Five-membered fused six-membered compounds, production methods, pharmaceutical compositions, and applications

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 the contents of the above Chinese patent applications. [Technical field] The present invention relates to five-membered fused six-membered compounds, preparation methods, pharmaceutical compositions and applications. [Background technology]

[0002] FLT3-like tyrosine kinase 3 (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, primarily internal tandem duplications in the juxtamembrane domain (FLT3-ITD) and point mutations or deletions in the tyrosine kinase domain (FLT3-TKD), 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 (e.g., RAS, PI3K, and STAT5), resulting in hematopoietic cell survival, proliferation, differentiation, and resistance to apoptosis. In addition, the mutant-to-wild-type allele ratio, insertion site, ITD length, karyotype, and the presence of NPM1 mutations may influence the prognostic value of FLT3-ITD in newly diagnosed patients with FLT3-ITD-mutant AML (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.). Because high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) have not been successful in completely improving prognosis and patients are prone to short survival and relapse, FLT3 kinase inhibitors have become a focus of therapeutic research for AML. First-generation FLT3 inhibitors such as lestaurtinib, 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, although not a suitable monotherapy, can be used in combination with cytarabine, daunorubicin, and cytarabine (FDA-approved) for the treatment of adult FLT3-mutated AML. Second-generation FLT3 kinase inhibitors, such as gilteritinib, crenolanib, and quizartinib, are more selective, active, and less toxic, but still have some off-target effects.

[0003] Currently, three FLT3 inhibitors (quizartinib, gilteritinib, and midostaurin) are approved for sale in Japan and / or the United States and are used as monotherapy or in combination with conventional chemotherapy drugs to treat patients with AML. These inhibitors have shown favorable clinical efficacy and have improved the prognosis of AML patients to some extent. When used as monotherapy, disease relapse occurs quickly, and target-dependent and non-target-dependent resistance develops. 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-resistance mutation site. Activation of related signaling pathways can also compensate for inhibition of the FLT3 signaling pathway. Currently, researchers are attempting to reduce the incidence of non-targeted drug resistance by directly inhibiting relevant signaling pathways (e.g., PI3K / AKT and / or RAS / MEK / MAPK) or by co-inhibiting signaling pathways related to cell survival through drug combinations, but the effectiveness has been 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 a certain period of treatment with quizartinib and gilteritinib, pFLT3 and pSTAT5 expression were reduced, but no significant inhibition of tumor cell proliferation was observed. Furthermore, elevated IRAK4 phosphorylation levels were observed in many recurrent cases, and co-administration of IRAK4 inhibitors reduced tumor cell viability, suggesting that IRAK4 could be used as a target for non-targeted drug resistance.

[0004] Interleukin-1 receptor-associated kinases (IRAKs) are serine / threonine protein kinases belonging to the tyrosine-like kinase (TLK) family, of which IRAK1 and IRAK4 possess kinase activity. IRAKs are 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, resulting in the activation of NF-kB. Aberrant activation of the IRAK pathway in tumor cells further exacerbates 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.) Dual-targeting FLT3 / IRAK4 compounds have been developed that have potential clinical value, can improve patient outcomes, and reduce drug resistance. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides a five-membered fused six-membered compound, a preparation method, a pharmaceutical composition, and applications. 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 patient prognosis and reduce drug resistance.

[0006] The present invention provides a five-membered fused six-membered compound represented by formula I or a pharmaceutically 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 atoms above and the ring Cy 3 or N and R 2 The atoms above 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 heteroatoms 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 which 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 which 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 are each independently hydrogen, halogen, 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 substituted with 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 a 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 a 6- to 10-membered aryl group substituted with, or unsubstituted or 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 1, 2 or 3, 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 1, 2 or 3, 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 types selected from N, S, and O, and the number of heteroatoms is 1, 2, or 3; 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 1, 2, or 3; 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 are each independently 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 represents 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 substituted with 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 a 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 1, 2 or 3; 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 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; 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 1, 2, or 3; 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 1, 2, or 3; 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 a cycloalkyl group substituted with, or unsubstituted or with one or more R 4-5 the heteroatom of said 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 said 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; 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 one or more R 4-1-5 a 3- to 11-membered heterocycloalkyl group substituted with one or more heteroatoms selected from N, S and O, the number of heteroatoms being 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 a 6- to 10-membered aryl group substituted with, or unsubstituted or substituted with one or more R a-5 a 5- to 10-membered heteroaryl group substituted with R a , and R b form a 3- to 11-membered heterocyclic ring together with atoms bonded thereto; 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 1, 2, or 3; 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 1, 2, or 3; 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 pharmaceutically 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 upper atom is the ring Cy 3 or N and R 2 The atoms above and the ring Cy 2 Forming Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of said 5-membered heteroaromatic ring is one or more heteroatoms 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 which 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 which 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 are each independently hydrogen, halogen, 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 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 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7are each independently 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 substituted with 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 a 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 a 6- to 10-membered aryl group substituted with, or unsubstituted or substituted with one or more R 1-1-7 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; 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 1, 2, or 3; 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 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; 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, halogen, oxo, [ka] or a hydroxyl group; R 2 represents 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, oxo, 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 substituted with 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 a 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 1, 2, or 3; 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 1, 2, or 3; 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 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; R 2-1-1 , R 2-1-3 , R 2-1-4 and R 2-1-5 are each independently an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, 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 a cycloalkyl group substituted with, or unsubstituted or with one or more R 4-5 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 a 3- to 10-membered cycloalkyl group substituted with, or unsubstituted or 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 a 6- to 10-membered aryl group substituted with, or unsubstituted or substituted with one or more R a-5 a 5- to 10-membered heteroaryl group substituted with R a , and R b form a 3- to 11-membered heterocyclic ring together with atoms bonded thereto; 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 1, 2, or 3; 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 1, 2, or 3; 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 pharmaceutically 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 hetero ring, the hetero atom of the 5- or 6-membered hetero ring is N, and the number of hetero atoms is 1, 2, or 3.

[0009] 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.

[0010] In one preferred embodiment, R 1 are each 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 11-membered heterocycloalkyl group is one or two kinds 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 are each independently 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 are each independently a deuterium, 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.

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

[0014] In one preferred embodiment, R 1-1-1 are each independently 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 which 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 C1-C6 alkyl group substituted with one or more halogens, an unsubstituted or C1-C6 alkyl group substituted with one or more R 4-5 a phenyl group 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 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 one, two or three; the heteroatom of the 5- to 6-membered heteroaryl group is one or more types 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 an 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 are each independently a halogen, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, [ka] Or oxo.

[0028] In one preferred embodiment, R 4-5 are each independently an 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 a C1-C6 alkyl group substituted with R 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 heteroatoms 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 some 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 one or two.

[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] is.

[0040] In one preferred embodiment, R 1-1 , R 1-2 and R 1-4 are each independently a deuterium, an oxo, 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 of N, O and S, and the number of heteroatoms is one.

[0042] In one preferred embodiment, R 1-1 are each independently oxo, [ka] or unsubstituted or one or more R 1-1-4 is a C1-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 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, 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 C1-C6 alkoxy group substituted with one or more R 2-4 The heteroatom of the 3- to 6-membered heterocycloalkyl group is 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 C1-C6 alkoxy group substituted with one or more R 2-4 is a C1-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 halogen.

