prepared according to the preparation process for compound 98. Table 9 [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6]

[0251] Example 25: Preparation of Compound 100: 1-(2-fluoro-5-(((S)-3-methyl-4-(((1*r,4*S)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, and preparation of Compound 102-B: 1-(2-fluoro-5-(((S)-3-methyl-4-(((1r,4S)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0252] Step 1: Synthesis of (1r,4r)-4-(methoxy(methyl)carbamoyl)cyclohexane-1-carboxylate methyl ester A mixture of (1r,4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (10 g, 53.7 mmol), HATU (24.5 g, 64.4 mmol), DIEA (13.9 g, 107.4 mmol), and N,O-dimethylhydroxylamine hydrochloride (6.28 g, 64.4 mmol) in DCM (150 mL) was stirred at 25°C for 2 hours. The mixture was diluted with H2O (200 mL) and extracted with EA (200 mL x 2). The combined organic extracts were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was then purified by high-performance silica gel chromatography (ISCO®, 120g SepaFlash® silica gel high-performance chromatography column, eluent 0-30% petroleum ether / ethyl acetate, 100mL / min) to obtain the compound (1r,4r)-4-(methoxy(methyl)carbamoyl)cyclohexane-1-carboxylic acid methyl ester (7.0g, yield 57%) as a colorless oil. LCMS (ESI + ):m / z 230.4[M+H] + .

[0253] Step 2: Synthesis of (1r,4r)-4-hydroxymethyl-N-methoxy-N-methylcyclohexane-1-carboxamide At 0°C, LiBHEt3 is added to a mixture of (1r,4r)-4-(methoxy(methyl)carbamoyl)cyclohexane-1-carboxylate methyl ester (3g, 0.69 mmol) in THF (30 mL), and the mixture is stirred at 0°C for 2 hours. The reaction is quenched with NH4Cl aqueous solution (30 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic extract is washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which is used directly in the next step. Compound (1r,4r)-4-(hydroxymethyl)-N-methoxy-N-methylcyclohexane-1-carboxamide (2.64 g, crude product) is obtained as a colorless oil. LCMS (ESI + ):m / z 202.2[M+H] + .

[0254] Step 3: Synthesis of (1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methoxy-N-methylcyclohexane-1-carboxamide A mixture of (1r,4r)-4-(hydroxymethyl)-N-methoxy-N-methylcyclohexane-1-carboxamide (2.64 g, 13.1 mmol), imidazole (1.34 g, 19.7 mmol), and TBSCl (2.57 g, 17 mmol) in DCM (30 mL) is stirred at 25°C for 0.5 hours. The mixture is filtered and concentrated under reduced pressure to obtain the residue, which is purified by high-performance silica gel chromatography (ISCO®, 40 g SepaFlash® silica gel high-performance chromatography column, eluent 0-15% petroleum ether / ethyl acetate, 50 mL / min) to obtain compound (1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methoxy-N-methylcyclohexane-1-carboxamide (2.25 g, yield 54%) as a colorless oil. LCMS (ESI + ):m / z 316.3[M+H] + .

[0255] Step 4: Synthesis of 1-((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)ethane-1-one (1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-methoxy-N-methylcyclohexane-1-carboxamide (2.25 g, 7.13 mmol) is mixed with THF (30 mL) and MgBrMe (3.1 mL, 9.27 mmol, 3 M) is added, and the mixture is stirred at 0°C for 3 hours. The mixture is quenched with NH4Cl (aqueous solution, 30 mL) and extracted with EA (30 mL x 2). The combined organic extracts were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was then purified by high-performance silica gel chromatography (ISCO®, 20g SepaFlash® silica flash column, eluent 0-30% petroleum ether / ethyl acetate, 40 mL / min) to obtain compound 1-((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)ethane-1-one (1.7 g, yield 88%) as a colorless oil.

[0256] Step 5: Synthesis of (E)-1-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-3-(dimethylamino)prop-2-en-1-one A mixture of 1-((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)ethane-1-one (1.7 g, 6.28 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (2.2 g, 12.6 mmol) in dioxane (20 mL) is stirred at 100 °C for 5 hours. The mixture is concentrated under reduced pressure to obtain the residue, which is purified by high-performance silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent 15-30% petroleum ether / ethyl acetate, 50 mL / min) to obtain compound (E)-1-((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-3-(dimethylamino)prop-2-en-1-one (1.4 g, yield 68%) as a colorless oil. LCMS(ESI + ):m / z 326.3[M+H] + .

[0257] Step 6: Synthesis of ((1r,4r)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methanol and ((1r,4r)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexyl)methanol (E)-1-((1r,4r)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-3-(dimethylamino)prop-2-en-1-one (1.4 g, 4.3 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (930 mg, 6.45 mmol) are mixed in AcOH (10 mL) and H2O (10 mL) and stirred at 25°C for 2 hours. The mixture is quenched with NaHCO3 to adjust the pH to 8 and extracted with EA. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which is used directly in the next step. A mixture of the compounds ((1r,4r)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methanol and ((1r,4r)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexyl)methanol (460 mg, crude product) is obtained as a colorless oil. LCMS(ESI +): m / z 195.1[M+H] + .

[0258] Step 7: Synthesis of (1r,4r)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexane-1-carbaldehyde and (1r,4r)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexane-1-carbaldehyde A mixture of ((1r,4r)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methanol and ((1r,4r)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexyl)methanol (460 mg, 2.37 mmol) and PCC (765 mg, 3.55 mmol) in DCM (10 mL) was stirred at 25°C for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain the residue, which was then purified by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica gel high-performance chromatography column, eluent 20% petroleum ether / ethyl acetate, 36 mL / min). A mixture of the compounds (1r,4r)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexane-1-carbaldehyde and (1r,4r)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexane-1-carbaldehyde is 300 mg, with a yield of 65%, and is a colorless oil. LCMS (ESI + ):m / z 193.2[M+H] + .

[0259] Step 8: Synthesis of 1-(2-fluoro-5-(((S)-3-methyl-4-(((1r,4S)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione and 1-(2-fluoro-5-(((S)-3-methyl-4-(((1r,4S)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione Mixtures of (S)-1-(2-fluoro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg, 0.31 mmol), (1r,4r)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexane-1-carbaldehyde and (1r,4r)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexane-1-carbaldehyde (150 mg, 0.78 mmol) and DIEA (124 mg, 0.92 mmol) in MeOH (6 mL) are stirred at room temperature for 10 minutes. Add ZnCl2 (1 mL, 1 mmol, 1 M) and stir the mixture overnight at room temperature. Next, sodium borocyanohydride (39 mg, 0.62 mmol) is added, and the reaction mixture is stirred at room temperature for 1 hour. The mixture is concentrated under reduced pressure to obtain the residue, which is purified by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, eluent 0-10% DCM / MeOH, 36 mL / min) to obtain compound 1-(2-fluoro-5-(((S)-3-methyl-4-(((1r,4S)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyridine A mixture of midin-2,4(1H,3H)-dione and 1-(2-fluoro-5-(((S)-3-methyl-4-(((1r,4S)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg, yield 74%) is obtained as a yellow oily substance. LCMS (ESI + ):m / z 657.5[M+H] + .

