STING agonist

Abstract

The present disclosure relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an interferon gene stimulating factor (STING) agonist, a pharmaceutical composition comprising the same, and related methods and uses for treating or preventing diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Korean Patent Application No. 10-2022-0147897, filed on November 8, 2022, which is hereby incorporated by reference in its entirety. Background Art

[0003] Stimulator of interferon genes (STING) is a low molecular weight protein that is currently attracting much attention as a target for cancer therapy. STING is an adaptor protein in the cGAS (cyclic GMP-AMP synthase)-STING pathway, a sensing pathway that induces the activation of type I IFNs and other inflammatory cytokines, triggering antiviral and antitumor immune responses (Chen, Q. et al., “Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing”, Nat. Immunol., 2016, 17, 1142-1149; Woo, SR et al., “STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors”, Immunity, 2014, 41, 830-842). In addition, STING activates signal transducer and activator of transcription 6 (STAT6) and transcription factor interferon regulatory factor 3 (IRF3) through TANK-binding kinase 1 (TBK1) in antiviral and innate immune responses (Burdette DL, Vance RE, "STING and the innate immune response to nucleic acids in the cytosol", 2013, Nature Immunology, 14(1):19-26). STING agonists can also trigger the expression of cytokines, causing T cell-mediated innate immune responses, thereby inhibiting cancer cell growth. However, systemic delivery of STING agonists can cause widespread inflammation.

[0004] Various STING agonists have been tested in preclinical and clinical settings. Various agonists are being developed through various strategies, including CDN (cyclic dinucleotide) compounds (ADU-S100, BI-STING, GSK532, JNJ-4412, SB11285, MK-1454, TAK676, etc.), bacterial vectors (SYNB1891, STACT-TREX-1), non-cyclic dinucleotide (CDN) compounds (ALG-031048, JNJ-6196, MK-2118, MSA-1, MSA-2, CRD-5500, etc.), nanovaccines (PC7A NPs, cGAMP-NPs, etc.), and ADCs (XMT-2056, TAK500, etc.).

[0005] The most widely used preclinical compound, DMXAA (a vascular disruptor), was clinically used in combination with paclitaxel and carboplatin, but its efficacy was demonstrated to be lacking in Phase 3. Furthermore, ADU-S100, the first clinically used STING agonist, was discontinued in 2020.

[0006] Examples of STING agonists are disclosed in, for example, WO 2021 / 014365 (macrocyclic compounds as STING agonists), and US 2021 / 0139473 (heterocyclic amide compounds as protein modulators), US 2022 / 0073509 (heterocyclic compounds as STING activators), and KR 2022-0024467 (heterocyclic STING agonists), each of which is incorporated herein by reference in its entirety.

[0007] However, existing STING agonists appear to exhibit only limited bioavailability and require local administration to tumors due to overactivation of cytokine expression, or must be used in combination with other compounds. Therefore, there remains a need to develop therapeutically effective STING agonists. Summary of the Invention

[0008] In certain aspects, the present disclosure relates to compounds represented by structural formula (I), and pharmaceutically acceptable salts thereof:

[0009]

[0010] in:

[0011] T is the part that contains the stimulator of interferon genes (STING) agonist,

[0012] p is 1 or 2,

[0013] R 1is independently CH2OR at each occurrence 11 or COOR 12 ,

[0014] R 1a 、R 1b 、R 1c and R 11 is independently at each occurrence H or a hydroxy protecting group,

[0015] R 12 is independently at each occurrence H or a carboxyl protecting group,

[0016] R 2 and R 3 Each occurrence is independently H or alkyl, or R 2 and R 3 Together with the carbon atom to which it is attached, it forms a cycloalkyl group,

[0017] R 4 is independently selected at each occurrence from halogen, alkyl, CN and NO2,

[0018] k is independently 0, 1, 2 or 3 at each occurrence,

[0019] Y is independently selected at each occurrence from H, -C(O)NHL u U、-C(O)NR'(L u U)、-C(O)N(L u U)2 and -C(O)OH,

[0020] L u is the first connector at each occurrence,

[0021] U is independently selected at each occurrence from H, alkyl, amino, azido, ethynyl, alkylamino, heterocyclyl, alkoxy, -COOH, -P(O)(OH)2, -OH, -DBCO, and a saccharide, and

[0022] R' at each occurrence is independently selected from alkyl, cycloalkyl, alkoxy, alkylthio, mono- or dialkylamino, heteroaryl, and aryl.

[0023] In some aspects, the present disclosure relates to pharmaceutical compositions comprising a compound of the present disclosure, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0024] In some aspects, the present disclosure relates to a method for preventing or treating a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0025] In some aspects, the present disclosure relates to a method of inducing an immune response in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0026] In some aspects, the present disclosure relates to a method of modulating the activity of a STING adaptor protein, comprising contacting the STING adaptor protein with a compound of the present disclosure, e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1A : STING agonist compounds (compounds 214, 221 and 230) induce cytokine production (human CXCL-10).

[0028] Figure 1B : STING agonist compounds (compounds 214, 221 and 230) induce cytokine production (human IFNα).

[0029] Figure 2A : MDA-MB-468 tumor cells were treated with a STING agonist compound (Compound 313).

[0030] Figure 2B : BxPC3 tumor cells were treated with a STING agonist compound (Compound 313).

[0031] Figure 3A : When THP-1 is treated with a STING agonist compound (Compound 313), the costimulatory molecule CD86 is upregulated.

[0032] Figure 3B : When THP-1 is treated with a STING agonist compound (Compound 313), the class II MHC molecule HLA-DR is upregulated.

[0033] Figure 4A : STING agonist compounds (compounds 274 and 277) enhance CD8 + CD69 expression on T cells.

[0034] Figure 4B : STING agonist compounds (Compounds 274 and 277) enhance CD69 expression on NK cells.

[0035] Figure 5A : STING agonist compounds (compounds 344 and 361) enhance activation of CD8 + Expansion of T cells.

[0036] Figure 5B : STING agonist compounds (compounds 344 and 361) enhance the expansion of activated NK cells.

[0037] Figure 6A : Graphical representation of plasma PK in naive Balb / C mice following a single dose of a STING agonist compound (Compound 221).

[0038] Figure 6B : Graphical representation of plasma PK in naive Balb / C mice following a single dose of a STING agonist compound (Compound 277).

[0039] Figure 6C : Graphical representation of plasma PK in naive Balb / C mice following a single dose of a STING agonist compound (Compound 281).

[0040] Figure 6D : Graphical representation of plasma PK in naive Balb / C mice following a single dose of a STING agonist compound (Compound 274) compared to Comparative Compounds #1 and #2.

[0041] Figure 7A : Tumor volume (mm) after treatment with STING agonist compounds (compounds 214 and 221) in the CT26 syngeneic mouse model 3 When the tumor volume reaches 70 mm 3 Each compound was administered intravenously at 1.5 mg / kg every 3 or 4 days (three times in total).

[0042] Figure 7B : Body weight (%) after treatment with STING agonist compounds (compounds 214 and 221). When the tumor volume reached 70 mm 3 Each compound was administered intravenously at 1.5 mg / kg every 3 or 4 days (three times in total).

[0043] Figure 8 : Tumor volume (mm) after treatment with different doses of STING agonist compound (Compound 274) in CT26 mouse model 3 ).

[0044] Figure 9 : Tumor volume (mm) after treatment with STING agonist compounds (Compounds 274 and 281) compared to Comparative Compound #1 in the CT26 syngeneic mouse model. 3 When the tumor volume reaches 55 mm 3Each compound was administered intravenously at 0.5 mg / kg once a week for three weeks. The average tumor growth over time was monitored compared to Comparative Compound #1.

[0045] Figure 10A : Tumor volume (mm) after treatment with STING agonist compounds (Compounds 274, 313, 344, and 396) compared to comparator compound #3 in the CT26 syngeneic mouse model. 3 When the tumor volume reaches 80 mm 3 Each compound was administered intravenously at 0.3 mg / kg once a week for 3 weeks at 4°C. Tumor growth was monitored over time compared to comparative compound #3.

[0046] Figure 10B : Body weight (mm) after treatment with STING agonist compounds (Compounds 274, 313, 344, and 396) compared to Comparative Compound #3 in the CT26 syngeneic mouse model. 3 When the tumor volume reaches 80 mm 3 Each compound was administered intravenously at 0.3 mg / kg once a week for 3 weeks. Body weight was monitored over time compared to comparative compound #3.

[0047] Figure 11 : Tumor volume (mm) after treatment with STING agonist compounds (compounds 274 and 313) compared to comparator compounds #1 and #2 in the EMT6 syngeneic mouse model. 3 When the tumor volume reaches 100 mm 3 Each compound was administered intravenously at 0.125 mg / kg once a week for three weeks. The average tumor growth over time was monitored compared to Comparative Compounds #1 and #2.

[0048] Figure 12A : Tumor volume (mm) after treatment with different doses of STING agonist compound (Compound 313) in EMT6 model 3 ).

[0049] Figure 12B : Body weight (%) after treatment with different doses of STING agonist compound (Compound 313) in the EMT6 model. DETAILED DESCRIPTION

[0050] In certain aspects, the present disclosure relates to compounds represented by structural formula (I), and pharmaceutically acceptable salts thereof:

[0051]

[0052] in:

[0053] T is the part that contains the stimulator of interferon genes (STING) agonist,

[0054] p is 1 or 2,

[0055] R 1 is independently CH2OR at each occurrence 11 or COOR 12 ,

[0056] R 1a 、R 1b 、R 1c and R 11 is independently at each occurrence H or a hydroxy protecting group,

[0057] R 12 is independently at each occurrence H or a carboxyl protecting group,

[0058] R 2 and R 3 Each occurrence is independently H or alkyl, or R 2 and R 3 Together with the carbon atom to which it is attached, it forms a cycloalkyl group,

[0059] R 4 is independently selected at each occurrence from halogen, alkyl, CN and NO2,

[0060] k is independently 0, 1, 2 or 3 at each occurrence,

[0061] Y is independently selected at each occurrence from H, -C(O)NHL u U、-C(O)NR'(L u U)、-C(O)N(L u U)2 and -C(O)OH,

[0062] L u is the first connector at each occurrence,

[0063] U is independently selected at each occurrence from H, alkyl, amino, azido, ethynyl, alkylamino, heterocyclyl, alkoxy, -COOH, -P(O)(OH)2, -OH, -DBCO, and a saccharide, and

[0064] R' at each occurrence is independently selected from alkyl, cycloalkyl, alkoxy, alkylthio, mono- or dialkylamino, heteroaryl, and aryl.

[0065] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

[0066]

[0067] In some embodiments, p is 1 and T is a moiety represented by one of the following formulae:

[0068]

[0069] In some embodiments, T is a moiety represented by formula (IIc):

[0070]

[0071] in:

[0072] T through W 1 、W 2 , A, B or L 2 coupled to -C(O)OCR of formula (I) 2 R 3 - fragment,

[0073] M is N, C(X a R a ) or C(X b L 1 L 2 ),

[0074] Q is for -X a R a or -X b L 1 L 2 -,

[0075] W 1 and W 2 is independently selected at each occurrence from alkyl, amino, amide, carboxylic acid, ester, and hydrazide, for example, -C(O)NH-alkyl-N(alkyl)- or -C(O)NH-N(alkyl)-;

[0076] n and m are each independently 0, 1, 2 or 3,

[0077] Z is selected from alkylene, alkenylene and alkynylene,

[0078] A and B are each independently aryl or heteroaryl,

[0079] X a and X b are each independently selected from CH2, NH, O and S,

[0080] R ais selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)carboxylic acid, -(alkylene)guanidino, -(alkylene)NHC(O)CH2guanidino, -(alkylene)O(alkylene)guanidino and -O(alkylene)guanidino,

[0081] L 1 is selected from the group consisting of alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene and heteroarylene,

[0082] L 2 is a bond, or coupled to L 1 and comprising -C(O)O(CR 2 R 3 )-a linker moiety to a nitrogen atom of the fragment. Any suitable linker moiety may be used.

[0083] In some embodiments, Q is -X a R a .

[0084] In some embodiments, M is C(X a R a ).

[0085] In some embodiments, Q is -X a R a Or M is C(X a R a ).

[0086] In some embodiments, X a It's O.

[0087] In some embodiments, R a Selected from C 1-6 alkyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)carboxylic acid, and -(alkylene)guanidino.

[0088] In some embodiments, the alkyl group is C 1-6 Alkyl, for example C3 alkyl.

[0089] In some embodiments, the alkylene group is C 1-6 Alkylene, for example C3 alkylene.

[0090] In some embodiments, M is C(X a R a ), for example, M has a structure selected from the following:

[0091]

[0092] Among them is the point of attachment to the rest of the phenyl ring.

[0093] In some embodiments, Q is -X a R a , for example, Q has a structure selected from the following:

[0094]

[0095] Among them It is the point of attachment to the phenyl ring.

[0096] In some embodiments, M has the structure: Where n represents an integer from 1 to 15, for example Each of these is the point of attachment to the rest of the phenyl ring.

[0097] In some embodiments, Q has the structure: Where n represents an integer from 1 to 15, for example in It is the point of attachment to the phenyl ring.

[0098] In some embodiments, M is C(X b L 1 L 2- ) or Q is -X b L 1 L 2 -.

[0099] In some embodiments, L 2 Select from key,

[0100] and *heterocyclylene**, and wherein * is L 1 and ** is the connection point with -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0101] In some embodiments, T is represented by structural formula (IIa).

[0102] In some embodiments, the compound is

[0103] In some embodiments, T is represented by structural formula (IIb).

[0104] In some embodiments, the compound is

[0105] In some embodiments, T is represented by structural formula (IIc).

[0106] In some embodiments, T is determined by W 2 Coupling to -C(O)OCR 2 R 3 - fragment, and T is a moiety represented by formula (IIc1):

[0107]

[0108] in is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0109] In some embodiments, T is coupled to -C(O)OCR via B 2 R 3 - fragment, and T is a moiety represented by formula (IIc2):

[0110]

[0111] in is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0112] In some embodiments, T is determined by L 2 Coupling to -C(O)OCR 2 R 3 - fragment, and T is a moiety represented by formula (IIc3):

[0113]

[0114] in is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0115] In some embodiments, T is determined by L 2 Coupling to -C(O)OCR 2 R 3 - fragment, and T is a moiety represented by formula (IIc4):

[0116]

[0117] in is -C(O)O(CR 2R 3 ) - the connection point of the fragment.

[0118] In some embodiments, L 2 is the second linker. Any suitable linker moiety may be used.

[0119] In some embodiments, L 2 Select from key,

[0120]

[0121]

[0122] and *heterocyclylene**, and wherein * is L 1 and ** is the connection point with -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0123] In some embodiments, L 2 is a second connector comprising # OC(O)NR 5 -L 4 -NR 6 、 # OC(O)-L 4 -NR 6 or # OC(O)NR 5 -L 4 -(heterocyclylene), wherein:

[0124] The heterocyclic group includes -C(O)O(CR 2 R 3 )-fragment connected to the nitrogen atom, and wherein # is the same as L 1 The connection point,

[0125] L 4 is independently at each occurrence alkylene or arylenealkyl,

[0126] R 5 is independently selected at each occurrence from H, alkyl and dialkylaminoalkyl, and

[0127] R 6 is independently selected at each occurrence from H, alkyl, and dialkylaminoalkyl.

[0128] In some embodiments, L 2 Selected from

[0129] wherein ** indicates the -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0130] In some embodiments, L 2 Selected from

[0131] In some embodiments, L 2 yes

[0132] In some embodiments, p is 1 and T is a moiety represented by formula (IIc5):

[0133]

[0134] in:

[0135] T through L 2 coupled to the -C(O)OCR of the compound represented by structural formula (I) 2 R 3 - fragment,

[0136] W 1 and W 2 is independently selected at each occurrence from alkyl, amino, amide, carboxylic acid, ester and hydrazide,

[0137] n and m are each independently 0, 1, 2 or 3,

[0138] Z is selected from alkylene, alkenylene and alkynylene,

[0139] A and B are each independently aryl or heteroaryl,

[0140] X a and X b are each independently selected from CH2, NH, O and S,

[0141] R a is selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)carboxylic acid, -(alkylene)guanidino, -(alkylene)NHC(O)CH2guanidino, -(alkylene)O(alkylene)guanidino and -O(alkylene)guanidino,

[0142] L 1 is selected from the group consisting of alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene and heteroarylene,

[0143] L 2 Is a bond, coupled to L 1 and comprising -C(O)O(CR 2 R 3 )-a linker portion of a nitrogen atom of a fragment, or a second linker, and

[0144] Is with -C(O)OCR 2 R 3 -Connection point.

[0145] In some embodiments, L 2 is a second connector comprising # OC(O)NR 5 -L 4 -NR 6 、 # OC(O)-L 4 -NR 6 or # OC(O)NR 5 -L 4 -(heterocyclylene), wherein:

[0146] The heterocyclic group includes -C(O)O(CR 2 R 3 )-fragment connected to the nitrogen atom, and wherein # is the same as L 1 The connection point,

[0147] L 4 is independently at each occurrence alkylene or arylenealkyl,

[0148] R 5 is independently selected at each occurrence from H, alkyl and dialkylaminoalkyl, and

[0149] R 6 is independently selected at each occurrence from H, alkyl, and dialkylaminoalkyl.

[0150] In some embodiments, p is 2 and T is a moiety represented by one of the following structural formulas:

[0151]

[0152] in Is with -C(O)OCR 2 R 3 -Connection point.

[0153] In some embodiments, T is a moiety represented by structural formula (IIf), wherein T is represented by W1 、W 2 , A, B or L 2 Two of them are independently coupled to each -C(O)OCR of formula (I) 2 R 3 - Snippet:

[0154]

[0155] in:

[0156] M is N, C(X a R a ) or C(X b L 1 L 2 -),

[0157] Q is for -X a R a or -X b L 1 L 2 -,

[0158] W 1 and W 2 is independently selected at each occurrence from alkyl, amino, amide, carboxylic acid, ester and hydrazide,

[0159] n and m are each independently 0, 1, 2 or 3,

[0160] Z is selected from alkylene, alkenylene and alkynylene,

[0161] A and B are each independently a 5-membered heteroaryl group,

[0162] X a and X b are each independently selected from CH2, NH, O and S,

[0163] R a is independently selected at each occurrence from H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)carboxylic acid, -(alkylene)guanidino, -(alkylene)NHC(O)CH2guanidino, -(alkylene)O(alkylene)guanidino, and -O(alkylene)guanidino,

[0164] L 1 is independently selected at each occurrence from alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, and heteroarylene,

[0165] L 2 independently selected at each occurrence from a bond, coupled to the corresponding L 1and comprising a corresponding -C(O)O(CR 2 R 3 )-a linker portion of a nitrogen atom of the fragment, or a second linker.

[0166] In some embodiments, T is a moiety of formula (IId).

[0167] In some embodiments, T is a moiety of formula (IIe).

[0168] In some embodiments, the compound is

[0169] In some embodiments, T is a moiety of formula (IIf).

[0170] In some embodiments, T is determined by W 1 and W 2 Coupled to each -C(O)OCR 2 R 3 - fragment, and T is a moiety represented by formula (IIf1):

[0171]

[0172] Each of these is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0173] In some embodiments, T is coupled to each -C(O)OCR via A and B. 2 R 3 - fragment, and T is a moiety represented by formula (IIf2):

[0174]

[0175] Each of these is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0176] In some embodiments, T is passed through two L 2 Coupled to each -C(O)OCR 2 R 3 - fragment, and T is a moiety represented by formula (IIf3):

[0177]

[0178] Each of these is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0179] In some embodiments, L 2 Select from key,

[0180] and *heterocyclylene**, and wherein * is L 1 and ** is the connection point with -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0181] In some embodiments, each L 2 Independently includes # OC(O)NR 5 -L 5 -NR 6 、 # OC(O)-L 4 -NR 6 or # OC(O)NR 5 -L 5 -(heterocyclylene) wherein the heterocyclylene comprises a -C(O)O(CR 2 R 3 )-fragment connected to the nitrogen atom, where # is the nitrogen atom corresponding to L 1 The connection point,

[0182] Each L 5 are independently alkylene or aralkylene, and

[0183] Each R 5 and each R 6 Each is independently selected from H, alkyl and dialkylaminoalkyl.

[0184] In some embodiments, p is 1 and T is a moiety represented by formula (III):

[0185]

[0186] Where Q is the branch joint part,

[0187] T a and T b each independently comprises a moiety that is a stimulator of interferon genes (STING) agonist, and

[0188] is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0189] In some embodiments, T is a moiety represented by formula (IIIa):

[0190]

[0191] in:

[0192] is -C(O)O(CR 2 R 3 ) - the connection point of the fragment,

[0193] Ta and Tb are each independently a moiety represented by formula (IV):

[0194]

[0195] in:

[0196] Ta and Tb are independently transferred through W 1 、W 2 , A, B or L 2 coupled to -C(O)OCR of formula (I) 2 R 3 - fragment,

[0197] M is N, C(X a R a ) or C(X b L 1 L 2 -),

[0198] Q is for -X a R a or -X b L 1 L 2 -,

[0199] W 1 and W 2 is independently selected at each occurrence from alkyl, amino, amide, carboxylic acid, ester, and hydrazide, for example, -C(O)NH-(alkyl)-N(alkyl)-;

[0200] n and m are each independently 0, 1, 2 or 3,

[0201] Z is selected from alkylene, alkenylene and alkynylene,

[0202] A and B are each independently aryl or heteroaryl,

[0203] X a and X b are each independently selected from CH2, NH, O and S,

[0204] R a is selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)carboxylic acid, -(alkylene)guanidino, -(alkylene)NHC(O)CH2guanidino, -(alkylene)O(alkylene)guanidino and -O(alkylene)guanidino,

[0205] L 1 is selected from the group consisting of alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene and heteroarylene,

[0206] L 2 Is a bond, coupled to L 1 and comprising -C(O)O(CR 2 R 3 )-a linker portion of a nitrogen atom of the fragment, or a second linker.

[0207] In some embodiments, A and B are each independently a substituted or unsubstituted pyrazole or a substituted or unsubstituted oxazole.

[0208] In some embodiments, A and B are each independently a substituted pyrazole or a substituted oxazole, wherein the pyrazole and oxazole are each replaced by two C 1-3 Alkyl substitution.

[0209] In some embodiments, p is 1 and T is a moiety represented by formula (IIIb):

[0210]

[0211] is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

[0212] In some embodiments, A and B are each independently a 5-membered heteroaryl optionally substituted with 1 to 4 groups independently selected from halogen, OH, CN, NO2, amine, amide, amidine; -(CH2) q NR w R w1 ; C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl, wherein: each q is independently selected from 0, 1, 2 or 3, and Rw and R w1 are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl.

[0213] For example, A and B can each be independently selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, and isothiazole. In certain preferred embodiments, A and B are each pyrazole.

[0214] In some embodiments, A and B are each independently substituted or unsubstituted pyrazole. For example, in certain preferred embodiments, A and B are each substituted with two C 1-3 Alkyl-substituted pyrazoles.

[0215] In some embodiments, A and B are each independently substituted or unsubstituted oxazole. For example, in certain preferred embodiments, A and B are each substituted with two C 1-3 Alkyl-substituted oxazoles.

[0216] In some embodiments, A and B are each independently a substituted or unsubstituted pyrazole or a substituted or unsubstituted oxazole.

[0217] In some embodiments, A and B are each independently a substituted pyrazole or a substituted oxazole, wherein the pyrazole and oxazole are each replaced by two C 1-3 Alkyl substitution.

[0218] In some embodiments, A and B are each independently represented by one of the following structural formulas:

[0219]

[0220] where R x and R x1 are each independently selected from hydrogen, C 1-5 Alkyl, C 1-5 Haloalkyl, halogen, OH, -OP(O)(R y R y1 )2、-OR y 、-NR y R y1 、-OCOR y 、-CO2R y 、-SOR y 、-SO2R y 、-CONR y R y1 、-SO2NR y R y1 、-OCONR y R y1 、-NRy COR y1 、-NR y SOR y1 、-NR y CO2R y1 and -NR y SO2R y1 , and where R y and R y1 are each independently selected from hydrogen, C 1-10 Alkyl, C 2-10 Alkenyl and C 2-10 Alkynyl.

[0221] For example, A and B can each independently be represented by one of the following structural formulas:

[0222]

[0223] In some preferred embodiments, A and B are each represented by the following structural formula:

[0224]

[0225] In some embodiments, A and B are represented by the following structural formula:

[0226] In some embodiments, A and B are represented by the following structural formula:

[0227]

[0228] In some embodiments, A and B are represented by the following structural formula:

[0229]

[0230] In some embodiments, each occurrence of the first linker is independently selected from each occurrence of *(alkylene)O(alkylene)**, *(heteroalkylene)**, *(alkylene)**, *(heteroaralkylene)**, *(heteroalkylene)(heterocyclylene)**, *CH2CH2C(O)NHCH**, *(CH2CH2O) t -** and *(alkylene)(heteroarylene)(CH2CH2O) t **,

[0231] wherein * indicates a connection point to the -C(O)NH- fragment of the compound represented by structural formula (I), ** indicates a connection point to U, and t represents an integer from 1 to 15.

[0232] In some embodiments, the first linker is independently selected at each occurrence from *(CH2CH2O) tCH2**, *(CH2CH2O)2CH2CH2N(CH3)CH2**, *(CH2CH2O)2CH2CH2N(CH3)**, *(CH2CH2O) t **、*(CH2CH2O) t CH2CH2NH**, *CH2CH2**, *(CH2CH2O) t CH2**、*(CH2CH2O) t CH2CH2 heterocyclylene**, *(CH2CH2O) t CH2**、*(CH2CH2O) t CH2CH2** and *(CH2CH2O) t NH**.

[0233] In some embodiments, t represents an integer from 1 to 6. In other embodiments, t represents an integer from 1 to 3.

[0234] In some embodiments, U is H. In other embodiments, U is a reactive group. Any suitable reactive group can be used such that an additional moiety having a complementary reactive group can be coupled to a compound of Formula (I) by reaction with U. In some such embodiments, the reactive group is amino, azido, ethynyl, -COOH, -P(O)(OH)2, or -OH. In some embodiments, U is alkylamino, heterocyclyl, or alkoxy. In some embodiments, U is a heterocyclyl comprising a moiety that is a member of a group ... u In some embodiments, U is -N(alkyl)2, such as -N(CH3)2. In some embodiments, U is -(O)alkyl, such as -OCH3.

[0235] In some embodiments, U is -NH(CH3), -N(CH3)2, -OCH3, or

[0236] In some embodiments, the compound is selected from

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249] In some embodiments, U is a saccharide. In some embodiments, the saccharide is a glucuronide. In some embodiments, the glucuronide is

[0250] In some embodiments, the compound is selected from:

[0251]

[0252] In some embodiments, T is selected from:

[0253]

[0254]

[0255] In some embodiments, Y is selected from:

[0256]

[0257] wherein n represents an integer from 1 to 15. In some embodiments, Y is selected from:

[0258]

[0259]

[0260] In some embodiments, the compound is selected from:

[0261]

[0262] wherein n represents an integer from 1 to 15.

[0263] In some embodiments, the compound is selected from:

[0264]

[0265] In some embodiments, the compound is selected from:

[0266]

[0267]

[0268] wherein n represents an integer from 1 to 15.

[0269] In some embodiments, the compound is selected from:

[0270]

[0271]

[0272] In some embodiments, the present disclosure relates to pharmaceutical compositions comprising a compound of the present disclosure, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0273] In some embodiments, the present disclosure relates to a method for preventing or treating a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for treating or preventing a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof.

[0275] In some embodiments, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof.

[0276] In some embodiments, the disease mediated by STING is cancer.

[0277] In some embodiments, the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi sarcoma, and melanoma.

[0278] In some embodiments, the present disclosure relates to a method of inducing an immune response in a subject in need thereof, comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for inducing an immune response in a subject in need thereof.

[0280] In some embodiments, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in inducing an immune response in a subject in need thereof.

[0281] In some embodiments, said induction of said immune response is effective to prevent or treat a STING-mediated disease in said subject.

[0282] In some embodiments, the disease mediated by STING is cancer.

[0283] In some embodiments, the cancer is selected from lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

[0284] In some embodiments, the present disclosure relates to a method of modulating the activity of a STING adaptor protein, comprising contacting the STING adaptor protein with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, said compound increases said activity of said STING adaptor protein.

[0286] In some embodiments, the STING-mediated disease is cancer, a bacterial infection, a viral infection, a fungal infection, an immune-mediated disorder, a central nervous system disease, a peripheral nervous system disease, a neurodegenerative disease, a cerebrovascular disease, a peripheral arterial disease, a cardiovascular disease, an allergic disease, or inflammation. In specific embodiments, the STING-mediated disease is cancer or an infectious disease.

[0287] In some embodiments, the cancer is lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

[0288] In some embodiments, the pharmaceutical composition may further contain a pharmaceutically effective amount of a chemotherapeutic agent.

[0289] In some embodiments, the pharmaceutical composition may include one or more therapeutic adjuvants; and may further include a pharmaceutically acceptable excipient.

[0290] In some embodiments, the therapeutic adjuvant is an agent that exhibits a preventive, ameliorating, or therapeutic effect on a STING-mediated disease, or an agent that can reduce the manifestation of side effects that may occur when a therapeutic agent is administered for a STING-mediated disease, or it may be, but is not limited to, an agent that exhibits an immunopotentiating effect, and when administered in the form of a formulation together with the STING agent represented by the compound, it exhibits a therapeutically useful effect and / or improves the stability of a proteolytic enzyme, and / or reduces side effects that may occur when a STING agonist represented by the compound is administered, and / or any agent that exhibits an effect of maximizing the therapeutic effect by enhancing immunity may be administered in combination.

[0291] Combination therapy adjuvants include, for example, auristatin, bexarotene, bicalutamide, BMS184476, bleomycin, semadotin, chlorambucil, cyclophosphamide, docetaxel, docetaxel, carboplatin, carmustine, cisplatin, cryptophycin, decitabine, dolastatin, doxorubicin, mibobulin, isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, Taxanes, nilutamide, nivolumab, onapristone, paclitaxel, procarbazine, tamoxifen, tasonermine, tretinoin, vinblastine, vincristine, PD-1 antagonists, CTLA-4 antagonists, B7 co-stimulatory molecules, interleukin-2, interleukin-7, etc.

[0292] In some embodiments, the cancer is lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, or osteosarcoma. It can be selected from the group consisting of Kaposi's sarcoma and melanoma, but can be any cancer tumor for which the administration of a STING agonist represented by the compound can exhibit a therapeutic effect. In some embodiments, a method for preventing or treating a STING-mediated disease is provided, comprising administering a pharmaceutical composition to a patient. In addition, the compound of Formula 1 of the present invention can be used as an adjuvant in any of its tautomers, stereoisomers, and pharmaceutically acceptable salts for the treatment of other infectious diseases, diseases, or conditions, including cancer.

[0293] Combination therapy

[0294] In some embodiments, the compound, its optical isomers, its stereoisomers, its solvates, its tautomers, or its pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, can be used alone or in combination with one or more additional therapies (eg, drug treatments or treatments).

[0295] Combination therapy can, for example, combine two therapies or can combine three therapies (e.g., triple therapy of three therapeutic agents) or more. The dosage of one or more of the additional therapies (e.g., non-drug treatments or therapeutic agents) can be reduced from the standard dosage when administered alone.

