Five-membered fused six-membered compound, production method, pharmaceutical composition, and application

Abstract

The present invention discloses a 5-membered condensed 6-membered compound, a preparation method, a pharmaceutical composition, and an application. The 5-membered condensed 6-membered compound disclosed in the present invention is a compound represented by formula I, formula II, or formula III. The compound according to the present invention has an inhibitory effect on FLT3 and / or IRAK4. [Formula 1] TIFF2025501618000478.tif31170

Description

[Technical field]

[0001] [Incorporated by reference] This application claims priority to Chinese Application No. 2021115935774, filed on December 23, 2021. This application claims priority to Chinese Application No. 2022115806725, filed on December 6, 2022. This application incorporates by reference all of the contents of the above-mentioned Chinese patent applications. [Technical field] The present invention relates to a five-membered fused six-membered compound, a method for producing the same, a pharmaceutical composition, and applications. [Background technology]

[0002] FLT3 is a type III receptor tyrosine kinase, and its mutations are one of the most common genetic alterations and poor prognostic factors in patients with acute myeloid leukemia (AML). FLT3 mutations are mainly internal tandem duplication mutations in the juxtamembrane domain (FLT3-ITD) and point mutations or deletions in the tyrosine kinase domain (FLT3-TKD), which account for approximately 30% of AML patients (Kiyoi H, Kawashima N, Ishikawa Y. FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development. Cancer Sci. 2020 Feb; 111(2): 312-322). Activated FLT3 induces abnormalities in multiple intracellular signaling pathways (RAS, PI3K, STAT5, etc.), resulting in survival, proliferation, differentiation, and resistance to apoptosis of hematopoietic cells. In addition, the mutant-wild type allele ratio, insertion site, ITD length, karyotype, and the presence of NPM1 gene mutations may affect the prognostic effect of FLT3-ITD in newly diagnosed FLT3-ITD mutant AML patients (Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019 Feb;33(2):299-312. doi:10.1038 / s41375-018-0357-9.). Since high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot completely improve the prognosis, and patients have a short survival time and are prone to relapse, FLT3 kinase inhibitors have attracted attention in the treatment research of AML. First-generation FLT3 inhibitors such as lesuturtinib, sunitinib, sorafenib, ponatinib, and midostaurin are broad-spectrum inhibitors that can inhibit multiple kinases, but their efficacy is unfavorable, and when combined with chemotherapy, no clear effect is observed and toxicity increases significantly.For example, Midostaurin has poor efficacy when used alone, but when combined with Cytarabine, Daunorubicin, and Cytarabine (FDA approved), it can be used to treat FLT3-mutated AML in adults. Second-generation FLT3 kinase inhibitors such as Gilteritinib, Crenolanib, and Quizartinib are more selective, more active, and less toxic, but still have some off-target effects.

[0003] Currently, three FLT3 inhibitors (Quizartinib, Gilteritinib, Midostaurin) have been approved for sale in Japan and / or the United States and are used as monotherapy or in combination with conventional chemotherapy drugs to treat AML patients. These inhibitors have shown good therapeutic effects in clinical trials and have improved the prognosis of AML patients to some extent. When used as monotherapy, the disease quickly relapses and target-dependent and non-target-dependent resistance appears. Target-dependent mutations are well recognized in the activation loop (e.g., aspartate835, D835) and gating residues (e.g., phenylalanine691, F691), with the D835 mutation being the most common target-resistant mutation site. In addition, activation of related signaling pathways can also compensate for the inhibition of the FLT3 signaling pathway. Currently, researchers are trying to reduce the incidence of non-targeted drug resistance by directly inhibiting the relevant signaling pathways (e.g., PI3K / AKT and / or RAS / MEK / MAPK) or by co-inhibiting signaling pathways related to cell survival through the combination of drugs, but the effect is limited (Rabik CA,Wang J,Pratilas CA.FLT3-IRAK dual targeting:an exciting new therapeutic option guided by adaptive activation of immune response pathways.Ann Transl Med.2020 Apr;8(7):511.). After administration of Quizartinib and Gilteritinib for a certain period of time, the expression of pFLT3 and pSTAT5 was reduced, but no obvious inhibition of tumor cells was observed. In addition, in many recurrent cases, the phosphorylation level of IRAK4 was increased, but it was confirmed that the viability of tumor cells was reduced when IRAK4 inhibitors were used in combination, suggesting that IRAK4 can be used as a target for non-targeted drug resistance.

[0004] Interleukin-1 receptor-associated kinases (IRAKs) are serine / threonine protein kinases that belong to the tyrosine-like kinase (TLK) family, of which IRAK1 and IRAK4 have kinase activity. IRAKs are located downstream of the Toll-like receptor and IL-1R pathways and play an important role in innate immune signaling. Upon TLR stimulation, MYD88 is recruited, activating the receptor complex, which then forms a complex with IRAK4 to activate IRAK1. TRAF6 is then activated by IRAK1, which activates NF-kB. Aberrant activation of the IRAK pathway in tumor cells further exacerbates the disease through inflammatory responses in the tumor microenvironment. (Gummadi VR, Boruah A, Ainan BR, Vare BR, Manda S, Gondle HP, Kumar SN, Mukherjee S, Gore ST, Krishnamurthy NR, Marappan S, Nayak SS, Nellore K, Balasubramanian WR, Bhumireddy A, Giri S, Gopinath S, Samiulla DS, Daginakatte G, Basavaraju A, Chelur S, Eswarappa R, Belliappa C, Subramanya HS, Booher RN, Ramachandra M, Samajdar S. Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies. ACS Med Chem Lett. 2020 Oct 14;11(12):2374-2381.) FLT3 / IRAK4 dual targeting compounds have been developed that may have potential clinical value, improve patient prognosis, and reduce drug resistance. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides a 5-membered fused 6-membered compound, a preparation method, a pharmaceutical composition and application. The compound according to the present invention has an inhibitory effect on FLT3 and / or IRAK4, and has potential clinical application value, which can improve the prognosis of patients and reduce drug resistance.

[0006] The present invention provides a five-membered fused six-membered compound represented by formula I or a pharma- ceutically acceptable salt thereof: During the ceremony, [ka] Y is N or CH; E is N or CH; n is 1, 2 or 3; m is 1, 2 or 3; R 3 is hydrogen or absent, and R 3 If there is no N and the ring Cy 1 The above atom and the ring Cy 3 or N and R 2 The above atom and the ring Cy 2 Forming Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of the 5-membered heteroaromatic ring is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; Ring Cy 2 is a 5- to 9-membered heterocycle, the heteroatom of the 5- to 9-membered heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; Ring Cy 3 is a 5- to 9-membered oxo heterocycle, the heteroatom of the 5- to 9-membered oxo heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; R 1 each independently represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, [ka] -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 10-membered cycloalkyl group substituted with [ka] Unsubstituted or one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-5 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 1-6 a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 1-7 C1-C6 alkoxy group substituted with R 1-8 Hydroxyl group substituted with -O-COR a the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7 are each independently deuterium, halogen, oxo, [ka] Hydroxyl group, unsubstituted or one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, unsubstituted or one or more R 1-1-3 a C1-C6 alkoxy group substituted with [ka] Unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R 1-1-7 a 5- to 10-membered heteroaryl group substituted with ; a heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three, a heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three, R 1-8 is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 each independently represents deuterium, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, halogen, oxo, [ka] or a hydroxyl group, R 2 is hydrogen, halogen, cyano group, hydroxyl group, nitro group, [ka] -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 2-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 a 3- to 10-membered cycloalkyl group substituted with [ka] Unsubstituted or one or more R 2-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 2-5 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 2-6 a 5- to 10-membered heteroaryl group substituted with R 2-8 a hydroxyl group unsubstituted or substituted with one or more R 2-7 C1-C6 alkoxy group substituted with -O-COR a the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 2-1 , R 2-2 , R 2-4 , R 2-5 , R 2-6 , and R 2-7 are each independently deuterium, halogen, oxo, hydroxyl, unsubstituted or one or more R 2-1-1a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, unsubstituted or one or more R 2-1-3 a C1-C6 alkoxy group substituted with [ka] Unsubstituted or one or more R 2-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 2-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 2-8 is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, R 2-1-1 , R 2-1-3 , R 2-1-4 and R 2-1-5 are each independently deuterium, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, a halogen, an oxo group, or a hydroxyl group; R 4are each independently hydrogen, halogen, unsubstituted or one or more R 4-1 a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 4-2 an alkyl group substituted with, unsubstituted or one or more R 4-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 4-4 or a cycloalkyl group unsubstituted or substituted with one or more R 4-5 the heteroatom of said 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of said 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 4-1 and R 4-5 are each independently a halogen, [ka] Unsubstituted or one or more R 4-1-1 a C1-C6 alkoxy group substituted with [ka] Cyano group, oxo, hydroxyl group, or unsubstituted or one or more R 4-1-3 C1-C6 alkyl group, unsubstituted or substituted with one or more R 4-1-4 or an unsubstituted or substituted 3- to 10-membered cycloalkyl group with one or more R 4-1-5 a 3- to 11-membered heterocycloalkyl group substituted with; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 4-2 , R 4-3 , and R 4-4 each independently represents a hydroxyl group, a halogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens; [ka] oxo, or [ka] and R 4-1-1 , R 4-1-3 , R 4-1-4 , and R 4-1-5 are each independently a halogen, a hydroxyl group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, or a C1-C6 alkoxy group that is unsubstituted or substituted with one or more halogens; R 4-3-1 is H, a C1-C6 alkyl group or a C1-C6 alkoxy group, R a and R b are each independently H, unsubstituted or one or more R a-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R a-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R a-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R a-4 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R a-5 or R a , and R b form a 3- to 11-membered heterocycle together with atoms bonded thereto; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; R a-1 , R a-2 , R a-3 , R a-4 , and Ra-5 are each independently a halogen, a cyano group, a hydroxyl group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more types selected from N, S, and O, and the number of heteroatoms is one, two, or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more types selected from N, S, and O, and the number of heteroatoms is one, two, or three.

[0007] The present invention provides a five-membered fused six-membered compound represented by formula I or a pharma- ceutically acceptable salt thereof: During the ceremony, [ka] Y is N or CH; E is N or CH; n is 1, 2 or 3; m is 1, 2 or 3; R 3 is hydrogen or absent, and R 3 If there is no ring, N and Cy 1 The upper atom is the ring Cy 3 or N and R 2 The above atom and the ring Cy 2 Forming Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of the 5-membered heteroaromatic ring is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, Ring Cy 2 is a 5- to 9-membered heterocycle, the heteroatom of the 5- to 9-membered heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; Ring Cy 3is a 5- to 9-membered oxo heterocycle, the heteroatom of the 5- to 9-membered oxo heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; R 1 each independently represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, [ka] -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 10-membered cycloalkyl group substituted with [ka] Unsubstituted or one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-5 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 1-6 a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 1-7 C1-C6 alkoxy group substituted with R 1-8 Hydroxyl group substituted with -O-COR a the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7each independently represents a halogen, an oxo, [ka] Hydroxyl group, unsubstituted or one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, unsubstituted or one or more R 1-1-3 a C1-C6 alkoxy group substituted with [ka] Unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R 1-1-7 a 5- to 10-membered heteroaryl group substituted with; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 1-8is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 each independently represents an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, a halogen, an oxo, [ka] or a hydroxyl group; R 2 is hydrogen, halogen, cyano group, hydroxyl group, nitro group, [ka] -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 2-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 a 3- to 10-membered cycloalkyl group substituted with [ka] Unsubstituted or one or more R 2-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 2-5 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 2-6 a 5- to 10-membered heteroaryl group substituted with R 2-8a hydroxyl group unsubstituted or substituted with one or more R 2-7 C1-C6 alkoxy group substituted with -O-COR a the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 2-1 , R 2-2 , R 2-4 , R 2-5 , R 2-6 and R 2-7 are each independently a halogen, an oxo, a hydroxyl group, unsubstituted or one or more R 2-1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, unsubstituted or one or more R 2-1-3 a C1-C6 alkoxy group substituted with [ka] Unsubstituted or one or more R 2-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 2-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 2-8is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; R 2-1-1 , R 2-1-3 , R 2-1-4 and R 2-1-5 are each independently an unsubstituted or substituted C1-C6 alkyl group with one or more halogens, a halogen, an oxo, or a hydroxyl group; R 4 are each independently hydrogen, halogen, unsubstituted or one or more R 4-1 a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 4-2 an alkyl group substituted with, unsubstituted or one or more R 4-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 4-4 or a cycloalkyl group unsubstituted or substituted with one or more R 4-5 a 6- to 10-membered aryl group substituted with; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; R 4-1 and R 4-5 are each independently a halogen, [ka] Unsubstituted or one or more R 4-1-1 a C1-C6 alkoxy group substituted with [ka] Cyano group, oxo, hydroxyl group, or unsubstituted or one or more R 4-1-3 C1-C6 alkyl group, unsubstituted or substituted with one or more R 4-1-4 or an unsubstituted or substituted 3- to 10-membered cycloalkyl group with one or more R 4-1-5 a 3- to 11-membered heterocycloalkyl group substituted with; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 4-2 , R 4-3 and R 4-4 each independently represents a hydroxyl group, a halogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens; [ka] oxo, or [ka] and; R 4-1-1 , R 4-1-3 , R 4-1-4 and R 4-1-5 are each independently a halogen, a hydroxyl group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, or a C1-C6 alkoxy group that is unsubstituted or substituted with one or more halogens; R 4-3-1 is H, a C1-C6 alkyl group, or a C1-C6 alkoxy group; R a and R b are each independently H, unsubstituted or one or more R a-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R a-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R a-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more Ra-4 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R a-5 or R a , and R b form a 3- to 11-membered heterocycle together with atoms bonded thereto; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; R a-1 , R a-2 , R a-3 , R a-4 and R a-5 are each independently a halogen, a cyano group, a hydroxyl group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more types selected from N, S, and O, and the number of heteroatoms is one, two, or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more types selected from N, S, and O, and the number of heteroatoms is one, two, or three.

[0008] In a preferred embodiment, in the compound of formula I or a pharma- ceutically acceptable salt thereof, some groups are defined as follows, and other groups may be defined as in any one of the above embodiments (hereinafter simply referred to as "a preferred embodiment"): Ring Cy 2 is a 5- or 6-membered heterocycle, the heteroatom of the 5- or 6-membered heterocycle is N, and the number of heteroatoms is 1, 2 or 3.

[0009] In one preferred embodiment, the ring Cy 3 is an oxo 5- to 9-membered heterocycle, the heteroatom of the oxo 5- to 9-membered heterocycle is N, and the number of heteroatoms is 1, 2 or 3.

[0010] In one preferred embodiment, R 1 Each represents one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1 The 3- to 11-membered heterocycloalkyl group is a 3- to 11-membered heterocycloalkyl group substituted with one or two heteroatoms selected from N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0011] In one preferred embodiment, R 1-1 , R 1-2 and R 1-4 each independently represents a halogen, an oxo, a hydroxyl group, [ka] Unsubstituted or one or more R 1-1-3 a C1-C6 alkoxy group substituted with [ka] -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatoms of the 3- to 10-membered heterocycloalkyl group are one or two of N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0012] In one preferred embodiment, R 1-1 , R 1-2 and R 1-4 each independently represents deuterium, a halogen, an oxo group, a hydroxyl group, [ka] Unsubstituted or one or more R 1-1-3 a C1-C6 alkoxy group substituted with [ka] -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatoms of the 3- to 10-membered heterocycloalkyl group are one or two of N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0013] In one preferred embodiment, R 1-1-1 each independently represents a hydroxyl group, an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, oxo, [ka] Or a halogen.

[0014] In one preferred embodiment, R 1-1-1 each independently represents deuterium, a hydroxyl group, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, oxo, [ka] Or a halogen.

[0015] In one preferred embodiment, R 1-1-3 are each independently a hydroxyl group or a halogen.

[0016] In one preferred embodiment, R 1-1-4 are each independently a hydroxyl group or a halogen.

[0017] In one preferred embodiment, R 1-1-5 are each independently a hydroxyl group or a halogen.

[0018] In one preferred embodiment, R 1-1-3 are each independently deuterium, a hydroxyl group, or a halogen.

[0019] In one preferred embodiment, R 1-1-4 are each independently deuterium, a hydroxyl group, or a halogen.

[0020] In one preferred embodiment, each R 1-1-5 are each independently deuterium, a hydroxyl group, or a halogen.

[0021] In one preferred embodiment, R 2 is hydrogen, a hydroxyl group, a halogen, a cyano group, unsubstituted or one or more R 2-1 a 3- to 10-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 a 3- to 8-membered cycloalkyl group, unsubstituted or substituted with one or more R 2-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 2-7 C1-C6 alkoxy group substituted with R 2-8 The heteroatoms in the 3- to 10-membered heterocycloalkyl group are one or two types selected from N and O, and the number of heteroatoms is one, two or three.

[0022] In one preferred embodiment, R 2-1 , R 2-2 , R 2-4 and R 2-7 are each independently oxo, a hydroxyl group, a halogen, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0023] In one preferred embodiment, R 2-1 , R 2-2 , R 2-4 and R 2-7 are each independently deuterium, oxo, a hydroxyl group, a halogen, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0024] In one preferred embodiment, R 2-8 is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, the heteroatom of the 3- to 6-membered heterocycloalkyl group is one or more types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0025] In one preferred embodiment, R 4 are each independently hydrogen, halogen, an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, an unsubstituted or one or more R 4-5 phenyl groups, unsubstituted or substituted with one or more R 4-1 a 5- to 6-membered heteroaryl group unsubstituted or substituted with one or more R 4-3 and the heteroatom of the 3- to 6-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three. The heteroatom of the 5- to 6-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three.

[0026] In one preferred embodiment, R 4-1 are each independently oxo, a hydroxyl group, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0027] In one preferred embodiment, R 4-3 each independently represents a halogen, a C1-C6 alkyl group which is unsubstituted or substituted with one or more halogens, [ka] Or oxo.

[0028] In one preferred embodiment, R 4-5 are each independently oxo, a hydroxyl group, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0029] In one preferred embodiment, R 4-3-1 are each a C1 to C6 alkyl group or a C1 to C6 alkoxy group.

[0030] In one preferred embodiment, R a and R b are each independently hydrogen or unsubstituted or one or more R a-1 or R is a C1-C6 alkyl group substituted with a And R b form a 3- to 6-membered heterocycle together with the atoms bonded thereto. The heteroatom of the 3- to 6-membered heterocycle is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0031] In one preferred embodiment, R a-1 are each independently a C1 to C6 alkyl group, a halogen, or a hydroxyl group.

[0032] In some preferred embodiments, n is 1.

[0033] In some preferred embodiments, m is 1.

[0034] In some preferred embodiments, Y is N.

[0035] In certain preferred embodiments, E is CH.

[0036] In one preferred embodiment, R 3 is hydrogen.

[0037] In one preferred embodiment, R 1 is one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1 The heteroatom of the 3- to 10-membered heterocycloalkyl group is one or more of N, O and S, and the number of heteroatoms is 1 or 2.

[0038] In one preferred embodiment, R 1 is one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 6-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1 The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two of N, O and S, and the number of heteroatoms is one.

[0039] In one preferred embodiment, R 1 teeth [ka] a 3- to 6-membered cycloalkyl group substituted with one hydroxyl group, a 6-membered cycloalkyl group substituted with one -SO2-C1 to C6 alkyl group, or [ka] It is.

[0040] In one preferred embodiment, R 1-1 , R 1-2 and R 1-4 each independently represents a deuterium atom, an oxo group, a hydroxyl group, [ka] halogen, [ka] -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatom of the 3- to 10-membered heterocycloalkyl group is one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0041] In one preferred embodiment, R 1-1 , R 1-2 and R 1-4 are each independently a deuterium atom, a hydroxyl group, [ka] Oxo, halogen, -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 a 3- to 6-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two types of N, O or S, and the number of heteroatoms is one.

[0042] In one preferred embodiment, R 1-1 each independently represents oxo, [ka] or unsubstituted or one or more R 1-1-4 is a C1 to C6 alkyl group substituted with

[0043] In one preferred embodiment, R 1-2 are each independently a halogen, a hydroxyl group, or a -SO2-C1 to C6 alkyl group.

[0044] In one preferred embodiment, R 1-4 are each independently a deuterium atom, a hydroxyl group, [ka] Halogen, -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 C1-C6 alkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two of N, O and S, and the number of heteroatoms is one.

[0045] In one preferred embodiment, R 1-1-1 are each independently an oxo or hydroxyl group.

[0046] In one preferred embodiment, R 1-1-1 are each independently an oxo, halogen, or hydroxyl group.

[0047] In one preferred embodiment, R 1-1-4 are each independently a halogen.

[0048] In one preferred embodiment, R 1-1-5 are each independently a hydroxyl group.

[0049] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 6-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 C3-C6 cycloalkyl group, unsubstituted or substituted with one or more R 2-7C1-C6 alkoxy group substituted with, unsubstituted or substituted with one or more R 2-4 C1-C6 alkyl group substituted with R 2-8 The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two types selected from N and O, and the number of heteroatoms is one or two.

[0050] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 6-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-7 or an unsubstituted or one or more R 2-4 The heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from N and / or O, and the number of heteroatoms is one or two.

[0051] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-7 or an unsubstituted or one or more R 2-4 is a C1 to C6 alkyl group substituted with

[0052] In one preferred embodiment, R 2-8 is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group. The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two types selected from N and O, and the number of heteroatoms is one.

[0053] In one preferred embodiment, R 2-1 are each independently a hydroxyl group or a halogen.

[0054] In one preferred embodiment, R 2-2 are each independently a hydroxyl group.

[0055] In one preferred embodiment, R2-4 are each independently a hydroxyl group.

[0056] In one preferred embodiment, R 2-7 are each independently a halogen.

[0057] In one preferred embodiment, R 2-4 are each independently deuterium, a halogen, or a hydroxyl group.

[0058] In one preferred embodiment, R 2-7 are each independently deuterium or a halogen.

[0059] In one preferred embodiment, R 4 are each independently hydrogen, halogen, an alkyl group that is unsubstituted or substituted with one or more halogens, an alkyl group that is unsubstituted or substituted with one or more R 4-1 a 5- to 6-membered heteroaryl group unsubstituted or substituted with one or more R 4-5 or a phenyl group unsubstituted or substituted with one or more R 4-3 The heteroatom of the 5- to 6-membered heteroaryl group is N, and the number of heteroatoms is 1, 2 or 3. The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or more types selected from N, S and O, and the number of heteroatoms is 1 or 2 (preferably, R 4 are each independently unsubstituted or one or more R 4-1 a 5- to 6-membered heteroaryl group substituted with, wherein the heteroatom of the 5- to 6-membered heteroaryl group is N and the number of heteroatoms is 1 or 2.

[0060] In one preferred embodiment, R 4 are each independently unsubstituted or substituted with one or more R 4-1 is a pyridyl group substituted with

[0061] In one preferred embodiment, R 4-1 and R4-5 are each independently a C1 to C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0062] In one preferred embodiment, R 4-1 are each independently a C1 to C6 alkyl group that is unsubstituted or substituted with one, two, or three halogens.

[0063] In one preferred embodiment, R 4-3 are each independently a halogen or a C1 to C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0064] In one preferred embodiment, R a and R b are each independently H or a C1-C6 alkyl group, or R a And R b form a 3- to 6-membered heterocycle together with atoms bonded thereto. The heteroatom of the 3- to 6-membered heterocycle is S, and the number of heteroatoms is one.

[0065] In a preferred embodiment, the five-membered fused six-membered compound of formula I is a compound of formula Ia: [ka]

[0066] In a preferred embodiment, the five-membered fused six-membered compound of formula I is a compound of formula Ib: [ka]

[0067] In a preferred embodiment, the five-membered fused six-membered compound of formula I is a compound of formula Ic: [ka]

[0068] In one preferred embodiment, R 1 teeth, [ka] It is.

[0069] In one preferred embodiment, [ka] teeth, [ka] It is.

[0070] In one preferred embodiment, R 2 is a methoxy group, an isopropoxy group, a trifluoromethoxy group, a hydroxyl group, -OCD 3、 [ka] It is.

[0071] In one preferred embodiment, R 4 each independently represents a hydrogen atom, a bromine atom, a trifluoromethyl group, [ka] It is.

[0072] In one preferred embodiment, the ring Cy 1 teeth, [ka] It is.

[0073] In one preferred embodiment, the ring Cy 2 teeth, [ka] It is.

[0074] In one preferred embodiment, the ring Cy 3 teeth, [ka] It is.

[0075] In one preferred embodiment, [ka] teeth, [ka] It is.

