Nitrogen-containing heteroaryl compound as well as preparation method and application thereof

Abstract

The invention discloses a compound as shown in a formula (I-A) for treating cancer, and an isotope label, an enantiomer, a diastereoisomer, an atropisomer or a pharmaceutically acceptable salt thereof. The compound provided by the invention has better inhibitory activity on WRN and has a good application prospect.

Description

[0001] This application claims priority to Chinese Patent Application No. 202410779473X, filed on June 17, 2024, Chinese Patent Application No. 2024111093624, filed on August 13, 2024, Chinese Patent Application No. 2024116365771, filed on November 15, 2024, and Chinese Patent Application No. 2024117821574, filed on December 5, 2024. This application incorporates the entirety of the above-mentioned Chinese Patent Applications. TECHNICAL FIELD

[0002] The present application relates to a WRN inhibitor and its preparation method and application, in particular to a class of nitrogen-containing heteroaryl compounds, compositions thereof, and their use in the treatment and prevention of cancer. BACKGROUND

[0003] Tumor is an important disease affecting human health. In recent years, with the in-depth research, anti-tumor drug research and development has made a lot of breakthroughs, bringing new dawn to patients. However, for some tumors with systemic dissemination tendency and metastatic advanced tumors, chemotherapy is still the main treatment. Most of the chemotherapeutic drugs are cytotoxic drugs, which cannot distinguish normal cells and cancer cells, so they will have certain toxicity to normal cells in the body. Therefore, it is particularly urgent to develop a treatment strategy with better selectivity for tumor cells.

[0004] In 1946, Theodosius Dobzhansky discovered and named the “synthetic lethal” effect in fruit flies, where the simultaneous inactivation of two specific genes caused the death of the flies, while inactivation of either gene alone did not(Dobzhansky, T. Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura. Genetics, 1946, 31: 269-290). Today, the concept of synthetic lethality has been applied to cancer therapy, where tumors with inactivation (deletion or mutation) of one gene can be targeted for drug inhibition of another specific gene, resulting in cancer cell death but not normal cell death(Huang A, Garraway LA, Ashworth A, Weber B. Synthetic lethality as an engine for cancer drug target discovery. Nat Rev Drug Discov. 2020 Jan; 19(1): 23-38).The successful application of PARP inhibitors (Olaparib, Rucaparib and Niraparib) designed based on synthetic lethal interaction mechanism in the clinical treatment of Brca-mutated ovarian cancer confirmed the positive significance of synthetic lethality in clinical treatment (Kim G, et al. FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy. Clin Cancer Res. 2015, 21: 4257-4261; Shapira-Frommer R, et al. A phase 2 open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. Ann Oncol. 2015, 33(suppl): 2476; Mirza, M.R. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 2016, 375: 2154-2164).

[0005] Microsatellite is a short tandem repeat sequence widely existing in human genome. Compared with normal cells, microsatellite in tumor cells will change in length due to the insertion or deletion of repeat units, which is called microsatellite instability (MSI). MSI is prevalent in colorectal cancer (15%), gastric cancer (22%) and other solid tumors (Lorenzi M, Amonkar M, Zhang J, et al. Epidemiology of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) in solid tumors: a structured literature review [J]. Journal of Oncology, 2020, 2020: 1-17). According to the degree, MSI can be divided into three categories: microsatellite high instability (MSI-high, MSI-H), microsatellite low instability (MSI-low, MSI-L) and microsatellite stable (MSS). MSI cancer patients have better overall prognosis and lower risk of metastasis (Kang S et al. The significance of microsatellite instability in colorectal cancer after controlling for clinicopathological factors. Medicine (Baltimore). 2018, 97(9): e0019).This is in part related to the high mutational burden in MSI tumors leading to neoantigen generation, thus increasing immunogenicity and sensitivity to immune checkpoint inhibitors (Wang QX et al. The degree of microsatellite instability predicts response to PD-1 blockade immunotherapy in mismatch repair-deficient / microsatellite instability-high colorectal cancers. Exp Hematol Oncol. 2021, 10(1): 2; Lizardo D Yet al. Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside. Biochim Biophys Acta Rev Cancer. 2020, 1874(2): 188447; Corcoran RB, Grothey A. Efficacy of Immunotherapy in Microsatellite-Stable or Mismatch Repair Proficient Colorectal Cancer-Fact or Fiction? JAMA Oncol. 2020, 6(6): 823-824).However, a considerable proportion of MSI tumors do not respond or develop resistance to immunotherapy and chemotherapy (Le DT et al. Phase III Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High / Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J Clin Oncol. 2020, 38(1): 11-19; Overman MJ et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017, 18(9): 1182-1191; Fucà G et al. Ascites and resistance to immune checkpoint inhibition in dMMR / MSI-H metastatic colorectal and gastric cancers. J Immunother Cancer. 2022, 10(2): e004001.), so there is an urgent need for more effective targeted or combined treatment means.

[0006] WRN, as the only member of human RecQ helicase family with both helicase and exonuclease activity, plays an important role in DNA repair, replication, transcription and telomere maintenance. WRN consists of 1432 amino acids and has a molecular weight of 160 kD. In undamaged human cells, WRN is mainly located in the nucleolus; but after DNA damage, it will quickly transfer to other nuclear regions. WRN contains N-terminal 3'-5' exonuclease domain, ATPase domain, RQC domain (RecQ C-terminal), HRDC domain (Helicase-and-ribonuclease D-C-terminal), and C-terminal nuclear localization signal sequence in its protein structure (Kitano K. Structural mechanisms of human RecQ helicases WRN and BLM. Front Genet. 2014, 5: 366). WRN can recognize specific DNA secondary structures such as DNA bubbles, replication forks, Holliday junctions, G-quadruplexes, and triple helices, and promote their unwinding, thereby participating in the processes of DNA replication and repair (Constantinou A, Tarsounas M, Karow J K, et al. Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest [J]. EMBO reports, 2000, 1(1): 80-84.). WRN is a synthetic lethal target in MSI-H tumors (Chan E M, Shibue T, McFarland J M, et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers [J]. Nature, 2019, 568(7753): 551-556).In previous studies, WRN gene knockdown or knockout, WRN helicase function loss mutation, and small molecule WRN helicase inhibitors can significantly inhibit the cell growth of MSI-H tumors and the formation of mouse subcutaneous transplanted tumors (Ding Z, Zhang J, Pedamallu C S, et al. Identification and validation of WRN as a novel synthetic lethality target in context of microsatellite instability [J]. Cancer Research, 2020, 80(16_Supplement): 1377-1377; Picco G et al. Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair-Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy. Cancer Discov. 2021, 11(8): 1923-1937; Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. Elife. 2019, 8: e43333; Aggarwal M, Sommers J A, Shoemaker R H, et al. Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress [J]. Proceedings of the National Academy of Sciences, 2011, 108(4): 1525-1530).

[0007] WRN helicase activity has been shown to be essential for the survival of MSI cell lines and cell lines with mismatch repair defects (dMMR), and WRN deficient in helicase activity is not sufficient to rescue impaired cell viability caused by WRN knock-out or knock-down. The absence of WRN protein or the inhibition of its helicase activity prevents normal DNA damage and repair processes, leading to increased DNA double-strand breaks (DSBs) and subsequent growth arrest and cell death. Therefore, the development of WRN inhibitors with higher activity and selectivity can meet the urgent need for the treatment of MSI-H cancer or mismatch repair defect (dMMR) cancer.

[0008] Covalent inhibitors are a class of small molecule inhibitors that irreversibly bind to target protein residues through covalent bonds to exert their biological functions. Generally, covalent inhibition is a two-step process; first, the inhibitor reversibly binds to the target enzyme, bringing the electron-rich chemical warhead in the small molecule close to the active residues in the enzyme. In the second step, a covalent bond is formed between the two reactive entities of the inhibitor and the enzyme. Common covalent warheads include acrylamide, epoxy, chloroacetyl, and oxysulfonyl fluoride and sulfonyl fluoride, etc., and common amino acid active residues include cysteine, serine, tyrosine, lysine, and arginine and glutamic acid, etc. The first covalent inhibitors discovered were acetylsalicylic acid and penicillin. To date, more and more covalent inhibitors are being studied. Covalent inhibitors have high biochemical efficiency, strong and long-lasting effects, reduced dosing and dosing frequency, separation of pharmacodynamics and pharmacokinetics, rapid drug clearance while maintaining efficacy, the ability to prevent the development of drug resistance, the ability to target specific protein rare and non-conserved residues, and high selectivity. Therefore, covalent inhibitors will have good application prospects in the field of anti-tumor. SUMMARY

[0009] The present application provides a class of compounds, a preparation method and application thereof. The compound of the present application has good inhibitory activity on WRN.

[0010] The present application provides a compound as shown in formula (I-A), an isotopically labeled, enantiomer, diastereomer, atropisomer thereof or a pharmaceutically acceptable salt thereof:

[0011]

[0012] wherein,

[0013] Y is selected from CR 0 or N;

[0014] R 0 is hydrogen, C1-C6 alkyl, haloC1-C6 alkyl, -NR x0 R y0 ; Rx0 and R y0 each independently is selected from hydrogen, C1-C6alkyl, haloC1-C6alkyl;

[0015] R 1 is -(CR 11 R 12 ) m R 13 , m is 0, 1, 2 or 3; each R 11 and R 12 each independently is hydrogen, C1-C6alkyl, halo, haloC1-C6alkyl; R 13 is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8cycloalkenyl, unsubstituted or substituted benzoC3-C6cycloalkyl, unsubstituted or substituted benzo3-8 membered heterocyclyl; R 13 substituted in said group A is substituted with one or more substituents selected from group A1; group A1 substituents include: oxo (=0), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl unsubstituted or substituted with one or more substituents selected from group A1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR a1 R a2 , -CONR a1 R a2 , -NR a1 C(O)R a2 ; group A1 substituents include: deuterium, halogen, C1-C6alkoxy, haloC1-C6alkoxy, C3-C6cycloalkyl, cyano, hydroxyl, carboxyl, -NR a3 R a4 , -CONR a3 R a4 , -NR a3 C(O)R a4 ;

[0016] R 2 is -NR x R y , -CONR x R y , -NR x C(O)R y , -R 9 , -OR 10 ; R 9 and R 10selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl; R 9 and R 10 substituted means substituted with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR b1 R b2 , -CONR b1 R b2 , -NR b1 C(O)R b2 ;

[0017] R 3 is hydrogen or C1-C6alkyl;

[0018] R 4 is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 5-6 membered heterocyclyl; R 4 substituted means substituted with one or more substituents selected from Group C; Group C substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR c1 R c2 , -CONR c1 R c2 , -NR c1 C(O)R c2 ;

[0019] R 5 is hydrogen or deuterium;

[0020] R 6 is hydrogen or C1-C6alkyl;

[0021] or R 3 and R 6 together with the atom to which they are attached form a 4-6 membered heterocyclyl ring containing one N atom;

[0022] R7 is hydrogen, C1-C6alkyl or halogen;

[0023] R 8 is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 8 The substituents mentioned in R d1 are 1 or more substituents selected from the group D; the substituents of group D include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR d2 , -CONR d1 R d2 , -NR d1 C(O)R d2 ;

[0024] X 1 is N or CR 14 , X 2 is N or CR 15 , and at least one of X 1 and X 2 is N;

[0025] R 14 and R 15 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen or halogenated C1-C6alkyl;

[0026] R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R x , R y are each independently selected from the group consisting of hydrogen, C1-C6alkyl, halogenated C1-C6alkyl, C3-C6cycloalkyl;

[0027] and R 7 , respectively, are connected to the S atom and R denotes can be a geometric isomer of (Z) or (E); denotes the point of attachment of the group to the other position;

[0028] The marked C atom can be a chiral carbon atom or an achiral carbon atom; when the marked C atom is a chiral carbon atom, the configuration of the chiral carbon atom is S configuration or R configuration;

[0029] The heteroatom in the 3-8 membered heterocyclyl, 4-6 membered heterocyclyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-10 membered heteroaryl is independently selected from 1, 2, 3 or 4 of N, O and S.

[0030] In one embodiment, the compound represented by formula (I-A) has a structure as represented by formula (I):

[0031]

[0032] wherein,

[0033] R 0 is hydrogen, C1-C6alkyl, haloC1-C6alkyl, -NR x0 R y0 ; R x0 and R y0 are each independently selected from hydrogen, C1-C6alkyl, haloC1-C6alkyl;

[0034] R 1 is -(CR 11 R 12 ) m R 13 , m is 0, 1, 2 or 3; each R 11 and R 12 are each independently hydrogen, C1-C6alkyl, halo, haloC1-C6alkyl; R 13 is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8cycloalkenyl, unsubstituted or substituted benzoC3-C6cycloalkyl, unsubstituted or substituted benzo3-8 membered heterocyclyl; R 13 The substitution in R a1 is unsubstituted or substituted with one or more substituents selected from Group A; Group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl unsubstituted or substituted with one or more substituents selected from Group A1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR a2 , -CONR a1 R a2 , -NR a1 C(O)R a2; A1group substituents include: deuterium, halogen, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, cyano, hydroxy, carboxy, -NR a3 R a4 , -CONR a3 R a4 , -NR a3 C(O)R a4 ;

[0035] R 2 is -NR x R y , -CONR x R y , -NR x C(O)R y , -R 9 , -OR 10 ; R 9 and R 10 are selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl; the substitution in R 9 and R 10 means substitution by one or more substituents selected from group B; group B substituents include: deuterium, halogen, hydroxy, cyano, carboxy, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR b1 R b2 , -CONR b1 R b2 , -NR b1 C(O)R b2 ;

[0036] R 3 is hydrogen or C1-C6alkyl;

[0037] R 4 is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 5-6 membered heterocyclyl; the substitution in R 4The mentioned substitution means substituted by one or more substituents selected from group C; the substituents of group C include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR c1 R c2 , -CONR c1 R c2 , -NR c1 C(O)R c2 ;

[0038] R 5 is hydrogen or deuterium;

[0039] R 6 is hydrogen or C1-C6alkyl;

[0040] or R 3 and R 6 together with the atom to which they are attached form a 4-6 membered heterocyclyl ring containing one N atom;

[0041] R 7 is hydrogen, C1-C6alkyl or halogen;

[0042] R 8 is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 8 The mentioned substitution means substituted by one or more substituents selected from group D; the substituents of group D include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR d1 R d2 , -CONR d1 R d2 , -NR d1 C(O)R d2 ;

[0043] X 1 is N or CR 14 , X 2 is N or CR 15 , and at least one of X 1 and X 2 is N;

[0044] R14 and R 15 each independently is selected from hydrogen, C1-C6alkyl, halogen or halogenated C1-C6alkyl;

[0045] R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R x , R y each independently is selected from hydrogen, C1-C6alkyl, halogenated C1-C6alkyl, C3-C6cycloalkyl;

[0046] and R 7 each independently is selected from hydrogen, C1-C6alkyl, halogen or halogenated C1-C6alkyl; denotes the point of attachment of the group to the rest of the molecule; can be a geometric isomer of (Z) or (E); denotes the point of attachment of the group to the rest of the molecule;

[0047] the C atom marked with * can be a chiral carbon atom or an achiral carbon atom; when said C atom marked with * is a chiral carbon atom, the configuration of said chiral carbon atom is S configuration or R configuration;

[0048] the heteroatoms in said 3-8 membered heterocyclyl, 4-6 membered heterocyclyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-10 membered heteroaryl are independently selected from 1, 2, 3 or 4 N, O and S.