[0260] Step 9: Synthesis of 1-(2-fluoro-5-(((S)-3-methyl-4-(((1*r,4*S)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 1-(2-fluoro-5-(((S)-3-methyl-4-(((1r,4S)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione and 1-(2-fluoro-5-(((S)-3-methyl-4 -(((1r,4S)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg, 0.228 mmol) and TfOH (3 mL) mixed with TFA (3 mL) were stirred at 30°C for 1 hour. The reaction was quenched with aqueous NaHCO3 solution (30 mL) and extracted with EA (20 mL x 2). The combined organic extracts were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by preparative HPLC (TFA) to obtain compound 100:1-(2-fluoro-5-(((S)-3-methyl-4-(((1*r,4*S)-4-(1-methyl-1H-pyrazole-3-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (38 mg, yield 31%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 10.55(s,1H),8.57(d,J=7.1Hz,1H),7.54(d,J=2.1Hz,1H),7.51(d,J=2.1Hz,1H),6 .98(dd,J=7.1,1.9Hz,1H),6.00(d,J=2.2Hz,1H),3.75(d,J=5.1Hz,5H),3.67(s,4H) ),3.17(s,3H),2.97(s,3H),2.80(t,J=6.7Hz,3H),2.38(s,1H),2.00-1.87(m,3H), 1.74(d,J=11.5Hz,2H),1.45-1.34(m,2H),1.27(d,J=6.1Hz,3H),1.19-1.02(m,2H). LCMS(ESI + ):m / z 537.5[M+H] + . Chiral analysis: DAIEL CHIRALPAK AD (250mm x 30mm, 10um), mobile phase: [CO2-EtOH], B: 40%, isocratic elution mode, A / B = 1 / 1, 1.0 mL / min, temperature: 35℃, wavelength: 254 nm. Purity 90.82%, RT = 0.95 min.

[0261] Compound 102-B:1-(2-fluoro-5-(((S)-3-methyl-4-(((1r,4S)-4-(1-methyl-1H-pyrazole-5-yl)cyclohexyl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (62 mg, yield 51%) is obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.55(s,1H),8.57(d,J=7.1Hz,1H),7.54(s,1H),7.27(d,J=1.8Hz,1H),6. 98(dd,J=7.2,1.9Hz,1H),5.99(d,J=1.8Hz,1H),3.75(d,J=3.4Hz,5H),3.6 8(s,4H),2.98(d,J=12.0Hz,2H),2.80(t,J=6.7Hz,3H),2.63(dt,J=11.7,3 .3Hz,2H),2.37(s,1H),2.00-1.85(m,3H),1.78(s,2H),1.49-0.93(m,7H). LCMS(ESI+ ):m / z 537.5[M+H] + . Chiral analysis: DAIEL CHIRALPAK AD (250mm x 30mm, 10um), mobile phase: [CO2-EtOH], B: 40%, isocratic elution mode, A / B = 1 / 1, flow rate 1.0 mL / min, temperature: 35℃, wavelength: 254 nm.

[0262] Example 26: Preparation of Compound 131: (S)-1-(5-((4-(4-(1-ethyl-1H-pyrazole-3-yl)cyclohexyl)-3-methylpiperazine-1-yl)methyl)-2-fluoropyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0263] Step 1: Synthesis of 3-bromo-1-ethyl-1H-pyrazole Add NaH (653 mg, 60% of mineral oil) to a solution of 3-bromo-1H-pyrazole (2 g, 13.61 mmol) in DMF (6 mL). Stir the reaction mixture at 25°C for 30 minutes. Then add iodoethane to the mixture. Stir the mixture at room temperature for 2 hours. Quench the reaction by adding water. Extract the mixture with EA (50 mL). Wash the organic layer with brine (30 mL x 3), dry over Na2SO4, filter and concentrate to obtain the crude product, and purify it by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, eluent 1-6% petroleum ether / ethyl acetate, 36 mL / min) to obtain compound 3-bromo-1-ethyl-1H-pyrazole (1.63 g, yield 68%) as a colorless oil. LCMS (ESI + ):m / z 175.2[M+H] + .

[0264] Step 2: Synthesis of 1-ethyl-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrazole A mixture of 3-bromo-1-ethyl-1H-pyrazole (1.53 g, 8.74 mmol), 1,4-dioxaspiro[4,5]dec-7-ene-8-boronic acid pinacol ester (2.33 g, 8.74 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichlorodichloromethane complex (710 mg, 0.87 mmol), and K2CO3 (2.42 g, 17.48 mmol) in dioxane / H2O (20 mL / 5 mL) was stirred at 100°C for 3 hours under a nitrogen atmosphere. The mixture was then extracted with EA (40 mL). The organic layer was washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by high-performance silica gel chromatography (ISCO®, 25g SepaFlash® silica gel high-performance chromatography column, eluent 1-20% petroleum ether / ethyl acetate, 60 mL / min) to obtain compound 1-ethyl-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrazole (1.83 g, yield 89%) as a yellow oily substance. LCMS (ESI + ):m / z 235.3[M+H] + .

[0265] Step 3: Synthesis of 1-ethyl-3-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole Add 10% Pd / C (100 mg, wetted with 55% H2O) to a solution of 1-ethyl-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrazole (400 mg, 1.71 mmol) in EtOH (10 mL). Stir the reaction mixture under a hydrogen gas atmosphere at 40°C for 3 hours. Filter the mixture through a diatomaceous earth pad. Concentrate the filtrate to obtain a yellow oily substance (395 mg, 98%). LC-MS (ESI) + ):m / z 237.4[M+H] + .

[0266] Step 4: Synthesis of 4-(1-ethyl-1H-pyrazole-3-yl)cyclohexane-1-one Add 7 mL of 6N HCl aqueous solution to a 7 mL ketone solution of 1-ethyl-3-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole (395 mg, 1.18 mmol). Stir the reaction mixture overnight at 50°C. Adjust the pH of the mixture to 7-8 by adding saturated NaHCO3 aqueous solution dropwise. Extract the mixture with EA (30 mL). Wash the organic layer with saline solution, dry over Na2SO4, filter, and concentrate to obtain the crude product. Purify by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, eluent 1-25% petroleum ether / ethyl acetate, 36 mL / min) to obtain compound 4-(1-ethyl-1H-pyrazole-3-yl)cyclohexane-1-one (129 mg, yield 57%) as a colorless oil. LCMS (ESI + ):m / z 193.4[M+H] + . Step 5: Synthesis of (S)-1-(5-((4-(4-(1-ethyl-1H-pyrazole-3-yl)cyclohexyl)-3-methylpiperazine-1-yl)methyl)-2-fluoropyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione Add TEA (78 mg, 0.772 mmol) to a 5 mL solution of 4-(1-ethyl-1H-pyrazole-3-yl)cyclohexane-1-one (41 mg, 0.213 mmol) and INT-5 (100 mg, 0.193 mmol) in DCM (5 mL). Stir the mixture at room temperature for 10 minutes. Remove volatiles by reducing pressure to obtain a residue, and dissolve the residue in THF (5 mL). Add Ti(OiPr)4 (165 mg, 0.579 mmol) to the solution. Stir the mixture at 50°C for 1 hour. Then add NaBH3CN (24 mg, 0.386 mmol) to the mixture. Stir the reaction mixture at room temperature for 3 hours. Concentrate the mixture under reduced pressure to obtain a residue, and dissolve the residue in EA (10 mL). The solution was washed with saline solution, dried over Na2SO4, filtered, and volatiles were removed by reduced pressure to obtain the crude product. This was purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica flash column, eluent 1-5% DCM / MeOH, 35 mL / min) to obtain compound (S)-1-(5-((4-(4-(1-ethyl-1H-pyrazole-3-yl)cyclohexyl)-3-methylpiperazin-1-yl)methyl)-2-fluoropyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (60 mg, yield 47%) as a yellow solid. LCMS (ESI + ):m / z 657.7[M+H] + .

