Heterocyclic substituted sulfonamide compound, pharmaceutical composition comprising same, and use

Abstract

Disclosed are a heterocyclic substituted sulfonamide compound, a pharmaceutical composition comprising same, and a use. Provided are a compound represented by formula II, and a pharmaceutically acceptable salt thereof or a stereoisomer thereof. The compound has a strong inhibitory effect on CDK2 and CDK4, has no obvious inhibitory effect on CDK1, and therefore has a higher selectivity. High selectivity brings high safety. The compound has a good application prospect in the prevention and / or treatment of various diseases related to CDK2 and CDK4.

Description

Heterocycle-substituted sulfonamide compounds, pharmaceutical compositions thereof and uses thereof

[0001] This application claims priority to Chinese patent application 2024110235651 with a filing date of 2024 / 7 / 29 and Chinese patent application 2025105550307 with a filing date of 2025 / 4 / 29. This application incorporates the entirety of the aforementioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to heterocycle-substituted sulfonamide compounds, pharmaceutical compositions thereof and uses thereof. BACKGROUND

[0003] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases whose catalytic activity is regulated by interactions with cyclins and endogenous CDK inhibitors (CKIs). The close cooperation between these three ensures the orderly progression of the cell cycle. In addition to cell cycle regulation, CDKs are also involved in the regulation of gene transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal function, and spermatogenesis (Lim & Kaldis, 2013).

[0004] There are currently 20 members of the CDK family, designated as CDK1-CDK20. With the evolutionary expansion of the CDK family, they are mainly divided into two subfamilies, the cell cycle-related subfamily (CDK1, CDK4 and CDK5) and the transcription subfamily (CDK7, CDK8, CDK9, CDK11 and CDK20) (Malumbres, 2014).

[0005] Dysregulation of the cell cycle is associated with dysregulation of CDKs, which is a defining feature of cancer, ultimately promoting abnormal proliferation, thereby promoting tumorigenesis and disease progression. In this regard, over the past few decades, several CDK inhibitors (CDKIs) have been developed (first-, second- and third-generation CDKIs) to inhibit the proliferation of cancer cells. First- and second-generation CDKIs have not benefited much in the treatment of cancer patients due to their limited specificity and high toxicity. Third-generation CDKIs have achieved the most promising results at the preclinical and clinical levels, propelling them into the late stages of clinical trials for the treatment of various malignancies (particularly breast cancer) and completely changing the traditional treatment strategy (Mughal et al., 2023).

[0006] Third-generation CDKIs specifically target CDK4 / 6 with better selectivity and low toxicity, have been clinically proven safe and effective in the treatment of ER-positive HER2-negative breast cancer patients, which form CDK4 / 6-cyclin D complex by binding with cyclin D, phosphorylate retinoblastoma protein (Rb), release and activate the previously bound transcription factor E2F, and make the cell transition from Gl phase to S phase. CDK4 / 6 inhibitors induce cell arrest in Gl phase, showing a senescent phenotype. Selective CDK4 / 6 inhibitors such as Palbociclib, Ribociclib and Abemaciclib have been approved for the treatment of ER-positive HER2-negative breast cancer patients.

[0007] CDK2 is another CDK subtype that mainly functions in the G1 to S phase of the cell cycle. In the late Gl phase, CDK2 binds with cyclin E to form a proteasome complex CDK2-cyclin E and is activated, which promotes further phosphorylation of a series of substrates including Rb, and induces the sustained expression of transcription factor E2F, thereby regulating the smooth passage of cells through Gl phase. After entering the S phase, CDK2 binds with cyclin A to form a complex CDK2-cyclin A involved in the progression of the cell cycle S phase, and completes the replication of DNA. High expression of cyclin E and activation of complex CDK2-cyclin E are a mechanism for clinical breast cancer patients to be resistant to selective CDK4 / 6 inhibitors.

[0008] Evidence suggests that CDK2 inhibitors also have application prospects as cancer targets. First, a variety of genetic changes can up-regulate cyclin E1 levels and activate CDK2. CCNE1 gene amplification is found in a significant proportion of high-grade serous ovarian cancer (HGSOC), gastroesophageal cancer and uterine serous carcinoma, and CCNE1 amplification is associated with cyclin E1 overexpression, CDK2-dependent proliferation, chemotherapy resistance and poor prognosis. Second, in some lung cancer, colorectal cancer and hematological tumors, F-box family protein FBXW7 is inactivated, thereby inhibiting the degradation of cyclin E1. In addition, the possible acquired resistance of Luminal breast cancer to CDK4 / 6 inhibitors may be due to Cyclin E amplification or overexpression. This provides a theoretical basis for studying the inhibition of CDK2 in these tumors.

[0009] First, selective CDK2 inhibitors can target CDK2 alone in cancers where CDK2 is the main driver, avoiding the toxicity and dose-limiting of CDK4 / 6 inhibition. Second, in cancers where combined inhibition of CDK4 / 6 and CDK2 is needed, more flexible dosing can improve drug efficacy and patient tolerability. Third, selective CDK2 inhibitors can provide insights into the roles of CDK2 and CDK4 / 6 in different tumors. Further studies have found that CDK2 inhibitors have a wider development potential, and can be used as single agents for CCNE1-amplified ovarian cancer, MYCN-amplified neuroblastoma, KRAS-mutated lung cancer treatment, hormone-dependent breast cancer and prostate cancer, etc. (Tadesse et al., 2020). In combination: CDK2 combined with anti-mitotic therapy can produce a synergistic effect in TNBC, combined with PI3K inhibitors to synergistically inhibit CCNE1 amplification in serous uterine cancer, combined with CDK4 / 6 inhibitors or BRAF / HSP90 inhibitors to eliminate early adaptive rebound and solve drug resistance problems (Tadesse et al., 2020).

[0010] Several selective CDK2 inhibitors have entered early clinical trials, including INX315 (Incyclix Bio), PF-07104091 (Pfizer), BLU-222 (Blueprint Medicine), INCB123667 (Incyte), and ARTS-021 (Allorion Therapeutics). However, the selectivity of these selective CDK2 inhibitors is not perfect. So far, their effectiveness and safety in clinical trials have yet to be verified. Therefore, there is still a great clinical need to develop new CDK2 inhibitors with higher selectivity. CDK2 inhibitors with higher selectivity can safely address the unmet clinical need of patients who have developed resistance to CDK4 / 6 inhibitors, as well as provide a better treatment option for new precision medicine.

[0011] Incyte discloses an imidazole-substituted pyrimidine amine compound as a CDK2 inhibitor in patent US11427567B2.

[0012] CDK1 is the only essential CDK in the cell cycle (Santamaría et al., 2007), and knockout of CDK1 can cause mouse embryonic lethality, conditional knockout of CDK1 has a greater impact on liver and brain cells, especially on the reproductive cells of both sexes, causing devastating damage (Campbell et al., 2020). Most of the first and second generation CDK inhibitors in clinical trials inevitably target CDK1, which is an important factor for the lack of clinical benefits (Mughal et al., 2023). Therefore, the higher the selectivity of CDK1, the higher the expected clinical safety. Efficient inhibition of CDK2 activity and weak or no inhibition of CDK1 are the properties that the selective CDK2 inhibitor field dreams of. SUMMARY

[0013] The technical problem to be solved by the present application is to provide a high-selectivity CDK2 inhibitor and a stronger CDK4 inhibitor with a new structure. The present application aims to provide a heterocyclic sulfonamide compound, a pharmaceutical composition thereof and an application. The compound has a strong inhibitory effect on CDK2 and CDK4, and has no obvious inhibitory effect on CDK1, so it has higher selectivity. High selectivity brings higher safety, and has a good application prospect in the prevention and / or treatment of various diseases related to CDK2 and CDK4.

[0014] The present application provides a compound as shown in formula II, a pharmaceutically acceptable salt thereof or a stereoisomer thereof; characterized in that,

[0015] wherein,

[0016] The carbon atom marked with "*" represents R configuration, S configuration or a mixture of the two when it is a chiral carbon atom;

[0017] The carbon atom marked with "#" represents R configuration, S configuration or a mixture of the two independently when it is a chiral carbon atom;

[0018] R 1 halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, or "heteroatom selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl with 1 or more heteroatoms" optionally substituted with 1 or more R 1-1 halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, or "heteroatom selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl with 1 or more heteroatoms" optionally substituted with 1 or more R 1-2 halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, or "heteroatom selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl with 1 or more heteroatoms" optionally substituted with 1 or more R 1-3 halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, or "heteroatom selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl with 1 or more heteroatoms" optionally substituted with 1 or more R 1-4 halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, or "heteroatom selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl with 1 or more heteroatoms" optionally substituted with 1 or more R 10 halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, or "heteroatom selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl with 1 or more heteroatoms" optionally substituted with 1 or more R 1-5 halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, or "heteroatom selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl with 1 or more heteroatoms" optionally substituted with 1 or more R 1-6The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one or more heteroatoms.

[0019] R 2 It is hydrogen, halogen, hydroxyl, optionally coated with one or more R 2-1 Substituted C1-C6 alkoxy groups, optionally with one or more R groups 2-2 Replacement C6-C 10 Aryl, optionally with one or more R 2-3 The substituted "heteroatom is selected from one, two or three of N, O and S, and is a 3-8 membered heterocyclic alkyl group with one or more heteroatoms" and -NR 2-4 R 2-5 -SR 2-6 -OR 2-7 Or can be selected by one or more R 2-8 Substituted C1-C6 alkyl groups;

[0020] R 1-1 R 1-2 R 1-3 R 1-4 R 1-5 and R 1-6 Independently hydrogen, deuterium, -CN, halogen, -NR a R b Optional, one or more R 1- 1-1 Substituted C1-C6 alkyl groups or optionally with one or more R 1-1-2 Substituted C1-C6 alkoxy groups;

[0021] R a and R b Independently hydrogen or C1-C6 alkyl;

[0022] R 1-1-1 and R 1-1-2 Independent of hydrogen, deuterium, halogen, or -NR a R b ;

[0023] R 2-1 and R 2-8 Independently hydrogen, deuterium, halogen, hydroxyl, cyano, -NR a R b -C(=O)NR a R b Optional, one or more R 2- 1-1 Substituted C3-C6 cycloalkyl groups, optionally with one or more R 2-1-2substituted "3- to 6-membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," optionally substituted with 1 or more R 2-1-3 substituted C6-C 10 aryl, optionally substituted with 1 or more R 2-1-4 substituted C1-C6alkyl or optionally substituted with 1 or more R 2-1-5 substituted C1-C6alkyl or optionally substituted with 1 or more R

[0024] R 2-1-1 , R 2-1-2 , and R 2-1-3 are independently hydrogen, deuterium, halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, or -NR 2a substituted C1-C6alkyl or optionally substituted with 1 or more R 2b substituted C1-C6alkyl or optionally substituted with 1 or more R

[0025] R 2a , and R 2b are independently halogen;

[0026] R 2-1-4 , and R 2-1-5 are independently hydrogen, deuterium, halogen, or -NR a R b ;

[0027] R 2-2 , and R 2-3 are independently hydrogen, deuterium, halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, or -CN; 2-2-1 substituted C1-C6alkyl or optionally substituted with 1 or more R 2-2-2 substituted C1-C6alkyl or optionally substituted with 1 or more R

[0028] R 2-2-1 , and R 2-2-2 are independently hydrogen, deuterium, halogen, -NR a R b , or C1-C6alkoxy;

[0029] R 2-4 is independently hydrogen or C1-C6alkyl;

[0030] R 2-5 , R 2-6 , and R 2-7 are independently hydrogen, C1-C6alkyl, optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, or -CN; 2-5-1 substituted C6-C 10 aryl, optionally substituted with 1 or more R 2-5-2 substituted C3-C6cycloalkyl or optionally substituted with 1 or more R 2-5-3 substituted "3- to 6-membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and the number of heteroatoms is 1, 2, or 3," optionally substituted with 1 or more R

[0031] R 2-5-1 Independently halogenated, optionally by one or more R 2c Substituted C1-C6 alkyl groups, optionally with one or more R 2d Substituted C1-C6 alkoxy groups or -CN;

[0032] R 2c and R 2d Independently halogenated, C1-C6 alkoxy or -NR a R b ;

[0033] R 2-5-2 Independently Halogen, optionally with one or more R 2f Substituted C1-C6 alkyl groups or optionally with one or more R 2g Substituted C1-C6 alkyl groups;

[0034] R 2e Independently, it is a C1-C6 alkyl group;

[0035] R 2f and R 2g Independently halogen or -NR a R b ;

[0036] R 2-5-3 Independently halogenated, optionally by one or more R 2j Substituted C1-C6 alkyl groups, optionally with one or more R 2k Substituted C1-C6 alkoxy groups or -CN;

[0037] R 2j and R 2k Independently halogen, -NR a R b Or C1-C6 alkoxy groups;

[0038] Y 1 and Y 2 Independent for CR c Or N;

[0039] R c Hydrogen, optionally with one or more R c-1 Substituted C1-C6 alkyl groups, optionally with one or more R c-2 Substituted C1-C6 alkoxy, halogen, or cyano groups;

[0040] R c-1 and R c-2 Independently halogen or -NR a R b ;

[0041] For

[0042] R 3 independently hydrogen, deuterium, amino, cyano, optionally substituted C1-C6alkyl, halogen, optionally substituted C1-C6alkoxy, hydroxyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C6-C10aryl; 3-1 independently hydrogen, deuterium, amino, cyano, optionally substituted C1-C6alkyl, halogen, optionally substituted C1-C6alkoxy, hydroxyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C6-C10aryl; 3-2 independently hydrogen, deuterium, amino, cyano, optionally substituted C1-C6alkyl, halogen, optionally substituted C1-C6alkoxy, hydroxyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C6-C10aryl; 3-3 independently hydrogen, deuterium, amino, cyano, optionally substituted C1-C6alkyl, halogen, optionally substituted C1-C6alkoxy, hydroxyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C6-C10aryl; 3- 4 independently hydrogen, deuterium, amino, cyano, optionally substituted C1-C6alkyl, halogen, optionally substituted C1-C6alkoxy, hydroxyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C6-C10aryl; 3-5 independently hydrogen, deuterium, amino, cyano, optionally substituted C1-C6alkyl, halogen, optionally substituted C1-C6alkoxy, hydroxyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C6-C10aryl; 10 independently hydrogen, deuterium, amino, cyano, optionally substituted C1-C6alkyl, halogen, optionally substituted C1-C6alkoxy, hydroxyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C6-C10aryl;

[0043] R 3-1 , R 3-2 , R 3-3 , R 3-4 , and R 3-5 independently hydrogen, deuterium, halogen, or -NR a R b ;

[0044] n is 0, 1, 2, 3, or 4;

[0045] R 4 , and R 5 independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, or optionally substituted C3-C6cycloalkyl; 4-1 independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, or optionally substituted C3-C6cycloalkyl; 4-2 independently hydrogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, or optionally substituted C3-C6cycloalkyl; 4-3 independently hydrogen, deuterium, amino, cyano, optionally substituted C1-C6alkyl, halogen, optionally substituted C1-C6alkoxy, hydroxyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted C6-C10aryl;

[0046] or, R 4 , R 5 and the N to which they are attached form a "3-6 membered heterocycloalkyl having 1 nitrogen heteroatom";

[0047] R 4-1 , R 4-2 , and R 4-3 independently hydrogen, deuterium, or halogen;

[0048] m is 0 or 2; when m is 0, R 6 is absent;

[0049] when m is 2, the two R 6 together with the C to which they are attached form a C3-C6cycloalkyl; or, two adjacent R 6with the C to which they are attached to form a C3-C6cycloalkyl; or, two non-adjacent R 6 together with the C to which they are attached to form a -(CH2) m1 - a bridging moiety, m1 is 1 or 2.