[0296] In some embodiments, the compound, its optical isomers, its stereoisomers, its solvates, its tautomers, or its pharmaceutically acceptable salts, or a pharmaceutical composition comprising the same, is administered before, after, or concurrently with one or more such additional therapies.

[0297] In some embodiments, the compounds may be co-administered, for example, in a single pharmaceutical composition, or may be administered separately, and when administered separately, this may be done simultaneously or sequentially. Such sequential administration may be close in time or remote in time.

[0298] In some embodiments, the compound, additional therapy may be the administration of a side effect limiting agent. Examples of such side effect limiting agents are agents useful for treating nausea and may include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0299] In some embodiments, the compound, additional therapy includes non-drug therapy (e.g., surgery or radiation therapy). Examples of non-drug therapy include, but are not limited to, radiation therapy, cryotherapy, hyperthermia surgery (e.g., surgical removal of tumor tissue), and T cell acceptor transfer (ACT) therapy.

[0300] In some embodiments, the combination therapeutic agent may be a compound used to treat cancer or a condition related thereto, and suitable steroids include 21-acetoxypregnenolone, alcomethasone, algestone, amcinonide, beclomethasone, betamethasone, desonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortibazole, deflazacort, desonide, desoximethasone, dexamethasone, diflorasone, difluoroacetone ... flucortolone), difluprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, Fluperolone Acetate, Fluprednidene Acetate, Fluprednisolone, Flurandrenolide, Fluticasone Propionate Propionate, Formocortal, Halocinonide, Halobetasol, Propionate, Halometasone, Hydrocortisone, Lote Prednol etabonate, Mazipredone, Medrisone, Meprednisone, Methylprednisolone, Mometasone FuroateThe invention also includes, but is not limited to, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone venetonide, triamcinolone hexacetonide and salts or derivatives thereof.

[0301] In some embodiments, it can be a biological agent for treating cancer or a condition associated therewith (e.g., a cytokine (e.g., an interferon or an interleukin, such as IL-2)). In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof). Antibody-drug conjugates are also included.

[0302] In some embodiments, the immune checkpoint inhibitor can be a monospecific antibody such as a monoclonal antibody, a fusion protein such as an Fc-receptor fusion protein, more specifically, an inhibitor of CTLA-4 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or fusion protein), an inhibitor or antagonist of PD-1 (e.g., an inhibitory antibody or a small molecule inhibitor), an inhibitor or antagonist of PDL-1 (e.g., an inhibitory antibody or a small molecule inhibitor), a PDL-2 inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) (e.g., PDL-2 / Ig fusion protein), etc., but is not limited thereto.

[0303] In some embodiments, the anticancer agent can be, for example, a chemotherapeutic agent or a targeted therapy. Specifically, the anticancer agent includes mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, ureas substituted with anthraquinone, methylhydrazine derivatives, adrenocortical suppressants, adrenocortical steroids, progestogens, including estrogens, antiestrogens, androgens, antiandrogens and gonadotropin analogs. Other anticancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, docetaxel, ALK inhibitors, receptor tyrosine kinase (RTK) / growth factor receptor (e.g., inhibitors of downstream members of SHP2 inhibitors, SOS1) inhibitors, Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors, or mTOR inhibitors, Ras inhibitors. Preparations, Ras vaccines, inhibitors of the MAP kinase (MAPK) pathway (or "MAPK inhibitors"), RAS-RAF-interrupters or inhibitors of the ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway, PD-1 or PD-L1 antagonists, immunomodulatory imide (ImiD), GITR agonists, genetically engineered T cells (such as CAR-T cells), bispecific antibodies (such as BiTE), anti-PD-1, anti-PD-L1, anti-CTLA4, anti-LAG-3 and anti-OX40 agents, EGFR inhibitors, IGF-1R inhibitors, etc., but are not limited thereto.

[0304] In some embodiments, anti-angiogenic agents include, but are not limited to, chemical compositions synthetically prepared in vitro, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof.

[0305] In some embodiments, the autophagy inhibitor is chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil TM ), bafilomycin A1, 5-amino-4-imidazolecarboxamide nucleoside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatase, cAMP, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine nucleoside and vinblastine, but are not limited thereto.

[0306] Depending on the condition being treated, the compounds of the present disclosure may be used in combination with the agents described herein or other suitable agents. Therefore, in some embodiments, one or more compounds of the present disclosure will be co-administered with other therapeutic agents described herein. When used in combination therapy, the compounds described herein may be administered simultaneously or separately with the second agent. This combined administration may include the simultaneous administration of two agents in the same dosage form, the simultaneous administration of corresponding dosage forms, and separate administration. That is, the compounds described herein and any of the agents described herein may be formulated together into the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention and any of the therapeutic agents described herein may be administered simultaneously, with the two agents being in corresponding formulations. In another alternative, the compounds of the present disclosure may be administered, and subsequently any of the therapeutic agents described herein, or vice versa. In some embodiments of separate administration schemes, the compounds of the present invention and any of the therapeutic agents described herein may be administered a few minutes apart, or a few hours apart, or a few days apart.

[0307] In some embodiments of any of the methods described herein, a first therapeutic agent (eg, a compound of the invention) and one or more additional therapeutic agents can be administered simultaneously or sequentially in any order.

[0308] The compound described above in the pharmaceutical composition of the present invention is contained therein in a therapeutically effective amount or a preventive effective amount. The preferred dosage of the compound according to the present invention varies depending on the patient's condition and body weight, the severity of the disease, the form of the drug, the route of administration, and the duration, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound of formula (I) of the present invention can be administered in an amount of 0.0001 to 1000 mg / kg, preferably 0.01 to 500 mg / kg, divided into once a day to several times.

[0309] In the above-described composition, the compound of formula (I) may be incorporated in an amount of 0.0001 to 50% by weight based on the total weight of the total composition.

[0310] Pharmaceutical composition

[0311] The compositions and methods of the present disclosure can be used to treat individuals in need. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal such as a human, it is preferred to administer a composition or compound in the form of a pharmaceutical composition, which comprises, for example, a compound of the present disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or physiologically buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils (such as olive oil) or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are used to administer humans, especially for invasive routes of administration (i.e., routes of transmission or diffusion through epithelial barriers, such as injection or implantation), the aqueous solution is pyrogen-free, or substantially pyrogen-free. Excipients (e.g.) can be selected to achieve delayed release of the agent or selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in unit dosage form, such as tablets, capsules (including dispersed capsules and gelatin capsules), granules, lyophilized materials for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be presented in a transdermal delivery system (eg, a skin patch).The composition may also be presented in a solution suitable for topical administration such as an emulsion, cream, or ointment.

[0312] Pharmaceutically acceptable carriers may contain physiologically acceptable agents, for example, to stabilize compounds such as compounds of the present disclosure, increase their solubility, or increase their absorption. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or polydextrose; antioxidants such as ascorbic acid or glutathione; chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable carriers (including physiologically acceptable agents) depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix, into which compounds of the present disclosure may be incorporated. Liposomes (e.g., comprising phospholipids or other lipids) are physiologically acceptable and metabolizable non-toxic carriers that are relatively simple to prepare and administer.

[0313] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0314] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, Safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0315] The pharmaceutical composition (formulation) can be administered to a subject by any of a variety of routes of administration, including, for example, oral administration (e.g., as a bolus solution in the form of an aqueous or non-aqueous solution or suspension, tablets, capsules (including dispersible capsules and gelatin capsules), boluses, powders, granules, pastes applied to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (e.g., in the form of a patch applied to the skin); and topically (e.g., in the form of a cream, ointment, or spray applied to the skin). The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions useful therefor may be found in U.S. Patent Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

[0316] The formulation is preferably presented in unit dosage form and can be prepared by any method well known in the art of pharmaceutical preparation. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will depend on the host being treated and the specific mode of administration. The amount of active ingredient that can be combined with the carrier material to prepare a single dosage form will generally be the amount of compound that produces the therapeutic effect. This amount is generally (in percentage) in the range of about 1% to about 99% active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0317] Methods for preparing these formulations or compositions include the step of bringing into association the active compound (e.g., a compound of the present disclosure) with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately combining a compound of the present disclosure with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0318] The oral formulations of the present disclosure may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilizates, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, or elixirs or syrups, or tablets (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or mouthwashes, etc., each containing a predetermined amount of the compound of the present disclosure as the active ingredient. The composition or compound may also be administered in the form of a bolus, a syrup, or a paste.

[0319] To prepare solid dosage forms for oral administration (capsules (including dispersible capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers (e.g., sodium citrate or calcium hydrogen phosphate), and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) humectants, such as propylene glycol.

[0013] The pharmaceutical compositions may also include, for example, triols; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants such as paraffin wax; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) adsorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including spray-on capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also include a buffering agent. Solid compositions of a similar type may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (milk sugar) and high molecular weight polyethylene glycols.

[0320] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersant. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0321] Tablets and other solid dosage forms of pharmaceutical compositions (e.g., dragees, capsules (including dispersible capsules and gelatin capsules), pills, and granules) may optionally be scored or prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art). They may also be formulated using, for example, hydroxypropylmethylcellulose in varying proportions to provide a desired release profile, other polymer matrices, liposomes, and / or microspheres to provide slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent, in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium prior to use. These compositions may also optionally contain opacifying agents and may be compositions that release the active ingredient only or preferentially in a certain portion of the gastrointestinal tract in an optionally delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be microencapsulated, as appropriate, with one or more of the above-mentioned excipients.

[0322] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, lyophilizates for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0323] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0324] Suspensions, in addition to the active compounds, may contain suspending agents in the form of, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and astragalus, and mixtures thereof.

[0325] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0326] Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0327] Powders and sprays may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, for example butane and propane.

[0328] Transdermal patches have the additional advantage of providing control of the compound of the present disclosure to the delivery of the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the transdermal amount of the compound. The rate of this flow can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0329] As used herein, the phrase "parenteral administration" or "administered parenterally" means modes of administration other than enteral and topical administration, usually injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnical, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0330] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0331] These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may also be necessary to include isotonic agents, such as sugars, sodium chloride, etc. in the composition. In addition, prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption (such as aluminum monostearate and gelatin).

[0332] In some cases, in order to prolong the effect of a drug, it is necessary to slow down the absorption of a drug injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The absorption rate of a drug depends on its dissolution rate, which in turn can be determined by the size of the crystals and the crystalline form. Alternatively, parenteral drug forms can delay absorption by dissolving or suspending the drug in an oily vehicle.

[0333] Injectable depot formulations are made by forming a microencapsulation matrix of the target compound with a biodegradable polymer such as polylactide-polyglycolide. Depending on the drug-to-polymer ratio and the properties of the specific polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0334] For use in the disclosed methods, the active compound can be administered directly or in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) active ingredient and a pharmaceutically acceptable carrier.

[0335] The introduction method can also be provided by refillable or biodegradable devices. In recent years, a variety of slow-release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers, including hydrogels, including biodegradable and non-degradable polymers, can be used to form inserts that continuously release compounds at specific target sites.

[0336] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0337] The selected dosage concentration will depend upon a variety of factors, including the activity of the specific compound or combination of compounds employed, or their esters, salts, or amides; the route of administration; the time of administration; the rate of excretion of the specific compound employed; other drugs, compounds, and / or materials used in combination with the specific compound employed; the age, sex, weight, condition, general health, and prior medical history of the patient being treated; and like factors well known in the medical arts.

[0338] A physician or veterinarian of ordinary skill can easily determine and prescribe the therapeutically effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start administering a pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" means a concentration of the compound sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary according to the subject's weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the patient's condition, the condition being treated, the stability of the compound, and another type of therapeutic agent administered together with the compound of the present disclosure, if necessary. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) "Harrison's Principles of Internal Medicine", 13th edition, 1814-1882, incorporated herein by reference).

[0339] In general, a suitable daily dose of the active compound used in the compositions and methods of the present disclosure will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect. This effective dose will generally depend on the factors described above.

[0340] If desired, the effective daily dose of the active compound may optionally be administered in unit dosage form as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In certain embodiments of the present disclosure, the active compound may be administered twice or three times daily. In a preferred embodiment, the active compound will be administered once daily.

[0341] Patients receiving such treatment are any animal in need thereof, including primates, particularly humans; and other mammals, such as horses, cattle, pigs, sheep, cats, and dogs; and pets in general.

[0342] In certain embodiments, the compounds of the present disclosure may be administered alone or in combination with another type of therapeutic agent.

[0343] The present disclosure includes pharmaceutically acceptable salts of the compounds of the present disclosure for use in the compositions and methods of the present disclosure. In certain embodiments, the contemplated salts of the present disclosure include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, the salts encompassed by the present disclosure include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, danol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, the contemplated salts of the present disclosure include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In certain embodiments, the salts encompassed by the present disclosure include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, caprylic acid (decanoic acid), caprylic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclohexylaminesulfonic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, hexamethylenetetraminesulfonic acid, octanoic ... Lactobacic acid, gentisic acid, d-glucoheptanoic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenate.

[0344] Pharmaceutically acceptable acid addition salts may also exist in the form of various solvates, for example, with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates may also be prepared. Such solvates may originate from the solvent of crystallization, be inherent in the solvent of preparation or crystallization, or be admixed with such solvent.

[0345] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0346] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0347] definition

[0348] Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in connection with the chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein and their techniques are those well known and commonly used in the art.

[0349] The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Principles of Neural Science, McGraw-Hill Medical, New York, NY (2000); Motulsky, Intuitive Biostatistics, Oxford University Press, Inc. (1995); Lodish et al., Molecular Cell Biology, 4th ed., W.H. Freeman & Co., New York (2000); Griffiths et al., Introduction to Genetic Analysis, 7th ed., W.H. Freeman & Co., NY (1999); and Gilbert et al., Developmental Biology, 6th ed., Sinauer Associates, Sunderland, MA (1996). Associates, Inc., Sunderland, MA) (2000).

[0350] Unless otherwise defined herein, chemical terms used herein are used according to conventional usage in the art as exemplified by “The McGraw-Hill Dictionary of Chemical Terms,” Parker, S., ed., McGraw-Hill, San Francisco, CA (1985).

[0351] All of the above and any other publications, patents, and published patent applications mentioned in this application are expressly incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0352] The term "pharmaceutical agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound, a mixture of compounds), a biological macromolecule (e.g., a nucleic acid, an antibody (including portions thereof), and humanized, chimeric, and human antibodies and monoclonal antibodies, a protein or a portion thereof, such as a peptide, lipid, or carbohydrate), or an extract made from a biological material (e.g., a bacterial, plant, fungal, or animal (particularly mammalian) cell or tissue). Pharmaceutical agents include, for example, agents whose structures are known and agents whose structures are unknown.

[0353] "Patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (such as canines, felines, etc.), and rodents (such as mice and rats).

[0354] "Treating" a condition or patient means taking steps to obtain a favorable or desired result, including a clinical result. For the purposes of this disclosure, favorable or desired clinical results include, but are not limited to, alleviating or ameliorating one or more symptoms or conditions, reducing the severity of the disease, stabilizing the disease state (i.e., not worsening), preventing the spread of the disease, delaying or slowing the progression of the disease, improving or alleviating the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0355] The term "prevent" is art-recognized and well understood in the art when used with respect to conditions such as local recurrences (e.g., pain), diseases such as cancer, complex syndromes such as heart failure, or any other medical condition, and includes administering a composition that reduces the frequency of symptoms of a medical condition in a subject or delays its onset relative to a subject not receiving the composition. Thus, preventing cancer includes, for example, reducing the number of detectable cancerous growths in a patient population receiving prophylactic treatment relative to an untreated control population; and / or delaying the appearance of detectable cancerous growths in a treated population (e.g., to a statistically and / or clinically significant amount) relative to an untreated control population.

[0356] "Administering" a substance, compound, or agent to a subject can be performed using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinal, intracranially, and transdermally (by absorption, e.g., through a skin duct). The compound or agent can also be suitably introduced via a refillable or biodegradable polymer device or other device, such as a patch and pump or formulation that provides for extended, slowed, or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods.

[0357] The appropriate method of administering a substance, compound, or agent to a subject will also depend on, for example, the age and / or physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered orally to a subject, for example, by ingestion. In some embodiments, the orally administered compound or agent is in the form of an extended-release or slow-release formulation, or is administered using a device for such slow-release or extended-release.

[0358] As used herein, the phrase "administered in combination" refers to any form of administration of two or more different therapeutic agents such that the previously administered therapeutic agent is still effective in the body at the same time as the second agent is administered (e.g., both agents are effective in the patient's body at the same time, which may include a synergistic effect of the two agents). For example, different therapeutic compounds can be administered simultaneously or sequentially in the same formulation or in separate formulations. Thus, individuals receiving such treatments may benefit from the combined effects of the different therapeutic agents.

[0359] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or pharmaceutical agent is an amount of the drug or pharmaceutical agent that will have the intended therapeutic effect when administered to a subject. The full therapeutic effect may not occur with the administration of a single dose, and may occur only after a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount required for a subject will depend, for example, on the subject's size, health, and age, and the nature and extent of the condition being treated, such as cancer or MDS. One skilled in the art can readily determine the effective amount for a given situation by routine experimentation.

[0360] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" refers to an alkyl group that can be substituted as well as instances where the alkyl group is unsubstituted.

[0361] It will be understood that substituents and substitution patterns on the compounds of the present disclosure can be selected by one of ordinary skill in the art to produce chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art, as well as those given below. If a substituent is itself substituted with more than one group, it will be understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results.

[0362] As used herein, the term "optionally substituted" means that one to six hydrogen radicals in a given structure are replaced by a group of a specified substituent, including but not limited to hydroxy, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl)2. Preferably, "optionally substituted" means that one to four hydrogen radicals in a given structure are replaced by the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents mentioned above. It should be understood that the substituents may be further substituted.

[0363] As used herein, the term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon. For example, an alkyl group may have 1 to 10 carbon atoms (i.e., (C 1-10 ) alkyl) or 1 to 8 carbon atoms (i.e., (C 1-8 ) alkyl) or 1 to 6 carbon atoms (i.e., (C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., (C 1-4) alkyl). Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2C H3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH (CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2 CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3), but it is not limited thereto.

[0364] In addition, the term "alkyl" refers to a saturated aliphatic group, including straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic) groups, cycloalkyl substituted by alkyl, and alkyl substituted by cycloalkyl. In preferred embodiments, a straight-chain or branched alkyl group has 30 or fewer carbon atoms in its backbone (e.g., a straight-chain C 1-30 , branched chain C 3-30), and more preferably 20 or fewer. In certain embodiments, the alkyl group is unsubstituted unless otherwise specified. However, if not specified, the term "alkyl" as used throughout this specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter referring to alkyl moieties having substituents replacing hydrogens on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0365] As used herein, the term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group may include 2 to 8 carbon atoms (i.e., C 2-8 alkenyl) or 2 to 6 carbon atoms (ie, C 2-6 alkenyl) or 2 to 4 carbon atoms (ie, C 2-4 Examples of alkenyl groups are ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), 5-hexenyl (-CH2CH2CH2CH2CH=CH2) and 3-hexenyl (-CH2CH2CH ＝ In certain embodiments, alkenyl is unsubstituted unless otherwise specified.

[0366] The term "alkylene" as used herein refers to a group having 1 to 6 (C 1-6 ) carbon atoms. For example, a divalent saturated hydrocarbon group having 1 to 4 (C 1-4 ) carbon atoms. Examples include, but are not limited to, methylene, ethylene, trimethylene (propylene), and tetramethylene (n-butylene).

[0367] As used herein, the term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group may include 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl) or 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) or 2 to 4 carbon atoms (ie, C 2-4 Alkynyl). Examples of alkynyl are ethynyl (-C≡CH), propargyl (-CH2C≡CH) and -CH2-C≡C-CH3, but are not limited thereto. In certain embodiments, alkynyl is unsubstituted unless otherwise specified.

[0368] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0369] The term "amido" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0370] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0371] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0372] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0373] The term "alkyl" refers to a saturated aliphatic group, including straight chain alkyl, branched chain alkyl, cycloalkyl (alicyclic) groups, cycloalkyl substituted by alkyl, and alkyl substituted by cycloalkyl. In preferred embodiments, a straight chain or branched chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., a straight chain C 1-30 , branched chain C 3-30 ), and more preferably 20 or less.

[0374] Furthermore, the term "alkyl" as used throughout the specification, examples, and claims is intended to include unsubstituted and substituted alkyl groups, the latter referring to alkyl moieties having substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, and the like.

[0375] The term "C x-y ” or “C x -C y " when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups containing from x to y carbons in the chain. C0 alkyl represents hydrogen when the group is in the terminal position and represents a bond if it is internal. 1-6 Alkyl groups, for example, contain from one to six carbon atoms in the chain.

[0376] The prefix "ene" appended to a group indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0377] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0378] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0379] As used herein, the term "amido" refers to a group

[0380] (For example, a linker ),

[0381] where R 9 and R 10 Each independently represents hydrogen or a hydrocarbon group, or R 9 and R 10 Together with the nitrogen atom to which it is attached, the heterocycle completes a ring having 4 to 8 atoms in the ring structure.

[0382] The terms "amine" and "amino" are art-recognized and refer to unsubstituted and substituted amines and salts thereof, such as the moiety represented by

[0383]

[0384] where R 9 、R 10 and R 10' Each independently represents hydrogen or a hydrocarbon group, or R 9 and R 10 Together with the nitrogen atom to which it is attached, the heterocycle completes a ring having 4 to 8 atoms in the ring structure.

[0385] The term "aminoalkyl" as used herein refers to an alkyl group substituted with an amino group.

[0386] As used herein, the term "aralkyl" or "arylalkyl" refers to an alkyl group substituted with an aryl group.

[0387] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom in the ring is carbon. The ring is preferably a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, wherein two or more carbon atoms are shared by two adjacent rings, at least one of which is aromatic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic radicals. Aryl includes benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0388] The term "carbamate" is art-recognized and refers to a group

[0389]

[0390] where R 9 and R 10 independently represent hydrogen or a hydrocarbon group.

[0391] As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocyclyl group.

[0392] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring in a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, three, or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring in a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In exemplary embodiments, an aromatic ring (e.g., phenyl) can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle when valence permits. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decahydronaphthalene, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any position or positions capable of having a hydrogen atom.

[0393] As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocyclyl group.

[0394] The term "carbonate" is art-recognized and refers to the group -OCO2-.

[0395] As used herein, the term "carboxyl" refers to a group represented by the formula -CO2H.

[0396] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term "cycloalkyl" also includes polycyclic ring systems having two or more rings, wherein two or more carbon atoms are shared by two adjacent rings, wherein at least one of the rings is a cycloalkyl group and the substituents (e.g., R 100 ) is connected to the cycloalkyl ring, for example other ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic radical.Heteroaryl includes for example pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, benzodioxane, tetrahydroquinoline etc.The limiting examples of monocyclic cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

[0397] As used herein, the term "ester" refers to the group -C(O)OR 9 , where R 9 Represents a hydrocarbon group.

[0398] As used herein, the term "ether" refers to a hydrocarbon group attached to another hydrocarbon group through an oxygen. Thus, an ether substituent of a hydrocarbon group can be hydrocarbon-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl groups," which can be represented by the general formula alkyl-O-alkyl.

[0399] As used herein, the terms "halo" and "halogen" mean halogen and include chlorine, fluorine, bromine, and iodine.

[0400] As used herein, the terms "heteroarylalkyl," "hetaralkyl," and "heteroaralkyl" refer to an alkyl group substituted with a heteroaryl group.

[0401] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one non-carbon atom in the ring, wherein the atom may be selected from oxygen, nitrogen, and sulfur, and "heteroaryl" may include multiple condensed ring systems having at least one such aromatic ring. Multiple condensed ring systems are described further. Thus, "heteroaryl" may include a single aromatic ring having from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also exist in oxidized form, provided that the ring is aromatic. Examples of heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. In some embodiments, "heteroaryl" includes a polycondensed ring system (e.g., a ring system comprising 2, 3, or 4 rings), and the heteroaryl defined above can be formed by condensing with at least one ring selected from the following: heteroaryl (for example, 1,8-naphthyridinyl), heterocycle (for example, 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (for example, indazolyl). Thus, the heteroaryl group (single aromatic ring or polycondensed ring system) can have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. The polycondensed ring system can be such that the carbocyclic or heterocyclic portion of the condensed ring can be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups. The rings of the polycondensed ring system can be connected to each other by fusion, spirocyclic, and cross-linking bonds, as long as the valence requirements are met. The individual rings in the polycondensed ring system can be connected to each other in any order. The point of attachment of the heteroaryl or heteroaryl polycondensed ring system can be any suitable atom of the heteroaryl or heteroaryl polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). In addition, when referring to a specific atomic range member heteroaryl (e.g., (C5-C 10 ) heteroaryl), the atom range is understood to be relative to the total number of ring atoms of the heteroaryl and is understood to include carbon atoms and heteroatoms. For example, C5 heteroaryl may include thiazolyl and C 10Heteroaryl groups may include quinolyl. Examples of heteroaryl groups include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolylbenzofuranyl, benzimidazolyl, thiazolyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and 3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole, and are not limited thereto.

[0402] In addition, the term "heterocyclyl" or "heterocycle" as used herein refers to a monosaturated or partially unsaturated non-aromatic compound or a non-aromatic polycyclic ring system, wherein the ring includes at least one heteroatom (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has 5 to about 20 ring atoms, such as 3 to 12 ring atoms, such as 5 to 10 ring atoms. Thus, the term includes a monosaturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur. The rings of the polycondensed ring system can be connected to each other by fusion, spiro, and cross-linking bonds, as long as the valence requirements are met. Examples of heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like.

[0403] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom, having no =O or =S substituents and typically having at least one carbon-hydrogen bond and a primarily carbon backbone, but optionally including heteroatoms. Thus, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl groups, but substituents such as acetyl (which has a =O substituent on the attached carbon) and ethoxy (which is attached through oxygen rather than carbon) are not hydrocarbyl groups. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0404] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0405] The term "lower" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups having ten or less, preferably six or less atoms in the substituent. "Lower alkyl" for example refers to an alkyl group containing ten or less, preferably six or less, carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent as defined herein is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy group, respectively, whether occurring alone or in combination with other substituents, such as in hydroxyalkyl and aralkyl groups (in such cases, for example, the atoms in the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0406] The terms "polycyclic" and "polycycle" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic) in which two or more atoms are shared by two adjacent rings, e.g., the rings are "fused rings". Each ring in the polycyclic ring may be substituted or unsubstituted. In certain embodiments, each ring in the polycyclic ring contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0407] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0408] The term "sulfonamido" is art-recognized and refers to a group represented by the formula

[0409]

[0410] where R 9 and R 10 independently represents hydrogen or a hydrocarbon group.

[0411] The term "sulfoxide" is art-recognized and refers to the group -S(O)-.

[0412] The term "sulfonate" is art-recognized and refers to the group -SO3H, or a pharmaceutically acceptable salt thereof.

[0413] The term "sulfone" is art-recognized and refers to the group -S(O)2-.

[0414] The term "substituted" refers to a substituent group that partially has a hydrogen on one or more carbons that replace the main chain. It should be understood that "replacement" or "substituted" includes implicit restrictions, that is, this type of substitution is consistent with the allowed valence of the substituted atom and the substituent group, and the substitution produces a stable compound, such as it will not spontaneously be transformed, for example, by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For suitable organic compounds, permissible substituents can be one or more and the same or different. For the purposes of this disclosure, for example, the heteroatom of nitrogen can have a hydrogen substituent and / or any permitted substituent group of an organic compound that satisfies the heteroatom valence as described herein. Substituents may include any of the substituents described herein, for example, halogen, hydroxy, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moiety substituted on the hydrocarbon chain may itself be substituted where appropriate.

[0415] As used herein, the term "sulfanyl" refers to an alkyl group substituted with a thiol group.

[0416] As used herein, the term "thioester" refers to the group -C(O)SR 9 or –SC(O)R 9 ,

[0417] where R 9 Represents a hydrocarbon group.

[0418] As used herein, the term "thioether" is equivalent to an ether in which the oxygen is replaced by sulfur.

[0419] The term "urea" is art-recognized and can be represented by the following general formula

[0420]

[0421] where R 9 and R 10 independently represent hydrogen or a hydrocarbon group.

[0422] The term "azido" is art-recognized and can be represented by the following general formula

[0423]

[0424] The term "hydrazide group" is art-recognized and can be represented by the following general formula

[0425] (For example, a linker ),

[0426] where R 11 and R 12 independently represents hydrogen or a hydrocarbon group.

[0427] The term "guanidino" is art-recognized and can be represented by the following general formula

[0428]

[0429] where R 13 and R 14 independently represents hydrogen or a hydrocarbon group.

[0430] As used herein, the term "DBCO" refers to an optionally substituted dibenzocyclooctyne moiety, such as the following structure:

[0431]

[0432] As used herein, the term "modulate" includes inhibiting or suppressing a function or activity (eg, cell proliferation) as well as enhancing a function or activity.

[0433] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0434] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to acid addition salts or base addition salts that are suitable for use in treating a patient or are compatible with such treatment.

[0435] As used herein, the term "pharmaceutically acceptable acid addition salt" means any non-toxic organic or inorganic salt of any base compound represented by Formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts, such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids, such as p-toluenesulfonic acid and methanesulfonic acid. Mono- or di-acid salts can be formed, and such salts can be hydrated, dissolved or substantially anhydrous. In general, acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms. The selection of suitable salts is known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, may be useful, for example, in isolating compounds of Formula I for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0436] As used herein, the term "pharmaceutically acceptable base addition salt" means any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula I or any of its intermediates. Illustrative inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Illustrative organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline, or ammonia. The selection of suitable salts is known to those skilled in the art.

[0437] Many compounds suitable for use in the methods and compositions of the present invention have at least one stereogenic center in their structure. This stereogenic center can exist in an R or S configuration, with the R and S symbols being used in accordance with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The present disclosure encompasses all stereoisomeric forms, such as enantiomeric and diastereomeric forms (including all possible mixtures of stereoisomers) of a compound, salt, or mixture thereof. See, for example, WO 01 / 062726.

[0438] Additionally, certain compounds containing alkenyl groups may exist as either Z (same side) or E (different side) isomers. In each case, the disclosure includes both the mixture and the individual individual isomers.

[0439] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which is suitable for formulating a medicament for medical or therapeutic use.

[0440] As used herein, the terms "Log of Solubility," "LogS," or "logS" are used in the art to quantify the aqueous solubility of a compound. A compound's aqueous solubility significantly affects its absorption and distribution characteristics. Low solubility is often associated with poor absorption. The LogS value is the unit logarithm (base 10) of the solubility measured in moles / liter.

[0441] The term "cleavable group" refers to a chemical moiety that dissociates upon exposure to a stimulus (eg, acidic conditions, alkaline conditions, reducing conditions, oxidizing conditions, light, or heat) or an enzyme (eg, esterase).

[0442] Examples

[0443] Having generally described the invention, the same will be more readily understood by reference to the following examples, which are included merely to illustrate certain aspects and embodiments of the invention and are not intended to limit the invention.

[0444] Preparation of compounds

[0445] Preparation Example 1: Preparation of Intermediate Compound 2

[0446]

[0447] Preparation of intermediate compound 1

[0448] After dissolving 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (8 g, 51.9 mmol) in dichloromethane (50 mL), oxalyl chloride (4.97 mL, 57.1 mmol) and N,N-dimethylformamide (0.1 mL) were added at 0°C, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain Intermediate Compound 1.