[0059] In one preferred embodiment, R 4 are each independently hydrogen, halogen, an alkyl group unsubstituted or substituted with one or more halogens, an alkyl group 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 an unsubstituted or substituted phenyl group 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 a hetero atom, wherein the hetero atom of the 5- to 6-membered heteroaryl group is N, and the number of hetero atoms 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 the 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] is.

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

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

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

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

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

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

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

[0076] In a preferred embodiment, the five-membered fused six-membered compound represented by formula I or a pharmaceutically 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 pharmaceutically acceptable salt thereof: [ka] wherein 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 heteroatoms 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 N and the ring Cy 1 The atoms above, along with the atoms attached to them, form the ring Cy 3 Alternatively, N and R2 The atoms above, along 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 which 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 are each independently hydrogen, halogen, 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 awherein 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 1, 2, or 3; 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 1, 2, or 3; 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 substituted with 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 a 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 a 6- to 10-membered aryl group substituted with, or unsubstituted or 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 types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; 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 1, 2 or 3; R 1-8 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 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, 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 are each independently 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 a hydroxyl group substituted with 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, oxo, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, a 3- to 10-membered cycloalkyl group, or an unsubstituted or substituted 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 heteroatoms 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 heteroatoms 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 heteroatoms 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 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, R 2-1-1 are each independently a hydroxyl group, a halogen atom, an oxo group, 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 selected from N, S, and O, and the number of heteroatoms is 1, 2, or 3; R 2 is unsubstituted or contains one or more R2-1 is a 3- to 7-membered monoheterocycloalkyl group substituted with 1 is 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 a 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 a 6- to 10-membered aryl group substituted with, or unsubstituted or 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 types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; 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 1, 2 or 3; 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 heterocyclic ring together with atoms bonded thereto, 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 1, 2 or 3, the heteroatom of the 3- to 11-membered heterocyclic ring is one or more types 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-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, 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 a heteroatom selected from N, S, and O, the heteroatom of which is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; a 5- to 10-membered heteroaryl group substituted with a heteroatom selected from N, S, and O, the heteroatom of which 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 heteroatoms 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 pharmaceutically acceptable salt thereof: [ka] wherein m is 1, 2, or 3; E is N or CH; Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of said 5-membered heteroaromatic ring is one or more heteroatoms 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 N and the ring Cy 1 The atoms above, along with the atoms attached to them, form the ring Cy 3 Alternatively, N and R 2 The atoms above, along 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 which 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 are each independently hydrogen, halogen, 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 1, 2 or 3; 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 1, 2 or 3; R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7 are each independently 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 substituted with 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 a 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a, [ka] Unsubstituted or one or more R 1-1-8 a 6- to 10-membered aryl group substituted with, or unsubstituted or 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 types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; 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 1, 2 or 3; 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 types selected from N, S, and O, and the number of heteroatoms is 1, 2, or 3, 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 1, 2, or 3, 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, 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 a hydroxyl group substituted with 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 C1-C6 alkyl group substituted with one or more halogens, a 3- to 10-membered cycloalkyl group, or an unsubstituted or 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 heteroatoms selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; R 2-2 are each independently 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 types selected from N, S, and O, and the number of heteroatoms is 1, 2, or 3; 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 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 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 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, R 2-1-1are each independently a hydroxyl group, a halogen atom, an oxo group, 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 selected from N, S, and O, and the number of heteroatoms is 1, 2, or 3; R 2 is unsubstituted or contains 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 is 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 a 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 a 6- to 10-membered aryl group substituted with, or unsubstituted or substituted with one or more R 1-1-7a 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 1, 2 or 3, 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 1, 2 or 3, 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 heterocyclic ring together with atoms bonded thereto, 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 1, 2 or 3, the heteroatom of the 3- to 11-membered heterocyclic ring is one or more types 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, 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 1, 2 or 3; 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 1, 2 or 3; 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 heteroatoms 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 pharmaceutically 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, and the heteroatom of the 5-membered heteroaromatic ring is one or two kinds selected from N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0080] R 2 is unsubstituted or contains 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 is 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 a 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 1-1-8 a 6- to 10-membered aryl group substituted with, or unsubstituted or substituted with one or more R 1-1-7 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.

[0081] In one preferred embodiment, the ring Cy 2 is a 5- or 6-membered heterocyclic ring, the heteroatom of the 5- or 6-membered heterocyclic ring 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 a 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 heteroatom of the 3- to 11-membered heterocycloalkyl group is one or two kinds 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 heteroatom of the 3- to 11-membered heterocycloalkyl group is one or two kinds 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 are each independently a deuterium, 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. In one preferred embodiment, R 1-1 , R 1-2 and R 1-4 are each independently 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, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, oxo, [ka] Or a halogen.

[0087] In one preferred embodiment, R 1-1-1 are each independently 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, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, 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 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, and 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.

[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, and 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.

[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 is one or two.

[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 being one or more types selected from N, S and O, and the number of heteroatoms is one or two.

[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 which is one or more selected from N, S, and O, and the number of heteroatoms is one or two.

[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 is one or two.

[0099] In one preferred embodiment, R 2-8 represents a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, wherein 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.

[0100] In one preferred embodiment, R 4 are each independently unsubstituted or substituted with one or more R 4-5 a phenyl group 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 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 one, two, or three; the heteroatom of the 5- to 6-membered heteroaryl group is one or more types 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 an 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 are each independently a halogen, a C1-C6 alkyl group that 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 some 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 substituted with one or more R 2-1 is a 3- to 7-membered monoheterocycloalkyl group substituted with 1 is 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 and one or more R 1-1-5 a 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 types selected from N and O, and the number of heteroatoms is one or two.

[0107] In one preferred embodiment, R 2 is unsubstituted or contains 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 is 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 a 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 types 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 a 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 one or two.

[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 a 3- to 10-membered cycloalkyl group substituted with, 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 of N, O and S, and the number of heteroatoms 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] is.

[0114] In one preferred embodiment, R 1-1 , R 1-2 and R1-4 are each independently a deuterium, an oxo, 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 of N, O and S, and the number of heteroatoms is one.

[0116] In a preferred embodiment, R 1-1 are each independently 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 of N, O and S, and the number of heteroatoms is one.

[0117] In one preferred embodiment, R 1-2 are each independently a halogen, a hydroxyl group, or an -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 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.

[0118] In one preferred embodiment, R 1-1-1 are each independently 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, 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 a C1-C6 alkoxy group substituted with, or an unsubstituted or substituted group with 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.

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

[0129] In one preferred embodiment, R 4 is unsubstituted or substituted with one or more R 4-5 a phenyl group 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 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 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 a hetero atom, wherein the hetero atom of the 5- to 6-membered heteroaryl group is N, and the number of hetero atoms 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 are each independently a halogen, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, oxo, or [ka] 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] is.