[0050] In one embodiment of the present application, the compound represented by Formula II, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof;

[0051] wherein the carbon atom marked with "*" represents, when being a chiral carbon atom, R configuration, S configuration, or a mixture of the two;

[0052] the carbon atom marked with "#" represents, when being a chiral carbon atom, independently R configuration, S configuration, or a mixture of the two;

[0053] R 1 halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C 1-1 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R 1-2 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R 1-3 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R 1-4 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R 10 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R 1-5 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R 1-6 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R

[0054] R 2 halogen, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C6cycloalkyl, optionally substituted C6-C 2-1 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R 2-2 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R 10 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R 2-3 aryl, "heteroatoms selected from 1, 2, or 3 of N, O, and S, 1 or more in number, 5-10 membered heteroaryl" optionally substituted with 1 or more R 2-4 R 2-5 , -S-R 2-6 , -O-R 2-7 , or optionally substituted C1-C6alkyl; 2-8 R

[0055] R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , and R1-6 Independently hydrogen, deuterium, -CN, halogen, -NR a R b Optional by one or more R 1- 1-1 Substituted C1-C6 alkyl groups or optionally with one or more R 1-1-2 Substituted C1-C6 alkoxy groups;

[0056] R a and R b Independently hydrogen or C1-C6 alkyl;

[0057] R 1-1-1 and R 1-1-2 Independent of hydrogen, deuterium, halogen, or -NR a R b ;

[0058] R 2-1 and R 2-8 Independently hydrogen, deuterium, halogen, optionally with one or more R 2-1-1 Substituted C3-C6 cycloalkyl groups, optionally with one or more R 2-1-2 The substituted "heteroatom selected from one, two, or three of N, O, and S, and a 3-6 membered heterocyclic alkyl group having one, two, or three heteroatoms", optionally replaced by one or more R 2-1-3 Replacement C6-C 10 Aryl, optionally with one or more R 2-1-4 Substituted C1-C6 alkyl groups or optionally with one or more R 2-1-5 Substituted C1-C6 alkoxy groups;

[0059] R 2-1-1 R 2-1-2 and R 2-1-3 Independently hydrogen, deuterium, halogen, optionally with one or more R 2a Substituted C1-C6 alkyl groups or optionally with one or more R 2b Substituted C1-C6 alkoxy groups;

[0060] R 2a and R 2b Halogens are independent of each other;

[0061] R 2-1-4 and R 2-1-5 Independently hydrogen, deuterium, halogen, or -NR a R b ;

[0062] R 2-2 and R 2-3 Independently hydrogen, deuterium, halogen, optionally with one or more R 2-2-1 Substituted C1-C6 alkyl groups, optionally with one or more R2-2-2 substituted C1-C6alkyl or -CN;

[0063] R 2-2-1 and R 2-2-2 are independently hydrogen, deuterium, halogen, -NR a R b or C1-C6alkoxy;

[0064] R 2-4 are independently hydrogen or C1-C6alkyl;

[0065] R 2-5 , R 2-6 and R 2-7 are independently hydrogen, C1-C6alkyl, optionally substituted by 1 or more R 2-5-1 substituted C6-C 10 aryl, optionally substituted by 1 or more R 2-5-2 substituted C3-C6cycloalkyl or optionally substituted by 1 or more R 2-5-3 substituted “heteroatoms are selected from 1, 2, or 3 of N, O, and S, 3-6 membered heterocycloalkyl having 1, 2, or 3 heteroatoms”;

[0066] R 2-5-1 are independently halogen, optionally substituted by 1 or more R 2c substituted C1-C6alkyl, optionally substituted by 1 or more R 2d substituted C1-C6alkoxy or -CN;

[0067] R 2c and R 2d are independently halogen, C1-C6alkoxy or -NR a R b ;

[0068] R 2-5-2 are independently halogen, optionally substituted by 1 or more R 2f substituted C1-C6alkyl or optionally substituted by 1 or more R 2g substituted C1-C6alkyl;

[0069] R 2e are independently C1-C6alkyl;

[0070] R 2f and R 2g are independently halogen or -NR a R b ;

[0071] R 2-5-3 are independently halogen, optionally substituted by 1 or more R 2jsubstituted C1-C6alkyl, optionally substituted with 1 or more R 2k substituted C1-C6alkyl, optionally substituted with 1 or more R

[0072] R 2j and R 2k independently are halogen, -NR a R b or C1-C6alkoxy;

[0073] Y 1 and Y 2 independently are CR c or N;

[0074] R c is hydrogen, optionally substituted with 1 or more R c-1 substituted C1-C6alkyl, optionally substituted with 1 or more R c-2 substituted C1-C6alkyl, optionally substituted with 1 or more R

[0075] R c-1 and R c-2 independently are halogen or -NR a R b ;

[0076] is

[0077] R 3 independently are deuterium, amino, cyano, optionally substituted with 1 or more R 3-1 substituted C1-C6alkyl, halogen, optionally substituted with 1 or more R 3-2 substituted C1-C6alkyl, halogen, optionally substituted with 1 or more R 3-3 substituted C2-C6alkenyl, optionally substituted with 1 or more R 3- 4 substituted C2-C6alkynyl or optionally substituted with 1 or more R 3-5 substituted C6-C 10 aryl;

[0078] R 3-1 , R 3-2 , R 3-3 , R 3-4 and R 3-5 independently are hydrogen, deuterium, halogen or -NR a R b ;

[0079] n is 0, 1, 2, 3 or 4;

[0080] R 4 and R 5Independently hydrogen, optionally by one or more R 4-1 Substituted C1-C6 alkyl groups, optionally with one, two, or three R atoms. 4-2 Substituted C1-C6 alkoxy groups or optionally with one or more R groups 4-3 Substituted C3-C6 cycloalkyl groups;

[0081] Or, R 4 R 5 Together with the N atoms attached to them, they form "3-6 membered heterocyclic alkyl groups with N atoms and one heteroatom".

[0082] R 4-1 R 4-2 and R 4-3 It can be hydrogen, deuterium, or halogen independently;

[0083] m is 0 or 2; when m is 0, R 6 It does not exist;

[0084] When m is 2, two R atoms attached to the same C atom 6 Together with the C atoms they are attached to, they form C3-C6 cycloalkyl groups; or, two adjacent R atoms... 6 Together with the C atoms they are attached to, they form C3-C6 cycloalkyl groups; or, two non-adjacent R atoms... 6 Connect to form -(CH2) m1 - For the bridging part, m1 is 1 or 2.

[0085] The present invention also provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof;

[0086] in,

[0087] A carbon atom marked with an asterisk (*) indicates that when it is a chiral carbon atom, it has an R configuration, an S configuration, or a mixture of both.

[0088] A carbon atom marked with a "#" indicates that, when it is a chiral carbon atom, it is independently in the R configuration, S configuration, or a mixture of both.

[0089] R 1 Halogen, optionally subjected to one or more R 1-1 Substituted C1-C6 alkyl groups, optionally with one or more R 1-2 Substituted C1-C6 alkoxy groups, optionally with one or more R groups 1-3 Substituted C3-C6 cycloalkyl groups, optionally with one or more R 1-4 Replacement C6-C 10 Aryl, optionally with one or more R 1-5substituted "heteroatoms selected from 1, 2, or 3 of N, O, and S, 3- to 6- membered heterocycloalkyl of 1, 2, or 3 heteroatoms" or optionally substituted C6-C10aryl of 1, 2, or 3 heteroatoms; 1-6 substituted "heteroatoms selected from 1, 2, or 3 of N, O, and S, 3- to 6- membered heterocycloalkyl of 1, 2, or 3 heteroatoms" or optionally substituted C6-C10aryl of 1, 2, or 3 heteroatoms;

[0090] R 2 is hydrogen, halogen, hydroxyl, optionally substituted C1-C6alkyl of 1, 2, or 3 halogens, optionally substituted C1-C6alkoxy of 1, 2, or 3 halogens, -NR 2-1 substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C6-C10aryl, or optionally substituted 3- to 6-membered heterocycloalkyl of 1, 2, or 3 heteroatoms; 2-2 substituted C6-C10aryl, optionally substituted "heteroatoms selected from 1, 2, or 3 of N, O, and S, 3- to 6-membered heterocycloalkyl of 1, 2, or 3 heteroatoms," or -NR 10 substituted C6-C10aryl, optionally substituted "heteroatoms selected from 1, 2, or 3 of N, O, and S, 3- to 6-membered heterocycloalkyl of 1, 2, or 3 heteroatoms," or -NR 2-3 substituted "heteroatoms selected from 1, 2, or 3 of N, O, and S, 3- to 6- membered heterocycloalkyl of 1, 2, or 3 heteroatoms" or optionally substituted C6-C10aryl of 1, 2, or 3 heteroatoms; 2-4 R 2-5 , -S-R 2-6 , -O-R 2-7 , or optionally substituted C1-C6alkyl of 1, 2, or 3 halogens; 2-8 substituted C1-C6alkyl;

[0091] R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , and R 1-6 are independently deuterium, -CN, halogen, -NR a R b , optionally substituted C1-C6alkyl of 1, 2, or 3 halogens, or optionally substituted C1-C6alkoxy of 1, 2, or 3 halogens; 1-1-1 substituted C1-C6alkyl or optionally substituted C1-C6alkoxy; 1-1-2 substituted C1-C6alkyl;

[0092] R a , and R b are independently hydrogen or C1-C6alkyl;

[0093] R 1-1-1 , and R 1-1-2 are independently halogen or -NR a R b ;

[0094] R 2-1 , and R 2-8 are independently deuterium, halogen, optionally substituted C3-C6cycloalkyl of 1, 2, or 3 halogens, optionally substituted "heteroatoms selected from 1, 2, or 3 of N, O, and S, 3- to 6-membered heterocycloalkyl of 1, 2, or 3 heteroatoms," or optionally substituted C6-C10aryl of 1, 2, or 3 heteroatoms; 2-1-1 substituted C3-C6cycloalkyl, optionally substituted C6-C10aryl, or optionally substituted "heteroatoms selected from 1, 2, or 3 of N, O, and S, 3- to 6-membered heterocycloalkyl of 1, 2, or 3 heteroatoms"; 2-1-2 substituted "heteroatoms selected from 1, 2, or 3 of N, O, and S, 3- to 6- membered heterocycloalkyl of 1, 2, or 3 heteroatoms" or optionally substituted C6-C10aryl of 1, 2, or 3 heteroatoms; 2-1-3 substituted C6-C10aryl, optionally substituted "heteroatoms selected from 1, 2, or 3 of N, O, and S, 3- to 6-membered heterocycloalkyl of 1, 2, or 3 heteroatoms," or -NR10 Aryl, optionally with one or more R 2-1-4 Substituted C1-C6 alkyl groups or optionally with one or more R 2-1-5 Substituted C1-C6 alkoxy groups;

[0095] R 2-1-1 R 2-1-2 and R 2-1-3 Independently halogenated, optionally by one or more R 2a Substituted C1-C6 alkyl groups or optionally with one or more R 2b Substituted C1-C6 alkoxy groups;

[0096] R 2a and R 2b Halogens are independent of each other;

[0097] R 2-1-4 and R 2-1-5 Independently halogen or -NR a R b ;

[0098] R 2-2 and R 2-3 Independently halogenated, optionally by one or more R 2-2-1 Substituted C1-C6 alkyl groups, optionally with one or more R 2-2-2 Substituted C1-C6 alkoxy groups or -CN;

[0099] R 2-2-1 and R 2-2-2 Independent of halogen, -NR a R b Or C1-C6 alkoxy groups;

[0100] R 2-4 Independently hydrogen or C1-C6 alkyl;

[0101] R 2-5 R 2-6 and R 2-7 Independently hydrogen, C1-C6 alkyl, optionally with one or more R 2-5-1 Replacement C6-C 10 aryl, one or more R 2-5-2 The substituted C3-C6 cycloalkyl group or optionally with one or more R 2-5-3 The substituted heteroatom is selected from one, two, or three of N, O, and S, or from 3-6 membered heterocyclic alkyl groups having one, two, or three heteroatoms.

[0102] R 2-5-1 Independently halogenated, optionally by one or more R 2c Substituted C1-C6 alkyl groups, optionally with one or more R 2dSubstituted C1-C6 alkoxy groups or -CN;

[0103] R 2c and R 2d Independently halogenated, C1-C6 alkoxy or -NR a R b ;

[0104] R 2-5-2 Independently Halogen, optionally with one or more R 2f Substituted C1-C6 alkyl groups or optionally with one or more R 2g Substituted C1-C6 alkyl groups;

[0105] R 2e Independently, it is a C1-C6 alkyl group;

[0106] R 2f and R 2g Independently halogen or -NR a R b ;

[0107] R 2-5-3 Independently halogenated, optionally by one or more R 2j Substituted C1-C6 alkyl groups, optionally with one or more R 2k Substituted C1-C6 alkoxy groups or -CN;

[0108] R 2j and R 2k Independent of halogen, -NR a R b Or C1-C6 alkoxy groups;

[0109] Y 1 and Y 2 Independent for CR c Or N;

[0110] R c Hydrogen, optionally with one or more R c-1 Substituted C1-C6 alkyl groups, optionally with one or more R c-2 Substituted C1-C6 alkoxy, halogen, or cyano groups;

[0111] R c-1 and R c-2 Independently halogen or -NR a R b ;

[0112] for

[0113] R3 independently deuterium, optionally substituted Ci-C6alkyl, halogen, -OR 3-1 substituted Ci-C6alkyl, halogen, -OR 3-2 substituted Ci-C6alkyl, halogen, -OR

[0114] R 3-1 and R 3-2 independently halogen or -NR a R b ;

[0115] n is 0, 1, 2, 3, or 4;

[0116] R 4 and R 5 independently hydrogen, optionally substituted Ci-C6alkyl, halogen, -OR 4-1 substituted Ci-C6alkyl, halogen, -OR 4-2 substituted Ci-C6alkyl, halogen, -OR

[0117] R 4-1 and R 4-2 independently deuterium.

[0118] In certain preferred embodiments of the application, certain groups in the compounds (including compounds of Formula I and Formula II), pharmaceutically acceptable salts thereof, or stereoisomers thereof, are defined as follows, with the groups not mentioned being as described in any of the schemes of the application (simply "in a scheme of the application").

[0119] In a scheme of the application, each of the plurality is independently 1, 2, 3, 4, 5, 6, 7, or 8; for example, 1, 2, or 3.

[0120] In a scheme of the application, each of the halogens is independently fluorine, chlorine, bromine, or iodine; for example, fluorine and chlorine; further for example, fluorine.

[0121] In a scheme of the application, each of the Ci-C6alkyl groups and each of the Ci-C6alkyl groups in the substituted Ci-C6alkyl groups is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, or s-butyl; for example, methyl or ethyl.

[0122] In a scheme of the application, each of the Ci-C6alkoxy groups and each of the substituted Ci-C6alkoxy groups is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy; for example, methoxy or ethoxy; further for example, ethoxy.

[0123] In one aspect of the invention, the C3-C6 cycloalkyl group and the substituted C3-C6 cycloalkyl group are independently cyclopropyl, cyclobutyl, or cyclopentyl; for example, cyclopropyl or cyclobutyl.

[0124] In one embodiment of the present invention, each of the C6-C 10 aryl and each of the substituted C6-C 10 C6-C in aryl 10 The aryl group can be phenyl or naphthyl independently.

[0125] In one embodiment of the present invention, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group with two N heteroatoms; for example...

[0126] In one embodiment of the invention, each of the 3-6 membered heterocyclic alkyl groups is independently a 3-4 membered heterocyclic alkyl group; for example... For example,

[0127] In one embodiment of the present invention, the 3-8 membered heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group.

[0128] In one aspect of the present invention, the C2-C6 alkenyl groups and the substituted C2-C6 alkenyl groups are each independently C2-C4 alkenyl groups.