[0049] In one embodiment,

[0050] Y is selected from CR 0 or N;

[0051] R 0 is hydrogen, C1-C6alkyl, halogenated C1-C6alkyl, -NR x0 R y0 ; R x0 and R y0 each independently is selected from hydrogen, C1-C6alkyl, halogen or halogenated C1-C6alkyl;

[0052] R 1 is R 13 ; R 13substituted or unsubstituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8cycloalkenyl, unsubstituted or substituted benzo C3-C6cycloalkyl, unsubstituted or substituted benzo 3-8 membered heterocyclyl; R 13 substituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8cycloalkenyl, unsubstituted or substituted benzo C3-C6cycloalkyl, unsubstituted or substituted benzo 3-8 membered heterocyclyl; R a1 R a2 , -CONR a1 R a2 , -NR a1 C(O)R a2 ; the A1group substituents include: deuterium, halogen, C1-C6alkoxy, halo C1-C6alkoxy, C3-C6cycloalkyl, cyano, hydroxyl, carboxyl, -NR a3 R a4 , -CONR a3 R a4 , -NR a3 C(O)R a4 ;

[0053] R 2 is -NR x R y , -CONR x R y , -NR x C(O)R y , -R 9 , -OR 10 ; R 9 and R 10 are selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl; R 9 and R 10The substitution mentioned herein refers to substitution by one or more substituents selected from group B; group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR b1 R b2 -CONR b1 R b2 -NR b1 C(O)R b2 ;

[0054] R 3 It is hydrogen;

[0055] R 4 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted 5-6 membered heterocyclic group; R 4 The substitution mentioned herein refers to substitution by one or more substituents selected from group C; group C substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR c1 R c2 -CONR c1 R c2 -NR c1 C(O)R c2 ;

[0056] R 5 It is hydrogen or deuterium;

[0057] R 6 It is hydrogen;

[0058] Or R 3 and R 6 Together with the atoms connected to them, they form a 4-6 membered heterocyclic group containing one nitrogen atom;

[0059] R 7 It is hydrogen or halogen;

[0060] R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C8 cycloalkyl, or unsubstituted or substituted 4-6 membered heterocyclic group; R 8The substituents mentioned are meant to be substituted with one or more substituents selected from group D; the substituents of group D include: deuterium, halogen, hydroxy, cyano, carboxy, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR d1 R d2 , -CONR d1 R d2 , -NR d1 C(O)R d2 ;

[0061] X 1 is N or CR 14 , X 2 is N or CR 15 , and at least one of X 1 and X 2 is N;

[0062] R 14 and R 15 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen or halogenated C1-C6alkyl;

[0063] R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R x , R y are each independently selected from the group consisting of hydrogen, C1-C6alkyl, halogenated C1-C6alkyl, C3-C6cycloalkyl;

[0064] and R 7 , respectively, are connected to the S atom and R denotes the geometric isomers which can be (Z) or (E); denotes the point of attachment of the group to the other position;

[0065] the C atom marked with * can be a chiral carbon atom or an achiral carbon atom; when the C atom marked with * is a chiral carbon atom, the configuration of the chiral carbon atom is S configuration or R configuration;

[0066] The heteroatoms in the 3-8 membered heterocyclyl, 4-6 membered heterocyclyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-10 membered heteroaryl are independently selected from 1, 2, 3, or 4 of N, O, and S.

[0067] In one embodiment,

[0068] Y is selected from CR 0 or N; R 0 is hydrogen, C1-C2 alkyl, haloC1-C2 alkyl, -NR x0 R y0 ; R x0 and R y0 are each independently selected from hydrogen, C1-C2 alkyl; R 1 is R 13 ; R 13 is unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 4-6 membered heterocyclyl, unsubstituted or substituted 5-6 membered heteroaryl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted benzoC3-C4 cycloalkyl; R 13 The substituents in R a1 , -CONR a2 R a1 , -NR a2 C(O)R a1 ; the A1group substituents include deuterium, halogen, C1-C6 alkoxy, haloC1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxyl, carboxyl, -NR a2 R a3 , -CONR a4 R a3 , -NR a4 C(O)R a3 ;

[0069] R a4 is -NR 2 R x , -CONR y R x , -NR y C(O)R x , -R y , -OR 9 ; R 10 and R 9 are each independently selected from hydrogen, C1-C2 alkyl; R 10selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 4-6 membered heterocyclyl, unsubstituted or substituted 5-6 membered heteroaryl; R 9 and R 10 substituted means substituted with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR b1 R b2 , -CONR b1 R b2 , -NR b1 C(O)R b2 ;

[0070] R 3 is hydrogen;

[0071] R 4 is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 4 substituted means substituted with one or more substituents selected from Group C; Group C substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR c1 R c2 , -CONR c1 R c2 , -NR c1 C(O)R c2 ;

[0072] R 5 is hydrogen or deuterium;

[0073] R 6 is hydrogen;

[0074] or R 3 and R 6 together with the atom to which they are attached form a 4-6 membered heterocyclyl containing one N atom;

[0075] R 7 is hydrogen or halogen;

[0076] R 8 is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 8 substituted with one or more substituents selected from Group D; Group D substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR d1 R d2 , -CONR d1 R d2 , -NR d1 C(O)R d2 ;

[0077] X 1 is N or CR 14 , X 2 is N or CR 15 , and at least one of X 1 and X 2 is N;

[0078] R 14 and R 15 are each independently selected from hydrogen, C1-C6alkyl, halogen, or halogenated C1-C6alkyl;

[0079] R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R x , R y are each independently selected from hydrogen, C1-C6alkyl, halogenated C1-C6alkyl, C3-C6cycloalkyl;

[0080] and R 7 , respectively, are connected to the S atom and R represents can be a geometric isomer of (Z) or (E); represents the point of attachment of the group to the other position;

[0081] The *-marked C atom can be a chiral carbon atom or a non-chiral carbon atom; when the *-marked C atom is a chiral carbon atom, the configuration of the chiral carbon atom is S configuration or R configuration;

[0082] The heteroatoms in the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

[0083] In one implementation method

[0084] Y is selected from CR 0 Or N;

[0085] R 0 It can be hydrogen, methyl, or -NH2;

[0086] R 1 For R 13 ;R 13 The following are unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl, unsubstituted or substituted benzocyclopropyl, unsubstituted or substituted benzocyclobutyl, unsubstituted or substituted six-membered heterocyclic group, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted No substitution or substitution No substitution or substitution No substitution or substitution R 13 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, unsubstituted or substituted by one or more substituents selected from group A1, namely C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR a1 R a2 -CONR a1 R a2 -NR a1 C(O)R a2 Group A1 substituents include: deuterium, halogen, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxyl, carboxyl, -NR a3 R a4 -CONR a3 R a4 -NR a3 C(O)R a4 ;

[0087] R 2 For -NR x R y -CONRx R y , -NR x C(O)R y , -R 9 , -OR 10 ; R 9 and R 10 are selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted 4-6 membered heterocyclyl; the substitution in R 9 and R 10 is by one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR b1 R b2 , -CONR b1 R b2 , -NR b1 C(O)R b2 ;

[0088] R 3 is hydrogen;

[0089] R 4 is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl; the substitution in R 4 is by one or more substituents selected from Group C; Group C substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR c1 R c2 , -CONR c1 R c2 , -NR c1 C(O)R c2 ;

[0090] R 5 is hydrogen or deuterium;

[0091] R 6 is hydrogen;

[0092] or R 3 and R 6Together with the atoms connected to them, they form a 4-6 membered heterocyclic group containing one nitrogen atom;

[0093] R 7 It is hydrogen or halogen;

[0094] R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4-6 membered heterocyclic group; R 8 The substitution mentioned herein refers to substitution by one or more substituents selected from group D; group D substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR d1 R d2 -CONR d1 R d2 -NR d1 C(O)R d2 ;

[0095] X 1 For N or CR 14 X 2 For N or CR 15 And X 1 and X 2 At least one of them is N;

[0096] R 14 and R 15 Each is independently selected from hydrogen, C1-C6 alkyl, halogen, or halogenated C1-C6 alkyl;

[0097] R a1 R a2 R a3 R a4 R b1 R b2 R c1 R c2 R d1 R d2 R x R y Each is independently selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, and C3-C6 cycloalkyl;

[0098] With S atoms and R 7 Connected separately express It can be a geometric isomer of (Z) or (E); denotes the point of attachment of the group to the rest of the molecule;

[0099] the *-marked C atom can be a chiral carbon atom or an achiral carbon atom; when the *-marked C atom is a chiral carbon atom, the configuration of the chiral carbon atom is S-configuration or R-configuration;

[0100] the heteroatoms in the 4-6 membered heterocyclyl, 5-6 membered heteroaryl are independently selected from 1, 2, 3 or 4 of N, O and S.

[0101] In one embodiment, R 0 is hydrogen, C1-C2alkyl, haloC1-C2alkyl, -NR x0 R y0 ; R x0 and R y0 are each independently selected from hydrogen, C1-C2alkyl; preferably, R 0 is hydrogen, methyl or -NH2.

[0102] In one embodiment, R 1 is R 13 ; R 13 is selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl, unsubstituted or substituted benzocyclopropyl, unsubstituted or substituted benzocyclobutyl, unsubstituted or substituted six-membered heterocyclyl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted cyclopentenyl, unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted R 13 substituted means substituted with 1 or more substituents selected from Group A; Group A substituents include: oxo (=0), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

[0103] In one embodiment, R 1 is R 13 ; R 13 is selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted R 13 The substituents described in the present application mean being substituted with one or more substituents selected from Group A; Group A substituents include: oxo (=0), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

[0104] Preferably, Group A substituents in the present application include: oxo (=0), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

[0105] More preferably, Group A substituents in the present application include: halogen, hydroxyl, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy.

[0106] More preferably, Group A substituents in the present application include: halogen, hydroxyl, cyano, C1-C2 alkyl, deuterated C1-C2 alkyl, halogenated C1-C2 alkyl, C1-C2 alkoxy-substituted C1-C2 alkyl, C1-C2 alkoxy, halogenated C1-C2 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy.

[0107] In one embodiment, R 1 is selected from the following structures:

[0108] In one embodiment, R 2 is -NR x R y , -CONR x R y , -NRx C(O)R y , -R 9 ; R 9 is selected from unsubstituted or substituted C1-C6alkyl; R 9 substituted is meant substituted with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl; R x , R y are each independently selected from hydrogen or C1-C6alkyl, C3-C6cycloalkyl.

[0109] In one embodiment, R 2 is -NR x R y or -R 9 ; R 9 is selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 9 substituted is meant substituted with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl; R x , R y are each independently selected from hydrogen or C1-C6alkyl, C3-C6cycloalkyl.

[0110] In one embodiment, R 2 is -CF2R 9b ; R 9b is selected from C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, halogen, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6alkoxy substituted C1-C6alkyl.

[0111] In one embodiment, R 2 is methyl, ethyl, t-butyl,

[0112] In one embodiment, R 4 is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 4substituted with one or more substituents selected from Group C; Group C substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR c1 c2 c1 c2 c1 c2 c1 c2 each independently selected from hydrogen or C1-C6alkyl, C3-C6cycloalkyl.

[0113] In one embodiment, R 4 is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl; R 4 substituted with one or more substituents selected from Group C; Group C substituents include: halogen, hydroxyl, cyano, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy, halogenated C1-C6alkoxy.

[0114] In one embodiment, R 8 is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 8 substituted with one or more substituents selected from Group D; Group D substituents include: deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkoxy, amino, -N(CH3)2.

[0115] In one embodiment, R 8 is methyl, ethyl, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2,

[0116] In one embodiment, the compound of Formula (I-A) has a structure according to Formula (II) or Formula (III):

[0117]

[0118] wherein p is 1 or 2; X 1 , X 2 , R 1 , R 2 , R 4 , R​​​​​​​7 and R 8 are as defined above.

[0119] In one embodiment, the compound of Formula (I-A) has a structure according to Formula (IV), (V), (VI), or (VII):

[0120]

[0121] wherein,

[0122] X 1 is N or CH; X 2 is N or CH; and X 1 and X 2 are each N;

[0123] R 13 is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8cycloalkenyl, unsubstituted or substituted benzo C3-C6cycloalkyl, unsubstituted or substituted benzo 3-8 membered heterocyclyl; R 13 said substitution in R 4a is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8cycloalkenyl, unsubstituted or substituted benzo C3-C6cycloalkyl, unsubstituted or substituted benzo 3-8 membered heterocyclyl; R

[0124] n is 0, 1, or 2;

[0125] R 4a is halogen, hydroxyl, cyano, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl;

[0126] R 2 is -NR x R y , -CONR x R y , -NR x C(O)R y , -R 9 ; R 9 is selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 9The substitution mentioned herein refers to substitution by one or more substituents selected from group B; group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; R x R y Each is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0127] In one embodiment, the compound represented by formula (IA) has the following structure:

[0128]

[0129]

[0130] in,

[0131] R 13 It can be an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C3-C8 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-8 membered heterocyclic group, an unsubstituted or substituted 5-10 membered heteroaryl, an unsubstituted or substituted C3-C8 cycloalkenyl, an unsubstituted or substituted benzo[3-C6] cycloalkyl, or an unsubstituted or substituted benzo[3-8] membered heterocyclic group; R 13 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

[0132] In one implementation, in equations (V-1), (V-2), and (V-3), R 13 Selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution R 13The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

[0133] In one implementation, in equations (V-1), (V-2), and (V-3), R 13 Selected from the following structure:

[0134] In one embodiment, the compound represented by formula (IA) has the following structure:

[0135]

[0136] Among them, X 2 R 0 R 1 R 2 R 4 and R 8 The definition is the same as described above.

[0137] Preferably, in formula (IX),

[0138] X 2 For N or CH;

[0139] R 0 It is hydrogen or amino;

[0140] R 4 It is cyclopropyl or cyclobutyl;

[0141] R 1 Selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution R 1In the above mentioned substitutions are meant to be substituted by one or more substituents selected from group A; group A substituents include: oxo (=0), deuterium, halogen, hydroxy, cyano, carboxy, Ci-C6alkyl, deuterated Ci-C6alkyl, halogenated Ci-C6alkyl, Ci-C6alkoxy substituted Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, halogenated Ci-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, NH2, -CONH2, -NHC(O)CH3;

[0142] R 2 is -NR x R y or -R 9 ; R 9 is selected from unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted R 9 In the above mentioned substitutions are meant to be substituted by one or more substituents selected from group B; group B substituents include: deuterium, halogen, hydroxy, cyano, carboxy, Ci-C6alkyl, deuterated Ci-C6alkyl, Ci-C6alkoxy, C3-C6cycloalkyl; R x , R y are each independently selected from hydrogen or Ci-C6alkyl, C3-C6cycloalkyl;

[0143] R 8 is unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 8 In the above mentioned substitutions are meant to be substituted by one or more substituents selected from group D; group D substituents include: deuterium, halogen, Ci-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkoxy, amino, -N(CH3)2.

[0144] In formula (IX),

[0145] Preferably, X 2 is N.

[0146] Preferably, R 0 is hydrogen or amino.

[0147] Preferably, R 4 is cyclopropyl or cyclobutyl.

[0148] Preferably, R 1 is selected from

[0149] Preferably, R 2 is methyl, ethyl, tert-butyl,

[0150] Preferably, R8 is methyl, ethyl, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2,

[0151] In one embodiment, the compound of Formula (I-A) has the structure:

[0152]

[0153] R 7 is halogen;

[0154] R 13 is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8cycloalkenyl, unsubstituted or substituted benzo C3-C6cycloalkyl, unsubstituted or substituted benzo 3-8 membered heterocyclyl; R 13 substituted with one or more substituents selected from Group A; Group A substituents include: oxo (=0), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

[0155] In Formula (X), preferably, R 7 is halogen; R 13 is selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted R 13The substituents in the above mentioned groups are 1 or more substituents selected from the group A; the group A substituents include: oxo (=0), deuterium, halogen, hydroxy, cyano, carboxy, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

[0156] In formula (X), preferably, R 7 is halogen; R 13 is selected from the group consisting of:

[0157] In one embodiment, the compound of formula (I-A) has the following structure:

[0158]

[0159] R 4 is cyclopropyl or cyclobutyl;

[0160] R 1 is selected from the group consisting of unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted unsubstituted or substituted R 1 The substituents in the above mentioned groups are 1 or more substituents selected from the group A; the group A substituents include: oxo (=0), deuterium, halogen, hydroxy, cyano, carboxy, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3;

[0161] R 2 is -NR x R y or -R 9 ; R 9selected from the group consisting of unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R R 9 substituted with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl; R x , R y each independently selected from hydrogen or C1-C6alkyl, C3-C6cycloalkyl;

[0162] R 8 unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 8 substituted with one or more substituents selected from Group D; Group D substituents include: deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkoxy, amino, -N(CH3)2.