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

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

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

[0140] In a preferred embodiment, the five-membered fused six-membered compound represented by formula II or a pharmaceutically 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 pharmaceutically 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 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, E is N or CH; R 3 is hydrogen or absent, and R 3 If there is no N and the atoms on the ring Cy1, together with the atoms bonded to them, 3 Alternatively, N and R 2 The atoms above, along 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 heteroatoms 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 which 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 represents a 5- to 9-membered oxo heterocycle, the heteroatom of which 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 are each independently 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 one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with [ka] or -SO2-C1-C6 alkyl group, 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 1-1 are each independently a deuterium, a halogen, an oxo, 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 are each independently 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 5-membered fused 6-membered compounds represented by formula III satisfy one or more of the following conditions: (1) At least one R 1 is unsubstituted or substituted with 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 a hydroxyl group substituted with 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, oxo, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, a 3- to 10-membered cycloalkyl group, or an unsubstituted or substituted 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 heteroatoms 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 heteroatoms 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 types 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, halogen, 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 contains 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 is a 3- to 8-membered heterocycloalkyl group substituted with R 1-4 are each independently a hydroxyl group, deuterium, halogen, unsubstituted or one or more R 1-1-1 a 3- to 8-membered N or S heterocycloalkyl group, 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 in 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 contains 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 1, 2 or 3; 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 1, 2 or 3; 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 heteroatoms 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 a 6- to 10-membered aryl group substituted with, or unsubstituted or 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 types selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; 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 1, 2 or 3; 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 pharmaceutically 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, 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, along with the atoms attached to them, form the ring Cy 3 or N and R 2 The atoms above, along with the atoms attached to them, form the ring Cy 2 Forming Ring Cy 1 is a 5-membered heteroaromatic ring, the heteroatom of said 5-membered heteroaromatic ring is one or more heteroatoms 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 which 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 which 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 are each independently 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 one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with [ka] or -SO2-C1-C6 alkyl 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 1-1 are each independently 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 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 a hydroxyl group substituted with 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 C1-C6 alkyl group substituted with one or more halogens, a 3- to 10-membered cycloalkyl group, or an unsubstituted or 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 heteroatoms selected from N, S and O, and the number of heteroatoms is 1, 2 or 3; 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 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 types 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 atom, an oxo group, 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 selected from N, S, and O, and the number of heteroatoms is 1, 2, or 3; R 2 is unsubstituted or contains one or more R 2-7 When R is a C1-C6 alkoxy group substituted with 1 are each independently 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 contains 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 a heteroatom selected from N, S, and O, the heteroatom of which is one or more selected from N, S, and O, and the number of heteroatoms is one, two, or three; a 5- to 10-membered heteroaryl group substituted with a heteroatom selected from N, S, and O, the heteroatom of which 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 heteroatoms 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 a 6- to 10-membered aryl group substituted with, or 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 bform a 3- to 11-membered heterocyclic ring together with atoms bonded thereto, 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 1, 2 or 3, the heteroatom of the 3- to 11-membered heterocyclic ring is one or more types 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-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 five-membered fused six-membered compound represented by formula III or a pharmaceutically 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, and the number of heteroatoms is 1, and the heteroatom of the oxo 5-membered heterocycle is N, and 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 and the number of heteroatoms is 1, and the heteroatom of the oxo 5-membered heterocycle is N and the number of heteroatoms is 1.

[0145] In one preferred embodiment, the ring Cy 1 is a 5-membered heteroaromatic ring, and the heteroatom of the 5-membered heteroaromatic ring is one or two kinds 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 heterocyclic ring, the heteroatom of the 5- or 6-membered heterocyclic ring is N, and the number of heteroatoms is 1, 2, or 3.

[0147] 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.

[0148] In one preferred embodiment, R 1 are each independently 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 heteroatom of the 3- to 11-membered heterocycloalkyl group is one or two 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 one or more R 1-1-5 or a —SO2—C1 to 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 one or more R 1-1-5 a 3- to 10-membered cycloalkyl group substituted with [ka] or -SO2-C1-C6 alkyl group, wherein the heteroatoms of the 3- to 8-membered heterocycloalkyl group are one or two of N, S, and O, and the number of heteroatoms is 1, 2, or 3.

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

[0152] In a preferred embodiment, R 1-1 are each independently 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 hydroxyl group.

[0156] In one preferred embodiment, R 1-1-1 are each independently 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 a hydroxyl group substituted with, or unsubstituted or with one or more R 2-7 The heteroatoms of the 3- to 11-membered heterocycloalkyl group are one or two types 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 an 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 halogen atom, a hydroxyl group, or a hydroxyl group substituted with 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.

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

[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 halogen.

[0165] In one preferred embodiment, R 4 are each independently unsubstituted or substituted with one or more R 4-5 a phenyl group 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 N, 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 five-membered heteroaromatic ring, and the heteroatoms in the five-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- or 6-membered heterocycle, the heteroatom of the oxo 5- or 6-membered heterocycle is N, and the number of heteroatoms is one or two.

[0171] In one preferred embodiment, R 1 are each independently 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 of N, O, and S, and the number of heteroatoms is one or two.

[0172] In one preferred embodiment, R 1 are each independently 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 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 heteroatoms of the 3- to 6-membered heterocycloalkyl group are one or two 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] 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 of N, O and S, and the number of heteroatoms is one.

[0176] In one preferred embodiment, R 1-1 are each independently 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 of N, O and S, and the number of heteroatoms is one.

[0177] In one preferred embodiment, R 1-2 are each independently a halogen, a hydroxyl group, or an -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 of N, O, and S, and the number of heteroatoms 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 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 are each independently a halogen, an oxo, a hydroxyl group, [ka] Or it is 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 an unsubstituted or one or more halogen-substituted C1-C6 alkyl group, 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 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 one or more R 2-7 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 one or more R 2-7 The heteroatom of the 5- to 6-membered heterocycloalkyl group is N, and the number of heteroatoms is one.

[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 wherein 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 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] is.

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

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

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

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

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

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

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

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

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

[0210] In the present invention, the ring Cy 1 In the above formula, 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, the number of heteroatoms is 1 or 2, and it is preferably a piperazine ring or a piperidine ring.

[0212] In the present invention, the ring Cy 3 In the above formula, 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 contains 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 are each independently 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 one or more R 1-1 The 3- to 11-membered heterocycloalkyl group substituted with [ka] is.

[0215] In the present invention, R 1 is unsubstituted or contains one or more R 1-2 In the case where the 3- to 10-membered cycloalkyl group is a C3-C6 cycloalkyl group, the 3- to 10-membered cycloalkyl group 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, and 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 contains one or more R 1-4 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; 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 a halogen and Boc, or a 3- to 8-membered heterocycloalkyl group substituted with a halogen, wherein the heteroatom of the 3- to 8-membered heterocycloalkyl group is preferably N and / or O, and the number of heteroatoms is 1 or 2; a is a C1-C6 alkyl group, and R b is hydrogen, preferably the unsubstituted or one or more R 1-4 The C1-C6 alkyl group substituted with [ka] 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] 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 are each independently unsubstituted or substituted with one or more R 1-1-4 In the case where the C1-C6 alkyl group is a C1-C4 alkyl group substituted with , 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 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 contains one or more R 2-1 In the case of a 3- to 11-membered heterocycloalkyl group substituted with R, the 3- to 11-membered heterocycloalkyl group may be a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 11-membered heterocycloalkyl group is preferably N and / or O, the number of heteroatoms is 1 or 2, and the 3- 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, and each R is preferably independently a halogen, an oxo group, 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 contains 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 contains 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, and R b is hydrogen, and the unsubstituted or one or more R 2-4 The C1-C6 alkyl group substituted with [ka] may be.