[0267] Step 6: Synthesis of (S)-1-(5-((4-(4-(1-ethyl-1H-pyrazole-3-yl)cyclohexyl)-3-methylpiperazine-1-yl)methyl)-2-fluoropyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(5-((4-(4-(1-ethyl-1H-pyrazole-3-yl)cyclohexyl)-3-methylpiperazine-1-yl)methyl)-2-fluoropyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (60 mg, 0.091 mmol) is mixed with TFA / TfOH (2 mL / 2 mL) and stirred at 35°C for 1 hour. Saturated NaHCO3 aqueous solution is added to the reaction mixture to adjust the pH of the mixture to 7-8. The solution is extracted with EA (30 mL). The organic layer was washed with saline solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by preparative HPLC (FA conditions) to obtain (S)-1-(5-((4-(4-(1-ethyl-1H-pyrazole-3-yl)cyclohexyl)-3-methylpiperazin-1-yl)methyl)-2-fluoropyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (7.81 mg, yield 16%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.54(d,J=3.5Hz,1H),8.52(dd,J=7.2,4.0Hz,1H),7.61-7.45(m,2H),6.96(td,J=7.4,1.8Hz,1H),6.04(dd,J=25.0,2.2Hz,1H),4.09-3 .98(m,2H),3.74(td,J=6.6,4.3Hz,2H),3.59-3.45(m,2H),2.99-1.93(m,11H),1.80-1.21(m,8H),1.15-1.00(m,3H),0.94-0.80(m,3H). LCMS(ESI + ):m / z 537.6[M+H] + .

[0268] Example 27: The following compounds in Table 10 are prepared by the method described for compound 131 and by appropriate ketone derivatives. Table 10 [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

[0269] Example 28: Preparation of Compound 140: 1-(2-fluoro-5-(((S)-4-(((1*r,4*S)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0270] Step 1: Synthesis of (1r,4r)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexane-1-carboxylate methyl ester A mixture of (1s,4s)-4-hydroxycyclohexane-1-carboxylate methyl ester (3.7 g, 23.2 mmol), 4-fluoro-1H-pyrazole (2.0 g, 23.2 mmol), and triphenylphosphine (9.1 g, 34.8 mmol) in 50 mL of THF is cooled to 0°C. Diethyl azodicarboxylate (6.1 g, 34.8 mmol, dissolved in 20 mL of THF) is added. The reaction mixture is stirred at 40°C for 2 hours. The reaction is quenched with 200 mL of water and extracted with EA (50 mL x 2). The combined extracts were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by high-performance silica gel chromatography (ISCO®, 25g SepaFlash® silica flash column, eluent 0-15% petroleum ether / ethyl acetate, 45 mL / min) to obtain the compound (1r,4r)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexane-1-carboxylate methyl ester (400 mg, yield 8%) as a white solid. LCMS (ESI + ):m / z 227.3[M+H]+ .

[0271] Step 2: Synthesis of ((1r,4r)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexyl)methanol A 10 mL THF solution of (1r,4r)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexane-1-carboxylic acid methyl ester (400 mg, 1.8 mmol) is cooled to 0°C. Lithium aluminum hydride (2.5 N, 1.5 mL, 3.6 mmol) is added. The reaction mixture is stirred at 0°C for 1 hour. The reaction is quenched with H2O (100 mL) and extracted with EA (50 mL x 2). The extracts are combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue is purified by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, eluent 0-50% petroleum ether / ethyl acetate, 36 mL / min) to obtain the compound ((1r,4r)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexyl)methanol (270 mg, yield 77%) as a white solid. LCMS(ESI + ): m / z 199.3[M+H] + .

[0272] Step 3: Synthesis of (1r,4r)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexane-1-carbaldehyde Pyridinium chlorochromate (442 mg, 2.1 mmol) is added to 10 mL of DCM solution of ((1r,4r)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexyl)methanol (270 mg, 1.4 mmol). The reaction mixture is stirred at room temperature for 1 hour. The mixture is filtered and concentrated under reduced pressure to obtain the residue, which is purified by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, eluent 0-20% petroleum ether / ethyl acetate, 36 mL / min) to obtain the compound (1r,4r)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexane-1-carbaldehyde (167 mg, yield 63%) as a white solid. LCMS (ESI+ ): m / z 197.4[M+H] + .

[0273] Step 5: Synthesis of 1-(2-fluoro-5-(((S)-4-(((1r,4S)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of (S)-1-(2-fluoro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.21 mmol), (1r,4r)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexane-1-carbaldehyde (82 mg, 0.42 mmol), and DIEA (54 mg, 0.42 mmol) in MeOH (5 mL) is stirred at room temperature for 10 minutes. ZnCl2 (0.5 mL, 1 mmol, 2 M in THF) is added, and the mixture is stirred at room temperature overnight. Then NaBH3CN (27 mg, 0.42 mmol) is added, and the reaction mixture is stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the residue, which was purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica flash column, 0-10% DCM / MeOH eluent, 36 mL / min) to obtain compound 1-(2-fluoro-5-(((S)-4-(((1r,4S)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, yield 73%) as a yellow oily substance. LCMS (ESI + ):m / z 661.5[M+H] + .

[0274] Step 6: Synthesis of 1-(2-fluoro-5-(((S)-4-(((1r,4S)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Mix 1-(2-fluoro-5-(((S)-4-(((1r,4S)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.15 mmol), TfOH (2.5 mL), and TFA (2.5 mL) in a mixture and stir at 30°C for 1 hour. Quench the reaction with aqueous NaHCO3 solution (30 mL) and extract with EA (15 mL x 2). The combined extracts were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was then purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica flash column, 0-10% DCM / MeOH eluent, 36 mL / min) to obtain compound 1-(2-fluoro-5-(((S)-4-(((1r,4S)-4-(4-fluoro-1H-pyrazole-1-yl)cyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (50 mg, yield 61%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 10.52(s,1H),8.50(d,J=7.1Hz,1H),7.86(d,J=4.5Hz,1H),7.48(s,1H),7.40(d,J=4.4Hz,1H),6. 95(dd,J=7.1,1.8Hz,1H),3.98(ddt,J=11.9,7.8,3.9Hz,1H),3.74(t,J=6.7Hz,2H),3.46(d,J=6.0 Hz,2H),2.77(q,J=6.0,5.2Hz,3H),2.56(d,J=10.2Hz,2H),2.43(dd,J=12.4,8.8Hz,1H),2.39-2.3 1(m,1H),2.19(p,J=9.4Hz,2H),1.95(t,J=12.6,7.4Hz,5H),1.82-1.55(m,4H),1.12-0.86(m,5H). LCMS(ESI + ):m / z 541.4[M+H] + .

[0275] Example 29: The following compounds in Table 11 are prepared by the preparation method for compound 140. Table 11 [Table 11-1] [Table 11-2] [Table 11-3]

[0276] Example 30: Preparation of Compound 161: (S)-1-(2-fluoro-5-((3-methyl-4-(4-(4-methyl-1H-pyrazole-1-yl)cyclohexyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0277] Step 1: Synthesis of 1,4-dioxaspiro[4,5]decane-8-yl-4-methylbenzenesulfonate To 8 mL of pyridine solution of 1,4-dioxaspiro[4.5]decane-8-ol (1000 mg, 6.3 mmol), Tos-Cl (1450 mg, 7.6 mmol) is added. The reaction mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into 30 mL of H2O and extracted with EA. The organic layer is sequentially washed with 1N aqueous HCl (50 mL) and saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue is purified by high-performance silica gel chromatography (ISCO®, 25 g SepaFlash® silica flash column, eluent 0-30% petroleum ether / ethyl acetate, 40 mL / min) to obtain compound 1,4-dioxaspiro[4.5]decane-8-yl-4-methylbenzenesulfonate (1.06 g, yield 54%) as a white solid.