[0449] Preparation of intermediate compound 2

[0450] After intermediate compound 1 (crude material) was dissolved in acetone (100 mL), potassium thiocyanate (6.5 g, 67.5 mmol) was added at 0°C. After the reaction solution was stirred at room temperature for 30 minutes, hexane (100 mL) was added and the formed solid was filtered. The filtered solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate compound 2 (9.7 g, 95%).

[0451] 1 H-NMR (400MHz, CDCl3), δ7.78(d,1H),7.41(s,1H),7.38(d,1H),3.88(s,3H),2.57(s,3H). EI-MSm / z:[M+H] +196.00.

[0452] Preparation Example 2: Preparation of Intermediate Compound 5

[0453]

[0454] Preparation of intermediate compound 3

[0455] To methyl 4-chloro-3-methoxy-5-nitrobenzoate (15 g, 61.1 mmol) was added aqueous ammonia solution (28% to 30% ammonia, 200 mL). The reaction solution was stirred at 50° C. for 6 hours, cooled to room temperature, and then washed with water, filtered and lyophilized to give intermediate compound 3 (9.51 g, 68%).

[0456] 1 H-NMR (400MHz, CDCl3) δ8.29(s,1H),8.04(d,1H),7.87(d,1H),7.78(s,1H),4.01(s,3H).

[0457] Preparation of intermediate compound 4

[0458] Intermediate compound 3 (300 mg, 1.30 mmol) was added to dichloromethane (9 mL), and then aluminum chloride (1.04 g, 7.81 mmol) was added at 0° C. Under nitrogen, the reaction solution was stirred at room temperature for 21 hours. The reaction solution was added to ice water, and then the resulting solid was filtered and lyophilized to obtain intermediate compound 4 (223 mg, 79%).

[0459] 1 H-NMR (400MHz, CDCl3), δ11.73(s,1H),8.21(s,1H),7.92(s,1H),7.80(s,1H),7.66(s,1H).

[0460] Preparation of intermediate compound 5

[0461] Under nitrogen, intermediate compound 4 (2g, 9.23mmol) and cesium carbonate (3.61g, 11.08mmol) are added to N, N- dimethylformamide (15mL) at 0 DEG C, and then stirred for 5 minutes. Under nitrogen, trans-1,4- dibromo-2-butene (5.93g, 27.70mmol) is added to the reaction solution at room temperature, and stirred for 2 hours. The resulting solution is extracted with ethyl acetate (20mL×3) and washed with distilled water (15mL×2) and brine (15mL). The combined organic layer is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated. After solidifying with dichloromethane and hexane, it is filtered and dried to obtain intermediate compound 5 (2.53g, 78%).

[0462] 1 H-NMR (400MHz, CDCl3), δ8.23(s,2H),8.02(d,J=1.8Hz,2H),7.84(d,J=1.8Hz,2H),7.73(s,2H), 6.16-5.98(m,4H),5.70(s,1H),4.83(d,J=3.5Hz,4H),4.25(d,J=5.4Hz,1H),4.20-4.14(m,3H). EI-MSm / z:[M+H] + 350.98.

[0463] Preparation Example 3: Preparation of Intermediate Compound 9

[0464]

[0465] Preparation of intermediate compound 6

[0466] After dissolving 4-chloro-3-methoxy-5-nitro-benzamide (11.4 g, 61.57 mmol) in ethanol (100 mL), intermediate compound 3 (10 g, 43.4 mmol) and N,N-diisopropylethylamine (14.9 mL, 86.7 mmol) were added and stirred at 120° C. for 12 hours. The reaction solution was concentrated and diluted with diethyl ether (40 mL), and the resulting solid was then filtered and dried to give intermediate compound 6 (12.6 g, 76%).

[0467] 1 H-NMR(400MHz,DMSO-d6),δ8.18(d,1H),8.01(s,1H),7.73(t,1H),7.55(d,1H) ,7.31(s,1H),6.92(s,1H),5.53(s,2H),4.08(s,2H),3.47(s,2H),1.35(m,9H).

[0468] Preparation of intermediate compound 7

[0469] After dissolving Intermediate Compound 6 (10 g, 26.28 mmol) in methanol (90 mL), aqueous ammonia solution (28% to 30% ammonia, 90 mL) and sodium bisulfite (Na2S2O4, 45 g, 262.8 mmol) were added sequentially at 0°C, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Methanol (100 mL) was added to the reaction solution, and the resulting solid was filtered. The filtered solution was concentrated and then diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to obtain Intermediate Compound 7 (6.9 g, 75%).

[0470] 1 H-NMR(400MHz,DMSO-d6),δ7.62(br s,1H),6.98(br s,1H),6.92(t,1H),6.87(d,1H),6.79(d,1H),5.57(q,2H),4.67(br s,2H),3.82(br s,1H),3.76(s,3H),3.51(dd,4H),1.37(s,9H).

[0471] Preparation of intermediate compound 8

[0472] After dissolving Intermediate Compound 7 (6.9 g, 19.7 mmol) in N,N-dimethylformamide (50 mL), Intermediate Compound 2 (4.9 g, 25.59 mmol) was added at 0°C and stirred at room temperature for 30 minutes. Triethylamine (5.4 mL, 39.38 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (4.2 g, 27.56 mmol) were added at 0°C, and the mixture was stirred at room temperature for 17 hours. After concentrating the reaction solution, it was diluted with diethyl ether (20 mL), and the resulting solid was filtered to obtain Intermediate Compound 8 (7.7 g, 76%).

[0473] 1 H-NMR(400MHz,DMSO-d6),δ12.86(s,1H),8.02(s,1H),7.67(s,1H),7.40(m,2H),6.93(m,1H),6.65(s,1H),5.67 (m,2H),4.93(d,2H),4.61(q,2H),3.98(s,3H),3.51(m,2H),2.55(m,2H),2.18(s,3H),1.35(t,3H),1.32(s,9H).

[0474] Preparation of intermediate compound 9

[0475] After dissolving intermediate compound 8 (7.7 g, 15.05 mmol) in dichloromethane (25 mL) and methanol (25 mL), hydrochloric acid (4M 1,4-dioxane solution, 27 mL) was added and stirred for 2 hours and 30 minutes. The reaction solution was concentrated and diluted with diethyl ether (20 mL), and the resulting solid was filtered to obtain intermediate compound 9 (5.6 g, 76%).

[0476] 1 H-NMR(400MHz,DMSO-d6)δ8.02(s,1H),8.67(d,1H),7.41(d,1H),7.37(s,1H),6.66(s,1H),6.01( m,1H),5.65(m,1H),4.97(d,2H),4.60(q,2H),3.98(s,3H),2.66(m,5H),2.33(m,3H),1.35(m,3H). EI-MSm / z:[M+H] + 823.0.

[0477] Example 1: Preparation of intermediate compound 13

[0478]

[0479] Preparation of intermediate compound 10

[0480] After intermediate compound 5 (580 mg, 1.66 mmol) was dissolved in N,N-dimethylformamide (5 mL), morpholine (0.13 mL, 1.01 mmol) and cesium carbonate (590 mg, 1.81 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, diluted with dichloromethane and hexane, and the resulting solid was filtered and dried to obtain intermediate compound 10 (504 mg, 70%).

[0481] 1 H-NMR (400MHz, CDCl3), δ7.73–7.66(m,1H),6.03–5.84(m,1H),4.75(dd,J=5.0,1 .2Hz, 1H), 3.75-3.68 (m, 2H), 3.06 (dd, J = 6.0, 1.1Hz, 1H), 2.46 (t, J = 4.7Hz, 2H). EI-MSm / z:[M+H] + 356.09.

[0482] Preparation of intermediate compound 11

[0483] After intermediate compound 9 (818 mg, 1.68 mmol) and intermediate compound 10 (300 mg, 0.84 mmol) were dissolved in n-butanol (13 mL), N,N-diisopropylethylamine (0.74 mL, 4.21 mmol) was added at room temperature, heated to 120 ° C, and stirred for 24 hours. After the reaction solution was cooled to room temperature, the reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. After dilution with diethyl ether, the resulting solid was filtered and dried to give intermediate compound 11 (129 mg, 21%). EI-MSm / z: [M + H] + 731.03.

[0484] Preparation of intermediate compound 12

[0485] After intermediate compound 11 (129 mg, 0.17 mmol) was dissolved in methanol (2 mL) and distilled water (0.1 mL), aqueous ammonia solution (28% to 30% ammonia, 0.17 mL) and sodium bisulfite (Na2S2O4, 321 mg, 1.84 mmol) were added to the reaction solution under nitrogen. After stirring at room temperature for 1 hour, methanol (50 mL) was added to the reaction solution, and the resulting solid was filtered and concentrated to the filtered solution, and then diluted with dichloromethane (100 mL), washed with distilled water (50 mL), and the organic layer was dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to obtain intermediate compound 12 (126 mg, crude material). EI-MSm / z: [M+H] + 701.08.

[0486] Preparation of intermediate compound 13

[0487] After intermediate compound 12 (126 mg, 0.18 mmol, crude material) was dissolved in N, N-dimethylformamide (2 mL), intermediate compound 2 (39 mg, 0.2 mmol) was dissolved in N, N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) and triethylamine (0.04 mL, 0.27 mmol) were added and stirred at room temperature for 16 hours. The resulting material was concentrated under reduced pressure and purified by HPLC to obtain intermediate compound 13 (5.6 mg, 4%). EI-MS m / z: [M+H] + 862.03.

[0488] Example 2: Preparation of intermediate compound 18

[0489]

[0490] Preparation of intermediate compound 14

[0491] After dissolving intermediate compound 5 (265 mg, 0.76 mmol) in N,N-dimethylformamide (4 mL), piperidine-4-tert-butylcarbamate (167 mg, 0.83 mmol) and cesium carbonate (296 mg, 0.91 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL×2), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, diluted with dichloromethane and hexane, and the resulting solid was filtered and dried to give intermediate compound 14 (248 mg, 70%). EI-MSm / z: [M+H] + 469.06.

[0492] Preparation of intermediate compound 15

[0493] After intermediate compound 9 (628 mg, 1.3 mmol) and compound 14 (304 mg, 0.65 mmol) were dissolved in n-butanol (5 mL), diisopropylethylamine (0.56 mL, 3.24 mmol) was added at room temperature, heated to 120 ° C, and stirred for 24 hours. After the reaction solution was cooled to room temperature, the reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The reaction solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, diluted with dichloromethane and hexane, and the resulting solid was filtered and dried to obtain intermediate compound 15 (124 mg, 23%). EI-MSm / z: [M + H] + 844.02.

[0494] Preparation of intermediate compound 16

[0495] After intermediate compound 15 (124 mg, 0.15 mmol) was dissolved in methanol (4 mL) and distilled water (0.5 mL), aqueous ammonia solution (28% to 30% ammonia, 0.4 mL) and sodium bisulfite (Na2S2O4, 218 mg, 2.94 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL) and filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The washed material was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate compound 16 (119 mg, crude material). EI-MSm / z: [M+H] + 814.81.

[0496] Preparation of intermediate compound 17

[0497] After intermediate compound 16 (119 mg, 0.15 mmol, crude material) was dissolved in N, N-dimethylformamide (1 mL), intermediate compound 2 (32 mg, 0.16 mmol) was dissolved in N, N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (35 mg, 0.18 mmol) and triethylamine (0.06 mL, 0.44 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate compound 17 (36 mg, 25%). EI-MSm / z: [M+H] + 975.15.

[0498] Preparation of intermediate compound 18

[0499] After dissolving intermediate compound 17 (36 mg) in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added at 0°C under nitrogen. The reaction solution was stirred at room temperature for 2 hours, concentrated, and then purified by HPLC to obtain intermediate compound 18 (15.2 mg, 47%). EI-MS m / z: [M+H] + 875.06.

[0500] Example 3: Preparation of intermediate compound 23

[0501]

[0502] Preparation of intermediate compound 19

[0503] After intermediate compound 5 (500 mg, 1.43 mmol) was dissolved in N, N-dimethylformamide (5 mL), piperazine-1-carboxylic acid tert-butyl ester (320 mg, 1.71 mmol) and cesium carbonate (512 mg, 1.57 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated under reduced pressure, diluted with dichloromethane and hexane, and the resulting solid was filtered and dried to obtain intermediate compound 19 (472 mg, 72%).

[0504] 1H-NMR(400MHz,DMSO-d6),δ8.26(s,1H),8.06(s,1H),7.88(s,1H),7.78(s,1H),5.91 -5.83(m,2H),4.84(d,1H),3.29-3.27(m,4H),2.98(d,2H),2.73(t,4H),1.39(s,9H). EI-MSm / z:[M+H] + 455.11.

[0505] Preparation of intermediate compound 20

[0506] After intermediate compound 9 (495 mg, 1.02 mmol) and intermediate compound 19 (310 mg, 0.68 mmol) were dissolved in n-butanol (7 mL), diisopropylethylamine (0.59 mL, 3.41 mmol) was added at room temperature, heated to 120 ° C, and stirred for 24 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 20 (336 mg, 46%). EI-MSm / z: [M + H] + 830.01.

[0507] Preparation of intermediate compound 21

[0508] After intermediate compound 20 (336 mg, 0.31 mmol) was dissolved in methanol (10 mL) and distilled water (1 mL), aqueous ammonia solution (28% to 30% ammonia, 0.33 mL) and sodium bisulfite (Na2S2O4, 549 mg, 3.16 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL) and then filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to obtain intermediate compound 21 (153 mg, 60%, crude material). EI-MSm / z: [M+H] + 800.09.

[0509] Preparation of intermediate compound 22

[0510] After intermediate compound 21 (153 mg, 0.19 mmol, crude material) was dissolved in N, N- dimethylformamide (2 mL), intermediate compound 2 (45 mg, 0.23 mmol) was dissolved in N, N- dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N- (3- dimethylaminopropyl) -N'- ethylcarbodiimide hydrochloride (192 mg, 0.28 mmol) and triethylamine (0.1 mL, 0.76 mmol) were added and stirred at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate compound 22 (116 mg, 63%). EI-MSm / z: [M+H] + 961.07.

[0511] Preparation of intermediate compound 23

[0512] After dissolving Intermediate Compound 22 (41 mg) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added under nitrogen at 0° C. The reaction solution was stirred at room temperature for 2 hours, concentrated, and then purified by HPLC to obtain Intermediate Compound 23 (26 mg, 46%).

[0513] 1 H-NMR(400MHz,DMSO-d6),δ8.66(br s,1H),7.96(d,2H),7.65(s,2H),7.37(br s,2H),7.30(d,2H),6.53(d,2H),5.86-5.63(m,4H),4.93-4.89(m,4H),4.56-4.50(m,6H),3.71(s,3H),2.11(d,6H)1.30-1.25(m,6H). EI-MSm / z:[M+H] + 861.21.

[0514] Example 4: Preparation of Intermediate Compound 28

[0515]

[0516] Preparation of intermediate compound 24

[0517] 3-Oxopiperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.86 mmol) was dissolved in tetrahydrofuran (4 mL), and potassium hydroxide (57.7 mg, 1.02 mmol) and TBAB (tetrabutylammonium bromide, 55.3 mg, 0.17 mmol) were added in sequence, and then stirred at room temperature for 30 minutes. Intermediate compound 5 (300 mg, 0.858 mmol) was dissolved in THF (2 mL), and then slowly added to the reaction solution, and stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with distilled water (30 mL), and then dried over anhydrous magnesium sulfate. The reaction solution was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate compound 24 (213 mg, 52.9%).

[0518] 1 H-NMR(400MHz, CDCl3), δ8.26(br s,1H),8.06(s,1H),7.87(s,1H),7.78(s,1H),5.90-5.80(m,2H),4.84(d,J=4.4Hz,1H) ,4.00(d,J=4.8Hz,2H),3.92(s,2H),3.53-3.51(m,2H),3.27-3.24(m,2H),1.41(s,9H). EI-MSm / z:[M+H] + 469.07.

[0519] Preparation of intermediate compound 25

[0520] After intermediate compound 9 (440 mg, 0.91 mmol) and intermediate compound 24 (213 mg, 0.45 mmol) were dissolved in n-butanol (4.5 mL), diisopropylethylamine (0.43 mL, 2.49 mmol) was added at room temperature and stirred for 24 hours while heating to 120 ° C. The reaction solution was cooled to room temperature and then diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 25 (213 mg, 55.5%). EI-MSm / z: [M + H] + 844.04.

[0521] Preparation of intermediate compound 26

[0522] After intermediate compound 25 (210 mg, 0.25 mmol) was dissolved in methanol (6 mL) and distilled water (1 mL), aqueous ammonia solution (28% to 30%, 0.44 mL) and sodium bisulfite (Na2S2O4, 433 mg, 2.48 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour and 45 minutes, diluted with methanol (50 mL) and then filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate compound 26 (crude material). EI-MSm / z: [M+H] + 814.14.

[0523] Preparation of intermediate compound 27

[0524] After intermediate compound 26 (0.24mmol, crude material) was dissolved in N,N-dimethylformamide (2.5mL), intermediate compound 2 (50.9mg, 0.26mmol) was dissolved in N,N-dimethylformamide (1mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (68.1mg, 0.35mmol) and triethylamine (0.1mL, 0.71mmol) were added and stirred at room temperature for 18 hours and 30 minutes. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate compound 27 (48mg, 20%). EI-MS m / z: [M+H] + 975.19.

[0525] Preparation of intermediate compound 28

[0526] After dissolving Intermediate Compound 27 (48 mg) in dichloromethane (3.2 mL), trifluoroacetic acid (0.8 mL) was added under nitrogen at 0° C. The reaction solution was stirred at 0° C. for 40 minutes, concentrated, and then purified by HPLC to obtain Intermediate Compound 28 (10.2 mg, 17%).

[0527] 1H-NMR (400MHz, DMSO-d6), δ1.28 (br s, 2H), 9.13 (br s, 1H), 7.96 (d, J = 14.7Hz, 2H), 7.65 (s, 2H), 7.37 (br s,2H),7.30(s,2H),6.53(d,J=6.3Hz,2H),5.86-5.63(m,4H),4.92-4.89(m, 4H), 4.56-4.50 (m, 4H), 3.31 (s, 5H), 2.11 (d, J = 4.9Hz, 6H) 1.29-1.25 (m, 6H). EI-MSm / z:[M+H] + 875.11.

[0528] Example 5: Preparation of intermediate compound 33

[0529]

[0530] Preparation of intermediate compound 29

[0531] Under nitrogen, intermediate compound 4 (1.5 g, 6.93 mmol) and cesium carbonate (2.5 g, 7.62 mmol) were dissolved in N, N-dimethylformamide (6 mL) at 0 ° C and then stirred for 5 minutes. Under nitrogen, cis-1,4-dibromo-2-butene (3.7 g, 17.32 mmol) was added to the reaction solution at room temperature and stirred for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (20 mL×2) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The solid obtained by diluting with dichloromethane and hexane was filtered and dried to give intermediate compound 29 (1.64 g, 67%). EI-MSm / z: [M+H] + 351.23.

[0532] Preparation of intermediate compound 30

[0533] After intermediate compound 29 (450 mg, 1.29 mmol) was dissolved in N, N-dimethylformamide (5 mL), morpholine (0.1 mL, 1.17 mmol) and cesium carbonate (417 mg, 1.28 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and then dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated under reduced pressure, and the solid obtained by diluting with dichloromethane and hexane was filtered and dried to give intermediate compound 30 (298 mg, 71%). EI-MSm / z: [M + H] + 356.11.

[0534] Preparation of intermediate compound 31

[0535] After intermediate compound 9 (592 mg, 1.22 mmol) and intermediate compound 30 (290 mg, 0.82 mmol) were dissolved in n-butanol (6 mL), diisopropylethylamine (0.71 mL, 4.08 mmol) was added at room temperature and stirred for 24 hours while heating to 120 ° C. The reaction solution was cooled to room temperature and then diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The reaction solution was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 31 (174 mg, 29%). EI-MSm / z: [M+H] + 731.05.

[0536] Preparation of intermediate compound 32

[0537] After intermediate compound 31 (173 mg, 0.24 mmol) was dissolved in methanol (2 mL) and distilled water (0.1 mL), aqueous ammonia solution (28% to 30%, 0.34 mL, 4.76 mmol) and sodium bisulfite (Na2S2O4, 412 mg, 2.37 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL) and filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The washed material was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to give intermediate compound 32 (48 mg, crude material, 29%). EI-MSm / z: [M+H] + 701.22.

[0538] Preparation of intermediate compound 33

[0539] After intermediate compound 32 (48 mg, 0.07 mmol, crude material) was dissolved in N, N-dimethylformamide (1 mL), intermediate compound 2 (16 mg, 0.08 mmol) was dissolved in N, N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (16 mg, 0.09 mmol) and triethylamine (0.03 mL, 0.2 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC to obtain intermediate compound 33 (17.5 mg, 30%). EI-MS m / z: [M+H] + 862.08.

[0540] Example 6: Preparation of intermediate compound 38

[0541]

[0542] Preparation of intermediate compound 34

[0543] After intermediate compound 29 (649 mg, 1.86 mmol) was dissolved in N, N-dimethylformamide (6 mL), piperidine-4-tert-butylcarbamate (338 mg, 1.69 mmol) and cesium carbonate (660 mg, 2.03 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and then dried over anhydrous sodium sulfate. The obtained material was filtered and concentrated under reduced pressure, and the solid obtained by diluting with dichloromethane and hexane was filtered and dried to obtain intermediate compound 34 (628 mg, 79%).

[0544] 1 H-NMR (400MHz, DMSO), δ8.21 (s, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 6.16–6.01 (m, 2H), 4.82 (d, J = 3.5Hz, 2H), 4.17 (d, J = 5.5Hz, 2H). EI-MSm / z:[M+H] + 469.49.

[0545] Preparation of intermediate compound 35

[0546] After intermediate compound 9 (413 mg, 0.85 mmol) and intermediate compound 34 (600 mg, 1.28 mmol) were dissolved in n-butanol (8 mL), diisopropylethylamine (0.74 mL, 4.27 mmol) was added at room temperature and stirred for 24 hours while heating to 120 ° C. The reaction solution was cooled to room temperature and then diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The washed material was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 35 (147 mg, 20%). EI-MSm / z: [M + H] + 844.13.

[0547] Preparation of intermediate compound 36

[0548] After intermediate compound 35 (147 mg, 0.17 mmol) was dissolved in methanol (3 mL) and distilled water (0.1 mL), aqueous ammonia solution (28% to 30%, 0.25 mL) and sodium bisulfite (Na2S2O4, 303 mg, 1.74 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL) and then filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The washed material was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to give intermediate compound 36 (141 mg, crude material). EI-MSm / z: [M+H] + 814.81.

[0549] Preparation of intermediate compound 37

[0550] After intermediate compound 36 (141 mg, 0.17 mmol, crude material) was dissolved in N,N-dimethylformamide (1 mL), compound 2 (37 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (50 mg, 0.09 mmol) and triethylamine (0.03 mL, 0.22 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate compound 37 (48 mg, 28%). EI-MS m / z: [M+H] + 975.16.

[0551] Preparation of intermediate compound 38

[0552] After dissolving intermediate compound 37 (48 mg) in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added under nitrogen at 0°C. The reaction solution was stirred at room temperature for 2 hours, concentrated, and then purified by HPLC to obtain intermediate compound 38 (6.4 mg, 14%). EI-MS m / z: [M+H] + 875.17.

[0553] Example 7: Preparation of Intermediate Compound 43

[0554]

[0555] Preparation of intermediate compound 39

[0556] 3-Oxopiperazine-1-carboxylic acid tert-butyl ester (210mg, 1.05mmol) is dissolved in N, N-dimethylformamide (6mL), potassium hydroxide (66.2mg, 1.02mmol) is added and then stirred at room temperature for 30 minutes. After intermediate compound 29 (350mg, 1.20mmol) is dissolved in N, N-dimethylformamide (4mL), it is slowly added to the reaction solution and stirred at room temperature for 2 hours. The reaction solution is diluted with ethyl acetate (50mL), washed with distilled water (30mL), and then dried over anhydrous magnesium sulfate. The dried material is filtered, then concentrated under reduced pressure, and purified by column chromatography to obtain intermediate compound 39 (432mg, 92.0%).

[0557] 1 H-NMR(400MHz, CDCl3)δ7.80(s,1H),7.87(s,1H),7.62(s,1H),5.82-5.81(m, 2H),4.76,(d,1H),4.10-4.05(m,4H),3.65(t,2H),3.34(t,2H),1.47(s,9H). EI-MSm / z:[M+H] + 469.10.

[0558] Preparation of intermediate compound 40

[0559] After intermediate compound 9 (542 mg, 1.11 mmol) and intermediate compound 39 (350 mg, 0.746 mmol) were dissolved in n-butanol (4.5 mL), diisopropylethylamine (0.65 mL, 3.73 mmol) was added at room temperature and stirred for 24 hours while heating to 120 ° C. The reaction solution was cooled to room temperature and then diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 40 (135 mg, 21.4%). EI-MSm / z: [M+H] + 844.12.

[0560] Preparation of intermediate compound 41

[0561] After intermediate compound 40 (135 mg, 0.16 mmol) was dissolved in methanol (6 mL) and distilled water (1 mL), aqueous ammonia solution (28% to 30%, 0.3 mL) and sodium bisulfite (Na2S2O4, 278 mg, 1.59 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 2 hours, diluted with methanol (50 mL) and then filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to give intermediate compound 41 (91 mg, 69.8%). EI-MSm / z: [M+H] + 814.12.

[0562] Preparation of intermediate compound 42

[0563] After intermediate compound 41 (91 mg, 0.11 mmol) was dissolved in N, N- dimethylformamide (2.5 mL), intermediate compound 2 (32.7 mg, 0.16 mmol) was dissolved in N, N- dimethylformamide (1 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N- (3- dimethylaminopropyl) -N'- ethylcarbodiimide hydrochloride (34 mg, 0.22 mmol) and triethylamine (0.03 mL, 0.24 mmol) were added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate compound 42 (125 mg, crude material). EI-MSm / z: [M+H] + 975.17.

[0564] Preparation of intermediate compound 43

[0565] After intermediate compound 42 (125 mg, crude material) was dissolved in dichloromethane (3.2 mL), trifluoroacetic acid (0.8 mL) was added under nitrogen at 0° C. The reaction solution was stirred at 0° C. for 40 minutes, concentrated, and then purified by HPLC to give intermediate compound 43 (34 mg, 25%).

[0566] 1H-NMR(400MHz,DMSO-d6),δ12.84(bs,2H),9.16(bs,2H),7.97(d,2H),7.65(s,2H),7.36(s,2H),7.30(s,2H),6.53(d,2H),5.79(s,2H),5 .73-5.60(m,2H),4.90(bs,4H),4.55-4.50(m,6H),3.84(d,2H),3.73(s,2H),3.69(s,4H),2.11(d,6H),1.29-1.24(m,6H. EI-MSm / z: [M+H] + 875.13.

[0567] Example 8: Preparation of Intermediate Compound 48

[0568]

[0569] Preparation of intermediate compound 44

[0570] After intermediate compound 4 (2.0 g, 9.23 mmol) was dissolved in N, N-dimethylformamide (10 mL), 1,4-dibromo-2-butyne (5.8 g, 27.70 mmol) and cesium carbonate (3.6 g, 11.08 mmol) were added under nitrogen. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (100 mL), washed with distilled water (50 mL × 2), and dried over anhydrous sodium sulfate. The dried material was filtered and concentrated under reduced pressure, and the solid obtained by diluting with dichloromethane and hexane was filtered and dried to obtain intermediate compound 44 (2.0 g, 62%).

[0571] 1 H-NMR (400MHz, DMSO-d6), δ8.25(s,1H),8.12(s,1H),7.95(s,1H),7.80(s,1H),5.22(s,2H),4.34(t,J=5.5Hz,2H). EI-MSm / z:[M+H] + 348.99.

[0572] Preparation of intermediate compound 45

[0573] After intermediate compound 44 (300 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (3 mL), morpholine (0.09 mL, 1.03 mmol) and cesium carbonate (309 mg, 0.95 mmol) were added under nitrogen. The mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate (50 mL), washed with distilled water (50 mL × 2), and dried over anhydrous sodium sulfate. The dried material was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate compound 45 (230 mg, 75%).

[0574] 1 H-NMR (400 MHz, DMSO-d6) δ 8.25(s,1H),8.11(s,1H),8.01(s,1H),7.79(s,1H),5.17(s,2H),3.52(t,J=11.5Hz,4H),3.29(s,2H),2.36(t,J=11.0Hz,4H). EI-MSm / z:[M+H] + 354.13.

[0575] Preparation of intermediate compound 46

[0576] After intermediate compound 9 (500 mg, 1.03 mmol) and intermediate compound 45 (215 mg, 0.60 mmol) were dissolved in n-butanol (4 mL), diisopropylethylamine (0.53 mL, 3.03 mmol) was added at room temperature and stirred for 24 hours while heating to 120 ° C. The reaction solution was cooled to room temperature and then diluted with dichloromethane (100 mL) and methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The solid obtained by diluting with dichloromethane and diethyl ether was filtered and dried to give intermediate compound 46 (303 mg, 68%). EI-MSm / z: [M + H] + 729.11.

[0577] Preparation of intermediate compound 47

[0578] After intermediate compound 46 (303 mg, 0.41 mmol) was dissolved in methanol (10 mL) and distilled water (1 mL), aqueous ammonia solution (28% to 30% ammonia, 0.45 mL) and sodium bisulfite (Na2S2O4, 724 mg, 4.16 mmol) were added to the reaction solution under nitrogen. The mixture was stirred at room temperature for 1 hour, diluted with methanol (50 mL) and filtered. The filtrate was concentrated under reduced pressure, diluted with dichloromethane (100 mL) and methanol (20 mL), and then washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to give intermediate compound 47 (97 mg, 33%, crude material). EI-MSm / z: [M+H] + 699.07.

[0579] Preparation of intermediate compound 48

[0580] After intermediate compound 47 (97 mg, 0.14 mmol, crude material) was dissolved in N,N- dimethylformamide (1.5 mL), intermediate compound 2 (32 mg, 0.17 mmol) was dissolved in N,N- dimethylformamide (0.5 mL) under nitrogen and added thereto. After stirring at room temperature for 1 hour, N- (3- dimethylaminopropyl) -N '- ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol) and triethylamine (0.06 mL, 0.42 mmol) were added and stirred at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC to obtain intermediate compound 48 (38 mg, 32%).

[0581] 1 H-NMR (400MHz, MeOD-d4), δ7.60(d,J=1.3Hz,1H),7.58(d,J=1.3Hz,1H),7.44(d,J=1.4Hz,1H),7.31(d,J=1.4Hz,1H),6.60(d,J=0.6Hz,1H),6.58 (d,J=0.6Hz,1H),5.89-5.86(m,4H),5.04-5.01(m,4H),4.61-4.55(m,4H ),4.07(s,2H),3.71(s,3H),2.20(s,3H),2.18(s,3H),1.37-1.30(m,6H). EI-MSm / z:[M+H] + 860.08.