[0129] In one aspect of the present invention, the C2-C6 ynyl group and the substituted C2-C6 ynyl group are each of which are independently C2-C4 ynyl groups.

[0130] In one aspect of the present invention, R 1 It is defined as "a 5-10 membered heteroaryl group whose heteroatoms are selected from one, two or three of N, O and S, and whose heteroatoms number one or more".

[0131] In one aspect of the present invention, R 2 For optional use by one or more R 2-1 Substituted C1-C6 alkoxy or -OR 2-7 Preferably, it is selected by one or more R. 2-1 Substituted C1-C6 alkoxy groups.

[0132] In one aspect of the present invention, R 2-1 Independently hydroxyl, cyano, -NR a R b -C(=O)NR a R b"3- to 6-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" or C1-C6alkoxy; preferably hydroxy, cyano, -NR a R b or C1-C6alkoxy; further preferably -NR a R b .

[0133] In a certain embodiment of the application, R 2-7 is independently "3- to 6-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S".

[0134] In a certain embodiment of the application, R a and R b are independently C1-C6alkyl.

[0135] In a certain embodiment of the application, R 2 is C1-C6alkoxy.

[0136] In a certain embodiment of the application, Y 1 and Y 2 are independently CR c .

[0137] In a certain embodiment of the application, R c is hydrogen.

[0138] In a certain embodiment of the application, is

[0139] In a certain embodiment of the application, R 3 is independently C1-C6alkyl or halogen; preferably C1-C6alkyl.

[0140] In a certain embodiment of the application, n is 0 or 1 ; for example, 0.

[0141] In a certain embodiment of the application, R 4 and R 5 are independently hydrogen, C1-C6alkyl or C1-C6alkoxy; preferably hydrogen or C1-C6alkyl; further preferably C1-C6alkyl.

[0142] In a certain embodiment of the application, m is 0.

[0143] In a certain embodiment of the application, R 1 is

[0144] In a certain embodiment of the application, R 2 is

[0145] In one embodiment of the present application, R a and R b are independently hydrogen or methyl; preferably methyl.

[0146] In one embodiment of the present application, R 2 is

[0147] In one embodiment of the present application, R 3 is -CH3or F; preferably -CH3.

[0148] In one embodiment of the present application, R 4 is hydrogen, -CH3or -CD3; preferably hydrogen or -CH3; more preferably -CH3.

[0149] In one embodiment of the present application, R 5 is hydrogen, -CH3, methoxy, ethyl or -CD3; preferably hydrogen, -CH3or ethyl; more preferably -CH3.

[0150] In one embodiment of the present application, R 4 , R 5 form together with the N to which they are attached a

[0151] In one embodiment of the present application, when m is 2, the two R 6 form together with the C to which they are attached a C3-C6cycloalkyl group.

[0152] In one embodiment of the present application, when m is 2, the two adjacent R 6 form together with the C to which they are attached a C3-C6cycloalkyl group.

[0153] In one embodiment of the present application, is

[0154] In one embodiment of the present application, is

[0155] In one embodiment of the present application, is is preferably

[0156] In one embodiment of the present application, is for example,

[0157] In some embodiments of the present application, the compound of Formula I is any one of the following compounds of Formula I-1, For example,

[0158] In some embodiments of the present application, the compound of Formula I is any one of the following compounds of Formula I-1, For example,

[0159] wherein R 1 , R 2 , R 3 , R 4 , R 5 , n, the carbon atom marked with “*” and the carbon atom marked with “#” are defined as any embodiments of the present application.

[0160] The present application also provides a pharmaceutical composition comprising:

[0161] (1) the compound of Formula I, pharmaceutically acceptable salt thereof or stereoisomer thereof as described above; and

[0162] (2) a pharmaceutically acceptable excipient.

[0163] The present application also provides the use of the compound of Formula I, pharmaceutically acceptable salt thereof or stereoisomer thereof as described above, the pharmaceutical composition as described above, wherein the use is selected from:

[0164] (1) preparing a CDK2 inhibitor or a CDK4 inhibitor;

[0165] (2) preparing a medicament for treating or preventing a disease or disorder associated with cyclin-dependent kinase 2 (CDK2);

[0166] (3) preparing a medicament for treating and / or preventing a disease or disorder, which can be cancer; and

[0167] (4) preparing a medicament for treating or preventing a disease or disorder associated with cyclin-dependent kinase 4 (CDK4).

[0168] In the use, the CDK2 inhibitor or CDK4 inhibitor can be used in vivo in a mammalian organism; can also be used in vitro, mainly as experimental use, for example: providing comparison as a standard sample or control sample, or being prepared into a kit according to the conventional method in the art, to provide rapid detection of the inhibitory effect of CDK2 or CDK4.

[0169] In an aspect of the present application, the disease or disorder associated with cyclin-dependent kinase 2 (CDK2) is a CCNE1 abnormality-associated cancer; the CCNE1 abnormality can be amplification of the CCNE1 gene and / or overexpression of CCNE1.

[0170] In an aspect of the present application, the cancer is selected from the group consisting of ovarian cancer, gastric cancer, esophageal cancer, uterine serous carcinoma, lung cancer, colorectal cancer, breast cancer, and hematological neoplasms.

[0171] In an aspect of the present application, the disease or disorder associated with cyclin-dependent kinase 4 (CDK4) is breast cancer and / or multiple Rb pathway-dependent tumors.

[0172] In an aspect of the present application, the drug can be administered or used in combination with other types of drugs, covering the combination with VEGF / PI3K / Akt signaling pathway inhibitors, BRD4 inhibitors, BCL-2 inhibitors, BRAF / HSP90 inhibitors, CDK4 / 6 inhibitors, PARP inhibitors, endocrine therapy, chemotherapy, and radiotherapy. These combinations not only can enhance the efficacy, but also can overcome drug resistance, especially in tumors that are ineffective or resistant to CDK4 / 6 inhibitors, showing significant potential.

[0173] Definitions

[0174] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Furthermore, the following definitions are set out to illustrate and define the meanings and scope of the various terms used to describe the application.

[0175] The term "a plurality" refers to 1, 2, 3, 4, 5, 6, 7, or 8.

[0176] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0177] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0178] The term "alkoxy" refers to the group R Z -O-, wherein R Z is an alkyl group as defined above.

[0179] The term "cycloalkyl" refers to a saturated monocyclic ring group consisting solely of carbon atoms having the specified number of carbon atoms (e.g., C3-C6). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0180] The term "aryl" refers to a cyclic group consisting solely of carbon atoms (e.g., C6-Ci0aryl), having the number of ring atoms specified (e.g., 6-10), which is either monocyclic or polycyclic, and each ring in the ring system is aromatic (complies with Hückel's rule). Aryl rings include, but are not limited to, phenyl, naphthyl, and the like. 10 ) of carbon atoms. The term "heteroaryl" refers to a cyclic group having the number of ring atoms specified (e.g., 5-10 membered), the number of heteroatoms specified (e.g., 1, 2, or 3), and the type of heteroatoms specified (one, two, or three of N, O, and S), which is either monocyclic or polycyclic, and each ring in the ring system is aromatic (complies with Hückel's rule). Heteroaryl groups are attached to the remainder of the molecule through a carbon atom or a heteroatom; heteroaryl groups are attached to the remainder of the molecule through a ring having a heteroatom or a ring having no heteroatom. Heteroaryl groups include, but are not limited to, furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole, pyridine, pyrimidine, indole, benzopyrrole, and the like.

[0181] The term "heteroaryl" refers to a cyclic group having the number of ring atoms specified (e.g., 5-10 membered), the number of heteroatoms specified (e.g., 1, 2, or 3), and the type of heteroatoms specified (one, two, or three of N, O, and S), which is either monocyclic or polycyclic, and each ring in the ring system is aromatic (complies with Hückel's rule). Heteroaryl groups are attached to the remainder of the molecule through a carbon atom or a heteroatom; heteroaryl groups are attached to the remainder of the molecule through a ring having a heteroatom or a ring having no heteroatom. Heteroaryl groups include, but are not limited to, furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole, pyridine, pyrimidine, indole, benzopyrrole, and the like.

[0182] The term "heteroaryl" refers to a cyclic group having the number of ring atoms specified (e.g., 5-10 membered), the number of heteroatoms specified (e.g., 1, 2, or 3), and the type of heteroatoms specified (one, two, or three of N, O, and S), which is either monocyclic or polycyclic, and each ring in the ring system is aromatic (complies with Hückel's rule). Heteroaryl groups are attached to the remainder of the molecule through a carbon atom or a heteroatom; heteroaryl groups are attached to the remainder of the molecule through a ring having a heteroatom or a ring having no heteroatom. Heteroaryl groups include, but are not limited to, furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole, pyridine, pyrimidine, indole, benzopyrrole, and the like.

[0183] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having at least one location of unsaturation, i.e., a carbon-carbon sp triple bond (e.g., C2-C6alkynyl).

[0184] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having at least one location of unsaturation, i.e., a carbon-carbon sp triple bond (e.g., C2-C6alkynyl).

[0185] The term "pharmaceutically acceptable salt" includes "a pharmaceutically acceptable salt formed from an organic or inorganic acid" and "a pharmaceutically acceptable salt formed from an organic or inorganic base."

[0186] The term "stereoisomer" includes configurational isomers, wherein configurational isomers include optical isomers, e.g., enantiomers, diastereomers, or mixtures thereof.

[0187] The term "pharmaceutically acceptable excipient" means any formulation or carrier medium that does not interfere with the effectiveness of the active substance of the application, and is not toxic to the host or patient, and represents a representative excipient including water, oil, vegetable and mineral, paste base, lotion base, ointment base, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their formulations are known to those skilled in the art of cosmetics or topical medicine.

[0188] The term "pharmaceutical composition" means a mixture or solution of a therapeutically effective amount of an active pharmaceutical ingredient with a pharmaceutically acceptable excipient, ready for administration to a mammal, such as a human, in need thereof.

[0189] The term "treatment" relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein relates to the action of the verb to treat, as defined before.

[0190] The above-mentioned preferred conditions can be combined in any way, without departing from the general principles of the art, to obtain preferred embodiments of the present application.

[0191] The reagents and raw materials used in the present application are commercially available.

[0192] The positive progress effect of the present application is that a heterocyclic substituted sulfamide compound, a pharmaceutical composition thereof and application thereof are disclosed. A kind of compound with different structure from reported or disclosed compound is provided, with the following effects: ① CDK2 selective inhibitor. Compared with PF-07104091, the compound has stronger CDK2 target binding capacity and enzyme inhibition activity; relative to CDK2, CDK1 has higher selectivity; compared with PF-07104091, CDK2-dependent ovarian cancer has stronger in vitro anti-proliferation and in vivo antitumor effect. The heterocyclic substituted sulfamide compound has excellent CDK2 / CDK1 selectivity and higher safety; ② CDK4 inhibitor. The binding capacity of the compound to CDK4 target and enzyme inhibition activity are equivalent to Palbociclib, and similar anti-proliferation activity is shown in CDK4-dependent MCF-7 breast cancer cell line. The heterocyclic substituted sulfamide compound shows the activity of CDK2 / 4 dual inhibitor biased towards CDK2, with the potential to treat HR+HE2- breast cancer and CCNE1 abnormal cancer. BRIEF DESCRIPTION OF DRAWINGS

[0193] Figure 1 is the change of tumor volume of human ovarian cancer cell OVCAR3 tumor-bearing mice.

[0194] Figure 2 is the change of body weight of human ovarian cancer cell OVCAR3 tumor-bearing mice.

[0195] Figure 3 is the inhibition of downstream targets in tumor tissue by the compounds. DETAILED DESCRIPTION

[0196] The application is further illustrated by the following examples without thereby limiting the application to the examples described. The experimental methods in the following examples and experimental examples, unless otherwise specified, are selected according to the conventional methods and conditions, or according to the commercial instruction.

[0197] The starting materials or reagents used herein are commercially available or prepared by synthetic methods generally known in the art:

[0198] Example 1: 4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)piperidine-1- sulfonamide

[0199] Step one:

[0200] Into a reaction flask was added 2-amino-4-bromopyridin-3-ol hydrobromide (Intermediate 1, 2.70 g, 10.00 mmol), cesium carbonate (6.52 g, 20 mmol) and acetonitrile (30 mL). The mixture was stirred for 15 minutes and iodoe thane (2.34 g, 15.00 mmol) was added. The mixture was heated at 65-70 °C for 18 hours. The reaction was monitored by TLC and the reaction was cooled to room temperature. The resulting reaction slurry was filtered through celite and the filter cake was washed with dichloromethane. The organic phases were combined and concentrated. The residue was purified by column chromatography (ethyl acetate / dichloromethane = 1 / 5) to give white solid intermediate 2 (1.5 g, yield 69%).

[0201] LCMS (ESI) m / z: 217 [M+H] + .

[0202] 1H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 5.4 Hz, 1H), 6.73 (d, J = 5.3 Hz, 1H), 6.13 (s, 2H), 3.91 (q, J = 7.0 Hz, 2H, 1.35 (t, J = 7.7 Hz, 3H). C7H9BrN2O, (calculated M+H: 216.9971), LCMS (EI) M / e 216.9 (M++H).

[0203] Step two:

[0204] Intermediate 2 (1.50 g, 6.91 mmol) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 3, 2.21 g, 8.29 mmol) were dissolved in dioxane (20 mL), potassium phosphate (4.40 g, 20.73 mmol) and water (10 mL) were added, nitrogen was purged, catalyst XPhos Pd G2 (chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)) (27.2 mg, 34.55 μmol) was added, after addition, the temperature was raised to 85 °C and the reaction was allowed to proceed overnight. TLC was used to monitor the completion of the reaction. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (10 mL*2). The organic phases were combined and washed with saturated sodium chloride solution. Concentration and column chromatography (ethyl acetate / dichloromethane = 1 / 3) gave intermediate 4 (1.5 g, yield: 78% 1.5) as a yellow solid.

[0205] LCMS (ESI) m / z: 277 [M+H]+.

[0206] 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.00 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.77 (s, 2H), 5.62 (dd, J = 8.0, 4.0 Hz, 1H), 3.72 (q, J = 8.0 Hz, 2H), 3.46 (m, 1H), 3.23 (m, 1H), 1.63 (d, J = 8.0 Hz, 3H), 1.33 (t, J = 8.0 Hz, 3H), 1.05 (t, J = 8.0 Hz, 3H);

[0207] Step three:

[0208] Intermediate 4 (1.50 g, 5.39 mmol) was dissolved in dioxane (20 mL) and cooled to 10 °C, ethyl isothiocyanate (1.21 g, 8.08 mmol) was added. After addition, the temperature was raised to room temperature and the reaction was stirred for 16 hours. TLC was used to monitor the completion of the reaction, the reaction solution was quenched with saturated sodium chloride solution, the layers were separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give intermediate 5 as a yellow oily product, which was used directly in the next step.

[0209] LCMS (ESI) m / z: 408 [M+H]+.

[0210] 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 11.43 (s, 1H), 8.52 (s, 1H), 8.17 (d, J = 5.1 Hz, 1H), 8.13 (s, 1H), 7.63 (d, J = 5.1 Hz, 1H), 5.65 (q, J = 5.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.89 (q, J = 7.0 Hz, 2H), 3.48 (dq, J = 9.6, 7.0 Hz, 1H), 3.25 (dq, J = 9.6, 7.0 Hz, 1H), 1.64 (d, J = 6.0 Hz, 3H), 1.29 (m, 6H), 1.06 (t, J = 7.0 Hz, 3H).

[0211] Step four:

[0212] The crude intermediate 5 from previous step (2.20 g, 5.40 mmol) was dissolved in ethanol (30 mL), hydroxylamine hydrochloride (562.74 mg, 8.10 mmol) and N, N-diisopropylethylamine (1.05 g, 8.10 mmol) were added, nitrogen was purged, and the reaction mixture was stirred at 70 °C for 2 h. After the reaction mixture was cooled to room temperature, it was diluted with saturated aqueous NH4Cl and extracted with CH2Cl2. The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to give crude intermediate 6 which was used directly in the next step.