[0278] Step 2: Synthesis of 4-methyl-1-(1,4-dioxaspiro[4.5]decano-8-yl)-1H-pyrazole Add NaH (27 mg, 0.7 mmol) to 5 mL of DMF solution of 4-methyl-1H-pyrazole (55 mg, 0.7 mmol). Stir the reaction mixture at 25°C for 30 minutes. Then add 1,4-dioxaspiro[4,5]decane-8-yl-4-methylbenzenesulfonate (200 mg, 0.6 mmol). Stir the reaction mixture at 60°C for 5 hours. Quench the reaction with H2O (30 mL) and extract with EA (20 mL x 2). The combined extracts were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica flash column, eluent 0-15% petroleum ether / ethyl acetate, 36 mL / min) to obtain compound 4-methyl-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole (71 mg, yield 50%) as a colorless oil. LCMS (ESI + ):m / z 223.4[M+H] + .

[0279] Step 3: Synthesis of 4-(4-methyl-1H-pyrazole-1-yl)cyclohexane-1-one A mixture of 4-methyl-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole (70 mg, 0.3 mmol), TFA (3 mL), and H2O (1 mL) is stirred at 50°C for 1 hour. The reaction mixture is quenched with NaHCO3 aqueous solution (20 mL) and extracted with EA (15 mL x 2). The combined extract is washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue is purified by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica gel high-performance chromatography column, eluent 0-30% petroleum ether / ethyl acetate, 36 mL / min) to obtain compound 4-(4-methyl-1H-pyrazole-1-yl)cyclohexane-1-one (40 mg, yield 71%) as a colorless oil. LCMS (ESI + ):m / z 179.3[M+H] + .

[0280] Step 4: Synthesis of (S)-1-(2-fluoro-5-((3-methyl-4-(4-(4-methyl-1H-pyrazole-1-yl)cyclohexyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione Add TEA (78 mg, 0.772 mmol) to a 5 mL solution of 4-(4-methyl-1H-pyrazole-1-yl)cyclohexane-1-one (40 mg, 0.21 mmol) and INT-5 (100 mg, 0.20 mmol) in DCM (5 mL). Stir the mixture at room temperature for 10 minutes. Remove volatiles by reducing pressure to obtain a residue, and dissolve the residue in THF (5 mL). Add Ti(OiPr)4 (165 mg, 0.579 mmol) to the solution. Stir the mixture at 50°C for 1 hour. Then add NaBH3CN (24 mg, 0.386 mmol) to the mixture. Stir the reaction mixture at room temperature for 3 hours. Concentrate the mixture under reduced pressure to obtain a residue, and dissolve the residue in EA (10 mL). The solution was washed with saline solution, dried over Na2SO4, filtered, and volatiles were removed by reduced pressure to obtain the crude product. This was purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica flash column, 0-10% DCM / MeOH eluent, 36 mL / min) to obtain compound (S)-1-(2-fluoro-5-((3-methyl-4-(4-(4-methyl-1H-pyrazole-1-yl)cyclohexyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (80 mg, yield 60%) as a yellow oil. LCMS (ESI + ):m / z 643.7[M+H] + .

[0281] Step 5: Synthesis of (S)-1-(2-fluoro-5-((3-methyl-4-(4-(4-methyl-1H-pyrazole-1-yl)cyclohexyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-1-(2-fluoro-5-((3-methyl-4-(4-(4-methyl-1H-pyrazole-1-yl)cyclohexyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (80 mg, 0.1 mmol), TfOH (2.5 mL), and TFA (2.5 mL) mixture are stirred at 30°C for 1 hour. The reaction is quenched with NaHCO3 (aqueous solution, 30 mL) and extracted with EA (15 mL x 2). The combined extracts were washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica gel high-performance chromatography column, eluent 0-10% dichloromethane / methanol, 36 mL / min) to obtain compound (S)-1-(2-fluoro-5-((3-methyl-4-(4-(4-methyl-1H-pyrazole-1-yl)cyclohexyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (37 mg, yield 54%) as a white solid. LCMS (ESI + ):m / z 523.6[M+H] + .

[0282] Example 31: Preparation of Compound 162: (S)-1-(2-fluoro-5-((4-((1-(isopropylsulfonyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka]

[0283] Step 1: Synthesis of (S)-4-((4-((2-fluoro-3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-carboxylate tert-butyl ester A mixture of (S)-1-(2-fluoro-5-((3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.04 mmol), 4-formylpiperidine-1-carboxylate tert-butyl ester (333 mg, 1.56 mmol), and DIEA (268 mg, 2.08 mmol) in MeOH (5 mL) is stirred at room temperature for 10 minutes. ZnCl2 (1 mL, 2 mmol, 2 M in THF) is added, and the mixture is stirred at room temperature overnight. Then sodium borocyanohydride (131 mg, 2.08 mmol) is added, and the reaction mixture is stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the residue, which was purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica flash column, 0-10% DCM / MeOH eluent, 36 mL / min) to obtain compound (S)-4-((4-((2-fluoro-3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (470 mg, yield 67%) as a white solid. LCMS (ESI + ):m / z 678.6[M+H] + .

[0284] Step 2: Synthesis of (S)-1-(2-fluoro-5-((3-methyl-4-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (S)-4-((4-((2-fluoro-3-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (470 mg, 0.69 mmol), TfOH (2 mL), and TFA (2 mL) mixture are stirred at 30°C for 1 hour. The reaction is quenched with NaHCO3 (aqueous solution, 30 mL), extracted with EA (20 mL x 2), liquid-liquid-diluted, the organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a colorless oil (300 mg, yield 95%), which can be used in the next step without further purification. LCMS (ESI + ):m / z 458.5[M+H] + .

[0285] Step 3: Synthesis of (S)-4-((4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-fluoropyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-carboxylate tert-butyl ester Add ditert-butylcarbonate (283 mg, 1.30 mmol) to 5 mL of DCM solution of (S)-1-(2-fluoro-5-((3-methyl-4-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (300 mg, 0.65 mmol). Stir the reaction mixture at room temperature for 1 hour. The reaction mixture was washed with H2O (15 mL x 2), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by high-performance silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, 0-10% DCM / MeOH eluent, 36 mL / min) to obtain compound (S)-4-((4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-fluoropyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (340 mg, yield 82%) as a white solid. LCMS (ESI + ):m / z 558.5[M+H] + .

[0286] Step 4: Synthesis of (S)-1-(2-fluoro-5-((3-methyl-4-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of (S)-4-((4-((3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-fluoropyrazolo[1,5-a]pyridine-5-yl)methyl)-2-methylpiperazine-1-yl)methyl)piperidine-1-carboxylate tert-butyl ester (340 mg, 0.61 mmol) and HCl (2N, 2 mL) is stirred at 25°C for 1 hour. The reaction product is concentrated under reduced pressure to obtain a white solid (280 mg, yield 93%), which can be used in the next step without further purification. LCMS (ESI + ):m / z 458.4[M+H] + .