[0076] In a preferred embodiment, the five-membered fused six-membered compound represented by formula I or a pharma- ceutically acceptable salt thereof is any of the following compounds: [ka] [ka] [ka]

[0077] The present invention provides a five-membered fused six-membered compound represented by formula II, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, m is 1, 2 or 3; E is N or CH; Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of the 5-membered heteroaromatic ring is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, R 3 is hydrogen or absent, and R 3 If there is no ring, N and Cy 1 The atoms above, together with the atoms attached to them, form the ring Cy. 3 or N and R2 The atoms above, together with the atoms attached to them, form the ring Cy. 2 Forming Ring Cy 2 is a 5- to 9-membered heterocycle, the heteroatom of the 5- to 9-membered heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; Ring Cy 3 is a 5- to 9-membered oxo heterocycle, the heteroatom of the 5- to 9-membered oxo heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; R 1 each independently represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, [ka] -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1 a 3- to 11-membered heterocycloalkyl group substituted with one or more R 1-2 a 3- to 10-membered cycloalkyl group substituted with [ka] One or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-5 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 1-6 a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 1-7 C1-C6 alkoxy group substituted with R 1-8 Hydroxyl group substituted with -O-COR athe heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7 are each independently deuterium, halogen, oxo, [ka] Hydroxyl group, unsubstituted or one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, unsubstituted or one or more R 1-1-3 a C1-C6 alkoxy group substituted with [ka] Unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R 1-1-7a 5- to 10-membered heteroaryl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 1-8 is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, and the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 each independently represents deuterium, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, halogen, oxo, [ka] or a hydroxyl group, R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 a 3- to 8-membered cycloalkyl group, unsubstituted or substituted with one or more R 2-7 C1-C6 alkoxy group substituted with R 2-8 or one or more R 2-4 a C1-C6 alkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-1 and R2-7 are each independently deuterium, a hydroxyl group, a halogen, an oxo, an unsubstituted or substituted C1-C6 alkyl group with one or more halogens, a 3- to 10-membered cycloalkyl group, or an unsubstituted or substituted R 2-1-1 a 3- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-2 are each independently a deuterium atom, a halogen atom, a hydroxyl group, or a hydroxyl group substituted with a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-4 are each independently a deuterium atom, a halogen atom, a hydroxyl group, or a hydroxyl group substituted with a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-8 is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, and the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, R 2-1-1 are each independently a hydroxyl group, a halogen, an oxo, a C1-C6 alkyl group, a 3- to 10-membered cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group being one or more types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2 is unsubstituted or has one or more R2-1 and R is a 3- to 7-membered monoheterocycloalkyl group substituted with 1 One or more R 1-4 When R is a C1-C6 alkyl group substituted with 1-4 are each independently deuterium, halogen, hydroxyl, unsubstituted or one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, [ka] Unsubstituted or one or more R 1-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R 1-1-7 a 5- to 10-membered heteroaryl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R a and R b are each independently H, unsubstituted or one or more R a-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R a-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R a-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R a-4 a 6- to 10-membered aryl group unsubstituted or substituted with one or more Ra-5 is a 5- to 10-membered heteroaryl group substituted with Or, R a and R b form a 3- to 11-membered heterocycle together with atoms bonded thereto, the heteroatoms of the 3- to 11-membered heterocycloalkyl group are one or more selected from N, S and O, and the number of heteroatoms is one, two or three, the heteroatoms of the 3- to 11-membered heterocycle are one or more selected from N, S and O, and the number of heteroatoms is one, two or three, R a-1 , R a-2 , R a-3 , R a-4 and R a-5 are each independently a halogen, a cyano group, a hydroxyl group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, and the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, R 4 are each independently unsubstituted or substituted with one or more R 4-1 a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 4-5 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 4-3 a 3- to 11-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; a heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 4-1 and R 4-5 are each independently a halogen, [ka] Unsubstituted or one or more R 4-1-1 a C1-C6 alkoxy group substituted with [ka] Cyano group, oxo, hydroxyl group, or unsubstituted or one or more R 4-1-3 C1-C6 alkyl group, unsubstituted or substituted with one or more R 4-1-4 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 4-1-5 a 3- to 11-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 4-3 each independently represents a hydroxyl group, a halogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens; [ka] or oxo, R 4-1-1 , R 4-1-3 , R 4-1-4 and R 4-1-5 are each independently a halogen, a hydroxyl group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, or a C1-C6 alkoxy group that is unsubstituted or substituted with one or more halogens, the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more types selected from N, S and O, the number of heteroatoms is 1, 2 or 3, Each R 4-3-1 is hydrogen, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group.

[0078] The present invention provides a five-membered fused six-membered compound represented by formula II, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, m is 1, 2 or 3; E is N or CH; Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of the 5-membered heteroaromatic ring is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, R 3 is hydrogen or absent, and R 3 If there is no ring, N and Cy 1 The atoms above, together with the atoms attached to them, form the ring Cy. 3 or N and R 2 The atoms above, together with the atoms attached to them, form the ring Cy. 2 Forming Ring Cy 2 is a 5- to 9-membered heterocycle, the heteroatom of the 5- to 9-membered heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; Ring Cy 3 is a 5- to 9-membered oxo heterocycle, the heteroatom of the 5- to 9-membered oxo heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; R 1 each independently represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, [ka] -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 10-membered cycloalkyl group substituted with [ka] Unsubstituted or one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-5 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 1-6 a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 1-7 C1-C6 alkoxy group substituted with R 1-8 Hydroxyl group substituted with -O-COR a the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7 each independently represents a halogen, an oxo, [ka] Hydroxyl group, unsubstituted or one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, unsubstituted or one or more R 1-1-3 a C1-C6 alkoxy group substituted with [ka] Unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a, [ka] Unsubstituted or one or more R 1-1-8 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R 1-1-7 a 5- to 10-membered heteroaryl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 1-8 is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group; the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 each independently represents an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, a halogen, an oxo, [ka] or a hydroxyl group, R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 a 3- to 8-membered cycloalkyl group, unsubstituted or substituted with one or more R 2-7 C1-C6 alkoxy group substituted with R 2-8 or one or more R2-4 a C1-C6 alkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-1 and R 2-7 are each independently a hydroxyl group, a halogen, an oxo, an unsubstituted or substituted C1-C6 alkyl group with one or more halogens, a 3- to 10-membered cycloalkyl group, or an unsubstituted or substituted C1-C6 alkyl group with one or more R 2-1-1 a 3- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-2 each independently represents a hydroxyl group substituted with a halogen, a hydroxyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-4 each independently represents a hydroxyl group substituted with a halogen, a hydroxyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-8 represents a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, and the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, R 2-1-1are each independently a hydroxyl group, a halogen, an oxo, a C1-C6 alkyl group, a 3- to 10-membered cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group being one or more types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2 is unsubstituted or has one or more R 2-1 a 3- to 7-membered monoheterocycloalkyl group substituted with, or unsubstituted or substituted with one or more R 2-2 is a 3- to 6-membered cycloalkyl group substituted with R 1 One or more R 1-4 When R is a C1-C6 alkyl group substituted with 1-4 are each independently a halogen, [ka] Unsubstituted or one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, [ka] One or more R 1-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R 1-1-7a 5- to 10-membered heteroaryl group substituted with ; a heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three, a heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three, R a and R b are each independently H, unsubstituted or one or more R a-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R a-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R a-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R a-4 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R a-5 is a 5- to 10-membered heteroaryl group substituted with Or, R a and R b form a 3- to 11-membered heterocycle together with atoms bonded thereto, the heteroatoms of the 3- to 11-membered heterocycloalkyl group are one or more selected from N, S and O, the number of heteroatoms is one, two or three, the heteroatoms of the 3- to 11-membered heterocycle are one or more selected from N, S and O, the number of heteroatoms is one, two or three, R a-1 , R a-2 , R a-3 , R a-4 and R a-5are each independently a halogen, a cyano group, a hydroxyl group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, and the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, R 4 are each independently unsubstituted or substituted with one or more R 4-1 a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 4-5 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 4-3 a 3- to 11-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; a heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 4-1 and R 4-5 are each independently a halogen, [ka] Unsubstituted or one or more R 4-1-1 a C1-C6 alkoxy group substituted with [ka] Cyano group, oxo, hydroxyl group, or unsubstituted or one or more R 4-1-3 C1-C6 alkyl group, unsubstituted or substituted with one or more R 4-1-4 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 4-1-5a 3- to 11-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 4-3 each independently represents a hydroxyl group, a halogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens; [ka] or oxo, R 4-1-1 , R 4-1-3 , R 4-1-4 and R 4-1-5 are each independently a halogen, a hydroxyl group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, or a C1-C6 alkoxy group that is unsubstituted or substituted with one or more halogens, Each R 4-3-1 is hydrogen, a C1 to C6 alkyl group, or a C1 to C6 alkoxy group.

[0079] In a preferred embodiment, in the compound of formula II or a pharma- ceutically acceptable salt thereof, some groups are defined as follows, and other groups may be defined as in any one of the above embodiments (hereinafter simply referred to as "a preferred embodiment"): Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatoms in the 5-membered heteroaromatic ring are one or two types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0080] R 2 is unsubstituted or has one or more R 2-1 a 3- to 7-membered monoheterocycloalkyl group substituted with, or unsubstituted or substituted with one or more R 2-2 is a 3- to 6-membered cycloalkyl group substituted with R 1 One or more R 1-4 When R is a C1-C6 alkyl group substituted with1-4 are each independently halogen, unsubstituted or one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, [ka] One or more R 1-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R 1-1-7 and the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three. The heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three.

[0081] In one preferred embodiment, the ring Cy 2 is a 5- or 6-membered heterocycle, the heteroatom of the 5- or 6-membered heterocycle is N, and the number of heteroatoms is 1, 2 or 3.

[0082] In one preferred embodiment, the ring Cy 3 is a 5- to 9-membered oxo heterocycle, the heteroatom of the 5- to 9-membered oxo heterocycle is N, and the number of heteroatoms is 1, 2, or 3;

[0083] In one preferred embodiment, R 1 is one or more R 1-4 C1-C6 alkyl group substituted with one or more R 1-2a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1 The 3- to 11-membered heterocycloalkyl group is a 3- to 11-membered heterocycloalkyl group substituted with one or two heteroatoms selected from N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0084] In one preferred embodiment, R 1 is one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 3- to 10-membered cycloalkyl substituted with, or unsubstituted or substituted with one or more R 1-1 The 3- to 11-membered heterocycloalkyl group is a 3- to 11-membered heterocycloalkyl group substituted with one or two heteroatoms selected from N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0085] In one preferred embodiment, R 1-1 , R 1-2 and R 1-4 each independently represents deuterium, a halogen, an oxo group, a hydroxyl group, [ka] Unsubstituted or one or more R 1-1-3 a C1-C6 alkoxy group substituted with [ka] -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatoms of the 3- to 10-membered heterocycloalkyl group are one or two of N, S and O, and the number of heteroatoms is 1, 2 or 3. In one preferred embodiment, R 1-1 , R 1-2 and R 1-4 each independently represents a halogen, an oxo, a hydroxyl group, [ka] Unsubstituted or one or more R 1-1-3 a C1-C6 alkoxy group substituted with [ka] -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatoms of the 3- to 10-membered heterocycloalkyl group are one or two of N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0086] In one preferred embodiment, R 1-1-1 each independently represents a hydroxyl group, an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, oxo, [ka] Or a halogen.

[0087] In one preferred embodiment, R 1-1-1 each independently represents deuterium, a hydroxyl group, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, oxo, [ka] Or a halogen.

[0088] In one preferred embodiment, each R 1-1-1each independently represents a hydroxyl group, an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, oxo, [ka] Or a halogen.

[0089] In one preferred embodiment, R 1-1-3 are each independently deuterium, a hydroxyl group, or a halogen.

[0090] In one preferred embodiment, R 1-1-4 are each independently deuterium, a hydroxyl group, or a halogen.

[0091] In one preferred embodiment, R 1-1-5 are each independently deuterium, a hydroxyl group, or a halogen.

[0092] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 10-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 a 3- to 6-membered cycloalkyl group, unsubstituted or substituted with one or more R 2-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 2-7 or a C1-C6 alkoxy group substituted with R 2-8 The heteroatoms in the 3- to 10-membered heterocycloalkyl group are one or two types selected from N and O, and the number of heteroatoms is one, two or three.

[0093] In one preferred embodiment, R 2-1 and R 2-7are each independently deuterium, oxo, a hydroxyl group, a halogen, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, a 3- to 6-membered cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group being one or more types selected from N, S and O, and the number of heteroatoms is 1 or 2.

[0094] In one preferred embodiment, R 2-1 and R 2-7 are each independently deuterium, oxo, a hydroxyl group, a halogen, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, a 3- to 6-membered cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group being one or more types selected from N, S and O, and the number of heteroatoms is 1 or 2.

[0095] In one preferred embodiment, R 2-2 are each independently a hydroxyl group substituted with deuterium, a halogen, a hydroxyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group being one or more types selected from N, S and O, and the number of heteroatoms being 1 or 2.

[0096] In one preferred embodiment, R 2-2 are each independently a hydroxyl group or a hydroxyl group substituted with a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more types selected from N, S and O, and the number of heteroatoms is 1 or 2.

[0097] In one preferred embodiment, R 2-4are each independently a hydroxyl group substituted with deuterium, a halogen, a hydroxyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group being one or more types selected from N, S and O, and the number of heteroatoms being 1 or 2.

[0098] In one preferred embodiment, R 2-4 are each independently a hydroxyl group or a hydroxyl group substituted with a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group being one or more types selected from N, S and O, and the number of heteroatoms being 1 or 2.

[0099] In one preferred embodiment, R 2-8 represents a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, the heteroatom of the 3- to 6-membered heterocycloalkyl group being one or more types selected from N, S and O, and the number of heteroatoms being 1, 2 or 3.

[0100] In one preferred embodiment, R 4 are each independently unsubstituted or substituted with one or more R 4-5 phenyl groups, unsubstituted or substituted with one or more R 4-1 a 5- to 6-membered heteroaryl group unsubstituted or substituted with one or more R 4-3 and the heteroatom of the 3- to 6-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three. The heteroatom of the 5- to 6-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three.

[0101] In one preferred embodiment, R 4-1 and R 4-5 are each independently oxo, a hydroxyl group, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0102] In one preferred embodiment, R 4-3 each independently represents a halogen, a C1-C6 alkyl group which is unsubstituted or substituted with one or more halogens, [ka] Or oxo.

[0103] In one preferred embodiment, R 4-3-1 are each independently a C1 to C6 alkyl group or a C1 to C6 alkoxy group.

[0104] In certain preferred embodiments, E is CH.

[0105] In one preferred embodiment, R a and R b are each independently H or a C1-C6 alkyl group, or R a , and R b form a 3- to 6-membered heterocycle together with atoms bonded thereto, the heteroatom of the 3- to 6-membered heterocycle is S, and the number of heteroatoms is one.

[0106] In one preferred embodiment, R 2 is unsubstituted or has one or more R 2-1 and R is a 3- to 7-membered monoheterocycloalkyl group substituted with 1 One or more R 1-4 When R is a C1-C6 alkyl group substituted with 1-4 are each independently deuterium, hydroxyl, halogen, unsubstituted or one or more R 1-1-1 is a 3- to 8-membered heterocycloalkyl group substituted with one or more R 1-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a or [ka] The heteroatom in the 3- to 8-membered heterocycloalkyl group is one or two kinds selected from N and O, and the number of heteroatoms is one or two.

[0107] In one preferred embodiment, R 2 is unsubstituted or has one or more R 2-1 a 3- to 7-membered monoheterocycloalkyl group substituted with, or unsubstituted or substituted with one or more R 2-2 is a 3- to 6-membered cycloalkyl group substituted with R 1 One or more R 1-4 When R is a C1-C6 alkyl group substituted with 1-4 are each independently a halogen, [ka] Unsubstituted or one or more R 1-1-1 a 3- to 8-membered heterocycloalkyl group substituted with one or more R 1-1-5 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a or [ka] The heteroatom in the 3- to 8-membered heterocycloalkyl group is one or two kinds selected from N and O, and the number of heteroatoms is one or two.

[0108] In some preferred embodiments, m is 1.

[0109] In one preferred embodiment, R 3 is hydrogen.

[0110] In one preferred embodiment, R 1 is one or more R 1-4 C1-C6 alkyl group substituted with one or more R 1-2 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1The heteroatom of the 3- to 10-membered heterocycloalkyl group is one or more of N, O and S, and the number of heteroatoms is 1 or 2.

[0111] In one preferred embodiment, R 1 is one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 or an unsubstituted or one or more R 1-1 The heteroatom of the 3- to 10-membered heterocycloalkyl group is one or more of N, O and S, and the number of heteroatoms is 1 or 2.

[0112] In one preferred embodiment, R 1 is one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 6-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1 The heteroatom of the 3- to 8-membered heterocycloalkyl group is one or two types of N, O or S, and the number of the heteroatom is one.

[0113] In one preferred embodiment, R 1 teeth, [ka] a 3- to 6-membered cycloalkyl group substituted with one hydroxyl group, a 6-membered cycloalkyl group substituted with one -SO2-C1 to C6 alkyl group, or [ka] It is.

[0114] In one preferred embodiment, R 1-1 , R 1-2 and R1-4 each independently represents a deuterium atom, an oxo group, a hydroxyl group, [ka] Halogen, -SO2-C1 to C6 alkyl group, [ka] Unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatom of the 3- to 10-membered heterocycloalkyl group is one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0115] In one preferred embodiment, R 1-1 , R 1-2 and R 1-4 are each independently a deuterium atom, a hydroxyl group, [ka] Oxo, halogen, [ka] -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 a 3- to 6-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two types of N, O and S, and the number of heteroatoms is one.

[0116] In a preferred embodiment, R 1-1 each independently represents oxo, [ka] Unsubstituted or one or more R 1-1-4 C1-C6 alkyl group substituted with, or unsubstituted or one or more R 1-1-1 The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two types of N, O and S, and the number of the heteroatom is one.

[0117] In one preferred embodiment, R 1-2 are each independently a halogen, a hydroxyl group, or a -SO2-C1 to C6 alkyl group. In one preferred embodiment, R 1-4 are each independently a deuterium atom, a hydroxyl group, [ka] Halogen, -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 C1-C6 alkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two types of N, O and S, and the number of heteroatoms is one.

[0118] In one preferred embodiment, R 1-1-1 each independently represents oxo, halogen, [ka] Or a hydroxyl group.

[0119] In one preferred embodiment, R 1-1-4 are each independently a halogen.

[0120] In one preferred embodiment, R 1-1-5 are each independently a hydroxyl group.

[0121] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 8-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 C3-C6 cycloalkyl group, unsubstituted or substituted with one or more R 2-7 C1-C6 alkoxy group substituted with, unsubstituted or substituted with one or more R 2-4 C1-C6 alkyl group substituted with R 2-8 The heteroatoms in the 3- to 8-membered heterocycloalkyl group are one or two types selected from N and O, and the number of heteroatoms is one or two.

[0122] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 6-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-7 or an unsubstituted or substituted C1-C6 alkoxy group with one or more R 2-4 a C1-C6 alkyl group substituted with, wherein the heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from N and / or O, and the number of heteroatoms is 1 or 2.

[0123] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-7 or an unsubstituted or substituted C1-C6 alkoxy group with one or more R 2-4 is a C1 to C6 alkyl group substituted with

[0124] In one preferred embodiment, R 2-8 is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, the heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two types selected from N and O, and the number of heteroatoms is one.

[0125] In one preferred embodiment, R 2-1are each independently a hydroxyl group or a halogen.

[0126] In one preferred embodiment, R 2-2 are each independently a hydroxyl group.

[0127] In one preferred embodiment, R 2-4 are each independently deuterium, a hydroxyl group, or a halogen.

[0128] In one preferred embodiment, R 2-7 are each independently deuterium or a halogen.

[0129] In one preferred embodiment, R 4 is unsubstituted or substituted with one or more R 4-5 phenyl groups, unsubstituted or substituted with one or more R 4-1 a 5- to 6-membered heteroaryl group substituted with, or unsubstituted or substituted with one or more R 4-3 a 3- to 6-membered heterocycloalkyl group substituted with R, wherein the heteroatom of the 5- to 6-membered heteroaryl group is N and the number of heteroatoms is 1, 2 or 3; and the heteroatom of the 3- to 6-membered heterocycloalkyl group is one or more types selected from N, S and O and the number of heteroatoms is 1 or 2 (preferably, R 4 are each independently unsubstituted or substituted with one or more R 4-1 a 5- to 6-membered heteroaryl group substituted with, wherein the heteroatom of the 5- to 6-membered heteroaryl group is N and the number of heteroatoms is 1 or 2.

[0130] In one preferred embodiment, R 4 are each independently unsubstituted or substituted with one or more R 4-1 is a pyridyl group substituted with

[0131] In one preferred embodiment, R 4-1 and R 4-5are each independently a C1 to C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0132] In one preferred embodiment, R 4-1 are each independently a C1 to C6 alkyl group that is unsubstituted or substituted with one, two, or three halogens.

[0133] In one preferred embodiment, R 4-3 each independently represents a halogen, an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, oxo, or [ka] It is.

[0134] In one preferred embodiment, R 4-3-1 are each independently a C1 to C6 alkyl group or a C1 to C6 alkoxy group.

[0135] In a preferred embodiment, the 5- and 6-membered ring compounds of formula II are compounds of formula II-a, II-b, II-c, or II-d: [ka]

[0136] In one preferred embodiment, R 1 teeth, [ka] It is.

[0137] In one preferred embodiment, R 2 is a methoxy group, -OCD3, isopropoxy group, trifluoromethoxy group, [ka] It is.

[0138] In one preferred embodiment, R 4 are each independently [ka] It is.

[0139] In one preferred embodiment, the ring Cy 1 teeth, [ka] It is.

[0140] In a preferred embodiment, the five-membered fused six-membered compound represented by formula II or a pharma- ceutically acceptable salt thereof is any of the following compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0141] The present invention provides a five-membered fused six-membered compound represented by formula III, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, the ring Cy 4is an imidazole ring, an oxazole ring, a thiazole ring, a 5-membered heterocycle, or an oxo 5-membered heterocycle, the heteroatom of the 5-membered heterocycle being one or more selected from N, S, and O, the number of heteroatoms being 1, 2, or 3, n is 1, 2 or 3; m is 1, 2 or 3; X is N or C, Q is N or C, E is N or CH; R 3 is hydrogen or absent, and R 3 is not present, N and the atoms on the ring Cy1, together with the atoms bonded to them, are part of the ring Cy 3 or N and R 2 The atoms above, together with the atoms attached to them, form the ring Cy. 2 Forming Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of the 5-membered heteroaromatic ring is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, Ring Cy 2 is a 5- to 9-membered heterocycle, the heteroatom of the 5- to 9-membered heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; Ring Cy 3 is a 5- to 9-membered oxo heterocycle, the heteroatom of the 5- to 9-membered oxo heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; R 1 each independently represents one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1 a 3- to 11-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; R 1-4 are each independently unsubstituted or substituted with one or more R 1-1-1 a 3- to 8-membered heterocycloalkyl group substituted with deuterium, a hydroxyl group, a halogen, unsubstituted or substituted with one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with [ka] or -SO2-C1-C6 alkyl group, the heteroatoms of the 3- to 8-membered heterocycloalkyl group are N and / or O, and the number of heteroatoms is 1, 2 or 3; R 1-1 each independently represents deuterium, a halogen, an oxo group, a hydroxyl group, [ka] Unsubstituted or one or more R 1-1-1 a 3- to 8-membered heterocycloalkyl group substituted with, an unsubstituted or C1-C6 alkyl group substituted with one or more halogens, a 3- to 10-membered cycloalkyl group, or a 6- to 10-membered aryl group, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is N, and the number of heteroatoms is 1, 2, or 3; R 1-2 each independently represents deuterium, a hydroxyl group, a halogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens; [ka] or -SO2-C1 to C6 alkyl group; R 1-1-1 each independently represents a C1 to C6 alkyl group, oxo, halogen, [ka] or a hydroxyl group, R 1-1-5 are each independently an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, a halogen, an oxo group, or a hydroxyl group; [ka] but, [ka] and R 1 are each independently unsubstituted or one or more R 1-1 When the 3- to 11-membered heterocycloalkyl group substituted with is a 5-membered fused 6-membered compound represented by formula III satisfies one or more of the following conditions: (1) At least one R 1 is unsubstituted or has one or more R 1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] and the 3- to 11-membered heterocycloalkyl group is bicyclic; (2) At least one R 4 teeth [ka] is; (3)R 2 -OCD3, [ka] is; and (4) Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of the 5-membered heteroaromatic ring is N, the number of heteroatoms is 2, R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 a 3- to 8-membered cycloalkyl group, unsubstituted or substituted with one or more R 2-7 C1-C6 alkoxy group substituted with R 2-8 or one or more R 2-4a C1-C6 alkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-1 , R 2-2 and R 2-7 are each independently deuterium, a hydroxyl group, a halogen, an oxo, an unsubstituted or substituted C1-C6 alkyl group with one or more halogens, a 3- to 10-membered cycloalkyl group, or an unsubstituted or substituted R 2-1-1 a 3- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-4 are each independently a deuterium atom, a halogen atom, a hydroxyl group, or a hydroxyl group substituted with a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-8 is a 3- to 10-membered cycloalkyl group or a 3- to 11-membered heterocycloalkyl group, the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-1-1 are each independently deuterium, a hydroxyl group, a halogen, an oxo, a C1-C6 alkyl group, a 3- to 10-membered cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group being one or more types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2 is unsubstituted or has one or more R 2-7 When R is a C1-C6 alkoxy group substituted with 1 each independently represents one or more R 1-4a C1-C6 alkyl group substituted with one or more hydroxyl groups or halogens, a 3- to 10-membered cycloalkyl group substituted with one or more -SO2-R a a 3- to 10-membered cycloalkyl group substituted with [ka] Unsubstituted or one or more R 1-1-1 and R is a 3- to 8-membered heterocycloalkyl group substituted with 1-4 are each independently a hydroxyl group, deuterium, halogen, unsubstituted or one or more R 1-1-1 3- to 8-membered N or S heterocycloalkyl groups, unsubstituted or substituted with one or more R 1-1-5 3- to 6-membered cycloalkyl groups substituted with -SO2-R a , -SO-R a or [ka] wherein the heteroatoms of the 3- to 8-membered heterocycloalkyl group are N and / or S, and the number of heteroatoms is 1, 2 or 3; R 2 is unsubstituted or has one or more R 2-1 or an unsubstituted 3- to 6-membered cycloalkyl group, and each R1 is independently one or more R 1-4 When R is a C1-C6 alkyl group substituted with 1-4 are each independently unsubstituted or substituted with one or more R 1-1-1 a 3- to 8-membered heterocycloalkyl group substituted with deuterium, halogen, unsubstituted or one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with [ka] wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is N and / or O, and the number of heteroatoms is 1, 2 or 3; R 4are each independently unsubstituted or substituted with one or more R 4-1 a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 4-5 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 4-3 a 3- to 11-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; a heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 4-1 and R 4-5 are each independently a halogen, [ka] Unsubstituted or one or more R 4-1-1 a C1-C6 alkoxy group substituted with [ka] Cyano group, oxo, hydroxyl group, or unsubstituted or one or more R 4-1-3 C1-C6 alkyl group, unsubstituted or substituted with one or more R 4-1-4 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 4-1-5 a 3- to 11-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 4-3 each independently represents a hydroxyl group, a halogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens; [ka] or oxo, R 4-1-1 , R 4-1-3 , R4-1-4 and R 4-1-5 are each independently a halogen, a hydroxyl group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, or a C1-C6 alkoxy group that is unsubstituted or substituted with one or more halogens, the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more types selected from N, S and O, the number of heteroatoms is 1, 2 or 3, R 4-3-1 are each hydrogen, a C1-C6 alkyl group, or a C1-C6 alkoxy group, R a and R b are each independently H, unsubstituted or one or more R a-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R a-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R a-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R a-4 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R a-5 a 5- to 10-membered heteroaryl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; Or, R a and R b form a 3- to 11-membered heterocycle together with atoms bonded thereto, the heteroatoms of the 3- to 11-membered heterocycloalkyl group are one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R a-1 , R a-2 , R a-3 , R a-4 and R a-5are each independently a halogen, a cyano group, a hydroxyl group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more types selected from N, S, and O, and the number of heteroatoms is one, two, or three, and the heteroatom of the 5- to 10-membered heteroaryl group is one or more types selected from N, S, and O, and the number of heteroatoms is one, two, or three.