[0582] Example 9: Preparation of Intermediate Compound 55

[0583]

[0584] Preparation of intermediate compound 49

[0585] To a solution of 4-nitropyrazole (1g, 6.13mmol) in methanol (20mL) is added ammonia solution (28% to 30% ammonia, 2.2mL) and sodium bisulfite (7.7g). After stirring at room temperature for 1 hour, the reaction solution is filtered with diatomaceous earth, and the filtrate is evaporated under reduced pressure. Methanol (15mL) is added to the concentrated filtrate, and then di-tert-butyl dicarbonate (2.24mL, 9.73mmol) and triethylamine (1.86mL, 13.27mmol) are added at room temperature. The reaction solution is stirred at room temperature for 16 hours, and then diluted with ethyl acetate (50mL) and washed with distilled water (50mL×2). The organic layer is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography to obtain intermediate compound 49 (0.7g, 43%).

[0586] 1 H-NMR (400MHz, DMSO-d6) δ9.05(s,1H),7.44(s,1H),1.42(s,9H).

[0587] Preparation of intermediate compound 50

[0588] To a solution of intermediate compound 49 (0.7 g, 3.82 mmol) in N, N-dimethylformamide (15 mL) was added cesium carbonate (3.7 g, 11.46 mmol) and trans-1,4-dibromo-2-butene (2.45 g, 11.46 mmol). After stirring at room temperature for 2 hours, the reaction solution was diluted with ethyl acetate (50 mL) and then washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain intermediate compound 50 (867 mg, 71%).

[0589] 1 H-NMR(400MHz, CDCl3)δ7.66(s,1H),7.33(s,1H),6.24(s,1H),6.00–5.90(m,1H),5. 87(td,J=13.2,5.9Hz,1H), 4.69(d,J=5.6Hz,2H), 3.94(d,J=6.9Hz,2H), 1.50(s,9H). EI-MSm / z: [M+H]+317.26.

[0590] Preparation of intermediate compound 51

[0591] To a solution of intermediate compound 4 (540 mg, 2.5 mmol) in N, N-dimethylformamide (15 mL) was added cesium carbonate (894 mg, 2.75 mmol) and compound 50 (867 mg, 2.75 mmol). After stirring at room temperature for 2 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain intermediate compound 51 (830 mg, 73%).

[0592] 1 H-NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.24(s,1H),8.05(s,1H),7.88(s,1H),7.75(s,1H),7.65(s,1H),7.30(s,1H) ,6.08(d,J=15.4Hz,1H),5.86(d,J=15.8Hz,1H),4.82(d,J=5.4Hz,2H),4.74(d,J=5.9Hz,2H),1.44(d,J=2.3Hz,9H). EI-MSm / z:[M+H] + 452.31.

[0593] Preparation of intermediate compound 52

[0594] To a solution of intermediate compound 51 (830 mg, 1.83 mmol) and compound 9 (1.13 g, 2.76 mmol) in n-butanol (11 mL) was added N,N-diisopropylethylamine (1.6 mL, 9.18 mmol). The reaction solution was stirred at 0 ° C for 5 minutes, then heated to 120 ° C for 24 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 52 (420 mg, 28%). EI-MS m / z: [M + H] + 827.39.

[0595] Preparation of intermediate compound 53

[0596] To a solution of intermediate compound 52 (420 mg, 0.51 mmol) in methanol (5 mL) was added aqueous ammonia solution (28% to 30% ammonia, 1.8 mL, 12.66 mmol) and sodium bisulfite (882 mg, 5.06 mmol). After stirring at room temperature for 2.5 hours, the reaction solution was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure and purified by reverse phase column chromatography to give intermediate compound 53 (400 mg). EI-MS m / z: [M+H] + 797.48.

[0597] Preparation of intermediate compound 54

[0598] To a solution of intermediate compound 53 (400 mg, 0.51 mmol) in N,N-dimethylformamide (1.5 mL) was added compound 2 (109 mg, 0.55 mmol) in N,N-dimethylformamide (1 mL) at 0°C. After 30 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.1 mL, 0.61 mmol) and triethylamine (0.35 mL, 2.53 mmol) were added to the reaction solution. After stirring at room temperature for 15 hours, the reaction solution was concentrated under reduced pressure and purified by reverse phase chromatography to give intermediate compound 54 (97 mg, 20%).

[0599] Preparation of intermediate compound 55

[0600] To a solution of intermediate compound 54 (30 mg, 0.03 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at 0° C. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated and purified by HPLC to give intermediate compound 55 (10 mg, 27%).

[0601] 1 H-NMR (400MHz, CD3OD) δ7.80 (s, 1H), 7.57 (d, J = 11.4Hz, 3H), 7.29 (s, 1H), 7.23 ( s,1H),6.62(d,J=1.7Hz,1H),6.56(s,1H),5.85(d,J=18.0Hz,3H),5.70(d,J=15. 6Hz,1H),5.01(s,4H),4.63(s,3H),4.61–4.52(m,2H),4.45(s,2H),3.74(s,2H) ,3.31(m,3H),2.65(s,1H),2.20(d,J=12.3Hz,6H),1.34(dt,J=21.7,6.9Hz,6H). EI-MS m / z: [M+H] + 858.54.

[0602] Example 10: Preparation of Intermediate Compound 65

[0603]

[0604] Preparation of intermediate compound 56

[0605] Under nitrogen, cesium carbonate (11.2 g, 34.62 mmol) was added to a solution of intermediate compound 4 (5 g, 23.08 mmol) in N, N-dimethylformamide (30 mL) at 0 ° C. After 5 minutes, ethyl 4-bromobutyrate (5.4 g, 27.70 mmol) was added to the reaction solution at room temperature under nitrogen. After stirring for 2 hours, the reaction solution was diluted with ethyl acetate (60 mL) and washed with distilled water (15 mL × 2) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. After solidification with dichloromethane and hexane, the obtained solid was filtered and dried to give intermediate compound 56 (4.7 g, 61%), which was used without further purification.

[0606] 1 H-NMR (400MHz, CDCl3) δ8.28 (s, 1H), 8.04 (s, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 4.25 (m, 2H), 4.09-4.04 (q, J = 7.2Hz, 2H), 1.19-1.15 (t, J = 7.2Hz, 3H). EI-MSm / z:[M+H] + 331.20.

[0607] Preparation of intermediate compound 57

[0608] To a solution of intermediate compound 56 (4.5 g, 13.60 mmol) in ethanol (30 mL) was added tert-butyl (E)-(4-aminobut-2-ene-1-yl)carbamate (2.5 g, 13.60 mmol) and N,N-diisopropylethylamine (2.37 mL, 27.21 mmol). After stirring at 120 ° C for 12 hours, the reaction solution was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with distilled water (15 mL × 2) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to obtain intermediate compound 57 (4.5 g, 68%).

[0609] 1 H-NMR(400MHz,DMSO-d6)δ8.10(s,1H),8.01(s,1H),7.68(t,1H),7.58(s,1H),7.30(s,1H) ,6.90(s,1H),5.54(s,2H),4.10(m,6H),3.48(s,3H),2.07(m,2H)1.35(m,9H)1.17(m,4H). EI-MSm / z:[M+H] + 481.28.

[0610] Preparation of intermediate compound 58

[0611] To a solution of intermediate compound 57 (4.4 g, 9.156 mmol) in methanol (20 mL) was added aqueous ammonia solution (28% to 30% ammonia, 10 mL) and sodium bisulfite (Na2S2O4, 15 g, 91.6 mmol) at 0°C. After stirring at room temperature for 1.5 hours, the reaction solution was filtered through celite and methanol. The filtrate was concentrated under reduced pressure to give intermediate compound 58 (4 g, 96%). EI-MS m / z: [M+H] + 451.31.

[0612] Preparation of intermediate compound 59

[0613] To a solution of intermediate compound 58 (4.0 g, 8.87 mmol) in N,N-dimethylformamide (30 mL) was added compound 2 (1.9 g, 9.76 mmol) at 0 ° C. After stirring at room temperature for 30 minutes, triethylamine (3.7 mL, 26.63 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (2.7 g, 17.75 mmol) were added to the reaction solution at 0 ° C. The resulting reaction solution was stirred at room temperature for 17 hours. Then, the reaction solution was concentrated, and the resulting residue was purified by column chromatography to obtain intermediate compound 59 (3.8 g, 71%).

[0614] 1 H-NMR (400MHz, DMSO-d6) δ12.86(s,1H),7.99(s,1H),7.66(s,1H),7.37-7.35(m,2H),6.89(m,1H),6.63(s,1H),5.79-5.72(d,J=16Hz, 1H),5.58-5.54(d,J=16Hz,1H)4.94(s,2H),4.62(m,2H),4.22(s,3H),4.20(m,6H),2.31(m,3H),2.11(s,2H),1.36(m,9H),1.17(m,4H). EI-MSm / z:[M+H] + 612.31.

[0615] Preparation of intermediate compound 60

[0616] To a solution of intermediate compound 59 (3.8 g, 6.21 mmol) in dichloromethane (50 mL) was added hydrochloric acid (4 M 1,4-dioxane solution, 11.5 mL). After stirring for 2 hours, the reaction solution was concentrated and diluted with diethyl ether (20 mL). The resulting solid was filtered to obtain intermediate compound 60 (3.9 g, 99%).

[0617] 1 H-NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.88(m,2H),7.68(s,1H),7.39(s,2H),6.67(s,1H),6.08-6.04(d,J=16Hz,1H),5.59- 5.55(d,J=16Hz,1H),5.00(s,2H),4.61(m,2H),4.22(m,2H),4.10(m,2H),2.19(s,3H),2.11(m,2H),1.37(m,3H),1.19(m,3H). EI-MSm / z:[M+H] + 512.31.

[0618] Preparation of intermediate compound 61

[0619] To a solution of intermediate compound 60 (3.8 g, 6.63 mmol) and intermediate compound 51 (2 g, 4.42 mmol) in n-butanol (13 mL) was added N, N-diisopropylethylamine (3.85 mL, 22.13 mmol) at room temperature. After stirring at 100 ° C for 21 hours, the reaction solution was cooled to room temperature. The reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain intermediate compound 61 (1.6 g, 38%). EI-MSm / z: [M + H] + 926.98.

[0620] Preparation of intermediate compound 62

[0621] To a solution of intermediate compound 61 (1.6 g, 1.83 mmol) in methanol (8 mL) was added ammonia solution (28% to 30% ammonia, 3.2 mL) and sodium bisulfite (Na2S2O4, 3.1 g, 18.3 mmol) under nitrogen. The reaction solution was stirred at room temperature for 1 hour and then methanol (50 mL) was added, and the resulting solid was filtered out. The filtrate was concentrated and diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give intermediate compound 62 (1.4 g, 85%). EI-MSm / z: [M+H] + 897.05.

[0622] Preparation of intermediate compound 63

[0623] To a solution of intermediate compound 62 (1.35 g, 1.51 mmol) in N,N-dimethylformamide (10 mL) was added compound 2 (324 mg, 1.66 mmol) in N,N-dimethylformamide (1 mL) under nitrogen. The reaction solution was stirred at room temperature for 1 hour, and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (465 mg, 3.02 mmol) and triethylamine (0.63 mL, 4.53 mmol) were added. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 63 (560 mg, 35%). EI-MS m / z: [M+H] + 1057.96.

[0624] Preparation of intermediate compound 64

[0625] Under nitrogen, lithium hydroxide monohydrate (13.8 mg, 0.28 mmol) in distilled water (1 mL) was added to a solution of intermediate compound 63 (100 mg, 0.094 mmol) in methanol (2 mL) at -50°C. After stirring at 0°C for 2 hours, the reaction solution was acidified to pH 4 to 5 with acetic acid, and then concentrated and lyophilized to give intermediate compound 64 (100 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] + 1029.95.

[0626] Preparation of intermediate compound 65

[0627] To a solution of intermediate compound 64 (100 mg, 0.097 mmol, crude) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) under nitrogen at 0° C. After stirring at room temperature for 2 hours, the reaction solution was concentrated and purified by HPLC to give intermediate compound 65 (42 mg, 34%).

[0628] 1 H-NMR(400MHz,DMSO-d6)δ12.80(s,1H),9.77(s,2H),7.96(s,1H),7.87(m,2H),7.65(s,2H),7.53(s,1H),7.34(s,2H),7.28(s,2H),6.53( s,2H),5.79(m,3H),5.65(m,1H),4.90(s,4H),4.62(m,2H),4.50(m,6 H),3.92(m,3H),2.24(s,2H),2.11(m,6H),1.74(m,2H),1.26(m,6H). EI-MSm / z:[M+H] +929.98.

[0629] Example 11: Preparation of Intermediate Compound 69

[0630]

[0631] Preparation of intermediate compound 67

[0632] To a solution of intermediate compound 66 (300 mg, 0.32 mmol, intermediate compound 66 was prepared by the method described in International Patent Publication No. WO2022 / 155518A1) in dichloroethane (30 mL) was added boron tribromide (1.0 M in dichloromethane, 3.2 mL, 3.16 mmol). After stirring at reflux for 17 hours, the reaction solution was concentrated under reduced pressure and diluted with dichloromethane / diethyl ether (50 mL / 50 mL). The resulting solid was filtered to give intermediate compound 67 (280 mg, 84%). EI-MS m / z: [M+H] + 709.15.

[0633] Preparation of intermediate compound 68

[0634] To a solution of intermediate compound 67 (280 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (607 mg, 1.87 mmol) and intermediate compound 50 (101 mg, 0.32 mmol). After stirring at room temperature for 18 hours, the reaction solution was concentrated under reduced pressure and purified by reverse phase column chromatography to obtain intermediate compound 68 (158 mg, 62%). EI-MS m / z: [M+H] + 945.00.

[0635] Preparation of intermediate compound 69

[0636] To a solution of intermediate compound 68 (50 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) under nitrogen at 0° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated and the resulting residue was purified by HPLC to give intermediate compound 69 (8 mg).

[0637] 1H-NMR (400MHz, CD3OD) δ7.82(d,J=0.8Hz,1H),7.58(d,J=0.8Hz,1H),7.53(d,J=1.3Hz,1H),7.4 2(d,J=1.5Hz,1H),7.24(d,J=1.4Hz,1H),7.17(d,J=1.4Hz,1H),6.61(d,J=0.7Hz,1H),6.49(d, J=0.7Hz,1H),5.95–5.80(m,3H),5.78–5.67(m,1H),5.04(dd,J=17.4,3.9Hz,4H),4.67–4.57(m ,4H),4.57–4.46(m,4H),2.20(s,3H),2.16(s,3H),1.36(t,J=7.1Hz,3H),1.28(t,J=7.1Hz,3H). EI-MSm / z:[M+H] + 845.07.

[0638] Example 12: Preparation of Intermediate Compound 79

[0639]

[0640] Preparation of intermediate compound 70

[0641] Under nitrogen, sodium acetate (2.0 g, 24.4 mmol) was added to a solution of trans-1,4-dibromo-2-butene (10.4 g, 48.7 mmol) in N,N-dimethylformamide (30 mL) at 0 ° C. The reaction solution was stirred at room temperature for 17 hours, and then diluted with ethyl acetate (100 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to obtain intermediate compound 70 (2.98 g, 63%).

[0642] 1 H-NMR (400MHz, CDCl3) δ6.02-5.82 (m, 2H), 4.59 (d, J = 5.6Hz, 2H), 3.95 (d, J = 7.2Hz, 2H), 2.08 (s, 3H).

[0643] Preparation of intermediate compound 71

[0644] To a solution of intermediate compound 70 (838 mg, 4.34 mmol) in dichloromethane (60 mL) was added triethylamine (1.83 mL, 13.02 mmol) and tert-butyl (3-aminopropyl)carbamate (2.27 g, 13.02 mmol) in dichloromethane (40 mL) at 0°C. The reaction solution was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 71 (380 mg, 30%).

[0645] 1 H-NMR (400MHz, CDCl3) δ5.87-5.71(m,2H),4.99(s,1H),4.58-4.52(m,2H),3.26(d,J=5.7Hz,2H),3.2 3-3.18(m,2H),2.70-2.65(m,2H),2.07(d,J=2.7Hz,3H),1.68(d,J=6.6Hz,2H),1.45(d,J=2.6Hz,9H).

[0646] Preparation of intermediate compound 72

[0647] To a solution of intermediate compound 71 (790 mg, 2.76 mmol) in dichloromethane (10 mL) was added fluorenylmethoxycarbonyl chloride (Fmoc-Cl, 856 mg, 3.31 mmol) and N, N-diisopropylethylamine (0.78 mL, 5.52 mmol). After stirring at room temperature for 2 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to obtain intermediate compound 72 (1.4 g, 98%). EI-MSm / z: [M+H] + 509.19.

[0648] Preparation of intermediate compound 73

[0649] Potassium carbonate (1.96 g, 14.15 mmol) was added to a solution of intermediate compound 72 (790 mg, 2.76 mmol) in methanol (20 mL) at 0 ° C. After stirring at room temperature for 30 minutes, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was dissolved in dichloromethane (10 mL), and then 4-nitrophenyl (2- (trimethylsilyl) ethyl) carbonate (Teoc-PNP, 962 mg, 3.39 mmol) and N, N-diisopropylethylamine (0.80 mL, 5.66 mmol) were added, and the reaction solution was stirred at room temperature for 18 hours. The reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by column chromatography to give Intermediate Compound 73 (596 mg, 54%). EI-MS m / z: [M+H] + 389.28.

[0650] Preparation of intermediate compound 74

[0651] To a solution of intermediate compound 73 (300 mg, 0.77 mmol) in dichloromethane (5 mL) was added triethylamine (0.33 mL, 2.31 mmol) and methanesulfonyl anhydride (175 mg, 1.00 mmol) at 0 ° C. After stirring at room temperature for 1 hour, the reaction solution was diluted with dichloromethane (50 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate. It was filtered and concentrated under reduced pressure to give intermediate compound 74 (380 mg, crude material), which was used without further purification. EI-MS m / z: [M + H] + 467.17.

[0652] Preparation of intermediate compound 76

[0653] To a solution of intermediate compound 75 (450 mg, 0.62 mmol, intermediate compound 75 was prepared according to the method described in International Patent Publication No. WO2022 / 155518A1) in N,N-dimethylformamide (5 mL) was added cesium carbonate (811 mg, 2.49 mmol) and intermediate compound 74 (349 mg, 0.75 mmol) in N,N-dimethylformamide (2 mL). After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure, diluted with dichloromethane (50 mL) and methanol (10 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to give intermediate compound 76 (468 mg, 68%). EI-MSm / z: [M+H] + 1093.72.

[0654] Preparation of intermediate compound 77

[0655] To a solution of intermediate compound 76 (468 mg, 0.43 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.1 mL, 2.14 mmol). After stirring under reflux for 5 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography to give intermediate compound 77 (256 mg, 63%). EI-MS m / z: [M+H] + 950.12.

[0656] Preparation of intermediate compound 78

[0657] To a solution of intermediate compound 77 (256 mg, 0.27 mmol) in N,N-dimethylformamide (3 mL) was added N,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboximidamide (126 mg, 0.40 mmol) and triethylamine (0.11 mL, 0.81 mmol). After stirring at 60 ° C. for 17 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 78 (103 mg, 32%). EI-MS m / z: [M + H] + 1192.17.

[0658] Preparation of intermediate compound 79

[0659] To a solution of intermediate compound 78 (103 mg, 0.09 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) under nitrogen at 0° C. The reaction solution was stirred at room temperature for 2 hours. After concentration, the resulting residue was purified by HPLC to give intermediate compound 79 (48 mg, 45%).

[0660] 1 H-NMR (400MHz, CD3OD) δ7.29(d,J=1.4Hz,1H),7.26(d,J=1.4Hz,1H),6.59(d,J=0.6H z,1H),6.56(d,J=0.6Hz,1H),5.88–5.77(m,2H),5.75–5.69(m,2H),5.02(d,J=3.3Hz ,4H),4.64–4.50(m,6H),3.94(d,J=4.2Hz,2H),3.75(s,3H),3.42–3.32(m,4H),3.01 –2.93(m,2H),2.24–2.17(m,6H),1.97(p,J=7.8Hz,2H),1.34(dt,J=14.6,7.1Hz,6H). EI-MSm / z:[M+H] + 891.09.

[0661] Example 13: Preparation of Intermediate Compound 89

[0662]

[0663] Preparation of intermediate compound 80

[0664] To a solution of 4-piperidineethanol (5 g, 38.7 mmol) in dichloromethane (200 mL) was added triethylamine (8.1 mL, 58.05 mmol) and di-tert-butyl dicarbonate (9.78 mL, 42.57 mmol) under nitrogen. The reaction solution was stirred at room temperature for 3 hours, and then diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the obtained residue was purified by column chromatography to obtain intermediate compound 80 (7.25 g, 81.6%).

[0665] 1 H-NMR(CDCl3)δ:1.04-1.10(m,2H),1.48(s,9H),1.49-1.55(m,3H),1.60-1.66(m, 2H), 2.27 (s, 1H), 2.64 (t, J = 8.0Hz, 2H), 3.64 (t, J = 8.0Hz, 2H), 4.03-4.08 (m, 2H). EI-MSm / z:[M+Na] + 252.26.

[0666] Preparation of intermediate compound 81

[0667] Under nitrogen, oxalyl chloride (0.34 mL, 3.93 mmol) was slowly added to a solution of dimethyl sulfoxide (0.93 mL, 13.08 mmol) in dichloromethane (20 mL) at -78 ° C. After stirring for 30 minutes, intermediate compound 80 (1 g, 4.36 mmol) in dichloromethane (5 mL) was added to the reaction solution. The reaction solution was stirred at -50 ° C for 2 hours. Triethylamine (1.8 mL, 13.1 mmol) was added to the reaction solution. After warming to 0 ° C, stirring for 30 minutes, the reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the obtained residue was purified by column chromatography to obtain intermediate compound 81 (990 mg, 99%).

[0668] 1 H-NMR (300MHz, CDCl3), δ (ppm): 9.78 (br s, 1H), 4.08 (br d, 2H), 2.74 (br t,2H),2.39(d,2H),2.12-1.89(m,1H),1.79-1.64(m,2H),1.45(s,9H),1.26-1.10(m,2H). EI-MSm / z:[M+H] + 228.23.

[0669] Preparation of intermediate compound 82

[0670] Under nitrogen, to a solution of lithium chloride (17.2g, 40.65mmol) in acetonitrile (40mL) at room temperature, triethyl phosphonoacetate (7.33mL, 50.81mmol) was added. After stirring for 5 minutes, triethylamine (5.67mL, 40.65mmol) was added to the reaction solution at room temperature and kept for 10 minutes. Compound 81 (7.7g, 33.88mmol) in acetonitrile (60mL) was added to the reaction solution. After stirring at room temperature for 17 hours, the reaction solution was diluted with ethyl acetate (150mL) and washed with distilled water (150mL). The organic layer was dried over anhydrous magnesium sulfate. After filtering and concentrating under reduced pressure, the obtained residue was purified by column chromatography to obtain intermediate compound 82 (5.59g, 58.2%).

[0671] 1H-NMR (400MHz, CDCl3), δ (ppm): 6.96-6.88 (m, 1H), 5.85-5.811 (m, 1H), 4.08 (s, 2H), 3.73 (s, 3H), 2. 07-2.64(m,2H),2.17-2.13(m,2H),1.67(s,2H),1.59-1.55(m,1H),1.54(s,9H),1.18-1.11(m,2H). EI-MSm / z:[M+H] + 284.01.

[0672] Preparation of intermediate compound 83

[0673] Under nitrogen, diisobutylaluminum hydride (1.0 M cyclohexane solution, 19 mL, 19.00 mmol) was added to a solution of intermediate compound 82 (2.5 g, 8.82 mmol) in dichloromethane (30 mL) at -78 ° C. After stirring for 3 hours at -78 ° C, methanol (100 mL) was added to the reaction solution. The reaction solution was filtered through celite and washed with methanol. The filtrate was removed under reduced pressure and used without purification to give intermediate compound 83 (1.91 g, 84.8%).

[0674] 1 H-NMR (400MHz, CDCI3): δ = 5.70-5.65 (m, 2H), 4.18-4.01 (m, 4H), 2.69 (t, 2H, J = 12.6Hz), 2.02 (t, 2H, J = 5.6Hz), 1.72-1.62 (m, 3H), 1.47 (s, 9H), 1.1 1(qd,2H,J=12.2Hz,3.9Hz). EI-MSm / z:[M+H] + 256.06.

[0675] Preparation of intermediate compound 84

[0676] To a solution of intermediate compound 83 (1.91 g, 7.48 mmol) in dichloromethane (20 mL) was added triethylamine (1.6 mL, 11.2 mmol) and methanesulfonyl chloride (0.87 mL, 11.2 mmol) at 0 ° C. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was removed under reduced pressure and used without purification to obtain intermediate compound 84 (2.59 g, crude material).

[0677] Preparation of intermediate compound 85

[0678] To a solution of intermediate compound 5 (1 g, 4.62 mmol) in N, N-dimethylformamide (15 mL) was added potassium carbonate (766 mg, 5.54 mmol) and compound 84 (2.3 g, 6.94 mmol). After stirring at room temperature for 14 hours, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain intermediate compound 85 (1.18 g, 56.3%).

[0679] 1 H-NMR (400MHz, CDCI3): δ = 7.82-7.72, 5.83-5.69 (m, 2H), 4.80-4.71 (m, 2H), 4.04-4.03 (m, 2H), 2.65 (s, 2H), 2.05-1.93 (m, 1H), 1.07-1.04 (m, 2H). EI-MSm / z:[M+H] + 454.17.

[0680] Preparation of intermediate compound 86

[0681] To a solution of intermediate compound 85 (550 mg, 1.21 mmol) in n-butanol (5 mL) was added intermediate compound 9 (1.17 g, 2.42 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.06 mmol). After stirring at 0 ° C for 5 minutes, the reaction solution was heated to 120 ° C and stirred for 24 hours, and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The concentrated reaction product was purified by column chromatography to obtain intermediate compound 86 (157 mg, 15.6%). EI-MS m / z: [M + H] + 829.22.

[0682] Preparation of intermediate compound 87

[0683] To a solution of intermediate compound 86 (157 mg, 0.19 mmol) in methanol (3 mL) was added ammonia solution (28% to 30% ammonia, 0.5 mL, 4.74 mmol) and sodium bisulfite (Na2S2O4, 330 mg, 1.89 mmol). After stirring at room temperature for 1 hour, the reaction solution was filtered through celite and washed with methanol. After filtration, the filtrate was removed under reduced pressure and used without purification to give intermediate compound 87 (151 mg, crude material), which was used without further purification.

[0684] Preparation of intermediate compound 88

[0685] To a solution of intermediate compound 87 (151 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added compound 2 (40 mg, 0.21 mmol) at 0 ° C. The reaction solution was stirred for 30 minutes and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.04 mL, 0.24 mmol) and triethylamine (0.11 mL, 0.76 mmol) were added, and the reaction solution was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate compound 88 (100 mg, 54%). EI-MS m / z: [M+H] + 961.13.

[0686] Preparation of intermediate compound 89

[0687] To a solution of intermediate compound 88 (20 mg, 0.02 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL) under nitrogen at 0°C. The reaction solution was stirred at room temperature for 0.5 hours. After concentration, the resulting residue was purified by HPLC to give intermediate compound 89 (4.8 mg, 27%). EI-MS m / z: [M+H] + 861.30.

[0688] Example 14: Preparation of Intermediate Compound 95

[0689]

[0690] Preparation of intermediate compound 90

[0691] To a solution of 3-aminophenol (1 g, 9.16 mmol) in tetrahydrofuran (10 mL) was added di-tert-butyl dicarbonate (2.52 mL, 10.99 mmol). After stirring at room temperature for 16 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The reaction solution was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure and used without purification to give compound 90 (1.8 g, 93%).

[0692] 1 H-NMR (400MHz, CDCl3) δ9.24(s,1H),9.18(s,1H),6.88(m,2H),6.83(m,1H),6.35(m,1H),1.46(s,9H). EI-MSm / z:[M+H] + 209.10.

[0693] Preparation of intermediate compound 91

[0694] Under nitrogen, cesium carbonate (560 mg, 1.72 mmol) and intermediate compound 5 (551 mg, 1.57 mmol) were added to a solution of intermediate compound 90 (300 mg, 1.43 mmol) in N, N-dimethylformamide (5 mL) at 0 ° C. After stirring for 2 hours, the reaction solution was diluted with ethyl acetate (30 mL) and washed with distilled water (15 mL × 2) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was solidified by adding dichloromethane and diethyl ether, then filtered and dried to give intermediate compound 91 (474 mg, 69%), which was used without further purification.

[0695] 1 H-NMR(400MHz, CDCl3)δ9.29(s,1H),8.26(s,1H),8.06(s,1H),7.90(s,1H),7.75(s,1H),7.12(m,2H ),7.10(d,1H),6.56(m,1H),6.14(m,2H),4.87(d,J=3.6Hz,2H),4.57(d,J=3.2Hz,2H),1.46(s,9H). EI-MSm / z:[M+H] + 478.00.

[0696] Preparation of intermediate compound 92

[0697] To a solution of intermediate compound 9 (607 mg, 1.47 mmol) and intermediate compound 91 (470 mg, 0.98 mmol) in n-butanol (5 mL) was added diisopropylethylamine (0.68 mL, 3.93 mmol) at room temperature. After heating to 120 ° C. for 24 hours, the reaction solution was cooled to room temperature. The reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate compound 92 (100 mg, 12%), which was used without further purification. EI-MS m / z: [M + H] + 853.30.

[0698] Preparation of intermediate compound 93

[0699] To a solution of intermediate compound 92 (100 mg, 0.11 mmol) in methanol (5 mL) was added ammonia solution (28% to 30% ammonia, 0.209 mL) and sodium bisulfite (Na2S2O4, 204 mg, 1.172 mmol) under nitrogen. After stirring at room temperature for 1 hour, the reaction solution was diluted with methanol (50 mL) and then filtered. The filtrate was concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate compound 93 (100 mg, crude material), which was used without further purification. EI-MSm / z: [M+H] + 823.36.

[0700] Preparation of intermediate compound 94

[0701] Under nitrogen, to a solution of intermediate compound 93 (100 mg, 0.12 mmol, crude material) in N,N-dimethylformamide (2 mL) was added intermediate compound 2 (26 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) at 0 ° C. After stirring at room temperature for 1 hour. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (28 mg, 0.18 mmol) and triethylamine (0.05 mL, 0.36 mmol) were added to the reaction mixture. After stirring at room temperature for 13 hours, the reaction solution was concentrated under reduced pressure, solidified by dichloromethane and diethyl ether, then filtered and dried to give intermediate compound 94 (54 mg, 53%). EI-MSm / z: [M+H] + 984.84.

[0702] Preparation of intermediate compound 95

[0703] To a solution of intermediate compound 94 (50 mg, 0.061 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL) under nitrogen at 0°C. After stirring at room temperature for 40 minutes, the reaction solution was concentrated and purified by HPLC to give intermediate compound 95 (1.7 mg, 3%). EI-MS m / z: [M+H] + 884.37.

[0704] Example 15: Preparation of Intermediate Compound 104

[0705]

[0706] Preparation of intermediate compound 96

[0707] To a solution of methyl 3-nitrocinnamate (3.5 g, 16.89 mmol) in methanol (20 mL) and distilled water (5 mL) was added concentrated hydrochloric acid (0.25 mL) and iron powder (9 g, 161.15 mmol). After heating to reflux while stirring for 17 hours, the reaction solution was filtered through celite and concentrated under reduced pressure to give intermediate compound 96 (2.7 g, crude material) without purification.