[0287] Step 5: Synthesis of (S)-1-(2-fluoro-5-((4-((1-(isopropylsulfonyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione Add Et3N (39 mg, 0.39 mmol) to 5 mL of DCM solution of (S)-1-(2-fluoro-5-((3-methyl-4-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (60 mg, 0.13 mmol), and then add propane-2-sulfonyl chloride (19 mg, 0.13 mmol). Stir the reaction mixture at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by high-performance silica gel chromatography (ISCO®, 10g SepaFlash® silica flash column, 0-10% DCM / MeOH eluent, 36 mL / min) to obtain compound (S)-1-(2-fluoro-5-((4-((1-(isopropylsulfonyl)piperidine-4-yl)methyl)-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (13 mg, yield 17%) as a white solid. 1 H NMR(400MHz,Methanol-d4)δ 7.53(d,J=7.2Hz,1H),6.63(s,1H),6.20(dd,J=7.2,1.9Hz,1H),3.04(t,J=6.7Hz,2H),2.98(dq,J=13.1,2.4Hz,2H),2.80(d,J =6.1Hz,2H),2.48-2.39(m,2H),2.21-1.85(m,9H),1.68(s,2H),1.48(d,J=11.3Hz,1H),1.16-0.88(m,4H),0.58-0.33(m,11H). LCMS(ESI + ):m / z 564.5[M+H] +

[0288] Example 32: The following compounds in Table 12 are prepared by the preparation method for compound 162. Table 12 [Table 12-1] [Table 12-2]

[0289] Example 51: WIZ protein degradation test (HiBiT test) The following is an example of an experiment used to measure the WIZ degradation activity in the HT-1080 cell line. The HT-1080 cell line was purchased from the American Type Culture Collection (ATCC) (Cat#CCL-121) and subsequently modified to stably overexpress the GSPT(1-138) / G575N mutant and HiBiT-tagged WIZ isotype 3. The cells were cultured in DMEM medium, supplemented with 10% heat-sterilized FBS, 1X sodium pyruvate, 1X non-essential amino acids, 1X glutamine, 100 U / mL penicillin, and 100 ug / mL streptomycin. For the WIZ degradation test, approximately 10,000 modified HT-1080 cells were inoculated into 35 μl of medium, then inoculated into a 384-well plate (Cat#3764, Corning), and the test compound was pre-treated using an Echo 650 liquid handler (Beckman). The semi-logarithmic dose-response curve (DRC) typically contains 10 points, with the highest concentration being 10 μM and the lowest concentration being 0.316 nM. The measurement plate is incubated at 37°C under 5% CO2 conditions for 20 hours. Then, WIZ degradation is evaluated using Nano-Glo HiBiT solubility detection reagent according to the manufacturer's instructions. Emission intensity is measured using a Pherastar microplate reader (BMG Labtech). Data is processed using the Collaborative Drug Discovery Vault, and the degradation value (percentage compared to the DMSO control group) for each treated sample is calculated, using the DMSO control group as a reference. The EC of the compound is calculated using a 4-parameter logistic model. 50 and DC 50 The calculation formula is as follows: y=(A+((BA) / (1+((C / x)AD)))) A=Y min (The minimum WIZ level to normalize to the DMSO control group after compound treatment is determined by curve fitting.) B=Y max (Highest value, WIZ value in the DMSO control group) C=EC 50 D = Hill slope x=compound concentration EC 50 =y=(Y max -Y min Concentration of the compound when ) / 2 DC 50 =y=Sample concentration at 50% of the DMSO control group (WIZ degradation rate 50%) y = WIZ protein levels normalized to the DMSO control group D max =(1-Y min / Y max ) × 100% D max This represents the maximum percentage of WIZ degradation achievable at the highest treatment concentration of the compound. The results for the compound of the present invention and the three reference compounds are shown in Table 15.

[0290] Reference compound 1 is (S)-1-(5-((4-isobutyl-3-methylpiperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, and reference compound 2 is (S)-1-(5-((4-((4,4-difluorocyclohexyl)methyl)-3-methylpiperazine-1-yl)methyl)pyra The reference compound 3 is (S)-1-(5-((3-methyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-yl)methyl)pyrazolo[1,5-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. Reference compounds 1, 2, and 3 are Examples 203, 207, and 202 described in WO2022 / 195454, respectively. Table 15 WIZ protein degradation activity [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4]

[0291] Example 52: Fetal hemoglobin induction test after WIZ degradation First Generation Human CD34 + The cells are purchased from STEMCELL Technologies. The cells are sampled and isolated from peripheral blood leukocytes mobilized by G-CSF obtained from healthy donors. Erythrocyte-induced differentiation is performed using a two-step liquid culture system. During the first six days (Phase 1), the cells reach 1 × 10⁶ cells. 4Cells were grown at a density of cells / mL in StemSpan® SFEM II hematopoietic medium (STEMCELL Technologies), which contains rhIL-3 (Peprotech), rhIL-6 (Peprotech), rhSCF (Peprotech, Inc.), rhFlt3L (Peprotech), and an antibiotic-antifungal agent (Gibco®). Subsequently, in the presence of the test compound, the cells were divided into 5 × 10⁶ cells. 3 Cells are induced to differentiate into erythrocytes in IMDM (Gibco®) at a density of cells / mL for 7 days (stage 2). IMDM contains heparin (Millipore Sigma), human insulin (Millipore Sigma), human AB serum (Millipore Sigma), human total transferrin (Millipore Sigma), hydrocortisone (STEMCELL Technologies), rhIL-3 (Peprotech), rhEPO (Peprotech), rhSCF (Peprotech), and antibiotics-antifungal agents (Gibco®).

[0292] Fetal hemoglobin staining and flow cytometry Seven days after inducing fetal hemoglobin expression in the erythroid differentiation process, the cells are washed and resuspended in staining buffer (BD Biosciences), which is supplemented with human FcR blocker (Miltenyi Biotec), and then incubated at room temperature for 15 minutes. The cells are stained at room temperature in the dark for 20 minutes, and the expression of erythroid markers is confirmed using BV711-coupled anti-CD71 antibody (BD Biosciences) and APC-coupled anti-CD235a antibody (BD Biosciences). To prepare the fetal hemoglobin stained sample, the cells are first washed with staining buffer and incubated at room temperature in the dark using Cyto-Fast® Fix / PeR m Treat with buffer for 20 minutes. Next, use Cyto-Fast® PeR m Wash the cells with Wash solution, then stain them with FITC-coupled anti-HbF (Invitrogen) antibody at room temperature in the dark for 30 minutes. Finally, apply Cyto-Fast® PeRm The cells are washed with a washing solution, resuspended in staining buffer, and then subjected to flow cytometry analysis using a NovoCyte Quanteon flow cytometer (Agilent). The data is then analyzed using NovoExpress software (Agilent). Table 16 Inducible activity of compounds on HbF [Table 16]

[0293] Example 53: Pharmacokinetic studies after single intravenous injection and oral administration in mice Sample Collection and Preparation: After intravenous injection or oral administration of the test compound, a blood sample is collected and the collection time is recorded. Immediately after collection, the blood sample is transferred to a K2-EDTA-labeled centrifuge tube, then centrifuged and the plasma is collected. The plasma is then transferred to a pre-cooled centrifuge tube, rapidly frozen with dry ice, and stored in an ultra-low temperature refrigerator at -70±10°C until LC-MS / MS analysis. Pharmacokinetic data analysis: Using pharmacokinetic software, plasma drug concentration data of compounds is processed using a non-compartmental model. From the plasma concentration-time diagram, the peak concentration (C) is determined. max ), peak arrival time (T max ) and a quantifiable termination time can be directly obtained. Using the log-linear trapezoidal method, the half-life (T 1 / 2 ), apparent volume of distribution (Vss) and clearance (Cl), and time from 0 to endpoint - area under the plasma concentration curve (AUC) 0-inf Calculate the pharmacokinetic parameters of ). Table 17 Pharmacokinetic characteristics in mice [Table 17]