[0142] The present invention provides a five-membered fused six-membered compound represented by formula III, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, the ring Cy 4 is an imidazole ring, a 5-membered heterocycle, or an oxo 5-membered heterocycle, the heteroatom of the 5-membered heterocycle is one or more selected from N, S, and O, and the number of heteroatoms is 1, 2, or 3; n is 1, 2 or 3; m is 1, 2 or 3; X is N or C, Q is N or C, and E is N or CH; R 3 is hydrogen or absent, and R 3 If there is no N and the ring Cy 1 The atoms above, together with the atoms attached to them, form the ring Cy. 3 or N and R 2 The atoms above, together with the atoms attached to them, form the ring Cy. 2 Forming Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of the 5-membered heteroaromatic ring is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, Ring Cy 2is a 5- to 9-membered heterocycle, the heteroatom of the 5- to 9-membered heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; Ring Cy 3 is a 5- to 9-membered oxo heterocycle, the heteroatom of the 5- to 9-membered oxo heterocycle is one or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3, and at least one heteroatom is a N atom; R 1 each independently represents one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1 a 3- to 11-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; R 1-4 are each independently unsubstituted or substituted with one or more R 1-1-1 a 3- to 8-membered heterocycloalkyl group substituted with a hydroxyl group, a halogen, unsubstituted or substituted with one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with [ka] or -SO2-C1-C6 alkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3; R 1-1 each independently represents a halogen, an oxo, a hydroxyl group, [ka] Unsubstituted or one or more R 1-1-1a 3- to 8-membered heterocycloalkyl group substituted with, an unsubstituted or C1-C6 alkyl group substituted with one or more halogens, a 3- to 10-membered cycloalkyl group, or a 6- to 10-membered aryl group, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is N, and the number of heteroatoms is 1, 2, or 3; R 1-2 each independently represents a hydroxyl group, a halogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens; [ka] or -SO2-C1 to C6 alkyl group; R 1-1-1 are each independently a C1 to C6 alkyl group, oxo, or a hydroxyl group, R 1-1-5 are each independently an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, a halogen, an oxo group, or a hydroxyl group; R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 a 3- to 8-membered cycloalkyl group, unsubstituted or substituted with one or more R 2-7 C1-C6 alkoxy group substituted with R 2-8 or one or more R 2-4 a C1-C6 alkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-1 , R 2-2 and R 2-7 are each independently a hydroxyl group, a halogen, an oxo, an unsubstituted or substituted C1-C6 alkyl group with one or more halogens, a 3- to 10-membered cycloalkyl group, or an unsubstituted or substituted C1-C6 alkyl group with one or more R 2-1-1a 3- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-4 each independently represents a hydroxyl group substituted with a halogen, a hydroxyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is 1, 2, or 3; R 2-8 is a 3- to 10-membered cycloalkyl group or a 3- to 11-membered heterocycloalkyl group, the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-1-1 are each independently a hydroxyl group, a halogen, an oxo, a C1-C6 alkyl group, a 3- to 10-membered cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group being one or more types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2 is unsubstituted or has one or more R 2-7 When R is a C1-C6 alkoxy group substituted with 1 each independently represents one or more R 1-4 and R 1-4 are each independently a hydroxyl group, SO2-R a , -SO-R a or [ka] and R 2 is unsubstituted or has one or more R 2-1 or an unsubstituted 3- to 6-membered cycloalkyl group, and R 1 each independently represents one or more R 1-4When R is a C1-C6 alkyl group substituted with 1-4 are each independently unsubstituted or substituted with one or more R 1-1-1 a 3- to 8-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with [ka] wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is N, and the number of heteroatoms is 1, 2, or 3; R 4 are each independently unsubstituted or substituted with one or more R 4-1 a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 4-5 a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 4-3 a 3- to 11-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; a heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S and O, and the number of heteroatoms is one, two or three; R 4-1 and R 4-5 are each independently a halogen, [ka] Unsubstituted or one or more R 4-1-1 a C1-C6 alkoxy group substituted with [ka] Cyano group, oxo, hydroxyl group, or unsubstituted or one or more R 4-1-3 C1-C6 alkyl group, unsubstituted or substituted with one or more R 4-1-4 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 4-1-5a 3- to 11-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 4-3 each independently represents a hydroxyl group, a halogen, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens; [ka] or oxo, R 4-1-1 , R 4-1-3 , R 4-1-4 and R 4-1-5 are each independently a halogen, a hydroxyl group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, or a C1-C6 alkoxy group that is unsubstituted or substituted with one or more halogens, the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more types selected from N, S and O, the number of heteroatoms is 1, 2 or 3, Each R 4-3-1 is hydrogen, a C1-C6 alkyl group, or a C1-C6 alkoxy group, R a and R b are each independently H, unsubstituted or one or more R a-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R a-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R a-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R a-4 or an unsubstituted or substituted 6- to 10-membered aryl group substituted with one or more R a-5 is a 5- to 10-membered heteroaryl group substituted with Or, R a and R bform a 3- to 11-membered heterocycle together with atoms bonded thereto, the heteroatoms of the 3- to 11-membered heterocycloalkyl group being one or more selected from N, S and O, the number of heteroatoms being one, two or three, the heteroatoms of the 3- to 11-membered heterocycle being one or more selected from N, S and O, the number of heteroatoms being one, two or three, R a-1 , R a-2 , R a-3 , R a-4 and R a-5 are each independently a halogen, a cyano group, a hydroxyl group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more types selected from N, S, and O, and the number of heteroatoms is one, two, or three, and the heteroatom of the 5- to 10-membered heteroaryl group is one or more types selected from N, S, and O, and the number of heteroatoms is one, two, or three.

[0143] In a preferred embodiment, in the 5-membered fused 6-membered compound represented by formula III or a pharma- ceutically acceptable salt thereof, some groups are defined as follows, and other groups may be defined as in any one of the above embodiments (hereinafter simply referred to as "a preferred embodiment"): Ring Cy 4 is an imidazole ring, an oxazole ring, a thiazole ring, a 5-membered heterocycle, or an oxo 5-membered heterocycle, the heteroatom of the 5-membered heterocycle is O, the number of heteroatoms is 1, and the heteroatom of the oxo 5-membered heterocycle is N, the number of heteroatoms is 1.

[0144] In one preferred embodiment, the ring Cy 4 is an imidazole ring, a 5-membered heterocycle, or an oxo 5-membered heterocycle, the heteroatom of the 5-membered heterocycle is O, the number of heteroatoms is 1, and the heteroatom of the oxo 5-membered heterocycle is N, the number of heteroatoms is 1.

[0145] In one preferred embodiment, the ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of the 5-membered heteroaromatic ring is one or two types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0146] In one preferred embodiment, the ring Cy 2 is a 5- or 6-membered heterocycle, the heteroatom of the 5- or 6-membered heterocycle is N, and the number of heteroatoms is 1, 2 or 3.

[0147] In one preferred embodiment, the ring Cy 3 is an oxo 5- to 9-membered heterocycle, the heteroatom of the oxo 5- to 9-membered heterocycle is N, and the number of heteroatoms is 1, 2 or 3.

[0148] In one preferred embodiment, R 1 each independently represents one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R 1-1 The 3- to 11-membered heterocycloalkyl group is substituted with one or two heteroatoms selected from N, O and S, and the number of heteroatoms is one or two.

[0149] In one preferred embodiment, R 1-4 are each independently unsubstituted or substituted with one or more R 1-1-1 a 3- to 8-membered heterocycloalkyl group substituted with a hydroxyl group, a halogen, unsubstituted or substituted with one or more R 1-1-5 or a -SO2-C1-C6 alkyl group substituted with, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3.

[0150] In one preferred embodiment, R 1-4are each independently deuterium, unsubstituted or one or more R 1-1-1 a 3- to 8-membered heterocycloalkyl group substituted with a hydroxyl group, a halogen, unsubstituted or substituted with one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with [ka] or -SO2-C1-C6 alkyl group, the heteroatoms of the 3- to 8-membered heterocycloalkyl group being one or two of N, S and O, and the number of heteroatoms being 1, 2 or 3.

[0151] In one preferred embodiment, R 1-1 each independently represents an oxo group, a hydroxyl group, [ka] Or a C1 to C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0152] In a preferred embodiment, R 1-1 each independently represents a halogen, an oxo, a hydroxyl group, [ka] Unsubstituted or one or more R 1-1-1 or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3.

[0153] In one preferred embodiment, R 1-2 are each independently a hydroxyl group or a halogen.

[0154] In one preferred embodiment, R 1-2 are each independently a hydroxyl group, a -SO2-C1 to C6 alkyl group, or a halogen.

[0155] In one preferred embodiment, R 1-1-1 are each independently a C1 to C6 alkyl group, oxo, or a hydroxyl group.

[0156] In one preferred embodiment, R 1-1-1 each independently represents deuterium, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, oxo, [ka] It is a halogen or a hydroxyl group.

[0157] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 a 3- to 6-membered cycloalkyl group, unsubstituted or substituted with one or more R 2-4 C1-C6 alkyl group substituted with R 2-8 or an unsubstituted or substituted hydroxyl group with one or more R 2-7 The 3- to 11-membered heterocycloalkyl group is a C1-C6 alkoxy group substituted with one or two heteroatoms selected from N and O, and the number of heteroatoms is one or two.

[0158] In one preferred embodiment, R 2-1 and R 2-2 are each independently oxo, a hydroxyl group, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0159] In one preferred embodiment, R 2-1 and R 2-2 are each independently deuterium, oxo, halogen, a hydroxyl group, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0160] In one preferred embodiment, R 2-4 are each independently a hydroxyl group substituted with a halogen, a hydroxyl group, or a 3- to 8-membered heterocycloalkyl group, the heteroatoms of the 3- to 8-membered heterocycloalkyl group being one or two types of N, S, or O, and the number of heteroatoms is one or two.

[0161] In one preferred embodiment, R 2-4 are each independently a hydroxyl group substituted with deuterium, a halogen, a hydroxyl group, or a 3- to 8-membered heterocycloalkyl group, and the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or two types of N, S, or O, and the number of heteroatoms is one or two.

[0162] In one preferred embodiment, R 2-8 represents a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, the heteroatom of the 3- to 6-membered heterocycloalkyl group being one or two kinds selected from N and O, and the number of heteroatoms being one or two.

[0163] In one preferred embodiment, R 2-7 are each independently a halogen.

[0164] In one preferred embodiment, R 2-7 are each independently deuterium or a halogen.

[0165] In one preferred embodiment, R 4 are each independently unsubstituted or substituted with one or more R 4-5 phenyl groups, unsubstituted or substituted with one or more R 4-1 a 5- to 6-membered heteroaryl group substituted with, or unsubstituted or substituted with one or more R 4-3a 3- to 6-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 5- to 6-membered heteroaryl group is N and the number of heteroatoms is 1, 2 or 3; and the heteroatom of the 3- to 6-membered heterocycloalkyl group is one or more types selected from N, S and O, and the number of heteroatoms is 1 or 2.

[0166] In one preferred embodiment, R 4-1 and R 4-5 are each independently a C1 to C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0167] In one preferred embodiment, R 4-3 are each independently a halogen or a C1 to C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0168] In one preferred embodiment, the ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatoms of the 5-membered heteroaromatic ring are one or two types selected from N and O, and the number of heteroatoms is two.

[0169] In one preferred embodiment, the ring Cy 2 is a 5- or 6-membered heterocycle, the heteroatom of the 5- or 6-membered heterocycle is N, and the number of heteroatoms is 1 or 2.

[0170] In one preferred embodiment, the ring Cy 3 is an oxo 5- to 6-membered heterocycle, the heteroatom of the oxo 5- to 6-membered heterocycle is N, and the number of heteroatoms is 1 or 2.

[0171] In one preferred embodiment, R 1 each independently represents one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 6-membered cycloalkyl group, unsubstituted or substituted with one or more R 1-1The heteroatoms of the 3- to 6-membered heterocycloalkyl group are one or two types of N, O and S, and the number of heteroatoms is one or two.

[0172] In one preferred embodiment, R 1 each independently represents one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 6-membered cycloalkyl group, unsubstituted or substituted with one or more R 1-1 The heteroatoms of the 3- to 8-membered heterocycloalkyl group are one or two types of N, O and S, and the number of heteroatoms is one or two.

[0173] In one preferred embodiment, R 1 is one or more R 1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 a 3- to 6-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1 The 3- to 6-membered heterocycloalkyl group is substituted with one or two heteroatoms selected from N, O and S, and the number of heteroatoms is one or two.

[0174] In one preferred embodiment, R 1 teeth [ka] a 3- to 6-membered cycloalkyl group substituted with one hydroxyl group; a 6-membered cycloalkyl group substituted with one -SO2-C1 to C6 alkyl group; [ka] It is.

[0175] In one preferred embodiment, R 1-1 , R 1-2and R 1-4 are each independently a deuterium atom, a hydroxyl group, [ka] Oxo, halogen, [ka] -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-5 a 3- to 6-membered cycloalkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two types of N, O and S, and the number of heteroatoms is one.

[0176] In one preferred embodiment, R 1-1 each independently represents oxo, [ka] Unsubstituted or one or more R 1-1-4 C1-C6 alkyl group substituted with, or unsubstituted or substituted with one or more R 1-1-1 The heteroatom of the 3- to 6-membered heterocycloalkyl group is one or two types of N, O and S, and the number of the heteroatom is one.

[0177] In one preferred embodiment, R 1-2 are each independently a halogen, a hydroxyl group, or a -SO2-C1 to C6 alkyl group.

[0178] In one preferred embodiment, R 1-4 are each independently a deuterium atom, a hydroxyl group, [ka] Halogen, -SO2-C1-C6 alkyl group, unsubstituted or one or more R 1-1-4 or an unsubstituted or one or more R 1-1-1 The heteroatom of the 3- to 8-membered heterocycloalkyl group is one or two types of N, O or S, and the number of the heteroatom is one.

[0179] In one preferred embodiment, R 1-4 are each independently unsubstituted or substituted with one or more R 1-1-1 a 3- to 8-membered heterocycloalkyl group substituted with deuterium, a hydroxyl group, a halogen, unsubstituted or substituted with one or more R 1-1-5 or a -SO2-C1 to C6 alkyl group substituted with, and the heteroatom of the 3- to 8-membered heterocycloalkyl group is N, and the number of heteroatoms is one.

[0180] In one preferred embodiment, R 1-1 each independently represents a halogen, an oxo, a hydroxyl group, [ka] Or a C1 to C6 alkyl group that is unsubstituted or substituted with one or more halogens.

[0181] In one preferred embodiment, R 1-2 are each independently a hydroxyl group or a halogen.

[0182] In one preferred embodiment, R 1-1-1 are each independently a C1 to C6 alkyl group or a hydroxyl group.

[0183] In one preferred embodiment, R 1-1-1 are each independently a C1 to C6 alkyl group that is unsubstituted or substituted with one or more halogens, a halogen, or a hydroxyl group.

[0184] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-1 a 3- to 7-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 2-2 a 3- to 6-membered cycloalkyl group, unsubstituted or substituted with one or more R 2-4 C1-C6 alkyl group substituted with, or unsubstituted or substituted with one or more R 2-7 The heteroatoms of the 3- to 7-membered heterocycloalkyl group are one or two types selected from N and O, and the number of heteroatoms is one or two.

[0185] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-1 a 5- to 6-membered heterocycloalkyl group substituted with one or more R 2-4 C1-C6 alkyl group substituted with, or unsubstituted or substituted with one or more R 2-7 The 5- to 6-membered heterocycloalkyl group is a C1-C6 alkoxy group substituted with, and the heteroatoms of the 5- to 6-membered heterocycloalkyl group are one or two types selected from N and O, and the number of heteroatoms is one or two.

[0186] In one preferred embodiment, R 2 is unsubstituted or substituted with one or more R 2-1 a 5- to 6-membered heterocycloalkyl group substituted with one or more R 2-4 C1-C6 alkyl group substituted with, or unsubstituted or substituted with one or more R 2-7 and the heteroatom of the 5- to 6-membered heterocycloalkyl group is N, and the number of heteroatoms is 1.

[0187] In one preferred embodiment, R 2-1 and R 2-2 are each independently a hydroxyl group.

[0188] In one preferred embodiment, R 2-1are each independently a hydroxyl group or a halogen.

[0189] In one preferred embodiment, R 2 In the above, the 3- to 11-membered heterocycloalkyl group is a spiro ring or a 5-membered monocyclic ring.

[0190] In one preferred embodiment, R 2-4 are each independently a hydroxyl group.

[0191] In one preferred embodiment, R 2-4 are each independently a hydroxyl group, deuterium, or a halogen.

[0192] In one preferred embodiment, R 2-7 are each independently a halogen.

[0193] In one preferred embodiment, R 2-7 are each independently a halogen or deuterium.

[0194] In one preferred embodiment, R 4 are each independently unsubstituted or substituted with one or more R 4-1 a 5- to 6-membered heteroaryl group substituted with, or unsubstituted or substituted with one or more R 4-5 The heteroatom of the 5- to 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2.

[0195] In one preferred embodiment, R 4 are each independently unsubstituted or substituted with one or more R 4-1 is a pyridyl group substituted with

[0196] In one preferred embodiment, R 4-1 and R 4-5 are each independently a C1 to C6 alkyl group that is unsubstituted or substituted with one or more fluorines.

[0197] In one preferred embodiment, R 4-1 are each independently a C1 to C6 alkyl group that is unsubstituted or substituted with one, two, or three halogens.

[0198] In a preferred embodiment, the five-membered fused six-membered compound of formula III is a compound of formula III-a, III-d, III-e or III-b: [ka]

[0199] In a preferred embodiment, the five-membered fused six-membered compound of formula III is formula III-c, III-f, or III-g: [ka]

[0200] In one preferred embodiment, R 1 are each independently [ka] It is.

[0201] In one preferred embodiment, R 2 is a methoxy group, -OCD3, isopropoxy group, trifluoromethoxy group, hydroxyl group, [ka] It is.

[0202] In one preferred embodiment, R 4 each independently represents a hydrogen atom, a bromine atom, a trifluoromethyl group, [ka] It is.

[0203] In one preferred embodiment, the ring Cy 1 teeth, [ka] It is.

[0204] In one preferred embodiment, the ring Cy 2 teeth, [ka] It is.

[0205] In one preferred embodiment, the ring Cy 2 teeth, [ka] It is.

[0206] In one preferred embodiment, the ring Cy 3 teeth, [ka] It is.

[0207] In one preferred embodiment, [ka] teeth, [ka] It is.

[0208] In a preferred embodiment, the five-membered fused six-membered compound represented by formula III or a pharma- ceutically acceptable salt thereof is any of the following compounds: [ka] [ka] [ka]

[0209] In the present invention, R 3 When is H, the ring Cy 2 and ring Cy 3 does not exist.

[0210] In the present invention, the ring Cy 1 In the above, the heteroatom of the 5-membered heteroaromatic ring is one or more selected from N, S and O, the number of heteroatoms is two, and the 5-membered heteroaromatic ring is preferably an oxazole ring, a pyrazole ring, a thiazole ring, or an imidazole ring, for example, [ka]

[0211] In the present invention, the ring Cy 2 In the above, the 5- to 9-membered heterocycle may be a 6-membered heterocycle, the heteroatom of which is N and the number of heteroatoms is 1 or 2, and is preferably a piperazine ring or a piperidine ring.

[0212] In the present invention, the ring Cy 3 In the above, the 5- to 9-membered oxo heterocycle is a 6-membered heterocycle having one or two heteroatoms, in which the heteroatom is N, and is preferably an oxopiperazine ring or an oxopiperidine ring, for example: [ka]

[0213] In the present invention, R 1 When is a halogen, said halogen is fluorine, chlorine, bromine, or iodine.

[0214] In the present invention, R 1 is unsubstituted or has one or more R 1-1In the case where the heterocycloalkyl group is a 3- to 11-membered heterocycloalkyl group substituted with R, the 3- to 11-membered heterocycloalkyl group may be a 3- to 9-membered heterocycloalkyl group, and preferably, the 3- to 9-membered heterocycloalkyl group is a piperidyl group, a tetrahydropyrrolyl group, a 2-azaspiro[3.3]heptyl group, a 2-oxaspiro[3.3]heptyl group, a morpholinyl group, a tetrahydropyranyl group, an azabicyclo[2.2.1]heptyl group, a tetrahydrothiopyranyl group, a 2-azaspiro[3.5]nonane, a diazabicyclo[2.2.1]heptyl group, an azabicyclo[3.2.1]octyl group, an azaspiro[3.4]octane, or an oxabicyclo[3.2.1]octyl group, and preferably, R 1-1 each independently represents a halogen, a hydroxyl group, an oxo group, [ka] or a C1-C6 alkyl group substituted with one or more halogens or heterocycloalkyl groups, preferably the unsubstituted or 1-1 The 3- to 11-membered heterocycloalkyl group substituted with [ka] It is.

[0215] In the present invention, R 1 is unsubstituted or has one or more R 1-2 In the case where R is a 3- to 10-membered cycloalkyl group substituted with R, the 3- to 10-membered cycloalkyl group may be a C3-C6 cycloalkyl group, or may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclopropyl group, a cyclobutyl group, or a cyclohexyl group, and preferably R 1-2 are each independently -SO2-R a , halogen, or hydroxyl group; R a is a C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-2 The 3- to 10-membered cycloalkyl group substituted with [ka] It is preferable that:

[0216] In the present invention, R 1 is unsubstituted or has one or more R 1-4 when R is a C1-C6 alkyl group substituted with, the C1-C6 alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a primary pentyl group, a sec-pentyl group, a tert-pentyl group, or a neopentyl group, or may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an isopentyl group; preferably, R 1-4 are each independently deuterium, halogen, hydroxyl group, -SO2-R a , [ka] a 3- to 6-membered cycloalkyl group substituted with a hydroxyl group, a 3- to 8-membered heterocycloalkyl group substituted with a hydroxyl group, or a 3- to 8-membered heterocycloalkyl group substituted with oxo, a 3- to 8-membered heterocycloalkyl group substituted with halogen and Boc, or a 3- to 8-membered heterocycloalkyl group substituted with halogen, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is preferably N and / or O, the number of heteroatoms is 1 or 2, and R a is a C1-C6 alkyl group, R b is hydrogen, preferably the unsubstituted or one or more R 1-4 The C1-C6 alkyl group substituted with [ka] It is.

[0217] In the present invention, R 1-1 , R 1-2 , R 1-4 , R 1-5 , R1-6 and R 1-7 When each is independently a halogen, the halogen may be fluorine, chlorine, bromine, or iodine, for example fluorine.