[0708] 1 H-NMR (400MHz, DMSO-d6): δ7.48(d,J=15.8Hz,1H),7.06(t,J=7.8Hz,1H),6.85-6 .79(m,2H),6.65-6.61(m,1H),6.41(d,J=15.8Hz,1H),5.19(s,2H),3.71(s,3H).

[0709] Preparation of intermediate compound 97

[0710] To the solution of intermediate compound 96 (2.7g, 15.24mmol) dissolved in 1,4-dioxane (10mL), di-tert-butyl dicarbonate (3.85mL, 16.76mmol) and saturated sodium bicarbonate aqueous solution (3.2g, 38.09mmol) dissolved in water (50mL) were added. After stirring at room temperature for 21 hours, the reaction mixture was diluted with ethyl acetate (50mL) and washed with distilled water (50mL×2). The reaction solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain intermediate compound 97 (3g, 71%).

[0711] 1 H-NMR (CD3OD, 400MHz) δ7.65 (s, 1H), 7.62 (d, 1H, J = 16.1Hz), 7.43 (d, 1H, J = 7.6Hz), 7.28 ( t,1H,J=7.6Hz),7.20(d,1H,J=7.6Hz),6.47(d,1H,J=16.1Hz),3.76(s,3H),1.51(s,9H).

[0712] Preparation of intermediate compound 98

[0713] Under nitrogen, diisobutylaluminum hydride (1.0 M in cyclohexane, 19 mL, 18.75 mmol) was added to a solution of intermediate compound 97 (1.3 g, 4.69 mmol) in dichloromethane (20 mL) at -78 ° C. After stirring at -78 ° C for 3 hours, methanol (100 mL) was added to the reaction solution at room temperature. The reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 98 (815 mg, 70%). EI-MS m / z: [M + Na] + 272.05.

[0714] Preparation of intermediate compound 99

[0715] To a solution of intermediate compound 98 (800 mg, 3.21 mmol) in dichloromethane (16 mL) was added triethylamine (0.7 mL, 4.81 mmol) and methanesulfonyl chloride (0.3 mL, 3.53 mmol) at 0 ° C. After stirring at room temperature for 3 hours, the reaction solution was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 99 (1 g, 95%), which was used without further purification.

[0716] Preparation of intermediate compound 100

[0717] To a solution of intermediate compound 4 (762 mg, 3.52 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (663 mg, 4.8 mmol) and compound 99 (1.05 g, 3.2 mmol). After stirring at 50 ° C for 15 hours, the reaction solution was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 100 (815 mg, 57%), which was used without further purification. EI-MS m / z: [M + H] + 448.25.

[0718] Preparation of intermediate compound 101

[0719] To a solution of intermediate compound 100 (500 mg, 1.12 mmol) in n-butanol (6 mL) was added compound 9 (811 mg, 1.68 mmol) and N,N-diisopropylethylamine (0.8 mL, 4.47 mmol). After stirring at 0 ° C for 5 minutes, the reaction mixture was heated to 120 ° C and stirred for 23 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 101 (316 mg, 34%). EI-MSm / z: [M + H]+ 823.42.

[0720] Preparation of intermediate compound 102

[0721] To a solution of intermediate compound 101 (316 mg, 0.38 mmol) in methanol (6 mL) was added aqueous ammonia solution (28% to 30% ammonia, 0.7 mL, 9.6 mmol) and sodium bisulfite (Na2S2O4, 668 mg, 3.84 mmol). After stirring at room temperature for 1 hour, the precipitate was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure to give intermediate compound 102 (304 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] + 793.51.

[0722] Preparation of intermediate compound 103

[0723] To a solution of intermediate compound 102 (304 mg, 0.38 mmol) in N,N-dimethylformamide (2 mL) was added compound 2 (82 mg, 0.42 mmol) at 0 ° C. After stirring for 30 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.08 mL, 0.48 mmol) and triethylamine (0.21 mL, 1.54 mmol) were added to the reaction solution at room temperature and maintained for 15 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 103 (12 mg, 3%). EI-MSm / z: [M+H] + 954.47.

[0724] Preparation of intermediate compound 104

[0725] Under nitrogen, trifluoroacetic acid (0.4 mL) was added to a solution of intermediate compound 103 (12 mg, 0.001 mmol) in dichloromethane (1 mL) at 0°C. After stirring at room temperature for 0.5 hours, the reaction solution was concentrated. The resulting residue was purified by HPLC to give intermediate compound 104 (4.3 mg, 40%). EI-MS m / z: [M+H] + 855.46.

[0726] Example 16: Preparation of Intermediate Compound 110

[0727]

[0728] Preparation of intermediate compound 105

[0729] To a solution of tert-butyl propane-2-en-1-ylcarbamate (1.0 g, 6.44 mmol) in N,N-dimethylformamide (9 mL) and methanol (1 mL) was added trimethylsilyl azide (1.27 mL, 9.66 mmol) and copper (I) iodide (613 mg, 3.22 mmol). After stirring at 90 ° C for 18 hours, the reaction solution was diluted with ethyl acetate (200 mL) and washed with saturated aqueous ammonium chloride solution (50 mL × 2) and dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to obtain intermediate compound 105 (373 mg, 29%).

[0730] 1 H-NMR (400MHz, CDCl3) δ7.65 (s, 1H), 5.09 (s, 1H), 4.43 (d, J = 6.0Hz, 2H), 1.46 (s, 9H).

[0731] Preparation of intermediate compound 106

[0732] Under nitrogen, potassium carbonate (102 mg, 0.74 mmol) was added to a solution of intermediate compound 105 (122 mg, 0.62 mmol) and compound 5 (315 mg, 0.68 mmol) in N, N-dimethylformamide (55 mL) at room temperature. After stirring for 16 hours, the reaction solution was diluted with ethyl acetate (200 mL) and washed with distilled water (150 mL × 2) and brine (150 mL). The reaction solution was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the resulting residue was purified by column chromatography to obtain intermediate compound 106 (146 mg, 50%).

[0733] 1 H-NMR (400MHz, DMSO) δ8.27(s,1H),8.06(s,1H),7.86(d,J=8.3Hz,2H),7.78(s,1H),7.30(s,1H),6.17–6.07 (m,1H),5.97–5.93(m,1H),5.07(d,J=6.0Hz,2H),4.84(d,J=5.2Hz,2H),4.16(d,J=5.9Hz,2H),1.38(s,9H).

[0734] Preparation of intermediate compound 107

[0735] To a solution of intermediate compound 106 (265 mg, 0.57 mmol) and intermediate compound 9 (412 mg, 0.85 mmol) in n-butanol (3 mL) was added N,N-diisopropylethylamine (0.49 mL, 2.84 mmol) at room temperature. After heating to 100 ° C and stirring for 21 hours, the reaction solution was cooled to room temperature and diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 107 (352 mg, 73%). EI-MSm / z: [M + H] + 842.42.

[0736] Preparation of intermediate compound 108

[0737] To a solution of intermediate compound 107 (352 mg, 0.42 mmol) in methanol (10 mL) and distilled water (2 mL) was added ammonia solution (28% to 30% ammonia, 0.6 mL) and sodium bisulfite (Na2S2O4, 728 mg, 4.2 mmol) under nitrogen. After stirring at room temperature for 2 hours, the reaction solution was diluted with methanol (50 mL) and then filtered. The filtrate was concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate compound 108 (100 mg, 29%), which was used without further purification. EI-MSm / z: [M+H]+812.47.

[0738] Preparation of intermediate compound 109

[0739] To a solution of intermediate compound 108 (100 mg, 0.12 mmol) in N,N-dimethylformamide (3 mL) was added compound 2 (29 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) under nitrogen. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.03 mL, 0.17 mmol) and triethylamine (0.05 mL, 0.05 mmol) were added to the reaction solution at room temperature and kept for 16 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 109 (80 mg, 66%). EI-MSm / z: [M+H] + 973.54.

[0740] Preparation of intermediate compound 110

[0741] Under nitrogen, trifluoroacetic acid (1 mL) was added to a solution of intermediate compound 109 (80 mg, 0.08 mmol) in dichloromethane (3 mL) at -78°C. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 110 (25 mg, 35%).

[0742] 1 H-NMR (400MHz, DMSO) δ12.84(s,1H),8.19(s,2H),8.04–7.91(m,3H),7.65(s,2H),7.37(s,2H),7.30(s,2H),6.52(d,J=2.6Hz,2H),5.9 6–5.79(m,3H),4.95–4.87(m,6H),4.58–4.48(m,6H),4.10(q,J=5.7Hz,2H),3.70(s,3H),2.10(d,J=6.5Hz,6H),1.26(q,J=7.1Hz,6H). EI-MSm / z:[M+H] + 873.55.

[0743] Example 17: Preparation of Intermediate Compound 120

[0744]

[0745] Preparation of intermediate compound 111

[0746] To a solution of (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.2 g, 10.93 mmol) in dichloromethane (20 mL) was added dimethyl sulfoxide (5 mL), triethylamine (9.2 mL, 65.6 mmol) and sulfur trioxide pyridine complex (4.3 g, 27.33 mmol) at 0 ° C. After stirring at room temperature for 17 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL) and 0.1N hydrochloric acid solution (50 mL) and dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the product was purified by column chromatography to obtain intermediate compound 111 (1.65 g, 75%).

[0747] 1 H-NMR (400MHz, CDCl3) δ9.60–9.44(m,1H),4.13(d,J=61.6Hz,1H),3.62–3.40(m,2H),2.23–1.82(m,4H),1.46(d,J=19.7Hz,9H).

[0748] Preparation of intermediate compound 112

[0749] To a solution of lithium chloride (421 mg, 9.94 mmol) and trimethyl phosphonoacetate (2.2 g, 12.42 mmol) in acetonitrile (8 mL) was added triethylamine (1.4 mL, mmol) at 0 ° C. The reaction solution was stirred at room temperature for 10 minutes. Intermediate compound 111 (1.6 g, 8.28 mmol) in acetonitrile (12 mL) was added to the reaction solution. After stirring at room temperature for 17 hours, the reaction solution was diluted with diethyl ether (100 mL) and washed with saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the obtained residue was purified by column chromatography to obtain intermediate compound 112 (1.43 g, 67%).

[0750] 1 H-NMR (400MHz, CDCl3) δ6.14(t,J=10.0Hz,1H),5.74(d,J=11.4Hz,1H),5.32–5.22(m,1H),3.71(s,3H),3.59–3.34(m, 2H), 2.31 (d, J = 12.9Hz, 1H), 1.84 (ddt, J = 12.5, 8.4, 6.0Hz, 2H), 1.67 (dt, J = 13.2, 6.6Hz, 1H), 1.42 (d, J = 22.5Hz, 9H).

[0751] Preparation of intermediate compound 113

[0752] To a solution of intermediate compound 112 (700 mg, 2.74 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (219 mg, 5.48 mmol) in distilled water (10 mL) at 0 ° C. After stirring at room temperature for 17 hours, the reaction solution was diluted with ethyl acetate (200 mL) and washed with 1N hydrochloric acid solution (100 mL). The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give intermediate compound 113 (660 mg, 99%), which was used without further purification.

[0753] 1 H-NMR (400MHz, CDCl3) δ6.91(d,J=13.0Hz,1H),5.84(d,J=15.6Hz,1H),4.46(d,J =56.8Hz,1H),3.45(s,2H),2.10(s,1H),1.87(q,J=6.6Hz,5H),1.49–1.40(m,9H).

[0754] Preparation of intermediate compound 114

[0755] To a solution of intermediate compound 113 (660 mg, 2.74 mmol) in tetrahydrofuran (10 mL) was added isobutyl chloroformate (0.37 mL, 2.87 mmol) and triethylamine (0.46 mL, 3.28 mmol) at -78 ° C. After stirring at room temperature for 1 hour, methanol (5 mL) and sodium borohydride (310 mg, 8.21 mmol) were added to the reaction solution. The reaction solution was stirred at room temperature for 2 hours, diluted with ethyl acetate (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain intermediate compound 114 (494 mg, 79%).

[0756] 1 H-NMR (400MHz, CDCl3) δ5.66(s,1H),4.31(d,J=39.6Hz,1H),4.14(d,J=5.0Hz,2H),3.39(s,1 H), 2.01 (s, 1H), 1.94–1.76 (m, 3H), 1.71 (ddd, J = 11.0, 6.7, 3.1Hz, 4H), 1.45 (d, J = 6.8Hz, 9H).

[0757] Preparation of intermediate compound 115

[0758] To a solution of intermediate compound 114 (494 mg, 2.17 mmol) in dichloromethane (20 mL) was added N-methylmorpholine (0.48 mL, 4.34 mmol) and methanesulfonyl anhydride (416 mg, 2.39 mmol) at -78 ° C. After stirring at room temperature for 2 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate compound 115 (632 mg, 95%), which was used without further purification.

[0759] 1 H-NMR (400MHz, CDCl3) δ5.82(s,1H),5.67(s,1H),4.72(d,J=6.5Hz,2H),4.32(d,J=39.2Hz,1H),4.17 –4.09(m,1H),3.40(s,1H),3.02(s,3H),2.05(s,1H),1.84(p,J=6.4Hz,2H),1.58(s,2H),1.44(s,9H).

[0760] Preparation of intermediate compound 116

[0761] Under nitrogen, potassium carbonate (314 mg, 2.27 mmol) was added to a solution of intermediate compound 115 (632 mg, 2.07 mmol) and compound 5 (448 mg, 2.07 mmol) in N, N-dimethylformamide (15 mL) at room temperature. After stirring for 16 hours, the reaction solution was diluted with ethyl acetate (200 mL) and washed with distilled water (100 mL × 2) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 116 (563 mg, 63%).

[0762] 1 H-NMR (400MHz, DMSO) δ8.25(s,1H),8.04(d,J=1.9Hz,1H),7.89(s,1H),7.77(s,1H),5.92–5.82(m,1H),5.69–5.62(m, 1H), 4.83 (d, J = 5.9Hz, 2H), 4.21 (s, 1H), 3.29–3.19 (m, 2H), 1.77 (q, J = 6.7Hz, 2H), 1.65 (s, 1H), 1.33 (d, J = 27.7Hz, 9H).

[0763] Preparation of intermediate compound 117

[0764] To a solution of intermediate compound 116 (300 mg, 0.70 mmol) and intermediate compound 9 (511 mg, 0.98 mmol) in n-butanol (4 mL) was added N, N-diisopropylethylamine (0.61 mL, 3.52 mmol) at room temperature. After heating to 120 ° C and stirring for 20 hours, the reaction solution was cooled to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 117 (263 mg, 46%). EI-MSm / z: [M + H] + 801.41.

[0765] Preparation of intermediate compound 118

[0766] To a solution of intermediate compound 117 (263 mg, 0.32 mmol) in methanol (10 mL) and distilled water (2 mL) was added ammonia solution (28% to 30% ammonia, 0.5 mL) and sodium bisulfite (Na2S2O4, 572 mg, 3.28 mmol) under nitrogen. After stirring at room temperature for 2 hours, methanol (50 mL) was added to the reaction solution. The reaction mixture was filtered with diatomaceous earth and washed with methanol. The filtrate was concentrated and diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate compound 118 (223 mg, 88%) without purification. EI-MSm / z: [M+H] + 771.43.

[0767] Preparation of intermediate compound 119

[0768] To a solution of intermediate compound 118 (223 mg, 0.29 mmol) in N,N-dimethylformamide (2 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.07 mL, 0.43 mmol) and triethylamine (0.12 mL, 0.87 mmol) under nitrogen. After stirring at room temperature for 1 hour, intermediate compound 2 (47 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL) was added to the reaction solution. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 119 (99 mg, 36%). EI-MSm / z: [M+H] + 932.48.

[0769] Preparation of intermediate compound 120

[0770] Under nitrogen, trifluoroacetic acid (0.4 mL) was added to a solution of intermediate compound 119 (99 mg, 0.11 mmol) in dichloromethane (1.6 mL) at -78°C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 120 (56 mg, 64%).

[0771] Example 18: Preparation of Intermediate Compound 127

[0772]

[0773] Preparation of intermediate compound 121

[0774] To a solution of 5-nitroindole (1g, 6.13mmol) in methanol (15mL) was added palladium / charcoal (85mg). After stirring at room temperature for 3 hours under a hydrogen balloon, the reaction solution was passed through diatomaceous earth. The filtrate was concentrated under reduced pressure. The concentrated filtrate was dissolved in N,N-dimethylformamide (15mL) at room temperature, and then di-tert-butyl dicarbonate (1.3g, 6.13mmol) and diisopropylethylamine (0.79g, 6.13mmol) were added. After stirring at room temperature for 5 hours, the reaction mixture was diluted with ethyl acetate (50mL) and washed with saturated aqueous ammonium chloride solution (50mL×2) and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated under reduced pressure to give intermediate compound 121 (1.15g, 80%), which was used without further purification.

[0775] 1 H-NMR (400MHz, DMSO-d6) δ12.88(s,1H),9.25(s,1H),7.96(s,1H),7.87(s,1H),7.42(d,J=8.4Hz,1H),7.35(d,J=8.8Hz,1H),1.48(s,9H).

[0776] Preparation of intermediate compound 122

[0777] At room temperature, potassium carbonate (711 mg, 5.14 mmol) and trans-1,4-dibromo-2-butene (2.75 g, 12.86 mmol) were added to a solution of intermediate compound 121 (1 g, 4.28 mmol) in N, N-dimethylformamide (40 mL). Stirred at 60 ° C for 18 hours for 6 hours. The reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2) and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 122 (372 mg, 23%).

[0778] 1 H-NMR (400MHz, DMSO) δ9.21(s,1H),8.19(s,1H),7.85(s,1H),7.49(d,J=8.9Hz,1H),7.21(d,J=8.5Hz,1H),6.14(dd,J=1 5.1, 7.1Hz, 1H), 5.88 (q, J = 7.5Hz, 1H), 5.05 (d, J = 6.0Hz, 2H), 4.23 (d, J = 6.8Hz, 1H), 4.16 (d, J = 7.3Hz, 2H), 1.48 (s, 9H).

[0779] Preparation of intermediate compound 123

[0780] To a solution of intermediate compound 122 (369 mg, 1.0 mmol) in N, N-dimethylformamide (4 mL) was added 4-chloro-3-hydroxy-5-nitrobenzamide (182 mg, 0.84 mmol) and potassium carbonate (174 mg, 1.26 mmol) under nitrogen. After stirring at 50 ° C for 5 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 123 (312 mg, 74%).

[0781] 1 H-NMR (400MHz, DMSO-d6) δ9.23(s,1H),8.24(d,J=17.5Hz,2H),8.06(s,1H),7.87(d,J=13.6Hz,2H),7.78(s,1H),7.50(d,J=9.2Hz,1 H), 7.22 (d, J = 9.2Hz, 1H), 6.21 (dt, J = 15.8, 6.2Hz, 1H), 6.01–5.90 (m, 1H), 5.10 (d, J = 6.1Hz, 2H), 4.86 (d, J = 5.3Hz, 2H), 1.48 (s, 9H). EI-MSm / z:[M+H] + 502.31.

[0782] Preparation of intermediate compound 124

[0783] To a solution of intermediate compound 123 (310 mg, 0.62 mmol) and intermediate compound 9 (406 mg, 0.98 mmol) in n-butanol (6 mL) was added diisopropylethylamine (0.21 mL, 1.24 mmol) at room temperature. After heating to 120 ° C and stirring for 20 hours, the reaction solution was cooled to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. After dilution with dichloromethane and diethyl ether, the resulting solid was filtered. The solid was dried to obtain 124 (crude material), which was used without further purification. EI-MSm / z: [M+H] + 877.59.

[0784] Preparation of intermediate compound 125

[0785] To a solution of intermediate compound 124 (0.20 mmol, crude material) in methanol (7 mL) and distilled water (1 mL) was added ammonia solution (28% to 30% ammonia, 0.2 mL) and sodium bisulfite (Na2S2O4, 355 mg, 2.04 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with methanol (50 mL) and filtered. The filtrate was concentrated and diluted with acetonitrile (10 mL), and the resulting solid was filtered. The solid was dried to give intermediate compound 125 (crude material), which was used without further purification. EI-MSm / z: [M+H] + 847.58.

[0786] Preparation of intermediate compound 126

[0787] To a solution of intermediate compound 125 (0.20 mmol, crude material) in N,N-dimethylformamide (4 mL) was added intermediate compound 2 (47 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL) under nitrogen. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (47 mgmmol, 0.30 mmol) and triethylamine (0.72 mL, 0.61 mmol) were added to the reaction solution at room temperature and maintained for 16 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 126 (83 mg, 40%). EI-MSm / z: [M+H] + 1008.64.

[0788] Preparation of intermediate compound 127

[0789] Under nitrogen, trifluoroacetic acid (0.4 mL) was added to a solution of intermediate compound 126 (33 mg, 0.03 mmol) in dichloromethane (1.6 mL) at -78°C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 127 (11 mg, 27%).

[0790] 1H-NMR(400MHz,DMSO-d6)δ12.84(s,1H),8.25(s,1H),7.98(s,1H),7.93(s,1H),7. 68–7.60(m,3H),7.45(s,1H),7.37–7.28(m,3H),7.06(d,J=9.2Hz,1H),6.52(s,2H ),6.02(dt,J=14.1,6.5Hz,1H),5.79(s,2H),4.90(dd,J=20.3,7.7Hz,5H),4.52(d q,J=14.1,6.3Hz,5H),3.69(s,3H),2.10(d,J=10.6Hz,6H),1.25(q,J=7.9Hz,6H). EI-MS m / z:[M+H] + 908.54.

[0791] Example 19: Preparation of Intermediate Compound 133

[0792]

[0793] Preparation of intermediate compound 128

[0794] To a solution of tert-butyl carbazate (5 g, 37.83 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (60%, 3.8 g, 94.6 mmol) at 0 ° C. After stirring at 0 ° C for 0.5 hours, 1,3-dibromopropane (3.8 mL, 37.8 mmol) was added to the reaction solution at room temperature and maintained for 3 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with distilled water (150 mL × 2). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated. The resulting residue was purified by column chromatography to obtain intermediate compound 128 (3.9 g, 57%).

[0795] 1 H-NMR (400MHz, CDCl3) δ3.86 (s, 1H), 3.49–3.41 (m, 2H), 3.07–2.99 (m, 2H), 2.03 (p, J = 6.8Hz, 2H), 1.52–1.44 (m, 9H).

[0796] Preparation of intermediate compound 129

[0797] Under nitrogen, potassium carbonate (1.1 g, 8.58 mmol) was added to a solution of intermediate compound 128 (1.2 g, 6.86 mmol) and intermediate compound 5 (2.0 g, 5.72 mmol) in N,N-dimethylformamide (15 mL) at room temperature. After stirring for 18 hours, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with distilled water (100 mL × 2). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated. The resulting residue was purified by column chromatography to obtain intermediate compound 129 (2.0 g, 80%).

[0798] 1 H-NMR (400MHz, DMSO) δ8.28 (s, 1H), 8.05 (d, J = 2.1Hz, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 6.02–5.83 (m, 2H), 4.81 (d, J = 5.1Hz, 2H), 3.26 (d, J = 6.0Hz, 2H), 2.84 (t, J = 6.8Hz, 2H), 2.00 (t, J = 7.3Hz, 2H), 1.37 (s, 9H).

[0799] Preparation of intermediate compound 130

[0800] To a solution of intermediate compound 129 (2 g, 4.54 mmol) and intermediate compound 9 (4.7 g, 9.07 mmol) in n-butanol (35 mL) was added N,N-diisopropylethylamine (5.5 mL, 31.8 mmol) at room temperature and heated to 100 ° C. After stirring for 21 hours, the reaction mixture was cooled to room temperature and diluted with dichloromethane and diethyl ether. The obtained solid was filtered and washed with ether. The filtered solid was purified by column chromatography to obtain intermediate compound 130 (1.0 g, 28%). EI-MSm / z: [M+H] + 816.52.

[0801] Preparation of intermediate compound 131

[0802] To a solution of intermediate compound 130 (1.0 g, 1.29 mmol) in methanol (20 mL) and water (4 mL) was added ammonia solution (28% to 30% ammonia, 1.4 mL) and sodium bisulfite (Na2S2O4, 2.2 g, 12.87 mmol) under nitrogen. After stirring at room temperature for 2 hours, methanol (50 mL) was added to the reaction solution. The resulting solid was filtered. The filtrate was concentrated and diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated. The resulting residue was purified by column chromatography to obtain intermediate compound 131 (1.0 g, crude material). EI-MSm / z: [M+H]+ 786.58.

[0803] Preparation of intermediate compound 132

[0804] Under nitrogen, to a solution of intermediate compound 131 (1.0 g, 1.29 mmol) in N,N-dimethylformamide (6 mL) was added compound 2 (301 mg, 1.54 mmol) in N,N-dimethylformamide (3 mL) at room temperature. After stirring for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.34 mL, 1.93 mmol) and triethylamine (0.36 mL, 2.57 mmol) were added to the reaction mixture at room temperature and kept for 17 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 132 (545 mg, 44%). EI-MSm / z: [M+H] + 947.62.

[0805] Preparation of intermediate compound 133

[0806] A solution of intermediate compound 132 (63 mg, 0.07 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was added at -0 ° C under nitrogen. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain intermediate compound 133 (42 mg, 53%). EI-MS m / z: [M + H] + 847.55.

[0807] Example 20: Preparation of Intermediate Compound 139

[0808]

[0809] Preparation of intermediate compound 134

[0810] To a solution of intermediate compound 5 (300 mg, 0.86 mmol) in N,N-dimethylformamide (5 mL) was added sodium azide (84 mg, 1.29 mmol) at 0 ° C. After stirring at 0 ° C for 2 hours, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with distilled water (150 mL × 2). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and diluted with dichloromethane and hexane. The resulting solid was filtered and dried to give intermediate compound 134 (225 mg, 84%), which was used without further purification.

[0811] 1H-NMR (400MHz, DMSO) δ8.27(s,1H),8.07(d,J=1.7Hz,1H),7.90(s,1H),7.78(s,1H),6.11–5.94(m,2H),4.88(d,J=4.7Hz,2H),3.97(d,J=5.5Hz,2H).

[0812] Preparation of intermediate compound 135

[0813] To a solution of intermediate compound 134 (225 mg, 0.72 mmol) in ethanol (3 mL), dichloromethane (2 mL) and water (3 mL) was added tert-butyl prop-2-ynylcarbamate (145 mg, 0.94 mmol), copper (II) sulfate pentahydrate (36 mg, 0.14 mmol) and sodium L-ascorbate (57 mg, 0.29 mmol) at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane (100 mL) and methanol (10 mL) and washed with saturated aqueous ammonium chloride solution (50 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and then diluted with dichloromethane and hexane. The resulting solid was filtered and dried to give intermediate compound 135 (283 mg, 84%), which was used without further purification.

[0814] 1 H-NMR (400MHz, DMSO) δ8.27(s,1H),8.06(s,1H),7.86(d,J=8.3Hz,2H),7.78(s,1H),7.30(s,1H),6.17–6.07 (m,1H),5.97–5.93(m,1H),5.07(d,J=6.0Hz,2H),4.84(d,J=5.2Hz,2H),4.16(d,J=5.9Hz,2H),1.38(s,9H).

[0815] Preparation of intermediate compound 136

[0816] To a solution of intermediate compound 135 (243 mg, 0.52 mmol) and intermediate compound 9 (428 mg, 1.04 mmol) in n-butanol (3 mL) was added N, N-diisopropylethylamine (0.45 mL, 2.60 mmol) at room temperature. After heating to 100 ° C and stirring for 21 hours, the reaction solution was cooled to room temperature. The reaction solution was diluted with dichloromethane (100 mL) and methanol (20 mL) and washed with saturated aqueous ammonium chloride solution (50 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated. The resulting residue was purified by column chromatography to obtain intermediate compound 136 (241 mg, 55%). EI-MSm / z: [M + H]+ 842.54.

[0817] Preparation of intermediate compound 137

[0818] To a solution of intermediate compound 136 (241 mg, 0.29 mmol) in methanol (10 mL) and water (2 mL) was added ammonia solution (28% to 30% ammonia, 0.4 mL) under nitrogen, and sodium bisulfite (Na2S2O4, 498 mg, 2.86 mmol) was added to the reaction mixture. After stirring at room temperature for 2 hours, methanol (50 mL) was added to the reaction solution. The resulting solid was filtered. The filtrate was concentrated and diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give intermediate compound 137 (168 mg, crude material), which was used without further purification. EI-MSm / z: [M+H] + 812.54.

[0819] Preparation of intermediate compound 138

[0820] Under nitrogen, to a solution of intermediate compound 137 (168 mg, 0.21 mmol) in N,N-dimethylformamide (2 mL) at room temperature, compound 2 (48 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) was added to the reaction mixture. After stirring for 1 hour, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol) and triethylamine (0.09 mL, 0.62 mmol) were added to the reaction solution at room temperature and kept for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 138 (175 mg, 87%). EI-MSm / z: [M+H] + 973.60.

[0821] Preparation of intermediate compound 139

[0822] Under nitrogen, trifluoroacetic acid (0.5 mL) was added to a solution of intermediate compound 138 (72 mg, 0.07 mmol) in dichloromethane (2 mL) at -0°C. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 139 (51 mg, 56%). EI-MS m / z: [M+H] + 873.52.

[0823] Example 21: Preparation of Intermediate Compound 147

[0824]

[0825] Preparation of intermediate compound 140

[0826] To a solution of di-tert-butyl-iminodiacetate (684 mg, 3.15 mmol) in N,N-dimethylformamide (7 mL) was added cesium carbonate (1.12 mg, 3.43 mmol). After stirring at room temperature for 10 minutes, intermediate compound 5 (1 g, 2.86 mmol) was added to the reaction solution at room temperature and kept for 17 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 140 (1.05 g, 71%).

[0827] 1 H-NMR (400MHz, CDCl3) δ7.79(d,J=1.9Hz,1H),7.63(d,J=1.9Hz,1H),6.62(s,1H),5.95(dt,J=16.0, 5.2Hz, 1H), 5.81 (dt, J = 15.7, 5.6Hz, 1H), 4.74 (d, J = 5.4Hz, 2H), 4.24 (d, J = 5.1Hz, 2H), 1.48 (s, 18H).

[0828] Preparation of intermediate compound 141

[0829] To a solution of intermediate compound 140 (423 mg, 0.87 mmol) in methanol (4 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (105 mg, 2.61 mmol) in water (0.5 mL). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 141 (223 mg, 69%).

[0830] 1 H-NMR (400MHz, DMSO) δ8.24 (s, 1H), 8.04 (d, J = 2.2Hz, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7. 04(s,1H),5.95–5.72(m,2H),4.80(d,J=5.5Hz,2H),3.60(d,J=6.0Hz,2H),1.37(s,9H).

[0831] Preparation of intermediate compound 142

[0832] To a solution of intermediate compound 141 (650 mg, 1.68 mmol) and compound 9 (831 mg, 2.02 mmol) in n-butanol (8 mL) was added N,N-diisopropylethylamine (1.2 mL, 8.42 mmol) at -0 ° C. After stirring for 5 minutes, the reaction mixture was heated to 120 ° C and maintained for 20 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 142 (297 mg, 23%). EI-MS m / z: [M + H] + 761.45.