[0213] LCMS (ESI) m / z: 317 [M+H]+.

[0214] Step five:

[0215] The crude intermediate 6 from previous step (1.7 g, 5.37 mmol) was dissolved in acetonitrile, copper (II) bromide (1.26 g, 5.64 mmol) was added to give a dark solution. The reaction mixture was cooled to 5 °C, and tert-butyl nitrite (1.33 g, 12.90 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature and was stirred for 16 h. The reaction was monitored by TLC, and the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The combined organic phase was dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (ethyl acetate / n-hexane = 1 / 3) to give intermediate 7 (1.2 g, yield: 58%) as a white solid.

[0216] LCMS (ESI) m / z: 380 [M+H]+;

[0217] 1H NMR (400 MHz, DMSO) δ 8.68 (d, J = 7.1 Hz, 1H), 8.58 (s, 1H), 8.21 (s, 1H), 7.58 (d, J = 7.1 Hz, 1H), 5.65 (q, J = 5.9 Hz, IH), 4,65 (q, J = 7.0 Hz, 2H), 3.48 (dq, J = 9.6, 7.0 Hz, 1H), 3.27 (dq, J = 9.6, 7.0 Hz, IH), 1.65 (d, J = 6.0 Hz, 3H), 1.40 (t, J = 7.0 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H).

[0218] Step six:

[0219] Into a reaction vial was placed intermediate 7 (1.20 g, 3.16 mmol), intermediate 8 (758.5 mg, 3.79 mmol), sodium tert-butoxide (1.52 g, 15.78 mmol), t-BuBrettPhos Pd G3([(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) mesylate) (80.89 mg, 94.68 μmol) and dioxane. The reaction mixture was heated to 90 °C for 6 h under nitrogen protection. The reaction was monitored by TLC. When the reaction was completed, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give intermediate 9 as a crude product, which was used directly in the next step.

[0220] LCMS (ESI) m / z: 400 [M-Boc+H]+;

[0221] Step seven:

[0222] Into a reaction vial was placed intermediate 9 (1.58 g, 3.16 mmol) in THF (14 mL, 7 v), 1 N hydrochloric acid (9.5 mL, 9.5 mmol), and the reaction mixture was heated to 60 °C for 2 h. The reaction was monitored by TLC. When the reaction was completed, the reaction mixture was cooled to room temperature, and the pH was adjusted to 7 with 16% sodium hydroxide. The mixture was extracted with ethyl acetate (10 mL*2), and the organic phases were combined and concentrated. The slurry was diluted with n-heptane (10 mL), stirred at room temperature for 30 min, and then cooled to 0 °C. A solid was precipitated, which was filtered and dried to give intermediate 10 (1.0 g, yield: 96%) as a white solid.

[0223] LCMS (ESI) m / z: 328 [M+H]+;

[0224] Step eight:

[0225] Intermediate 10 (1.00 g, 3.05 mmol) was dissolved in 1,4-dioxane (15 mL), sulfonamide (intermediate 11, 296.5 mg, 3.08 mmol) was added, after addition, 110 °C was stirred for 12 hours. The reaction solution was concentrated, purified by column chromatography (DCM:MeOH = 20 / 1) to obtain example 1 white solid (180 mg, yield: 14%).

[0226] LCMS (ESI) m / z: 407 [M+H]+;

[0227] 1H NMR (400 MHz, DMSO) δ 13.09 (s, 1H), 8.32 (d, J = 7.0 Hz, 1H), 8.16 (d, J = 50.4 Hz, 2H), 7.17 (d, J = 7.0 Hz, 1H), 6.73 (s, 2H), 6.63 (d, J = 7.4 Hz, 1H), 4.54 (q, J = 7.0 Hz, 2H), 3.59 - 3.48 (m, 1H), 3.48 - 3.41 (m, 2H), 2.68 (d, J = 1.8 Hz, 2H), 2.04 (d, J = 10.0 Hz, 2H), 1.60 (s, 2H), 1.35 (t, J = 7.1 Hz, 3H).

[0228] Example 2: (3R,4S)-4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl)amino)-3-methylpiperidine-1 -sulfonamide

[0229] Step one:

[0230] Intermediate 12 (6.00 g, 40.10 mmol) was dissolved in dichloromethane (80 mL), triethylamine (10.48 g, 60.15 mmol) was added. Methanesulfonic anhydride (Ms20, 6.09 g, 60.15 mmol) was added portionwise, after addition, the reaction solution was stirred at 25 °C for 3 hours. TLC (V ethyl acetate:V n-hexane = 1:1, compound 10: Rf = 0.02, compound 11: Rf = 0.43) showed that the starting material was completely consumed. Then water (55 mL) and dichloromethane (30 mL) were added to the reaction solution and stirred, the organic phase was washed with saturated sodium chloride solution (35 mL), then anhydrous sodium sulfate was added and dried, filtered, and concentrated under reduced pressure to obtain yellow solid intermediate 13 (7.00 g, yield: 91%).

[0231] LCMS (ESI) m / z: 192 [M+H]+.

[0232] Step two:

[0233] Intermediate 13 (7.00 g, 36.60 mmol), S(-)-a-phenylethylamine (intermediate 14, 6.65 g, 54.90 mmol) were dissolved in tetrahydrofuran (80.0 mL), N,N- diisopropylethylamine (5.67 g, 43.92 mmol), sodium triacetoxyborohydride (11.7 g, 54.90 mmol) were added, after addition, the reaction was stirred at 20 °C for 5 hours. LCMS showed that the raw material was completely consumed. To the reaction solution, methanol (20 mL) was added to quench the reaction, then dichloromethane (80 mL), saturated sodium bicarbonate solution (50.0 mL) were added and stirred, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, stirred in ethyl acetate (70 mL), a large amount of white solid was precipitated, filtered, the filter cake was added with ethyl acetate (42 mL) and heated to 60 °C until completely dissolved, then cooled to room temperature, and white solid was precipitated. The white solid was recrystallized twice according to the above method to obtain intermediate 15 (3.50 g, yield: 32%).

[0234] Step three:

[0235] Toluene (280 mL) was added to intermediate 15 (27.6 g, 93.11 mmol), and red aluminum (Red-Al) toluene solution (70%, 94.2 g, 465.54 mmol) was added dropwise with stirring, bubbles were generated, after the addition was completed, the reaction was heated to reflux and stirred for 2 hours; LCMS showed that the reaction was completed, the reaction was cooled, water was added to quench the reaction, and no bubbles were generated, then sodium hydroxide solution (2 M) was added and stirred for 30 minutes, then extracted with ethyl acetate (200 mL*3), the organic phase was combined and washed twice with water (300 mL*2) and saturated sodium chloride solution (300 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, then purified by column chromatography (V methanol:V dichloromethane = 1:9) to obtain intermediate 16 (13.4 g, yield: 65%).

[0236] LCMS (ESI) m / z: 219 [M+H]+.

[0237] Step four:

[0238] Intermediate 16 (2.0 g, 9.16 mmol) was dissolved in 1,4-dioxane (20 mL), and aminosulfonamide (intermediate 17, 1.27 g, 10.99 mmol) was added, after the addition was completed, the reaction was stirred at room temperature for 4.5 hours; LCMS showed that the reaction was completed, then the reaction was quenched with water (20 mL), extracted with dichloromethane (40 mL*3), the organic phase was combined, concentrated under reduced pressure, and purified by column chromatography (V n-hexane:V ethyl acetate = 1:1) to obtain intermediate 18 (2.5 g, yield: 91%).

[0239] LCMS (ESI) m / z: 298 [M+H]+.

[0240] Step five:

[0241] Intermediate 18 (2.5 g, 8.41 mmol) was dissolved in methanol (20 mL), palladium hydroxide (590 mg, 4.20 mmol) was added at room temperature, after the addition was completed, the reaction liquid was stirred at room temperature for 16 hours under hydrogen atmosphere; LCMS monitoring reaction was completed, the reaction liquid was filtered with diatomite, washed with methanol, the filtrate was concentrated under reduced pressure to obtain intermediate 19 (1.62 g, yield: 100%).

[0242] LCMS (ESI) m / z: 194 [M+H]+

[0243] Step six:

[0244] Intermediate 7 (1.0 g, 2.63 mmol), intermediate 19 (762 mg, 3.94 mmol), t-BuBrettPhos PdG3 (2-amino-1,1'-biphenyl-2-yl)palladium(II), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl methanesulfonate, 67 mg, 78.90 μmol) and sodium tert-butoxide (758 mg, 7.89 mmol) were dissolved in 1,4-dioxane (10 mL) at room temperature, after the addition was completed, the reaction liquid was stirred in a 90°C oil bath under nitrogen protection for 6 hours; LCMS monitoring reaction was completed, the reaction liquid was cooled and filtered with diatomite, washed with ethyl acetate, the filtrate was concentrated under reduced pressure, purified by column chromatography (V dichloromethane:V methanol = 97:3) to obtain intermediate 20 (803 mg, yield: 61%).

[0245] LCMS (ESI) m / z: 493 [M+H]+.

[0246] Step seven:

[0247] Intermediate 20 (798 mg, 1.62 mmol) was dissolved in tetrahydrofuran (THF, 10 mL), 1N hydrochloric acid aqueous solution (1.8 mL, 1.78 mmol) was added dropwise at room temperature, after the addition was completed, the reaction liquid was raised to 60°C and stirred for 2 hours; LCMS monitoring reaction was completed; the reaction was lowered to room temperature, the pH was adjusted to about 14 with sodium hydroxide solution (2M), then extracted with ethyl acetate (40 mL*2), the organic phase was combined and concentrated under reduced pressure, purified by column chromatography (V dichloromethane:V methanol = 95:5) to obtain example 2 (550 mg, yield: 80%).

[0248] LCMS (ESI) m / z: 421 [M+H]+

[0249] 1H NMR (400 MHz, DMSO) δ 13.09 (s, 1H), 8.32 (d, J = 7.0 Hz, 2H), 8.12 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.76 - 6.60 (m, 3H), 4.54 (q, J = 7.0 Hz, 2H), 3.82 - 3.67 (m, 1H), 3.25 - 3.22 (m, 1H), 3.16 - 3.13 (m, 1H), 2.91 - 2.89 (m, 2H), 2.31 - 2.20 (m, 1H), 1.91 - 1.69 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H).

[0250] Example 3 (3R,4S)-4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl)amino)-3-fluoropiperidine-1 -sulfonamide

[0251] Step one:

[0252] Intermediate 21 (5.9 g, 27.16 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and S(-)-a-phenethylamine (intermediate 14, 4.94 g, 40.74 mmol) and N,N-diisopropylethylamine (DIEA, 5.27 g, 40.74 mmol) were added sequentially at room temperature. After stirring for 20 minutes, the reaction system was placed in an ice water bath at 0 °C, and sodium triacetylborohydride (STAB, 9.8 g, 46.24 mmol) was added in portions. After the addition was completed, the reaction system was slowly raised to room temperature and stirring was continued for 16 hours. After the reaction was confirmed to be complete by LC-MS monitoring, methanol (20 mL) was added to quench the reaction. The reaction solution was transferred to a separatory funnel, diluted with dichloromethane (100 mL), and then saturated sodium bicarbonate solution (50 mL) was slowly added dropwise, and stirred for 30 minutes. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL x 2). The combined organic phases were washed sequentially with saturated sodium bicarbonate solution (50 mL x 2) and saturated sodium chloride solution (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure concentration. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2:1, v / v) to obtain intermediate 22 (7.5 g, yield 85%).

[0253] LCMS (ESI) m / z: 322.2 [M+H]+.

[0254] Step two:

[0255] Intermediate 22 (6 g, 18.61 mmol) was dissolved in 1,4-dioxane (10.0 mL), and a solution of hydrochloric acid in 1,4-dioxane (4 N, 60 mL) was slowly added at room temperature (20 °C). After the addition was completed, the reaction system was stirred at 20 °C for 15 h. After the starting material was completely consumed as confirmed by LC-MS monitoring, the reaction solution was filtered, and the filter cake was collected. The filter cake was adjusted to a pH of about 14 with a 1 N sodium hydroxide solution, and then extracted with ethyl acetate (60 mL x 3). The organic phase was washed with saturated sodium chloride solution (30 mL x 2). After the organic phase was dried over anhydrous sodium sulfate, it was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 23 (4.1 g, yield 99%).

[0256] LCMS (ESI) m / z: 219.2 [M+H]+.

[0257] Step three

[0258] Intermediate 23 (4.1 g, 18.44 mmol) was dissolved in 1,4-dioxane (80 mL), and then sulfonamide (intermediate 11, 17.8 g, 184.43 mmol) was added. The reaction system was heated to 100 °C and stirred overnight (about 12 h). After the starting material was completely consumed as confirmed by LC-MS monitoring, the reaction solution was concentrated under reduced pressure to remove the solvent. Water (50 mL) and ethyl acetate (60 mL, 50 mL x 2) were added to the concentrated residue for extraction. The organic phase was washed with saturated sodium chloride solution (70 mL x 2). After the organic phase was dried over anhydrous sodium sulfate, it was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3:2, v / v) to obtain intermediate 24 (4.9 g, yield 88%).

[0259] LCMS (ESI) m / z: 302.1 [M+H]+.

[0260] Step four

[0261] Intermediate 24 (4.9 g, 16.26 mmol) was dissolved in methanol (20 mL), and palladium hydroxide (Pd(OH)2, 10 wt%, 456 mg, 325.17 µmol) and a hydrochloric acid / ethyl acetate solution (4.2 mL, 4 M) were sequentially added at room temperature. The reaction system was transferred to a hydrogen environment, and stirred at room temperature for 16 h. After the reaction was completed as confirmed by LC-MS monitoring, the reaction solution was filtered through diatomite, and the filter cake was washed with methanol. The filtrates were combined and concentrated under reduced pressure to about 5 g. Ethanol (10 mL) was added to the concentrate, and stirred for 2 h to precipitate a white solid. The solid was collected by filtration and dried to obtain the hydrochloride form of intermediate 25 (2.5 g, yield 65%).

[0262] LCMS (ESI) m / z: 198.1 [M+H]+

[0263] Step five:

[0264] Intermediate 7 (500 mg, 1.31 mmol), intermediate 25 (460 mg, 1.97 mmol), t-BuBrettPhos Pd G3 (34 mg, 39.45 µmol) and sodium tert-butoxide (631 mg, 6.57 mmol) were sequentially dissolved in anhydrous 1,4-dioxane (10 mL) at room temperature. The reaction system was transferred to a nitrogen atmosphere, heated to 90 °C in an oil bath and stirred for 6 hours. After confirming the completion of the reaction by LC-MS monitoring, the reaction was cooled to room temperature, filtered through diatomite, and the filter cake was washed with ethyl acetate. The filtrates were combined and the solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 97:3, v / v) to obtain intermediate 26 (456 mg, yield 69%) as a yellow solid.

[0265] LCMS (ESI) m / z: 497.2 [M+H]+.

[0266] Step six:

[0267] Intermediate 26 (456 mg, 918.31 µmol) was dissolved in tetrahydrofuran (10 mL), and aqueous hydrochloric acid (2 mL, 1M) was slowly added dropwise at room temperature. After the dropwise addition was completed, the reaction system was heated to 60 °C and stirred for 2 hours. After confirming the completion of the reaction by LC-MS monitoring, the reaction was cooled to room temperature, and the pH was adjusted to about 14 with sodium hydroxide solution (2M). Then extracted with ethyl acetate (40 mL x 2), the organic phase was combined, and the solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 95:5, v / v) to obtain the target compound Example 3 (280 mg, yield: 71%).