[0163] In Formula (XI), preferably,

[0164] X 2 is N;

[0165] R 0 is hydrogen or amino;

[0166] R 4 is cyclopropyl or cyclobutyl;

[0167] R 1 selected from the group consisting of

[0168] R 2 is methyl, ethyl, tert-butyl,

[0169] R 8 is methyl, ethyl, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2,

[0170] In a particular embodiment, the compound of Formula (I-A) according to the present application is selected from the group consisting of:

[0171]

[0172]

[0173]

[0174] In the specific embodiments, the compound of formula (I-A) is selected from the following compounds:

[0175]

[0176]

[0177] The present application also provides a preparation method of the compound of formula (I), a pharmaceutically acceptable salt thereof, an isotopically labeled compound thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof. Specifically, the preparation method includes the following methods:

[0178] Method 1:

[0179]

[0180] Step 1: Compound a-1 reacts with compound R 2 to obtain compound a-2 through nucleophilic reaction or metal reagent catalyzed coupling reaction; or compound a-1 reacts with a boron reagent containing R 2 , a tin reagent containing R 2 , a zinc reagent containing R 2 , a Grignard reagent containing R 2 , or a carboxylic acid containing R 2 to obtain compound a-2 through coupling reaction; or compound a-1 reacts with a boron reagent (such as isopropenyl boronic acid pinacol ester, 2-(1-cyclopropylethenyl) boronic acid pinacol ester, etc.) or a tin reagent (such as tributyl(1-ethoxyvinyl)tin, etc.) through coupling reaction, and then the obtained ketone carbonyl intermediate is treated through acidic condition or oxidation condition to obtain compound a-2; wherein, X 1 , X 2 and R 2 are defined as described above; Y 1 and Y 2 are each independently selected from F, Cl, Br, I, OTs, OMs, OTf; Y 3 is selected from C1-C6 alkyl, benzyl; the metal reagent can be a reagent containing Pd, Cu, Ni or Fe, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4, CuI, NiCl2, FeCl3, Fe(acac)3; the boron reagent containing R 2 may be R 2 B(OH)2, R 2 B(Pin); the tin reagent containing R 2 may be R 2 Sn(Bu)3; the zinc reagent containing R 2 may be (R 2)2Zn, R 2 ZnCl, R 2 ZnBr; said Grignard reagent containing R 2 may be R 2 MgCl, R 2 MgBr; said carboxylic acid containing R 2 may be R 2 COOH; said acidic condition can be carried out in the presence of trifluoroacetic acid, p-toluenesulfonic acid or hydrochloric acid; said oxidation condition can be carried out in the presence of K2OsO4 / NaIO4, RuCl3 / Oxone or O3;

[0181] Step 2: compound a-2 reacts with compound R 1 H via nucleophilic reaction or metal reagent catalyzed coupling reaction to obtain compound a-3; or compound a-2 reacts with boron reagent containing R 1 , tin reagent containing R 1 , zinc reagent containing R 1 , Grignard reagent containing R 1 or carboxylic acid containing R 1 via coupling reaction to obtain compound a-3; wherein, R 1 is defined as above; said metal reagent can be Pd, Cu, Ni or Fe containing reagent, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4, Cul, NiCl2, FeCl3, Fe(acac)3; said boron reagent containing R 1 may be R 1 B(OH)2, R 1 B(Pin); said tin reagent containing R 1 may be R 1 Sn(Bu)3; said zinc reagent containing R 1 may be (R 1 )2Zn, R 1 ZnCl, R 1 ZnBr; said Grignard reagent containing R 1 may be R 1 MgCl, R 1 MgBr; said carboxylic acid containing R 1 may be R 1 COOH;

[0182] Step 3: compound a-3 undergoes hydrolysis reaction under basic or acidic condition to obtain compound a-4; said basic condition can be carried out in the presence of inorganic base (such as LiOH, NaOH); said acidic condition can be carried out in the presence of trifluoroacetic acid or hydrochloric acid;

[0183] Step 4: condensation of compound a-4 with amine a-5 to give compound (I); wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same as defined above.

[0184] Method 2:

[0185]

[0186] Step 1: nucleophilic reaction or metal reagent catalyzed coupling reaction of compound a-6 with compound R 2 H to give a-7; or metal reagent catalyzed coupling reaction of compound a-6 with boron reagent containing R 2 , tin reagent containing R 2 , zinc reagent containing R 2 , Grignard reagent containing R 2 or carboxylic acid containing R 2 to give compound a-7; or metal reagent catalyzed coupling reaction of compound a-6 with boron reagent (such as isopropenyl boronic acid pinacol ester, 2-(1-cyclopropylethenyl)boronic acid pinacol ester, etc.) or tin reagent (such as tributyl(1-ethoxyvinyl)tin, etc.), followed by acid treatment or oxidation treatment to give the ketone carbonyl intermediate, and then reaction with fluorination reagent to give compound a-7; wherein X 1 , X 2 and R 2 are the same as defined above; Y 2 is selected from F, Cl, Br, I, OTs, OMs, OTf; Y 3 is selected from C1-C6 alkyl, benzyl; the metal reagent can be Pd, Cu, Ni or Fe containing reagent, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4, CuI, NiCl2, FeCl3, Fe(acac)3; the boron reagent containing R 2 can be R 2 B(OH)2, R 2 B(Pin); the tin reagent containing R 2 can be R 2 Sn(Bu)3; the zinc reagent containing R 2 can be (R 2 )2Zn, R 2 ZnCl, R 2 ZnBr; the Grignard reagent containing R 2 can be R 2 MgCl, R 2MgBr; the R-containing 2 Carboxylic acids can be R 2 COOH; the acidic conditions can be carried out in the presence of trifluoroacetic acid, p-toluenesulfonic acid, or hydrochloric acid; the oxidation conditions can be carried out in the presence of K2OsO4 / NaIO4, RuCl3 / Oxone, or O3; the fluorinating agent can be DAST, BAST, or SF4.

[0187] Step 2: Compound a-7 reacts with a halogenating reagent to give compound a-8; wherein, Y 1a The halogenating agent is selected from F, Cl, Br, and I; the halogenating agent can be SelectFluor, NBS, NCS, NIS, or dibromohydantoin.

[0188] Step 3: Compound a-8 and compound R 1 H undergoes a nucleophilic reaction or a metal reagent-catalyzed coupling reaction to give compound a-3; or compound a-8 reacts with R-containing compounds under metal reagent catalysis. 1 Boron reagents, containing R 1 Tin reagents, containing R 1 Zinc reagents, containing R 1 Grignard reagents or reagents containing R 1 The carboxylic acid undergoes a coupling reaction to give compound a-3; wherein, R 1 The definition is the same as described above; the metal reagent can be a reagent containing Pd, Cu, Ni, or Fe, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4, CuI, NiCl2, FeCl3, Fe(acac)3; the R-containing reagent... 1 Boron reagents can be R 1 B(OH)2, R 1 B(Pin); the one containing R 1 The tin reagent can be R 1 Sn(Bu)3; the R-containing 1 The zinc reagent can be (R) 1 )2Zn、R 1 ZnCl, R 1 ZnBr; the R-containing 1 Grignard reagents can be R 1 MgCl, R 1 MgBr; the R-containing 1 Carboxylic acids can be R 1 COOH;

[0189] Fourth step: compound a-3 undergoes hydrolysis reaction under basic or acidic condition to obtain compound a-4; the basic condition can be carried out in the presence of inorganic base (such as LiOH, NaOH); the acidic condition can be carried out in the presence of trifluoroacetic acid or hydrochloric acid;

[0190] Fifth step: compound a-4 undergoes condensation reaction with amine a-5 to obtain compound (I); wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same as defined above.

[0191] Method three:

[0192]

[0193] First step: compound a-9 undergoes nucleophilic reaction or metal reagent catalyzed coupling reaction with compound R 1 H to obtain compound a-10; or compound a-9 undergoes coupling reaction with boron reagent containing R 1 , tin reagent containing R 1 , zinc reagent containing R 1 or carboxylic acid containing R 1 under the catalysis of metal reagent to obtain compound a-10; wherein, X 1 , X 2 and R 1 are the same as defined above; Y 1 is selected from F, Cl, Br, I, OTs, OMs, OTf; Y 4 is selected from Cl, Br, I, OTs, OMs, OTf; the metal reagent can be Pd, Cu or Ni containing reagent, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(OAc)2, Pd(PPh3)4, CuI, NiCl2; the boron reagent containing R 1 can be R 1 B(OH)2, R 1 B(Pin); the tin reagent containing R 1 can be R 1 Sn(Bu)3; the zinc reagent containing R 1 can be (R 1 )2Zn, R 1 ZnCl, R 1 ZnBr; the carboxylic acid containing R 1 can be R 1 COOH;

[0194] Step 2: Compound a-10 undergoes metal reagent catalyzed insertion carbonylation reaction to obtain compound a-11; wherein Y 3 is selected from C1-C6 alkyl, benzyl; the metal reagent can be a Pd-containing reagent, such as Pd(dppf)Cl2, Pd(PPh3)Cl2;

[0195] Step 3: Compound a-11 undergoes Sandmeyer reaction to obtain compound a-12; wherein Y 2a is selected from F, Cl, Br, I;

[0196] Step 4: Compound a-12 undergoes nucleophilic reaction or metal reagent catalyzed coupling reaction with compound R 2 H to obtain a-3; or compound a-12 undergoes coupling reaction with boron reagent containing R 2 , tin reagent containing R 2 , zinc reagent containing R 2 , Grignard reagent containing R 2 , or carboxylic acid containing R 2 under the catalysis of metal reagent to obtain compound a-3; or compound a-12 undergoes coupling reaction with boron reagent (such as isopropenyl boronic acid pinacol ester, 2-(1-cyclopropylethenyl) boronic acid pinacol ester, etc.) or tin reagent (such as tributyl(1-ethoxyvinyl)tin, etc.) under the catalysis of metal reagent, and then the obtained ketone carbonyl intermediate is treated by acidic condition or oxidation condition, and then reacts with fluorination reagent to obtain compound a-3; wherein the definition of R 2 is the same as described above; the metal reagent can be a Pd-, Cu-, Ni- or Fe-containing reagent, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4, CuI, NiCl2, FeCl3, Fe(acac)3; the boron reagent containing R 2 can be R 2 B(OH)2, R 2 B(Pin); the tin reagent containing R 2 can be R 2 Sn(Bu)3; the zinc reagent containing R 2 can be (R 2 )2Zn, R 2 ZnCl, R 2 ZnBr; the Grignard reagent containing R 2 can be R 2 MgCl, R 2 MgBr; the carboxylic acid containing R 2 can be R 2COOH; the acidic condition can be carried out in the presence of trifluoroacetic acid, p-toluene sulfonic acid or hydrochloric acid; the oxidative condition can be carried out in the presence of K2OsO4 / NaIO4, RuCl3 / Oxone or O3; the fluorinating reagent can be DAST, BAST, SF4;

[0197] Step 5: compound a-3 undergoes hydrolysis reaction under basic or acidic condition to obtain compound a-4; the basic condition can be carried out in the presence of inorganic base (such as LiOH, NaOH); the acidic condition can be carried out in the presence of trifluoroacetic acid or hydrochloric acid;

[0198] Step 6: compound a-4 undergoes condensation reaction with amine a-5 to obtain compound (I); wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same as previously defined.

[0199] Method four:

[0200]

[0201] Step 1: compound a-13 undergoes nucleophilic reaction or metal reagent catalyzed coupling reaction with compound R 2 H to obtain compound a-14; or compound a-13 undergoes coupling reaction with boron reagent containing R 2 , tin reagent containing R 2 , zinc reagent containing R 2 or carboxylic acid containing R 2 under catalysis of metal reagent to obtain compound a-14; or compound a-13 undergoes coupling reaction with boron reagent (such as isopropenyl boronic acid pinacol ester, 2-(1-cyclopropylethenyl) boronic acid pinacol ester, etc.) or tin reagent (such as tributyl(1-ethoxyvinyl)tin, etc.) under catalysis of metal reagent, and then the obtained ketone carbonyl intermediate is treated by acidic condition or oxidative condition, and then reacts with fluorinating reagent to obtain compound a-14; wherein, X 1 , X 2 and R 2 are the same as previously defined; Y 1 and Y 2 are selected from F, Cl, Br, I, OTs, OMs, OTf; Y 3 is selected from C1-C6 alkyl, benzyl; the metal reagent can be Pd, Cu or Ni containing reagent, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4, CuI, NiCl2; the boron reagent containing R 2 can be R 2B(OH)2, R 2 B(Pin); the tin reagent containing R 2 may be R 2 Sn(Bu)3; the zinc reagent containing R 2 may be (R 2 )2Zn, R 2 ZnCl, R 2 ZnBr; the carboxylic acid containing R 2 may be R 2 COOH; the acidic condition may be carried out in the presence of trifluoroacetic acid, p-toluenesulfonic acid or hydrochloric acid; the oxidizing condition may be carried out in the presence of K2OsO4 / NaIO4, RuCl3 / Oxone or O3; the fluorinating reagent may be DAST, BAST, SF4;

[0202] Step 2: Sandmeyer reaction of compound a-14 to give a-2;

[0203] Step 3: nucleophilic reaction or metal reagent catalyzed coupling reaction of compound a-2 with compound R 1 H to give compound a-3; or coupling reaction of compound a-2 with boron reagent containing R 1 , tin reagent containing R 1 , zinc reagent containing R 1 , Grignard reagent containing R 1 or carboxylic acid containing R 1 to give compound a-3; wherein R 1 is as previously defined; the metal reagent may be Pd, Cu, Ni or Fe containing reagent such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4, CuI, NiCl2, FeCl3, Fe(acac)3; the boron reagent containing R 1 may be R 1 B(OH)2, R 1 B(Pin); the tin reagent containing R 1 may be R 1 Sn(Bu)3; the zinc reagent containing R 1 may be (R 1 )2Zn, R 1 ZnCl, R 1 ZnBr; the Grignard reagent containing R 1 may be R 1 MgCl, R 1 MgBr; the carboxylic acid containing R 1 may be R 1 COOH;

[0204] Fourth step: compound a-3 undergoes hydrolysis reaction under basic or acidic conditions to obtain compound a-4; the basic condition can be carried out in the presence of inorganic base (such as LiOH, NaOH); the acidic condition can be carried out in the presence of trifluoroacetic acid or hydrochloric acid;

[0205] Fifth step: compound a-4 undergoes condensation reaction with amine a-5 to obtain compound (I); wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same as defined above.

[0206] Method five:

[0207]

[0208] First step: compound a-15 undergoes coupling reaction with boron reagent or tin reagent under the catalysis of metal reagent, and then is treated by acidic condition hydrolysis or oxidation condition to obtain compound a-16; wherein, X 1 and X 2 are the same as defined above; Y 1 is selected from F, Cl, Br, I, OTs, OMs, OTf; Y 2b is selected from Cl, Br, I, OTs, OMs, OTf; Y 3 is selected from C1-C6 alkyl, benzyl; Z is selected from C1-C6 alkyl, C3-C6 cycloalkyl; the metal reagent can be Pd-containing reagent, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4; the boron reagent can be isopropenyl boronic acid pinacol ester, 2-(1-cyclopropylethenyl) boronic acid pinacol ester; the tin reagent can be tributyl(1-ethoxyvinyl)tin; the acidic condition can be carried out in the presence of trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid; the oxidation condition can be carried out in the presence of K2OsO4 / NaIO4, RuCl3 / Oxone or O3;

[0209] Second step: compound a-16 undergoes Sandmeyer reaction to obtain a-17;

[0210] Third step: compound a-17 undergoes nucleophilic reaction or metal reagent catalyzed coupling reaction with compound R 1 H to obtain compound a-18; or compound a-17 undergoes metal reagent catalyzed coupling reaction with boron reagent containing R 1 , tin reagent containing R 1 , zinc reagent containing R 1 or R 1to give compound a-18; wherein, R 1 is as defined above; the metal reagent can be Pd, Cu or Ni containing reagent, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4, CuI, NiCl2; the boron reagent containing R 1 can be R 1 B(OH)2, R 1 B(Pin); the tin reagent containing R 1 can be R 1 Sn(Bu)3; the zinc reagent containing R 1 can be (R 1 )2Zn, R 1 ZnCl, R 1 ZnBr; the carboxylic acid containing R 1 can be R 1 COOH;

[0211] Fourth step: compound a-18 reacts with fluorination reagent to give compound a-19; wherein, the fluorination reagent can be DAST, BAST, SF4;

[0212] Fourth step: compound a-19 undergoes hydrolysis reaction under basic or acidic condition to give compound a-20; the basic condition can be carried out in the presence of inorganic base (such as LiOH, NaOH); the acidic condition can be carried out in the presence of trifluoroacetic acid or hydrochloric acid;

[0213] Fifth step: compound a-20 reacts with amine a-5 to give compound (I-1); wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above.