[0225] In the present invention, R 2is unsubstituted or contains one or more R 2-7 In the case where R is a C1-C6 alkoxy group substituted with R, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, or may be 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 may be a methoxy group, an ethoxy group, or an isopropoxy group; 2-7 are each 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 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 2-7are each independently 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 atom, 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 contains one or more R 4-1 In the case where R is a 5- to 10-membered heteroaryl group substituted with R, the 5- to 10-membered heteroaryl group may be a 6-membered heteroaryl group, and the 6-membered heteroaryl group is preferably a pyridazinyl group or a pyridyl group, and R 4-1 are each independently a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more halogens, and the unsubstituted or one or more R 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 contains one or more R 4-5 When R is a 6- to 10-membered aryl group substituted with 4-5 are 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 contains one or more R 4-3 When R is a 3- to 11-membered heterocycloalkyl group substituted with R, the 3- to 11-membered heterocycloalkyl group is a 6-membered heterocycloalkyl group, preferably a piperazinyl group, a piperidyl group, a thiomorpholinyl group, or a morpholinyl group, and R 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 that is unsubstituted or substituted with one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, and 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, or 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 that is 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 heteroatom of the 5-membered heterocycle is 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 atoms bonded thereto, the 3- to 11-membered heterocyclic group may be a 3- to 6-membered heterocycloalkyl group, and the heteroatom of the 3- to 6-membered heterocycloalkyl group is preferably N, O, or S, and the number of heteroatoms is one, and the 3- to 11-membered heterocyclic ring is [ka] may be.

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

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

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

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

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

[0245] The present invention further provides a method for preparing a five-membered fused six-membered compound of formula I, formula II or formula III, comprising: The method for producing the five-membered fused six-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, and 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 five-membered fused six-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, and 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 five-membered fused six-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 described 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 conventional base for this type of reaction in the art, and is 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 known 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 commonly 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 pharmaceutically 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0255] The present invention further provides a use of substance Z in the manufacture of a medicament for inhibiting FLT3 and / or IRAK4 or for treating and / or preventing an FLT3 and / or IRAK4-related disease, wherein substance Z is a five-membered fused six-membered compound represented by formula I, formula II or formula III, or a pharmaceutically acceptable salt thereof.

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

[0257] The hematological tumor may be one or more selected from acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous 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 1 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 not limited to, rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetes (e.g., type 1 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 pharmaceutically acceptable salt thereof.

[0264] Unless otherwise specified, the terms used in the present invention have the following meanings.

[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 expressed as "absent," the structures on both sides of the linking group are directly linked by a single bond. For example, in the case of "-ABC-," if B is absent, "-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 bonded to a non-oxygen atom or the lone pair thereon is replaced with an oxygen. For example, [ka] When is substituted with oxo, [ka] And [ka] When is substituted with oxo, [ka] This becomes:

[0270] The term "cycloalkyl group" refers to a group having a specified number of carbon atoms (e.g., C3 to C6). 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). Examples of 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 another group as a linking group (e.g., a piperidyl group is [ka] 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 another group as a linking group (e.g., a piperidine ring may be [ka] The heterocycle may be a monocyclic, fused, bridged, or spiro ring, and 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 may be aromatic (complying with Hückel's rule). Aryl groups are bonded to other fragments in the molecule via a ring that may or may not be aromatic. Examples of aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0275] The term "heteroaryl group" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10, 5-8), 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), 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 either an aromatic or non-aromatic ring. Examples of 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 indicates that the group is connected 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 An aryl group is a group having C6 to C 10 Three aryl groups in R 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 "pharmaceutically 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 the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, ammonium, and the like. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, acetate, trifluoroacetate, sulfate, methanesulfonate, and the like. 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 pharmaceuticals, including all substances contained in drug formulations, excluding 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. Mammals include, but are 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 arbitrarily combining the above-mentioned preferred conditions, provided that this does not violate common knowledge in the art.

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

[0287] The positive and innovative effect of the present invention is that when FLT3 inhibitors are used as monotherapy, disease relapse is rapid and both target-dependent and non-target-dependent drug resistance occur. Although the incidence 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 compounds of the present invention have inhibitory activity against FLT3 and / or IRAK4. As dual-targeted inhibitors of FLT3 and IRAK4, the compounds developed by the present invention have potential clinical application value, and are expected to improve patient prognosis and reduce the possibility of drug resistance. DETAILED DESCRIPTION OF THE INVENTION

[0288] The present invention will be further described below using examples, but the present invention is not limited to these examples. In the following examples, experimental methods for which specific conditions are not 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) was added TEA (triethylamine) (1.48 g, 14.63 mmol, 2.04 mL), and the reaction mixture was stirred at 25 °C for 4 h until the reaction was complete. HO (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), dried over anhydrous NaSO, filtered, and distilled under reduced pressure to give 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 tetrahydrofuran (THF) (10 mL), potassium carbonate (1.46 g, 10.59 mmol, 639.02 mmol) and tetrabutylammonium bromide (4.55 g, 14.12 mmol) were added. The reaction mixture was stirred at 60 °C for 20 h until the reaction was complete. The reaction mixture was diluted with HO (50 mL). The resulting mixture was extracted with EA (ethyl acetate) (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by silica gel chromatography eluting with DCM:MeOH = 70 / 1 to give II-1-2 (0.4 g, 34.11% yield) as a yellow solid. 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 HO (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 × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude brown solid 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 hours. The reaction mixture was diluted with water (50 mL), extracted with EA (ethyl acetate) (20 mL × 3), and the combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give a 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 N protection, and methylmagnesium chloride (160.75 mg, 2.15 mmol) was slowly added over 30 min. The reaction mixture was stirred at 0 °C for 3 h, diluted with water (50 mL), extracted with EA (ethyl acetate) (20 mL × 3), and the combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give 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 1,4-dioxane solution (10 mL) of 6-methoxy-5-nitro-2H-indazole (1 g, 26 mmol) and II-1-1 (2.2 g, 7.8 mmol), TBAB (5 g, 15.5 mmol) and K2CO3 (2.9 g, 20.7 mmol) were added. The reaction mixture was stirred at room temperature for 16 h until the reaction was complete. After dilution with water (10 mL), the resulting mixture was extracted with EA (ethyl acetate) (10 mL x 3). The combined organic phase was washed with brine (20 mL), 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 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), and Pd / C (10%, 20 mg) was added. The mixture was purged with H2 three times and then reacted at room temperature for 12 hours until the reaction was complete. The reaction mixture was filtered to remove the Pd / C, and the filter cake was washed with methanol (3 mL). The filtrate was distilled under reduced pressure to give the 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. The mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction mixture was purified by C18 column chromatography to give the 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)Cl (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 a nitrogen atmosphere for 4 h until the reaction was complete. The reaction mixture was diluted with HO (10 mL) and extracted with EA (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo 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 for 3 h under a nitrogen atmosphere until the reaction was complete. The reaction mixture was diluted with HO (10 mL), and the solution was acidified with stirring to pH = 3–4. The mixture was extracted with EA (10 mL × 3), and the combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo 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 a nitrogen atmosphere for 4 h until the reaction was complete. The reaction mixture was diluted with HO (10 mL) and extracted with EA (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by C18 column chromatography to give 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) was added lithium hydroxide (46.51 mg, 1.94 mmol), and the reaction mixture was stirred at 25 °C for 3 h under N protection. The reaction mixture was diluted with HO (30 mL), and the resulting solution was stirred at 0 °C to adjust the pH to 3–4. It was then extracted with EA (30 mL × 3). The combined organic phase was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude white solid 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), and DIPEA (190.09 mg, 1.47 mmol, 256.18 μL) was added PyBOP (459.23 mg, 882.48 μmol), 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). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, 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). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, 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 A reaction flask was charged with 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). The resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled, quenched by the addition of diethylamine (10.0 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: EA / PE = 1:1 to 1:0) to give 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, the mixture 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 NaSO, 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 Iron powder (3.4 g, 60.6 mmol) was added to a suspension of II-3-2 (4.0 g, 17.3 mmol) and NHCl (3.27 g, 60.6 mmol) in ethanol (200 mL) and water (70 mL) at room temperature. The mixture was heated to 60 °C and stirred for 2 h. The mixture was cooled to room temperature and filtered through a diatomaceous earth pad. The filtrate was concentrated to a volume of approximately 50 mL to form a suspension. The suspension was filtered, and the filter cake was washed with water (100 mL × 2), suctioned onto the funnel for 1 h, and the diatomaceous earth pad was washed with DCM (80.03 M × 3). The washings were concentrated to dryness. The resulting crude extract was purified by column chromatography eluting 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 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, and EA (30 mL) and water (50 mL) were added. The organic layer was separated. The aqueous phase was extracted with EA (50 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and distilled under reduced pressure to obtain the crude product. The resulting 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(PPh)Cl (bistriphenylphosphine palladium dichloride, 0.22 g, 0.36 mmol), and CuI (0.12 g, 0.6 mmol) were added to DMF (20 mL), and the mixture was heated at 90 °C for 5 h under nitrogen protection. After cooling to room temperature, saturated NH Cl solution (50 mL) was added to the mixture, and the mixture was extracted with EA (50 mL × 3). The combined organic layer was dried over anhydrous Na SO , 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, yield 72.5%). 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 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 crude product II-3-6.