[0294] Conclusions from pharmacokinetic studies: Compared to reference compound 1, compounds 1 and 100 of the present invention exhibit lower clearance, better oral exposure, and higher oral bioavailability.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer, Equation (I): 【Chemistry 1】 Here, X １ and X ２ Each is independent, bonded, -(CH ２ ) ｎ -, -CH(R １ ) (CH ２ ) ｎ -, -C(O)- and S(O) ２ - Selected from the group consisting of, Ring A is C ６ -C １０ independently selected from the group consisting of an aryl group, a monocyclic 5- or 6-membered heteroaryl group, a bicyclic 9- or 10-membered heteroaryl group, and a tricyclic 12-, 13- or 14-membered heteroaryl group, wherein each said heteroaryl group independently has 1, 2 or 3 heteroatoms selected from the group consisting of O, S and N as ring members, and wherein said aryl group and heteroaryl group are optionally substituted by the same or different 1 to 6 substituents R ２ and Ring B is C ３ -C ８ Cycloalkyl groups, 4-10 membered monocyclic or bicyclic heterocyclic groups, C ６ -C １０ A cycloalkyl group is independently selected from the group consisting of an aryl group and a 5- to 10-membered heteroaryl group, where the heterocyclic group and the heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and N as ring members, where the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each have 1 to 6 identical or different substituents R ３ It can be arbitrarily replaced by, Ring C is, 【Chemistry 2】 , C ３ -C ８ Cycloalkyl groups, 3- to 8-membered heterocyclic groups, C ６ -C １０ Aryl group condensation C ５ -C １０ Cycloalkyl groups, C ６ -C １０ Heteroaryl group condensation C ５ -C １０ Cycloalkyl groups, C ６ -C １０ Aryl group condensation 5-10 member heterocyclic group and C ６ -C １０ A heterocyclic group is independently selected from the group consisting of a heteroaryl group condensation and a 5- to 10-membered heterocyclic group, wherein the heterocyclic group and the heteroaryl group have 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N as ring members, wherein the C ６ -C １０ Aryl group condensation C ５ -C １０ Cycloalkyl groups, C ６ -C １０ Heteroaryl group condensation C ５ -C １０ Cycloalkyl groups, C ６ -C １０ Aryl group condensation 5-10 member heterocyclic group and C ６ -C １０ The heteroaryl group condensation 5-10 member heterocyclic group has 1-6 identical or different substituents R ４ It can be arbitrarily replaced by, Ring D is C ３ -C ８ Cycloalkyl groups, 3- to 8-membered heterocyclic groups, C ６ -C １０ A cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group are independently selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, where the heterocyclic group and the heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and N as ring members, where the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each have 1 to 6 identical or different substituents R ５ It can be arbitrarily replaced by, Ring E does not exist, C ３ -C ８ Cycloalkyl groups, 3- to 8-membered heterocyclic groups, C ６ -C １０ A cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group are independently selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, where the heterocyclic group and the heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and N as ring members, where the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each have 1 to 6 identical or different substituents R ６ It can be arbitrarily replaced by, Here, n is 0, 1, 2, or 3. - (CH ２ ) ｎ The H in the - stands for deuterium, C stands for deuterium. １ -C ６ They can be optionally substituted with alkyl groups and halogens. Each R １ H, deuterium, C １ -C ６ Independently selected from the group consisting of alkyl groups and halogens, Each R ２ These are hydrogen, halogen, hydroxyl group, nitro group, cyano group, and C １ -C ６ Alkyl and C １ -C ６ Independently selected from the group consisting of haloalkyl groups, Each R ３ and R ５ is independently selected from the group consisting of hydrogen, halogen, hydroxy group, nitro group, cyano group, C １ -C ６ alkyl group, C ２ -C ６ alkenyl group, C ２ -C ６ alkynyl group, C １ -C ６ alkoxy group, C ２ -C ６ alkenyloxy group, C ２ -C ６ alkynyloxy group, C ２ -C ６ alkanoyl group, C ２ -C ６ alkyl ester, C １ -C ６ thioalkyl group, C １ -C ６ haloalkyl group, C １ -C ６ haloalkoxy group, hydroxy C １ -C ６ alkyl group, C ３ -C ７ cycloalkyl group and 3- to 8-membered heterocyclic group, where the cycloalkyl group and the heterocyclic group are optionally substituted by halogen, CN and OMe, Each R ４ and R ６ are hydrogen, halogen, C １ -C ６ alkyl group, C １ -C ６ haloalkyl group, C １ -C ６ alkoxy group, C １ -C ６ haloalkoxy group, -CN, -OH, C ３ -C ８ cycloalkyl group, 3- to 8-membered heterocyclic group, nitro group, amino group, mercapto group, -COOH, C ２ -C ６ alkenyl group, C ２ -C ６ alkynyl group, C ２ -C ６ alkenyloxy group, C ２ -C ６ alkynyloxy group, C ２ -C ６ alkanoyl group, C ２ -C ６ alkyl ester, C １ -C ６ thioalkyl group, hydroxy C １ -C ６ alkyl group, amino C １ -C ６ alkyl group, (mono- and di-C １ -C ６ alkylamino)C ０ -C ４ alkyl group, -C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl), -O-C ０ -C ４ alkyl(C ３ -C ７ cycloalkyl), -C ０ -C ４ alkyl-(phenyl), -C ０ ​​​​​​​​​​​ １ -C ６ Alkyl alkyl group, -C ０ -C ４ Alkyl C(O)OC １ -C ６ C having one, two, or three heteroatoms independently selected from alkyl groups, N, O, and S. ０ -C ４ Alkyl-(4-7 member heterocyclic alkyl) and C having 1, 2, or 3 heteroatoms independently selected from N, O, and S. ０ -C ４ Alkyl-(5 or 6-membered unsaturated or aromatic heterocyclic),-C(O)OR ７ , -C ０ -C ４ Alkyl NR ７ R ８ , -C(O)NR ７ R ８ , -SO ２ R ７ , -SO ２ NR ７ R ８ , -OC(O)R ７ and C(NR ７ ) NR ７ R ８ Independently selected from the group consisting of, where R ７ and R ８ is hydrogen, C １ -C ６ Alkyl alkyl group, -C ０ -C ４ Alkyl (C ３ -C ７ Cycloalkyl) and O-C ０ -C ４ Alkyl (C ３ -C ７ A compound independently selected from the group consisting of cycloalkyl compounds, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