[0214] Method six:

[0215]

[0216] First step: compound a-21 reacts with compound R 1 H to give compound a-22 through nucleophilic reaction or metal reagent catalyzed coupling reaction; or compound a-21 reacts with boron reagent containing R 1 , tin reagent containing R 1 , zinc reagent containing R 1 or carboxylic acid containing R 1 under the catalysis of metal reagent to give compound a-21; wherein, X 1 , X 2and R 1 are as defined above; Y 1 is selected from F, Cl, Br, I, OTs, OMs, OTf; the metal reagent can be a Pd-, Cu- or Ni-containing reagent, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4, CuI, NiCl2; the boron reagent containing R 1 can be R 1 B(OH)2, R 1 B(Pin); the tin reagent containing R 1 can be R 1 Sn(Bu)3; the zinc reagent containing R 1 can be (R 1 )2Zn, R 1 ZnCl, R 1 ZnBr; the carboxylic acid containing R 1 can be R 1 COOH;

[0217] Step 2: nucleophilic addition of compound a-22 with a Grignard reagent containing Z, a lithium reagent containing Z or a zinc reagent containing Z to obtain compound a-23; wherein Z is selected from C1-C6alkyl, C3-C6cycloalkyl; the Grignard reagent containing Z can be ZMgCl, ZMgBr; the lithium reagent containing Z can be ZLi; the zinc reagent containing Z can be (Z)2Zn, ZZnCl, ZZnBr;

[0218] Step 3: reaction of compound a-23 with an oxidizing agent to obtain compound a-24; wherein the oxidizing agent can be MnO2, SO3 / pyridine, Dess-Martin oxidizing agent, pyridinium chlorochromate, Swern oxidizing agent, Corey-Kim oxidizing agent, NaClO / TEMPO, Oxone, Fe(NO3)3;

[0219] Step 4: reaction of compound a-24 with a fluorinating reagent to obtain compound a-25; wherein the fluorinating reagent can be DAST, BAST, SF4;

[0220] Step 5: reaction of compound a-25 with an oxidizing agent to obtain compound a-26; wherein the oxidizing agent can be SeO2, IBX;

[0221] Step 6: reaction of compound a-26 with an oxidizing agent to obtain compound a-20; wherein the oxidizing agent can be Oxone, HIO4, NaClO2 / NaH2PO4 / isobutene, CrO3 / H2SO4;

[0222] Step 7: condensation of compound a-20 with amine a-5 to give compound (I-1); wherein R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined above.

[0223] Method 7:

[0224]

[0225] Step 1: reaction of compound a-27 with p-toluenesulfonyl chloride in the presence of dimethyl sulfoxide to give compound a-28; wherein Y 3 is selected from C1-C6 alkyl, benzyl; Pg is selected from Cbz;

[0226] Step 2: reaction of compound a-28 with an amino acid derivative to give compound a-29; wherein R 2 is as defined above;

[0227] Step 3: ring closure of compound a-29 under hydrogenation conditions catalyzed by a metal reagent, such as Pd on charcoal, palladium hydroxide, and oxidation to give compound a-30; wherein the metal reagent can be a Pd-containing reagent, such as palladium on charcoal, palladium hydroxide; the oxidizing reagent can be SO3 / pyridine;

[0228] Step 4: reaction of compound a-30 with a halogenating reagent or a sulfonylating reagent to give compound a-31; wherein Y 1 is selected from F, Cl, Br, I, OTs, OMs, OTf; the halogenating reagent can be phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, sulfonyl fluoride; the sulfonylating reagent can be p-toluenesulfonyl chloride, triflic anhydride, methanesulfonic anhydride;

[0229] Step 5: nucleophilic reaction or metal reagent catalyzed coupling reaction of compound a-31 with compound R 1 H to give compound a-32; or coupling reaction of compound a-31 with a boron reagent containing R 1 , a tin reagent containing R 1 , a zinc reagent containing R 1 , a Grignard reagent containing R 1 , or a carboxylic acid containing R 1 under the catalysis of a metal reagent to give compound a-32; wherein R 1 is as defined above; the metal reagent can be a Pd-, Cu-, Ni-, or Fe-containing reagent, such as Pd(dppf)Cl2, Pd(PPh3)Cl2, Pd(PPh3)4, CuI, NiCl2, FeCl3, Fe(acac)3; the metal reagent containing R1 The boron reagent can be R 1 B(OH)2, R 1 B(Pin); the R 1 The tin reagent can be R 1 Sn(Bu)3; the R 1 The zinc reagent can be (R 1 )2Zn, R 1 ZnCl, R 1 ZnBr; the R 1 The Grignard reagent can be R 1 MgCl, R 1 MgBr; the R 1 The carboxylic acid can be R 1 COOH;

[0230] Step 6: Compound a-32 is subjected to hydrolysis reaction under basic or acidic conditions to obtain compound a-33; the basic condition can be carried out in the presence of inorganic base (such as LiOH, NaOH); the acidic condition can be carried out in the presence of trifluoroacetic acid or hydrochloric acid;

[0231] Step 7: Compound a-33 is subjected to condensation reaction with amine a-5 to obtain compound (I-2); wherein R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the same meaning as described above.

[0232] The application also provides a pharmaceutical composition comprising the above-mentioned compound represented by formula (I), pharmaceutically acceptable salt thereof, isotope marker thereof, solvate thereof, solvate of the pharmaceutically acceptable salt thereof or prodrug thereof and pharmaceutical adjuvant.

[0233] In the composition, the amount of the compound represented by formula (I), pharmaceutically acceptable salt thereof, isotope marker thereof, solvate thereof, solvate of the pharmaceutically acceptable salt thereof or prodrug thereof can be an effective treatment amount.

[0234] The application also provides use of the above-mentioned compound represented by formula (I), pharmaceutically acceptable salt thereof, isotope marker thereof, solvate thereof, solvate of the pharmaceutically acceptable salt thereof or prodrug thereof in preparation of WRN inhibitor or medicine; the medicine is a medicine for treating and / or preventing diseases by inhibiting WRN.

[0235] The present application also provides a use of the above-mentioned compound represented by formula (I), pharmaceutically acceptable salt thereof, isotope label thereof, solvate thereof, solvate of the pharmaceutically acceptable salt thereof or prodrug thereof in the preparation of a drug for treating and / or preventing cancer.

[0236] The present application also provides a treatment method for treating and / or preventing cancer, which administers a therapeutically effective amount of the above-mentioned compound represented by formula (I), pharmaceutically acceptable salt thereof, isotope label thereof, solvate thereof, solvate of the pharmaceutically acceptable salt thereof or prodrug thereof to a patient.

[0237] The term "pharmaceutically acceptable" means relatively non-toxic, safe, suitable for patient use.

[0238] The term "pharmaceutically acceptable salt" means a salt of a compound with a pharmaceutically acceptable acid or base. When a compound contains relatively acidic functionalities, base addition salts can be obtained by contacting the compound with a sufficient amount of the pharmaceutically acceptable base in a suitable inert solvent. Where the compound contains relatively basic functionalities, acid addition salts can be obtained by contacting the compound with a sufficient amount of the pharmaceutically acceptable acid in a suitable inert solvent. For a detailed description of the preparation of pharmaceutical salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0239] The term "solvate" means a compound formed by the combination of a compound with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are classified into stoichiometric solvates and non-stoichiometric solvates.

[0240] The term "solvate of a pharmaceutically acceptable salt" means a compound formed by the combination of a compound with a pharmaceutically acceptable acid or base, a solvent (including but not limited to: water, methanol, ethanol, etc.). The amount of solvent can be stoichiometric or non-stoichiometric.

[0241] The "-" at the end of a group means that the group is attached to the rest of the molecule at that point. For example, CH3-C(=O)- means acetyl.

[0242] In , the wavy line indicates the point of attachment of the group to the rest of the molecule.

[0243] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0244] The term "oxo" refers to =O, an oxygen atom replacing two hydrogens on the same carbon atom, i.e., a carbonyl group replacing a methylene group.

[0245] The term "alkyl" refers to a straight or branched-chain, u-valent hydrocarbon radical having the indicated number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0246] The term "alkoxy" refers to the group R X -O-, R X The term "alkyl" is defined hereinabove. Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, and the like.

[0247] The term "alkenyl" refers to a straight or branched-chain, unsaturated, u-valent hydrocarbon radical having the indicated number of carbon atoms (e.g., C2-C6) with one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 double bonds. Alkenyl groups include, but are not limited to, ethenyl, and the like.

[0248] The term "alkynyl" refers to a straight or branched-chain, unsaturated, u-valent hydrocarbon radical having the indicated number of carbon atoms (e.g., C2-C6) with one or more (e.g., 1, 2, or 3) carbon-carbon triple bonds. Alkenyl groups include, but are not limited to, ethynyl, and the like.

[0249] The term "cycloalkyl" refers to a cyclic, saturated, u-valent hydrocarbon radical having the indicated number of carbon atoms (e.g., C3-C6) which is monocyclic, bridged, or spirocyclic. Cycloalkyl groups include, but are not limited to: and the like.

[0250] The term "cycloalkenyl" refers to an alicyclic hydrocarbon radical containing 1, 2, or 3 double bonds having the indicated number of carbon atoms (e.g., C3-C12, C3-C8, C3-C6). Cycloalkyl groups include, but are not limited to: and the like.

[0251] The term "cycloalkoxy" refers to the group R Y -O-, R Y The term "cycloalkyl" is defined hereinabove. Cycloalkoxy groups include, but are not limited to, cyclopropyloxy and the like.

[0252] The term "aryl" refers to a u-valent aromatic carbocyclic radical having the indicated number of carbon atoms (e.g., C6-C 10) of the present application, the term "aryl" refers to a cyclic, unsaturated, monovalent hydrocarbon group which is monocyclic or polycyclic (e.g., 2 or 3), sharing two atoms and one bond between single rings when polycyclic, and each ring of which is aromatic. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0253] In the present application, the term "heterocyclyl" refers to a non-aromatic cyclic group comprising at least one carbon atom and at least one (e.g., 1-3) ring heteroatom selected from N, O, S, wherein the sulfur atom is optionally oxidized or aminated. Examples of "heterocyclyl" groups can be specifically groups formed by replacing one or more ring carbons of a cycloalkyl group as defined in the present application with a moiety selected from -O-, -N=, -NR-, -S-, -S(=O)-, and -S(=O)2-,

[0254] wherein R is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or a nitrogen protecting group (e.g., benzyloxycarbonyl, p-methoxybenzyl carbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, and the like). "Heterocyclyl" groups include monocyclic and fused, bridged, spiro, and the like bicyclic structures and can be partially or fully saturated, e.g., 4-10 membered saturated or unsaturated heterocyclyl, 4-6 membered saturated or unsaturated heterocyclyl, 3-8 membered heterocyclyl, 3-6 membered heterocyclyl, and the like; such as tetrahydrofuranyl, pyrrolidinyl, oxetanyl, oxepanyl, azetidinyl, oxiranyl, aziridinyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, azepanyl, oxepanyl, and the like. For example, the heterocyclyl groups of the present application can be preferably selected from the following groups:

[0255]

[0256] In the present application, the term "heteroaryl" refers to a monocyclic or bicyclic or fused polycyclic ring aromatic hydrocarbon group having the specified number of ring atoms (e.g., 5-10 membered), which contains at least one (e.g., 1-3) ring heteroatom independently selected from N, O, and S (e.g., N) in the ring, with the remaining ring atoms being carbon atoms; such as imidazolyl, pyridyl, pyrrolyl, thiazolyl, furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, pyrimidinyl, 1,2,4-triazolyl, benzoxazolyl, imidazopyridinyl, triazolopyridinyl, benzofuranyl, pyrazolopyrimidinyl, benzodioxolyl, indolyl, quinolinyl, isoquinolinyl, and the like.

[0257] The term "heteroaromatic ring" satisfies at least one of the following conditions, with the remaining definition being the same as the term "heteroaryl": 1, linked to the rest of the molecule by more than one single bond; 2, sharing two atoms and one bond with the rest of the molecule.

[0258] The term "isotopically-labeled" refers to a compound in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into a compound of the application include isotopes of H, C, N, O, S, F, and CI, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the application that contain the above isotopes and / or other isotopes of other atoms are within the scope of the application. Certain isotopically-labeled compounds of the present application, for example those into which radioactive isotopes such as 3 H and 14 C) are incorporated can be used in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H), and carbon-14, i.e., 14 C), isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H or D), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, therefore, can be preferred in some circumstances. Compounds of the present application can be particularly defined as substituted with deuterium or tritium. Moreover, the presence of deuterium or tritium in a substituent group not specifically named as deuterium or tritium does not exclude the presence of deuterium or tritium, but rather deuterium or tritium can also be contained.

[0259] The term "therapeutically effective amount" refers to the amount of a compound that, when administered to a patient, is sufficient to effect treatment for a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, and the like, but can be adjusted by one of skill in the art as necessary.

[0260] The term "pharmaceutically acceptable excipient" refers to all substances, other than the active pharmaceutical ingredient, contained in a pharmaceutical preparation, which are generally divided into two categories: excipients and additives. For details, please refer to the "People's Republic of China Pharmacopoeia (2020 Edition)", Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0261] The term "treatment" refers to eliminating the cause or relieving the symptoms.

[0262] The term "prevention" refers to reducing the risk of developing a disease.

[0263] The term "patient" refers to any animal, usually a mammal, such as a human, in need of treatment or prevention of a disease. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0264] On the basis of common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e., to obtain each preferred example of the present application.

[0265] The reagents and raw materials used in the present application are commercially available.

[0266] The positive progress effect of the present application is that the compound of the present application has better WRN inhibitory activity. BRIEF DESCRIPTION OF DRAWINGS

[0267] Figure 1 Tumor growth curve of the control group and Cpd-1 in the pharmacodynamic evaluation experiment of the mouse SW48 human colon cancer xenograft tumor model;

[0268] Figure 2 Tumor growth curve of the control group and Cpd-19 in the pharmacodynamic evaluation experiment of the mouse SW48 human colon cancer xenograft tumor model;

[0269] Figure 3 Tumor growth curve of the control group and Cpd-19 in the pharmacodynamic evaluation experiment of the mouse SW48 human colon cancer xenograft tumor model;

[0270] Figure 4 Tumor growth curve of the control group and Cpd-19 in the pharmacodynamic evaluation experiment of the mouse SW48 human colon cancer xenograft tumor model. DETAILED DESCRIPTION

[0271] 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, where no specific conditions are indicated, were carried out according to standard methods and conditions, or according to the instructions of the commercial suppliers.

[0272] In each of the examples, 1 HNMR was recorded by BRUKER AVANCE NEO 400MHz, JNM-ECZ400s type nuclear magnetic resonance instrument, the chemical shift was expressed as δ (ppm): liquid chromatography-mass spectrometry (LCMS) was recorded by Shimadzu LC-20AD, Agilent 1260 type mass spectrometer: preparative HPLC separation used WATERS2545, Shimadzu LP-20AP type liquid chromatograph.