[0314] DMF (50.0 mL) was added to the crude product II-3-6 and stirred at 80 °C for 16 h. The mixture was quenched by adding saturated NaHCO3 solution and extracted with EA. The combined organic phase was washed with saturated NH4Cl solution and brine, dried over anhydrous Na2SO4, and concentrated to give the crude product. Purification by silica gel column chromatography (EA / PE = 100:0 to 80:20) gave 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 atmospheric pressure and H2 atmosphere for 2 hours. 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) and 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. To the reaction mixture, EtOAc (50.0 mL) and saturated NaHCO were added, followed by extraction and separation. The organic phase was washed with saturated NaHCO (20.0 mL) and brine (20.0 mL), dried, filtered, and evaporated 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 complete. The solution was concentrated under reduced pressure, and the crude product was purified by HPLC to give 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) were added SEMCl (14.96 g, 0.09 mol) and KCO (19.7 g, 0.142 mol), 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 vacuo 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) was added dropwise a solution of NBS (10.68 g, 0.06 mol) in DCM / DMF (50 mL, 1:1) at room temperature. After the addition was complete, 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 vacuo 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 N protection, 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)pyridine (1.32 g, 0.006 mol), Pd(dppf)Cl (1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II), 0.49 g, 0.0006 mol), and KCO (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), 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 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) was added LiOH (431.1 mg, 18 mmol) and HO (3 M). 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, resulting in the precipitation of a large amount of white solid. 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 hours until the reaction was complete. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture, and the phases were separated. 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) were added tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (329.35 mg, 1.18 mmol) and CsCO (384.68 mg, 1.18 mmol). The reaction mixture was stirred at 70 °C for 4 hours until the reaction was complete. The reaction mixture was cooled to room temperature, and 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 phases were 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 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 II-5-6 (44 mg, 0.066 mmol) was added in portions to 4 M HCl in dioxane (3 mL) at 0 °C. After the entire addition, the mixture was stirred at room temperature for 16 h until the reaction was complete. After filtration, the filter cake was thoroughly washed with diethyl ether. The filter cake was then dissolved in deionized water, and the solution was frozen to give 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) and 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 mixture, and the mixture was extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo 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) was added LiOH (0.9 g, 36.6 mmol) and HO (20 mL). The mixture was stirred at room temperature for 16 hours 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. 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. The reaction mixture was diluted with water and extracted with EA (50 × 3 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 using a C18 column to give 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) in 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 complete. 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 under vacuum to give 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), CsCO (841 mg, 2.58 mmol), and DMF (30 mL) was stirred at 70 °C for 4 hours until the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc (30 × 2 mL). The combined organic layers were 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 To a solution of II-6-6 (150 mg, 0.26 mmol) in dioxane (7 mL) was added dropwise HCl-dioxane (2 M, 7 mL) at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 1 h until the reaction was complete. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC to give 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 heated in a microwave reactor at 120 °C for 1 hour until the reaction was complete. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were 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 hours 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 the addition of 6-methoxy-2H-indazol-5-amine (0.65 g, 4.0 mmol). The mixture was stirred 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). 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), CsCO (2.0 g, 6.3 mmol), and DMF (20 mL) was stirred at 70 °C for 4 hours until the reaction was complete. The reaction solution was diluted with water (30 mL) and ethyl acetoacetate (3 × 80 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 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 complete, the mixture was stirred at 0°C for 4 hours until the reaction was complete. Ethyl ether was added to the reaction solution, which was then filtered and dried under vacuum to give the 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 h until the reaction was complete. 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 brine (20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (mobile phase 0-20% ethyl acetate / petroleum ether) to give yellow solid product II-9-A-1 (1.5 g, 28.51% yield). MS(ESI)m / z:377.4[M+H] + .