2. A compound represented by formula (Ia) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer, Equation (Ia): 【Transformation 3】 Here, X １ and X ２ Each is independent, bonded, -(CH ２ ) ｎ -, -CH(R １ ) (CH ２ ) ｎ -, -C(O)- and S(O) ２ - Selected from the group consisting of, Ring A is C ６ -C １０ The heteroaryl groups are independently selected from the group consisting of aryl groups, monocyclic 5- or 6-membered heteroaryl groups, bicyclic 9- or 10-membered heteroaryl groups, and tricyclic 12-, 13-, or 14-membered heteroaryl groups, where each heteroaryl group independently has one, two, or three heteroatoms selected from the group consisting of O, S, and N as ring members, where the aryl group and heteroaryl group have one to six identical or different substituents R ２ It can be arbitrarily replaced by, Ring B is C ３ -C ８ Cycloalkyl groups, 4-10 membered monocyclic or bicyclic heterocyclic groups, C ６ -C １０ A cycloalkyl group, a heteroalkyl group, an aryl group, and a heteroaryl group are independently selected from the group consisting of an aryl group and a 5-10 membered heteroaryl group, where the heterocyclic group and the heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and N as ring members, where the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group each have 1 to 6 identical or different substituents R ３ It can be arbitrarily replaced by, Ring C is, 【Chemistry 4】 , C ６ -C １０ Aryl group condensation C ５ -C ７ Cycloalkyl groups, C ６ -C １０ Heteroaryl group condensation C ５ -C ７ Cycloalkyl groups, C ６ -C １０ Aryl group condensation 5-7 membered heterocyclic group and C ６ -C １０ A heterocyclic group is independently selected from the group consisting of a heteroaryl group condensation and a 5-7 membered heterocyclic group, wherein the heterocyclic group and the heteroaryl group have 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N as ring members, wherein the C ６ -C １０ Aryl group condensation C ５ -C ７ Cycloalkyl groups, C ６ -C １０ Heteroaryl group condensation C ５ -C ７ Cycloalkyl groups, C ６ -C １０ Aryl group condensation 5-7 membered heterocyclic group and C ６ -C １０ The heteroaryl group condensation 5-7 membered heterocyclic group has 1-6 identical or different substituents R ４ It can be arbitrarily replaced by, Ring D is C ３ -C ８ Cycloalkyl groups, 3- to 8-membered heterocyclic groups, C ６ -C １０ A cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group are independently selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, where the heterocyclic group and the heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and N as ring members, where the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each have 1 to 6 identical or different substituents R ５ It can be arbitrarily replaced by, Ring E is C ３ -C ８ Cycloalkyl groups, 3- to 8-membered heterocyclic groups, C ６ -C １０ A cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group are independently selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, where the heterocyclic group and the heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and N as ring members, where the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group each have 1 to 6 identical or different substituents R ６ It can be arbitrarily replaced by, Here, n is 0, 1, 2, or 3. - (CH ２ ) ｎ The H in the - stands for deuterium, C stands for deuterium. １ -C ６ They can be optionally substituted with alkyl groups and halogens. Each R １ H, deuterium, C １ -C ６ Independently selected from the group consisting of alkyl groups and halogens, Each R ２ These are hydrogen, halogen, hydroxyl group, nitro group, cyano group, and C １ -C ６ Alkyl and C １ -C ６ Independently selected from the group consisting of haloalkyl groups, Each R ３ and R ５ These are hydrogen, halogen, hydroxyl group, nitro group, cyano group, and C １ -C ６ Alkyl alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl ester, C １ -C ６ Thioalkyl groups, C １ -C ６ Haloalkyl group, C １ -C ６ Haloalkoxy group, hydroxy C １ -C ６ Alkyl alkyl group, C ３ -C ７ A group independently selected from the group consisting of cycloalkyl groups and 3- to 8-membered heterocyclic groups, wherein the cycloalkyl group and heterocyclic group are optionally substituted with halogens, CN, and OMe. Each R ４ and R ６ These are, independently, hydrogen, halogen, and C １ -C ６ Alkyl alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ A compound selected from the group consisting of a haloalkoxy group, -CN, and OH, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

3. A compound represented by formula (I'), (I''), or (I'''), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, Equation (I'): 【Transformation 5】 Equation (I''): 【Transformation 6】 Equation (I'''): 【Transformation 7】 Here, R ｍ is halogen, C １ -C ６ Alkyl alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Independently selected from the group consisting of haloalkoxy groups, -CN, and OH, X' １ is, -(CH ２ ) ｍ -, -CH(R ｎ３ ) (CH ２ ) ｍ -, -C(O)- or S(O) ２ - and Ring B' is C ３ -C ８ Cycloalkyl groups, 4-10 membered monocyclic or bicyclic heterocyclic groups, C ６ -C １０ Independently selected from the group consisting of aryl groups and 5- to 10-membered heteroaryl groups, where the heterocyclic group and the heteroaryl group each independently have 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and N as ring members. R ｎ１ and R ｎ２ These are, independently, halogen and C １ -C ６ Alkyl alkyl group, C １ -C ６ Alkoxy group, -CN, -OH, C ３ -C ８ Cycloalkyl groups, 4-10 membered monocyclic or bicyclic heterocyclic groups, C ６ -C １０ Selected from the group consisting of aryl groups and 5- to 10-membered heteroaryl groups, where the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are halogens, C １ -C ６ Alkyl alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, -CN, -OH, C ３ -C ８ Optionally substituted with one to six identical or different substituents selected from the group consisting of cycloalkyl groups, 4- to 10-membered monocyclic or bicyclic heterocyclic groups, - (CH ２ ) ｍ The H in the - stands for deuterium, C stands for deuterium. １ -C ６ They can be optionally substituted with alkyl groups and halogens. m is 0, 1, 2, or 3, and the compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

4. Ring A is a 9-membered heteroaryl group, and preferably, ring A is 【Chemistry 8-1】 And, Here, 【Chemistry 8-2】 These are single or double bonds, R ２ These are hydrogen, halogen, hydroxyl group, nitro group, cyano group, and C １ -C ６ Alkyl and C １ -C ６ Independently selected from the group consisting of haloalkyl groups, Y １ , Y ２ , Y ３ , Y ４ and Y ５ Each is independently selected from the group consisting of C, CH, N, O, S, and CO. W １ , W ２ , W ３ and W ４ Each is independently selected from the group consisting of C and N. The compound described in claim 2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

5. Ring B is 【Chemistry 9】 and 【Chemistry 10】 Selected from the group consisting of, Y ６ It was independently selected from the group consisting of CH and N, Z １ and Z ２ Each is independently selected from the group consisting of CH and N, Each R ３ These are hydrogen, halogen, hydroxyl group, nitro group, cyano group, and C １ -C ６ Alkyl alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl ester, C １ -C ６ Thioalkyl groups, C １ -C ６ Haloalkyl group, C １ -C ６ Haloalkoxy group, hydroxy C １ -C ６ Alkyl alkyl group, C ３ -C ７ A group independently selected from the group consisting of cycloalkyl groups and 3- to 8-membered heterocyclic groups, wherein the cycloalkyl group and heterocyclic group are optionally substituted with halogens, CN, and OMe. p is 0, 1, 2, 3, or 4. The compound according to any one of the above claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

6. The formulas (II-1) to (II-3) are: Formula (II-1): 【Chemistry 11】 Formula (II-2): 【Chemistry 12】 Formula (II-3): 【Chemistry 13】 Here, each X ２ The bond is -(CH ２ ) ｎ -, -CH(R １ ) (CH ２ ) ｎ -, -C(O)- and S(O) ２ - is independently selected from the group consisting of, Y ６ It was independently selected from the group consisting of CH and N, p is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. R １ , R ２ , R ３ Rings D and E are defined as in claim 2. The compound described in claim 2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

7. The compound has a structure represented by formula (III), Formula (III): 【Chemistry 14】 R ２ , R ３ , X ２ , p, Y ６ Rings D and E are as defined in claim 6. The compound according to claim 6, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

8. The compound has a structure represented by formula (IV), Formula (IV): 【Chemistry 15】 R ２ , R ３ , X ２ , Y ６ Rings D and E are as defined in claim 6. The compound described in claim 6, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

9. The compound has a structure represented by a chemical formula selected from the following formulas, Formula (IV-1): 【Chemistry 16】 Formula (IV-2): 【Chemistry 17】 Here, R ２ , R ３ , X ２ , Y ６ Rings D and E are as defined in claim 8. The compound according to claim 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

10. The compound has a structure represented by a chemical formula selected from the following formulas, Formula (V-1): [Chemistry 18] Formula (V-2): 【Chemistry 19】 Formula (V-3): 【Chemistry 20】 Formula (V-4): 【Chemistry 21】 R ２ , R ３ , X ２ , Y ６ Rings D and E are as defined in claim 8. The compound according to claim 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