[0218] In the present invention, R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7 are each independently unsubstituted or one or more R 1-1-1 In the case of a 3- to 11-membered heterocycloalkyl group substituted with, the 3- to 11-membered heterocycloalkyl group is preferably a 3- to 7-membered heterocycloalkyl group, the heteroatom of the 3- to 11-membered heterocycloalkyl group is preferably N and / or O, the number of heteroatoms is preferably 1 or 2, and the 3- to 11-membered heterocycloalkyl group is preferably a tetrahydropyrrolyl group, an oxetanyl group, or a spiroheptyl group containing oxygen and / or nitrogen, for example, [ka] It is.

[0219] In the present invention, R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7 each independently is unsubstituted or represents one or more R 1-1-4 In the case where it is a C1 to C6 alkyl group substituted with, the C1 to C6 alkyl group may be a C1 to C4 alkyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, or may be an isopropyl group, a methyl group, or an ethyl group.

[0220] In the present invention, R 1-1-1are each independently a C1 to C6 alkyl group, the C1 to C6 alkyl group may be a C1 to C4 alkyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, or may be a methyl group or an ethyl group.

[0221] In the present invention, R 2 When is a halogen, the halogen may be fluorine, chlorine, bromine, or iodine.

[0222] In the present invention, R 2 is unsubstituted or has one or more R 2-1 In the case of a 3-membered to 11-membered heterocycloalkyl group substituted with R, the 3-membered to 11-membered heterocycloalkyl group may be a 3-membered to 8-membered heterocycloalkyl group, the heteroatom of the 3-membered to 11-membered heterocycloalkyl group is preferably N and / or O, the number of heteroatoms is 1 or 2, and the 3-membered to 11-membered heterocycloalkyl group is preferably a piperidyl group, a tetrahydropyrrolyl group, a 2-azaspiro[3.3]heptyl group, a 2-oxaspiro[3.3]heptyl group, a morpholinyl group, a tetrahydropyranyl group, an oxetanyl group, an azabicyclo[2.2.1]heptyl group, or a diazabicyclo[2.2.1]heptyl group, each R2-1 is preferably independently a halogen, an oxo, or a hydroxyl group, and the unsubstituted or one or more R 2-1 The 3- to 8-membered heterocycloalkyl group substituted with [ka] It is preferable that:

[0223] In the present invention, R 2 is unsubstituted or has one or more R 2-2In the case where R is a 3- to 10-membered cycloalkyl group substituted with R, the 3- to 10-membered cycloalkyl group may be a C3-C6 cycloalkyl group, or may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclopropyl group, a cyclobutyl group, or a cyclohexyl group; 2-2 are preferably each independently a halogen or a hydroxyl group, and are unsubstituted or substituted with one or more R 2-2 The 3- to 10-membered cycloalkyl group substituted with [ka] It is preferable that:

[0224] In the present invention, R 2 is unsubstituted or has one or more R 2-4 In the case where R is a C1-C6 alkyl group substituted with R, the C1-C6 alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a primary pentyl group, a sec-pentyl group, a tert-pentyl group, or a neopentyl group, or may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an isopentyl group; 2-4 are each independently deuterium, halogen, hydroxyl group, -SO2-R a or [ka] Preferably, R a is a C1-C6 alkyl group, R b is hydrogen, and the unsubstituted or one or more R 2-4 The C1-C6 alkyl group substituted with [ka] may be also possible.

[0225] In the present invention, R 2is unsubstituted or has one or more R 2-7 In the case where R is a C1-C6 alkoxy group substituted with, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a primary butoxy group, a sec-butoxy group, or a tert-butoxy group, or a methoxy group, an ethoxy group, or an isopropoxy group; 2-7 are each preferably independently deuterium or halogen, and the unsubstituted or one or more R 2-7 The C1 to C6 alkoxy group substituted with is preferably a methoxy group, an isopropoxy group, a deuterated methoxy group, or a trifluoromethoxy group.

[0226] In the present invention, R 2 R 2-8 If R is a hydroxyl group substituted with 2-8 may be a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, the heteroatom of the 3- to 6-membered heterocycloalkyl group is oxygen, the number of heteroatoms is one, and the R 2-8 The hydroxyl group substituted with [ka] It is preferable that:

[0227] In the present invention, R 2-1 , R 2-2 , R 2-4 , R 2-5 , R 2-6 and R 2-7 When each is independently a halogen, the halogen may be fluorine, chlorine, bromine, or iodine, for example, fluorine.

[0228] In the present invention, R 2-1 , R 2-2 , R 2-4 , R 2-5 , R 2-6 and R 2-7each independently represents unsubstituted or one or more R 2-1-1 In the case where the 3- to 11-membered heterocycloalkyl group is a 5- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 11-membered heterocycloalkyl group is preferably N and / or O, and the number of heteroatoms is 1 or 2, and the unsubstituted or one or more R 2-1-1 The 3- to 11-membered heterocycloalkyl group substituted with is preferably a tetrahydropyrrolyl group, an oxetanyl group, or a spiroheptyl group containing one oxygen and / or one nitrogen, for example: [ka]

[0229] In the present invention, R 2-1-1 are each independently a C1 to C6 alkyl group, the C1 to C6 alkyl group may be a C1 to C4 alkyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, or may be a methyl group or an ethyl group.

[0230] In the present invention, R 4 is unsubstituted or has one or more R 4-1 In the case where R is a 5- to 10-membered heteroaryl group substituted with 4-1 are each preferably independently a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more halogens, and the unsubstituted or 4-1 The 5- to 10-membered heteroaryl group substituted with [ka] It is preferable that:

[0231] In the present invention, R 4 is unsubstituted or has one or more R 4-5 In the case where R is a 6- to 10-membered aryl group substituted with 4-5 is preferably each independently a C1 to C6 alkyl group, or a C1 to C6 alkyl group substituted with one or more halogens.

[0232] In the present invention, R 4 is unsubstituted or has one or more R 4-3 In the case where R is a 3- to 11-membered heterocycloalkyl group substituted with 4-3 are each independently a halogen, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more halogens, oxo, or [ka] Preferably, R 4-3-1 is hydrogen, a C1-C6 alkyl group, or a C1-C6 alkoxy group, and the unsubstituted or one or more R 4-3 The 3- to 8-membered heterocycloalkyl group substituted with [ka] It is more preferable that:

[0233] In the present invention, R 4 When each is independently a halogen, the halogen may be fluorine, chlorine, bromine, or iodine, for example bromine.

[0234] In the present invention, R 4-1is a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, may be an isopropyl group, a methyl group, or an ethyl group, the halogen may be fluorine, chlorine, bromine, or iodine, for example, fluorine, and the C1-C6 alkyl group unsubstituted or substituted with one or more halogens is preferably a C1-C6 alkyl group substituted with fluorine, for example, a difluoromethyl group, or a trifluoromethyl group.

[0235] In the present invention, R 4-3 is a C1-C6 alkyl group, the C1-C6 alkyl group may be a C1-C4 alkyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, or may be a methyl group or an ethyl group.

[0236] In the present invention, R 4-3-1 is a C1-C6 alkyl group, the C1-C6 alkyl group may be a C1-C4 alkyl group, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, or may be a methyl group or an ethyl group.

[0237] In the present invention, the ring Cy 4 is a 5-membered heterocycle, the heteroatoms of the 5-membered heterocycle are one or two selected from N, S and O, and the number of heteroatoms is one or two, for example, [ka]

[0238] In the present invention, the ring Cy 4is an oxo 5-membered heterocycle, the heteroatoms of the oxo 5-membered heterocycle are one or two selected from N and S, the number of heteroatoms is one or two, and the oxo 5-membered heterocycle is [ka] It is preferable that:

[0239] In the present invention, R a and R b When these form a 3- to 11-membered heterocyclic ring together with the atom bonded thereto, the 3- to 11-membered heterocyclic ring group may be a 3- to 6-membered heterocycloalkyl group, the heteroatom of the 3- to 6-membered heterocycloalkyl group is preferably N, O or S, the number of heteroatoms is one, and the 3- to 11-membered heterocyclic ring is [ka] may be also possible.

[0240] In the present invention, preferably, [ka] teeth, [ka] It is.

[0241] In the present invention, preferably, -SO2-R a teeth, [ka] It is.

[0242] In the present invention, preferably, [ka] teeth, [ka] It is.

[0243] In the present invention, preferably, [ka] teeth [ka] It is.

[0244] In the present invention, preferably, [ka] teeth [ka] It is.

[0245] The present invention further provides a method for preparing a five-membered fused six-membered compound of formula I, II or III, comprising: The method for producing the 5-membered condensed 6-membered compound represented by formula I includes the following steps: in a solvent, in the presence of a base and a condensing agent, a compound represented by formula IA and a compound represented by formula IB are subjected to the following condensation reaction: [ka] R 3 is hydrogen, n, m, Y, E, R 3 , TamakiCy 1 , TamakiCy 2 , TamakiCy 3 , R 1 , R 2 , and R 4 The definition of is as above, The method for producing the 5-membered condensed 6-membered compound represented by formula II includes the following steps: in a solvent, in the presence of a base and a condensing agent, a compound represented by formula II-A and a compound represented by formula II-B are subjected to the following condensation reaction: [ka] R 3is hydrogen, n, m, E, R 3 , TamakiCy 1 , TamakiCy 2 , TamakiCy 3 , R 1 , R 2 , and R 4 The definition of is as above, The method for producing the 5-membered condensed 6-membered compound represented by formula III includes the following steps: in a solvent, in the presence of a base and a condensing agent, a compound represented by formula III-A and a compound represented by formula III-B are subjected to the following condensation reaction: [ka] R 3 is hydrogen, and n, m, E, X, Q, R 3 , TamakiCy 1 , TamakiCy 2 , TamakiCy 3 , TamakiCy 4 , R 1 , R 2 and R 4 The definition is as stated above.

[0246] In the present invention, the solvent is a common solvent for this type of reaction in the art, preferably an amide solvent, more preferably DMF, for example anhydrous DMF.

[0247] In the present invention, the amount of the solvent used is the amount of a solvent normally used in the art, and preferably, the volume molar ratio of the solvent to the compound represented by formula IA, the compound represented by formula II-A, or the compound represented by formula III-A is (20-5):1 mL / mmol, for example, 12:1 mL / mmol or 12.5:1.

[0248] In the present invention, the base is a common base for this type of reaction in the art, preferably a nitrogen-containing organic base, such as N,N-diisopropylethylamine.

[0249] In the present invention, the amount of the base used is the amount of a base normally used in the art, and preferably the molar ratio of the base to the compound represented by formula IA, the compound represented by formula II-A, or the compound represented by formula III-A is (1-5):1, for example, 1.5:1, 2:1, or 3:1.

[0250] In the present invention, the condensing agent is a condensing agent for this type of reaction in the art, and is preferably a phosphate-based condensing agent, such as bromotripyrrolidinophosphonium hexafluorophosphate or O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0251] In the present invention, the amount of the condensing agent used is the amount of a condensing agent normally used in the art, and preferably the molar ratio of the condensing agent to the compound represented by formula IA, the compound represented by formula II-A, or the compound represented by formula III-A is (1-2):1, for example, 1:1, 1.2:1, 1.3:1, or 1.5:1.

[0252] In the present invention, the reaction temperature of the condensation reaction is a normal reaction temperature in the art, and is preferably -10°C to 30°C, for example, 0°C.

[0253] The present invention further provides a pharmaceutical composition comprising the five-membered fused six-membered compound represented by formula I, formula II or formula III or a pharma- ceutically acceptable salt thereof, and a pharmaceutical auxiliary.

[0254] The present invention further provides a pharmaceutical composition comprising the five-membered fused six-membered compound represented by formula I, formula II or formula III or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0255] The present invention further provides a use of substance Z in the manufacture of a medicament for the treatment and / or prevention of an FLT3 and / or IRAK4 inhibitor or an FLT3 and / or IRAK4-related disease, wherein substance Z is a 5-membered fused 6-membered compound represented by formula I, formula II or formula III, or a pharma- ceutically acceptable salt thereof.

[0256] The FLT3-related disease includes hematological and / or solid tumors.

[0257] The blood tumor may be one or more selected from acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, acute anaplastic leukemia, anaplastic large cell lymphoma, prolymphocytic leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma, multiple myeloma, myeloproliferative disorders, mantle cell lymphoma, and adult new-onset acute myeloid leukemia.

[0258] The solid tumor may be one or more selected from colorectal cancer, renal cell carcinoma, non-small cell lung cancer, bladder cancer, ovarian cancer, breast cancer, pancreatic cancer, gastric adenocarcinoma, prostate cancer, and lung cancer.

[0259] The IRAK4-associated disease includes an autoimmune disease, an inflammatory disease, a cardiovascular disease, cancer, or a central nervous system disease.

[0260] The autoimmune disease may be one or more selected from rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes (e.g., type I diabetes), psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome.

[0261] The inflammatory disease may be one or more selected from, but is not limited to, rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes (e.g., type I diabetes), psoriasis, psoriatic arthritis, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome.

[0262] The cardiovascular disease may be stroke or atherosclerosis.

[0263] The present invention further provides a method for treating and / or preventing an FLT3 and / or IRAK4-related disease, the method comprising administering to a patient an effective amount of substance Z, wherein substance Z is a compound represented by formula I, formula II or formula III or a pharma- ceutically acceptable salt thereof.

[0264] Unless otherwise specified, the meanings of terms in the present invention are as follows.

[0265] The terms "compound" and "pharmaceutically acceptable salt" mean that, when tautomers exist, they may exist as a single tautomer or a mixture thereof, and it is preferred that the more stable tautomer exists predominantly.

[0266] When a linking group is represented as "not present", the structures on both sides of the linking group are directly linked by a single bond. For example, in the case of "-ABC-", when B does not exist, "-ABC-" becomes "-AC-".

[0267] term [ka] means present or absent.

[0268] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0269] The term "oxo" means that a hydrogen or lone pair of electrons on a non-oxygen atom is replaced with an oxygen. For example, [ka] When is substituted with oxo, [ka] And then, [ka] When is substituted with oxo, [ka] It becomes.

[0270] The term "cycloalkyl group" refers to a group having a specified number of carbon atoms (e.g., C3-C 10 ) and means a saturated monocyclic cyclic group consisting of only carbon atoms. Here, examples of the monocycloalkyl group include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0271] The term "alkyl group" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0272] The term "heterocycloalkyl group" refers to a cyclic group having a specified number of ring atoms (e.g., 3-11, 3-8), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), where the heteroatom may or may not be attached to other groups as a linking group (e.g., a piperidyl group is [ka] etc.), monocyclic, fused, bridged, or spirocyclic, and each ring is saturated. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidyl, and the like.

[0273] The term "heterocycle" refers to a cyclic group having a specified number of ring atoms (e.g., 3-11, 3-8), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), where the heteroatom may or may not be bonded to other groups as a linking group (e.g., a piperidine ring is [ka] etc.), a monocyclic ring, a fused ring, a bridged ring, or a spiro ring. Examples of the heterocycle include, but are not limited to, an azetidine ring, a tetrahydropyrrole ring, a tetrahydrofuran ring, a morpholine ring, and a piperidine ring.

[0274] The term "aryl group" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C 10 ) and refers to a cyclic group consisting of only carbon atoms, which may be monocyclic or polycyclic, and at least one ring is aromatic (complies with Hückel's rule). Aryl groups are bonded to other fragments in the molecule through a ring that may or may not be aromatic. Aryl groups include, but are not limited to, phenyl, naphthyl, etc.

[0275] The term "heteroaryl group" refers to a cyclic group having a specific number of ring atoms (e.g., 5-10, 5-8), a specific number of heteroatoms (e.g., 1, 2, or 3), a specific type of heteroatom (one or more of N, O, and S), which may be monocyclic or polycyclic, and in which at least one ring is aromatic (complies with Hückel's rule). Heteroaryl groups are bonded to other fragments in the molecule through rings that are aromatic or non-aromatic. Heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

[0276] A "-" at the end of a group means that the group is attached to another fragment in the molecule through that site. For example, CH3-C(=O)- refers to an acetyl group.

[0277] In structural fragments [ka] means that the structural fragment is connected to another fragment in the molecule through that site. For example, [ka] refers to an acetyl group.

[0278] The term "plurality" means two, three, four, or five.

[0279] In the definition of a compound, any variable (e.g., R 1-1 ) appear multiple times, their definitions are independent of each other and do not affect each other. For example, three R 1-1 C6~C substituted with 10 Aryl groups are C6 to C 10 R with three aryl groups 1-1 and three R 1-1 This means that the definitions are independent of each other and do not affect each other.

[0280] The term "pharmaceutical acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and compatible with patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting a sufficient amount of a pharmaceutically acceptable base with the free form of the compound in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, etc. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the free form of the compound in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, acetate, trifluoroacetate, sulfate, methanesulfonate, etc. For more information, see Handbook of PHARMACEUTICAL SALTS: PROPERTIES, SELECTION, AND USE (P Heinrich STAHL, 2002).

[0281] The term "pharmaceutical auxiliary substances" refers to excipients and additives used in the production and formulation of pharmaceutical products, including all substances contained in drug preparations, except for active ingredients. For details, see the Pharmacopoeia of the People's Republic of China (2020 edition) and the Handbook of Pharmaceutical (Raymond CRowe, 2009).

[0282] The term "treatment" means any of the following: (1) alleviating one or more biological symptoms of a disease; (2) inhibiting one or more points in the biological cascade that causes a disease; or (3) slowing the progression of one or more biological symptoms of a disease.

[0283] The term "prevention" means reducing the risk of developing a disease.

[0284] The term "patient" refers to any animal that has received or will receive treatment, preferably a mammal, and most preferably a human, including, but not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0285] Various preferred embodiments of the present invention can be obtained by combining the above preferred conditions in any desired manner without going against the common knowledge of the art.

[0286] All of the reagents and raw materials used in the present invention are commercially available.

[0287] The positive and progressive effect of the present invention is that when FLT3 inhibitors are used as monotherapy, the disease recurs early and target-dependent and non-target-dependent drug resistance occurs. Although the rate of non-target drug resistance can be reduced by using drugs that jointly inhibit signaling pathways related to cell survival, the effect is still limited. The compound according to the present invention has an inhibitory effect on FLT3 and / or IRAK4. As a dual-target inhibitor of FLT3 and IRAK4, the compound developed by the present invention has potential clinical application value, and is expected to improve the prognosis of patients and reduce the possibility of drug resistance. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0288] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of these examples. In the following examples, experimental methods for which no specific conditions are described are selected according to conventional methods and conditions or product instructions.

[0289] Example II-1: Synthesis of II-1 [ka]

[0290] Step 1: Synthesis of II-1-1 To a solution of 4-methylbenzenesulfonyl chloride (1.12 g, 5.85 mmol), 3-(2-hydroxyethyl)pyrrolidin-2-one (0.63 g, 4.88 mmol), DMAP (4-dimethylaminopyridine) (29.80 mg, 243.89 μmol), and anhydrous DCM (dichloromethane) (6 mL), TEA (triethylamine) (1.48 g, 14.63 mmol, 2.04 mL) was added, and the reaction mixture was stirred at 25 °C for 4 h until the reaction was complete. H2O (50 mL) was added to the reaction mixture and stirred for 5 min. The resulting mixture was extracted with EA (ethyl acetate) (40 mL × 3), and the combined organic phase was washed with brine (20 mL), then dried over anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain the crude product II-1-1 (1 g, crude product) as a white solid. MS(ESI)m / z:284.3[M+H] + .

[0291] Step 2: Synthesis of II-1-2 To a solution of methyl 5-nitro-2H-indazole-6-carboxylate (780.57 mg, 3.53 mmol) and II-1-1 (2 g, 7.06 mmol) in THF (tetrahydrofuran) (10 mL), potassium carbonate (1.46 g, 10.59 mmol, 639.02 mmol) and tetrabutylammonium bromide (4.55 g, 14.12 mmol) are added, and the reaction mixture is stirred at 60 °C for 20 h until the reaction is complete. The reaction mixture is diluted with H2O (50 mL), and the resulting mixture is extracted with EA (ethyl acetate) (30 mL x 3), and the combined organic phase is washed with saturated brine (20 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by silica gel chromatography, eluted with DCM:MeOH = 70 / 1, to give yellow solid product II-1-2 (0.4 g, 34.11% yield). MS(ESI)m / z:333.3[M+H] + .

[0292] Step 3: Synthesis of II-1-3 To a solution of II-1-2 (0.28 g, 842.58 μmol) in ethanol (3 mL), Fe (564.7 mg, 10.11 mmol), ammonium chloride (540.84 mg, 10.11 mmol, 353.49 μL), and H2O (1 mL) were added, and the reaction mixture was reacted at 70 °C for 4.5 h. The mixture was diluted with water (50 mL) and extracted with EA (ethyl acetate) (30 mL x 3). The combined organic phase was washed with brine (10 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to give the brown solid crude product II-1-3 (0.2 g, crude). MS (ESI) m / z: 303.3 [M+H] + .

[0293] Step 4: Synthesis of II-1-4 To a solution of 2-(2-methyl-4-pyridyl)oxazole-4-carboxylic acid (64.84 mg, 317.54 μmol), II-1-3 (0.08 g, 264.61 μmol), DIPEA (DIPEA is N,N-diisopropylethylamine) (68.40 mg, 529.23 μmol, 92.18 μL), and anhydrous DMF (4 mL) was added PyBOP (bromotripyrrolidinophosphonium hexafluorophosphate) (165.24 mg, 317.54 μmol) and the reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was diluted with water (50 mL) and the resulting mixture was extracted with EA (ethyl acetate) (20 mL×3). The combined organic phase was washed with brine (20 mL), then dried over anhydrous Na2SO4, filtered and concentrated to give the yellow solid crude product II-1-4 (0.15 g, 96.05% yield). MS (ESI) m / z: 489.5 [M+H] + .

[0294] Step 5: Synthesis of II-1 A solution of II-1-4 (0.15 g, 307.07 mmol), lithium chloride (130.17 mg, 3.07 mmol, 62.94 μL), and anhydrous THF (4 mL) was stirred at 0° C. under the protection of N2, and methylmagnesium chloride (160.75 mg, 2.15 mmol) was added slowly over 30 min. The reaction mixture was stirred for 3 h at 0° C., and then diluted with water (50 mL). The resulting mixture was extracted with EA (ethyl acetate) (20 mL×3), and the combined organic phase was washed with brine (20 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the white solid product II-1 (0.014 g, 9.33% yield). MS (ESI) m / z: 489.5 [M+H] + , 1 H NMR (500MHz, DMSO-d6) δ: 11.89(s, 1H), 8.97(s, 1H), 8.70(dd, J=5.0, 1.0Hz , 1H), 8.63(s,1H), 8.37(d,J=1.0Hz,1H), 7.84~7.81(m,2H), 7.62(s,1H), 7. 60(s,1H), 6.21(s,1H), 4.55~4.48(m,2H), 3.17~3.08(m,2H), 2.61(s,3H), 2.35~2.30(m,1H), 2.13~2.07(m,2H), 1.91~1.83(m,1H), 1.68~1.61(m,7H).

[0295] Example II-2: Synthesis of II-2 [ka]

[0296] Step 1: Synthesis of II-2-1 To a solution of 6-methoxy-5-nitro-2H-indazole (1 g, 26 mmol), II-1-1 (2.2 g, 7.8 mmol) in 1,4-dioxane (10 mL), TBAB (5 g, 15.5 mmol) and K2CO3 (2.9 g, 20.7 mmol) were added, and the reaction was stirred at room temperature for 16 h until the reaction was complete. Water (10 mL) was added for dilution, and the resulting mixture was extracted with EA (ethyl acetate) (10 mL x 3), and the combined organic phase was washed with brine (20 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a pale yellow solid product II-2-1 (173 mg, 11% yield). MS (ESI) m / z: 305.1 [M+H] + .

[0297] Step 2: Synthesis of II-2-2 II-2-1 (173 mg, 0.57 mmol) was dissolved in methanol (5 mL), Pd / C (10%, 20 mg) was added, and the mixture was purged with H2 three times, and then the mixture was reacted at room temperature for 12 hours until the reaction was completed. The reaction solution was filtered to remove Pd / C, the filter cake was washed with methanol (3 mL), and the filtrate was distilled under reduced pressure to obtain a pale yellow solid product II-2-2 (156 mg, 99% yield). MS (ESI) m / z: 275.1 [M+H] + .

[0298] Step 3: Synthesis of II-2 II-2-2 (50 mg, 0.18 mmol) was dissolved in DMF (2 mL), and PyBOP (190 mg, 0.36 mmol) and DIPEA (71 mg, 0.55 mmol) were added, and the mixture was stirred at room temperature for 2 hours until the reaction was completed. The reaction solution was purified by C18 column chromatography to obtain a pale yellow solid product II-2 (26 mg, 31% yield). MS (ESI) m / z: 461.2 [M+H] + , 1H NMR (500MHz, DMSO-d6)δ:9.59(s,1H), 9.11(s,1H), 8.76(d,J=5.0Hz,1H),8.61(s,1H), 8.39(s,1H), 7.93(s,1H), 7.86(d,J=5.0Hz,1H), 7.69( s,1H), 7.22(s,1H), 4.52(m,2H), 4.08(s,3H), 3.23~3.15(m,2H), 2.68( s,3H), 2.37(m,1H), 2.19~2.13(m,2H), 1.90(m,1H), 1.70~1.65(m,1H).