[0268] LCMS (ESI) m / z: 425.2 [M+H]+

[0269] 1H NMR (400 MHz, DMSO) δ 13.14 (s, 1H), 8.26 (t, J = 43.4 Hz, 3H), 7.20 (d, J = 7.0 Hz, 1H), 6.92 - 6.65 (m, 3H), 5.05 (d, J = 48.7 Hz, 1H), 4.55 (q, J = 7.0 Hz, 2H), 3.87 - 3.66 (m, 2H), 3.55 - 3.52 (d, J = 11.3 Hz, 1H), 2.87 (dd, J = 37.0, 13.0 Hz, 1H), 2.73 (d, J = 9.7 Hz, 1H), 1.89 (s, 2H), 1.35 (t, J = 7.0 Hz, 3H).

[0270] Example 4 4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N- dimethylpiperidine-1 -sulfonamide

[0271] Step one

[0272] Intermediate 27 (5.0 g, 24.96 mmol) was dissolved in anhydrous dichloromethane (20 mL), triethylamine (5.05 g, 37.45 mmol) was added, then the reaction system was placed in an ice water bath at 0 °C. Dimethylamine sulfonyl chloride (intermediate 28, 5.38 g, 49.93 mmol) was slowly added under stirring. After the addition was completed, the reaction system was restored to room temperature and stirred for 16 hours. After confirming the completion of the reaction by LC-MS monitoring, the reaction was quenched by adding water (20 mL) to the reaction solution, and extracted with dichloromethane (20 mL x 3). The organic phases were combined and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2:1, v / v) to obtain intermediate 29 (5.3 g, yield 69%) as a colorless liquid.

[0273] LCMS (ESI) m / z: 308.2 [M+H]+.

[0274] Step two

[0275] Intermediate 29 (2.0 g, 6.51 mmol) was dissolved in 1,4-dioxane (10 mL), and a hydrochloric acid / 1,4-dioxane solution (10 mL, 4M) was added under the condition of an ice water bath at 0 °C. After the addition was completed, the reaction solution was stirred at room temperature for 16 hours; after the reaction was completed by LCMS monitoring, ether (20 mL) was added to the reaction solution and stirred for 10 minutes, then filtered, washed with ether, and the filter cake was dried to obtain intermediate 30 (980 mg, yield: 61%) as a white solid.

[0276] LCMS (ESI) m / z: 208.1 [M+H]+.

[0277] Step three

[0278] Intermediate 7 (1 g, 2.63 mmol), intermediate 30 (960 mg, 3.94 mmol), t-BuBrettPhos Pd G3 (112 mg, 131.49 µmol, 5 mol%) and sodium tert-butoxide (1.25 g, 13.15 mmol) were sequentially dissolved in anhydrous 1,4-dioxane (15 mL) at room temperature. The reaction system was transferred to nitrogen protection, heated to 90°C and stirred for 10 hours. After confirming the completion of the reaction by LC-MS monitoring, the reaction was cooled to room temperature, filtered through diatomite, and the filter cake was washed with ethyl acetate. The filtrate was combined and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 97:3, v / v) to obtain intermediate 31 (958 mg, yield 71%) as a yellow solid.

[0279] LCMS (ESI) m / z: 507.2 [M+H]+.

[0280] Step four

[0281] Intermediate 31 (958 mg, 1.89 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and 1M aqueous hydrochloric acid (5.6 mL, 5.67 mmol) was slowly added dropwise at room temperature. After the dropwise addition was completed, the reaction system was heated to 60°C and stirred for 2 hours. After confirming the completion of the reaction by LC-MS monitoring, the reaction was cooled to room temperature, and the pH was adjusted to 14 with sodium hydroxide solution (2M). Then extracted with ethyl acetate (30 mL x 2), combined the organic phase, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 95:5, v / v) to obtain the target compound Example 4 (660 mg, yield 80%).

[0282] LCMS (ESI) m / z: 435.2 [M+H]+

[0283] 1H NMR (400 MHz, DMSO) δ 13.11 (s, 1H), 8.32 (d, J = 7.0 Hz, 2H), 8.13 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 3.71 - 3.60 (m, 1H), 3.60 - 3.51 (m, 2H), 3.06 - 2.95 (m, 2H), 2.76 (s, 6H), 2.05 - 1.94 (m, 2H), 1.61 - 1.47 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H).

[0284] Example 5 (3R, 4S)-4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl)amino)-N,3-dimethylpiperidine-1 -sulfonamide

[0285] Using the same experimental procedure as in Example 2, substituting N- methylaminosulfonyl chloride (CAS: 10438-96-7) for intermediate 17, gave the title compound.

[0286] LCMS (ESI) m / z: 435.2 [M+H]+

[0287] 1H NMR (400 MHz, DMSO) δ 13.09 (s, 1H), 8.32 (d, J = 4.0 Hz, 2H), 8.12 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.04 - 6.99 (m, J = 4.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.54 (q, J = 6.7 Hz, 2H), 3.84 - 3.78 (m, 1H), 3.29 - 3.18 (m, 2H), 3.04 - 3.01 (m, 2H), 2.54 (d, J = 4.0 Hz, 3H), 2.22 - 2.17 (m, 1H), 1.87 - 1.69 (m, 2H), 1.35 (t, J = 6.0 Hz, 3H), 0.93 (d, J = 8.0 Hz, 3H).

[0288] Example 6 (3R, 4S)-4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl)amino)-N-ethyl-3-methylpiperidine-1 -sulfonamide

[0289] Using the same experimental procedure as in Example 2, substituting N- ethylaminosulfonyl chloride (CAS: 16548-07-5) for intermediate 17, gave the title compound.

[0290] LCMS (ESI) m / z: 449.2 [M+H]+

[0291] 1H NMR (400 MHz, DMSO) δ 13.09 (s, 1H), 8.31 (d, J = 7.0 Hz, 1H), 8.22 (s, 2H), 7.14 (t, J = 14.7 Hz, 2H), 6.73 (d, J = 8.0 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 3.86 - 3.75 (m, 1H), 3.29 - 3.15 (m, 2H), 3.07 - 2.88 (m, 4H), 2.25 - 2.13 (m, 1H), 1.90 - 1.62 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H).

[0292] Example 7 (3R)-4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl)amino)-N,N,3-trimethylpiperidine-1 -sulfonamide

[0293] Using the same experimental method as Example 2, intermediate 17 was replaced by dimethylsulfamoyl chloride (CAS: 13360-57-1) to synthesize.

[0294] LCMS (ESI) m / z: 449.2 [M+H]+

[0295] 1H NMR (400 MHz, DMSO) δ 13.10 (s, 1H), 8.38 - 8.24 (m, 2H), 8.12 (s, 1H), 7.16 (d, J = 7.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 3.88 - 3.82 (m, 1H), 3.38 - 3.35 (m, 1H), 3.31 - 3.26 (m, 1H), 3.22 - 3.11 (m, 2H), 2.78 (s, 6H), 2.18 - 2.13 (m, 1H), 1.85 - 1.65 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H).

[0296] Example 8 (3R)-4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl)amino)-N,N,3-trimethylpiperidine-1 -sulfonamide

[0297] Using the same experimental method as Example 2, N-(trideuteromethyl)sulfamoyl chloride (CAS: 3002057-21-5) was used to replace intermediate 17 to synthesize to give.

[0298] LCMS (ESI) m / z: 438 [M+H]+

[0299] 1H NMR (400 MHz, DMSO) δ 13.09 (s, 1H), 8.32 (d, J = 4.0 Hz, 2H), 8.12 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.04 - 6.99 (m, J = 4.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.54 (q, J = 6.7 Hz, 2H), 3.84 - 3.78 (m, 1H), 3.29 - 3.18 (m, 2H), 3.04 - 3.01 (m, 2H), 2.22 - 2.17 (m, 1H), 1.87 - 1.69 (m, 2H), 1.35 (t, J = 6.0 Hz, 3H), 0.93 (d, J = 8.0 Hz, 3H).

[0300] Using the experimental method described in Example 3, appropriate starting materials were selected to prepare Examples 9-11

[0301] Example 9 4-((8-Ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-3-fluoro-N-methylpiperidine-1-sulfonamide

[0302] LCMS (ESI) m / z: 439 [M+H]+

[0303] 1H NMR (400 MHz, DMSO) δ 13.08 (s, 1H), 8.27 (t, J = 43.4 Hz, 3H), 8.01 (d, J = 7.0 Hz, 1H), 6.80 - 6.60 (m, 3H), 5.21 (d, J = 48.7 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 4.05 - 3.91 (m, 2H), 3.55 - 3.52 (d, J = 11.3 Hz, 1H), 2.87 (dd, J = 37.0, 13.0 Hz, 1H), 2.73 (d, J = 9.7 Hz, 1H), 2.58 (d, J = 7.0 Hz, 3H), 2.25 - 1.88 (m, 2H), 1.42 (t, J = 7.0 Hz, 3H).

[0304] Example 10 4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N- ethyl-3-fluoropiperidine-1 -sulfonamide

[0305] LCMS (ESI) m / z: 453 [M+H]+

[0306] 1 H NMR (500 MHz, Chloroform-d) δ 8.79 (d, J = 7.1 Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.01 (dd, J = 3.4, 1.7 Hz, 1H), 7.81 (d, J = 7.1 Hz, 1H), 6.44 (t, J = 6.2 Hz, 1H), 6.27 (d, J = 7.0 Hz, 1H), 5.25 (m, J = 4.3 Hz), 4.25 (m, J = 6.6, 1.4 Hz), 4.05 (m, J = 25.1, 7.0, 5.7, 4.6 Hz, 1H), 3.53 (m, J = 25.3, 12.5, 4.2 Hz, 1H), 3.45 - 3.38 (m, 1H), 3.42 - 3.32 (m, 1H), 3.19 (m, J = 12.3, 10.3, 7.7 Hz, 1H), 2.93 (m, J = 7.4, 6.1 Hz, 2H), 2.14 (m, J = 12.5, 10.4, 7.7, 5.8 Hz, 1H), 1.99 (m, J = 12.3, 10.4, 7.7, 5.8 Hz, 1H), 1.42 (t, J = 6.6 Hz, 3H), 1.24 (t, J = 7.3 Hz, 3H).

[0307] Example 11 4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-3- fluoro-N-(methyl-d3)piperidine-1 -sulfonamide

[0308] LCMS (ESI) m / z: 442 [M+H]+

[0309] 1H NMR (400 MHz, DMSO) δ 13.08 (s, 1H), 8.27 (t, J = 43.4 Hz, 3H), 8.01 (d, J = 7.0 Hz, 1H), 6.80 - 6.60 (m, 3H), 5.21 (d, J = 48.7 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 4.05 - 3.91 (m, 2H), 3.55 - 3.52 (d, J = 11.3 Hz, 1H), 2.87 (dd, J = 37.0, 13.0 Hz, 1H), 2.73 (d, J = 9.7 Hz, 1H), 2.25 - 1.88 (m, 2H), 1.42 (t, J = 7.0 Hz, 3H).

[0310] Prepared according to the synthetic protocol described in Example 4 using the appropriate starting materials to give Examples 12-21

[0311] Example 12 4-((8-Ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N- methylpiperidine-1 -sulfonamide

[0312] LCMS (ESI) m / z: 421 [M+H]+

[0313] 1 1H NMR (400 MHz, DMSO) δ 13.11 (s, 1H), 8.32 (d, J = 7.0 Hz, 2H), 8.13 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 3.71 - 3.60 (m, 1H), 3.60 - 3.51 (m, 2H), 3.06 - 2.95 (m, 2H), 2.66 (s, 3H), 2.05 - 1.94 (m, 2H), 1.61 - 1.47 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H).

[0314] Example 13 4-((8-Ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N- ethylpiperidine-1 -sulfonamide

[0315] LCMS (ESI) m / z: 435 [M+H]+

[0316] 1H NMR (400 MHz, DMSO) δ 13.09 (s, 1H), 8.33 - 8.22 (m, 3H), 7.14 (t, J = 16.1 Hz, 2H), 6.73 (d, J = 8.0 Hz, 1H), 4.69 (s, 1H), 4.53 (q, J = 7.0 Hz, 2H), 3.86 - 3.75 (m, 1H), 3.47 - 3.43 (m, 2H), 3.30 - 3.14 (m, 2H), 3.04 - 2.93 (m, 3H), 2.24 - 2.15 (m, 1H), 1.88 - 1.67 (m, 2H), 1.36 (t, J = 7.0 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H).

[0317] Example 14 4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-(methyl-d3)piperidine-1-sulfonamide

[0318] LCMS (ESI) m / z: 424 [M+H]+

[0319] 1 H NMR (400 MHz, DMSO) δ 13.11 (s, 1H), 8.32 (d, J = 7.0 Hz, 2H), 8.13 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 4.53 (q, J = 7.0 Hz, 2H), 3.71 - 3.60 (m, 1H), 3.60 - 3.51 (m, 2H), 3.06 - 2.95 (m, 2H), 2.05 - 1.94 (m, 2H), 1.61 - 1.47 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H).

[0320] Example 15 8-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N-dimethyl-5-azaspiro[2.5]octane-5-sulfonamide

[0321] LCMS (ESI) m / z: 461 [M+H]+

[0322] 1H NMR (500 MHz, Methanol-d4) δ 8.80 (d, J = 7.1 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.01 (m, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 4.9 Hz, 1H), 4.24 (m, 2H), 4.08 (m, 1H), 3.44 - 3.28 (m, 2H), 3.20 (m, 1H), 2.98 (d, J = 12.4 Hz, 1H), 2.80 (s, 6H), 2.01 - 1.74 (m, 2H), 1.39 (t, J = 6.6 Hz, 3H), 1.27 - 1.08 (m, 2H), 0.85 - 0.67 (m, 2H).

[0323] Example 16 9-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N- dimethyl-6-azaspiro[3.5]nonane-6-sulfonamide

[0324] LCMS (ESI) m / z: 475 [M+H]+

[0325] 1 H NMR (500 MHz, Methanol-d4) δ 8.80 (d, J = 7.1 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.01 (dd, J = 3.4, 1.7 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 5.7 Hz, 1H), 4.27 - 4.21 (m, 2H), 4.15 - 4.11 (m, 1H), 3.49 (d, J = 12.3 Hz, 1H), 3.44 - 3.37 (m, 1H), 3.23 - 3.16 (m, 1H), 2.80 (d, J = 1.1 Hz, 6H), 1.97 - 1.89 (m, 1H), 1.87 - 1.71 (m, 3H), 1.70 - 1.53 (m, 4H), 1.39 (t, J = 6.6 Hz, 3H).

[0326] Example 17 5-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N- dimethyl-2-azabicyclo[4.1.0]heptane-2-sulfonamide

[0327] LCMS (ESI) m / z: 447 [M+H]+

[0328] 1H NMR (500 MHz, Methanol-d4) δ 8.80 (d, J = 7.1 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.01 (dd, J = 3.4, 1.7 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 4.9 Hz, 1H), 4.27 - 4.21 (m, 2H), 4.03 - 3.98 (m, 1H), 3.81 (td, J = 6.9, 6.1 Hz, 1H), 3.52 - 3.45 (m, 1H), 3.40 - 3.31 (m, 1H), 2.78 (s, 6H), 2.28 - 2.08 (m, 2H), 1.93 - 1.79 (m, 2H), 1.72 - 1.66 (m, 1H), 1.39 (t, J = 6.6 Hz, 3H).

[0329] Example 18 4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N- dimethyloctahydro-1H-cyclopenta[b]pyridine-1 -sulfonamide

[0330] LCMS (ESI) m / z: 475 [M+H]+

[0331] 1 H NMR (500 MHz, Methanol-d4) δ 8.80 (d, J = 7.1 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.01 (dd, J = 3.4, 1.7 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.10 (d, J = 6.4 Hz, 1H), 4.30 - 4.15 (m, 2H), 4.09 - 3.98 (m, 1H), 3.71 (q, J = 5.2 Hz, 1H), 3.53 - 3.42 (m, 1H), 3.33 - 3.26 (m, 1H), 2.78 (s, 6H), 2.61 (dd, J = 6.6, 5.3 Hz, 1H), 2.08 - 1.77 (m, 4H), 1.74 - 1.51 (m, 4H), 1.39 (t, J = 6.6 Hz, 3H).