11. Ring D is C ３ -C ７ Cycloalkyl (preferably C ３ -C ６ A cycloalkyl group and a heterocyclic group (preferably a 4-7 membered heterocyclic group) are selected from the group consisting of these groups, where the cycloalkyl group and the heterocyclic group are each of the same or different substituents R ５ It can be arbitrarily replaced by, Preferably, ring D is 【Chemistry 22】 、 【Chemistry 23】 、 【Chemistry 24】 and 【Chemistry 25】 Selected from the group consisting of, Here, each R ５ These are hydrogen, halogen, hydroxyl group, nitro group, cyano group, and C １ -C ６ Alkyl alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl ester, C １ -C ６ Thioalkyl groups, C １ -C ６ Haloalkyl group, C １ -C ６ Haloalkoxy group, hydroxy C １ -C ６ Alkyl alkyl group, C ３ -C ７ A group independently selected from the group consisting of cycloalkyl groups and 3- to 8-membered heterocyclic groups, wherein the cycloalkyl groups and heterocyclic groups are optionally substituted with halogens, CN, and OMe, or two R atoms on non-adjacent carbon atoms. ５ These, together with the non-adjacent carbon atoms to which they are bonded, form a bridging ring. Y ７ It was independently selected from the group consisting of CH and N, q is 0, 1, 2, or 3, and more preferably, ring D is 【Chemistry 26】 、 【Chemistry 27】 、 【Chemistry 28】 、 【Chemistry 29】 、 【Transformation 30】 、 【Chemistry 31】 and 【Chemistry 32】 Selected from the group consisting of, More precisely, each R ５ These are hydrogen, halogen, hydroxyl group, nitro group, cyano group, and C １ -C ３ Alkyl alkyl group, C ３ -C ７ Cycloalkyl groups, C １ -C ３ Independently selected from the group consisting of haloalkyl groups, Here, if q is 2 or greater, then two R ５ They can optionally combine with the atoms to which they are bonded to form a carbocyclic or heterocyclic ring. The compound described in claim 2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

12. The compound has a structure represented by a chemical formula selected from the following formulas, Equation (VI-1): 【Transformation 33】 Equation (VI-2): 【Transformation 34】 Equation (VI-3): 【Chemistry 35】 Equation (VI-4): 【Transformation 36】 Here, Y ６ It was independently selected from the group consisting of CH and N, Y ７ It was independently selected from the group consisting of CH and N, Each R ５ These are hydrogen, halogen, hydroxyl group, nitro group, cyano group, and C １ -C ６ Alkyl alkyl group, C ２ -C ６ Alkenyl group, C ２ -C ６ Alkynyl group, C １ -C ６ Alkoxy group, C ２ -C ６ Alkenyloxy group, C ２ -C ６ Alkynyloxy group, C ２ -C ６ Alkanoyl group, C ２ -C ６ Alkyl ester, C １ -C ６ Thioalkyl groups, C １ -C ６ Haloalkyl group, C １ -C ６ Haloalkoxy group, hydroxy C １ -C ６ Alkyl alkyl group, C ３ -C ７ A group independently selected from the group consisting of cycloalkyl groups and 3- to 8-membered heterocyclic groups, wherein the cycloalkyl groups and heterocyclic groups are optionally substituted with halogens, CN, and OMe, or two R atoms on non-adjacent carbon atoms. ５ These, together with the non-adjacent carbon atoms to which they are bonded, form a bridging ring. q is 0, 1, 2, or 3. R ２ , R ３ , X ２ And ring E is as defined in claim 2, The compound described in claim 2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

13. The compound has a structure represented by a chemical formula selected from the following formulas, Formula (VII-1): 【Chemistry 37】 Formula (VII-2): 【Transformation 38】 Here, R ２ , R ３ , R ５ , X ２ , q, Y ６ And ring E is as defined in claim 12, The compound according to claim 12, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

14. The compound has a structure represented by a chemical formula selected from the following formulas, Formula (VIII-1): 【Chemistry 39】 Formula (VIII-2): 【Chemistry 40】 Here, R ２ , R ３ , R ５ , X ２ , q, Y ６ And ring E is as defined in claim 13, The compound according to claim 13, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

15. Ring E is a 5- to 9-membered heteroaryl group, and each heteroaryl group independently has 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and N as ring members, and the heteroaryl group has 1 to 3 identical or different substituents R ６ It can be arbitrarily replaced by, Here, each R ６ is hydrogen, halogen, C １ -C ６ Alkyl alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, -CN, -OH, C ３ -C ８ A group independently selected from the group consisting of cycloalkyl groups and 3- to 8-membered heterocyclic groups, The compound according to any one of the above claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

16. Ring E is C ３ -C ６ Selected from the group consisting of cycloalkyl groups, 4-6 membered heterocyclic groups, thiazolyl groups, imidazolyl groups, oxazolyl groups, isoxazolyl groups, 1,2,3-triazolyl groups, 1,2,4-triazolyl groups, phenyl groups, pyridinyl groups, pyrimidinyl groups, pyridadinyl groups, pyrazinyl groups, pyrazolyl groups, and indazolyl groups, where the cycloalkyl groups, heterocyclic groups, thiazolyl groups, imidazolyl groups, oxazolyl groups, isoxazolyl groups, 1,2,3-triazolyl groups, 1,2,4-triazolyl groups, phenyl groups, pyridinyl groups, pyrimidinyl groups, pyridadinyl groups, pyrazinyl groups, pyrazolyl groups, and indazolyl groups are each one or two different substituents R ６ It can be arbitrarily replaced by, Here, each R ６ is hydrogen, halogen, C １ -C ６ Alkyl alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, C ２ -C ６ Alkynyl group, C ２ -C ６ Alkynyloxy group, -CN, -OH, C ３ -C ８ Cycloalkyl groups, 3- to 8-membered heterocyclic groups, C ５ -C １０ Independently selected from the group consisting of heteroaryl groups, e is 0, 1, 2, 3, 4, or 5. More precisely, ring E is 【Chemistry 41】 Selected from the group consisting of, Here, each R ６ is hydrogen, halogen, C １ -C ６ Alkyl alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, C １ -C ６ Haloalkoxy group, -CN, -OH, C ３ -C ８ Independently selected from the group consisting of cycloalkyl groups and 3- to 8-membered heterocyclic groups, e is 0, 1, 2, 3, 4, or 5. More preferably, ring E is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, 【Chemistry 42】 Selected from, The compound according to any one of the above claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

17. The compound is selected from the group consisting of the following: The compound according to any one of the above claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. 【Chemistry 43-1】 【Chemistry 43-2】 【Chemistry 43-3】 【Chemistry 43-4】 【Chemistry 43-5】 【Chemistry 43-6】 【Chemistry 43-7】 【Chemistry 43-8】 【Chemistry 43-9】

18. The compound is selected from the group consisting of the following: The compound according to any one of the above claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. 【Chemistry 44-1】 【Chemistry 44-2】 【Chemistry 44-3】

19. A pharmaceutical composition, The pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

20. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer, in the manufacture of a drug for the treatment of a disease or disorder affected by the degradation of WIZ protein.

21. A method for treating a disease or disorder in a person requiring this, The aforementioned disease or disorder is selected from sickle cell anemia and β-Ceratophilic anemia. The method described above includes administering to a subject requiring such treatment an effective amount of the compound described in any one of claims 1 to 18 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. A method for treating a disease or disorder in a person requiring this treatment.

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