[0299] Example II-8: Synthesis of II-8 [ka]

[0300] Step 1: Synthesis of II-8-1 A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)-2-(trifluoromethyl)pyridine (286.32 mg, 1.05 mmol), methyl 2-bromooxazole-4-carboxylate (0.18 g, 873.81 μmol), Pd(dppf)Cl2 (115.24 mg, 0.16 mmol), cesium carbonate (569.41 mg, 1.75 mmol), and anhydrous 1,4-dioxane (6 mL) was stirred at 80° C. under nitrogen atmosphere for 4 h until the reaction was completed. The reaction solution was diluted with H2O (10 mL) and extracted with EA (10 mL×3) by stirring. The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to give the crude product. The crude product was purified by silica gel chromatography, eluting with PE / EA=10:3 to give a white solid product II-8-1 (0.23 g, 84.66% yield). MS(ESI)m / z:272.0[M+H] + .

[0301] Step 2: Synthesis of II-8-2 To a solution of II-8-1 (0.23 g, 845.03 μmol), HO (1 mL), and THF (3 mL), lithium hydroxide (40.48 mg, 1.69 mmol) was added and stirred at 25 °C under nitrogen atmosphere for 3 h until the reaction was complete. The reaction mixture was diluted with HO (10 mL) and the solution was acidified to pH = 3-4 with stirring. The mixture was extracted with EA (10 mL x 3), and the combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuum to give the white solid product II-8-2 (0.2 g, crude). MS (ESI) m / z: 259.0 [M+H] + .

[0302] Step 3: Synthesis of II-8 A mixture of II-8-2 (67.76 mg, 262.47 μmol), II-2-2 (0.06 g, 218.72 μmol), DIPEA (56.54 mg, 437.45 μmol, 76.19 μL), anhydrous DMF (5 mL), and PYBOP (136.59 mg, 262.47 μmol) was reacted at 25 °C under nitrogen atmosphere for 4 hours until the reaction was completed. The reaction solution was diluted with H2O (10 mL), stirred and extracted with EA (10 mL x 3), and the combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to obtain the crude product. The crude product was purified by C18 column chromatography to obtain the brown solid product II-8 (0.01 g, 8.44% yield). MS (ESI) m / z: 515.1 [M + H] + . 1 H NMR(500MHz,DMSO-d6)δ:9.56(s,1H), 9.15(s,1H), 9.04(d,J=5Hz,1H), 8.51(s,1H), 8.36(s,1H), 8.33(s,1H), 7.62(s,1H) , 7.16(s,1H), 4.55~4.42(m,2H), 4.00(s,3H), 3.18~3.14(m,2H), 2.20~2.09(m,1H), 2.08~2.00(m,1H), 1.88~1.81(m,3H).

[0303] Example II-4: Synthesis of II-4 [ka]

[0304] Step 1: Synthesis of II-4-1 To a solution of methyl 2-bromooxazole-4-carboxylate (0.2 g, 970.90 μmol), HO (1 mL), and THF (3 mL), lithium hydroxide (46.51 mg, 1.94 mmol) was added, and the reaction mixture was stirred at 25 °C under N protection for 3 h. The reaction mixture was diluted with HO (30 mL), and the resulting solution was stirred at 0 °C to lower the pH to 3-4, extracted with EA (30 mL × 3), and the combined organic phase was washed with brine, then dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the white solid crude product II-4-1 (0.18 g). MS (ESI) m / z: 190.9 [M+H] + .

[0305] Step 2: Synthesis of II-4-2 To a solution of II-4-1 (169.41 mg, 882.48 μmol), 6-methoxy-2H-indazol-5-amine (0.12 g, 735.40 μmol), anhydrous DMF (7 mL), DIPEA (190.09 mg, 1.47 mmol, 256.18 μL), PyBOP (459.23 mg, 882.48 μmol) was added and the reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (20 mL × 3), and the combined organic phase was washed with brine (20 mL), then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography eluting with PE:EA = 3:2 to give the yellow solid product II-4-2 (0.15 g, 55.98% yield). MS(ESI)m / z:338.1[M+H] + .

[0306] Step 3: Synthesis of II-4 To a solution of II-4-2 (0.03 g, 88.99 μmol) and anhydrous 1,4-dioxane (3 mL), DIPEA (57.50 mg, 444.93 μmol, 77.50 μL) and II-1-1 (252.14 mg, 889.87 μmol) were added, and the reaction mixture was stirred at 100 °C for 36 h. The mixture was diluted with water (50 mL) and extracted with EA (20 mL × 3), and the combined organic phase was washed with brine (20 mL), then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give the off-white solid product II-4 (0.005 g, 12.29% yield). MS (ESI) m / z: 449.2 [M+H] + , 1 H NMR(500MHz,DMSO-d6)δ:9.30(s,1H), 8.97(s,1H), 8.49(s,1H), 8.31(d,J=0.9Hz,1H), 7.61(s,1H), 7.13(s,1H), 5.34-5.31(m,1H) ), 4.48-4.43(m,2H), 3.96(s,3H), 3.15-3.10(m,2H), 2.38-2.34(m,1H), 2.03-1.99(m,1H),1.99-1.97(m,1H), 1.62-1.58(m,1H).

[0307] Example II-3F: Synthesis of II-3F [ka]

[0308] Step 1: Synthesis of II-3-1 Into a reaction flask, 2-bromo-5-methoxypyridine (9.5 g, 50.53 mmol), m-CPBA (metachloroperbenzoic acid) (13.0 g, 75.8 mmol), and 1,2-dichloroethane (95.0 mL) were added, and the resulting mixture solution was stirred at 60 °C for 2 h. The reaction mixture was cooled, and diethylamine (10.0 mL) was added to quench the reaction, and the mixture was concentrated in vacuum. The residue was purified by silica gel column chromatography (eluent: EA / PE = 1:1 to 1:0) to obtain product II-3-1 (8.1 g, 78.6% yield). MS (ESI) m / z: 204.0 [M+H]+ .

[0309] Step 2: Synthesis of II-3-2 To a stirred solution of II-3-1 (6.0 g, 29.4 mmol) in concentrated sulfuric acid (18.0 mL), concentrated nitric acid (6.0 mL) was added dropwise at 0° C., and the mixture was then heated. After stirring at 25° C., it was heated to 90° C. and reacted for 2 h. After cooling to 20° C., the mixture was poured onto ice and NaOH (40 wt.%) was carefully added to adjust the pH to 14. After extracting the mixture with DCM (100.0 mL×3), the combined organic phase was washed with saturated NaCl solution (30.0 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the yellow solid product II-3-2 (4.0 g, 59% yield). MS(ESI) m / z: 233.0 [M+H] + .

[0310] Step 3: Synthesis of II-3-3 To a suspension of II-3-2 (4.0 g, 17.3 mmol) and NHCl (3.27 g, 60.6 mmol) in ethanol (200.0 mL) and water (70.0 mL) at room temperature, iron powder (3.4 g, 60.6 mmol) was added. The mixture was heated to 60° C. and stirred for 2 h, the mixture was cooled to room temperature, filtered through a diatomaceous earth pad, and the filtrate was concentrated to a volume of about 50.0 mL to form a suspension. The suspension was filtered, the filter cake was washed with water (100 mL×2), suctioned on the funnel for 1 h, the diatomaceous earth pad was washed with DCM (80.03 M×3), and the washings were concentrated to dryness. The resulting crude extract was purified by column chromatography, eluted with a gradient of 0-5% MeOH / DCM to give product II-3-3 (2.6 g, 74% yield). MS(ESI)m / z: 203.0[M+H] + .

[0311] Step 4: Synthesis of II-3-4 To a solution of II-3-3 (3.0 g, 14.8 mmol) and DIPEA (11.4 g, 88.7 mmol) in THF (150.0 mL) was added CbzCl (benzyl chloroformate) (7.5 g, 43.9 mmol). The reaction was stirred at 25 °C for 16 h until completion. The reaction mixture was distilled under reduced pressure, EA (30.0 mL) and water (50.0 mL) were added, and the organic layer was separated. The aqueous phase was extracted with EA (50.0 mL x 3), and the combined organic layer was dried over anhydrous Na2SO4, filtered, and distilled under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel column chromatography (eluent: PE / EA = 3 / 1) to obtain product II-3-4 (1.6 g, 32% yield). MS (ESI) m / z: 336.0 [M + H] + .

[0312] Step 5: Synthesis of II-3-5 II-3-4 (1.0 g, 2.98 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (0.80 g, 3.57 mmol), TEA (4.2 g, 4.17 mmol), Pd(PPh3)2Cl2 (bistriphenylphosphinepalladium dichloride, 0.22 g, 0.36 mmol), and CuI (0.12 g, 0.6 mmol) were added to DMF (20.0 mL), and the mixture was heated at 90 °C under nitrogen protection for 5 h. After cooling to room temperature, saturated NH4Cl solution (50.0 mL) was added to the mixture, and the mixture was extracted with EA (50.0 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH=100:1 to 30:1) to give product II-3-5 (1.0 g, 72.5% yield). MS(ESI)m / z: 466.2[M+H] + .

[0313] Step 6: Synthesis of II-3-7 II-3-5 (1.0 g, 2.15 mmol.) and O-(2,4-dinitrophenyl)hydroxylamine (0.86 g, 4.3 mmol.) were added to MeCN (60.0 mL), and the reaction mixture was stirred at 50° C. for 20 h until the reaction was complete. The mixture was distilled under reduced pressure to give the crude product II-3-6.

[0314] The crude product II-3-6 was added with DMF (50.0 mL) and stirred at 80 °C for 16 h. It was quenched by adding saturated NaHCO3 solution and extracted with EA. The combined organic phase was washed with saturated NH4Cl solution, brine, dried over anhydrous Na2SO4, and concentrated to give the crude product. It was purified by silica gel column chromatography (EA / PE=100:0 to 80:20) to give the product II-3-7 (120 mg, 11.7% yield). MS(ESI) m / z: 481.2 [M+H] + .

[0315] Step 7: Synthesis of II-3-8 Pd / C (0.1 g) was added to a solution of II-3-7 (120 mg, 0.25 mmol) in methanol (14.0 mL), and the mixture was stirred at room temperature under H2 atmosphere for 2 h under normal pressure. The reaction mixture was filtered through diatomaceous earth and washed with 20 mL of MeOH / DCM (10:1). The filtrate was distilled under reduced pressure to give product II-3-8 (70 mg, 81% yield). MS(ESI) m / z: 347.2 [M+H] + .

[0316] Step 8: Synthesis of II-3-9 To a solution of 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (53.0 mg, 0.26 mmol) in DMF (10.00 mL), DIPEA (40.0 mg, 0.31 mmol), HATU (2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (132.0 mg, 0.35 mmol) were added and stirred at 0°C for 0.5 h. Then, II-3-8 (60.0 mg, 0.173 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. EtOAc (50.0 mL) and saturated NaHCO3 were added to the reaction mixture, followed by extraction and separation. The organic phase was washed with saturated NaHCO3 (20.0 mL) and brine (20.0 mL), dried, filtered, and distilled under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (DCM / MeOH=20:1) gave product II-3-9 (60.0 mg, 65% yield). MS(ESI)m / z:533.2[M+H] + .

[0317] Step 9: Synthesis of II-3F A mixture of II-3-9 (60.0 mg, 0.11 mmol) and hydrochloric acid / dioxane (4N, 2.0 mL) was stirred at room temperature for 1 hour until the reaction was completed. The solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain product II-3F (6.0 mg). MS (ESI) m / z: 433.2 [M+H] + , 1 H NMR(400MHz,MeOD-d4)δ:8.74(s,1H), 8.63(d,J=5.2Hz,1H), 8.54(s,2H), 8.22(s,1H), 7.97(s,1H), 7.89(d,J=4.9Hz,1 H), 6.38(s,1H), 4.08(s,3H), 3.52-3.41(m,2H), 3.10-3.24(m,3H), 2.65(s,3H), 2.34-2.20(m,2H), 2.05-1.86(m,2H).

[0318] Example II-5C: Synthesis of II-5C [ka]

[0319] Step 1: Synthesis of II-5-1 To a solution of ethyl 1H-imidazole-2-carboxylate (10 g, 0.071 mol) in DMF (60 mL), SEMCl (14.96 g, 0.09 mol) and K2CO3 (19.7 g, 0.142 mol) were added and the reaction mixture was stirred at room temperature for 16 h until the reaction was complete. The reaction mixture was diluted with ethyl acetate (100 mL), the solution was washed with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 × 3 mL). The combined organic layers were washed with brine (100 × 3 mL), dried over magnesium sulfate, filtered, and concentrated in vacuum to give the crude product. The crude product was purified by silica gel flash column chromatography to give the white solid product II-5-1 (10 g, 52.6% yield). MS (ESI) m / z: 271.0 [M+H] + .

[0320] Step 2: Synthesis of II-5-2 To a solution of II-5-1 (10 g, 0.04 mol) in DCM / DMF (50 mL, 1:1) at room temperature, a solution of NBS (10.68 g, 0.06 mol) in DCM / DMF (50 mL, 1:1) was added dropwise. After the addition was completed, the reaction mixture was stirred at room temperature for 16 h until the reaction was complete. The reaction mixture was diluted with ethyl acetate (100 mL), the solution was washed with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100×3 mL). The combined organic layers were washed with brine (100×3 mL), dried over magnesium sulfate, filtered, and concentrated in vacuum to give the crude product. The crude product was purified by silica gel flash column chromatography to give the white solid product II-5-2 (2.17 g, 14.29% yield). MS(ESI)m / z: 349.0[M+H] + .

[0321] Step 3: Synthesis of II-5-3 Under N2 protection, 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)pyridine (1.32 g, 0.006 mol), Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II), 0.49 g, 0.0006 mol), and K2CO3 (2.49 g, 0.018 mol) were added to a solution of II-5-2 (2 g, 0.006 mol) in DMF (12 mL). The reaction mixture was stirred at 85 °C for 16 h until the reaction was complete. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The solution was washed with water (100 mL), the aqueous phase was extracted with ethyl acetate (100 × 3 mL), and the combined organic layers were washed with brine (100 × 3 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel flash column chromatography to give a yellow solid product II-5-3 (1.2 g, 54.5% yield). MS(ESI) m / z: 362.0[M+H] + .

[0322] Step 4: Synthesis of II-5-4 To a solution of II-5-3 (1.3 g, 3.6 mol) in ethanol (3 mL) and THF (3 mL), LiOH (431.1 mg, 18 mmol) and HO (3 M) were added. The mixture was stirred at room temperature for 16 h until the reaction was complete. The reaction mixture was adjusted to pH = 2-3 with 3 M HCl, and a large amount of white solid was precipitated. After filtration, the filter cake was washed with water (60 mL) and concentrated to dryness to give the white solid product II-5-4 (700 mg, 58.3% yield). MS (ESI) m / z: 334.0 [M+H] + .

[0323] Step 5: Synthesis of II-5-5 A solution of II-5-4 (600 mg, 1.8 mmol), 6-methoxy-2H-indazol-5-amine (195.6 mg, 1.2 mmol), HATU (1.1 g, 2.88 mmol), and DIPEA (620.35 mg, 4.8 mmol) in DMF (30 mL) was stirred at room temperature for 16 h until the reaction was complete. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture, and after phase separation, the aqueous phase was extracted with ethyl acetate (30 × 3 mL). The combined organic phase was washed with brine (30 × 3 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by pre-TLC to give the yellow solid product II-5-5 (300 mg, 34.8% yield). MS (ESI) m / z: 479.0 [M+H] + .

[0324] Step 6: Synthesis of II-5-6 To a solution of II-5-5 (280 mg, 0.59 mmol) in DMF (10 mL) was added tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (329.35 mg, 1.18 mmol) and Cs2CO3 (384.68 mg, 1.18 mmol). The reaction mixture was stirred at 70 °C for 4 h until the reaction was complete. The reaction mixture was cooled to room temperature, ethyl acetate (30 mL) and water (30 mL) were added, the phases were separated, and the aqueous phase was extracted with ethyl acetate (30 × 3 mL). The combined organic phase was washed with brine (30 × 3 mL), dried over magnesium sulfate, filtered, and concentrated in vacuum to give the crude product. The crude product was purified by preparative HPLC to give the white solid product II-5-6 (44 mg, 11.3% yield). MS (ESI) m / z: 662.0 [M+H] + .

[0325] Step 7: Synthesis of II-5C Under 0°C condition, II-5-6 (44 mg, 0.066 mmol) was added in portions to 4M HCl in dioxane (3 mL), and after the entire addition, the mixture was stirred at room temperature for 16 hours until the reaction was complete. After filtration, the filter cake was thoroughly washed with diethyl ether. Then, the filter cake was dissolved in deionized water, and the solution was frozen to obtain the white solid product II-5C (24 mg, 80.0% yield). MS (ESI) m / z: 432.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:9.79(s,1H), 9.54-9.30(m,2H), 8.78(d,J=6.4Hz,1H), 8.66(s,1H), 8.60(s,1H), 8.38(s,1H), 8.32(d,J=6.4Hz,1H), 8. 10(s,1H), 7.58(s,1H), 5.08-5.28(m,1H), 4.16(s,3H), 3.54-3.37(m,2H ), 3.24-3.15(m,2H), 2.84(s,3H), 2.52-2.37(m,2H), 2.25-2.09(m,2H).

[0326] Example II-6: Synthesis of II-6 [ka]

[0327] Step 1: Synthesis of II-6-1 To a solution of ethyl 2-bromooxazole-4-carboxylate (5 g, 22.7 mmol) and dioxane (54 mL), tert-butyl piperazine-1-carboxylate (4.65 g, 25 mmol), TEA (6.9 g, 68.2 mmol) were added. The mixture was stirred at 120 °C for 1 h until the reaction was complete. Water was added to dilute the reaction solution, and it was extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to give the crude product. The crude product was purified by flash chromatography (PE / EtOAc = 2 / 1) to give the yellow solid product II-6-1 (6.5 g, 88.0% yield). MS (ESI) m / z: 326.1 [M+H] + .

[0328] Step 2: Synthesis of II-6-2 To a solution of II-6-1 (4 g, 12.2 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL), LiOH (0.9 g, 36.6 mmol) and HO (20 mL) were added. The mixture was stirred at room temperature for 16 h until the reaction was complete. The reaction solution was concentrated in vacuo to give the white solid product II-6-2 (3.6 g, 99.0% yield). MS (ESI) m / z: 298.2 [M+H] + .

[0329] Step 3: Synthesis of II-6-3 A mixture of II-6-2 (3.6 g, 12 mmol), HATU (10.9 g, 28.8 mmol), DIPEA (6.2 g, 48 mmol), and DMF (70 mL) was stirred at room temperature for 10 min, and then 6-methoxy-2H-indazol-5-amine (1.6 g, 9.6 mmol) was added and stirred at room temperature for 16 h until the reaction was complete. Water was added to dilute the reaction solution, and the mixture was extracted with EA (50 × 3 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuum to obtain the crude product. The crude product was purified by C18 column to obtain the yellow solid product II-6-3 (2.0 g, 37.7% yield). MS (ESI) m / z: 443.1 [M+H] + .

[0330] Step 4: Synthesis of II-6-4 To a solution of II-6-3 (2.0 g, 4.5 mmol) and DCM (80 mL) was added TFA (12 mL) dropwise at 0° C., and the mixture was stirred at 0° C. for 0.5 h until the reaction was complete. The mixture was concentrated to give a yellow solid product II-6-4 (1.4 g, 93% yield). MS (ESI) m / z: 343.1 [M+H] + .

[0331] Step 5: Synthesis of II-6-5 A solution of II-6-4 (1.4 g, 4.0 mmol), CH3COOH (0.5 g, 8.0 mmol), EDCI (2.3 g, 12.0 mmol), HOBT (1.6 g, 12.0 mmol), DIPEA (4.2 g, 32.0 mmol), and DMF (35 mL) was stirred at room temperature for 16 h until the reaction was completed. MTBE and DCM (MTBE:DCM=3:1) were added to the reaction solution and stirred vigorously for 1 h. After filtration, the filter cake was washed and dried in vacuum to obtain the white solid product II-6-5 (0.33 g, 21.4% yield). MS(ESI)m / z:385.2[M+H] + .

[0332] Step 6: Synthesis of II-6-6 A mixture of II-6-5 (330 mg, 0.86 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (481 mg, 1.72 mmol), Cs2CO3 (841 mg, 2.58 mmol), and DMF (30 mL) was stirred at 70 °C for 4 h until the reaction was complete. Water was added to dilute the reaction solution, and the mixture was extracted with EtOAc (30 × 2 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give the white solid product II-6-6 (100 mg, 20.5% yield). MS (ESI) m / z: 568.2 [M+H] + .

[0333] Step 7: Synthesis of II-6 HCl-dioxane (2M, 7 mL) was added dropwise to a solution of II-6-6 (150 mg, 0.26 mmol) in dioxane (7 mL) at 0°C. After the addition was completed, the mixture was stirred at 0°C for 1 h until the reaction was completed. The reaction solution was concentrated, and the crude product was purified by preparative HPLC to obtain the white solid product II-6 (16.69 mg, 13.0% yield). MS(ESI)m / z: 468.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ:9.36(s,1H), 8.56(s,1H), 8.30(s,1H), 8.28(s,1H), 7.12(s,1H), 4.50-4.39(m,1H) , 3.96(s,3H), 3.62-3.50(m,6H), 3.48-3.44(m,2H), 3.18-3.08(m,2H), 2.76-2.60(m,2H), 2.10-1.88(m,7H).

[0334] Example II-7C: Synthesis of II-7C [ka]

[0335] Step 1: Synthesis of II-7-1 A mixture of ethyl 2-bromooxazole-4-carboxylate (5.0 g, 22.7 mmol), thiomorpholine 1,1-dioxide (5.2 g, 38.6 mmol), triethylamine (9.2 g, 90.8 mmol), and 1,4-dioxane (102 mL) was reacted in a microwave reactor at 120 °C for 1 h until the reaction was complete. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to give the yellow solid product II-7-1 (1.8 g, 29% yield). MS (ESI) m / z: 275.0 [M+H] + .

[0336] Step 2: Synthesis of II-7-2 To a solution of II-7-1 (1.2 g, 4.4 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL), LiOH (0.3 g, 13.1 mmol) and HO (20 mL) were added, and the mixture was stirred at room temperature for 16 h until the reaction was complete. The reaction solution was concentrated in vacuo to give the white solid product II-7-2 (0.6 g, 56% yield). MS (ESI) m / z: 247.0 [M+H] + .

[0337] Step 3: Synthesis of II-7-3 A solution of II-7-2 (2 g, 8.0 mmol), HATU (7.3 g, 19.2 mmol), DIPEA (4.1 g, 32.1 mmol), and DMF (60 mL) was stirred at room temperature for 10 min, followed by addition of 6-methoxy-2H-indazol-5-amine (0.65 g, 4.0 mmol), followed by stirring at room temperature for 16 h until the reaction was complete. The reaction solution was diluted with water (50 mL) and ethyl acetoacetate (3×100 mL), and the combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by high performance chromatography (DCM / EtOAc=5 / 1) to give the yellow solid product II-7-3 (0.8 g, 25% yield). MS (ESI) m / z: 392.0 [M+H] + .

[0338] Step 4: Synthesis of II-7-4 A mixture of II-7-3 (800 mg, 2.1 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.2 g, 4.2 mmol), Cs2CO3 (2.0 g, 6.3 mmol), and DMF (20 mL) was stirred at 70 °C for 4 h until the reaction was complete. The reaction solution was diluted with water (30 mL) and ethyl acetoacetate (3 × 80 mL), and the combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give the yellow solid product II-7-4 (40 mg, 4% yield). MS (ESI) m / z: 575.2 [M+H] + .

[0339] Step 5: Synthesis of II-7C HCl-dioxane (1 mL) was added dropwise to a solution of II-7-4 (31 mg, 0.05 mmol) in dioxane (2 mL) at 0°C. After the addition was completed, the mixture was stirred at 0°C for 4 hours until the reaction was completed. Ethyl ether was added to the reaction solution, which was then filtered and dried in vacuum to obtain a white solid product II-7C (25.28 mg, 99% yield). MS (ESI) m / z: 475.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ:9.32(s,1H), 9.25-9.18(br,1H), 9.09-8.96(br,1H), 8.54(s,1H), 8.32(s,1H), 8.31(s,1H), 7.13 (s,1H), 4.82-4.68(m,1H), 4.15-3.87(m,7H), 3.46-3.38(m,2H), 3.35-3.26(m,4H), 3.16-3.08(m,2H), 2.42-2.29(m,4H).

[0340] Example II-9C: Synthesis of II-9C [ka]

[0341] Step 1: Synthesis of II-9-A-1 Under a nitrogen atmosphere, a mixture of 6-methoxy-5-nitro-2H-indazole (2.7 g, 13.98 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (5.47 g, 19.57 mmol), cesium carbonate (13.66 g, 41.93 mmol), and anhydrous N,N-dimethylformamide (12 mL) was heated to 110 ° C. and stirred for 0.5 hours until the reaction was completed. Water (50 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL × 3) and washed with saturated saline (20 mL), and then the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure in vacuum to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-20% ethyl acetate / petroleum ether) to obtain a yellow solid product II-9-A-1 (1.5 g, yield 28.51%). MS(ESI)m / z:377.4[M+H] + .