[0833] Preparation of intermediate compound 143

[0834] To a solution of intermediate compound 142 (294 mg, 0.39 mmol) in methanol (6 mL) was added ammonia solution (28% to 30% ammonia, 0.7 mL, 9.5 mmol) and sodium bisulfite (Na2S2O4, 672 mg, 3.86 mmol). After stirring at room temperature for 1 hour, the resulting solid was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure to give intermediate compound 143 (202 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] + 731.5.

[0835] Preparation of intermediate compound 144

[0836] To a solution of intermediate compound 143 (202 mg, 0.28 mmol) in N,N-dimethylformamide (1 mL) was added compound 149 (30 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL). After stirring at 0 ° C. for 30 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (43.7 mg, 0.28 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 144 (122 mg, 49%). EI-MSm / z: [M+H] + 892.5.

[0837] Preparation of intermediate compound 145

[0838] To a solution of intermediate compound 144 (50 mg, 0.05 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.2 mL) at -0°C. The reaction mixture was warmed to room temperature and stirred under nitrogen for 1 hour, then concentrated under reduced pressure to give intermediate compound 145 (63 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] +792.53.

[0839] Preparation of intermediate compound 146

[0840] To a solution of intermediate compound 145 (35.4 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (0.04 mL, 0.22 mmol), carbonyldiimidazole (22 mg, 0.13 mmol) and 1-(tert-butoxycarbonyl)piperazine (25 mg, 0.13 mmol). After stirring at room temperature for 20 hours, the reaction solution was concentrated under reduced pressure to give intermediate compound 146 (45 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] + 1004.59.

[0841] Preparation of intermediate compound 147

[0842] To a solution of intermediate compound 146 (45 mg, 0.04 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at -0°C. After stirring at room temperature under nitrogen for 1 hour, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give intermediate compound 147 (5.4 mg, 9.5%).

[0843] Example 22: Preparation of Intermediate Compound 151

[0844]

[0845] Preparation of intermediate compound 148

[0846] To a solution of 4-ethyl-2-methyl-oxazole-5-carboxylic acid (100 mg, 0.64 mmol, prepared according to the method described in Chinese Patent Publication No. CN 111471056A) in tetrahydrofuran (1 mL) was added oxalyl chloride (0.82 mL, 0.96 mmol) and N,N-dimethylformamide (0.1 mL) at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 148 (crude material), which was used without further purification.

[0847] Preparation of intermediate compound 149

[0848] To a solution of intermediate compound 148 (crude material) in acetone (1 mL) was added potassium thiocyanate (125 mg, 1.28 mmol) at 0°C. After stirring at room temperature for 30 minutes, hexane (10 mL) was added to the reaction solution. The resulting solid was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 149 (64 mg, 50%).

[0849] 1 H-NMR (400MHz, CDCl3), δ2.90 (q, J=7.6Hz, 2H), 2.54 (s, 3H), 2.72 (t, J=7.6Hz, 3H). EI-MSm / z:[M+H] + 197.21.

[0850] Preparation of intermediate compound 150

[0851] To a solution of intermediate compound 53 (112 mg, 0.14 mmol) in N,N-dimethylformamide (1.5 mL) was added compound 149 (30 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL). After stirring at 0 ° C. for 30 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (43.7 mg, 0.28 mmol) and triethylamine (0.06 mL, 0.42 mmol) were added to the reaction solution and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 150 (25 mg, 19%). EI-MSm / z: [M+H] + 959.24.

[0852] Preparation of intermediate compound 151

[0853] To a solution of intermediate compound 150 (25 mg, 0.03 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.2 mL) at -0°C. After stirring at room temperature for 2 hours, the reaction solution was concentrated. The resulting residue was purified by HPLC to give intermediate compound 151 (9.3 mg, 42%).

[0854] 1 H-NMR(400MHz,DMSO-d6)δ8.00–7.83(m,2H),7.65(s,1H),7.54(s,1H),7.36(s,1 H),7.31(s,1H),6.51(s,1H),5.91(d,J=15.0Hz,1H),5.76(d,J=14.3Hz,2H),4.8 9(s,3H),4.66(d,J=5.9Hz,1H),4.51(d,J=7.3Hz,2H),3.71(s,2H),2.82(q,J=7. 9Hz, 1H), 2.40 (s, 2H), 2.10 (s, 2H), 1.25 (t, J = 7.2Hz, 2H), 1.02 (t, J = 7.7Hz, 2H). EI-MS m / z: [M+H] + 859.27.

[0855] Example 23: Preparation of Intermediate Compound 155

[0856]

[0857] Preparation of intermediate compound 152

[0858] To a solution of 4-ethyl-2-methylthiazole-5-carboxylic acid (100 mg, 0.58 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (0.75 mL, 0.87 mmol) and N,N-dimethylformamide (0.1 mL) at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 152 (crude material), which was used without further purification.

[0859] Preparation of intermediate compound 153

[0860] To a solution of intermediate compound 152 (crude material) in acetone (1 mL) was added potassium thiocyanate (113 mg, 1.16 mmol) at 0°C. After stirring at room temperature for 30 minutes, hexane (10 mL) was added to the reaction mixture. The resulting solid was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 153 (21 mg, 16%). EI-MS m / z: [M+H] + 213.20.

[0861] Preparation of intermediate compound 154

[0862] To a solution of intermediate compound 53 (166 mg, 0.15 mmol) in N,N-dimethylformamide (1.5 mL) was added intermediate compound 153 (35 mg, 0.16 mmol) dissolved in N,N-dimethylformamide (1 mL) at 0 ° C. After stirring for 30 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (46 mg, 0.29 mmol) and triethylamine (0.06 mL, 0.44 mmol) were added to the reaction solution at room temperature and kept for 15 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 154 (30 mg, 21%). EI-MSm / z: [M+H] + 975.26.

[0863] Preparation of intermediate compound 155

[0864] To a solution of intermediate compound 154 (30 mg, 0.03 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.2 mL) at -0°C. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 155 (18 mg, 68%).

[0865] 1 H-NMR (400MHz, DMSO-d6) δ7.88(d,J=14.1Hz,1H),7.82(s,1H),7.56(d,J=8.4Hz,1H ),7.47(s,0H),7.30-7.21(m,2H),6.45(s,1H),5.77(dq,2H),4.81(d,J=17.4Hz,2H ),4.60(d,J=6.0Hz,1H),4.51(s,1H),4.44(d,J=7.7Hz,1H),3.64(s,2H),3.03(q,J =7.9Hz,2H),2.66(s,2H),2.02(s,2H),1.19(t,J=7.4Hz,2H),1.07(t,J=7.7Hz,2H). EI-MSm / z:[M+H] + 875.24.

[0866] Example 24: Preparation of Intermediate Compound 160

[0867]

[0868] Preparation of intermediate compound 156

[0869] To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (100 mg, 0.54 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (285 mg, 0.88 mmol) and trans-1,4-dibromo-2-butene (625 mg, 2.92 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 156 (592 mg, 94%), which was used without further purification.

[0870] Preparation of intermediate compound 157

[0871] To a solution of intermediate compound 156 (592 mg, 1.55 mmol) in methanol (10 mL) was added hydrazine monohydrate (0.2 mL, 4.64 mmol). After stirring at room temperature for 1 hour, dichloromethane and diethyl ether were added to the reaction solution. The resulting solid was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 157 (352 mg, 90%).

[0872] Preparation of intermediate compound 158

[0873] To a solution of intermediate compound 157 (350 mg, 1.39 mmol) in dichloromethane (20 mL) was added N, N'-diisopropylethylamine (1.2 mL, 6.93 mmol) and bis(pentafluorophenyl) carbonate (1.6 g, 4.16 mmol) at -0 ° C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. Dichloromethane and hexane were added to the reaction mixture. The resulting solid was filtered and dried to give intermediate compound 158 (310 mg, 24%), which was used without further purification.

[0874] Preparation of intermediate compound 159

[0875] To a solution of intermediate compound 158 (97 mg, 0.11 mmol) in N, N-dimethylformamide (2 mL) was added intermediate compound 75 (50 mg, 0.05 mmol) and N, N-diisopropylethylamine (0.05 mL, 0.26 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. Dichloromethane and hexane were added to the reaction mixture. The resulting solid was filtered and dried to give intermediate compound 159 (59 mg, crude material), which was used without further purification.

[0876] Preparation of intermediate compound 160

[0877] To a solution of intermediate compound 159 (59 mg, crude material) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) at -0°C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 160 (30 mg, 45%).

[0878] Example 25: Preparation of Intermediate Compound 164

[0879]

[0880] Preparation of intermediate compound 161

[0881] To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (100 mg, 0.54 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (285 mg, 0.88 mmol) and trans-1,4-dibromo-2-butene (625 mg, 2.92 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 161 (111 mg, 62%). EI-MSm / z: [M+H] + 304.11.

[0882] Preparation of intermediate compound 162

[0883] To a solution of intermediate compound 66 (50 mg, 0.07 mmol) in N, N-dimethylformamide (2 mL) was added cesium carbonate (34 mg, 0.1 mmol) and intermediate compound 161 (23 mg, 0.08 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane (20 mL) and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 162 (16 mg, 24%). EI-MSm / z: [M+H] + 946.27.

[0884] Preparation of intermediate compound 163

[0885] To a solution of intermediate compound 162 (67 mg, 0.07 mmol) in acetic acid (1 mL) was added zinc powder (46 mg). After stirring at room temperature for 2 hours, the reaction mixture was filtered through celite and then washed with methanol. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 163 (3.2 mg, 3.6%). EI-MS m / z: [M+H] + 916.03.

[0886] Preparation of intermediate compound 164

[0887] To a solution of intermediate compound 163 (43 mg, 0.05 mmol) in methanol (1.5 mL) was added lithium hydroxide monohydrate (24 mg, 0.14 mmol) dissolved in water (0.5 mL) at -50 ° C. After stirring at 0 ° C for 20 hours, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 164 (1 mg, 1.7%). EI-MS m / z: [M + H] + 902.00.

[0888] Example 26: Preparation of Intermediate Compound 166

[0889]

[0890] Preparation of intermediate compound 165

[0891] To a solution of intermediate compound 145 (40 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL) was added triethylamine (0.10 mL, 0.745 mmol) and N,N-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboximidamide (17 mg, 0.06 mmol). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 165 (37 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] + 1035.01.

[0892] Preparation of intermediate compound 166

[0893] To a solution of intermediate compound 165 (45 mg, 0.04 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) at -0°C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give intermediate compound 166 (23.8 mg, 46%). EI-MS m / z: [M+H] + 835.09.

[0894] Example 27: Preparation of Intermediate Compound 168

[0895]

[0896] Preparation of intermediate compound 167

[0897] To a solution of intermediate compound 67 (2.0 g, 2.07 mmol, intermediate compound 67 was prepared according to the method described in International Patent Publication No. WO 2022 / 155518A1) in N,N-dimethylformamide (20 mL) was added cesium carbonate (5.4 g, 16.54 mmol) and intermediate compound 50 (654 mg, 2.07 mmol) in N,N-dimethylformamide (5 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and chloroform (100 mL) and methanol (20 mL) were added and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography to give intermediate compound 167 (958 mg, 38%). EI-MS m / z: [M+H] + 1179.46.

[0898] Preparation of intermediate compound 168

[0899] To a solution of intermediate compound 167 (40 mg, 0.03 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) at -0°C. After stirring at room temperature under nitrogen for 1.5 hours, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give intermediate compound 168 (17 mg, 29%). EI-MS m / z: [M+H] + 979.29.

[0900] Example 28: Preparation of Intermediate Compound 175

[0901]

[0902] Preparation of intermediate compound 169

[0903] To a solution of 4-aminopyrazole (5.89 g, 70.8 mmol) in tetrahydrofuran (200 mL) was added triethylamine (15 mL, 106.13 mmol) and di-tert-butyl dicarbonate (48.8 mL, 212.26 mmol) under nitrogen. After stirring at room temperature for 20 hours, ethyl acetate (50 mL) was added to the reaction mixture and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 169 (5.9 g, 29%).

[0904] 1 H-NMR (400MHz, CDCl3) δ8.19 (s, 1H), 7.63 (s, 1H), 6.34 (s, 1H), 1.64 (d, J = 3.9Hz, 9H), 1.52 (s, 9H).

[0905] Preparation of intermediate compound 170

[0906] To a solution of intermediate compound 169 (1.1 g, 3.88 mmol) in acetonitrile (30 mL) was added potassium carbonate (590 mg, 4.27 mmol), 18-crown-6 (513 mg, 1.94 mmol) and methyl acrylate (367 mg, 4.27). After stirring at room temperature for 30 minutes, ethyl acetate (50 mL) was added to the reaction solution and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 170 (1.38 g, 96%).

[0907] 1 H-NMR (400MHz, CDCl3) δ7.77 (s, 1H), 7.27 (d, J = 3.1Hz, 1H), 3.92 (dt, J = 9.4, 5.8Hz, 2H), 3.71–3.65 (m, 3H), 2.68–2.59 (m, 2H), 1.65 (q, J = 2.4Hz, 9H), 1.54–1.48 (m, 9H). EI-MSm / z:[M+H] + 370.32.

[0908] Preparation of intermediate compound 171

[0909] To a solution of intermediate compound 170 (1.38 g, 3.73 mmol) in methanol (20 mL) was added potassium carbonate (770 mg, 5.6 mmol) at -0 ° C. After stirring at room temperature for 30 minutes, ethyl acetate (50 mL) was added to the reaction solution and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 171 (950 mg, 94%).

[0910] 1 H-NMR (400MHz, CDCl3) δ7.66 (s, 1H), 7.53 (s, 1H), 3.96–3.87 (m, 2H), 3.67 (s, 3H), 2.64 (p, J = 5.0Hz, 2H), 1.50 (s, 9H).

[0911] Preparation of intermediate compound 172

[0912] To a solution of intermediate compound 171 (167 mg, 0.62 mmol) in N,N-dimethylformamide (30 mL) was added cesium carbonate (303 mg, 0.93 mmol) and trans-1,4-dibromo-2-butene (397 mg, 1.86 mmol). After stirring at room temperature for 3 hours, ethyl acetate (50 mL) was added to the reaction solution and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 172 (177 mg, 71%). EI-MSm / z: [M+H] + 402.24.

[0913] Preparation of intermediate compound 173

[0914] To a solution of intermediate compound 66 (264 mg, 0.37 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (179 mg, 0.43 mmol) and compound 172 (177 mg, 0.44 mmol). After stirring at room temperature for 12 hours, ethyl acetate (50 mL) was added to the reaction solution and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 173 (133 mg, 34%). EI-MSm / z: [M + H] + 1045.34.

[0915] Preparation of intermediate compound 174

[0916] To a solution of intermediate compound 173 (150 mg, 0.14 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.25 mL) at -0° C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to give intermediate compound 174 (135 mg, crude material), which was used without further purification.

[0917] Preparation of intermediate compound 175

[0918] To a solution of intermediate compound 174 (135 mg, crude material) in methanol (1 mL) was added lithium hydroxide monohydrate (11.7 mg, 0.28 mmol) dissolved in water (1 mL) at -45 ° C. After stirring at -0 ° C for 2 hours, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain intermediate compound 175 (34 mg, 42%). EI-MS m / z: [M + H] + 902.

[0919] Example 29: Preparation of Intermediate Compound 178

[0920]

[0921] Preparation of intermediate compound 176

[0922] To a solution of intermediate compound 49 (300 mg, 1.64 mmol) in N, N-dimethylformamide (10 mL) was added cesium carbonate (693 mg, 2.13 mmol) and 1,4-dibromo-2-butene (1.04 g, 4.91 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (2 × 50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 176 (320 mg, 62%).

[0923] Preparation of intermediate compound 177

[0924] To a solution of intermediate compound 66 (400 mg, 0.42 mmol, intermediate compound 66 was prepared according to the method described in International Patent Publication No. WO2022 / 155518A1) in N,N-dimethylformamide (5 mL) was added cesium carbonate (548 mg, 1.68 mmol) and intermediate compound 176 (158 mg, 0.50 mmol) in N,N-dimethylformamide (2 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. Dichloromethane (50 mL) and methanol (10 mL) were added to the reaction mixture and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 177 (246 mg, 61%). EI-MSm / z: [M+H] + 956.52.

[0925] Preparation of intermediate compound 178

[0926] To a solution of intermediate compound 177 (246 mg, 0.26 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at -0°C. After stirring at room temperature under nitrogen for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 178 (92 mg, 30%). EI-MS m / z: [M+H] + 856.48.

[0927] Example 30: Preparation of Intermediate Compound 187

[0928]

[0929] Preparation of intermediate compound 179

[0930] To a solution of 3-bromopropanol (2.0 g, 14.39 mmol) in acetone (30 mL) was added potassium thiocyanate (1.8 g, 15.83 mmol) under nitrogen at -0°C. After stirring at room temperature for 17 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate Compound 179 (1.26 g, 65%).

[0931] 1 H-NMR (400MHz, CDCl3) δ3.65(q,J=5.6Hz,2H),3.01(dq,J=9.3,3.3Hz,2H),2.39–2.30(m,3H),2.04(t,J=5.8Hz,1H),1.83(q,J=6.0Hz,2H).

[0932] Preparation of intermediate compound 180

[0933] To a solution of intermediate compound 179 (1.26 g, 9.39 mmol) in dichloromethane (30 mL) was added imidazole (958 mg, 14.08 mmol) and triisopropylsilyl chloride (2.0 g, 10.33 mmol) at -0 ° C. After stirring at room temperature for 4 hours, the reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated aqueous ammonium chloride solution (70 mL) and distilled water (70 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 180 (2.7 g, 99%).

[0934] 1 H-NMR (400MHz, CDCl3) δ3.74 (q, J = 5.4Hz, 2H), 2.99 (q, J = 6.3Hz, 2H), 2.35–2.30 (m, 3H), 1.81 (q, J = 6.2Hz, 2H), 1.06 (s, 21H).

[0935] Preparation of intermediate compound 181

[0936] To a solution of intermediate compound 180 (2.7 g, 9.29 mmol) in methanol (30 mL) was added iodomethane (0.69 mL, 10.2 mmol) and potassium carbonate (4.1 g, 30.25 mmol) at -0 ° C. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with dichloromethane (100 mL) and washed with distilled water (70 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 181 (1.73 g, 65%).

[0937] 1 H-NMR (400MHz, CDCl3) δ3.86–3.73(m,2H),2.60(tt,J=7.0,2.5Hz,2H),2.11(q,J=2.3Hz,3H),1.82(q,J=6.2Hz,2H),1.15–1.02(m,21H).

[0938] Preparation of intermediate compound 182

[0939] To a solution of intermediate compound 181 (1.2 g, 4.57 mmol) in methanol (20 mL) was added iodobenzene diacetate (3.7 g, 11.43 mmol) and ammonium carbonate (1.3 g, 13.71 mmol) at -0°C. After stirring and refluxing for 2 hours, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give compound 182 (1.5 g, crude material).

[0940] 1 H-NMR (400MHz, CDCl3) δ3.84 (q, J = 5.4Hz, 2H), 3.28–3.21 (m, 2H), 3.03–2.97 (m, 3H), 2.11–2.03 (m, 2H), 1.06 (d, J = 4.4Hz, 21H).

[0941] Preparation of intermediate compound 183

[0942] To a solution of intermediate compound 182 (1.5 g, crude material) in dichloromethane (20 mL) was added pyridine (0.71 mL, 8.86 mmol) and ethyl chloroformate (0.51 mL, 5.31 mmol) at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane (100 mL) and washed with 0.5 N hydrochloric acid solution (70 mL) and distilled water (70 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 183 (1.47 g, 91%).

[0943] 1H-NMR (400MHz, CDCl3) δ4.15 (s, 2H), 3.83 (t, J = 5.2Hz, 2H), 3.51 (d, J = 10.0Hz ,2H),3.25(s,3H),2.10(s,2H),1.29(t,J=5.8Hz,3H),1.06(d,J=4.3Hz,21H).

[0944] Preparation of intermediate compound 184

[0945] To a solution of intermediate compound 183 (1.5 g, 4.02 mmol) in dichloromethane (30 mL) was added hydrochloric acid (4 M 1,4-dioxane solution, 12 mL) at 0 ° C. After stirring for 2.5 hours, the reaction mixture was concentrated. Ethyl acetate (100 mL) and distilled water (70 mL) were added to the reaction mixture. The obtained aqueous layer was concentrated. Dichloromethane (50 mL) and methanol (5 mL) were added to the reaction mixture. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate compound 184 (752 mg, 89%).

[0946] 1 H-NMR (400MHz, CDCl3) δ4.14(tt,J=8.5,4.5Hz,2H),3.81(t,J=5.4Hz,2H),3.67–3 .42(m,2H),3.31–3.25(m,3H),2.16(q,J=6.1Hz,2H),1.29(dt,J=8.7,4.8Hz,3H).

[0947] Preparation of intermediate compound 185

[0948] To a solution of intermediate compound 184 (50 mg, 0.24 mmol) in dichloromethane (3 mL) was added triethylamine (0.07 mL, 0.48 mmol) and methanesulfonyl anhydride (50 mg, 0.29 mmol) at -0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane (50 mL) and washed with distilled water (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give intermediate compound 185 (50 mg, 73%), which was used without further purification.

[0949] 1H-NMR (400MHz, CDCl3) δ4.41 (d, J=5.9Hz, 2H), 4.15 (dq, J=10.5, 3.7Hz, 2H), 3.51 (d, J=53.9H z, 2H), 3.30 (q, J = 2.4Hz, 3H), 3.06 (q, J = 2.4Hz, 3H), 2.40 (d, J = 8.7Hz, 2H), 1.35–1.25 (m, 3H).

[0950] Preparation of intermediate compound 186

[0951] To a solution of intermediate compound 66 (100 mg, 0.11 mmol, intermediate compound 66 was prepared according to the method described in International Patent Publication No. WO2022 / 155518A1) in N,N-dimethylformamide (2 mL) was added cesium carbonate (113 mg, 0.35 mmol) and intermediate compound 185 (36 mg, 0.13 mmol) dissolved in N,N-dimethylformamide (1 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. Dichloromethane (50 mL) and methanol (10 mL) were added to the reaction mixture and washed with distilled water (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 186 (48 mg, 50%). EI-MSm / z: [M+H] + 914.41.

[0952] Preparation of intermediate compound 187

[0953] To a solution of intermediate compound 186 (48 mg, 0.05 mmol) in ethanol (20 mL) was added sodium ethoxide (21% w / w ethanol, 0.24 mL, 0.64 mmol). After stirring and refluxing for 14 hours, the reaction mixture was concentrated. The resulting residue was purified by HPLC to give intermediate compound 187 (25 mg, 55%). EI-MS m / z: [M+H] + 842.39.

[0954] Example 31: Preparation of Intermediate Compound 197

[0955]

[0956] Preparation of intermediate compound 188

[0957] To a solution of intermediate compound 4 (400 mg, 1.85 mmol) in N, N-dimethylformamide (5 mL) was added cesium carbonate (782 mg, 2.40 mmol) and compound 185 (584 mg, 2.03 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous ammonium chloride solution (50 × 2 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 188 (600 mg, 80%).

[0958] 1 H-NMR (400MHz, CDCl3) δ7.85 (s, 1H), 7.73 (d, J = 4.3Hz, 1H), 4.38 (q, J = 6.0Hz, 2H), 4.13 (q, J = 6.5Hz, 2H) ,3.81–3.65(m,1H),3.54(d,J=14.8Hz,1H),3.37–3.25(m,3H),2.56–2.48(m,2H),1.29(q,J=6.6Hz,3H).

[0959] Preparation of intermediate compound 189

[0960] To a solution of intermediate compound 188 (600 mg, 1.47 mmol) in ethanol (10 mL) was added tert-butyl (E)-(4-aminobut-2-en-1-yl)carbamate (548 mg, 2.94 mmol) and triethylamine (0.62 mL, 4.41 mmol). After stirring at 120 ° C. for 20 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 189 (550 mg, 67%). EI-MS m / z: [M + H] + 558.31.

[0961] Preparation of intermediate compound 190

[0962] To a solution of intermediate compound 189 (550 mg, 0.99 mmol) in methanol (5 mL) and distilled water (1 mL) was added ammonia solution (28% to 30% ammonia, 1 mL) and sodium bisulfite (Na2S2O4, 1.7 g, 9.86 mmol) at -0°C. After stirring at room temperature for 1.5 hours, methanol (10 mL) was added to the reaction solution. The resulting solid was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. The reaction mixture was added and washed with distilled water (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 190 (339 mg, 65%), which was used without further purification. EI-MSm / z: [M+H]+ 528.39.

[0963] Preparation of intermediate compound 191

[0964] To a solution of intermediate compound 190 (339 mg, 0.64 mmol) in N,N-dimethylformamide (3 mL) was added intermediate compound 2 (150 mg, 0.77 mmol) at -0 ° C. After stirring at room temperature for 30 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (160 mg mmol, 0.84 mmol) and triethylamine (0.05 mL, 0.38 mmol) were added to the reaction solution at room temperature and maintained for 17 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 191 (390 mg, 88%). EI-MSm / z: [M+H] + 689.37.

[0965] Preparation of intermediate compound 192

[0966] To a solution of intermediate compound 191 (390 mg, 0.57 mmol) in dichloromethane (5 mL) and methanol (1 mL) was added hydrochloric acid (4 M 1,4-dioxane solution, 1.5 mL). After stirring for 2 hours, the reaction mixture was concentrated. Diethyl ether (20 mL) was added to the reaction mixture. The resulting solid was filtered and dried to give intermediate compound 192 (360 mg, 96%). EI-MS m / z: [M+H] + 589.38.

[0967] Preparation of intermediate compound 193

[0968] To a solution of intermediate compound 192 (360 mg, 0.54 mmol) in n-butanol (3 mL) was added compound 51 (170 mg, 0.38 mmol) and triethylamine (0.26 mL, 1.88 mmol) at -0 ° C. After stirring at 120 ° C for 24 hours, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 193 (127 mg, 34%). EI-MS m / z: [M + H] + 1004.40.

[0969] Preparation of intermediate compound 194

[0970] To a solution of intermediate compound 193 (127 mg, 0.13 mmol) in methanol (5 mL) and distilled water (1 mL) was added ammonia solution (28% to 30% ammonia, 0.2 mL) and sodium bisulfite (220 mg, 1.26 mmol) at -0 ° C. After stirring at room temperature for 2.5 hours, methanol (10 mL) was added to the reaction mixture. The resulting solid was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. Dichloromethane (60 mL) was added to the reaction mixture and washed with distilled water (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give intermediate compound 194 (74 mg, 60%), which was used without further purification. EI-MS m / z: [M + H] + 974.47.

[0971] Preparation of intermediate compound 195

[0972] To a solution of intermediate compound 194 (74 mg, 0.08 mmol) in N,N-dimethylformamide (1 mL) was added compound 2 (18 mg, 0.09 mmol) at -0 ° C. After stirring at room temperature for 15 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (19 mg mmol, 0.10 mmol) and triethylamine (0.05 mL, 0.38 mmol) were added to the reaction mixture at room temperature and kept for 15 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 195 (42 mg, 49%). EI-MSm / z: [M+H] + 1135.55.

[0973] Preparation of intermediate compound 196

[0974] To a solution of intermediate compound 195 (42 mg, 0.04 mmol) in ethanol (2 mL) was added sodium ethoxide (21% w / w ethanol, 0.14 mL, 0.37 mmol). After stirring at reflux for 7 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 196 (50 mg, crude material), which was used without further purification. EI-MS m / z: [M+H] + 1063.53.

[0975] Preparation of intermediate compound 197

[0976] To a solution of intermediate compound 196 (50 mg, crude material) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) under nitrogen at -0°C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 197 (23 mg, 49%).

[0977] 1 H-NMR (400MHz, DMSO) δ7.96 (d, J = 20.3Hz, 2H), 7.86 (d, J = 0.8Hz, 1H), 7.67 (dd, J = 14.8 ,1.2Hz,2H),7.41–7.36(m,2H),7.28(dd,J=7.1,1.4Hz,2H),6.53(s,2H),5.87–5.54( m,5H),4.95–4.85(m,4H),4.54(dq,J=20.2,6.5Hz,6H),4.47–4.41(m,2H),4.01(t,J= 6.1Hz, 3H), 2.12 (d, J = 7.1Hz, 6H), 2.00 (q, J = 7.1Hz, 2H), 1.27 (dt, J = 9.3, 7.1Hz, 6H). EI-MSm / z:[M+H] + 963.53.

[0978] Example 32: Preparation of Intermediate Compound 199

[0979]

[0980] Preparation of intermediate compound 198

[0981] To a solution of intermediate compound 64 (90 mg, 0.08 mmol) in N,N-dimethylformamide (10 mL) was added alendronic acid (80 mg, 0.32 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 91 mg, 0.24 mmol) and triethylamine (0.04 mL, 0.32 mmol) under nitrogen. After stirring at room temperature for 3 days, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 198 (32 mg, 31%). EI-MS m / z: [M+H] + 1262.42.

[0982] Preparation of intermediate compound 199

[0983] Under nitrogen, trifluoroacetic acid (1 mL) was added to a solution of intermediate compound 198 (32 mg, 0.02 mmol) in dichloromethane (3 mL) at 0°C. After stirring at room temperature for 0.5 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 199 (14 mg, 47%). EI-MS m / z: [M+H] + 1162.53.

[0984] Preparation Example 4: Preparation of Intermediate Compound 204

[0985]

[0986] Preparation of intermediate compound 204

[0987] Under nitrogen, to a solution of intermediate compound 203 (2.0 g, 2.74 mmol, compound 203 was prepared according to the method described in International Patent Publication No. WO 2018 / 182341 A1) in N,N-dimethylformamide (10 mL) was added bis(pentafluorophenyl) carbonate (881 mg, 2.23 mmol) and N,N-diisopropylethylamine (0.66 mL, 3.72 mmol) at 0 ° C. After stirring at room temperature for 17 hours, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 204 (1.38 g, 98%).

[0988] 1 H-NMR (400MHz, CDCl3) δ8.14(s,1H),7.52(d,J=8.8Hz,2H),7.10(d,J=8.4Hz,1H),5.41-5.30(m ,4H),4.25-4.18(m,1H),3.73(s,4H),3.59(s,3H),3.43(d,J=1.4Hz,3H),2.06(d,J=2.0Hz,9H). EI-MSm / z:[M+H] + 751.96.

[0989] Preparation Example 5: Preparation of Intermediate Compound 207

[0990]

[0991] Preparation of intermediate compound 206

[0992] Under nitrogen, to a solution of intermediate compound 205 (162 mg, 0.33 mmol, compound 205 was prepared according to the method described in International Patent Publication No. WO 2018 / 182341 A1) in N,N-dimethylformamide (3 mL) were added 2,5,8,11,14,17-hexaoxa nonadecan-19-amine (100 mg, 0.33 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 154 mg, 0.41 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.68 mmol) at 0°C. After stirring at room temperature for 2 hours, the reaction solution was diluted with ethyl acetate (50 mL) and then washed with saturated aqueous sodium bicarbonate solution (50 mL) and distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give Intermediate Compound 206 (185 mg, 72%). EI-MS m / z: [M+Na] + 784.18, [M+H] + 762.17.