[0332] Example 19 5-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N- dimethyl-2-azabicyclo[2.2.1]heptane-2-sulfonamide

[0333] LCMS (ESI) m / z: 447 [M+H]+

[0334] 1 H NMR (500 MHz, Methanol-d4) δ 8.80 (d, J = 7.1 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.01 (dd, J = 3.4, 1.7 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.03 (d, J = 5.1 Hz, 1H), 4.28 - 4.16 (m, 3H), 3.96 - 3.90 (m, 1H), 3.61 (dd, J = 12.4, 2.7 Hz, 1H), 2.96 (dd, J = 12.5, 2.6 Hz, 1H), 2.78 (s, 6H), 2.66 (dt, J = 5.4, 2.7 Hz, 1H), 2.21 - 2.15 (m, 1H), 2.09 - 2.01 (m, 1H), 1.90 - 1.78 (m, 2H), 1.39 (t, J = 6.6 Hz, 3H).

[0335] Example 20 5-((8-Ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N- dimethyl-2-azabicyclo[2.2.2]octane-2-sulfonamide

[0336] LCMS (ESI) m / z: 461 [M+H]+

[0337] 1 H NMR (500 MHz, Methanol-d4) δ 8.80 (d, J = 7.1 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.01 (dd, J = 3.4, 1.7 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.13 (d, J = 5.9 Hz, 1H), 4.28 - 4.20 (m, 2H), 4.11 - 4.16 (m, 1H), 3.77 - 3.84 (m, 1H), 3.67 (dd, J = 12.4, 4.3 Hz, 1H), 2.90 (dd, J = 12.5, 4.2 Hz, 1H), 2.78 (s, 6H), 2.65 - 2.58 (m, 1H), 2.38 - 2.31 (m, 1H), 2.14 - 2.07 (m, 1H), 1.98 - 1.83 (m, 2H), 1.75 - 1.60 (m, 2H), 1.39 (t, J = 6.6 Hz, 3H).

[0338] Example 21 N-(1-(Aziridin-1-ylsulfonyl)piperidin-4-yl)-8-ethoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine

[0339] LCMS (ESI) m / z: 433 [M+H]+

[0340] 1 H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J = 7.1 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.01 (dd, J = 3.4, 1.7 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.38 (d, J = 6.4 Hz, 1H), 4.27 - 4.21 (m, 2H), 3.96 - 3.88 (m, 1H), 3.45 - 3.37 (m, 2H), 3.19 - 3.10 (m, 6H), 1.92 - 2.02 (m, 2H), 1.84 - 1.75 (m, 2H), 1.39 (t, J = 6.6 Hz, 3H).

[0341] Example 22 4-((8-(2-hydroxyethoxy)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl)amino)-N,N-dimethylpiperidine-1 -sulfonamide

[0342] LCMS (ESI) m / z: 451 [M+H]+

[0343] 1 H NMR (400 MHz, DMSO) δ 13.08 (s, 1H), 8.38 - 8.32 (m, 3H), 7.20 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.10 (s, 1H), 4.51 (t, J = 6.0 Hz, 1H), 3.77 (d, J = 4.0 Hz, 2H), 3.67 - 3.54 (m, 3H), 3.04 - 2.97 (m, 2H), 2.77 (m, 6H), 2.02 - 1.97 (m, 2H), 1.58 - 1.50 (m, 2H).

[0344] Example 23 4-((8-(cyanomethoxy)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl)amino)-N,N-dimethylpiperidine-1 -sulfonamide

[0345] LCMS (ESI) m / z: 446 [M+H]+

[0346] 1H NMR (400 MHz, DMSO) δ 13.21 (s, 1H), 8.44 (d, J = 7.0 Hz, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.24 (d, J = 7.1 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 5.62 (s, 2H), 3.67 (tt, J = 13.9, 7.0 Hz, 1H), 3.58 (dd, J = 9.2, 3.5 Hz, 2H), 3.06 - 2.96 (m, 2H), 2.77 (s, 6H), 2.01 (dd, J = 13.6, 3.7 Hz, 2H), 1.60 - 1.49 (m, 2H).

[0347] Example 24 4-((8-(2-methoxyethoxy)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl)amino)-N,N-dimethylpiperidine-1 -sulfonamide

[0348] LCMS (ESI) m / z: 465 [M+H]+

[0349] 1 H NMR (400 MHz, DMSO) δ 13.07 (s, 1H), 8.45 (s, 1H), 8.32 (d, J = 4.0 Hz, 1H), 8.18 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 4.65 - 4.63 (m, 2H), 3.70 - 3.55 (m, 5H), 3.32 (s, 3H), 3.04 - 2.97 (m, 2H), 2.77 (s, 6H), 2.02 - 1.97 (m, 2H), 1.58 - 1.49 (m, 2H).

[0350] Example 25 4-(8-(2-(dimethylamino)ethoxy)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl)amino)-N,N-dimethylpiperidine-1 -sulfonamide

[0351] LCMS (ESI) m / z: 478 [M+H]+

[0352] 1H NMR (400 MHz, DMSO) δ 13.21 (s, 1H), 8.44 (d, J = 7.0 Hz, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.24 (d, J = 7.1 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 5.62 (s, 2H), 3.67 (tt, J = 13.9, 7.0 Hz, 1H), 3.58 (dd, J = 9.2, 3.5 Hz, 2H), 3.06 - 2.96 (m, 2H), 2.77 (s, 6H), 2.01 (dd, J = 13.6, 3.7 Hz, 2H), 1.60 - 1.49 (m, 2H).

[0353] Experimental Example 1: Testing of compounds on CDK2 / 1 enzyme activity at molecular level

[0354] The testing of CDK2 / 1 enzyme activity tests the inhibition of CDK enzyme catalyzed phosphorylation by compounds using Mobility Shift Assay (MSA).

[0355] Preparation of compounds in the testing of CDK1: The compound is diluted 10 times with DMSO (the storage concentration of the compound is 10 mM, and the concentration is 1 mM at this time, which is the highest concentration point), and 4 times gradient dilution is carried out in DMSO with the highest concentration point as the first point, and there are 10 gradients in total.

[0356] Preparation of compounds in the testing of CDK2: The compound is diluted 2000 times with DMSO (the storage concentration of the compound is 10 mM, and the concentration is 5 μM at this time, which is the highest concentration point), and 4 times gradient dilution is carried out in DMSO with the highest concentration point as the first point, and there are 10 gradients in total.

[0357] Take 6 μL of the above prepared 10 gradient samples into 44 μL of ddH2O, transfer 2 μL to a 384-well analysis plate (the final test concentration, the test concentration range of CDK1 is 20 μM to 0.076 nM, and the test concentration range of CDK2 is 100 nM to 0.0004 nM, 0.015 nM CDK2 / Cyclin E1 (Biortus) working solution 5 μL or 0.01 nM CDK1 / Cyclin B1 (Biortus) working solution 5 μL is added to each well, pre-incubated for 30 min, 5 μL of substrate mixture (2 μM CDK7tide and 2 mM adenosine triphosphate) is added to each well (scilight-peptide and VWR), incubated at 27°C for 70 min, quenched with 4 μL of 150 mM EDTA, and the values are read on a Caliper EZ Reader II. IC 50Values were obtained by fitting using PRISM software and log(inhibitor) vs response-Variable slope model.

[0358] The compounds of the present application have strong catalytic inhibition ability on CDK2 / Cyclin E1, and better selectivity on CDK1 / CDK2. Specifically, the compounds have stronger catalytic inhibition ability on CDK2 / Cyclin E1 than the reference PF07104091, INC-Ref, Examples 1 and 4. Meanwhile, the selectivity data on CDK1 / Cyclin B1 show that the compounds have higher selectivity than PF07104091 and INC-Ref. See Table 1 below.

[0359] Table 1

[0360] *INC-Ref is the compound disclosed in the patent WO 2023172921 Al of Incyte

[0361] The above experiment was repeated, and PF07104091 was replaced with the compounds of Examples 22-25, and fresh preparation was used. See Table 2 below.

[0362] Table 2

[0363] Experimental Example 2: Test of affinity of compounds on CDK2, CDK1 at cell level

[0364] The method of NanoBRET was used to detect the affinity of the compound to CDK2, CDK1 at the cellular level. NanoLuc fusion protein CDK1 (NV2701, 1 pg / pL) or CDK2 (NV2781, 1 pg / pL) and CCNB1 expression vector (NV2601, 1 pg / pL) or CCNE1 expression vector (NV2641, 1 pg / pL) were transiently transfected into HEK 293 cells (ATCC, CRL-1573): 1 pg NanoLuc fusion protein and 9 pg expression vector were added to 1 mL of culture medium (opti-MEM) and mixed well with 20 mL of cell culture medium. Plate in 384-well and incubate overnight, add different dilutions of compound or tracer (Promega, N2640), the compound is diluted with DMSO, 4-fold dilution, 10 concentration gradients, add 2.5 pL of intermediate concentration of compound to each well, the final compound concentration of CDK1 ranges from 10 pM to 0.0381 nM, the final compound concentration of CDK2 ranges from 100 nM to 0.0004 nM, the final DMSO concentration is 0.1%; the tracer DMSO stock solution is diluted with tracer dilution buffer (Promega, N2640), add 2.5 pL of tracer dilution to each well to make the final concentration of tracer 0.5 pM and the final concentration of DMSO 1%, incubate in a 37°C 5% CO2 incubator for 2 hours, add 3X NanoBRET Nano-Glo substrate (Promega, N2160) 60 pM, 25 pL per well, use Envision instrument (2105) to measure the donor signal at 450 nm and the acceptor signal at 610 nm, divide the acceptor emission value (650 nm) by the donor emission value (460 nm) of each sample to generate the original BRET ratio value, after background correction, convert to mBU value = [(acceptor sample / donor sample) - (acceptor no tracer control / donor no tracer control)] x 1000. Calculate the inhibition rate = (mBU_AVE of negative controls - mBU_sample) / (mBU_negative control - mBU_AVE of positive control) * 100. 50 The IC50values were obtained by using PRISM software and fitting with the log(inhibitor) vs response-Variable slope model, see Table 3 below.

[0365] The above experiment was repeated using freshly prepared PF07104091, INC-Ref, together with Example 13 and Example 4, the above experiment was repeated twice, and the average of the two experiments was taken. See Table 4 below for details.

[0366] In summary, the compounds of this application exhibit strong catalytic inhibition of CDK2 / Cyclin E1 and good selectivity for CDK1 / CDK2. Specifically, compared with reference PF07104091, INC-Ref, the test compounds show strong catalytic inhibition of CDK2 / Cyclin E1 and high selectivity for CDK1 / Cyclin B1.

[0367] Table 3

[0368] Table 4

[0369] Experimental Example 3: Assay of the enzyme activity of compounds against CDK4 at the molecular level

[0370] use The method detects the inhibition of CDK4 enzyme activity by compounds at the molecular level. In white OptiPlates... TM In a -384 microplate, add 10 μL of kinase reaction mixture to each well. This mixture includes 0.5 nM CDK4 / Cyclin D1 (Invitrogen, Cat. No. PV4436), 50 nM substrate (PerkinElmer, Cat. No. TRF0128-M), and pre-diluted compounds of varying concentrations mixed in a buffer solution (50 mM HEPES (pH 7.5), 0.01% Brij-35, 10 mM MgCl2, 1 mM EDTA, 1 mM DTT dissolved in ddH2O). Pre-incubate for 15 minutes to achieve a final compound concentration range of 10 μM to 0.1694 nM. Add 350 μM ATP working solution (the above buffer solution) to initiate the reaction and incubate at room temperature for 60 minutes. After the reaction was complete, LANCE Eu-anti-P-4E-BP1 antibody (PerkinElmer, Cat. No. TRF0216-M) was added for detection. After incubation at room temperature for 60 minutes, the fluorescence signal was detected at 665 nm using Envision, and data were collected. CDK4 enzyme activity was calculated based on the fluorescence signal intensity. The signal intensity is proportional to the degree of substrate phosphorylation, thus reflecting the inhibition of CDK4 enzyme activity. The IC50 values ​​were obtained using PRISM software and fitted with a log(inhibitor) vs response-variable slope model, as shown in Table 5 below.

[0371] The compounds in this application exhibit strong catalytic inhibition of CDK4 / Cyclin D1, demonstrating excellent inhibitory activity. Specifically, the tested compounds show strong catalytic inhibition of CDK4 / Cyclin D1, with inhibitory activity comparable to that of the CDK4 / 6 inhibitor Palbociclib.

[0372] Table 5

[0373] Experimental Example 4: Anti-proliferative activity test of compounds on CDK2 dependent human ovarian tumor cells

[0374] The anti-proliferative test of compounds on human ovarian cancer cells was detected by CyQUANT method. OVCAR-3 cells were purchased from ATCC (HTB-161™), and the cells were recovered. After the cell state was stable, the cells were collected, and the viable cell count was greater than 90%. 500 cells were seeded into a 384-well plate. The next day, an equal proportion dilution series of the compound was added, with a 3-fold gradient dilution, a total of 10 gradient concentrations. 400 nL of the diluted compound was transferred to a 384-well plate containing 39.6 μL of medium and mixed well. The final concentration range was 10,000 nM to 0.51 nM. The blank control well only contained medium without cells, and the solvent control well contained 0.1% DMSO (total volume of 40 μL per well). After incubation for 6 days, on the 7th day, 400 rpm centrifugation for 30 seconds, the supernatant was removed, and 25 μL of NF dye reagent (Invitrogen, C35006) diluted 501 times with HBSS buffer was added. Incubation was carried out at 37°C for 60 minutes in the dark. Envision reading: excitation wavelength of 485 nm, emission detection wavelength of 530 nm. The inhibition rate (IR) was calculated: IR (%) = (1 - (RLU compound - RLU blank control) / (RLU solvent control - RLU blank control)) * 100%. IC values were obtained by fitting using PRISM software and in the log(inhibitor) vs response-Variable slope model, see Table 6 below. 50

[0375] The anti-proliferative activity of the compounds of the present application on CDK2 dependent human ovarian cancer cells OVCAR3 is better. Specifically, the anti-proliferative activity of the test compounds on CDK2 dependent human ovarian cancer cells OVCAR3 is stronger than that of the reference PF07104091, INC-Ref.

[0376] Table 6

[0377] Experimental Example 5: Anti-proliferative activity test of compounds on CDK4 dependent human breast cancer cells

[0378] The anti-proliferative test of compounds on human breast cancer cells was detected by ATP-based ​CellTiter-Glo® Luminescent Cell Viability Assay. The MCF-7 cells (Nanjing Keye, CBP60380) were routinely resuscitated, and when the cell state was stable, the cells were collected, and the viable cell count was greater than 90%. 1500 cells were seeded into a 96-well plate, and the next day, an equal dilution series of concentrations of the compound of the example (the highest concentration was 10 μM, with a 4-fold dilution, a total of 8 concentrations) was added. The Max well was added with buffer only, and the Min well was added with 20 μM Capivasertib (Selleck, S8019). Incubation was performed for 6 days, and on the 7th day, 50 μL of CellTiter-Glo® Luminescent Cell Viability Assay. The MCF-7 cells (Nanjing Keye, CBP60380) were routinely resuscitated, and when the cell state was stable, the cells were collected, and the viable cell count was greater than 90%. 1500 cells were seeded into a 96-well plate, and the next day, an equal dilution series of concentrations of the compound of the example (the highest concentration was 10 μM, with a 4-fold dilution, a total of 8 concentrations) was added. The Max well was added with buffer only, and the Min well was added with 20 μM Capivasertib (Selleck, S8019). Incubation was performed for 6 days, and on the 7th day, 50 μL of

[0379] The compound of the present application has better anti-proliferative activity on CDK4-dependent human breast cancer cells. Specifically, compared with the CDK4 / 6 inhibitor Palbociclib, the test compound has stronger anti-proliferative activity on MCF-7.