[0342] Step 2: Synthesis of II-9-A Under a nitrogen atmosphere, a mixture of II-9-A-1 (0.42 g, 1.12 mmol), ammonium chloride (596.85 mg, 11.16 mmol), iron powder (623.18 mg, 11.16 mmol), ethanol (3 mL), and water (1 mL) was heated to 70 °C and reacted for 4 hours until the reaction was completed. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (20 mL), water (40 mL) was added to the filtrate, the filtrate was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated saline (20 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase 100% ethyl acetate) to obtain a yellow solid product II-9-A (0.28 g, yield 45.11%). MS (ESI) m / z: 347.4 [M + H] + .

[0343] Step 3: Synthesis of II-9-1 To a solution of methyl 2-phenyloxazole-4-carboxylate (210.00 mg, 1.03 mmol), HO (1 mL), and THF (3 mL), lithium hydroxide (49.50 mg, 2.07 mmol) was added, and the reaction mixture was stirred for 2 h at 25 °C under nitrogen atmosphere until the reaction was complete. The reaction mixture was diluted with HO (10 mL), stirred and extracted with EA (10 mL x 3), and the combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuum to give the white solid product II-9-1 (0.18 g). The crude product was used directly in the next step. MS (ESI) m / z: 190.0 [M+H] + .

[0344] Step 4: Synthesis of II-9-2 A mixture of II-9-A (0.07 g, 202.07 μmol), II-9-1 (45.87 mg, 242.48 μmol), DIPEA (31.34 mg, 242.48 μmol, 42.23 μL), anhydrous DMF (5 mL), and PyBOP (210.31 mg, 404.13 μmol) was stirred at 25 °C under nitrogen atmosphere for 4 h until the reaction was completed. The reaction solution was diluted with H2O (10 mL) and extracted with EA (10 mL x 3) by stirring. The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography and eluted with PE / EA = 1:1 to obtain the white solid product II-9-2 (0.07 g, 64.87% yield). MS(ESI)m / z:518.2[M+H] + .

[0345] Step 5: Synthesis of II-9C To a solution of II-9-2 (0.07 g, 135.25 μmol) and DCM (2 mL), HCl-dioxane (4 M, 676.23 μL) was added dropwise. After the addition was completed, the reaction mixture was stirred for 2 h at 25 °C under nitrogen atmosphere until the reaction was complete. The reaction mixture was concentrated in vacuum to give the white solid product II-9C (0.033 g, 52.13% yield). MS (ESI) m / z: 418.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ:9.57(s,1H),9.39(d,J=10.1Hz,1H), 9.27-9.15(m,1H), 8.94(s,1H), 8.60(s,1H), 8.37(s,1H), 8.13-8.0 4(m,2H), 7.66-7.59(m,3H), 7.20(s,1H), 4.80-4.74(m,1H), 4.03(s,3H), 3.48-3.38(m,2H), 3.16-3.06(m,2H), 2.39-2.25(m,4H).

[0346] With reference to Example II-8 and Example II-9C, the following products were finally synthesized. [Table 1(1)] [Table 1(2)]

[0347] Example II-10C: Synthesis of II-10C [ka]

[0348] Step 1: Synthesis of II-10-1 A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)pyridine (226.97 mg, 1.11 mmol), methyl 2-bromooxazole-5-carboxylate (0.19 g, 922.36 μmol), Pd(dppf)Cl2 (33.74 mg, 46.12 μmol), cesium carbonate (601.04 mg, 1.84 mmol), and anhydrous dioxane (6 mL) was stirred at 80 °C under nitrogen atmosphere for 4 h until the reaction was completed. The reaction solution was diluted with H2O (20 mL) and extracted with EA (15 mL × 3) by stirring. The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with DCM / MeOH=10:1 to give a brown solid product II-10-1 (0.22 g, 62.15% yield). MS(ESI)m / z:205.0[M+H] + .

[0349] Step 2: Synthesis of II-10-2 To a solution of II-10-1 (220.00 mg, 1.08 mmol), HO (1 mL), and THF (3 mL), lithium hydroxide (51.61 mg, 2.15 mmol) was added and stirred for 2 h at 25 °C under nitrogen atmosphere until the reaction was complete. The reaction mixture was diluted with HO (15 mL) and the solution was acidified to pH = 3-4 with stirring. The mixture was extracted with EA (10 mL x 3), and the combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuum to give the brown solid product II-10-2 (0.2 g). The crude product was used directly in the next step, MS (ESI) m / z: 191.0 [M+H] + .

[0350] Step 3: Synthesis of II-10-3 A mixture of II-9-A (0.07 g, 202.07 μmol), II-10-2 (46.11 mg, 242.48 μmol), DIPEA (52.23 mg, 404.13 μmol, 70.39 μL), anhydrous DMF (5 mL), and PyBOP (126.18 mg, 242.48 μmol) was stirred for 4 h at 25 °C under nitrogen atmosphere until the reaction was completed. The reaction solution was diluted with H2O (20 mL) and extracted with EA (20 mL x 3) by stirring. The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the brown solid product II-10-3 (0.025 g, 23.86% yield). MS (ESI) m / z: 519.2 [M + H] + .

[0351] Step 4: Synthesis of II-10C To a solution of II-10-3 (0.025 g, 48.21 μmol) and DCM (2 mL), HCl-dioxane (4 M, 241.05 μL) was added dropwise. After the addition was completed, the mixture was stirred at 25° C. under nitrogen atmosphere for 2 h until the reaction was completed. The reaction mixture was concentrated in vacuum to obtain the crude product, which was purified by C18 column chromatography to obtain the white solid product II-10C (0.005 g, 21.89% yield). MS (ESI) m / z: 419.1 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ:9.72(s,1H), 9.57(s,1H), 9.06(d,J=12.2Hz,1H), 8.89-8.81(m,2H), 8.58(s,1H), 8.36(s,1H), 8.04-7.95(m,2H), 7.18(s,1H), 5.38-5.26(m,1H), 4.02(s,3H), 3.64-3.52(m,2H), 3.41-3.37(m,2H), 2.15-1.77(m,5H).

[0352] Example II-11C: Synthesis of II-11C [ka]

[0353] Step 1: Synthesis of II-11-1 A mixture of 1H-pyrazole-3-carboxylate (275 mg, 2.18 mmol), 4-bromo-2-methylpyridine (375.11 mg, 2.18 mmol), potassium carbonate (602.74 mg, 4.36 mmol), copper iodide (41.53 mg, 218.06 μmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (124.07 mg, 872.23 μmol, 137.55 μL), and DMF (3 mL) was stirred at 110 °C under nitrogen atmosphere for 3 hours until the reaction was completed. The reaction mixture was cooled to 25 °C and concentrated in vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain white solid product II-11-1 (353 mg, 74.52% yield). MS (ESI) m / z: 218.1 [M+H] + .

[0354] Step 2: Synthesis of II-11-2 LiOH (55.12 mg, 2.30 mmol) was added to a solution of II-11-1 (100 mg, 460.36 μmol), methanol (4 mL), and HO (2 mL) at 0° C. After the addition was complete, the mixture was stirred at 25° C. under nitrogen for 3 hours until the reaction was complete. The reaction mixture was concentrated in vacuum, diluted with water, and the solution was acidified with stirring until pH=4. It was then concentrated in vacuum to give the white solid product II-11-2 (160 mg). The crude product was used directly in the next step and was shown to be stable by HPLC. MS(ESI) m / z: 204.0 [M+H] + .

[0355] Step 3: Synthesis of II-11-3 DIPEA (235.04 mg, 1.82 mmol) was added dropwise to a solution of II-9-A (210 mg, 606.20 μmol), II-11-2 (321.33 mg, 727.43 μmol), PyBOP (643.46 mg, 618.25 μmol), and THF (3.95 mL) at 0° C. under nitrogen atmosphere. After the addition was completed, the mixture was stirred at 25° C. for 1 h until the reaction was complete. The reaction mixture was concentrated in vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography and eluted with DCM / CH3OH=20 / 1 to obtain the white solid product II-11-3 (140 mg, 39.10% yield). MS(ESI)m / z:532.2[M+H] + .

[0356] Step 4: Synthesis of II-11C HCl-dioxane (4M, 738.3μL) was added dropwise to a solution of II-11-3 (157mg, 295.33μmol) and DCM (5mL) at 25℃. After the addition was completed, the mixture was stirred at 25℃ for 1h until the reaction was complete. The reaction mixture was filtered, the filter cake was washed with DCM (20mL), and dried in vacuum to give the white solid product II-11C (130mg, 89.36% yield). MS(ESI)m / z:432.2[M+H] + . 1H NMR(500MHz,DMSO-d6)δ:9.64(s,1H), 9.34-9.25(m,1H), 9.16-9.10(m,1H), 9.08(d,J=2.6Hz,1H), 8.90(d,J=6.5Hz,1H), 8.44(s,2H), 8.36(s,1H), 8.33( d,J=6.2Hz,1H), 7.26(d,J=2.6Hz,1H), 7.18(s,1H), 4.86-4.75(m,1H), 4.00( s,3H), 3.52-3.41(m,2H), 3.18-3.06(m,2H), 2.80(s,3H), 2.38-2.25(m,4H).

[0357] Example II-14C: Synthesis of II-14C [ka]

[0358] Step 1: Synthesis of II-14-1 To a solution of 6-methoxy-5-nitro-1H-indazole (5 g, 25.89 mmol) and DCM (150 mL) was added AlCl3 (10.3 g, 77.66 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 h until the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (80 mL × 3). The combined organic layers were concentrated and the crude product was purified on a silica gel column to give the brown solid product II-14-1 (2.4 g, 53% yield). MS (ESI) m / z: 180.1 [M+H] + .

[0359] Step 2: Synthesis of II-14-2 To a solution of II-14-1 (2.3 g, 12.8 mmol) in DMF (40 mL) at room temperature, 2-iodopropane (3.41 g, 15.4 mmol) and K2CO3 (3.55 g, 25.6 mmol) were added. The resulting mixture was subsequently stirred at room temperature for 16 h until the reaction was completed. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (40 mL x 3). The combined organic layer was concentrated and the crude product was purified by silica gel column to give brown solid product II-14-2 (2.2 g, 72% yield). MS (ESI) m / z: 222.0 [M+H] + .

[0360] Step 3: Synthesis of II-14-3 To a solution of II-14-2 (2.2 g, 9.95 mmol) and K2CO3 (9.74 g, 29.86 mmol) in DMF (120 mL) at 25 °C, tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (5.55 g, 19.91 mmol) was added. The mixture was stirred at 70 °C for 4 h until the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (40 mL × 3). The combined organic layer was concentrated and the crude product was purified by silica gel column to give white solid product II-14-3 (0.9 g, 43% yield). MS (ESI) m / z: 405.1 [M+H] + .

[0361] Step 4: Synthesis of II-14-4 To a mixture of II-14-3 (700 mg, 1.732 mmol) and THF (10 mL) at room temperature, Pd / C (140 mg, 10% purity) was added. The mixture was stirred under hydrogen atmosphere at 25° C. for 16 h until the reaction was complete. The resulting mixture was filtered and concentrated to give the brown solid product II-14-4 (540 mg, 76% yield). MS (ESI) m / z: 375.2 [M+H] + .

[0362] Step 5: Synthesis of II-14-5 To a solution of II-14-4 (440 mg, 1.17 mmol) in DMF (20 mL) was added HATU (666.9 mg, 1.75 mmol), DIPEA (453.5 mg, 3.51 mmol), and 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (240.0 mg, 1.17 mmol). The mixture was stirred at 25 °C for 16 h until the reaction was complete. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were concentrated and the crude product was purified by silica gel column to give white solid product II-14-5 (450 mg, 65% yield). MS (ESI) m / z: 561.1 [M+H] + .

[0363] Step 6: Synthesis of II-14C To a solution of II-14-5 (450 mg, 0.803 mmol) in EA (3 mL) was added HCl-dioxane (2 M, 8 mL) at 0° C. The mixture was stirred at 25° C. for 16 h until the reaction was complete. Ethyl ether (10 mL) was added to the reaction mixture, which was then filtered and dried in vacuum to give the white solid product II-14C (394.51 mg, 94% yield). MS (ESI) m / z: 460.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:9.77(s,1H), 9.14(s,1H), 9.08-8.99(m,1H), 8.97-8. 85(m,1H), 8.82(d,J=5.5Hz,1H), 8.62(s,1H),8.35(s,1H), 8.05(s,1H), 7.95(d ,J=6.1Hz,1H), 7.22(s,1H), 4.90-4.81(m,1H), 4.80-4.71(m,1H), 3.49-3.38(m ,2H), 3.19-3.04(m,2H), 2.70(s,3H), 2.35-2.24(m,4H), 1.48(d,J=6.0Hz,6H).

[0364] Example II-15C: Synthesis of II-15C [ka]

[0365] Step 1: Synthesis of INT-01-1 A mixture of 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (200.0 mg, 0.698 mmol) and SOCl2 (5.0 mL) was stirred at 70 °C for 2 h until the reaction was completed. The reaction mixture was concentrated under reduced pressure, the crude product was dissolved in DCM (5.0 mL), and this solution was added to a mixture of 3,5-dimethoxybenzylamine (245.0 mg, 1.47 mmol) and ET3N (297.0 mg, 2.94 mmol) in DCM (5.0 mL). The resulting solution was refluxed for 1 h until the reaction was completed. The reaction mixture was poured into water, the mixture was extracted with EA, and the combined organic phase was washed with brine, dried, and concentrated to give the crude product. The crude product was purified by preparative TLC (eluent: EA / PE=1:1) to give INT-01-1 (132.0 mg, 41% yield). MS(ESI)m / z:354.1[M+H] + .

[0366] Step 2: Synthesis of INT-01 To a solution of INT-01-1 (132.0 mg, 0.40 mmol) and DCM (3.0 mL), TFA (1.0 mL) was added, and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with DCM. The combined organic phase was washed with brine, dried, and concentrated to give the crude product. The crude product was purified by preparative TLC (eluent: DCM / MeOH=20:1) to give the product INT-01 (65.0 mg, 81% yield). MS(ESI)m / z: 204.0[M+H] + .

[0367] Step 3: Synthesis of II-15-1 At 0°C, NBS (17.8 g, 100.0 mmol) was added portionwise to a solution of 4-methoxy-2-aminopyridine (9.5 g, 76.6 mmol) and MeCN (200.0 mL) with stirring. After the addition was complete, the mixture was stirred at 10-15°C for 1 h until the reaction was complete. The solvent was removed by distillation under reduced pressure, DCM was added, washed with saturated Na2CO3 solution, dried and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH=300:1-50:1) to give product II-15-1 (8.3 g, 55% yield). MS(ESI)m / z:203.0[M+H] + .

[0368] Step 4: Synthesis of II-15-2 II-15-1 (1.3 g, 6.4 mol) and tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (2.0 g, 6.4 mol) were mixed in ethanol (40.0 mL), and the resulting mixture was refluxed for 16 h until the reaction was complete. The solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: DCM / MeOH=300:1 to 50:1) to obtain II-15-2 (1.4 g, 54% yield). MS(ESI)m / z: 412.1[M+H] + .

[0369] Step 5: Synthesis of II-15-3 To a solution of II-15-2 (50.0 mg, 0.108 mmol) and dioxane (5.0 mL), INT-01 (49.0 mg, 0.244 mmol), trans-dichlorobis(tri-o-tolylphosphine)palladium(II) (9.6 mg, 0.012 mmol), XantPhos (4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 7.09 mg, 0.012 mmol), and Cs2CO3 (119 mg, 0.366 mmol) were added. The resulting solution was heated under nitrogen atmosphere at 120 °C for 4 hours until the reaction was complete. The reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by preparative TLC (eluent: DCM / MeOH = 30:1) to give product II-15-3 (35.0 mg, 54.6% yield). MS(ESI)m / z:533.2[M+H] + .

[0370] Step 6: Synthesis of II-15C To a solution of II-15-3 (35.0 mg, 0.066 mmol) and DCM (3.0 mL), HCl / dioxane (4 M, 1.0 mL) was added, and the resulting solution was stirred at room temperature for 1 h until the reaction was complete. The solution was concentrated and lyophilized to give the white solid product II-15C (15.0 mg). MS (ESI) m / z: 433.1 [M+H] + . 1 H NMR(400MHz,MeOD-d4)δ:9.70(s,1H), 9.00(s,1H), 8.89(d,J=6.1Hz,1H), 8.57(s,1H), 8.48(d,J=6.5Hz,1H), 7.99(s,1H), 7.41( s,1H), 4.28(s,3H), 3.70-3.63(m,1H), 3.59-3.53(m,2H), 3.28-3.17(m,2H), 2.91(s,3H), 2.45-2.32(m,2H), 2.10-1.99(m,2H).

[0371] Example II-28: Synthesis of II-28 [ka]

[0372] Step 1: Synthesis of II-28-1 A mixture of (2,4-dimethoxyphenyl)formamide (3.8 mL, 29 mmol), methyl 4,6-dichloronicotinate (5.0 g, 24 mmol), triethylamine (4.1 mL, 30 mmol), and acetonitrile (50 mL) was stirred overnight at 25 °C. The mixture was concentrated, and the residue was added with EA and saturated aqueous ammonium chloride solution, diluted with stirring, and extracted with EA (30 mL x 3). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA:heptane = 3:1) to give the product II-28-1 (6.6 g, 81% yield), which was used directly in the next step. MS (ESI) m / z: 337.8 [M + H] + .

[0373] Step 2: Synthesis of II-28-2 II-28-1 (4.7 g, 140 mmol), methyl pent-4-enoate (3.13 g, 280 mmol), TEA (19.8 g, 1.96 mmol), Pd(PPh3)2Cl2 (1.02 g, 14 mmol), and CuI (0.53 g, 28 mmol) were mixed in a DMF (100.0 mL) solution, and the mixture was reacted under nitrogen atmosphere at 80 °C for 5 h with stirring. After the reaction solution was cooled to room temperature, saturated NH4Cl solution (50.0 mL) was added to the reaction solution and extracted with EA (50.0 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 10:1 to 1:1) to obtain the desired product II-28-2 (4 g, 70% yield). MS(ESI)m / z:413.2[M+H] + .

[0374] Step 3: Synthesis of II-28-3 At 25° C., TFA (10.0 m) was slowly added dropwise to a stirred solution of II-28-2 (3.0 g, 0.12 mmol) and DCM (3.0 mL). After the addition was completed, the mixture was stirred for 1 h. The reaction solution was concentrated to dryness under vacuum to give the desired product II-28-3 (1.9 g). MS (ESI) m / z: 263.1 [M+H]+ .

[0375] Step 4: Synthesis of II-28-4 At 25°C, DMAP (88.6mg, 0.725mol), Boc2O (10.0g, 10.87mol) were added to a solution of II-28-3 (1.9g, 7.25mol), TEA (4.0g, 21.7mol), and THF (150.0mL), and the mixture was stirred for 16 hours until the reaction was completed. After the mixture was concentrated under reduced pressure, EA (30.0mL) and water (50.0mL) were added to the residue, and the organic layer was separated. The aqueous phase was extracted with EA (100mL x 3), and the combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 30:1 to 5:1) to obtain II-28-4 (1.7g, yield 64.9%). MS (ESI) m / z: 363.1 [M+H] + .

[0376] Steps 5 & 6: Synthesis of II-28-5 & II-28-6 II-28-4 (1.7 g, 4.7 mmol) was added to a solution of O-(2,4-dinitrophenyl)hydroxylamine (3.7 g, 18.8 mmol) and ACN (60.0 mL), and the reaction mixture was stirred at 60 °C for 20 h. The mixture was evaporated to dryness to give crude product II-28-5. Then, DMF (50.0 mL) was added to the crude product and stirred at 80 °C for 16 h until the reaction was complete. Saturated NaHCO3 solution was added and extracted with EA (100 mL × 3). The combined organic phase was washed with saturated NH4Cl solution (200 mL), saturated brine (200 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1)) to give product II-28-6 (200 mg, yield 11.3%). MS(ESI)m / z:378.1[M+H] + . 1H NMR (400MHz, CDCl3) δ10.01(s,1H), 9.11(s,1H), 8.32(s,1H), 6.17(s,1H), 3.94(s,3) H), 3.71(d,J=12.8Hz,3H), 3.13(t,J=7.6Hz,2H), 2.79(t,J=7.6Hz,2H), 1.54(s,9H).

[0377] Step 7: Synthesis of II-28-7 To a solution of II-28-6 (100.0 mg, 0.265 mmol) and DCM (3.0 mL) at 25°C, HCl-dioxane (4 M, 1.0 mL) was added, and the resulting solution was stirred for 1 h. The reaction solution was concentrated under reduced pressure to dryness, and the pH of the residue was adjusted to 7-8 with saturated NaHCO3 solution. Then, the solution was extracted with DCM (30 mL x 3), and the combined organic layer was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by preparative thin layer chromatography (DCM:MeOH = 50:1) to give II-28-7 (55.0 mg, 69.4% yield). MS (ESI) m / z: 278.1 [M + H] + .

[0378] Step 8: Synthesis of II-28-8 A mixture of 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (122.0 mg, 0.54 mmol) and SOCl2 (5.0 mL) was stirred at 70 °C for 2 h, and the reaction mixture was concentrated under reduced pressure. DIPEA (92.8 mg, 0.72 mmol, dissolved in 5.0 mL DCM) was added to the residue, and the resulting solution was added to a solution of II-28-7 (50.0 mg, 0.18 mmol) in DCM (5.0 M). The mixture was then heated to reflux for 1 h. After cooling to room temperature, the reaction mixture was poured into water (20.0 mL) and extracted with EA (20 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography (DCM:MeOH = 20:1) to give the desired product II-28-8 (50.0 mg, 56% yield). MS(ESI)m / z:464.1[M+H] + .

[0379] Step 9: Synthesis of II-28 At 0° C., to a solution of II-28-8 (50.0 mg, 0.11 mmol) in THF (10.00 mL) was added CH3MgBr (1 M in THF, 1.3 mL, 1.29 mmol). The resulting mixture was stirred at 25° C. for 16 h under nitrogen atmosphere. The reaction solution was quenched with saturated NH4Cl solution (10.0 mL) and extracted with DCM (15.0 ml×2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (DCM:MeOH=20:1) to give the white solid product II-28 (6.2 mg). MS(ESI) m / z: 464.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.92(s,1H), 9.04(s,1H), 8.70(d,J=5.1Hz,1H), 8.54(s,1H), 8.43(s,1H), 7.95-7.65(m,2H) , 6.39(s,1H), 6.32(s,1H), 4.28(s,1H), 2.96-2.70(m,2H), 2.61(s,3H), 1.87-1.73(m,2H), 1.67(s,6H), 1.15(s,6H).

[0380] With reference to Example II-28, the following product was finally synthesized. [Table 2]

[0381] Example II-49: Synthesis of II-49 [ka]

[0382] Step 1: Synthesis of II-49-1-P2 To a solution of methyl 5-nitro-2H-indazole-6-carboxylate (1 g, 4.52 mmol) and DMF (10 mL) were added Cs2CO3 (2.62 g, 13.56 mmol), 4-bromo-2-methyl-butan-2-ol (1.13 g, 6.78 mmol) at 25 °C, and the mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with H2O (30 mL) and extracted with EA (30 mL × 3). The combined organic layer was washed with saturated brine (30 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a yellow solid crude product. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give a pale yellow solid product II-49-1-P (2510.00 mg, 1.66 mmol, yield 35.24%). MS(ESI)m / z:308.1[M+H] + II-49-1-P2: 1 H NMR (400MHz, CDCl3) δ8.40(s,1H), 8.23(s,1H), 8.01(s,1H), 4.68(t,J=8.0Hz,2H), 3.92(s,3H), 2.22(t,J=8.0Hz,2H), 1.30(s,6H).

[0383] Step 2: Synthesis of II-49-2 To a mixture of II-49-1-P2 (0.5 g, 1.63 mmol), EtOH (6 mL), and H2O (2.5 mL), NH4Cl (43.00 mg, 811.32 umol) and iron powder (908.72 mg, 16.27 mmol) were added, and the mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with H2O (20 mL), and then extracted with EA (20 mL × 3). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. A yellow solid product II-49-2 (400.00 mg) was obtained. MS (ESI) m / z: 278.1 [M + H] + .

[0384] Step 3: Synthesis of II-49-3 To a stirred solution of II-49-2 (400 mg, 1.44 mmol) and THF (10 mL) at 0 °C, a solution of methylmagnesium chloride in THF (1 M, 7.21 mmol, 7.2 mL) was added, and the mixture was continuously stirred for 16 h. The reaction mixture was diluted with H2O (20 mL), and the pH of the solution was adjusted to 7-8 with aqueous NH4Cl (1 M), and extracted with EA (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19 × 150 mm, both solvents contained 0.1% ammonium bicarbonate) to give the yellow oily product II-49-3 (210.00 mg, 681.42 μmol, 47.24% yield). MS(ESI)m / z:278.2[M+H] + .