[0342] Step 2: Synthesis of II-9-A 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 under a nitrogen atmosphere and reacted for 4 hours until the reaction was complete. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (20 mL), water (40 mL) was added to the filtrate, and the filtrate was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase 100% ethyl acetate) to obtain the yellow solid product II-9-A (0.28 g, 45.11% yield). 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) was added lithium hydroxide (49.50 mg, 2.07 mmol). The reaction mixture was stirred for 2 h at 25 °C under a nitrogen atmosphere until the reaction was complete. The reaction mixture was diluted with HO (10 mL) and extracted with EA (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo 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 a nitrogen atmosphere for 4 h until the reaction was complete. The reaction mixture was diluted with HO (10 mL) and extracted with EA (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography eluting with PE / EA = 1:1 to give 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 complete, the reaction mixture was stirred for 2 h at 25 °C under a nitrogen atmosphere until the reaction was complete. The reaction mixture was concentrated in vacuo 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)Cl (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 a nitrogen atmosphere for 4 h until the reaction was complete. The reaction mixture was diluted with HO (20 mL) and extracted with EA (15 mL × 3) with stirring. The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 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, yield 62.15%). 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 a nitrogen atmosphere until the reaction was complete. The reaction mixture was diluted with HO (15 mL), and the solution was acidified with stirring to pH = 3-4. The mixture was extracted with EA (10 mL × 3), and the combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo 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 at 25 °C under a nitrogen atmosphere for 4 h until the reaction was complete. The reaction mixture was diluted with HO (20 mL) and extracted with EA (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give 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 complete, the mixture was stirred at 25 °C under a nitrogen atmosphere for 2 h until the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by C18 column chromatography to give 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-methylpyrazole-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 a nitrogen atmosphere for 3 h until the reaction was complete. The reaction mixture was cooled to 25 °C and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give the 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 a nitrogen atmosphere for 3 hours until the reaction was complete. The reaction mixture was concentrated in vacuo, diluted with water, and acidified with stirring until pH = 4. The mixture was then concentrated in vacuo to give the white solid product II-11-2 (160 mg). The crude product was used directly in the next step. 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) under a nitrogen atmosphere at 0 °C. After the addition was complete, the mixture was stirred at 25 °C for 1 h until the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography eluting with DCM / CHOH = 20 / 1 to give 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 To a solution of II-11-3 (157 mg, 295.33 μmol) in DCM (5 mL) was added dropwise HCl-dioxane (4 M, 738.3 μL) at 25 °C. After the addition was complete, the mixture was stirred at 25 °C for 1 h until the reaction was complete. The reaction mixture was filtered, and the filter cake was washed with DCM (20 mL). It was then dried under vacuum to give the white solid product II-11C (130 mg, 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 AlCl (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 HO (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 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 hours until the reaction was complete. The reaction mixture was diluted with HO (50 mL) and extracted with EA (40 mL × 3). The combined organic layers were concentrated, and the crude product was purified by silica gel column chromatography 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 KCO (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 HO (50 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were concentrated, and the crude product was purified by silica gel column chromatography to give the 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 a hydrogen atmosphere at 25 °C for 16 hours until the reaction was complete. The resulting mixture was filtered and concentrated to give a 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) were 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 HO (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were concentrated, and the crude product was purified by silica gel column chromatography to give the 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 hours until the reaction was complete. Ethyl ether (10 mL) was added to the reaction mixture, which was then filtered and dried under 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 complete. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in DCM (5.0 mL). 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 complete. The reaction mixture was poured into water, and the mixture was extracted with EA. 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) was added TFA (1.0 mL), and the resulting solution was stirred at room temperature for 1 hour. 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 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) at 0 °C 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, and DCM was added. The mixture was 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 to 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 hours 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) in 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 CsCO (119 mg, 0.366 mmol) were added. The resulting solution was heated at 120 °C under a nitrogen atmosphere for 4 h until the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated. 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 diluted with EA and saturated aqueous ammonium chloride solution with stirring and extracted with EA (30 mL × 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 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-ynoate (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 DMF (100 mL) and stirred at 80 °C for 5 h under a nitrogen atmosphere. After cooling to room temperature, saturated NH4Cl solution (50 mL) was added and extracted with EA (50 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE:EA = 10:1 to 1:1) to give 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 mL) 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 To a solution of II-28-3 (1.9 g, 7.25 mol), TEA (4.0 g, 21.7 mol), and THF (150.0 mL) at 25 °C, DMAP (88.6 mg, 0.725 mol) and BocO (10.0 g, 10.87 mol) were added, and the mixture was stirred for 16 h until the reaction was complete. The mixture was concentrated under reduced pressure, and EA (30.0 mL) and water (50.0 mL) were added to the residue, and the organic layer was separated. The aqueous phase was extracted with EA (100 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (PE:EA = 30:1 to 5:1) to give II-28-4 (1.7 g, 64.9% yield). 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. DMF (50.0 mL) was then added to the crude product, and the mixture was stirred at 80 °C for 16 h until the reaction was complete. Saturated NaHCO3 solution was added, and the mixture was extracted with EA (100 mL × 3). The combined organic phase was washed with saturated NH4Cl solution (200 mL) and 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, 11.3% yield). 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) in DCM (3.0 mL) was added HCl-dioxane (4 M, 1.0 mL) at 25 °C, and the resulting solution was stirred for 1 h. The reaction mixture was concentrated to dryness under reduced pressure, and the pH of the residue was adjusted to 7-8 with saturated NaHCO3 solution. The solution was then extracted with DCM (30 mL x 3). 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 To a solution of II-28-8 (50.0 mg, 0.11 mmol) in THF (10.00 mL) at 0 °C, CHMgBr (1 M THF solution, 1.3 mL, 1.29 mmol) was added. The resulting mixture was stirred at 25 °C under a nitrogen atmosphere for 16 h. The reaction solution was quenched with saturated NH Cl 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 Na SO , 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 products were 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) in DMF (10 mL) was added CsCO (2.62 g, 13.56 mmol) and 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 HO (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL × 3), dried over anhydrous NaSO, 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 the pale yellow solid product II-49-1-P (2510.00 mg, 1.66 mmol, 35.24% yield). 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 HO (2.5 mL), NH4Cl (43.00 mg, 811.32 μmol) 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 HO (20 mL) and 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 stirred for 16 h. The reaction mixture was diluted with HO (20 mL), and the pH of the solution was adjusted to 7–8 with aqueous NH4Cl (1 M), followed by extraction with EA (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. 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 II-49-3 (210.00 mg, 681.42 μmol, 47.24% yield) as a yellow oil. 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) was added II-49-3 (53.72 mg, 193.68 μmol), HATU (220.80 mg, 581.05 μmol), and DIPEA (25.18 mg, 1931.68 μmol) at 25 °C, and the mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with HO (10 mL), and extracted with DCM (10 mL × 3). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 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 a 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) was added KCO (3.08 g, 22.34 mmol), and the mixture was stirred at 50 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with HO (80 mL) and extracted with chloroform:isopropanol = 3:1 (30 mL × 3). The combined organic layers were dried over anhydrous NaSO, 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, CsCO (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 HO (80 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous NaSO, 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 / HO (5 / 5 mL) at 25 °C, NaSO (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: Synthesize 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) was added DIEA (74 mg, 0.569 mmol) at 25 °C, and the mixture was stirred for 16 h until the reaction was complete. The reaction mixture was diluted with HO (30 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over anhydrous NaSO, 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 HO (100 mL) and extracted with DCM (200 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give yellow solid product II-95-1 (7.9 g), which was used directly in the next reaction without any 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 CsCO (17.604 g, 54.00 mmol), and the mixture was stirred at 70 °C for 16 h. The mixture was diluted with HO (150 mL) and extracted with EtOAc (300 mL). The combined organic layers were dried over anhydrous NaSO, 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 HO (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 HO (40 mL) and extracted with EtOAc (80 mL). The combined organic layers were 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 mixture was diluted with HO (40 mL) and extracted with DCM (80 mL). The combined organic layer was dried over anhydrous NaSO and concentrated. 