[0380] Table 7

[0381] Experimental Example 6: Anti-tumor effect of the compound on a human ovarian cancer cell OVCAR3 transplanted tumor mouse model

[0382] Further in vivo verification was performed on Example 4, and a CDK2-dependent OVCAR3 cell line mouse subcutaneous transplanted tumor model was selected. Human ovarian cancer cells OVCAR3 (ATCC, HTB-161) were cultured in a single layer in vitro, and the culture conditions were RPMI1640 culture medium with 20% fetal bovine serum, 1% penicillin-streptomycin solution, 0.01 mg / mL bovine insulin, and 37°C 5% CO2 incubator. Routine digestion treatment was performed with trypsin-EDTA twice a week. When the cell saturation was 80%-90%, the cells were collected, counted, and 0.2 mL of 1x107 OVCAR3 cells were subcutaneously inoculated into the right back of each mouse (PBS: Matrigel = 1:1). When the average tumor volume reached 149 mm3, the grouping and drug administration were started, and the day was set as Day 0. The tumor volume and mouse body weight were monitored twice a week, and the drug treatment was performed for 28 days.

[0383] Tumor diameters were measured with vernier caliper. The tumor volume was calculated by the formula: V=0.5a x b2, where a and b represent the long diameter and short diameter of the tumor, respectively. The antitumor efficacy of the compounds was evaluated by the relative tumor shrinkage rate Reg%. Reg% reflects the ratio of tumor volume shrinkage after treatment. Reg%=(V0-Vt) / V0 x 100%, where V0 is the tumor volume measured at the time of grouping (i.e. d0), and Vt is the tumor volume at a certain measurement time.

[0384] Statistical analysis was performed using Prism software, including the mean (Mean) and standard error (SEM) of tumor volume at each time point for each group. For statistical analysis of TV, the original data of TV at each measurement were used for comparison of differences between groups, and two-way ANOVA was used to analyze the double factors of administration and time. Tukey's multiple comparisons test was used for testing, and p<0.05 was considered to be statistically significant.

[0385] The compounds of the present application have better inhibitory effect on human ovarian cancer cell OVCAR3 xenografts. Specifically, the results are shown in Figures 1 and 2, where “*”, p<0.05; “**”, p<0.01; “***”, p<0.001; “****”, p<0.0001. Comparison between multiple groups was performed by two-way ANOVA (Tukey). Compared with the reference PF07104091, INC-Ref, the inhibitory effect of the compound of Example 4 on tumor growth is the strongest at the same dose. The body weight change of each treatment group is not obvious, indicating that the mice have good tolerance.

[0386] Inhibition of downstream target points in tumor tissues by the compound of Experimental Example 7

[0387] After treatment of the OVCAR3 cell line subcutaneous xenograft model in each treatment group for 28 days, the tumor tissues were collected to detect the expression levels of pRB(S780), pRB(S807 / 811), pRB(T821) and total-Rb proteins in OVCAR-3 tumor tissue samples.

[0388] About 50-100 mg of frozen tumor tissue was placed on dry ice, 350 μL of complete cell lysis solution (containing 1% protease inhibitors and phosphatase inhibitors) was added, the tissue was broken up using a Tissue grinder for 5 minutes, and the tissue lysate was placed on ice for 30 minutes. Centrifugation was performed at 12,000 rpm, 4°C for 10 minutes, the supernatant was taken and placed in a new 1.5 mL centrifuge tube, protein quantification was performed using a BCA quantitative kit, according to the quantitative results, the sample protein concentration was uniformly adjusted to 2 μg / μL, and LDS loading buffer (4X) and sample reducing agent (10X) were added, the sample was heated at 100°C for 10 minutes. Western blotting was carried out, 10 μL was loaded per well in the SDS-PAGE gel, electrophoresis was carried out at 80 volts for 30 minutes, and then at 120 volts for 90 minutes, membrane transfer was carried out using an iBlot2 membrane transfer kit and a membrane transfer instrument for 7 minutes, the membrane was cut according to the molecular weight of the protein to be detected, the membrane was washed with 1xTBST for 3 times, 5 minutes each time, primary antibody Phospho-Rb(Ser807 / 811)(CST, 8516S), Phospho-Rb(Ser780)(CST, 8180S), Phospho-Rb(T821)(CST, 32015), Total Rb(CST, 9313S), and β-Actin Antibody(CST, 4967s) were added and incubated at 4°C overnight, the membrane was washed with 1xTBST for 3 times, 10 minutes each time, secondary antibody Goat anti-Rabbit IgG-HRP(Thermo fisher, 31462) was added and incubated at room temperature for 1 hour, the membrane was washed with 1xTBST for 3 times, 10 minutes each time, HRP substrate in the West Femto ultra-sensitive chemiluminescence kit was added, chemiluminescence was carried out, and chemiluminescence was detected on a Tanon5200 Multi machine and photographed and saved. Quantitative analysis was carried out using Alpha View software to quantitatively analyze the density intensity of the immunoblotting luminescence band. β-Actin (β-actin) is a housekeeping protein, and the consistency of the loading amount is detected in the immunoblotting detection.

[0389] The compound of the present application has strong inhibitory effect on each phosphorylated Rb and total Rb. Specifically, the results of Western blotting are shown in Figure 3. The results show that, compared with the reference PF07104091, INC-Ref, the inhibitory strength of Example 4 on each phosphorylated Rb and total Rb is better than that of the reference.

[0390] In summary, the compounds of this application target both CDK2 and CDK4. Specifically, biological testing results for Example 4 show CDK2 targeting, demonstrating target-related antitumor activity and superior performance compared to the reference PF07104091 (INC-Ref) in terms of in vitro enzyme activity, target affinity, target-related antiproliferative activity, and in vivo antitumor activity. Furthermore, Example 4 exhibits some CDK4 targeting, demonstrating superior antiproliferative activity in target-related cell lines compared to the CDK4 / 6 inhibitor Palbociclib.

[0391] In summary, this invention discloses a novel thiazole-substituted pyrimidine amine compound with a chemical structure different from previously reported or disclosed CDK2 inhibitors. Unexpectedly, it was discovered that this invention exhibits higher CDK2 selectivity and some CDK4 targeting. Its superior selectivity is expected to lead to higher clinical safety and patient compliance, demonstrating significant clinical anti-tumor drug value and potential applications.

Claims

1. A compound as shown in Formula II, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; characterized in that, wherein, the carbon atom with "*" represents, when a chiral carbon atom, R configuration, S configuration, or a mixture of both; the carbon atom with "#" represents, when a chiral carbon atom, independently R configuration, S configuration, or a mixture of both; R 1 halogen, CrC6alkyl optionally substituted with 1 or more R 1-1 halogen, CrC6alkyl optionally substituted with 1 or more R 1-2 halogen, CrC6alkyl optionally substituted with 1 or more R 1-3 halogen, CrC6alkyl optionally substituted with 1 or more R 1-4 halogen, CrC6alkyl optionally substituted with 1 or more R 10 halogen, CrC6alkyl optionally substituted with 1 or more R 1-5 halogen, CrC6alkyl optionally substituted with 1 or more R 1-6 halogen, CrC6alkyl optionally substituted with 1 or more R R 2 halogen, hydroxyl, optionally substituted Ci-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C6-Cio aryl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, -OR 2-1 2-2 10 2-3 2-4 2-5 2-6 2-7 2-8 halogen, hydroxyl, optionally substituted Ci-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted C6-Cio aryl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, -OR​​​​​​​​ R 1-1 R 1-2 R 1-3 R 1-4 R 1-5 and R 1-6 Independently hydrogen, deuterium, -CN, halogen, -NR a R b Optional, one or more R 1- 1-1 Substituted C1-C6 alkyl groups or optionally with one or more R 1-1-2 Substituted C1-C6 alkoxy groups; R a and R b are independently hydrogen or C1-C6alkyl; R 1-1-1 and R 1-1-2 are independently hydrogen, deuterium, halogen or -NR a R b ; R 2-1 and R 2-8 Independently hydrogen, deuterium, halogen, hydroxyl, cyano, -NR a R b -C(=O)NR a R b Optional, one or more R 2- 1-1 Substituted C3-C6 cycloalkyl groups, optionally with one or more R 2-1-2 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms, optionally replaced by one or more R... 2-1-3 Replacement C6-C 10 Aryl, optionally with one or more R 2-1-4 Substituted C1-C6 alkyl groups or optionally with one or more R 2-1-5 Substituted C1-C6 alkoxy groups; R 2-1-1 , R 2-1-2 , and R 2-1-3 are independently hydrogen, deuterium, halogen, C1-C6alkyl optionally substituted with 1 or more R 2a , or C1-C6alkoxy optionally substituted with 1 or more R 2b ; R 2a and R 2b independently halogen; R 2-1-4 and R 2-1-5 are independently hydrogen, deuterium, halogen, or -NR a R b ; R 2-2 and R 2-3 are independently hydrogen, deuterium, halogen, C1-C6 alkyl optionally substituted with 1 or more R 2-2-1 , C1-C6 alkoxy optionally substituted with 1 or more R 2-2-2 , or -CN; R 2-2-1 and R 2-2-2 are independently hydrogen, deuterium, halogen, -NR a R b or C1-C6alkoxy; R 2-4 independently hydrogen or Ci-C6alkyl; R 2-5 R 2-6 and R 2-7 Independently hydrogen, C1-C6 alkyl, optionally with one or more R 2-5-1 Replacement C6-C 10 Aryl, optionally with one or more R 2-5-2 The substituted C3-C6 cycloalkyl group or optionally with one or more R 2-5-3 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms. R 2-5-1 Independently halogenated, optionally by one or more R 2c Substituted C1-C6 alkyl groups, optionally with one or more R 2d Substituted C1-C6 alkoxy groups or -CN; R 2c and R 2d are independently halogen, Ci-C6alkoxy or -NR a R b ; R 2-5-2 independently halogen, optionally substituted C1-C6alkyl or optionally substituted C1-C6alkoxy; 2f halogen, optionally substituted C1-C6alkyl or optionally substituted C1-C6alkoxy; 2g halogen, optionally substituted C1-C6alkyl or optionally substituted C1-C6alkoxy; R 2e independently C1-C6alkyl; R 2f and R 2g are independently halogen or -NR a R b ; R 2-5-3 Independently halogenated, optionally by one or more R 2j Substituted C1-C6 alkyl groups, optionally with one or more R 2k Substituted C1-C6 alkoxy groups or -CN; R 2j and R 2k independently halogen, -NR a R b or C1-C6alkoxy; Y 1 and Y 2 independently CR c or N; R c hydrogen, Ci-C6alkyl optionally substituted with 1 or more R c-1 substituted with 1 or more R c-2 substituted with 1 or more R substituted with 1 or more R R c-1 and R c-2 are independently halogen or -NR a R b ; For R 3 Independently deuterium, amino, or cyano, optionally bounded by one or more R groups. 3-1 Substituted C1-C6 alkyl, halogen, optionally with one or more R 3-2 Substituted C1-C6 alkoxy, hydroxyl, optionally with one or more R 3-3 The substituted C2-C6 alkenyl group, optionally with one or more R 3- 4 The substituted C2-C6 ynyl group or optionally with one or more R groups 3-5 Replacement C6-C 10 Aryl; R 3-1 , R 3-2 , R 3-3 , R 3-4 and R 3-5 are independently hydrogen, deuterium, halogen or -NR a R b ; n is 0, 1, 2, 3, or 4; R 4 and R 5 independently hydrogen, C1-C6alkyl optionally substituted with 1, 2, or 3 R 4-1 independently hydrogen, C1-C6alkyl optionally substituted with 1, 2, or 3 R 4-2 independently hydrogen, C1-C6alkyl optionally substituted with 1, 2, or 3 R 4-3 independently hydrogen, C1-C6alkyl optionally substituted with 1, 2, or 3 R or R 4 or R 5 and the N to which they are attached together form "3-6 membered heterocycloalkyl having 1 heteroatom which is N"; R 4-1 , R 4-2 , and R 4-3 are independently hydrogen, deuterium, or halogen; m is 0 or 2; when m is 0, R 6 absent; when m is 2, two R attached to the same C atom 6 with the C to which they are attached form a C3-C6cycloalkyl; or, two non-adjacent R 6 with the C to which they are attached form a C3-C6cycloalkyl; or, two non-adjacent R 6 attached form -(CH2) m1 - a bridging moiety, m1 being 1 or 2.

2. The compound of formula II as claimed in claim 1, its pharmaceutically acceptable salt, or its stereoisomer; characterized in that, wherein, the carbon atom with "*" represents, when a chiral carbon atom, R configuration, S configuration, or a mixture of both; the carbon atom with "#" represents, when a chiral carbon atom, independently R configuration, S configuration, or a mixture of both; R 1 halogen, CrC6alkyl optionally substituted with 1 or more R 1-1 halogen, CrC6alkyl optionally substituted with 1 or more R 1-2 halogen, CrC6alkyl optionally substituted with 1 or more R 1-3 halogen, CrC6alkyl optionally substituted with 1 or more R 1-4 halogen, CrC6alkyl optionally substituted with 1 or more R 10 halogen, CrC6alkyl optionally substituted with 1 or more R 1-5 halogen, CrC6alkyl optionally substituted with 1 or more R 1-6 halogen, CrC6alkyl optionally substituted with 1 or more R R 2 It is hydrogen, halogen, hydroxyl, optionally coated with one or more R 2-1 Substituted C1-C6 alkoxy groups, optionally with one or more R groups 2-2 Replacement C6-C 10 Aryl, optionally with one or more R 2-3 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-8 membered heterocyclic alkyl group with one or more heteroatoms. 2-4 R 2-5 -SR 2-6 -OR 2-7 Or be selected by one or more R 2-8 Substituted C1-C6 alkyl groups; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , and R 1-6 are independently hydrogen, deuterium, -CN, halogen, -N(R a R b , optionally substituted Ci-C6alkyl, or optionally substituted Ci-C6alkoxy; and 1- 1-1 Ci-C6alkyl optionally substituted with 1 or more R 1-1-2 Ci-C6alkoxy optionally substituted with 1 or more R R a and R b are independently hydrogen or C1-C6alkyl; R 1-1-1 and R 1-1-2 are independently hydrogen, deuterium, halogen or -NR a R b ; R 2-1 and R 2-8 Independently hydrogen, deuterium, halogen, or optionally substituted by one or more R 2-1-1 Substituted C3-C6 cycloalkyl groups, optionally with one or more R 2-1-2 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms, optionally replaced by one or more R... 2-1-3 Replacement C6-C 10 Aryl, optionally with one or more R 2-1-4 Substituted C1-C6 alkyl groups or optionally with one or more R 2-1-5 Substituted C1-C6 alkoxy groups; R 2-1-1 , R 2-1-2 , and R 2-1-3 are independently hydrogen, deuterium, halogen, C1-C6alkyl optionally substituted with 1 or more R 2a , or C1-C6alkoxy optionally substituted with 1 or more R 2b ; R 2a and R 2b independently halogen; R 2-1-4 and R 2-1-5 are independently hydrogen, deuterium, halogen, or -NR a R b ; R 2-2 and R 2-3 independently hydrogen, deuterium, halogen, C1-C6alkyl optionally substituted with 1 or more R 2-2-1 substituted C1-C6alkyl, C1-C6alkoxy optionally substituted with 1 or more R 2-2-2 substituted C1-C6alkyl, C1-C6alkoxy optionally substituted with 1 or more R R 2-2-1 and R 2-2-2 are independently hydrogen, deuterium, halogen, -NR a R b or C1-C6 alkoxy; R 2-4 independently hydrogen or Ci-C6alkyl; R 2-5 R 2-6 and R 2-7 Independently hydrogen, C1-C6 alkyl, optionally with one or more R 2-5-1 Replacement C6-C 10 Aryl, optionally with one or more R 2-5-2 The substituted C3-C6 cycloalkyl group or optionally with one or more R 2-5-3 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-6 membered heterocyclic alkyl group with one, two, or three heteroatoms. R 2-5-1 Independently halogenated, optionally by one or more R 2c Substituted C1-C6 alkyl groups, optionally with one or more R 2d Substituted C1-C6 alkoxy groups or -CN; R 2c and R 2d are independently halogen, Ci-C6alkoxy or -NR a R b ; R 2-5-2 independently halogen, optionally substituted C1-C6alkyl or optionally substituted C1-C6alkoxy; 2f halogen, optionally substituted C1-C6alkyl or optionally substituted C1-C6alkoxy; 2g halogen, optionally substituted C1-C6alkyl or optionally substituted C1-C6alkoxy; R 2e independently C1-C6alkyl; R 2f and R 2g are independently halogen or -NR a R b ; R 2-5-3 Independently halogenated, optionally by one or more R 2j Substituted C1-C6 alkyl groups, optionally with one or more R 2k Substituted C1-C6 alkoxy groups or -CN; R 2j and R 2k are independently halogen, -NR a R b or C1-C6alkoxy; Y 1 and Y 2 independently CR c or N; R c hydrogen, Ci-C6-alkyl optionally substituted by 1 or more R c-1 substituted by 1 or more R c-2 substituted by 1 or more R substituted by 1 or more R R c-1 and R c-2 are independently halogen or -NR a R b ; For R 3 Independently deuterium, amino, or cyano, optionally bounded by one or more R groups. 3-1 Substituted C1-C6 alkyl, halogen, optionally with one or more R 3-2 Substituted C1-C6 alkoxy, hydroxyl, optionally with one or more R 3-3 The substituted C2-C6 alkenyl group, optionally with one or more R 3- 4 The substituted C2-C6 ynyl group or optionally with one or more R groups 3-5 Replacement C6-C 10 Aryl; R 3-1 , R 3-2 , R 3-3 , R 3-4 and R 3-5 are independently hydrogen, deuterium, halogen or -NR a R b ; n is 0, 1, 2, 3, or 4; R 4 and R 5 are independently hydrogen, C1-C6alkyl optionally substituted with 1, 2, or 3 R 4-1 , C1-C6alkoxy optionally substituted with 1, 2, or 3 R 4-2 , or C3-C6cycloalkyl optionally substituted with 1 or more R 4-3 ; or R 4 or R 5 and the N to which they are attached together form "3-6 membered heterocycloalkyl having 1 heteroatom which is N"; R 4-1 , R 4-2 , and R 4-3 are independently hydrogen, deuterium, or halogen; m is 0 or 2; when m is 0, R 6 absent; when m is 2, two R attached to the same C atom 6 form, together with the C to which they are attached, a C3-C6cycloalkyl; or, two adjacent R 6 form, together with the C to which they are attached, a C3-C6cycloalkyl; or, two non-adjacent R 6 attached form, together with the C to which they are attached, a C3-C6cycloalkyl; or, two non-adjacent R m1 - bridging moiety, m1 being 1 or 2.