[0385] Step 4: Synthesis of II-49 To a mixture of 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (50.00 mg, 193.68 μmol) and DCM (20 mL) at 25° C., II-49-3 (53.72 mg, 193.68 μmol), HATU (220.80 mg, 581.05 μmol), and DIPEA (25.18 mg, 1931.68 μmol) were added, and the mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure, then diluted with H2O (10 mL), and extracted with DCM (10 mL×3). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; both solvents contained 0.1% ammonium bicarbonate) to give the yellow solid product II-49 (19.50 mg, 41.23 μmol, 21.29% yield). MS(ESI) m / z: 464.2 [M+H] + . 1H NMR(400MHz,MeOD-d4)δ8.62(s,1H), 8.61(s,1H), 8.58(d,J=6.0Hz,1H), 8.18(s,1H), 7.99(s,1H), 7. 91(s,1H), 7.62(s,1H), 4.56-4.51(m,2H), 2.63(s,3H), 2.16-2.12(m,2H), 1.74(s,6H), 1.24(s,6H).

[0386] With reference to Examples II-1, II-8 and II-49, the following products were finally synthesized.

[0387] [Table 3(1)] [Table 3(2)] [Table 3(3)] [Table 3(4)] [Table 3(5)] [Table 3(6)] [Table 3(7)]

[0388] Example II-64: Synthesis of II-64 [ka]

[0389] Step 1: Synthesis of II-64-1 To a solution of II-14-1 (2 g, 11.17 mmol), 3-iodooxetane (3.08 g, 16.76 mmol), and DMF (50 mL), K2CO3 (3.08 g, 22.34 mmol) was added, and the mixture was stirred at 50 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with H2O (80 mL) and extracted with chloroform:isopropanol = 3:1 (30 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by high-performance silica gel column chromatography and preparative TLC to give the brown solid product II-64-1 (230 mg, 9% yield). MS (ESI) m / z: 236.1 [M + H] + .

[0390] Step 2: Synthesis of II-64-2 To a solution of II-64-1 (300 mg, 1.276 mmol), KI (21 mg, 0.128 mmol), 3-(2-bromoethyl)pyrrolidin-2-one (490 mg, 2.553 mmol), and DMF (6 mL) at 25 °C, Cs2CO3 (832 mg, 2.553 mmol) was added and the mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with H2O (80 mL) and extracted with EA (20 mL × 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give the white solid product II-64-2 (120 mg, 27% yield). MS (ESI) m / z: 347.1 [M+H] + .

[0391] Step 3: Synthesis of II-64-3 To a solution of II-64-2 (250 mg, 0.722 mmol) in THF / H2O (5 / 5 mL) at 25 °C, Na2S2O4 (629 mg, 3.613 mmol) was added, and the mixture was stirred for 4 h until the reaction was complete. The resulting mixture was concentrated to give the crude product. The crude product was purified by reverse phase column chromatography to give the brown solid product II-64-3 (45 mg, 20% yield). MS (ESI) m / z: 317.1 [M+H] + .

[0392] Step 4: Synthesizing II-64 To a solution of II-64-3 (30 mg, 0.095 mmol), 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (58 mg, 0.285 mmol), HATU (108 mg, 0.285 mol), and DMF (3 mL) at 25 °C, DIEA (74 mg, 0.569 mmol) was added and the mixture was stirred for 16 h until the reaction was complete. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (10 mL x 3), and the combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography and preparative HPLC to give the white solid product II-64 (5.31 mg, 11% yield). MS (ESI) m / z: 503.1 [M+H] + .

[0393] Example II-95: Synthesis of II-95 [ka]

[0394] Step 1: Synthesis of II-95-1 To a solution of tetrahydro-2H-thiopyran-4-ol (5.0 g, 42.30 mmol), MsCl (6.24 g, 54.47 mmol), and DCM (50 mL) at 0° C., TEA (12.83 g, 127.03 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was diluted with H2O (100 mL) and extracted with DCM (200 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the yellow solid product II-95-1 (7.9 g), which was used as is in the next reaction without the need for purification.

[0395] Step 2: Synthesis of II-95-2 To a solution of 6-methoxy-5-nitro-2H-indazole (5.32 g, 27.01 mmol), II-95-1 (7.9 g, 40.93 mmol), and DMF (40 mL) was added Cs2CO3 (17.604 g, 54.00 mmol), and the mixture was stirred at 70 °C for 16 h. The mixture was diluted with H2O (150 mL) and extracted with EtOAc (300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by high-performance silica gel column chromatography and reverse phase column chromatography to give the yellow solid product II-95-2 (0.63 g, 8% yield). MS (ESI) m / z: 294.0 [M+H] + .

[0396] Step 3: Synthesis of II-95-3 To a solution of II-95-2 (670 mg, 2.28 mmol), DMF (10 mL), and EtOH (20 mL) was added NH4Cl (610 mg, 11.40 mmol) and H2O (5 mL), the mixture was heated to 60 °C, and iron powder (640 mg, 11.43 mmol) was added. The mixture was stirred at 90 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was diluted with H2O (40 mL) and extracted with EtOAc (80 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the yellow solid product II-95-3 (500 mg, 83% yield). MS (ESI) m / z: 264.1 [M+H] + .

[0397] Step 4: Synthesis of II-95-4 To a solution of II-95-3 (500 mg, 1.89 mmol), 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (582 mg, 2.84 mmol), DIEA (733 mg, 5.26 mmol), and DMF (8 mL) at 25° C., HATU (1.73 g, 4.55 mmol) was added, and the mixture was stirred for 4 h. The reaction solution was diluted with H2O (40 mL), extracted with DCM (80 mL), and the combined organic layer was dried over anhydrous Na2SO4 and concentrated, and the residue was washed with DMF (2 mL) to give a white solid crude product. The filtrate was purified by reverse phase column chromatography to give the white solid product II-95-4 (200 mg, 24% yield). MS (ESI) m / z: 450.1 [M+H] + .

[0398] Step 5: Synthesis of II-95-5 To a mixture of II-95-4 (500 mg, 1.11 mmol), MeOH (10 mL) and DCM (10 mL) at 25 °C, a solution of NAIO4 (240 mg, 1.17 mmol) and H2O (2.0 mL) was added, and the mixture was stirred continuously for 16 h. The reaction was quenched with Na2SO3 (saturated, 15 mL), diluted with H2O (20 mL), and extracted with DCM (80 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the white solid product II-95-5 (250 mg, 48% yield). MS (ESI) m / z: 466.1 [M+H] + .

[0399] Step 6: Synthesis of II-95-6 To a solution of II-95-5 (50 mg, 0.11 mmol), tert-butyl carbamate (25 mg, 0.21 mmol), PhI(OAc)2 (53 mg, 0.16 mmol), MgO (18 mg, 0.45 mmol), and DCM (5 mL) was added Rh2(OAc)4 (122 mg, 0.27 mmol) and the mixture was stirred at 40 °C for 3 h. The reaction was diluted with H2O (30 mL) and extracted with DCM (80 mL). The combined organic layers were concentrated and purified by reverse phase column chromatography to give the white solid product II-95-6 (20 mg, 31% yield). MS (ESI) m / z: 581.0 [M+H]+ .

[0400] Step 7: Synthesis of II-95 At 25° C., II-95-6 (20 mg, 0.03 mmol) was added to HCl-dioxane (1 M, 2 mL) and stirred for 3 h until the reaction was complete. The reaction mixture was filtered and the filter cake was washed with a small amount of dioxane. The filter cake was dried in vacuum to give the yellow solid product II-95 (7.26 mg, 50% yield). MS (ESI) m / z: 481.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.55(s,1H), 9.19(s,1H), 8.85(d,J=5.6Hz,1H), 8.56(d,J=5.6Hz,1H), 8.43(d,J=12.4Hz,1H), 8.26(s,1H), 8. 15(d,J=5.2Hz,1H), 7.21(d,J=7.6Hz,1H), 5.06-4.97(m,1H), 4.29-4.08(m,4H), 4.03(d,J=5.2Hz,3H), 2.78(s,3H), 2.69-2.57(m,4H).

[0401] Example II-96: Synthesis of II-96 [ka]

[0402] To a solution of II-95-4 (50 mg, 0.11 mmol) and DCM (4 mL) at 0° C., m-CPBA (28 mg, 0.17 mmol) was added and the mixture was stirred at 25° C. for 2 h. The mixture was quenched with saturated aqueous Na2SO3 (30 mL) and extracted with DCM (60 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC to give the yellow solid product II-96 (5.94 mg, 11% yield). MS (ESI) m / z: 482.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ9.54(s,1H), 9.05(s,1H), 8.70(d,J=5.2Hz,1H), 8.56(s,1H), 8.39(s,1H), 7.87(s,1H), 7.80(d,J=5.2Hz,1H), 7.19(s,1H), 4.91-4.82(m,1H), 4.03(s,3H), 3.50-3.41(m,2H), 3.28-3.23(m,2H), 2.62(s,3H), 2.60-2.54(m,2H), 2.45-2.38(m,2H).

[0403] With reference to Example II-95, the following products could finally be synthesized.

[0404] [Table 4]

[0405] Example II-98: Synthesis of II-98 [ka]

[0406] Step 1: Synthesis of II-98-1 To a solution of 6-bromo-5-nitro-1H-indazole (4 g, 16.7 mmol), DHP (2.8 g, 33.3 mmol), and DCM (50 mL) at 0 °C, TsOH (627 mg, 3.3 mmol) was added and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with H2O (120 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give the yellow solid product II-98-1 (4.8 g, 88% yield). MS (ESI) m / z: 326.0 [M+H] + . 1H NMR:(400MHz,DMSO-d6)δ8.63(s,1H), 8.38(s,2H), 6.0-5.98(m,1H), 3.89(d,J=11.6Hz,1H), 3 .80-3.78(m,1H), 2.38-2.35(m,1H), 2.05-1.97(m,2H), 1.75-1.71(m,1H), 1.60-1.57(m,2H).

[0407] Step 2: Synthesis of II-98-2 To a solution of II-98-1 (500 mg, 1.54 mmol), 3,3-difluoropyrrolidine hydrochloride (220 mg, 1.54 mmol), Xantphos (179 mg, 0.31 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), and dioxane (15 mL) at 25 °C, Cs2CO3 (1.5 mg, 4.62 mmol) was added, and the mixture was reacted at 140 °C by microwave irradiation for 1 h. The reaction mixture was diluted with H2O (80 mL) and extracted with EA (30 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by high-performance silica gel column chromatography to give the brown solid product II-98-2 (70 mg, 12% yield). MS (ESI) m / z: 353.1 [M+H] + .

[0408] Step 3: Synthesis of II-98-3 To a solution of II-98-2 (800 mg, 2.272 mmol), NH4Cl (508 mg, 9.088 mmol), and EtOH / H2O (20 / 5 mL) at 60 °C, iron powder (486 mg, 9.088 mmol) was added and the mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by reverse-phase column chromatography to give the white solid product II-98-3 (100 mg, 14% yield). MS (ESI) m / z: 323.0 [M+H] + .

[0409] Step 4: Synthesis of II-98-4 To a solution of II-98-3 (100 mg, 0.31 mmol), 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (126 mg, 0.62 mmol), HATU (283 mg, 0.74 mmol), and DMF (6 mL) at 25° C., DIEA (160 mg, 1.24 mmol) was added. The mixture was then stirred for 16 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography to give the brown solid product II-98-4 (120 mg, 76% yield). MS (ESI) m / z: 509.2 [M+H] + .

[0410] Step 5: Synthesis of II-98-5 To a mixture of II-98-4 (120 mg, 0.236 mmol) and 1,4-dioxane (1 mL) at 0° C., HCl-1,4-dioxane (1 M, 5 mL) was added, and the mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give the white solid product II-98-5 (80 mg, 80% yield). MS (ESI) m / z: 425.1 [M+H] + .

[0411] Step 6: Synthesis of II-98 To a solution of II-98-5 (100 mg, 0.236 mmol), KI (19.5 mg, 0.118 mmol), 4-bromo-2-methylbutan-2-ol (78 mg, 0.472 mmol), and DMF (5 mL) at 25 °C, K2CO3 (97.7 mg, 0.708 mmol) was added. The mixture was then stirred for 16 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (10 mL × 3), and the combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative thin layer chromatography and reverse phase column chromatography to give the white solid product II-98 (5.58 mg, 4% yield). MS (ESI) m / z: 511.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.07(s,1H), 9.04(s,1H), 8.71(d,J=5.2Hz,1H), 8.56(s,1H), 8.36(s,1H), 7.87(s,1H), 7.76(d,J=5.2Hz,1H), 7 .57(s,1H), 4.51(s,1H), 4.47-4.43(m,2H), 3.58(t,J=12.4Hz,2H), 3.35-3.31(m,2H), 2.62-2.57(m,5H), 2.04-1.96(m,2H), 1.15(s,6H).

[0412] By referring to Example II-98, the following product was finally synthesized.

[0413] [Table 5]

[0414] Example II-111: Synthesis of II-111 [ka]

[0415] Step 1: Synthesis of II-111-1 To a solution of II-98-1 (4.1 g, 15.6 mmol) and 1,4-dioxane (15 mL), tributyl(1-ethoxyethenyl)stannane (5.45 g, 15.1 mmol) and TEA (3.2 g, 31.5 mmol) were added, and the mixture was stirred at 25 °C for 15 min under nitrogen atmosphere. Then, Pd(PPh3)2Cl2 (0.9 g, 1.3 mmol) was added, and the resulting mixture was stirred at 100 °C for 16 h. The reaction solution was cooled to room temperature and diluted with saturated aqueous potassium fluoride solution (50 mL). Insoluble materials were removed by filtration, and the filtrate was extracted with EtOAc (60 mL × 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give yellow oily product II-111-1 (2.9 g, 72.7% yield). MS(ESI)m / z:318.1[M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.47(s,1H), 8.36(s,1H), 7.94(s,1H), 6.03(dd,J=9.2,2.0Hz,1H), 4.62(d,J=2.4Hz,1H), 4 .48(d,J=2.4Hz,1H), 3.83(m,4H), 2.37(m,1H), 2.01(s,2H), 1.75(m,1H), 1.64-1.54(m,2H), 1.19(t,J=7.2Hz,3H).

[0416] Step 2: Synthesis of II-111-2 To a solution of II-111-1 (2.5 g, 7.9 mmol), acetone (15 mL), and water (15 mL), TsOH (0.15 g, 0.8 mmol) was added and the mixture was stirred at 50° C. for 2 h. Water (30 mL) was added for dilution and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the white solid product II-111-2 (1.8 g, 78.8% yield). MS (ESI) m / z: 290.1 ​​[M+H] + .

[0417] Step 3: Synthesis of II-111-3 At 25°C, a solution of II-111-2 (2.0g, 6.92mmol) and THF (20mL) was added with a solution of trifluoromethyltrimethylsilane (2.04M, 13.84mmol) in THF (27.6M), stirred for 15 minutes, and then tetrabutylammonium fluoride (TBAF) (6.92mL, 6.92mmol) was added. The mixture was then reacted at room temperature for 16 hours by microwave irradiation. The reaction solution was poured into a saturated NH4Cl solution, and extracted with ethyl acetate (50mL x 2). The combined organic layer was washed with saturated brine (100mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by high-performance silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a yellow solid product II-111-3 (1.4g, 22.5% yield). MS (ESI) m / z: 360.1 [M + H] + .

[0418] Step 4: Synthesis of II-111-4 To a solution of II-111-3 (0.6 g, 1.7 mmol) and MeOH (10 mL) at 25° C., Pd / C (0.3 g, 10% purity) was added, and the mixture was stirred and purged with H2 three times, then stirred under H2 atmosphere for 16 h. The resulting mixture was filtered and concentrated to give the brown solid product II-111-4 (0.5 g, 91% yield). MS(ESI) m / z: 330.1 [M+H] + .

[0419] Step 5: Synthesis of II-111-5 To a solution of II-111-4 (0.5 g, 1.6 mmol), 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (0.3 g, 1.6 mmol), HATU (0.7 g, 1.9 mmol), and DMF (5.0 mL) at 25 °C, DIEA (0.4 g, 3.1 mmol) was added and the mixture was stirred for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography (DCM:MeOH = 20:1) to give the yellow solid product II-111-5 (0.44 g, 54% yield). MS (ESI) m / z: 516.1 [M + H] + .

[0420] Step 6: Synthesis of II-111-6 To a solution of II-111-5 (200 mg, 0.39 mmol) and DCM (10 mL) at 0° C., TFA (2.0 mL) was added dropwise, and the mixture was stirred at 25° C. for 16 h. The reaction was concentrated to dryness, and water (10 mL) and EtOAc (30 mL) were added to separate the organic phase. The organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the yellow solid product II-111-6 (82 mg, yield: 48.6%). MS(ESI)m / z: 432.1[M+H] + .

[0421] Step 7: Synthesis of II-111 To a solution of II-111-6 (100.0 mg, 0.2 mmol) in DMF (5 mL) was added NaH (28.0 mg, 0.6 mmol) at 0° C., and the mixture was stirred under nitrogen atmosphere for 1 h, after which a solution of 4-bromo-2-methylbutan-2-ol (41.7 mg, 0.25 mmol) in DMF (1 mL) was added to the mixture at 0° C. The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL×3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give the white solid product II-111 (21.16 mg, 20.4% yield). MS(ESI)m / z:518.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.74(s,1H), 8.96(s,1H), 8.76-8.68(m,2H), 8.42(s,1H), 7.99(s,1H), 7.83(s, 1H), 7.80(d,J=5.2Hz,2H), 4.54-4.46(m,3H), 2.61(s,3H), 2.08-2.02(m,2H), 1.98(s,3H), 1.16(s,6H).

[0422] Example II-122: Synthesis of II-122 [ka]

[0423] Step 1: Synthesis of II-122-1 Concentrated sulfuric acid (125 mL) was cooled to 0° C., and then 6-chloropyridin-3-ol (25 g, 0.195 mol) was added in portions with stirring. While maintaining the temperature at 0° C., potassium nitrate (35.5 g, 0.351 mol) was added in portions, and the resulting mixture was stirred at 25° C. for 4 h. After completion of the reaction, the reaction mixture was quenched with ice water (100 mL), and the resulting solid was filtered and dried under vacuum to obtain product II-122-1 (26 g, 92% yield). MS (ESI) m / z: 174.9 [M+H] + .

[0424] Step 2: Synthesis of II-122-2 II-122-1 (15 g, 85.7 mmol) was dissolved in methanol (150 mL) and Raney nickel (wet, 7.0 g) was added. The mixture was purged with hydrogen three times and then stirred under hydrogen atmosphere (~1-2 atm) at 25°C for 16 hours. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to give crude product II-122-2 (17 g). MS (ESI) m / z: 145.1 [M+H] + .

[0425] Step 3: Synthesis of II-122-3 To a solution of II-122-2 (14.5 g, 0.100 mol) and pyridine (150 mL) at 25° C., potassium ethyl xanthate (21.6 g, 0.300 mol) was added, and the resulting mixture was stirred at 100° C. under nitrogen atmosphere for 12 h. The reaction mixture was quenched with ice water (30 mL), pyridine was removed under vacuum, and the reaction mixture was acidified to pH=1.0 with concentrated HCl. Filtration and drying in vacuum afforded the desired product II-122-3 (18 g, 95% yield). MS(ESI) m / z: 186.9[M+H] + .

[0426] Step 4: Synthesis of II-122-4 To a solution of II-122-3 (11.0 g, 58.8 mmol) and ethyl acetate (150 mL), K2CO3 (8.10 g, 58.8 mmol) was added, followed by iodomethane (8.35 g, 58.8 mmol). The resulting mixture was stirred at 25 °C for 3 h. After the reaction was completed, water (100 mL) and ethyl acetate (200 mL) were added to the reaction solution and the phases were separated. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was slurried in ethyl acetate:n-hexane = 1:9 to give off-white solid compound II-122-4 (5.0 g, 42% yield). MS (ESI) m / z: 201.1 [M + H] + . 1H NMR (CDCl3,400MHz): δ7.65(d,J=8.4Hz,1H), 7.20(d,J=8.4Hz,1H), 2.79(s,3H).

[0427] Step 5: Synthesis of II-122-5 Morpholine (5.73 g, 65.7 mmol) was added to a solution of II-122-4 (2.20 g, 10.9 mmol) and THF (50 mL) at 25° C., and the mixture was stirred at reflux for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove THF, and then the reaction was quenched with ice water (20 mL). Filtration and vacuum drying gave the product II-122-5 (2.20 g, 84% yield). MS (ESI) m / z: 240.1 [M+H] + . 1 H NMR (CDCl3,400MHz): δ7.38(d,J=8.4Hz,1H), 6.94(d,J=8.0Hz,1H), 3.83-3.81(m,4H), 3.77-3.75(m,4H).

[0428] Step 6: Synthesizing II-122-6 Concentrated sulfuric acid (15M) was cooled to 0°C, II-122-5 (2.20g, 9.17mmol) was added in portions, followed by potassium nitrate (1.76g, 17.41mmol) in portions, and the resulting mixture was stirred at 25°C for 12 hours. After completion of the reaction, the reaction mixture was quenched with ice water (100M). The resulting solid was filtered and dried under vacuum to give the product II-122-6 (2.0g, 76% yield). MS(ESI) m / z: 285.1[M+H] + . 1H NMR (DMSO-d 6, 300): δ8. 60(s, 1), 3 75(S, 8R).

[0429] Step 7: Synthesis of II-122-7 To a solution of II-122-6 (800 mg, 2.81 mmol) and anhydrous DMF (10 mL), tributyl(1-ethoxyvinyl)tin (2.03 g, 5.63 mmol) and Pd(PPh3)Cl2 (197 mg, 0.281 mmol) were added, and the mixture was stirred at 110 °C for 2 h. After the reaction was completed, it was cooled to 0 °C, THF (10 mL) was added, and then 2NHCl (10 mL) was added. The resulting mixture was stirred at 25 °C for 2 h and basified to pH 8-9 with saturated NaHCO3. It was filtered through diatomaceous earth, and the aqueous phase was extracted with EtOAc (30 mL × 3), and the combined organic layer was washed with saturated brine (50 mL), dried (anhydrous Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography (10-100% ethyl acetate / heptane) to give a pale yellow solid product II-122-7 (600 mg, 73% yield). MS (ESI) m / z: 293.1 [M+H] + .

[0430] Step 8: Synthesis of II-122-8 To a mixture of II-122-7 (350 mg, 1.19 mmol), EtOH (10 mL), and water (2.5 mL), iron powder (334 mg, 5.97 mmol) and ammonium chloride (193 mg, 3.57 mmol) were added. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 3 h. After the reaction was completed, the mixture was filtered through diatomaceous earth and washed with DCM (containing 10% MeOH, 30 mL x 3). The filtrate was washed with saturated brine (50 mL), dried (anhydrous Na2SO4), filtered, and concentrated to give the crude product II-122-8 (310 mg, 88% yield), which was used directly in the next step. MS (ESI) m / z: 263.1 [M+H] + . 1 H NMR (DMSO-d6,400MHz): δ7.24(s,1H), 7.15(s,1H), 3.73(s,4H), 3.61(s,4H), 2.53(s,3H).

[0431] Step 9: Synthesis of II-122-9 To a solution of II-122-8 (120 mg, 0.456 mol) and pyridine (5.0 mL), 2-(2-methylpyridin-4-yl)oxazole-4-carbonyl chloride (203 mg, 0.912 mmol) was added, and the system was heated to 80°C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction solution was spin-dried, and the crude product was purified by silica gel column chromatography (10-100% ethyl acetate / heptane) to obtain a brown solid product II-122-9 (100 mg, 49% yield). MS (ESI) m / z: 449.1 [M+H] + .

[0432] Step 10: Synthesis of II-122 Under ice-water bath condition, methylmagnesium bromide solution (2.7 mL, 2.67 mmol) was added to a mixture of II-122-9 (120 mg, 0.267 mmol) and anhydrous THF (10 mL). The resulting mixture was stirred at 25 °C for 3 h and quenched with saturated ammonium chloride solution. The resulting solution was extracted with EtOAc (30 mL x 3), and the combined organic layer was washed with saturated brine (50 mL), dried (anhydrous Na2SO4), filtered and concentrated. Purification by preparative HPLC gave yellow solid II-122 (30 mg, 24% yield). MS (ESI) m / z: 465.1 [M+H] + . 1 H NMR (DMSO-d6,400MHz): δ12.09(s,1H), 9.01(s,1H), 8.74(s,1H), 8.70(d,J=5.2Hz,1H), 7.9 1-7.72(m,2H), 6.44(s,1H), 3.84-3.72(m,4H), 3.72-3.61(m,4H), 2.61(s,3H), 1.60(s,6H).

[0433] With reference to Example II-122, the following products could finally be synthesized: [Table 6(1)] [Table 6(2)] [Table 6(3)] [Table 6(4)]

[0434] Example II-131: Synthesis of II-131 [ka]

[0435] Step 1: Synthesis of II-131-1 A mixture of II-8-2 (50 mg, 0.2 mmol), NH4Cl (21 mg, 0.4 mmol), EDCI (56 mg, 0.3 mmol), HOBT (39 mg, 0.3 mmol), DIEA (125 mg, 1.0 mmol), and DMF (6 mL) was stirred at 25 °C for 16 h. Water (10 mL) and EtOAc (30 mL × 3) were added for extraction. The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by flash silica gel column chromatography (DCM:MeOH = 10:1) to give the yellow solid product II-131-1 (40 mg, 77.5% yield). MS (ESI) m / z: 258.0 [M + H] + .