[0273] In the following experimental description, the following abbreviations can be used:

[0274]

[0275] Preparation of intermediate INT-1:

[0276]

[0277] Step one: (S)-(1-cyclopropyl-2-hydroxyethyl) tert-butyl carbamate

[0278] (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid INT-1-1 (10.0 g, 46.5 mmol) was dissolved in tetrahydrofuran (100 mL), and borane (66.6 mL, 66.6 mmol, 1M THF solution) was slowly added dropwise at 0°C, and the system was stirred at room temperature for 2 hours. Then methanol (60 mL) was slowly added dropwise to quench the reaction, and the crude product was concentrated under vacuum and reduced pressure, and purified by column chromatography (PE:EA = 3:1) to obtain compound INT-1-2 (6.80 g, 72.7%, colorless oil).

[0279] Step two: (S)-(1-cyclopropyl-2-formyl) tert-butyl carbamate

[0280] (S)-(l-cyclopropyl-2-hydroxyethyl)carbamic acid tert-butyl ester INT-1-2 (6.30 g, 31.3 mmol) was dissolved in dichloromethane (70 mL) and the system was stirred at 0 °C for 10 min, then Dess-Martin Oxidizing reagent (15.9 g, 37.6 mmol) was added slowly and the system was stirred at room temperature for 2 h. After the reaction was completed, saturated sodium bicarbonate solution (50 mL) was added slowly dropwise and extracted with ethyl acetate (100 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product which was purified by column chromatography (PE:EA = 4:1) to give compound INT-1-3 (1.60 g, crude, colorless oil).

[0281] Step three: (S,E)-(l-cyclopropyl-3-(methylsulfonyl)allyl)carbamic acid tert-butyl ester

[0282] Compound (S)-(l-cyclopropyl-2-oxoethyl)carbamic acid tert-butyl ester INT-1-3 (1.40 g, 7.03 mmol) and diethyl methylsulfinylmethylphosphonate INT-1-4 (1.62 g, 7.03 mmol) were dissolved in tetrahydrofuran (15 mL), potassium carbonate (2.43 g, 17.6 mmol) was added and the system was stirred at 60 °C under nitrogen protection for 4 h. After the reaction was completed, it was filtered and concentrated, and the residue was purified by column chromatography (PE:EA = 2:1) to give the product INT-1-5 (1.30 g, crude, white solid). The crude product was dissolved in ethyl acetate (10 mL), petroleum ether was slowly added until solid precipitated. The compound INT-1-5 (850 mg, yield 43.9%, white solid) was obtained by filtration. LCMS calc. for C8H 14 NO4S [M+H-C4H8] + : m / z = 222.0; Found: 222.0; Chiral HPLC ee% = 97.2.

[0283] Step four: (S,E)-l-cyclopropyl-3-(methylsulfonyl)propyl-2-ene-l-amine p-toluenesulfonic acid salt

[0284] (S,E)-(l-cyclopropyl-3-(methylsulfonyl)allyl)carbamic acid tert-butyl ester INT-1-5 (850 mg, 3.09 mmol) was dissolved in acetonitrile (8.5 mL), p-toluenesulfonic acid (638 mg, 3.70 mmol) was added and the system was stirred at 50 °C for 6 h. After the reaction was completed, it was concentrated under reduced pressure to give compound INT-1 (1.00 g, crude, white solid). 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 3H), 7.48 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.03 (dd, J = 15.4, 1.2 Hz, 1H), 6.75 (dd, J = 15.4, 6.2 Hz, 1H), 3.41 - 3.27 (m, 1H), 3.07 (s, 3H), 2.29 (s, 3H), 1.74 (s, 1H), 1.05 (dt, J = 9.3, 4.5 Hz, 1H), 0.63 (d, J = 8.1 Hz, 2H), 0.56 - 0.49 (m, 1H), 0.47 - 0.38 (m, 1H).

[0285] Example 1: (S,E)-N-(1-cyclopropyl-3-methanesulfonyl-prop-2-enyl)-5-(1,1- difluoroethyl)-6-phenylpyrazine-2-carboxamide

[0286]

[0287] Step one: 3-amino-6-chloro-5-(1-ethoxyvinyl)pyrazine-2-carboxylic acid methyl ester

[0288] A solution of Cpd-1-1 (24.8 g, 112 mmol), Pd(PPh3)2Cl2(7.84 g, 11.2 mmol), lithium chloride (16.6 g, 391 mmol) and tributyl(1-ethoxyvinyl)tin (60.5 g, 168 mmol) in N,N-dimethylformamide (250 mL) was stirred at 100 °C for 2 hours under argon atmosphere. Cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 7:3) to give compound Cpd-1-2 (16.2 g, yield 56.3%, yellow solid). LCMS calculated for C 10 H 13 ClN3O3[M+H] + : m / z = 258.1 ; found: 258.1 ; 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 2H), 4.64 (d, J = 2.8 Hz, 1H), 4.58 (d, J = 2.8 Hz, 1H), 3.93 - 3.88 (m, 2H), 3.86 (s, 3H), 1.30 (t, J = 6.8 Hz, 3H).

[0289] Step two: 5-acetyl-3-amino-6-chloropyrazine-2-carboxylic acid methyl ester

[0290] To a solution of compound Cpd-1-2 (16.2 g, 62.9 mmol) in tetrahydrofuran (400 mL) was added p-toluenesulfonic acid (21.7 g, 126 mmol) at room temperature. The mixture was stirred for 1 h. The reaction was quenched by adding saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by trituration with dichloromethane to give compound Cpd-1-3 (10.3 g, yield 71.4%, yellow solid). LCMS calculated for C8H9ClN3O3[M+H] + : m / z = 230.0; found: 230.1.

[0291] Step three: 5-acetyl-6-chloropyrazine-2-carboxylic acid methyl ester

[0292] To a solution of compound Cpd-1-3 (1.00 g, 4.36 mmol) in tetrahydrofuran (5 mL) was added tert-butyl nitrite (3.59 g, 34.8 mmol) at room temperature. The mixture was stirred at 70 °C for 3 h. The mixture was cooled and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 4:1) to give compound Cpd-1-4 (500 mg, yield 53.5%, white solid). LCMS calculated for C8H8ClN2O3[M+H] + : m / z = 215.0; found: 215.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 3.96 (s, 3H), 2.67 (s, 3H).

[0293] Step four: 5-acetyl-6-phenylpyrazine-2-carboxylic acid methyl ester

[0294] A mixture of Cpd-1-4 (696 mg, 3.24 mmol), phenylboronic acid (791 mg, 6.49 mmol), potassium carbonate (1.35 mg, 9.73 mmol) and tetrakis(triphenylphosphine)palladium (375 mg, 325 μmol) in a mixture of dioxane (20 mL) and water (2 mL) was stirred at 110 °C for 2 h under argon protection. The mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 mL x 2), the organic layers were combined, washed with water (50 mL x 2), dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (PE:EA = 4:1) to give Cpd-1-5 (500 mg, yield 60.2%, white solid). LCMS calculated for C 14 H 13 N2O3[M+H] + : m / z = 257.1; found: 257.0.

[0295] Step five: 5-(1, 1 -difluoroethyl)-6-phenylpyrazine-2-carboxylic acid methyl ester

[0296] To a solution of compound Cpd-1-5 (210 mg, 820 μmol) in dichloromethane (1 mL) was added diethylamine sulfide (2 mL) under argon atmosphere. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by dropwise addition to 0 °C aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (100 mL x 2). The combined organic phase was washed with water (50 mL x 2), dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (PE:EA = 17:3) to give compound Cpd-1-6 (65.0 mg, yield 28.5%, white solid). LCMS calculated for C 14 H 13 F2N2O2[M+H] + : m / z = 279.1 ; found: 279.5.

[0297] Step six: 5-(1, 1 -difluoroethyl)-6-phenylpyrazine-2-carboxylic acid

[0298] To a solution of Cpd-1-6 (65.0 mg, 234 μmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added a solution of lithium hydroxide (17.0 mg, 708 μmol) in water (1 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, diluted with water (20 mL), adjusted to pH 5-6 with 1 N hydrochloric acid and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with water (50 mL x 2), dried over sodium sulfate, filtered and concentrated to give Cpd-1-7 (62.0 mg, crude, white solid). LCMS calculated for C 13 H 11 F2N2O2[M+H] + : m / z = 265.1 ; found: 265.1.

[0299] Step seven: (S,E)-N-(1-cyclopropyl-3-methanesulfonyl-prop-2-enyl)-5-(1, 1 - difluoroethyl)-6-phenylpyrazine-2-carboxamide

[0300] A solution of INT-1 (90.0 mg, 259 pmol), Cpd-1-7 (62.0 mg, 234 pmol), N,N- diisopropylethylamine (91.0 mg, 705 pmol) and HATU (107 mg, 282 pmol) in N,N- dimethylformamide (3 mL) was stirred at room temperature for 1 h. The system was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 2), the combined organic phase was washed with water (50 mL x 2), dried over sodium sulfate, concentrated, and the residue was purified by prep to give compound Cpd-1 (36.4 mg, 36.9%, white solid). LCMS calculated for C 20 H 22 F2N3O3S [M+H] + : m / z = 422.1 ; found: 422.1. 1 H NMR (400 MHz, DMSO-d6) d 9.24 (d, J = 7.9 Hz, 2H), 7.63 (dd, J = 6.3, 3.0 Hz, 2H), 7.56 - 7.49 (m, 3H), 6.94 - 6.79 (m, 2H), 4.07 (td, J = 9.1, 4.9 Hz, 1H), 3.00 (s, 3H), 2.01 (t, J = 19.3 Hz, 3H), 1.34 - 1.24 (m, 1H), 0.58 (qd, J = 8.5, 4.4 Hz, 1H), 0.53 - 0.41 (m, 2H), 0.34 (td, J = 8.7, 4.4 Hz, 1H).

[0301] Example 2: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-((1,1-difluoro)cyclopropylmethyl)-6-phenylpyrazine-2-carboxamide

[0302]

[0303] Step one: 2-(1-cyclopropylethenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0304] A mixture of Cpd-2-1 (5.00 g, 75.6 mmol), bis(pinacolato)diboron (19.2 g, 75.6 mmol), palladium acetate (849 mg, 3.78 mmol), 2,2,2-trifluoroethanol (15.1 g, 151 mmol), tricyclohexylphosphine (2.12 g, 7.56 mmol) and bromobenzene (11.9 g, 751 mmol) in toluene (50 mL) was stirred at 80 °C for 16 h under nitrogen. The mixture was cooled, filtered, the filtrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 50:1) to give Cpd-2-2 (2.88 g, yield 19.6%, yellow oil).

[0305] Step two: 6-chloro-5-(1-cyclopropylethenyl)pyrazine-2-carboxylic acid methyl ester

[0306] A mixture of Cpd-2-3 (2.00 g, 7.95 mmol), Cpd-2-2 (7.72 g, 39.8 mmol), Pd(dppf)Cl2(659 mg, 795 μmol) and potassium phosphate (3.38 g, 15.9 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was heated to 50 °C and stirred for 2 h under nitrogen. The mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1) to give compound Cpd-2-4 (1.35 g, yield 71.1%, yellow solid). LCMS calc. for C 11 H 12 ClN2O2[M+H] + : m / z = 239.1; Found: 239.1.

[0307] Step three: 6-chloro-5-(cyclopropylcarbonyl)pyrazine-2-carboxylic acid methyl ester

[0308] To a solution of Cpd-2-4 (1.40 g, 5.87 mmol) in tetrahydrofuran (20 mL) and water (20 mL) was added potassium osmate (91.3 mg, 293 μmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h, then sodium periodate (3.76 g, 17.6 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:THF = 10:1) to give compound Cpd-2-5 (630 mg, 44.6% yield, yellow solid). LCMS calc. for C 10 H 10 ClN2O3[M+H] + : m / z = 241.0; Found: 241.0.

[0309] Step four: 6-chloro-5-((1,1 -difluoro)cyclopropylmethyl)pyrazine-2-carboxylic acid methyl ester

[0310] A solution of compound Cpd-2-5 (700 mg, 2.91 mmol) and BAST (20 mL) in toluene (20 mL) was stirred at 50 °C for 20 h. The reaction was cooled to room temperature and quenched by the addition of saturated sodium carbonate solution (20 mL). The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1) to give compound Cpd-2-6 (135 mg, 17.7% yield, yellow solid). LCMS calc. for C 10 H 10 ClF2N2O2[M+H] + : m / z = 263.0; Found: 263.0.

[0311] Step five: 5-((1,1 -difluoro)cyclopropylmethyl)-6-phenylpyrazine-2-carboxylic acid methyl ester

[0312] A mixture of Cpd-2-6 (150 mg, 571 μmol), phenylboronic acid (83.6 mg, 685 μmmol), Pd(dppf)Cl2(47.3 mg, 57.1 μmol) and potassium phosphate (242 mg, 1.14 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated to 90 °C under nitrogen and stirred for 2 h. The reaction was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic layers were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1) to give compound Cpd-2-7 (63.0 mg, yield 36.3%, yellow oil). LCMS calc. for C 16 H 15 F2N2O2[M+H] + :m / z = 305.1; Found: 305.2.

[0313] Step six: 5-((1,1-difluoro)cyclopropylmethyl)-6-phenylpyrazine-2-carboxylic acid

[0314] A mixture of Cpd-2-7 (100 mg, 381 μmol) and lithium hydroxide (45.6 mg, 1.90 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was stirred at room temperature for 1 h. The mixture was adjusted to pH 3 with 1 N hydrochloric acid and extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give Cpd-2-8 (60.0 mg, crude, yellow oil). LCMS calc. for C 15 H 13 F2N2O2[M+H] + :m / z = 291.1; Found: 291.2.

[0315] Step seven: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-((1,1-difluoro)cyclopropylmethyl)-6-phenylpyrazine-2-carboxamide

[0316] To a solution of Cpd-2-8 (50.0 mg, 172 μmol) and INT-1 (65.8 mg, 189 μmol) in acetonitrile (1 mL) was added triethylamine (174 mg, 1.73 mmol) and CMPI (88.0 mg, 344 μmol), the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, the residue was purified by Prep-HPLC to give compound Cpd-2 (38.5 mg, yield 24.7%, white solid). LCMS calc. for C 22 H 24 F2N3O3S [M+H] + : m / z = 448.1 ; Found: 448.3. 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 9.23 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 3.0 Hz, 2H), 7.51 (t, J = 3.2 Hz, 3H), 6.92 - 6.82 (m, 2H), 4.07 (td, J = 9.1, 4.7 Hz, 1H), 3.02 (d, J = 12.9 Hz, 3H), 1.98 - 1.87 (m, 1H), 1.33 - 1.24 (m, 1H), 0.67 (d, J = 8.2 Hz, 2H), 0.62 - 0.53 (m, 3H), 0.51 - 0.42 (m, 2H), 0.37 - 0.33 (m, 1H).

[0317] Example 3: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l-difluoro-2- methoxyethyl)-6-phenylpyrazine-2-carboxamide

[0318]

[0319] Step one: 2-(3-methoxyprop-l-en-2-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

[0320] To a mixture of Cpd-3-1 (5.00 g, 71.3 mmol), bis(pinacolato)diboron (18.1 g, 71.3 mmol), copper(I) chloride (706 mg, 7.13 mmol), sodium tert-butoxide (1.03 g, 10.7 mmol) and tri-tert-butylphosphine tetrafluoroborate (2.48 g, 8.56 mmol) in toluene (50 mL) was added methanol (5.77 mL, 142 mmol) dropwise at 0 °C under nitrogen protection. The reaction mixture was allowed to warm to room temperature and stirred for another 2 h, then quenched by the addition of methanol (2 mL), filtered, and the filtrate was concentrated and purified by column chromatography on silica gel (PE:THF = 10:1) to give compound Cpd-3-2 (7.73 g, 54.7% yield, colorless liquid). LCMS calc. for C 10 H 20 BO3[M+H] + :m / z = 199.1; Found: 199.2.