3. The compound of formula II as claimed in claim 2, its pharmaceutically acceptable salt, or its stereoisomer; characterized in that, said compound being a compound of formula II, wherein, the carbon atom with "*" represents, when a chiral carbon atom, R configuration, S configuration, or a mixture of both; the carbon atom with "#" represents, when a chiral carbon atom, independently R configuration, S configuration, or a mixture of both; R 1 halogen, CrC6alkyl optionally substituted with 1 or more R 1-1 halogen, CrC6alkyl optionally substituted with 1 or more R 1-2 halogen, CrC6alkyl optionally substituted with 1 or more R 1-3 halogen, CrC6alkyl optionally substituted with 1 or more R 1-4 halogen, CrC6alkyl optionally substituted with 1 or more R 10 halogen, CrC6alkyl optionally substituted with 1 or more R 1-5 halogen, CrC6alkyl optionally substituted with 1 or more R 1-6 halogen, CrC6alkyl optionally substituted with 1 or more R R 2 It is hydrogen, halogen, hydroxyl, optionally coated with one or more R 2-1 Substituted C1-C6 alkoxy groups, optionally with one or more R groups 2-2 Replacement C6-C 10 Aryl, optionally with one or more R 2-3 The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 3-8 membered heterocyclic alkyl group with one or more heteroatoms. 2-4 R 2-5 -SR 2-6 -OR 2-7 Or be selected by one or more R 2-8 Substituted C1-C6 alkyl groups; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , and R 1-6 are independently deuterium, -CN, halogen, -NR a R b , C1-C6 alkyl optionally substituted with 1 or more R 1-1-1 , or C1-C6 alkoxy optionally substituted with 1 or more R 1-1-2 ; R a and R b are independently hydrogen or C1-C6alkyl; R 1-1-1 and R 1-1-2 are independently halogen or -NR a R b ; R 2-1 and R 2-8 Independently deuterium, halogen, or optionally by one or more R 2-1-1 Substituted C3-C6 cycloalkyl groups, optionally with one or more R 2-1-2 The substituted heteroatom is selected from one, two, or three of N, O, and S, or is a 3-6 membered heterocyclic alkyl group having one, two, or three heteroatoms, or is optionally replaced by one or more R... 2-1-3 Replacement C6-C 10 Aryl, optionally with one or more R 2-1-4 Substituted C1-C6 alkyl groups or optionally with one or more R 2-1-5 Substituted C1-C6 alkoxy groups; R 2-1-1 , R 2-1-2 , and R 2-1-3 are independently halogen, C1-C6alkyl optionally substituted with 1 or more R 2a , or C1-C6alkoxy optionally substituted with 1 or more R 2b ; R 2a and R 2b independently halogen; R 2-1-4 and R 2-1-5 are independently halogen or -NR a R b ; R 2-2 and R 2-3 independently halogen, C1-C6alkyl optionally substituted with 1 or more R 2-2-1 independently halogen, C1-C6alkyl optionally substituted with 1 or more R 2-2-2 independently halogen, C1-C6alkyl optionally substituted with 1 or more R R 2-2-1 and R 2-2-2 are independently halogen, -NR a R b or C1-C6alkoxy; R 2-4 independently hydrogen or Ci-C6alkyl; R 2-5 R 2-6 and R 2-7 Independently hydrogen, C1-C6 alkyl, optionally with one or more R 2-5-1 Replacement C6-C 10 aryl, one or more R 2-5-2 The substituted C3-C6 cycloalkyl group or optionally with one or more R 2-5-3 The substituted heteroatom is selected from one, two, or three of N, O, and S, or from 3-6 membered heterocyclic alkyl groups having one, two, or three heteroatoms. R 2-5-1 Independently halogenated, optionally by one or more R 2c Substituted C1-C6 alkyl groups, optionally with one or more R 2d Substituted C1-C6 alkoxy groups or -CN; R 2c and R 2d independently are halogen, Ci-C6alkoxy or -NR a R b ; R 2-5-2 independently halogen, optionally substituted C1-C6alkyl or optionally substituted C1-C6alkoxy; 2f halogen, optionally substituted C1-C6alkyl or optionally substituted C1-C6alkoxy; 2g halogen, optionally substituted C1-C6alkyl or optionally substituted C1-C6alkoxy; R 2e independently C1-C6alkyl; R 2f and R 2g are independently halogen or -NR a R b ; R 2-5-3 Independently halogenated, optionally by one or more R 2j Substituted C1-C6 alkyl groups, optionally with one or more R 2k Substituted C1-C6 alkoxy groups or -CN; R 2j and R 2k are independently halogen, -NR a R b or C1-C6alkoxy; Y 1 and Y 2 independently CR c or N; R c hydrogen, Ci-C6alkyl optionally substituted with 1 or more R c-1 substituted with 1 or more R c-2 substituted with 1 or more R substituted with 1 or more R R c-1 and R c-2 are independently halogen or -NR a R b ; For R 3 independently deuterium, optionally substituted Ci-C6alkyl, halogen, optionally substituted Ci-C6alkoxy, or hydroxyl; n is 0, 1, 2, 3, or 4; 3-1 independently deuterium, optionally substituted Ci-C6alkyl, halogen, optionally substituted Ci-C6alkoxy, or hydroxyl; n is 0, 1, 2, 3, or 4; 3-2 independently deuterium, optionally substituted Ci-C6alkyl, halogen, optionally substituted Ci-C6alkoxy, or hydroxyl; n is 0 R 3-1 and R 3-2 are independently halogen or -NR a R b ; n is 0, 1, 2, 3, or 4; R 4 and R 5 independently are hydrogen, C1-C6alkyl optionally substituted with 1 or more R 4-1 independently are hydrogen, C1-C6alkyl optionally substituted with 1, 2, or 3 R 4-2 independently are hydrogen, C1-C6alkyl optionally substituted with 1, 2, or 3 R R 4-1 and R 4-2 are independently deuterium.

4. The compound of formula II as described in any one of claims 1-3, its pharmaceutically acceptable salt, or its stereoisomer; characterized in that, which satisfies one or more of the following conditions: (1) each of said plurality is independently 1, 2, 3, 4, 5, 6, 7, or 8; for example, 1, 2, or 3; (2) each of said halogen is independently fluorine, chlorine, bromine, or iodine; for example, fluorine; (3) each of said C1-C6 alkyl and C1-C6 alkyl in each of said substituted C1-C6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, or s-butyl; for example, methyl or ethyl; (4) each of said C1-C6 alkoxy and C1-C6 alkoxy in each of said substituted C1-C6 alkoxy is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy; for example, methoxy or ethoxy; further for example, ethoxy; (5) each of said C3-C6 cycloalkyl and C3-C6 cycloalkyl in each of said substituted C3-C6 cycloalkyl is independently cyclopropyl or cyclobutyl; (6) Each of the C6-C mentioned 10 aryl and each of the substituted C6-C 10 C6-C in aryl 10 The aryl group can be phenyl or naphthyl independently; (7) the 5-10 membered heteroaryl group contains N as a heteroatom, and the 5-6 membered heteroaryl group contains two heteroatoms, which are both N; for example, (8) each of said 3-6 membered heterocycloalkyl is independently 3-4 membered heterocycloalkyl; and (9) said 3-8 membered heterocycloalkyl is 3-6 membered heterocycloalkyl.

5. The compound of formula II as described in any one of claims 1-3, its pharmaceutically acceptable salt, or its stereoisomer; characterized in that, which satisfies one or more of the following conditions: (1) R 1 is "5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1 or more"; (2) R 2 is C1-C6alkoxy; (3) Y 1 and Y 2 independently CR c ; (4) R c is hydrogen; (5) For (6) R 3 independently C1-C6alkyl or halogen; preferably C1-C6alkyl; (7) n is 0 or 1; and (8) R 4 and R 5 independently are hydrogen, C1-C6alkyl or C1-C6alkoxy; preferably hydrogen or C1-C6alkyl.

6. The compound of formula II as described in any one of claims 1-3, its pharmaceutically acceptable salt, or its stereoisomer; characterized in that, which satisfies one or more of the following conditions: (1) R 1 To (2) R 2 To (3) R 3 is -CH3or F; preferably -CH3; (4)R 4 It is hydrogen or -CH3; (5) R 5 is hydrogen, -CH3, methoxy, ethyl or -CD3; preferably hydrogen, -CH3or ethyl; and (6) For 7. The compound of any one of claims 1-3, represented by Formula II, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; wherein which satisfies one or more of the following conditions: (1) each of said C3-C6 cycloalkyl and C3-C6 cycloalkyl in each of said substituted C3-C6 cycloalkyl is independently cyclopropyl, cyclobutyl, or cyclopentyl; (2) each said 3-6 membered heterocycloalkyl is independently (3) each of said C2-C6 alkenyl and C2-C6 alkenyl in each of said substituted C2-C6 alkenyl is independently C2-C4 alkenyl; (4) each of said C2-C6 alkynyl and C2-C6 alkynyl in each of said substituted C2-C6 alkynyl is independently C2-C4 alkynyl; (5) n is 0; (6) m is 0; and (7) R 4 and R 5 independently C1-C6alkyl; preferably; which satisfies one or more of the following conditions: (1)R 4 It is hydrogen, -CH3 or -CD3; preferably -CH3; (2) R 5 is -CH3; (3) When m is 2, the two R atoms connected to the same C atom 6 Together with the C atoms they are attached to, they form C3-C6 cycloalkyl groups. and (4) when m is 2, two adjacent R 6 with the C to which they are attached to form a C3-C6cycloalkyl group is more preferably; which satisfies one or two of the following conditions: (1) R 4 (2) R 5 with the N to which they are attached to form and (2) For 8. The compound of any one of claims 1-3, represented by Formula II, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; wherein, which satisfies one or more of the following conditions: (1) each said 3-6 membered heterocycloalkyl is independently (2) R 2 C1-C6alkyl or -O-R 2-1 substituted by 1 or more R 2-7 ; preferably C1-C6alkyl or -O-R 2-1 substituted by 1 or more R (3) R 2-1 independently hydroxy, cyano, -NR a R b , -C(=O)NR a R b , "3-6 membered heterocycloalkyl with 1, 2 or 3 heteroatoms selected from N, O and S, the number of heteroatoms being 1, 2 or 3" or C1-C6alkoxy; preferably hydroxy, cyano, -NR a R b or C1-C6alkoxy; further preferably -NR a R b ; (4) R 2-7 independently "3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, the number of heteroatoms being 1, 2 or 3"; (5) R a and R b independently C1-C6alkyl; and (6) For Preferably preferably; which satisfies one or more of the following conditions: (1) R 2 To (2) R a and R b are independently hydrogen or methyl; preferably methyl; and (3) For For example, 9. The compound of any one of claims 1-3, represented by Formula II, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; wherein The compound as shown in Formula I is any one of the following structures, For example, 10. A compound of Formula II, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to any one of claims 1-9; wherein, The compound as shown in formula II is a compound as shown in formula I-1, For example, 11. A pharmaceutical composition, characterized by, the pharmaceutical composition comprises: (1) a compound as shown in Formula II, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to any one of claims 1-10; and (2) a pharmaceutically acceptable excipient.

12. Use of a compound of Formula II, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a pharmaceutical composition of claim 11, according to any one of claims 1-10, wherein, the use is selected from: (1) preparing a CDK2 inhibitor or a CDK4 inhibitor; (2) preparing a medicament for treating or preventing a disease or disorder associated with cyclin-dependent kinase 2 (CDK2); (3) preparing a medicament for treating and / or preventing a disease or disorder, which can be cancer; and (4) preparing a medicament for treating or preventing a disease or disorder associated with cyclin-dependent kinase 4 (CDK4).

13. Use according to claim 12, characterized in that, which satisfies one or both of the following conditions: (1) the disease or disorder associated with cyclin-dependent kinase 2 (CDK2) is a CCNE1 abnormality-related cancer; the CCNE1 abnormality can be amplification of the CCNE1 gene and / or overexpression of CCNE1; (2) the disease or disorder associated with cyclin-dependent kinase 4 (CDK4) is breast cancer and / or multiple Rb pathway-dependent tumors.

14. The use according to claim 12, characterized in that, which satisfies one or both of the following conditions: (1) the cancer is selected from ovarian cancer, gastric cancer, esophageal cancer, uterine serous carcinoma, lung cancer, colorectal cancer, breast cancer, and hematological tumor; (2) the medicament can be administered or used in combination with other types of drugs, covering the combination with VEGF / PI3K / Akt signaling pathway inhibitors, BRD4 inhibitors, BCL-2 inhibitors, BRAF / HSP90 inhibitors, CDK4 / 6 inhibitors, PARP inhibitors, endocrine therapy, chemotherapy, and radiotherapy.

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