[0436] Step 2: Synthesis of II-131-2 At 0° C., to a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (10 g, 50.5 mmol) and EtOAc (20 mL) was added n-CPBA (14.8 g, 85.76 mmol). The mixture was stirred at 55° C. for 5.5 h. The reaction solution was poured into Na2SO3 solution, and the product was extracted with EA (50 mL×3). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give yellow solid product II-131-2 (8.8 g, 81.4% yield). 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1), 8.29(s,1), 8.13(s,1).

[0437] Step 3: Synthesis of II-131-3 To a solution of II-131-2 (8.8 g, 41.12 mmol) and MeCN (150 mL) at 25° C., triethylamine (8.5 g, 84.0 mmol), TMSCN (8.4 g, 8.4.67 mmol) were added. The mixture was stirred at 80° C. for 16 h, H2O (40 mL) was added to dilute the reaction mixture, and extracted with EtOAc (60 mL×3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the yellow solid product II-131-3 (8.6 g, 91.7% yield). MS (ESI) m / z: 224.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ14.38(s,1), 8.88(s,1), 8.34(s,1).

[0438] Step 4: Synthesis of II-131-4 To a solution of II-131-3 (2 g, 9.0 mmol) and THF (20.0 mL) at 0° C., methylmagnesium bromide (9.0 mL, 27.0 mmol) was added. The mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (60 mL×3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the yellow solid product II-131-4 (1.0 g, 46.3% yield). 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H), 8.23(s,1H), 2.66(s,3H).

[0439] Step 5: Synthesis of II-131-5 To a solution of II-131-4 (1.4 g, 5.8 mmol), DHP (1.0 g, 11.7 mmol), and DCM (15 mL) at 0° C., TsOH (0.2 g, 1.2 mmol) was added. The mixture was stirred at 0° C. for 0.5 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30×3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography (PE:EtOAc=5:1) to give the white solid product II-131-5 (1.6 g, 85.1% yield). MS (ESI) m / z: 324.1 [M+H] + .

[0440] Step 6: Synthesizing II-131-6 A mixture of II-131-5 (126.0 mg, 0.39 mmol), II-131-1 (300.0 mg, 1.2 mmol), Xantphos (34.0 mg, 0.06 mmol), Cs2CO3 (381.0 mg, 1.2 mmol), Pd2(dba)3 (36 mg, 0.04 mmol), and 1,4-dioxane (10.0 mL) was reacted at 140 °C by microwave irradiation for 1 hour. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with saturated saline (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by high-performance silica gel column chromatography (DCM:MeOH = 10:1) to obtain a yellow solid product II-131-6 (90 mg, yield 46.0%). MS(ESI)m / z:501.1[M+H] + .

[0441] Step 7: Synthesis of II-131-7 To a solution of II-131-6 (200 mg, 0.4 mmol) and THF (5.0 mmol) at 0 °C, 2 M methylmagnesium bromide in tetrahydrofuran (2.0 M, 4.0 mmol) was added. The mixture was stirred at 70 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by flash silica gel column chromatography (DCM:MeOH = 10:1) to give the yellow solid product II-131-7 (150 mg, 72.8% yield). MS (ESI) m / z: 517.1 [M + H] + .

[0442] Step 8: Synthesis of II-131-8 To a solution of II-131-7 (200 mg, 0.39 mmol) and DCM (10 mL) at 0° C., TFA (2.0 mL) was added and the mixture was stirred at 25° C. for 16 h. The mixture was concentrated, and the residue was stirred with water (10 mL) to adjust the pH to 8, and extracted with EtOAc (10 mL×3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the yellow solid product II-131-8 (50 mg, 29.6% yield). MS (ESI) m / z: 433.1 [M+H] + .

[0443] Step 9: Synthesis of II-131 At 0°C, NaH (15.0 mg, 0.3 mmol) was added to a solution of II-131-8 (50.0 mg, 0.1 mmol) in DMF (5 mL) and stirred under nitrogen atmosphere for 1 h. Then, a solution of 4-bromo-2-methylbutanol (25.0 mg, 0.2 mmol) in DMF (1 mL) was added to the mixture while maintaining the temperature at 0°C. The reaction mixture was stirred at 25°C for 16 h. Extracted with water (10 mL) and EtOAc (30 mL x 3), the combined organic layer was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by high performance liquid chromatography to give the white solid product II-131 (2.5 mg, 4.3% yield). MS (ESI) m / z: 519.2 [M+H] +.

[0444] Evaluation of kinase activity inhibition by compounds Using an experimental method based on fluorescent microfluidic mobility detection, the IC of compounds for competitive binding to ATP by the kinases IRAK4 and FLT3 were calculated. 50 The values ​​were measured. The starting detection concentration of the compounds was 10 μM and diluted in a 4-fold gradient to 0.38 nM in duplicate. Commercially available staurosporine was used as a standard control in the experiments.

[0445] Reagent and consumable information is as follows: IRAK4 kinase (Carna, Cat. No. 09-145, Lot. No. 14CBS-0020H) FLT3 kinase (Carna, Cat. No. 08-154, Lot. No. 07CBS-2350) Substrate peptide FAM-P2 (GL Biochem, Cat. No. 112394, Lot. No. P131014-XP112394) Substrate peptide FAM-P8 (GL Biochem, Cat. No. 112396, Lot. No. P170731-SY112396) ATP (Adenosine triphosphate, Sigma, Cat. No. A7699-1G, CAS No. 987-65-5) DMSO (Dimethylsulfoxide, Sigma, Cat. No. D2650) EDTA (Ethylenediaminetetraacetic acid, Sigma, Cat. No. E5134, CAS No. 60-00-4) Staurosporine (Selleckchem, Cat. No. S1421) HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, Gibco, Cat. No. 15630-080) Brij-35 solution (polyoxyethylene lauryl ether, Sigma, Cat. No. B41840-100 mL) DTT (Dithiothreitol, Sigma, Cat. No. D0632-20G) 0.2% Coating Reagent #3 (0.2% Coating Reagent, Perkin Elmer, Cat. No. 760050) 96-well plate (Corning, Cat. No. 3365) 384-well plate (Corning, Cat. No. 3573)

[0446] Experimental procedure 1) FLT3 and IRAK4 kinases were dissolved in kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01% Brij-35) to final concentrations of 0.9 nM, 30 nM and 6 nM, respectively.

[0447] 2) The substrate peptides FAM-P2 and FAM-P8 were dissolved in ATP and the above kinase buffer. The final concentrations of the substrate peptides FAM-P2 and ATP for measuring FLT3 were 3 μM and 97 μM, respectively, and the final concentrations of the substrate peptides FAM-P8 and ATP for measuring IRAK4 were 3 μM and 10 μM, respectively.

[0448] 3) Compound dilution: Compounds were first diluted to 50 μM and then diluted in a 4-fold gradient with DMSO, where a solution without compound and kinase was the blank control and corresponds to the "Min" value shown below. A solution without compound but with kinase, adenosine triphosphate, DMSO, and buffer was the positive control and corresponds to the "Max" value shown below.

[0449] 4) Kinase reaction and termination: 10 μL of kinase buffer was added to a 384-well plate containing 5 μL of the compound to be measured and incubated at room temperature for 10 minutes. 10 μL of buffer containing substrate peptide and adenosine triphosphate was added to the 384-well plate and incubated at 28° C. for 1 hour, after which 25 μL of stop solution (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2% Coating Reagent #3, and 0.015% Brij-35) was added to each well to terminate the reaction.

[0450] 5) Data reading: The conversion rate data was read using CaliperEZ ReaderII equipment. Setting conditions: downstream voltage-500V, upstream voltage-2250V, reference pressure-0.5PSI, sorting pressure-1.2PSI.

[0451] 6) Data calculation: Copy the conversion rate data from CaliperEZ ReaderII and convert the conversion rate into inhibition rate data. The calculation formula is as follows: Inhibition rate (%) = (maximum value - conversion rate) / (maximum value - minimum value)*100% IC using XLFit Excel Add-in version 5.4.0.8 50 Fit the values. Fitting formula: Y=Bottom+(Top-Bottom) / (1+(IC 50 / X)^HillSlope)

[0452] Kinase activity data is shown in Table 1.

[0453] [Table 7(1)] [Table 7(2)]

[0454] In the above table, "ND" stands for not detected.

[0455] IC of compounds killing MV4-11 cells50 Measurement of values Reagent and consumable information is as follows: MV4-11 cells (ATCC, Cat.No.CRL-9591) DPBS (Dulbecco's Phosphate Buffer, Biosera, Cat. No. LM-S2041 / 500) IMDM medium (Thermo, Cat. No. 12440053) Fetal bovine serum (Biological, Cat. No. 04-002-1A) Penicillin-streptomycin solution (Invitrogen, Cat. No. 15140122) Dimethyl sulfoxide (Sigma, Cat. No. D2650) CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat. No. G7573) 96-well plate (Corning, Cat. No. 3903)

[0456] CTG experimental procedure 1.MV-4-11 cells were cultured in IMDM complete medium (IMDM + 10% fetal bovine serum + 1% Penicillin-Streptomycin, a mixture of penicillin and streptomycin). 2. MV-4-11 cells in good condition were collected and washed twice with DPBS (Dulbecco's phosphate buffered saline). 3. Resuspend MV-4-11 cells in IMDM complete medium to a cell density of 1.11 x 10 6 The concentration was adjusted to cells / mL, and 90 μL was added to each well of a 96-well plate. 4. Prepare a 10x concentration compound solution in IMDM complete medium, add 10μL of the 10x concentration compound solution to the cells in the 96-well plate, mix evenly, then place the 96-well plate in a 37℃, 5% CO2 incubator and incubate for 72 hours. 5. After incubation, the 96-well plate was removed and equilibrated at room temperature for 30 minutes, after which 100 μL of CellTiter Glo reagent was added to each well and mixed evenly on a horizontal shaker for 2 minutes. 6. The 96-well plate was removed and equilibrated at room temperature for 10 minutes, and the chemiluminescence values ​​were detected by a plate reader.

[0457] The cell killing activity data are shown in Table 2.

[0458] [Table 8(1)] [Table 8(2)]

Claims

1. A five-membered fused six-membered compound represented by formula II or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, m is 1, 2 or 3; E is N or CH; R 1 is unsubstituted or substituted with one or more R １－１ a 3- to 11-membered heterocycloalkyl group substituted with one or more R １－２ a 3- to 10-membered cycloalkyl group substituted with one or more R １－４ C substituted with １ ~C ６ an alkyl group, the heteroatom of the 3- to 11-membered heterocycloalkyl group being one or more selected from N, S and O, and the number of heteroatoms being 1, 2 or 3; R １－１ , R １－２ and R 1-4 are each independently deuterium, halogen, oxo, 【Chemistry 2】 Hydroxyl group, unsubstituted or one or more R １－１－１ a 3- to 11-membered heterocycloalkyl group substituted with cyano, an unsubstituted or １－１－３ C substituted with １ ~C ６ Alkoxy groups, 【Chemistry 3】 Unsubstituted or one or more R １－１－４ C substituted with １ ~C ６ Alkyl group, unsubstituted or one or more R １－１－５ a 3- to 10-membered cycloalkyl group substituted with -SO ２ -R ａ , 【Chemistry 4】 the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R １－１－１ , R １－１－３ , R １－１－４ and R 1-1-5 are each independently deuterium, unsubstituted or substituted with one or more halogens. １ ~C ６ Alkyl group, halogen, oxo, 【Chemistry 5】 or a hydroxyl group, R a and R b are each independently H or an unsubstituted C 1 -C 6 alkyl group; R ２ is unsubstituted or substituted with one or more R ２－１ a 3- to 11-membered heterocycloalkyl group unsubstituted or substituted with one or more R ２－７ C substituted with １ ~C ６ Alkoxy group, R ２－８ or one or more R ２－４ C substituted with １ ~C ６ an alkyl group, the heteroatom of the 3- to 11-membered heterocycloalkyl group being one or more selected from N, S and O, and the number of heteroatoms being 1, 2 or 3; R 2-1 is deuterium, a halogen or a hydroxyl group; R 2-4 are deuterium, halogen or hydroxyl groups; R 2-7 is a C alkyl group that is unsubstituted or substituted with one or more halogens, a hydroxyl group, a halogen atom, an oxo group, or a C alkyl group that is unsubstituted or substituted with one or more halogens. １ ~C ６ is an alkyl group, R ２－８ is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, and the heteroatom of the 5- to 10-membered heteroaryl group is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three, R ４ is unsubstituted or substituted with one or more R ４－１ a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R ４－５ a 6- to 10-membered aryl group substituted with, the heteroatom of the 5- to 10-membered heteroaryl group being one or more selected from N, S and O, the number of heteroatoms being 1, 2 or 3; R ４－１ and R ４－５ are each independently halogen, unsubstituted or one or more R ４－１－１ C substituted with １ ~C ６ an alkoxy group, a cyano group, an oxo group, a hydroxyl group, or an unsubstituted or one or more R ４－１－３ C substituted with １ ~C ６ is an alkyl group, R ４－１－１ and R 4-1-3 are each independently a halogen, a hydroxyl group, or a C substituted or unsubstituted with one or more halogens. １ ~C ６ an alkyl group or an unsubstituted or substituted C with one or more halogens; １ ~C ６ A five-membered fused six-membered compound of formula II, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkoxy group;

2. The five-membered fused six-membered compound satisfies one or more of the following conditions: (1) R １ is unsubstituted or is substituted with one or more R １－１ When R is a 3- to 11-membered heterocycloalkyl group substituted with R, the 3- to 11-membered heterocycloalkyl group is a 3- to 9-membered heterocycloalkyl group, １－１ each independently represents a halogen, a hydroxyl group, an oxo group, 【Chemistry 6】 or C substituted with one or more halogen or heterocycloalkyl groups; １ ~C ６ is an alkyl group, (2) R １ is one or more R １－２ When the 3- to 10-membered cycloalkyl group is a 3- to 10-membered cycloalkyl group substituted with ３ ~C ６ is a cycloalkyl group, R １－２ Each independently represents -SO ２ -R ａ , halogen, or hydroxyl group; R ａ is C １ ~C ６ is an alkyl group, (3) R １ is one or more R １－４ C substituted with １ ~C ６ When it is an alkyl group, １ ~C ６ The alkyl group is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a primary pentyl group, a sec-pentyl group, a tert-pentyl group, or a neopentyl group; R １－４ each independently represents deuterium, a halogen, a hydroxyl group, or -SO ２ -R ａ , 【Chemistry 7】 a 3- to 6-membered cycloalkyl group substituted with a hydroxyl group, a 3- to 8-membered heterocycloalkyl group substituted with a hydroxyl group, or a 3- to 8-membered heterocycloalkyl group substituted with oxo, a 3- to 8-membered heterocycloalkyl group substituted with halogen and Boc, or a 3- to 8-membered heterocycloalkyl group substituted with halogen, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is N and / or O, and the number of heteroatoms is 1 or 2; ａ is C １ ~C ６ is an alkyl group, R ｂ is hydrogen, (4) R １－１ , R １－２ and when R 1-4 are each independently a halogen, said halogen is fluorine, chlorine, bromine, or iodine; (5) R １－１ , R １－２ and R 1-4 are each independently unsubstituted or one or more R １－１－１ when it is a 3- to 11-membered heterocycloalkyl group substituted with (6) R １－１ , R １－２ and R 1-4 are each independently unsubstituted or one or more R １－１－４ C substituted with １ ~C ６ When it is an alkyl group, １ ~C ６ The alkyl group is C １ ~C ４ is an alkyl group, (7) R １－１－１ Each of them is independently C １ ~C ６ When it is an alkyl group, １ ~C ６ The alkyl group is C １ ~C ４ is an alkyl group, (8) R ２ is unsubstituted or is substituted with one or more R ２－１ When R is a 3- to 11-membered heterocycloalkyl group substituted with R, the 3- to 11-membered heterocycloalkyl group is a 3- to 8-membered heterocycloalkyl group, ２－１ are each independently a halogen or a hydroxyl group; (9) R ２ is one or more R ２－４ C substituted with １ ~C ６ When it is an alkyl group, １ ~C ６ The alkyl group is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a primary pentyl group, a sec-pentyl group, a tert-pentyl group, or a neopentyl group; R ２－４ are each independently a deuterium, a halogen, or a hydroxyl group; (10) R ２ is unsubstituted or is substituted with one or more R ２－７ C substituted with １ ~C ６ When it is an alkoxy group, １ ~C ６ The alkoxy group is C １ ~C ４ is an alkoxy group, R ２－７ are each independently deuterium or a halogen; (11) R ２ R ２－８ When R is a hydroxyl group substituted with ２－８ is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, the heteroatom of the 3- to 6-membered heterocycloalkyl group is oxygen, and the number of heteroatoms is one; (12) R ２－１ , R 2-4 and R ２－７ are each independently a halogen, said halogen is fluorine, chlorine, bromine, or iodine; (13) R ４ is unsubstituted or is substituted with one or more R ４－１ When the 5- to 10-membered heteroaryl group is a 6-membered heteroaryl group, R ４－１ are each independently １ ~C ６ C substituted with an alkyl group or one or more halogens １ ~C ６ is an alkyl group, (14) R ４－１ C is unsubstituted or substituted with one or more halogens １ ~C ６ When it is an alkyl group, １ ~C ６ The alkyl group is C １ ~C ４ 2. The compound of claim 1, wherein the halogen is fluorine, chlorine, bromine, or iodine, or a 5-membered fused 6-membered compound of formula II or a pharma- ceutically acceptable salt thereof.

3. The five-membered fused six-membered compound satisfies one or more of the following conditions: (1) R １ is unsubstituted or is substituted with one or more R １－１ When the heterocycloalkyl group is a 3- to 11-membered heterocycloalkyl group substituted with R １－１ The 3- to 11-membered heterocycloalkyl group substituted with 【Chemistry 8】 and (2) When R 1 is a 3- to 10-membered cycloalkyl group substituted with one or more R 1-2 , the 3- to 10-membered cycloalkyl group substituted with one or more R 1-2 is 【Chemistry 9】 and (3) When R 1 is a C 1 -C 6 alkyl group substituted with one or more R 1-4 , the C 1 -C 6 alkyl group substituted with one or more R 1-4 is 【Chemistry 10】 and (4) When R 1-1 , R 1-2 and R 1-4 are each independently a halogen, the halogen is fluorine; (5) When R 1-1 , R 1-2 and R 1-4 are each independently a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted with one or more R 1-1-1 , the 3- to 11-membered heterocycloalkyl group is, 【Chemistry 11】 and (6) When R 1-1 , R 1-2 and R 1-4 are each independently a C 1 -C 6 alkyl group substituted with one or more R 1-1-4 , the C 1 -C 6 alkyl group is an isopropyl group, a methyl group or an ethyl group; (7) When R 1-1-1 are each independently a C 1 to C 6 alkyl group, the C 1 to C 6 alkyl group is a methyl group or an ethyl group; (8) When R 2 is a 3- to 11-membered heterocycloalkyl group which is unsubstituted or substituted with one or more R 2-1 , the 3- to 11-membered heterocycloalkyl group is a 3- to 8-membered heterocycloalkyl group, and the 3- to 8-membered heterocycloalkyl group which is unsubstituted or substituted with one or more R 2-1 , is 【Chemistry 12】 and (9) When R 2 is a C 1 -C 6 alkyl group substituted with one or more R 2-4 , the C 1 -C 6 alkyl group substituted with one or more R 2-4 is 【Chemistry 13】 and (10) When R 2 is a C 1 -C 6 alkoxy group which is unsubstituted or substituted with one or more R 2-7 , the C 1 -C 6 alkoxy group which is unsubstituted or substituted with one or more R 2-7 is a methoxy group, an isopropoxy group, a deuterated methoxy group, or a trifluoromethoxy group; (11) When R 2 is a hydroxyl group substituted with R 2-8 , the hydroxyl group substituted with R 2-8 is 【Chemistry 14】 and (12) When R 2-1 and R 2-7 are each independently a halogen, the halogen is fluorine; (13) When R 4 is a 5- to 10-membered heteroaryl group which is unsubstituted or substituted with one or more R 4-1 , the 5- to 10-membered heteroaryl group which is unsubstituted or substituted with one or more R 4-1 is 【Chemistry 15】 and (14) When R 4 is a 6- to 10-membered aryl group unsubstituted or substituted with one or more R 4-5 , the 6- to 10-membered aryl group is a phenyl group, and R ４－５ are each independently a C 1 -C 6 alkyl group or a C 1 -C 6 alkyl group substituted with one or more halogens. １ ~C ６ 3. The 5-membered fused 6-membered compound of formula II according to claim 2, wherein the 5-membered fused 6-membered compound is an alkyl group, or a pharma- ceutically acceptable salt thereof.

4. The five-membered fused six-membered compound satisfies one or more of the following conditions: (1) R 1-1 , R 1-2 and R 1-4 are each independently a deuterium atom, an oxo group, or a hydroxyl group; 【Chemistry 16】 halogen, 【Chemistry 17】 -SO2-C1-C6 alkyl group, C1-C6 alkyl group unsubstituted or substituted with one or more R1-1-4, 3- to 10-membered cycloalkyl group unsubstituted or substituted with one or more R1-1-5, or 3- to 10-membered heterocycloalkyl group unsubstituted or substituted with one or more R1-1-1, the heteroatom of said 3- to 10-membered heterocycloalkyl group being one or more of N, S and O, the number of heteroatoms being 1, 2 or 3, (2) R 1-1-1 is independently an oxo, halogen or hydroxyl group; (3) R 1-1-4 are each independently a halogen; (4) R 1-1-5 are each independently a hydroxyl group; (5) R 2 is a 3- to 6-membered heterocycloalkyl group which is unsubstituted or substituted with one or more R 2-1 , a C 1 -C 6 alkoxy group which is unsubstituted or substituted with one or more R 2-7 , a C 1 -C 6 alkyl group which is substituted with one or more R 2-4 , or a hydroxyl group which is substituted with R 2-8 , the heteroatom of the 3- to 6-membered heterocycloalkyl group is one or more selected from N and O, and the number of heteroatoms is 1 or 2, (6) R 2-8 is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, the heteroatom of the 3- to 6-membered heterocycloalkyl group is one selected from N and O, and the number of heteroatoms is one; (7) R 2-1 is each independently a hydroxyl group or a halogen; (8) R 2-4 are each independently deuterium, halogen, or a hydroxyl group; (9) R 2-7 are each independently deuterium or halogen; (10) R 4 is independently a 5- to 6-membered heteroaryl group which is unsubstituted or substituted with one or more R 4-1 , or a phenyl group which is unsubstituted or substituted with one or more R 4-5 , the heteroatom of the 5- to 6-membered heteroaryl group is N, and the number of heteroatoms is 1, 2, or 3; (11) The 5-membered fused 6-membered compound represented by formula II according to claim 1, wherein R 4-1 and R 4-5 are each independently a C 1 -C 6 alkyl group that is unsubstituted or substituted with one or more halogens, or a pharma- ceutical acceptable salt thereof.

5. The five-membered fused six-membered compound satisfies one or more of the following conditions: (1) R 1-4 is a hydroxyl group, a halogen, or a 3- to 11-membered heterocycloalkyl group substituted with one or more R 1-1-1 , and the 3- to 11-membered heterocycloalkyl group is 【Chemistry 18】 and R 1-1-1 is halogen; (2) R 2-4 is a hydroxyl group; (3) The five-membered fused six-membered compound represented by formula II according to claim 4, or a pharma- ceutically acceptable salt thereof, wherein R2-7 is halogen.

6. R 1 is 【Chemistry 19】 2. The five-membered fused six-membered compound of formula II according to claim 1, wherein:

7. R 2 is 【Chemistry 20】 a methoxy group, an isopropoxy group, a deuterated methoxy group or a trifluoromethoxy group; 【Chemistry 21】 and R 4 is 【Chemical 22】 Phenyl group, 【Chemistry 23】 2. The five-membered fused six-membered compound of formula II according to claim 1, wherein:

8. A method for producing a five-membered condensed six-membered compound represented by formula II according to claim 1, comprising the step of carrying out the following condensation reaction between a compound represented by formula II-A and a compound represented by formula II-B in a solvent in the presence of a base and a condensing agent. 【Chemistry 24】

9. A pharmaceutical composition comprising a five-membered fused six-membered compound represented by formula II according to claim 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

10. A method for inhibiting kinase activity of FMS-like tyrosine kinase 3 (FLT3) in a subject, comprising administering to the subject a therapeutically effective amount of a five-membered fused six-membered compound represented by formula II described in claim 1 or a pharma- ceutically acceptable salt thereof.

11. A method for inhibiting the kinase activity of interleukin-1 receptor-associated kinase 4 (IRAK4) in a subject, comprising administering to the subject a therapeutically effective amount of a five-membered fused six-membered compound represented by formula II described in claim 1 or a pharma- ceutically acceptable salt thereof.

12. A five-membered fused six-membered compound represented by formula II, having any of the following structures, or a pharma- ceutically acceptable salt thereof. 【Chemistry 25】 【Chemistry 26】 【Chemical 27】 【Chemistry 28】 【Chemical 29】 【Chemistry 30】

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