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) was added a solution of NAIO (240 mg, 1.17 mmol) and HO (2.0 mL) at 25 °C, and the mixture was stirred for 16 h. The reaction was quenched with NaSO (saturated, 15 mL), diluted with HO (20 mL), and extracted with DCM (80 mL). The combined organic layer was dried over anhydrous NaSO, 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) (53 mg, 0.16 mmol), MgO (18 mg, 0.45 mmol), and DCM (5 mL) was added Rh(OAc) (122 mg, 0.27 mmol), and the mixture was stirred at 40 °C for 3 h. The reaction mixture was diluted with HO (30 mL) and extracted with DCM (80 mL). The combined organic layer was 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 II-95-6 (20 mg, 0.03 mmol) was added to HCl-dioxane (1 M, 2 mL) at 25 °C 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 under 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 NaSO (30 mL) and extracted with DCM (60 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC to give 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 were finally 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) was added TsOH (627 mg, 3.3 mmol) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with HO (120 mL) and extracted with EA (30 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give 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), Pd(dba) (137 mg, 0.15 mmol), and dioxane (15 mL) at 25 °C, CsCO (1.5 mg, 4.62 mmol) was added, and the mixture was reacted at 140 °C under microwave irradiation for 1 h. The reaction mixture was diluted with HO (80 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous NaSO, 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), NHCl (508 mg, 9.088 mmol), and EtOH / HO (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 HO (50 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over anhydrous NaSO, 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) was added DIEA (160 mg, 1.24 mmol) at 25 °C. The mixture was then stirred for 16 h. The reaction mixture was diluted with HO (30 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over anhydrous NaSO, 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) was added KCO (97.7 mg, 0.708 mmol) at 25 °C. The mixture was then stirred for 16 h. The reaction mixture was diluted with HO (30 mL) and extracted with EA (10 mL × 3). The combined organic layer was dried over anhydrous NaSO, 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 products were 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) in 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 a nitrogen atmosphere. Pd(PPh3)2Cl2 (0.9 g, 1.3 mmol) was then added, and the resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with saturated aqueous potassium fluoride (50 mL). Insoluble materials were removed by filtration, and the filtrate was extracted with EtOAc (60 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give II-111-1 (2.9 g, 72.7% yield) as a yellow oil. 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) was added TsOH (0.15 g, 0.8 mmol), 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 NaSO, 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 A solution of II-111-2 (2.0 g, 6.92 mmol) in THF (20 mL) was added with a solution of trifluoromethyltrimethylsilane (2.04 M, 13.84 mmol) in THF (27.6 M) at 25 °C. After stirring for 15 min, tetrabutylammonium fluoride (TBAF) (6.92 mL, 6.92 mmol) was added. The mixture was then reacted at room temperature for 16 h under microwave irradiation. The reaction solution was poured into saturated NH₄Cl solution and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by high-performance silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give the yellow solid product II-111-3 (1.4 g, 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) in MeOH (10 mL) at 25 °C, Pd / C (0.3 g, 10% purity) was added. The mixture was purged with H2 three times while stirring, and then stirred under H2 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 HO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous NaSO, 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) in 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 mixture 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 NaSO, 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. The mixture was stirred under a nitrogen atmosphere for 1 h, and then 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 layers were washed with saturated brine (50 mL), dried over anhydrous NaSO, 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 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 the reaction was completed, the reaction mixture was quenched with ice water (100 mL). The resulting solid was filtered and dried under vacuum to give 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 a hydrogen atmosphere (~1-2 atm) at 25 °C for 16 h. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo 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 for 12 h under a nitrogen atmosphere. The reaction mixture was quenched with ice water (30 mL), the pyridine was removed under vacuum, and the reaction mixture was acidified with concentrated HCl to a pH of approximately 1.0. Filtration and vacuum drying 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 mixture, 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 compound II-122-4 (5.0 g, 42% yield) as an off-white solid. 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 To a solution of II-122-4 (2.20 g, 10.9 mmol) and THF (50 mL) at 25 °C, morpholine (5.73 g, 65.7 mmol) was added, and the mixture was stirred under reflux for 12 hours. After completion of the reaction, 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 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: Synthesize II-122-6 Concentrated sulfuric acid (15 M) was cooled to 0 °C, and II-122-5 (2.20 g, 9.17 mmol) was added in portions, followed by potassium nitrate (1.76 g, 17.41 mmol), and the resulting mixture was stirred at 25 °C for 12 h. After completion of the reaction, the reaction mixture was quenched with ice water (100 M). The resulting solid was filtered and dried under vacuum to give product II-122-6 (2.0 g, 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) were added tributyl(1-ethoxyvinyl)tin (2.03 g, 5.63 mmol) and Pd(PPh3)Cl2 (197 mg, 0.281 mmol), and the mixture was stirred at 110 °C for 2 h. After the reaction was completed, the mixture was cooled to 0 °C, and THF (10 mL) was added, followed by 2N HCl (10 mL). The resulting mixture was stirred at 25 °C for 2 h and basified with saturated NaHCO3 to pH 8-9. The mixture was filtered through diatomaceous earth, and the aqueous phase was extracted with EtOAc (30 mL × 3). 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 a nitrogen atmosphere for 3 h. After the reaction was complete, 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 NaSO), 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 mixture was heated to 80 °C and stirred for 12 h. After completion of the reaction, the reaction mixture was spin-dried, and the crude product was purified by silica gel column chromatography (10-100% ethyl acetate / heptane) to obtain the 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 To a mixture of II-122-9 (120 mg, 0.267 mmol) and anhydrous THF (10 mL) under ice-water bath conditions, methylmagnesium bromide solution (2.7 mL, 2.67 mmol) was added. 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 × 3), and the combined organic layer was washed with saturated brine (50 mL), dried (anhydrous Na2SO4), filtered, and concentrated. Purification by preparative HPLC afforded 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 vacuo. 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, n-CPBA (14.8 g, 85.76 mmol) was added to a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (10 g, 50.5 mmol) and EtOAc (20 mL). The mixture was stirred at 55 °C for 5.5 h. The reaction solution was poured into NaSO 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 NaSO, 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) and TMSCN (8.4 g, 8.467 mmol) were added. The mixture was stirred at 80 °C for 16 h, and then HO (40 mL) was added to dilute the reaction mixture, which was then extracted with EtOAc (60 mL × 3). The combined organic layers were dried over anhydrous NaSO, 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 HO (40 mL) and extracted with EtOAc (60 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated to give 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 HO (20 mL) and extracted with EtOAc (30 × 3 mL). The combined organic layers were dried over anhydrous NaSO, 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: Synthesize 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 under microwave irradiation for 1 h. 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 brine (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 give the yellow solid product II-131-6 (90 mg, 46.0% yield). 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 mL) at 0 °C, a 2 M solution of 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 HO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous NaSO, 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) in 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, followed by extraction with EtOAc (10 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous NaSO, 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 To a solution of II-131-8 (50.0 mg, 0.1 mmol) in DMF (5 mL) was added NaH (15.0 mg, 0.3 mmol) at 0 °C and stirred under a nitrogen atmosphere for 1 h. After that, 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. The mixture was extracted with water (10 mL) and 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 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 IC of compounds for competitive binding to ATP by the kinases IRAK4 and FLT3 using an experimental method based on fluorescent microfluidic mobility detection 50 The values ​​were measured. The starting detection concentration of the compound was 10 μM, and the compound was diluted in a 4-fold gradient to 0.38 nM and measured in duplicate. In the experiments, commercial staurosporine was used as a standard control.