[0321] Step two: 6-chloro-5-(3-methoxyprop-1-en-2-yl)pyrazine-2-carboxylic acid methyl ester

[0322] A mixture of compound Cpd-2-3 (1.20 g, 4.77 mmol), Cpd-3-2 (1.42 g, 7.16 mmol), Pd(dppf)Cl2(349 mg, 477 μmol) and potassium phosphate (1.52 g, 7.16 mmol) in 1,4-dioxane (15 mL) / water (3 mL) was heated to 50 °C and stirred for 2 h. The reaction mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1) to give compound Cpd-3-3 (315 mg, 27.2% yield, yellow solid). LCMS calc. for C 10 H 12 ClN2O3[M+H] + :m / z = 243.1; Found: 243.2.

[0323] Step three: 6-chloro-5-(2-methoxyacetyl)pyrazine-2-carboxylic acid methyl ester

[0324] To a mixture of Cpd-3-3 (205 mg, 845 μmol) in tetrahydrofuran (5 mL) and water (2 mL) was added potassium osmate (13.2 mg, 42.2 μmol) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 0.5 h, then sodium periodate (452 mg, 2.11 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:THF = 10:1) to give Cpd-3-4 (35.0 mg, 16.9% yield, yellow oil). LCMS calc. for C9H 10 ClN2O4[M+H] + : m / z = 245.0; Found: 245.1.

[0325] Step Four: 6-Chloro-5-(l,l-difluoro-2-methoxyethyl)pyrazine-2-carboxylic acid methyl ester

[0326] A mixture of Cpd-3-4 (35.0 mg, 143 μmol) and BAST (0.5 mL) in toluene (2 mL) was stirred at 50 °C for 2 h. The mixture was cooled to room temperature, quenched with saturated aqueous sodium carbonate solution (20 mL), extracted with ethyl acetate (20 mL x 2), and the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1) to give Cpd-3-5 (31.0 mg, 81.3% yield, yellow oil). LCMS calc. for C9H 10 ClF2N2O3[M+H] + : m / z = 267.0; Found: 267.0.

[0327] Step Five: 5-(l,l-Difluoro-2-methoxyethyl)-6-phenylpyrazine-2-carboxylic acid methyl ester

[0328] A mixture of Cpd-3-5 (17.0 mg, 139 μmol), phenylboronic acid (25.4 mg, 209 μmol), Pd(dppf)Cl2(9.64 mg, 11.6 μmol) and potassium phosphate (49.4 mg, 233 μmol) in 1,4-dioxane (15 mL) and water (3 mL) was heated to 50 °C under nitrogen for 2 h. The reaction was cooled, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1) to give Cpd-3-6 (22.0 mg, 61.4% yield, yellow oil). LCMS calc. for C 15 H 15 F2N2O3[M+H] + m / z = 309.1; Found: 309.1.

[0329] Step six: 5-(1,1-difluoro-2-methoxyethyl)-6-phenylpyrazine-2-carboxylic acid

[0330] A mixture of Cpd-3-6 (20.0 mg, 64.9 μmol) and lithium hydroxide (3.11 mg, 130 μmol) in tetrahydrofuran (2 mL) and water (0.5 mL) was stirred at room temperature for 1 h. The reaction was adjusted to pH 3 by the addition of 1 N hydrochloric acid and extracted with ethyl acetate (10 mL x 2), the combined organic phases were dried and concentrated to give Cpd-3-7 (20.0 mg, crude, yellow oil). LCMS calc. for C 14 H 13 F2N2O3[M+H] + m / z = 295.1; Found: 295.1.

[0331] Step seven: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoro-2- methoxyethyl)-6-phenylpyrazine-2-carboxamide

[0332] To a solution of Cpd-3-7 (20.0 mg, 68.0 μmol) and INT-1 (28.3 mg, 81.6 μmol) in acetonitrile (1 mL) was added triethylamine (68.8 mg, 680 μmol) and CMPI (26.1 mg, 102 μmol), the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by Prep-HPLC to give Cpd-3 (6.71 mg, yield 21.8%, white solid). LCMS calc. for C 21 H 24 F2N3O4S[M+H] + :m / z = 452.1; Found: 452.3; 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (t, J = 4.3 Hz, 2H), 7.66-7.63 (m, 2H), 7.53-7.47 (m, 3H), 6.92-6.82 (m, 2H), 4.11-4.04 (m, 3H), 3.30 (s, 3H), 3.00 (s, 3H), 1.32-1.24 (m, 1H), 0.62-0.55 (m, 1H), 0.52-0.42 (m, 2H), 0.37-0.33 (m, 1H).

[0333] Example 4: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(ethyl(methyl)amino)-6- phenylpyrazine-2-carboxamide

[0334]

[0335] Step one: 5-(ethyl(methyl)amino)pyrazine-2-carboxylic acid methyl ester

[0336] A solution of compound Cpd-4-1 (2.00 g, 11.6 mmol), N-methylethanamine (719 mg, 12.2 mmol) and potassium carbonate (3.20 g, 23.2 mmol) in acetonitrile (20 mL) was stirred at 100 °C for 2 hours, LCMS showed the reaction was completed. The mixture was cooled and filtered, the filtrate was concentrated, the residue was purified by silica gel column chromatography (EA 100%) to give compound Cpd-4-2 (1.35 g, yield 59.7%, orange solid). LCMS calc. for C9H 14 N3O2[M+H] + : m / z = 196.1; Found: 196.2.

[0337] Step two: 6-bromo-5-(ethyl(methyl)amino)pyrazine-2-carboxylic acid methyl ester

[0338] A solution of compound Cpd-4-2 (1.30 g, 6.66 mmol) and N-bromosuccinimide (1.30 g, 7.33 mmol) in acetonitrile (15 mL) was stirred at room temperature for 2 hours, LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (PE:EA = 10:1) to give compound Cpd-4-3 (1.68 g, yield 92.0%, yellow oil). LCMS calc. for C9H 13 BrN3O2[M+H] + : m / z = 274.0 / 276.0; Found: 274.1 / 276.0.

[0339] Step three: 5-(ethyl(methyl)amino)-6-phenylpyrazine-2-carboxylic acid methyl ester

[0340] A mixture of Cpd-4-3 (400 mg, 1.46 mmol), phenylboronic acid (267 mg, 2.19 mmol), Pd(dppf)Cl2(107 mg, 146 μmol) and potassium carbonate (504 mg, 3.65 mmol) in 1,4-dioxane and water (10 mL, 4:1) was stirred at 100 °C for 2 hours under argon protection. Cooled to room temperature, the reaction was diluted with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL x 2), the aqueous phase was diluted with saturated brine solution (20 mL) again and extracted with acetonitrile (20 mL). The organic phases were combined, washed with saturated brine solution (40 mL) and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (PE:EA = 20:1) to give Cpd-4-4 (366 mg, yield 92.5%, colorless liquid). LCMS calc. for C 15 H 18 N3O2[M+H] + : m / z = 272.1; Found: 272.3.

[0341] Step four: 5-(ethyl(methyl)amino)-6-phenylpyrazine-2-carboxylic acid

[0342] To a mixture of Cpd-4-4 (100 mg, 369 μmol) in tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL) was added lithium hydroxide (17.7 mg, 737 μmol) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction was adjusted to pH 6-7 with 1 N hydrochloric acid and concentrated under reduced pressure. The residue was co-evaporated with acetonitrile (20 mL) twice to give Cpd-4-5 (95.0 mg, crude, white solid) which was used directly in the next step. LCMS calc. for C 14 H 16 N3O2[M+H] + : m / z = 258.1 ; Found: 258.1.

[0343] Step five: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(ethyl(methyl)amino)- 6-phenylpyrazine-2-carboxamide

[0344] A mixture of Cpd-4-5 (95.0 mg, 370 μmol), INT-1 (97.1 mg, 554 μmol), diisopropylethylamine (143 mg, 1.10 mmol) and HATU (281 mg, 738 μmol) in N,N- dimethylformamide (3 mL) was stirred at room temperature for 1 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated aqueous sodium bicarbonate (30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC to give Cpd-4 (83.5 mg, yield 54.5%, white solid). LCMS calc. for C 21 H 27 N4O3S[M+H] + : m / z = 415.2 ; Found: 415.3; 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 8.8 Hz, 1H), 8.58 (s, 1H), 7.80 - 7.73 (m, 2H), 7.51 (t, J = 7.2 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H), 6.91 (dd, J = 15.2, 5.6 Hz, 1H), 6.79 (dd, J = 15.2, 1.2 Hz, 1H), 4.05 (dd, J = 14.4, 8.8 Hz, 1H), 3.39 (q, J = 7.2 Hz, 2H), 3.01 (s, 3H), 2.72 (s, 3H), 1.32 - 1.21 (m, 1H), 1.02 (t, J = 7.2 Hz, 3H), 0.63 - 0.27 (m, 4H).

[0345] Example 5: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l- difluoroethyl)-6-(3-fluorophenyl)pyrazine-2-carboxamide

[0346]

[0347] Step one: 5-(l,l-difluoroethyl)-6-(3-fluorophenyl)pyrazine-2-carboxylic acid methyl ester

[0348] BAST (3.5 mL) was added to a solution of compound Cpd-1-4 (280 mg, 1.30 mmol) in toluene (7 mL) and the system was stirred at 60 °C for 1 h. The reaction was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10: 1) to give compound Cpd-5-1 (200 mg, yield 64.9%, yellow oil). LCMS calc. for C8H8ClF2N2O2[M+H] + : m / z = 237.0; Found: 237.1.

[0349] Step two: 5-(l,l-difluoroethyl)-6-(3-fluorophenyl)pyrazine-2-carboxylic acid

[0350] Cpd-5-1 (200 mg, 850 μmol), (3-fluorophenyl)boronic acid (237 mg, 1.69 mmol), tetrakis(triphenylphosphine)palladium (97.7 mg, 80.0 μmol) and potassium phosphate (359 mg, 1.69 mmol) were stirred in a mixture of dioxane (5 mL) and water (1 mL) at 100 °C for 2 h. Cooled to room temperature, adjusted pH to 3 with 1 N hydrochloric acid and extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-5-2 (170 mg, crude, yellow solid). LCMS calc. for C 13 H 10 F3N2O2[M+H] + : m / z = 283.1; Found: 283.1.

[0351] Step three: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l- difluoroethyl)-6-(3-fluorophenyl)pyrazine-2-carboxamide

[0352] To a solution of compound Cpd-5-2 (170 mg, crude), INT-1 (106 mg, 600 pmol), triethylamine (305 mg, 3.01 mmol) in dichloromethane (5 mL) was added HATU (275 mg, 720 pmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford Cpd-5 (61.2 mg, yield 20.8%, white solid). LCMS calc. for C 20 H 21 F3N3O3S[M+H] + : m / z = 440.1 ; Found: 439.9; 1 H NMR (400 MHz, DMSO-d6) δ 9.28 - 9.26 (m, 2H), 7.58 - 7.46 (m, 3H), 7.40 - 7.35 (m, 1H), 6.88 - 6.82 (m, 2H), 4.10 - 4.04 (m, 1H), 3.01 (s, 3H), 2.03 (t, J = 19.2 Hz, 3H), 1.33 - 1.24 (m, 1H), 0.62 - 0.56 (m, 1H), 0.53 - 0.36 (m, 2H), 0.35 - 0.31 (m, 1H).

[0353] Example 6: (S,E)-6-(Cyclopent-l-en-l-yl)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- (l,l-difluoroethyl)pyrazine-2-carboxamide

[0354]

[0355] Step one: 6-(Cyclopent-l-en-l-yl)-5-(l,l-difluoroethyl)pyrazine-2-carboxylic acid methyl ester

[0356] A mixture solution of Cpd-5-1 (236 mg, 1.00 mmol), 1-cyclopentenyl boronic acid (223 mg, 2.00 mmol), potassium phosphate (423 mg, 2.00 mmol) and tetrakis(triphenylphosphine)palladium (115 mg, 100 μmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 100 °C for 1 h under nitrogen atmosphere. The mixture was cooled, concentrated, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 8:1) to give Cpd-6-1 (170 mg, yield 63.5%, white solid). LCMS calc. for C 13 H 15 F2N2O2[M+H] + :m / z = 269.1; Found: 269.3.

[0357] Step two: 6-(cyclopent-1-en-1-yl)-5-(1,1-difluoroethyl)pyrazine-2-carboxylic acid

[0358] A solution of lithium hydroxide (30.4 mg, 1.27 mmol) in water (1 mL) was added to a solution of Cpd-6-1 (170 mg, 630 μmol) in tetrahydrofuran (1 mL) and methanol (1 mL) at room temperature and stirred for 1 h. The mixture was concentrated, diluted with water (30 mL), adjusted to pH 5-6 with 1 N hydrochloric acid and extracted with ethyl acetate (50 mL x 2), the combined organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-6-2 (193 mg, crude, white solid). LCMS calc. for C 12 H 13 F2N2O2[M+H] + :m / z = 255.1; Found: 255.2.

[0359] Step three: (S,E)-6-(cyclopent-1-en-1-yl)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)pyrazine-2-carboxamide

[0360] A mixture of compound Cpd-6-2 (93.0 mg, 370 pmol), INT-1 (140 mg, 400 pmol), diisopropylethylamine (189 mg, 1.46 mmol) and HATU (181 mg, 480 pmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 1 h. The system was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2), the combined organic layers were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by Prep-HPLC to give Cpd-6 (67.2 mg, yield 44.6%, white solid). LCMS calc. for C 19 H 24 F2N3O3S [M+H] + : m / z = 412.1 ; Found: 412.2; 1 H NMR (400 MHz, DMSO-d6) d 9.14 (d, J = 8.8 Hz, 1H), 9.07 (s, 1H), 6.92 (dd, J = 15.3, 5.2 Hz, 1H), 6.85 (d, J = 15.4 Hz, 1H), 6.19 (s, 1H), 4.07 (td, J = 9.1, 5.4 Hz, 1H), 3.02 (s, 3H), 2.95 - 2.86 (m, 2H), 2.58 (td, J = 7.5, 2.4 Hz, 2H), 2.11 - 1.99 (m, 5H), 1.32 (qt, J = 9.3, 4.7 Hz, 1H), 0.64 - 0.57 (m, 1H), 0.49 (dtd, J = 26.9, 9.1, 5.0 Hz, 2H), 0.35 (td, J = 9.0, 4.7 Hz, 1H).

[0361] Example 7: (S,E)-3-amino-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(l,l- difluoroethyl)-6-phenylpyridinamide

[0362]

[0363] Step one: 3-amino-5-(l-ethoxyvinyl)pyridine carboxylate

[0364] A mixture of Cpd-7-1 (25.0 g, 108 mmol), tri-n-butyl(1-ethoxyvinyl)tin (39.1 g, 108 mmol) and Pd(Ph3P)2Cl2(7.59 g, 10.8 mmol) in dry N,N-dimethylformamide (100 mL) was stirred at 100 °C for 8 h under argon. The reaction was cooled, filtered and concentrated. The residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with water (200 mL x 2), saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (EA:DCM = 1:10) to give Cpd-7-2 (20.8 g, 86.5% yield, yellow solid). LCMS calc. for C 11 H 15 N2O3[M+H] + : m / z = 223.1; Found: 223.1.

[0365] Step two: 5-acetyl-3-amino pyridine-2-carboxylic acid methyl ester

[0366] To a solution of Cpd-7-2 (20.8 g, 93.6 mmol) in dichloromethane (50 mL) and methanol (5 mL) was added hydrochloric acid (140 mL, 562 mmol, 4 N in ethyl acetate) and stirred at room temperature for 16 h. The reaction was concentrated, diluted with water (200 mL) and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane / methanol (10:1) (200 mL x 10), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give Cpd-7-3 (17.3 g, 95.4% yield, yellow solid). LCMS calc. for C9H 11 N2O3[M+H] + : m / z = 195.1; Found: 195.0.