[0993] Preparation of intermediate compound 207

[0994] Under nitrogen, bis(pentafluorophenyl) carbonate (115 mg, 0.29 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.36 mmol) were added to a solution of intermediate compound 206 (185 mg, 0.24 mmol) in dichloromethane (5 mL) at 0 ° C. After stirring at room temperature for 5 hours, the reaction solution was diluted with dichloromethane (15 mL) and washed with distilled water (15 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 207 (92 mg, 39%). EI-MSm / z: [M + H] + 972.13.

[0995] Example 33: Preparation of Compound 214

[0996]

[0997] Preparation of intermediate compound 208

[0998] Under nitrogen, to a solution of piperidine-4-tert-butylcarbamate (1.2 g, 5.99 mmol) in N,N-dimethylformamide (15 mL) at room temperature was added compound 5 (2.2 g, 6.59 mmol) and then cesium carbonate (2.14 g, 6.59 mmol). After stirring for 16 hours, distilled water (100 mL) was added to the reaction solution and extracted with ethyl acetate (200 mL × 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 208 (1.92 g, 70%).

[0999] 1 H-NMR (400MHz, CDCl3) δ7.69 (s, 2H), 4.43 (m, 1H), 4.22 (t, J = 6.4Hz, 2H), 3.46 (m, 1H), 2.85-2 .82(m,2H),2.53(t,J=7.2Hz,2H),2.12-2.01(m,4H),1.94-1.91(m,2H),1.44-1.42(m,10H). EI-MSm / z:[M+H] + 457.52.

[1000] Preparation of intermediate compound 209

[1001] To a solution of intermediate compound 208 (1.30 g, 2.85 mmol) and compound 9 (2.75 g, 5.69 mmol) in n-butanol (30 mL) was added N,N-diisopropylethylamine (2.48 mL, 14.22 mmol). After stirring at 120 ° C for 48 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The reaction mixture was diluted with acetonitrile and diethyl ether to precipitate a solid, and then filtered. The solid was dried to give intermediate compound 209 (2.48 g, 84%), which was used without further purification. EI-MS m / z: [M + H] + 832.09, [M / 2+H] + 416.82.

[1002] Preparation of intermediate compound 210

[1003] To a solution of intermediate compound 209 (2.48 g, 2.39 mmol) in methanol (50 mL) was added sodium bisulfite (Na2S2O4, 4.17 g, 23.95 mmol) and ammonia solution (28% to 30% ammonia, 4.6 mL, 59.9 mmol) in distilled water (30 mL). After stirring at room temperature for 2.5 hours, the precipitate was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography to give intermediate compound 210 (1.4 g, 73%). EI-MS m / z: [M+H] + 802.25.

[1004] Preparation of intermediate compound 211

[1005] To a solution of intermediate compound 210 (760 mg, 0.95 mmol) in N,N-dimethylformamide (15 mL) was added compound 2 (241 mg, 1.23 mmol) in N,N-dimethylformamide (5 mL). After stirring for 30 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (221 mg, 1.42 mmol) and triethylamine (0.26 mL, 1.89 mmol) were added to the reaction solution at room temperature and maintained for 15 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 211 (730 mg, 79%). EI-MSm / z: [M+H] + 963.04, [M / 2+H] + 482.36.

[1006] Preparation of intermediate compound 212

[1007] Under nitrogen, trifluoroacetic acid (0.4 mL) was added to a solution of intermediate compound 211 (730 mg, 0.76 mmol) in dichloromethane (8 mL) at 0°C. After stirring at room temperature for 0.5 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 212 (830 mg, 90%).

[1008] 1H-NMR (400MHz, DMSO-d6) δ12.85 (s, 1H), 8.00 (s, 2H), 7.66 (d, J = 7.2Hz, 2H), 7.38 ( s,2H),7.30(s,2H),6.52(d,J=5.2Hz,2H),5.75(d,J=20.8Hz,2H),4.90(s,4H),4.5 3(d,J=7.8Hz,4H),4.01(s,2H),3.69(s,3H),3.06(s,3H),2.92(d,J=12.5Hz,2H), 2.12 (s, 6H), 2.06 (d, J = 13.4Hz, 2H), 1.68 (d, J = 13.8Hz, 2H), 1.28 (t, J = 7.1Hz, 6H). EI-MSm / z:[M+H] + 863.07, [M / 2+H] + 432.34.

[1009] Preparation of intermediate compound 213

[1010] To a solution of intermediate compound 212 (68 mg, 0.05 mmol) in N,N-dimethylformamide (3 mL) was added compound 11 (38 mg, 0.05 mmol) and N,N'-diisopropylethylamine (0.045 mL, 0.25 mmol). After stirring at room temperature for 15 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 213 (60 mg, 89%). EI-MS m / z: [M+Na] + 1453.26, [M+H] + 1431.27, [M / 2+H] + 716.55.

[1011] Preparation of intermediate compound 214

[1012] Under nitrogen, to a solution of intermediate compound 213 (60 mg, 0.042 mmol) in methanol (1.5 mL) was added lithium hydroxide monohydrate (7.04 mg, 0.17 mmol) in distilled water (1.5 mL) at -50°C. After stirring at 0°C for 3 hours, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain intermediate compound 214 (32 mg, 59%).

[1013] Example 34: Preparation of Compound 221

[1014]

[1015] Preparation of intermediate compound 215

[1016] A solution of tert-butyl 3-oxopiperazine-1-carboxylate (569mg, 2.84mmol) was dissolved in tetrahydrofuran (12mL), and potassium hydroxide (159mg, 2.84mmol) and TBAB (tetrabutylammonium bromide, 152mg, 0.47mmol) were added and stirred at room temperature for 30 minutes. Intermediate compound 5 (800mg, 2.37mmol) in tetrahydrofuran (4mL) was added to the reaction mixture at room temperature and kept for 2 hours. The reaction mixture was diluted with ethyl acetate (50mL) and washed with saturated aqueous ammonium chloride solution (50 × 2mL) and dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain intermediate compound 215 (760mg, 70.2%).

[1017] 1 H-NMR (400MHz, DMSO-d6) δ8.27(s,1H),8.05(d,J=1.7Hz,1H),7.84(d,J=1.9Hz,1H),7.77(s,1H),4.24(t,J=6.0Hz,2H) ,3.86(s,2H),3.53(dt,J=13.4,5.8Hz,4H),3.37(t,J=5.4Hz,2H),2.02(td,J=11.2,4.8Hz,2H),1.41(d,J=3.2Hz,9H). EI-MSm / z:[M+H] + 457.08.

[1018] Preparation of intermediate compound 216

[1019] To a solution of intermediate compound 215 (296 mg, 0.45 mmol) was added intermediate compound 9 (440 mg, 0.91 mmol) and N,N-diisopropylethylamine (0.43 mL, 2.49 mmol) at room temperature. After stirring at 120 ° C for 24 hours, the reaction solution was cooled to room temperature and diluted with dichloromethane (100 mL), methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate compound 216 (crude material), which was used without further purification. EI-MSm / z: [M + H] + 832.05, [M / 2+H] + 366.77.

[1020] Preparation of intermediate compound 217

[1021] To a solution of intermediate compound 216 (crude material, 0.45mmol) in methanol (10mL) was added sodium bisulfite (Na2S2O4, 433mg, 2.48mmol) and ammonia solution (28% to 30% ammonia, 0.55mL). After stirring at room temperature for 3 hours, the precipitate was filtered with celite and washed with methanol. The filtrate was concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane (100mL) and methanol (20mL) and washed with distilled water (50mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 217 (229mg, 43%), which was used without further purification. EI-MSm / z: [M+H] + 802.11, [M / 2+H] + 365.25.

[1022] Preparation of intermediate compound 218

[1023] To a solution of intermediate compound 217 (229 mg, 0.28 mmol) in N,N-dimethylformamide (4 mL) was added intermediate compound 2 (83.6 mg, 0.42 mmol) in N,N-dimethylformamide (1 mL) at -0 ° C. After stirring for 30 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (88.6 mg, 0.57 mmol) and triethylamine (0.09 mL, 0.63 mmol) were added to the reaction solution at room temperature and maintained for 19 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 218 (110 mg, 40%). EI-MSm / z: [M+H] + 963.19, [M / 2+H] + 482.31.

[1024] Preparation of intermediate compound 219

[1025] To a solution of intermediate compound 218 (50 mg) in dichloromethane (1.4 mL) was added trifluoroacetic acid (0.6 mL) under nitrogen at 0° C. After stirring at room temperature for 40 minutes, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 219 (33 mg, 52%).

[1026] 1H-NMR(400MHz,DMSO-d6)δ12.81(s,1H),9.09(s,2H),7.97(d,J=19.3Hz,2H),7.64(s,2H),7 .36(d,J=13.6Hz,2H),7.31(s,1H),7.25(s,1H),6.55(s,1H),6.52(s,1H),5.86(d,J=15.9Hz ,1H),5.76(d,J=15.8Hz,1H),4.96(s,2H),4.88(d,J=4.9Hz,2H),4.53(t,J=7.9Hz,4H),3.95 (s,2H),3.71(s,3H),3.65(s,2H),2.12(d,J=5.9Hz,6H),1.75(s,2H),1.27(q,J=7.7Hz,6H). EI-MSm / z:[M+H] + 863.09, [M / 2+H] + 432.41.

[1027] Preparation of intermediate compound 220

[1028] To a solution of intermediate compound 219 (20 mg, 0.017 mmol) in N,N-dimethylformamide (2 mL) was added compound 11 (12.3 mg, 0.05 mmol) and N,N-diisopropylethylamine (0.014 mL, 0.083 mmol). After stirring at room temperature for 15 hours, the reaction solution was concentrated under reduced pressure and purified by column chromatography to give intermediate compound 220 (23 mg, 97%). EI-MS m / z: [M+Na] + 1453.19, [M+H] + 1431.19, [M / 2+H] + 716.48.

[1029] Preparation of Compound 221

[1030] Under nitrogen, to a solution of intermediate compound 220 (23 mg, 0.016 mmol) in methanol (1 mL) was added lithium hydroxide monohydrate (1.67 mg, 0.06 mmol) in distilled water (1 mL) at -50°C. After stirring at 0°C for 3 hours, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 221 (4.4 mg, 21%).

[1031] 1H-NMR (400MHz, DMSO-d6) δ12.80(s,1H),8.31(s,1H),7.95(d,J=13.8Hz,2H),7.82(s,1H),7.64(d,J=4.1Hz,2H),7.52(d,J=8 .5Hz,1H),7.37-7.21(m,5H),6.57(s,1H),6.50(s,1H),5.90-5.80(m,1H),5.76(d,J=15.6Hz,1H),5.15(d,J=6.8Hz,1H),5.08 (s,2H),4.96(s,2H),4.88(s,1H),4.51(dt,J=21.9,7.3Hz,4H),3.97(d,J=9.5Hz,1H),3.87(d,J=17.5Hz,4H),3.69(s,3H),3. 52(s,4H),3.46(d,J=3.7Hz,3H),3.28(s,2H),3.19(s,1H),2.11(d,J=15.9Hz,6H),1.68(s,2H),1.27(dt,J=21.1,7.0Hz,6H). EI-MS m / z:[M+H] + 1291.07, [M+H] + 646.39.

[1032] Example 35: Preparation of Compound 230

[1033]

[1034] Preparation of intermediate compound 222

[1035] To a solution of 3-aminobenzyl alcohol (800 mg, 6.49 mmol) in tetrahydrofuran (9.3 mL) was added di-tert-butyl dicarbonate (1.64 mL, 7.14 mmol). After stirring at room temperature for 24 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 222 (1.45 g, 99%).

[1036] 1 H-NMR (400MHz, CDCl3) δ7.44(s,1H),7.28(d,J=8.0Hz,1H),7.22(d,J=8.1Hz,1H),7.04(d,J=7.3Hz,1H),6.50(s,1H),4.66(s,2H),1.52(s,9H).

[1037] Preparation of intermediate compound 223

[1038] To a solution of intermediate compound 222 (700 mg, 3.13 mmol) in dichloromethane (5 mL) was added triethylamine (0.65 mL, 4.70 mmol) and methanesulfonyl chloride (0.29 mL, 3.76 mmol) at 0° C. After stirring at 0° C. for 3 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 223 (508 mg, 53%).

[1039] 1 H-NMR (400MHz, CDCl3) δ9.45 (s, 1H), 7.61 (s, 1H), 7.41 (d, J = 8.2Hz, 1H), 7.29 (d, J =16.0Hz,1H),7.03(d,J=7.5Hz,1H),5.19(s,2H),3.24-3.19(m,3H),1.48(s,9H).

[1040] Preparation of intermediate compound 224

[1041] To a solution of intermediate compound 4 (300 mg, 1.38 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (287 mg, 2.08 mmol) and compound 223 (500.9 mg, 1.66 mmol). After stirring at 50 ° C for 1 hour, the reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate compound 224 (487 mg, 83%), which was used without further purification.

[1042] 1 H-NMR (400MHz, DMSO-d6) δ9.44(s,1H),8.27(s,1H),8.07(d,J=1.7Hz,1H),7.98(d,J=1.8Hz,1H),7.78(s,1 H),7.62(s,1H),7.46-7.39(m,1H),7.30(t,J=7.8Hz,1H),7.09(d,J=7.5Hz,1H),5.33(s,2H),1.48(s,9H). EI-MSm / z:[M+H] + 422.13.

[1043] Preparation of intermediate compound 225

[1044] To a solution of intermediate compound 224 (350 mg, 0.83 mmol) and intermediate compound 9 (683 mg, 1.41 mmol) in n-butanol (6 mL) was added N, N-diisopropylethylamine (0.79 mL, 2.84 mmol) at room temperature. After heating to 120 ° C and stirring for 40 hours, the reaction solution was cooled to room temperature. The reaction mixture was diluted with dichloromethane (100 mL), methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After adding dichloromethane and diethyl ether, the residual solid was filtered. The residual solid was dried to obtain 225 (crude material), which was used without further purification. EI-MSm / z: [M+H] + 797.08.

[1045] Preparation of intermediate compound 226

[1046] After intermediate compound 225 (crude material, 0.83 mmol) was dissolved in methanol (14 mL) and distilled water (2 mL), aqueous ammonia solution (28% to 30%, 1.05 mL) and sodium bisulfite (Na2S2O4, 1.05 g, 6.02 mmol) were added under nitrogen. After stirring at room temperature for 1 hour, the reaction solution was diluted with methanol (50 mL) and then filtered. The filtrate was concentrated under reduced pressure. The reaction mixture was diluted with ethyl acetate (100 mL) and methanol (20 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate compound 226 (crude material), which was used without further purification. EI-MSm / z: [M+H] + 767.08.

[1047] Preparation of intermediate compound 227

[1048] To a solution of intermediate compound 226 (0.83 mmol, crude material) in N,N-dimethylformamide (5 mL) was added compound 2 (100 mg, 0.52 mmol) in N,N-dimethylformamide (1 mL) under nitrogen. After stirring at -0 ° C for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (114 mg, 0.65 mmol) and triethylamine (0.18 mL, 1.29 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 227 (128 mg, 32%). EI-MSm / z: [M+H] + 928.02.

[1049] Preparation of intermediate compound 228

[1050] Under nitrogen, trifluoroacetic acid (0.6 mL) was added to a solution of intermediate compound 227 (50 mg) in dichloromethane (2.4 mL) at 0° C. After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 228 (17 mg, 27%).

[1051] 1 H-NMR (400MHz, DMSO-d6) δ7.97 (s, 1H), 7.66 (d, J = 9.3Hz, 2H), 7.43 (s, 1H), 7.37 (s ,1H),7.28(s,1H),7.14(t,J=7.8Hz,1H),7.06(s,1H),6.93(s,1H),6.51(d,J=7.0H z,2H),5.85-5.74(m,1H),5.68-5.58(m,1H),5.07(s,2H),4.88(dd,J=18.8,5.6Hz ,4H),4.54-4.49(m,4H),3.64(s,3H),2.10(d,J=4.4Hz,6H),1.25(q,J=7.6Hz,6H). EI-MS m / z:[M+H] + 828.07.

[1052] Preparation of intermediate compound 229

[1053] To a solution of intermediate compound 228 (40 mg, 0.03 mmol) in N,N-dimethylformamide (2 mL) was added compound 11 (25 mg, 0.03 mmol), N,N-diisopropylethylamine (0.027 mL, 0.15 mmol) and HOAt (1-hydroxy-7-azabenzotriazole, 0.9 mg, 0.01 mmol). After stirring at room temperature for 19 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 229 (crude material), which was used without further purification. EI-MS m / z: [M+H] + 1395.83.

[1054] Preparation of Compound 230

[1055] Under nitrogen, to a solution of intermediate compound 229 (81 mg, 0.051 mmol) in methanol (0.7 mL) and tetrahydrofuran (0.7 mL) was added lithium hydroxide monohydrate (10.76 mg, 0.25 mmol) in distilled water (0.9 mL) at -45 ° C. After stirring at 0 ° C for 1 hour, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain compound 230 (3.9 mg, 8.9%).

[1056] 1 H-NMR (400MHz, DMSO-d6) δ12.81(s,3H),9.81(s,1H),8.29(s,1H),7.96(s,2H),7.88(s,1H),7.66(d,J=11.3Hz,2H),7.61(s,1H),7. 52(d,J=8.6Hz,1H),7.44(s,1H),7.34(t,J=9.1Hz,3H),7.25(d,J=8.6Hz,2H),7.08(t,J=7.9Hz,1H),6.83(d,J=7.6Hz,1H),6.49(d, J=16.8Hz,2H),5.82(d,J=14.8Hz,1H),5.61(d,J=15.2Hz,2H),5.15(d,J=6.8Hz,1H),5.08(d,J=21.2Hz,4H),4.88(dd,J=35.7,5.6H z, 4H), 4.49 (dq, J = 14.0, 7.2Hz, 4H), 3.96 (d, J = 9.5Hz, 1H), 3.62-3.28 (m, 15H), 2.09 (d, J = 9.3Hz, 6H), 1.24 (dt, J = 14.2, 7.0Hz, 6H). EI-MSm / z:[M+H] + 1445.20.

[1057] Example 36: Preparation of Compound 239

[1058]

[1059] Preparation of intermediate compound 231

[1060] To a solution of 4-aminophenylethanol (2 g, 14.96 mmol) in tetrahydrofuran (50 mL) was added di-tert-butyl dicarbonate (3.8 mL, 16.46 mmol) at 0 ° C. After stirring at room temperature for 6 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The reaction solution was concentrated under reduced pressure to give intermediate compound 231 (3 g, 85%), which was used without further purification.

[1061] 1 H-NMR (400MHz, CDCl3) δ7.30 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 3.83 (q, J = 6.4 Hz, 2H), 2.82 (t, J = 6.5 Hz, 2H), 1.52 (s, 9H).

[1062] Preparation of intermediate compound 232

[1063] To a solution of intermediate compound 231 (850 mg, 3.58 mmol) in dichloromethane (15 mL) was added triethylamine (0.75 mL, 5.37 mmol) and methanesulfonyl chloride (0.41 mL, 5.37 mmol) at 0 ° C. After stirring at room temperature for 2 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The reaction solution was concentrated under reduced pressure to give intermediate compound 232 (114 mg, crude material), which was used without further purification.

[1064] Preparation of intermediate compound 233

[1065] To a solution of intermediate compound 4 (703 mg, 3.25 mmol) in N,N-dimethylformamide (6 mL) was added potassium carbonate (673 mg, 4.88 mmol) and intermediate compound 232 (1.1 g, 3.57 mmol). After stirring at 50 ° C for 22 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (15 mL × 2) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The reaction solution was concentrated under reduced pressure to obtain intermediate compound 233 (1.06 g, 74%).

[1066] 1H-NMR (400MHz, DMSO-d6) δ9.21(s,1H),8.22(s,1H),7.97(d,J=1.7Hz,1H),7.82(d,J=1.8Hz,1H),7.71(s,1 H), 7.34 (d, J = 8.2Hz, 2H), 7.19 (d, J = 8.3Hz, 2H), 4.33 (t, J = 6.7Hz, 2H), 3.00 (t, J = 6.7Hz, 2H), 1.42 (s, 9H). EI-MSm / z:[M+H] + 436.13.

[1067] Preparation of intermediate compound 234

[1068] To a solution of intermediate compound 233 (530 mg, 1.22 mmol) and intermediate compound 9 (650 mg, 1.58 mmol) in n-butanol (6 mL) was added N,N-diisopropylethylamine (0.95 mL, 2.84 mmol) at room temperature. After stirring at 120 ° C for 21 hours, the reaction solution was diluted with dichloromethane (100 mL) and washed with distilled water (50 mL×2). The organic layer was dried over anhydrous magnesium sulfate and filtered. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 234 (657 mg, 67%). EI-MSm / z: [M+H] + 436.13.

[1069] Preparation of intermediate compound 235

[1070] To a solution of intermediate compound 234 (373 mg, 0.46 mmol) in methanol (5 mL) was added aqueous ammonia solution (28% to 30% ammonia, 0.82 mL) and sodium bisulfite (Na2S2O4, 800 mg, 46 mmol) under nitrogen. After stirring at room temperature for 30 minutes, methanol (50 mL) was added to the reaction solution. The resulting solid was filtered and washed with methanol. The filtrate was concentrated and diluted with dichloromethane (100 mL), methanol (20 mL), and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The reaction solution was concentrated under reduced pressure to obtain intermediate compound 235 (360 mg, crude material), which was used without further purification. EI-MSm / z: [M+H] + 781.21.

[1071] Preparation of intermediate compound 236

[1072] To a solution of intermediate compound 235 (360 mg, 0.46 mmol) in N,N-dimethylformamide (2 mL) was added compound 2 (98 mg, 0.51 mmol) in N,N-dimethylformamide (1 mL) under nitrogen. After stirring at room temperature for 30 minutes, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.18 mL, 1.01 mmol) and triethylamine (0.2 mL, 1.38 mmol) were added to the reaction mixture. After stirring at room temperature for 1.5 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 236 (137 mg, 32%). EI-MSm / z: [M+H] + 943.1.

[1073] Preparation of intermediate compound 237

[1074] To a solution of intermediate compound 236 (50 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL) under nitrogen at 0° C. After stirring at room temperature for 40 minutes, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford intermediate compound 237 (14 mg, 31%).

[1075] 1 H-NMR (400MHz, DMSO-d6) δ7.91(d,J=12.5Hz,1H),7.60(d,J=12.4Hz,1H),7.28(t,J=7.0H z,2H),7.14(d,J=8.0Hz,1H),7.05(d,J=7.9Hz,1H),6.48(d,J=14.1Hz,1H),5.72(d,J=9.4 Hz,2H),4.85(s,1H),4.65(s,1H),4.46(p,J=7.1Hz,2H),4.14(t,J=6.7Hz,1H),3.67(s,2H ), 2.79 (t, J = 6.7Hz, 1H), 2.46 (s, 2H), 2.05 (d, J = 8.9Hz, 3H), 1.21 (dt, J = 10.6, 7.4Hz, 3H). EI-MSm / z:[M+H] + 842.14.

[1076] Preparation of intermediate compound 238

[1077] To a solution of intermediate compound 237 (50 mg, 0.06 mmol) in N,N-dimethylformamide (1 mL) was added intermediate compound 11 (50 mg, 0.07 mmol), N,N'-diisopropylethylamine (0.05 mL, 0.3 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt, 1.6 mg, 0.012 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 238 (114 mg), which was used without further purification. EI-MS m / z: [M+H] + 1410.5.

[1078] Preparation of Compound 239

[1079] Under nitrogen, to a solution of intermediate compound 238 (114 mg, 0.08 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) was added lithium hydroxide monohydrate (20 mg, 0.48 mmol) in distilled water (0.75 mL) at -50°C. After stirring at 0°C for 2 hours, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 239 (29 mg, 24%).

[1080] 1 H-NMR (400MHz, DMSO-d6) δ9.63(s,1H),8.25(s,1H),7.92(s,2H),7.80(s,1H),7.60(d,J=11.1Hz,2H),7.46(d,J =8.5Hz,1H),7.34-7.24(m,5H),7.20(d,J=8.6Hz,1H),7.02(d,J=8.2Hz,2H),6.47(s,2H),5.10(d,J=6.7Hz,1H) ,5.04(s,2H),4.84(s,2H),4.72(s,2H),4.49-4.41(m,4H),4.10(s,2H),3.91(d,J=9.3Hz,1H),3.67(s,3H),3.2 3(s,2H),2.74(s,2H),2.04(d,J=11.7Hz,5H),1.86(s,1H),1.20(dt,J=12.8,7.0Hz,6H),0.81(d,J=11.8Hz,1H). EI-MSm / z:[M+H] + 1269.52.

[1081] Example 37: Preparation of Compound 252

[1082]

[1083] Preparation of intermediate compound 240

[1084] To a solution of diethyl malonate (2 g, 12.49 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% dispersion in mineral oil, 0.9 g, 24.93 mmol) at 0 ° C. After stirring at 0 ° C for 0.5 hours, 2-chloro-5-nitropyridine (2.08 g, 13.11 mmol) was added to the reaction solution at room temperature and kept for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 240 (3.3 g, 94%).

[1085] 1 H-NMR (400MHz, CDCl3) δ9.37(d,J=2.7Hz,1H),8.51(dt,J=8.7,2.4Hz,1H),7.77(d d,J=8.7,1.6Hz,1H),5.06(d,J=1.5Hz,1H),4.35-4.19(m,4H),1.33-1.25(m,6H). EI-MSm / z:[M+H] + 283.41.

[1086] Preparation of intermediate compound 241

[1087] To a solution of intermediate compound 240 (3.3 g, 11.69 mmol) in dimethyl sulfoxide (33 mL) was added sodium chloride (0.72 g, 12.27 mmol) in water (0.3 mL). After stirring at 120 ° C for 5 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 241 (1.27 g, 51%).

[1088] 1 H-NMR (400MHz, CDCl3) δ9.38 (d, J=2.7Hz, 1H), 8.46 (dd, J=8.4, 3.0Hz, 1H), 7.54 (dd, J= 8.5, 2.3Hz, 1H), 4.26-4.16 (m, 2H), 3.98 (d, J = 2.3Hz, 2H), 1.28 (td, J = 7.3, 2.3Hz, 3H). EI-MSm / z:[M+H] + 211.39.

[1089] Preparation of intermediate compound 243

[1090] To a solution of intermediate compound 241 (775 mg, 3.68 mmol) in methanol (15 mL) was added palladium / charcoal (10% wt. Pd / C, 77 mg). After stirring at room temperature for 3 hours under a hydrogen balloon, the reaction solution was filtered with diatomaceous earth. The filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 1,4-dioxane (12 mL) at room temperature, and then di-tert-butyl dicarbonate (885 mg, 4.06 mmol) was added. After stirring at 100 ° C for 17 hours, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain intermediate compound 243 (906 mg, 87%).

[1091] 1 H-NMR (400MHz, CDCl3) δ8.36 (d, J = 2.6Hz, 1H), 7.98-7.93 (m, 1H), 7.29-7.19 (m, 1H), 4.17 (qd ,J=7.2,2.0Hz,2H),3.78(d,J=2.0Hz,2H),1.52(d,J=2.3Hz,9H),1.25(td,J=7.2,2.1Hz,3H). EI-MSm / z:[M+H] + 281.30.

[1092] Preparation of intermediate compound 244

[1093] To a solution of intermediate compound 243 (906 mg, 3.23 mmol) in tetrahydrofuran (10 mL) was slowly added lithium borohydride (1 M in tetrahydrofuran, 9.69 mL, 9.69 mmol) at 0 ° C. After stirring at room temperature for 4 hours, the reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (15 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 244 (294 mg, 38%).

[1094] 1 H-NMR (400MHz, CDCl3) δ8.65 (s, 1H), 8.16 (s, 1H), 7.43 (d, J = 8.6Hz, 1H), 6.59 ( s, 1H), 4.05 (q, J = 5.8Hz, 2H), 3.40 (t, J = 6.2Hz, 2H), 2.65 (bs, 1H), 1.53 (s, 9H). EI-MS m / z:[M+H] + 239.29.

[1095] Preparation of intermediate compound 245

[1096] Under nitrogen, triethylamine (0.22 mL, 1.60 mmol) and methanesulfonyl chloride (0.11 mL, 1.36 mmol) were added to a solution of intermediate compound 244 (294 mg, 1.23 mmol) in dichloromethane (6 mL) at 0°C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 245 (390 mg, 99%).

[1097] 1 H-NMR (400MHz, CDCl3) δ8.47(d,J=2.6Hz,1H),7.99(s,1H),7.20(d,J=8.5Hz,1H),6.8 3-6.76(m,1H),4.62(t,J=6.6Hz,2H),3.20(t,J=6.5Hz,2H),2.92(s,3H),1.53(s,9H). EI-MSm / z:[M+H] + 317.57.

[1098] Preparation of intermediate compound 246

[1099] To a solution of intermediate compound 4 (220 mg, 1.02 mmol) in N, N-dimethylformamide (3 mL) was added potassium carbonate (210 mg, 1.52 mmol) and compound 245 (385 mg, 1.22 mmol). After the reaction mixture was stirred at 50 ° C for 15 hours, the reaction temperature was raised to 80 ° C and stirred for 4 hours. The reaction solution was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 246 (270 mg, 60%).

[1100] 1 H-NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.54(s,1H),8.28(s,1H),8.02(s,1H),7.91(s,1H),7.81(d,J=8.5Hz ,1H),7.76(s,1H),7.30(d,J=8.5Hz,1H),4.55(t,J=6.7Hz,2H),3.20(t,J=6.6Hz,2H),1.47(d,J=1.8Hz,9H). EI-MSm / z:[M+H] + 437.26.

[1101] Preparation of intermediate compound 247

[1102] A solution of intermediate compound 246 (270 mg, 0.62 mmol) and intermediate compound 9 (508 mg, 1.05 mmol) was dissolved in n-butanol (5 mL) at room temperature, and N,N-diisopropylethylamine (0.59 mL, 3.40 mmol) was then added. After stirring at 120° C. for 18 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 247 (200 mg, 39%). EI-MS m / z: [M+H] + 812.48.

[1103] Preparation of intermediate compound 248

[1104] To a solution of intermediate compound 247 (213 mg, 0.26 mmol) in methanol (7 mL) and distilled water (1 mL) was added ammonia solution (28% to 30% ammonia, 0.25 mL) and sodium bisulfite (Na2S2O4, 456 mg, 2.62 mmol) at -0 ° C. After stirring at room temperature for 1 hour, methanol (50 mL) was added to the reaction solution. The resulting solid was filtered and washed with methanol. The filtrate was concentrated under reduced pressure and diluted with acetonitrile. The resulting solid was filtered to give intermediate compound 248 (crude material), which was used without further purification. EI-MSm / z: [M+H]+782.35.

[1105] Preparation of intermediate compound 249

[1106] To a solution of intermediate compound 248 (crude material, 0.26 mmol) in N,N-dimethylformamide (3 mL) was added compound 2 (58 mg, 0.30 mmol) in N,N-dimethylformamide (1 mL) at -0 ° C. After stirring at room temperature for 1 hour, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (58 mg, 0.37 mmol) and triethylamine (0.10 mL, 0.75 mmol) were added to the reaction solution. After stirring at room temperature for 20 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 249 (116 mg, 49%). EI-MSm / z: [M+H] + 943.49.

[1107] Preparation of intermediate compound 250

[1108] To a solution of intermediate compound 249 (50 mg) in dichloromethane (1.6 mL) was added trifluoroacetic acid (0.4 mL) under nitrogen at 0° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give intermediate compound 250 (25 mg, 36%).