[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 (Dimethyl sulfoxide, 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 operation method 1) FLT3 and IRAK4 kinases were dissolved in kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl 2 , 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 the above kinase buffer with ATP. The final concentrations of the substrate peptides FAM-P2 and ATP for FLT3 assay were 3 μM and 97 μM, respectively. The final concentrations of the substrate peptides FAM-P8 and ATP for IRAK4 assay were 3 μM and 10 μM, respectively.

[0448] 3) Compound dilution: First, the compound was diluted to 50 μM and then diluted 4-fold with DMSO. Here, a solution without compound and kinase was the blank control and corresponds to the "minimum" value shown below. A solution without compound but containing kinase, adenosine triphosphate, DMSO, and buffer was the positive control and corresponds to the "maximum" 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 target compound and incubated at room temperature for 10 minutes. 10 μL of buffer containing the substrate peptide and adenosine triphosphate was added to the 384-well plate and incubated at 28°C for 1 hour. The reaction was terminated by adding 25 μL of stop solution (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2% Coating Reagent #3, and 0.015% Brij-35) to each well.

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

[0451] 6) Data calculation: Copy the conversion rate data from CaliperEZ Reader II 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% 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 are shown in Table 1.

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

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

[0455] IC of compound killing ability against 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 Buffered Saline, 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. A 10x compound solution was prepared in IMDM complete medium, and 10 μL of the 10x compound solution was added to the cells in the 96-well plate and mixed evenly. The 96-well plate was then placed in a 37°C, 5% CO2 incubator and incubated for 72 hours. 5. After incubation, the 96-well plate was removed and equilibrated at room temperature for 30 minutes. Then, 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 value was 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 pharmaceutically acceptable salt thereof, 【Chemical 1】 During the ceremony, m is 1, 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, 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 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 a cyano group, an unsubstituted or substituted 3- to 11-membered heterocycloalkyl group, 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 substituted with 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 groups, halogens, oxo groups, 【Chemistry 5】 or a hydroxyl group, R ａ and R ｂ are each independently H or unsubstituted C １ ~C ６ is an 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 a hydroxyl group substituted with one or more R ２－４ C substituted with １ ~C ６ an alkyl 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 1, 2, or 3; R ２－１ is deuterium, a halogen, or a hydroxyl group, R ２－４ is deuterium, a halogen, or a hydroxyl group, R ２－７ is a C substituted with deuterium, a hydroxyl group, a halogen, an oxo group, or one or more halogen atoms. １ ~C ６ is an alkyl group, 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 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, 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, wherein 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 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 unsubstituted or substituted 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 represented by formula II, or a pharmaceutically acceptable salt thereof, wherein The five-membered fused six-membered compound satisfies one or more of the following conditions: (1) When R 1 is a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted with one or more R 1-1 , the 3- to 11-membered heterocycloalkyl group is a 3- to 9-membered heterocycloalkyl group, and each R 1-1 is independently a halogen, a hydroxyl group, an oxo, 【Chemistry 6】 or a C 1 -C 6 alkyl group substituted with one or more halogen or heterocycloalkyl groups; (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 is a C 3 -C 6 cycloalkyl group, each R 1-2 is independently —SO 2 —R a , a halogen, or a hydroxyl group, and R a is a C 1 -C 6 alkyl group; (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 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, and R 1-4 are each independently deuterium, a halogen, a hydroxyl group, —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 a halogen and Boc, or a 3- to 8-membered heterocycloalkyl group substituted with a 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, R a is a C 1 -C 6 alkyl group, and R b is hydrogen; (4) When R 1-1 , R 1-2 and R 1-4 are each independently a halogen, the halogen is fluorine, chlorine, bromine or iodine; (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 a 3- to 7-membered heterocycloalkyl group; (6) When R 1-1 , R 1-2 and R 1-4 are each independently a C 1 -C 6 alkyl group that is unsubstituted or substituted with one or more R 1-1-4 , the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl 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 C 1 to C 4 alkyl group; (8) When R 2 is a 3- to 11-membered heterocycloalkyl group 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 each R 2-1 is independently a halogen or a hydroxyl group; (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 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, and each R 2-4 is independently deuterium, a halogen, or a hydroxyl group; (10) When R 2 is a C 1 -C 6 alkoxy group unsubstituted or substituted with one or more R 2-7 , the C 1 -C 6 alkoxy group is a C 1 -C 4 alkoxy group, and R 2-7 are each independently deuterium or halogen; (11) When R 2 is a hydroxyl group substituted with R 2-8 , 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 oxygen, and the number of heteroatoms is one; (12) When R 2-1 , R 2-4 and R 2-7 are each independently a halogen, the halogen is fluorine, chlorine, bromine or iodine; (13) When R 4 is a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 4-1 , the 5- to 10-membered heteroaryl group is a 6-membered heteroaryl group, and each R 4-1 is independently a C 1 -C 6 alkyl group or a C 1 -C 6 alkyl group substituted with one or more halogens; (14) When R 4-1 is a C 1 -C 6 alkyl group that is unsubstituted or substituted with one or more halogens, the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, the halogen is fluorine, chlorine, bromine, or iodine, and One or more of the following conditions are met: (1) When R 1 is a 3- to 11-membered heterocycloalkyl group which is unsubstituted or substituted with one or more R 1-1 , the 3- to 11-membered heterocycloalkyl group which is unsubstituted or substituted with one or more R 1-1 is: 【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 to C 6 alkyl group substituted with one or more R 1-1-4 , the C 1 to 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 unsubstituted or substituted with one or more R 2-7 , the C 1 -C 6 alkoxy group 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 unsubstituted or substituted with one or more R 4-1 , the 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R 4-1 is 【Chemistry 15】 and (14) A 5-membered fused 6-membered compound represented by formula II, or a pharmaceutically acceptable salt thereof, wherein 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 to C 6 alkyl group or a C 1 to C 6 alkyl group substituted with one or more halogens.

2. 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, an oxo, a hydroxyl group, 【Chemistry 16】 halogen, 【Chemistry 17】 -SO ２ -C １ ~C ６ alkyl group, unsubstituted or substituted with one or more R １－１－４ C substituted with １ ~C ６ 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 a 3- to 10-membered heterocycloalkyl group substituted with, wherein the heteroatoms of the 3- to 10-membered heterocycloalkyl group are one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; (2) R １－１－１ are each 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 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 C substituted with １ ~C ６ an alkoxy group, one or more R ２－４ C substituted with １ ~C ６ alkyl group or R ２－８ a hydroxyl group substituted with, wherein 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 one or two; (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 are 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 are each independently 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 a phenyl group substituted with, wherein the heteroatom of said 5- to 6-membered heteroaryl group is N, and the number of heteroatoms is 1, 2 or 3; (11) R ４－１ and R ４－５ are each independently an unsubstituted or one or more halogen-substituted C １ ~C ６ 2. The five-membered fused six-membered compound of formula II according to claim 1, wherein the five-membered fused six-membered compound is an alkyl group, or a pharmaceutically acceptable salt thereof.

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

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

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

6. A method for producing the five-membered fused 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】

7. A pharmaceutical composition comprising the five-membered fused six-membered compound represented by formula II of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. A five-membered fused six-membered compound represented by formula II according to claim 1 or a pharmaceutically acceptable salt thereof, which is administered to a subject to inhibit the kinase activity of FMS-like tyrosine kinase 3 (FLT3) in the subject.

9. A five-membered fused six-membered compound represented by formula II or a pharmaceutically acceptable salt thereof according to claim 1, which is administered to a subject to inhibit the kinase activity of interleukin-1 receptor-associated kinase 4 (IRAK4) in the subject.

10. A five-membered fused six-membered compound having any of the following structures, or a pharmaceutically acceptable salt thereof: 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical formula 28】 ​ 【Chemistry 30】

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