[0367] Step three: 5-acetyl-3-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridine-2- carboxylic acid methyl ester

[0368] A solution of Cpd-7-3 (4.30 g, 22.1 mmol), Boc20 (11.2 mL, 48.7 mmol) and 4-dimethylaminopyridine (810 mg, 6.64 mmol) in tetrahydrofuran (50 mL) was stirred at 50 °C for 2 h. The reaction was concentrated and purified by silica gel column chromatography (PE:EA = 10:1) to give Cpd-7-4 (3.82 g, 43.7% yield, white solid). LCMS calc. for C 19 H 27N2O7[M+H] + : m / z = 395.2; Found: 395.3.

[0369] Step four: 3-[Bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-5-(1,1- difluoroethyl)pyridine-2-carboxylic acid methyl ester

[0370] Cpd-7-4 (3.82 g, 9.69 mmol) and DAST (10 mL) in dichloromethane (5 mL) was stirred at room temperature for 60 h under argon. Upon completion of the reaction, the reaction mixture was added dropwise into ice-cold saturated aqueous sodium bicarbonate solution (200 mL) and stirred for 30 min, extracted with dichloromethane (200 mL x 2), the combined organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 10:1) to give Cpd-7-5 (3.00 g, yield 74.4%, white solid). LCMS calc. for C 19 H 27 F2N2O6[M+H] + : m / z = 417.2; Found: 417.3.

[0371] Step five: 3-Amino-5-(1,1 -difluoroethyl)pyridine-2-carboxylic acid methyl ester

[0372] A solution of compound Cpd-7-5 (3.00 g, 7.20 mmol) and hydrochloric acid (40 mL, 160 mmol, 4 N in ethyl acetate) in dichloromethane (20 mL) was stirred at room temperature for 16 h. Concentration, the residue was diluted with water (100 mL) and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give Cpd-7-6 (1.55 g, yield 99.5%, yellow solid). LCMS calc. for C9H 11 F2N2O2[M+H] + : m / z = 217.1 ; Found: 217.1.

[0373] Step six: 3-Amino-6-bromo-5-(1,1 -difluoroethyl)pyridine-2-carboxylic acid methyl ester

[0374] To a solution of Cpd-7-6 (1.55 g, 7.17 mmol) in acetonitrile (20 mL) was added N-bromosuccinimide (1.66 g, 9.32 mmol) under ice-bath. The system was warmed to room temperature and stirred for 2 h. The reaction was concentrated and the residue was purified by column chromatography on silica gel (PE:EA = 5:1) to give Cpd-7-7 (1.46 g, 69.0% yield, yellow solid). LCMS calc. for C9H 10 BrF2N2O2[M+H] + : m / z = 295.0 / 297.0; Found: 295.0 / 297.0.

[0375] Step Seven: Methyl 3-amino-5-(l,l-difluoroethyl)-6-phenylpyridine-2-carboxylate

[0376] A mixture of Cpd-7-7 (915 mg, 3.10 mmol), phenylboronic acid (756 mg, 6.20 mmol), potassium phosphate (1.32 g, 6.20 mol) and tetrakis(triphenylphosphine)palladium (358 mg, 310 μmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was stirred at 100 °C for 1 h under argon. The mixture was cooled, concentrated and diluted with water (100 mL). The mixture was extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 4:1) to give Cpd-7-8 (846 mg, 93.4% yield, yellow solid). LCMS calc. for C 15 H 15 F2N2O2[M+H] + : m / z = 293.1; Found: 293.2.

[0377] Step Eight: 3-Amino-5-(l,l-difluoroethyl)-6-phenyl-pyridine-2-carboxylic acid

[0378] A solution of lithium hydroxide (19.2 mg, 800 μmol) in water (1 mL) was added to a mixture of Cpd-7-8 (117 mg, 400 μmol) in tetrahydrofuran (1 mL) and methanol (1 mL). The mixture was stirred at room temperature for 1 h. The reaction was concentrated and diluted with water (30 mL). The pH was adjusted to 5-6 with 1 N hydrochloric acid and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give Cpd-7-9 (94.0 mg, crude, white solid). LCMS calc. for C 14 H 13 F2N2O2[M+H]+ m / z = 279.1 ; Found: 279.4.

[0379] Step nine: 3-amino-N-[(E,S)-1-cyclopropyl-3-methylsulfonyl-prop-2-enyl]-5-(1,1- difluoroethyl)-6-phenylpyridine-2-carboxamide

[0380] A mixture of Cpd-7-9 (94.0 mg, 340 μmol), INT-1 (129 mg, 370 μmol), diisopropylethylamine (175 mg, 1.35 mmol) and HATU (167 mg, 440 μmol) in N,N- dimethylformamide (3 mL) was stirred at room temperature for 1 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give Cpd-7 (70.5 mg, yield 47.9%, white solid). LCMS calc. for C 21 H 24 F2N3O3S [M+H] + m / z = 436.1 ; Found: 436.3; 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8.7 Hz, 1H), 7.53 (s, 1H), 7.42 (s, 5H), 7.05 (s, 2H), 6.88 (dd, J = 15.3, 5.7 Hz, 1H), 6.76 (d, J = 15.3 Hz, 1H), 3.96 (dd, J = 14.7, 8.9 Hz, 1H), 3.00 (s, 3H), 1.62 (t, J = 19.1 Hz, 3H), 1.33 - 1.19 (m, 1H), 0.61 - 0.44 (m, 2H), 0.42 - 0.25 (m, 2H).

[0381] Example 8: (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6- phenylpyrazine-2-carboxamide

[0382]

[0383] Step one: (S)-(1-cyclobutyl-2-hydroxyethyl) tert-butylcarbamate

[0384] A solution of Cpd-8-1 (900 mg, 3.93 mmol), N,N'-carbonyldiimidazole (827 mg, 5.10 mmol) and 4-dimethylaminopyridine (2.40 mg, 19.6 μmol) in tetrahydrofuran (9 mL) was stirred at room temperature for 1 h under nitrogen, then placed in an ice bath, water (2 mL) was added, sodium borohydride (223 mg, 5.89 mmol) was added slowly, and the mixture was stirred at room temperature for 1 h. The reaction mixture was placed in an ice bath, citric acid monohydrate (1.73 g, 8.24 mmol) was added, and the mixture was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 3:1) to give Cpd-8-2 (690 mg, 81.6% yield, yellow oil). LCMS calc. for C 11 H 22 NO3[M+H] + : m / z = 216.2; Found: 216.1.

[0385] Step Two: (S)-(1-cyclobutyl-2-oxoethyl) tert-butylcarbamate

[0386] A solution of Cpd-8-2 (690 mg, 3.21 mmol) and Dess-Martin periodinane (2.72 g, 6.41 mmol) in dichloromethane (15 mL) was stirred at room temperature for 2 h under nitrogen. The mixture was filtered, the filtrate was added to saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 5:1) to give Cpd-8-3 (280 mg, 40.9% yield, white solid). LCMS calc. for C 11 H 20 NO3[M+H] + : m / z = 214.1; Found: 214.2.

[0387] Step Three: (S,E)-(1-cyclobutyl-3-(methylsulfonyl)allyl) tert-butylcarbamate

[0388] Sodium hydride (57.8 mg, 1.44 mmol, 60% content) was slowly added to a solution of diethyl ((methylsulfonyl)methyl)phosphonate (332 mg, 1.44 mmol) in tetrahydrofuran (6 mL) under ice water bath and stirred for 1 h. Cpd-8-3 (280 mg, 1.31 mmol) was slowly added to the above solution and stirring was continued for 1.5 h. LCMS indicated complete consumption of starting material and detection of desired compound. Saturated aqueous ammonium chloride solution (100 mL) was added to the system and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, dried and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to give Cpd-8-4 (160 mg, yield 42.2%, white solid). LCMS calc. for C 13 H 24 NO4S [M+H] + : m / z = 290.1 ; Found: 290.2.

[0389] Step four: (S,E)-1-cyclobutyl-3-(methylsulfonyl)prop-2-en-1-amine p-toluenesulfonate

[0390] A solution of compound Cpd-8-4 (150 mg, 518 μmol) and p-toluenesulfonic acid (107 mg, 622 μmol) in acetonitrile (3 mL) was stirred at 50 °C for 12 h. LCMS indicated complete consumption of starting material and detection of desired compound. The reaction mixture was filtered to give Cpd-8-5 (160 mg, yield 85.6%, white solid). LCMS calc. for C8H 16 NO2S [M-C7H8O3S] + : m / z = 190.1 ; Found: 190.2.

[0391] Step five: (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6- phenylpyrazine-2-carboxamide

[0392] A mixture of compound Cpd-1-7 (85.0 mg, 303 pmol), Cpd-8-5 (131 mg, 363 pmol), HATU (131 mg, 363 pmol) and diisopropylethylamine (117 mg, 908 pmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 1 h. LCMS detection showed the complete consumption of starting material and detection of desired compound. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined and dried to concentrate to give a crude product, which was purified by Prep-HPLC to give Cpd-8 (63.5 mg, yield 48.1%, white solid). LCMS calc. for C 21 H 24 F2N3O3S[M+H] + : m / z = 436.1 ; Found: 436.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.98 (d, J = 9.0 Hz, 1H), 7.65-7.60 (m, 2H), 7.55-7.50 (m, 3H), 6.86 (d, J = 15.3 Hz, 1H), 6.73 (dd, J = 15.3, 6.3 Hz, 1H), 4.82-4.76 (m, 1H), 2.99 (s, 3H), 2.70-2.64 (m, 1H), 2.06-1.97 (m, 5H), 1.85-1.71 (m, 4H).

[0393] Example 9: (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-5-(3-methylazetidin-1- yl)-6-phenylpyrazine-2-carboxamide

[0394]

[0395] Step one: 5-(3-methylazetidin-1-yl)pyrazine-2-carboxylic acid methyl ester

[0396] A mixture of Cpd-9-1 (500 mg, 2.9 mmol), 3-methylazetidine (327 mg, 3.04 mmol) and triethylamine (880 mg, 7.69 mmol) in acetonitrile (10 mL) was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 3:1) to give compound Cpd-9-2 (732 mg, crude, colorless oil). LCMS calc. for C 10 H 14 N3O2[M+H] + : m / z = 208.1 ; Found: 208.1.

[0397] Step two: 6-bromo-5-(3-methylazetidin-l-yl)pyrazine-2-carboxylic acid methyl ester

[0398] A solution of Cpd-9-2 (600 mg, 2.90 mmol) and N-bromosuccinimide (567 mg, 3.18 mmol) in acetonitrile (12 mL) was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE:EA = 3: 1) to give compound Cpd-9-3 (826 mg, yield 99.7%, white solid). LCMS calc. for C 10 H 13 BrN3O2[M+H] + : m / z = 286.0 / 288.0; Found: 285.9 / 287.9.

[0399] Step three: 5-(3-methylazetidin-l-yl)-6-phenylpyrazine-2-carboxylic acid methyl ester

[0400] A mixture of Cpd-9-3 (500 mg, 1.75 mmol), phenylboronic acid (320 mg, 2.62 mmol), potassium phosphate (927 mg, 4.37 mmol) and Pd(dppf)Cl2(420 mg, 520 μmol) in a mixture of dioxane (15 mL) and water (5 mL) was stirred at 80 °C for 1 h under argon protection. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE:EA = 5: 1) to give compound Cpd-9-4 (360 mg, yield 72.7%, white solid). LCMS calc. for C 16 H 18 N3O2[M+H] + : m / z = 284.1; Found: 284.2.

[0401] Step four: 5-(3-methylazetidin-l-yl)-6-phenylpyrazine-2-carboxylic acid

[0402] A solution of lithium hydroxide (91.3 mg, 3.81 mmol) in water (0.5 mL) was added to a solution of Cpd-9-4 (360 mg, 1.27 mmol) in methanol (3 mL) at room temperature, and the mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH 2 with 1 N HC1 and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give Cpd-9-5 (226 mg, yield 66.1%, white solid). LCMS calc. for C 15 H 16N3O2 [M+H] + : m / z = 270.1 ; Found: 270.2.

[0403] Step five: (S,E)-N-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(3- methylazetidin-l-yl)-6-phenylpyrazine-2-carboxamide

[0404] A mixture of compound Cpd-9-5 (67.3 mg, 250 μmol), Cpd-8-5 (82.0 mg, 230 μmol), HATU (130 mg, 340 μmol) and diisopropylethylamine (117 mg, 908 μmol) in N,N- dimethylformamide (4 mL) was stirred at room temperature for 1 h. LCMS indicated that the starting material was consumed completely and the desired compound was detected. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was combined and dried to give a crude product, which was purified by Prep-HPLC to give Cpd-9 (50.0 mg, yield 49.3%, white solid). LCMS calc. for C 23 H 29 N4O3S [M+H] + : m / z = 441.2; Found: 441.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.33 (d, J = 9.2 Hz, 1H), 7.85 - 7.59 (m, 2H), 7.55 - 7.31 (m, 3H), 7.00 - 6.51 (m, 2H), 4.77 - 4.71 (m, 1H), 3.88 - 3.83 (m, 2H), 3.29 (s, 2H), 2.98 (s, 3H), 2.74 - 2.56 (m, 2H), 1.98 - 1.94 (m, 2H), 1.88 - 1.66 (m, 4H), 1.09 (d, J = 6.8 Hz, 3H).

[0405] Example 10: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3- methylazetidin-l-yl)-6-phenylpyrazine-2-carboxamide

[0406]

[0407] To a solution of Cpd-9-5 (100 mg, 371 μmol) and INT-1 (129 mg, 371 μmol) in acetonitrile (1 mL) was added triethylamine (376 mg, 3.71 mmol) and CMPI (190 mg, 743 μmol), the mixture was stirred at room temperature for 1 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated, the residue was purified by Prep-HPLC to give compound Cpd-10 (48.4 mg, yield 30.4%, white solid). LCMS calc. for C 22 H 27 N4O3S [M+H] + : m / z = 427.2; Found: 427.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.61 (m, 2H), 7.72 - 7.67 (m, 2H), 7.53 - 7.44 (m, 3H), 6.90 (dd, J = 15.3, 5.6 Hz, 1H), 6.77 (d, J = 15.4 Hz, 1H), 4.04 (dd, J = 14.4, 8.7 Hz, 1H), 3.88 - 3.79 (m, 2H), 3.33 - 3.38 (m, 1H), 3.30 (s, 1H), 3.00 (s, 3H), 2.62 (td, J = 13.7, 7.0 Hz, 1H), 1.27 (tt, J = 12.8, 4.5 Hz, 1H), 1.09 (d, J = 6.9 Hz, 3H), 0.60 - 0.29 (m, 4H).

[0408] Example 11: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(2- hydroxyphenyl)-5-(3-methylazetidin-l-yl)pyrazine-2-carboxamide

[0409]

[0410] Step one: 6-(2-hydroxyphenyl)-5-(3-methylazetidin-l-yl)pyrazine-2-carboxylic acid methyl ester

[0411] A mixture of Cpd-9-3 (700 mg, 2.45 mmol), 2-hydroxybenzeneboronic acid (506 mg, 3.67 mmol), potassium phosphate (1.30 g, 6.12 mmol) and Pd(dppf)Cl2(200 mg, 245 pmol) in dioxane (15 mL) and water (5 mL) was stirred at 80 °C for 1 h under argon. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 5:1) to give compound Cpd-11-1 (520 mg, 70.9% yield, white solid). LCMS calc. for C 16 H 18 N3O3[M+H] + : m / z = 300.1 ; Found: 300.0.

[0412] Step two: 6-(2-hydroxyphenyl)-5-(3-methylazetidin-l-yl)pyrazine-2-carboxylic acid

[0413] A solution of lithium hydroxide (91.3 mg, 3.81 mmol) in water (0.5 mL) was added to a solution of Cpd-11-1 (360 mg, 1.20 mmol) in methanol (3 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH 2 with 1 N HC1 and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give Cpd-11-2 (330 mg, 98.2% yield, white solid). LCMS calc. for C 15 H 14 N3O3[M-H] - : m / z = 284.1 ; Found: 284.1.