[1109] 1 H-NMR (400MHz, DMSO-d6) δ7.94(s,2H),7.64(d,J=10.4Hz,2H),7.54(q,J=9.0Hz,2H),7.37(s,2H),7.32(d,J=16.5Hz,2H),6.48(d,J=26.9Hz,2H ),5.69(s,2H),4.86(s,2H),4.76(s,2H),4.48(p,J=7.0Hz,4H),4.38(t, J=6.5Hz, 2H), 3.70 (s, 3H), 2.09 (d, J=7.0Hz, 6H), 1.23 (q, J=6.4Hz, 6H). EI-MSm / z:[M+H] + 843.41.

[1110] Preparation of intermediate compound 251

[1111] To a solution of intermediate compound 250 (46 mg, 0.04 mmol) in N,N-dimethylformamide (2 mL) was added intermediate compound 11 (29 mg, 0.04 mmol), N,N-diisopropylethylamine (0.03 mL, 0.16 mmol) and HOAt (1-hydroxy-7-azabenzotriazole, 0.9 mg, 0.01 mmol). After stirring at room temperature for 21 hours, the reaction mixture was diluted with ethyl acetate (20 mL), washed with distilled water (8 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 251 (crude material), which was used without further purification. EI-MS m / z: [M+H]+1410.60.

[1112] Preparation of compound 252

[1113] Under nitrogen, to a solution of intermediate compound 251 (crude material, 0.04 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) was added lithium hydroxide monohydrate (7.45 mg, 0.18 mmol) in distilled water (0.3 mL) at -45 ° C. After stirring at 0 ° C for 1 hour, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain compound 252 (10.5 mg, 23.4%, 2 steps).

[1114] 1H-NMR (400MHz, DMSO) δ10.04(s,1H),8.60(s,1H),8.28(s,1H),7.95(s,1H),7.87(s,2H),7.63(d,J=3.7Hz, 2H),7.51(d,J=8.6Hz,1H),7.37-7.28(m,4H),7.28-7.20(m,2H),6.50(d,J=13.4Hz,2H),5.74(s,2H),5.14( d,J=11.1Hz,3H),4.87(s,2H),4.74(s,2H),4.49(d,J=7.6Hz,4H),4.36(s,2H),3.96(d,J=9.4Hz,2H),3.72- 3.46 (m, 13H), 3.38 (d, J = 6.3Hz, 3H), 3.27 (s, 3H), 3.02 (s, 2H), 2.08 (d, J = 5.2Hz, 6H), 1.23 (d, J = 6.5Hz, 6H). EI-MSm / z:[M+H] + 1270.66.

[1115] Example 38: Preparation of Intermediate Compound 254

[1116]

[1117] Preparation of intermediate compound 253

[1118] To a solution of intermediate compound 228 (70 mg, 0.06 mmol) in N,N-dimethylformamide (3 mL) was added compound 207 (45 mg, 0.05 mmol), N,N'-diisopropylethylamine (0.045 mL, 0.25 mmol) and HOAt (1-hydroxy-7-azabenzotriazole, 2.5 mg, 0.02 mmol). After stirring at room temperature for 15 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give intermediate compound 253 (74 mg, 98%). EI-MS m / z: [M+Na] + 1637.23, [M+H] + 1615.23, [M / 2+H] + 808.62.

[1119] Preparation of compound 254

[1120] Under nitrogen, to a solution of intermediate compound 253 (74 mg, 0.045 mmol) in methanol (1.5 mL) was added lithium hydroxide monohydrate (7.68 mg, 0.18 mmol) in distilled water (1.5 mL) at -50°C. After stirring at 0°C for 3 hours, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 254 (29 mg, 43%).

[1121] 1 H-NMR (400MHz, DMSO-d6) δ9.80(s,1H),8.28(d,J=5.8Hz,1H),7.95(s,2H),7.87(d,J=2.3Hz,1H),7.66(d,J=11.5Hz,2H),7.60(s,1H),7.55-7. 48(m,1H),7.44(s,1H),7.32(d,J=8.3Hz,3H),7.25(d,J=8.5Hz,2H),7. 08(t,J=7.8Hz,1H),6.83(d,J=7.6Hz,1H),6.48(d,J=16.9Hz,2H),5.81( d,J=15.3Hz,1H),5.65-5.56(m,1H),5.13(d,J=6.9Hz,1H),5.10(s,2H) ,5.05(s,2H),4.92(s,1H),4.83(d,J=5.6Hz,2H),4.49(dd,J=13.1,6.9 Hz, 4H), 3.96 (d, J = 9.5Hz, 1H), 3.61 (s, 2H), 3.51 (d, J = 22.0Hz, 20H), 3.22 (d, J = 1.5Hz, 3H), 2.08 (d, J = 9.3Hz, 6H), 1.23 (dt, J = 14.2, 7.1Hz, 6H). EI-MSm / z:[M+H] + 1476.67, [M / 2+H] + 739.23.

[1122] Example 39: Preparation of Intermediate Compound 262

[1123]

[1124] Preparation of intermediate compound 255

[1125] To a solution of 2-(2-(2-azidoethoxy)ethoxy)ethan-1-amine (2 g, 11.48 mmol) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate (3.16 mL, 13.78 mmol) and triethylamine (3.16 mL 13.78 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 1N aqueous hydrochloride solution (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 255 (3 g, crude material), which was used without further purification.

[1126] 1 H-NMR (400MHz, CDCl3) δ5.02 (br, 1H), 3.69-3.59 (m, 6H), 3.56 (t, J = 4.8Hz, 2H), 3.42 (t, J = 4.8Hz, 2H), 3.33 (d, J = 4.4Hz, 2H), 1.45 (s, 9H).

[1127] Preparation of intermediate compound 256

[1128] To a solution of intermediate compound 255 (1.9 g, 6.93 mmol) in methanol (20 mL) was added palladium / charcoal (10% wt. Pd / C, 190 mg). After stirring at room temperature for 3 hours under a hydrogen balloon, the reaction solution was passed through celite. The filtrate was concentrated under reduced pressure to give intermediate compound 256 (1.7 g, crude material), which was used without further purification.

[1129] 1 H-NMR (400MHz, CDCl3) δ5.19(br,1H),3.63-3.54(m,6H),3.32(s,2H),2.94(s,2H),2.60(s,2H),1.44(s,9H).

[1130] Preparation of intermediate compound 257

[1131] To a solution of intermediate compound 256 (452 mg, 1.82 mmol) in methanol (10 mL) and distilled water (1 mL) was added paraformaldehyde (175 mg, 3.65 mmol) and sodium cyanoborohydride (251 mg, 4.00 mmol) and zinc chloride (99 mg, 0.98 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with dichloromethane (20 mL) / methanol (2 mL) and washed with distilled water (10 mL), and dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain intermediate compound 257 (207 mg, 41%).

[1132] 1 H-NMR (400MHz, CDCl3) δ5.20 (br, 1H), 3.61-3.31 (m, 8H), 3.31 (d, J = 4.0Hz, 2H), 2.52 (t, J = 5.6Hz, 2H), 2.27 (s, 6H), 1.44 (s, 9H).

[1133] Preparation of intermediate compound 258

[1134] To a solution of intermediate compound 257 (207 mg, 0.75 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with dichloromethane / methanol (10 / 1, 20 mL × 2) and washed with 3N aqueous sodium hydroxide solution (5 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 258 (105 mg, 80%), which was used without further purification.

[1135] 1 H-NMR (400MHz, CDCl3)) δ3.62 (s, 4H), 3.58 (t, J = 4.4Hz, 2H), 2.86 (t, J = 4.0Hz, 2H), 2.52 (d, J = 4.0Hz, 2H), 1.67 (br, 2H).

[1136] Preparation of intermediate compound 259

[1137] To a solution of intermediate compound 258 (240 mg, 0.49 mmol) in N,N-dimethylformamide (10 mL) was added intermediate compound 205 (105 mg, 0.59 mmol), N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU, 244 mg, 0.64 mmol), N,N-diisopropylethylamine (0.19 mL, 0.99 mmol) at -0 ° C. After warming to room temperature and stirring under nitrogen for 3 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 259 (380 mg, crude material), which was used without further purification. EI-MSm / z: [M+H] + 643.41.

[1138] Preparation of intermediate compound 260

[1139] To a solution of intermediate compound 259 (490 mg, 0.76 mmol) in dichloromethane (10 mL) was added bis(pentafluorophenyl) carbonate (361 mg, 0.92 mmol) and N,N-diisopropylethylamine (0.4 mL, 0.29 mmol) at 0 ° C. After warming to room temperature and stirring under nitrogen for 5 hours. The reaction mixture was diluted with dichloromethane (15 mL) and washed with distilled water (15 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 260 (400 mg, crude material), which was used without further purification. EI-MSm / z: [M + H] + 853.39.

[1140] Preparation of intermediate compound 261

[1141] To a solution of intermediate compound 237 (60 mg, 0.05 mmol) in N,N-dimethylformamide (3 mL) was added compound 260 (52 mg, 0.06 mmol), N,N-diisopropylethylamine (0.04 mL, 0.26 mmol) and HOAt (1-hydroxy-7-azabenzotriazole, 1.4 mg, 0.01 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 261 (80 mg, crude material), which was used without further purification. EI-MS m / z: [M+1 / 2] + 756.82, [M+H] + 1511.96.

[1142] Preparation of Compound 262

[1143] Under nitrogen, to a solution of intermediate compound 261 (crude material, 80 mg, 0.053 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) was added lithium hydroxide monohydrate (22 mg, 0.53 mmol) in distilled water (1 mL) at -50 ° C. After stirring at 0 ° C. for 3 hours, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain compound 262 (12.2 mg, 17%). EI-MSm / z: [M / 2 + H] + 686.25.

[1144] Example 40: Preparation of Compound 270

[1145]

[1146] Preparation of intermediate compound 263

[1147] To a solution of 2-(2-(2-chloroethoxy)ethoxy)ethan-1-ol (10 g, 59.3 mmol) in N,N-dimethylformamide (30 mL) was added sodium azide (4.63 g, 71.2 mmol) at 0°C. After stirring at 100°C for 16 hours, the reaction mixture was diluted with chloroform (50 mL) and washed with distilled water (15 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give intermediate compound 263 (10.8 g, crude material), which was used without further purification.

[1148] 1 H-NMR (400MHz, CDCl3) δ3.74(t,J=5.0Hz,2H),3.71-3.65(m,6H),3.64–3.59(m,2H),3.40(t,J=5.0Hz,2H),2.34(t,J=6.2Hz,1H). EI-MSm / z:[M+Na] + 198.25.

[1149] Preparation of intermediate compound 264

[1150] To a solution of intermediate compound 263 (2 g, 12.49 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% dispersion in mineral oil, 501 mg, 20.9 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 minutes. Tert-butyldimethylsilyl chloride (2.3 mL, 12.6 mmol) was added to the reaction mixture and stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (20 mL × 3) and washed with brine (15 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 264 (3.05 g, 92%).

[1151] 1 H-NMR (400MHz, CDCl3) δ3.77 (t, J = 5.3 Hz, 2H), 3.72-3.62 (m, 6H), 3.57 (t, J = 5.4 Hz, 2H), 3.39 (t, J = 5.1 Hz, 2H), 0.90 (s, 9H), 0.07 (s, 6H). EI-MSm / z:[M+Na] + 312.36, [M+H] + 290.38.

[1152] Preparation of intermediate compound 265

[1153] To a solution of intermediate compound 264 (3.05 g, 10.5 mmol) in tetrahydrofuran (30 mL) was added triphenylphosphine (4.63 g, 71.2 mmol). After stirring at 100° C. for 16 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 265 (1.5 g, 54%), which was used without further purification.

[1154] 1 H-NMR (400MHz, CDCl3) δ3.77 (t, J = 5.5Hz, 2H), 3.68-3.65 (m, 2H), 3.64-3.61 (m, 2H), 3.56 (t, J=5.4Hz, 2H), 3.51 (t, J=5.2Hz, 2H), 2.86 (t, J=5.3Hz, 2H), 0.89 (s, 9H), 0.07 (s, 6H). EI-MSm / z:[M+H] + 264.38.

[1155] Preparation of intermediate compound 266

[1156] To a solution of intermediate compound 265 (2.20 g, 4.54 mmol) in N, N-dimethylformamide (12 mL) was added intermediate 205 (1.44 g, 5.45 mmol), N, N, N', N'-tetramethyl-O-(1H-benzotriazole-1-yl) uronium hexafluorophosphate (HBTU, 2.24 g, 5.90 mmol), N, N-diisopropylethylamine (1.6 mL, 9.08 mmol) at -0 ° C. After warming to room temperature and stirring under nitrogen for 3 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate aqueous solution (50 mL) and distilled water (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 266 (830 mg, crude material).

[1157] 1 H-NMR (400MHz, CDCl3) δ7.96(s,1H),7.46(d,J=8.5Hz,1H),7.36(d,J=6.0Hz,1H),7.04(d,J=8.4Hz,1H),5.43–5.22(m,4H),4.6 7(s,2H),4.20(d,J=9.3Hz,1H),3.77–3.72(m,6H),3.69–3.65(m,6H),3.55(t,J=5.5Hz,3H),2.05(s,9H),0.05(d,J=1.4Hz,6H). EI-MSm / z:[M+Na] + 752.41, [M+H] +730.44.

[1158] Preparation of intermediate compound 267

[1159] To a solution of intermediate compound 266 (830 mg, 1.14 mmol) in dichloromethane (5 mL) was added bis(pentafluorophenyl) carbonate (538 mg, 1.36 mmol) and N,N-diisopropylethylamine (0.59 mL, 3.41 mmol) at 0 ° C. After warming to room temperature and stirring under nitrogen for 3 hours. The reaction mixture was diluted with dichloromethane (15 mL) and washed with distilled water (15 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate compound 267 (270 mg, 25%).

[1160] 1 H-NMR (400MHz, CDCl3) δ8.11(d,J=2.6Hz,1H),7.51(d,J=8.4Hz,1H),7.37(s,1H),7.09(d,J=8.5Hz,1H),5.45-5.31(m,3H),5.30-5 .27(m,3H),4.22(d,J=9.1Hz,1H),3.80-3.64(m,13H),3.56(t,J=5.6Hz,3H),2.06(s,9H),0.91-0.86(m,9H),0.05(t,J=1.2Hz,6H). EI-MSm / z:[M+H] + 940.43.

[1161] Preparation of intermediate compound 268

[1162] To a solution of intermediate compound 267 (75.4 mg, 0.06 mmol) in N,N-dimethylformamide (2 mL) was added compound 237 (65.8 mg, 0.07 mmol), N,N-diisopropylethylamine (0.06 mL, 0.32 mmol) and HOAt (1-hydroxy-7-azabenzotriazole, 1.7 mg, 0.01 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 268, which was used without further purification. EI-MS m / z: [M / 2+H] + 799.81.

[1163] Preparation of intermediate compound 269

[1164] To a solution of intermediate compound 268 (101 mg, 0.06 mmol) in methanol (1 mL) was added lithium hydroxide monohydrate (13 mg, 0.32 mmol) in distilled water (0.75 mL) at -50°C under nitrogen. After stirring at 0°C for 2 hours, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction mixture was concentrated under reduced pressure to give intermediate compound 269 (crude material), which was used without further purification. EI-MS m / z: [M / 2+H] + 730.34.

[1165] Preparation of Compound 270

[1166] To a solution of intermediate compound 269 (0.06 mmol, crude material) in dichloromethane (2 mL) was added trifluoroacetic acid (0.6 mL) at 0°C under nitrogen. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to give compound 270 (53.8 mg, 54%; 2 steps). EI-MS m / z: [M+H] + 1344.70, [M / 2+H] + 673.21.

[1167] Example 41: Preparation of Compound 272

[1168]

[1169] Preparation of intermediate compound 271

[1170] To a solution of intermediate compound 55 (39 mg, 0.03 mmol) in N,N-dimethylformamide (2 mL) was added intermediate compound 204 (25 mg, 0.03 mmol), N,N'-diisopropylethylamine (0.03 mL, 0.16 mmol) and HOAt (1-hydroxy-7-azabenzotriazole, 0.4 mg, 0.003 mmol). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure to give intermediate compound 271 (crude material), which was used without further purification. EI-MS m / z: [M+H] + 1425.67.

[1171] Preparation of compound 272

[1172] Under nitrogen, to a solution of intermediate compound 271 (crude material, 0.03 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) was added lithium hydroxide monohydrate (13.5 mg, 0.3 mmol) in distilled water (0.7 mL) at -45 ° C. After stirring at 0 ° C for 1 hour, the reaction mixture was adjusted to pH 4 to 5 with acetic acid. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain compound 272 (14 mg).

[1173] 1 H-NMR (400MHz, DMSO-d6) δ9.51(s,1H),8.29(s,1H),7.95(d,J=15.5Hz,2H),7.83(s,1H),7.64(d,J= 6.9Hz,2H),7.48(d,J=8.6Hz,1H),7.36-7.28(m,4H),7.24(d,J=8.6Hz,1H),6.51(s,2H),5.91-5.88 (m,1H),5.79(s,2H),5.69-5.64(m,1H),5.14(d,J=6.7Hz,1H),5.05(s,2H),4.89(d,J=10.7Hz,3H), 4.54-4.49(m,6H),3.96(d...

Claims

1. A compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, in: T is the part that contains the stimulator of interferon genes (STING) agonist, p is 1 or 2, R 1 is independently CH2OR at each occurrence 11 or COOR 12 , R 1a 、R 1b 、R 1c and R 11 is independently at each occurrence H or a hydroxy protecting group, R 12 is independently at each occurrence H or a carboxyl protecting group, R 2 and R 3 Each occurrence is independently H or alkyl, or R 2 and R 3 Together with the carbon atom to which it is attached, it forms a cycloalkyl group, R 4 is independently selected at each occurrence from halogen, alkyl, CN and NO2, k is independently 0, 1, 2 or 3 at each occurrence, Y is independently selected at each occurrence from H, -C(O)NHL u U、-C(O)NR'(L u U)、-C(O)N(L u U)2 and -C(O)OH, L u is the first connector at each occurrence, U is independently selected at each occurrence from H, alkyl, amino, azido, ethynyl, alkylamino, heterocyclyl, alkoxy, -COOH, -P(O)(OH)2, -OH, -DBCO, and a saccharide, and R' at each occurrence is independently selected from alkyl, cycloalkyl, alkoxy, alkylthio, mono- or dialkylamino, heteroaryl, and aryl.

2. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (Ia):

3. The compound according to claim 1 or 2, wherein p is 1 and T is a moiety represented by one of the following structural formulas: in It is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

4. The compound according to claim 1 or 2, wherein T is a moiety represented by formula (IIc): in: T through W 1 、W 2 , A, B or L 2 coupled to -C(O)OCR of formula (I) 2 R 3 - fragment, M is N, C(X a R a ) or C(X b L 1 L 2 -), Q is for -X a R a or -X b L 1 L 2 -, W 1 and W 2 is independently selected at each occurrence from alkyl, amino, amide, carboxylic acid, ester and hydrazide, for example -C(O)NH-alkyl-N(alkyl)- or -C(O)NH-N(alkyl)-; n and m are each independently 0, 1, 2 or 3, Z is selected from alkylene, alkenylene and alkynylene, A and B are each independently aryl or heteroaryl, X a and X b are each independently selected from CH2, NH, O and S, R a is selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)carboxylic acid, -(alkylene)guanidino, -(alkylene)NHC(O)CH2guanidino, -(alkylene)O(alkylene)guanidino and -O(alkylene)guanidino, L 1 is selected from the group consisting of alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene and heteroarylene, L 2 is a bond, or coupled to L 1 and comprising a nitrogen atom coupled to a -C(O)O(CR 2 R 3 )-linker portion of the fragment.

5. The compound according to claim 4, wherein X a It's O.

6. The compound according to claim 4 or 5, wherein R a Selected from C 1-6 alkyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)carboxylic acid, and -(alkylene)guanidino.

7. The compound according to any one of claims 4 to 6, wherein L 2 Select from key, and *heterocyclylene**, and wherein * is L 1 and is the connection point with -C(O)O(CR 2 R 3 ) - the connection point of the fragment. The compound according to claim 3 , wherein T is represented by structural formula (IIa).

9. The compound according to claim 8, wherein the compound is 10. The compound according to claim 3, wherein T is represented by structural formula (IIb).

11. The compound according to claim 10, wherein the compound is 12. The compound according to any one of claims 4 to 6, wherein T is replaced by W 2 -C(O)OCR coupled to the compound represented by structural formula (I) 2 R 3 - fragment, and T is a moiety represented by formula (IIc1): in It is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

13. The compound according to any one of claims 4 to 6, wherein T is coupled to -C(O)O(CR 2 R 3 )-fragment, and T is a moiety represented by formula (IIc2): in It is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

14. The compound according to any one of claims 4 to 6, wherein T is replaced by L 2 -C(O)O(CR 2 R 3 )-fragment, and T is a moiety represented by formula (IIc3): in It is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

15. The compound according to any one of claims 4 to 6, wherein T is replaced by L 2 -C(O)O(CR 2 R 3 )-fragment, and T is a moiety represented by formula (IIc4): in It is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

16. The compound according to any one of claims 14 to 15, wherein L 2 Select from key, and *heterocyclylene**, and wherein * is L 1 and is the connection point with -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

17. The compound according to claim 14 or 15, wherein L 2 is a second connector comprising # OC(O)NR 5 -L 4 -NR 6 、 # OC(O)-L 4 -NR 6 or # OC(O)NR 5 -L 4 -(heterocyclylene), wherein: The heterocyclic group comprises a nitrogen atom and -C(O)O(CR 2 R 3 )-fragment connection, and where # is the same as L 1 The connection point, L 4 is independently at each occurrence alkylene or arylenealkyl, and R 5 is independently selected at each occurrence from H, alkyl and dialkylaminoalkyl, and R 6 is independently selected at each occurrence from H, alkyl, and dialkylaminoalkyl.

18. The compound according to claim 17, wherein L 2 Selected from Wherein ** indicates the -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

19. The compound according to claim 18, wherein L 2 Selected from 20. The compound according to claim 19, wherein L 2 yes 21. The compound of claim 1, wherein p is 1 and T is a moiety represented by formula (IIc5): in: T through L 2 -C(O)O(CR 2 R 3 ) fragment, W 1 and W 2 is independently selected at each occurrence from alkyl, amino, amide, carboxylic acid, ester and hydrazide, n and m are each independently 0, 1, 2 or 3, Z is selected from alkylene, alkenylene and alkynylene, A and B are each independently aryl or heteroaryl, X a and X b are each independently selected from CH2, NH, O and S, R a is selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)carboxylic acid, -(alkylene)guanidino, -(alkylene)NHC(O)CH2guanidino, -(alkylene)O(alkylene)guanidino and -O(alkylene)guanidino, L 1 is selected from the group consisting of alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene and heteroarylene, L 2 Is a bond, coupled to L 1 and comprising a nitrogen atom coupled to a -C(O)O(CR 2 R 3 )-the linker portion of the fragment, or the second linker, in It is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

22. The compound according to claim 21, wherein L 2 is a second connector comprising # OC(O)NR 5 -L 4 -NR 6 、 # OC(O)-L 4 -NR 6 or # OC(O)NR 5 -L 4 -(heterocyclylene), wherein: The heterocyclic group comprises a nitrogen atom and -C(O)O(CR 2 R 3 )-fragment connection, and where # is the same as L 1 The connection point, L 4 is independently at each occurrence alkylene or arylenealkyl, R 5 is independently selected at each occurrence from H, alkyl and dialkylaminoalkyl, and R 6 is independently selected at each occurrence from H, alkyl, and dialkylaminoalkyl.

23. The compound according to claim 1 or 2, wherein p is 2 and T is a moiety represented by one of the following structural formulas: Each of these It is -C(O)O(CR 2 R 3 )-fragment, or T is a moiety represented by structural formula (IIf), wherein T is independently connected by W 1 、W 2 , A, B or L 2 Two of the -C(O)OCR in formula (I) are coupled to each 2 R 3 - Snippet: in: M is N, C(X a R a ) or C(X b L 1 L 2 -), Q is for -X a R a or -X b L 1 L 2 -, W 1 and W 2 is independently selected at each occurrence from alkyl, amino, amide, carboxylic acid, ester and hydrazide, n and m are each independently 0, 1, 2 or 3, Z is selected from alkylene, alkenylene and alkynylene, A and B are each independently a 5-membered heteroaryl group, X a and X b are each independently selected from CH2, NH, O and S, R a is independently selected at each occurrence from H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)carboxylic acid, -(alkylene)guanidino, -(alkylene)NHC(O)CH2guanidino, -(alkylene)O(alkylene)guanidino, and -O(alkylene)guanidino, L 1 is independently selected at each occurrence from alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, and heteroarylene, L 2 independently selected at each occurrence from a bond, coupled to the corresponding L 1 and comprising a nitrogen atom coupled to the corresponding -C(O)O(CR 2 R 3 )-linker portion of the fragment, or the second linker.

24. The compound of claim 23, wherein T is a moiety of formula (IId).

25. The compound of claim 23, wherein T is a moiety of formula (IIe).

26. The compound of claim 25, wherein the compound is 27. The compound of claim 23, wherein T is a moiety of formula (IIf).

28. The compound according to claim 23, wherein T is replaced by W 1 and W 2 Coupled to each -C(O)O(CR 2 R 3 )-fragment, and T is a moiety represented by formula (IIf1): Each of these It is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

29. The compound of claim 23, wherein T is coupled to each -C(O)O(CR 2 R 3 )-fragment, and T is a moiety represented by formula (IIf2): Each of these It is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

30. The compound according to claim 23, wherein T is connected by two L 2 Coupled to each -C(O)O(CR 2 R 3 )-fragment, and T is a moiety represented by formula (IIf3): Each of these It is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

31. The compound of claim 30, wherein each L 2 Independently includes # OC(O)NR 5 -L 5 -NR 6 、 # OC(O)-L 4 -NR 6 or # OC(O)NR 5 -L 5 -(heterocyclylene) wherein the heterocyclylene comprises a nitrogen atom and a corresponding -C(O)O(CR 2 R 3 )-fragment connection, where # is the corresponding L 1 The connection point, Each L 5 are independently alkylene or aralkylene, and Each R 5 and each R 6 Each is independently selected from H, alkyl and dialkylaminoalkyl.

32. The compound of claim 1 or 2, wherein p is 1 and T is a moiety represented by formula (III): Where Q is the branch joint part, T a and T b each independently comprises a moiety that is a stimulator of interferon genes (STING) agonist, and It is -C(O)O(CR 2 R 3 ) - the connection point of the fragment.

33. The compound of claim 32, wherein T is a moiety represented by formula (IIIa): in: is -C(O)O(CR 2 R 3 ) - the connection point of the fragment, T a and T b are each independently a moiety represented by formula (IV): in: Ta and Tb are independently transferred through W 1 、W 2 , A, B or L 2 coupled to -C(O)OCR of formula (I) 2 R 3 - fragment, M is N, C(X a R a ) or C(X b L 1 L 2 -), Q is for -X a R a or -X b L 1 L 2 -, W 1 and W 2 is independently selected at each occurrence from alkyl, amino, amide, carboxylic acid, ester and hydrazide, for example -C(O)NH-(alkyl)-N(alkyl)-; n and m are each independently 0, 1, 2 or 3, Z is selected from alkylene, alkenylene and alkynylene, A and B are each independently aryl or heteroaryl, X a and X b are each independently selected from CH2, NH, O and S, R a is selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)carboxylic acid, -(alkylene)guanidino, -(alkylene)NHC(O)CH2guanidino, -(alkylene)O(alkylene)guanidino, and -O(alkylene)guanidino, L 1 is selected from the group consisting of alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, and heteroarylene, L 2 is a bond, or coupled to L 1 and comprising a nitrogen atom coupled to -C(O)O(CR 2 R 3 )-linker portion of the fragment, or the second linker.

34. The compound of any one of claims 4 to 7, 10 to 23, 27 to 31 and 33, wherein A and B are each independently a substituted or unsubstituted pyrazole, or a substituted or unsubstituted oxazole.

35. The compound of claim 34, wherein A and B are each independently a substituted pyrazole or a substituted oxazole, wherein the pyrazole and oxazole are each replaced by two C 1-3 Alkyl substitution.

36. The compound of any one of claims 1 to 35, wherein the first linker is independently selected at each occurrence from *(alkylene)O(alkylene)**, *(heteroalkylene)**, *(alkylene)**, *(heteroaralkylene)**, *(heteroalkylene)(heterocyclylene)**, *CH2CH2C(O)NHCH**, *(CH2CH2O) t -** and *(alkylene)(heteroarylene)(CH2CH2O) t **, wherein * indicates a connection point to the -C(O)NH- fragment of the compound represented by structural formula (I), ** indicates a connection point to U, and t represents an integer from 1 to 15.

37. The compound of claim 36, wherein the first linker is independently selected at each occurrence *(CH2CH2O) t CH2**、*(CH2CH2O)2CH2CH2N(CH3)CH2**、 *(CH2CH2O)2CH2CH2N(CH3)**、*(CH2CH2O) t **、*(CH2CH2O) t CH2CH2NH**、 *CH2CH2**、*(CH2CH2O) t CH2**、*(CH2CH2O) t CH2CH2 heterocyclylene**, *(CH2CH2O) t CH2**、*(CH2CH2O) t C H2CH2** and *(CH2CH2O) t NH**.

38. A compound according to claim 36 or claim 37, wherein t represents an integer from 1 to 6. The compound according to claim 38 , wherein t represents an integer from 1 to 3.

40. The compound of any one of claims 1 to 39, wherein U is H at each occurrence.

41. The compound of any one of claims 1 to 39, wherein U at each occurrence is independently selected from alkyl, amino, azido, ethynyl, alkylamino, heterocyclyl, alkoxy, -COOH, -P(O)(OH)2, -DBCO, and -OH.

42. The compound according to claim 41, wherein the heterocyclic group comprises at least one u The nitrogen at the point of attachment.

43. The compound of claim 1, wherein the compound is 44. The compound of any one of claims 1 to 39, wherein U at each occurrence is a saccharide.

45. The compound of claim 44, wherein the saccharide is a glucuronide.

46. The compound of claim 45, wherein the glucuronide is 47. The compound according to claim 46, wherein the compound is selected from 48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47 and a pharmaceutically acceptable excipient.

49. A method of preventing or treating a disease mediated by stimulator of interferon genes (STING) in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1 to 47 or a pharmaceutical composition according to claim 48.

50. The method of claim 49, wherein the disease mediated by STING is cancer.

51. The method of claim 50, wherein the cancer is selected from the group consisting of lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi sarcoma, and melanoma.

52. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1 to 47 or a pharmaceutical composition according to claim 48.

53. The method of claim 52, wherein the induction of the immune response is effective to prevent or treat a STING-mediated disease in the subject.

54. The method of claim 53, wherein the disease mediated by STING is cancer.

55. The method of claim 54, wherein the cancer is selected from the group consisting of lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.

56. A method of modulating the activity of a STING adaptor protein, comprising contacting the STING adaptor protein with a compound according to any one of claims 1 to 47.

57. The method of claim 56, wherein the compound increases the activity of the STING adaptor protein.

58. The method of any one of claims 49-51, further comprising administering to the subject one or more additional therapeutic agents.

59. The method of any one of claims 52-55, further comprising administering to the subject one or more additional therapeutic agents.

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