[0414] Step three: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-(2-hydroxyphenyl)-5-(3- methylazetidin-l-yl)pyrazine-2-carboxamide

[0415] A mixture of compound Cpd-11-5 (330 mg, 1.16 mmol), INT-1 (294 mg, 1.39 mmol), HATU (792 mg, 2.08 mmol) and diisopropylethylamine (598 mg, 4.63 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 h. LCMS indicated the starting material was consumed completely and the desired compound was detected. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3), the organic phase was combined and dried to give a crude product, which was purified by Prep-HPLC to give Cpd-11 (13.8 mg, yield 2.65%, white solid). LCMS calc. for C 22 H 27 N4O4S [M+H] + : m / z = 443.2; Found: 443.5; 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.59 (s, 1H), 8.49 (d, J = 8.8 Hz, 1H), 7.37 - 7.19 (m, 2H), 6.91 (dd, J = 8.0, 3.2 Hz, 2H), 6.89 - 6.82 (m, 1H), 6.74 (dd, J = 15.2, 1.2 Hz, 1H), 3.99 (dd, J = 14.8, 8.8 Hz, 1H), 3.83 (t, J = 8.0 Hz, 2H), 3.33 - 3.31 (m, 2H), 3.00 (s, 3H), 2.63 - 2.56 (m, 1H), 1.37 - 1.17 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H), 0.56 - 0.51 (m, 1H), 0.50 - 0.43 (m, 1H), 0.41 - 0.35 (m, 1H), 0.33 - 0.29 (m, 1H).

[0416] Example 12: (S,E)-N-(1-cyclopropyl-3-((3-(dimethylamino)propyl)sulfonyl)allyl)-5- (1,1-difluoroethyl)-6-phenylpyrazine-2-carboxamide

[0417]

[0418] Step one: 3-((tert-butoxycarbonyl)amino)propyl methyl sulfonate

[0419] To a solution of Cpd-12-1 (5.00 g, 28.5 mmol) in dichloromethane (100 mL) was added triethylamine (4.62 g, 45.7 mmol) at 0 °C, followed by dropwise addition of methanesulfonyl chloride (4.25 g, 37.1 mmol), the system was stirred at 0 °C for 1 h, then poured into water (100 mL), extracted with dichloromethane (100 mL x 3), the combined organic phase was dried and concentrated to give compound Cpd-12-2 (7.80 g, crude, yellow oil). LCMS calc. for C9H 19 NO5SNa[M+Na] + :m / z = 276.1; Found: 276.1.

[0420] Step two: S-[3-(tert-butylcarbonylamino)propyl] ethyl sulfide

[0421] A solution of Cpd-12-2 (7.80 g, 30.8 mmol) and potassium thioacetate (4.22 g, 37.0 mmol) in N,N-dimethylformamide (100 mL) was stirred at 65 °C for 12 h. Cooled to room temperature, quenched with water (50 mL), extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 1:3) to give compound Cpd-12-3 (2.20 g, yield 30.7%, yellow oil). LCMS calc. for C 10 H 19 NO3SNa[M+Na] + :m / z = 256.1; Found: 256.1.

[0422] Step three: tert-butyl N-(3-mercapto propyl)carbamate

[0423] A mixture of Cpd-12-3 (2.10 g, 9.00 mmol) and potassium carbonate (3.73 g, 27.0 mmol) in methanol (15 mL) and water (15 mL) was stirred at 50 °C for 5 h, LCMS showed the reaction was completed. The reaction was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give Cpd-12-4 (1.60 g, crude, yellow oil). LCMS calc. for C8H 17 NO2SNa[M+Na] + :m / z = 214.1; Found: 214.1.

[0424] Step four: tert-butyl N-[3-(diethoxyphosphorylmethylsulfanyl)propyl]carbamate

[0425] A mixture of Cpd-12-4 (100 mg, 522 μmol), diethyl chloromethylphosphonate (117 mg, 627 μmol), tetrabutylammonium iodide (386 mg, 1.05 mmol), and cesium carbonate (204 mg, 627 μmol) in N,N-dimethylformamide (2 mL) was stirred at 70 °C for 12 h under nitrogen. Cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (PE:EA = 3:1) to give compound Cpd-12-5 (100 mg, 50.4% yield, yellow oil). LCMS calc. for C8H 21 NO3PS[M+H-C5H8O2] + : m / z = 242.1 ; Found: 242.2.

[0426] Step five: tert-butyl N-[3-(diethoxyphosphorylmethylsulfonyl)propyl]carbamate

[0427] A solution of Cpd-12-5 (2.00 g, 5.86 mmol) and 3-chloroperbenzoic acid (2.02 g, 11.7 mmol) in dichloromethane (40 mL) was stirred at room temperature for 1 h. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (PE:EA = 10:1) to give compound Cpd-12-6 (700 mg, 32.0% yield, yellow oil). LCMS calc. for C8H 21 NO5PS[M+H-C5H8O2] + : m / z = 274.1 ; Found: 274.1.

[0428] Step six: 3-(diethoxyphosphorylmethylsulfonyl)propylamine

[0429] Trifluoroacetic acid (0.2 mL) was added to a solution of Cpd-12-6 (500 mg, 134 μmol) in dichloromethane (0.8 mL), the system was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to give compound Cpd-12-7 (35.0 mg, crude, colorless oil). LCMS calc. for C8H 21 NO5PS[M+H] + : m / z = 274.1 ; Found: 274.1.

[0430] Step seven: 3-(diethoxyphosphorylmethylsulfonyl)-N,N-dimethylpropan-1 -amine

[0431] Triethylamine (44.4 mg, 439 μmol) was added to a solution of Cpd-12-7 (35.0 mg, 110 μmol) in methanol (2 mL), then acetic acid (26.4 mg, 439 μmol), aqueous formaldehyde (35.7 mg, 439 μmol, 37.0% content) and sodium triacetoxyborohydride (93.1 mg, 439 μmol) were added successively at 0 °C. The system was stirred at 0 °C for 1 h. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-12-8 (20.0 mg, crude, white solid). LCMS calc. for C 10 H 25 NO5PS [M+H] + : m / z = 302.1 ; Found: 302.2.

[0432] Step eight: (S)-2-amino-2-cyclopropylethanol

[0433] INT-1-2 (800 mg, 3.97 mmol) was dissolved in hydrochloric acid (8 mL, 4N solution in dioxane), the system was stirred at room temperature for 2 h, then concentrated to give compound Cpd-12-8 (700 mg, crude, yellow oil), which was directly used in the next step.

[0434] Step nine: 5-(1,1 -difluoroethyl)-6-phenylpyrazine-2-carboxylic acid perfluorophenyl ester

[0435] A solution of Cpd-1-7 (500 mg, 1.89 mmol) and perfluorophenyl trifluoroacetate (1.06 g, 3.78 mmol) in pyridine (5 mL) was stirred at 60 °C for 1 h. Cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-12-9 (800 mg, crude, yellow oil). LCMS calc. for C 19 H 10 F7N2O2 [M+H] + : m / z = 431.1 ; Found: 431.0.

[0436] Step ten: (S)-N-(1-cyclopropyl-2-hydroxyethyl)-5-(1,1-difluoroethyl)-6-phenylpyrazine-2- carboxamide

[0437] A solution of Cpd-12-9 (800 mg, 1.86 mmol), Cpd-12-8 (511 mg, 3.72 mmol) and diisopropylethylamine (961 mg, 7.44 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h, LCMS showed the reaction was completed. The system was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 8:1) to give compound Cpd-12-10 (600 mg, yield 92.9%, white solid). LCMS calc. for C 18 H 20 F2N3O2[M+H] + : m / z = 348.1 ; Found: 348.2.

[0438] Step eleven: (S)-N-(1-cyclopropylacetaldehyde)-5-(1,1-difluoroethyl)-6-phenylpyrazine-2-carboxamide

[0439] A solution of Cpd-12-10 (150 mg, 432 μmol) and Dess-Martin oxidizing agent (274 mg, 648 μmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to give compound Cpd-12-11 (88.0 mg, yield 53.1%, white solid). LCMS calc. for C 18 H 18 F2N3O2[M+H] + : m / z = 346.1 ; Found: 346.2.

[0440] Step twelve: (S,E)-N-(1-cyclopropyl-3-((3-(dimethylamino)propyl)sulfonyl)allyl)-5-(1,1-difluoroethyl)-6-phenylpyrazine-2-carboxamide

[0441] A mixture of Cpd-12-8 (76.8 mg, 255 μmol), Cpd-12-11 (88.0 mg, 255 μmol) and potassium carbonate (176 mg, 1.27 mmol) in tetrahydrofuran (2 mL) was stirred at 60 °C for 16 h under nitrogen protection. The reaction was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) and Chiral-HPLC resolution to give compound Cpd-12 (4.26 mg, yield 3.39%, white solid). LCMS calc. for C24 H 31 F2N4O3S[M+H] + :m / z = 493.2; Found: 493.4; 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 2.8 Hz, 2H), 7.55 - 7.47 (m, 3H), 6.89 (dd, J = 15.2, 6.0 Hz, 1H), 6.77 (d, J = 15.2 Hz, 1H), 4.06 (dd, J = 14.8, 8.8 Hz, 1H), 3.14 - 3.00 (m, 2H), 2.28 (t, J = 6.8 Hz, 1H), 2.15 - 1.89 (m, 9H), 1.78 - 1.60 (m, 2H), 1.38 - 1.18 (m, 1H), 0.62 - 0.28 (m, 4H).

[0442] Example 13: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3- methylazetidin-l-yl)-6-phenylpicolinamide

[0443]

[0444] Step one: 6-bromo-5-(3-methylazetidin-l-yl)pyridine carboxylate

[0445] To a solution of Cpd-13-1 (500 mg, 2.14 mmol) and 3-methylazetidine hydrochloride (182 mg, 2.56 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (589 mg, 4.27 mmol) at room temperature. The mixture was stirred at 110 °C for 5 h. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10: 1) to give Cpd-13-2 (460 mg, yield 68.0%, colorless oil). LCMS calc. for C 11 H 14 BrN2O2[M+H] + :m / z = 285.0 / 287.0; Found: 285.1 / 287.1.

[0446] Step two: 5-(3-methylazetidin-l-yl)-6-phenylpyridine carboxylate

[0447] To a mixture of Cpd-13-2 (400 mg, 1.40 mmol) and phenylboronic acid (205 mg, 1.68 mmol) in dioxane (1 mL) and water (0.25 mL) was added potassium phosphate (596 mg, 2.81 mmol) and Pd(dppf)Cl2(57.3 mg, 70.1 μmol) at room temperature. The mixture was stirred at 90 °C for 1 h under nitrogen atmosphere. The reaction was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase column chromatography (H20:CH3CN = 10:1) to give compound Cpd-13-3 (370 mg, 93.4% yield, yellow solid). LCMS calc. for C 17 H 19 N2O2[M+H] + :m / z = 283.1; Found: 283.2.

[0448] Step three: 5-(3-methylazetidin-l-yl)-6-phenylpyridine carboxylic acid

[0449] To a mixture of Cpd-13-2 (400 mg, 1.40 mmol) and phenylboronic acid (205 mg, 1.68 mmol) in dioxane (1 mL) and water (0.25 mL) was added potassium phosphate (596 mg, 2.81 mmol) and Pd(dppf)Cl2(57.3 mg, 70.1 μmol) at room temperature. The mixture was stirred at 90 °C for 1 h under nitrogen atmosphere. The reaction was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase column chromatography (H20:CH3CN = 10:1) to give compound Cpd-13-3 (370 mg, 93.4% yield, yellow solid). LCMS calc. for C 16 H 17 N2O2[M+H] + :m / z = 283.1; Found: 283.2.

[0450] Step four: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-methylazetidin-l- yl)-6-phenylpyridine carboxamide

[0451] To a solution of Cpd-13-4 (250 mg, 932 pmol) and INT-1 (388 mg, 1.12 mmol) in acetonitrile (3 mL) was added 2-chloro-l-methylpyridinium iodide (357 mg, 1.40 mmol) and triethylamine (283 mg, 2.80 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give Cpd-13 (65.0 mg, yield 16.4%, white solid). LCMS calc. for C 23 H 28 N3O3S [M+H] + : m / z = 426.2; Found: 426.3; 1 H NMR (400 MHz, DMSO-d6) d 8.56 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.64 - 7.62 (m, 2H), 7.48 (t, J = 7.4 Hz, 2H), 7.43 - 7.39 (m, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.90 (dd, J = 15.3, 5.6 Hz, 1H), 6.76 (d, J = 15.4 Hz, 1H), 4.02 (dd, J = 14.6, 8.8 Hz, 1H), 3.68 (td, J = 7.9, 2.7 Hz, 2H), 3.13 - 3.09 (m, 2H), 3.00 (s, 3H), 2.59 (dt, J = 20.6, 7.1 Hz, 1H), 1.31 - 1.23 (m, 1H), 1.08 (d, J = 6.9 Hz, 3H), 0.60 - 0.28 (m, 4H).

[0452] Example 14: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5,6-bis(3- methylazetidin-l-yl)pyrazine-2-carboxamide

[0453]

[0454] Step one: 6-chloro-5-(3-methylazetidin-l-yl)pyrazine-2-carboxylic acid methyl ester

[0455] A solution of Cpd-9-2 (414 mg, 2.00 mmol) and N-chlorosuccinimide (320 mg, 2.40 mmol) in N,N-dimethylformamide (10 mL) was stirred at 50 °C for 2 h. Cooled to room temperature, the system was diluted with water (50 mL), extracted with ethyl acetate (80 mL x 2), the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to give compound Cpd-14-1 (420 mg, yield 87.0%, colorless oil). LCMS calc. for C 10 H 13 ClN3O2[M+H] + :m / z = 242.1; Found: 242.0.

[0456] Step two: 5,6-bis(3-methylazetidin-l-yl)pyrazine-2-carboxylic acid methyl ester

[0457] A solution of Cpd-14-1 (193 mg, 800 μmol), 3-methylazetidine hydrochloride (172 mg, 1.60 mmol) and diisopropylethylamine (1.03 g, 7.99 mmol) in dimethyl sulfoxide (3 mL) was stirred at 120 °C for 2 h. Cooled to room temperature, the system was diluted with water (30 mL), extracted with ethyl acetate (50 mL x 2), the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to give compound Cpd-14-2 (190 mg, yield 86.1%, white solid). LCMS calc. for C 14 H 20 N4O2Na[M+Na] + :m / z = 299.2; Found: 299.1.

[0458] Step three: 5,6-bis(3-methylazetidin-l-yl)pyrazine-2-carboxylic acid

[0459] To a solution of Cpd-14-2 (100 mg, 360 pmol) in tetrahydrofuran (0.50 mL), water (0.50 mL) and methanol (0.50 mL) was added lithium hydroxide (17.3 mg, 720 pmol) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction was adjusted to pH 5-6 with 1 N hydrochloric acid and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with water (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-14-3 (110 mg, crude, yellow solid) which was used directly in the next step. LCMS calc. for C 13 H 19 N4O2[M+H] + : m / z = 263.1 ; Found: 262.8.

[0460] Step four: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5,6-bis(3- methylazetidin-l-yl)pyrazine-2-carboxamide

[0461] To a solution of Cpd-14-3 (100 mg, 380 pmol), INT-1 (96.8 mg, 460 pmol), HATU (174 mg, 460 pmol) and diisopropylethylamine (98.5 mg, 760 pmol) in N,N- dimethylformamide (3 mL) was stirred at room temperature for 1 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give Cpd-14 (55.2 mg, yield 34.5%, white solid). LCMS calc. for C 20 H 30 N5O3S[M+H] + : m / z = 420.2 ; Found: 420.4; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 8.9 Hz, 1H), 8.16 (s, 1H), 6.91 (dd, J = 15.3, 5.6 Hz, 1H), 6.78 (d, J = 15.3 Hz, 1H), 4.18 - 4.07 (m, 4H), 4.04 (dd, J = 14.8, 8.9 Hz, 1H), 3.56 (dd, J = 14.3, 6.4 Hz, 4H), 3.02 (s, 3H), 2.72 (td, J = 13.8, 7.0 Hz, 2H), 1.30 - 1.24 (m, 1H), 1.24 - 1.17 (m, 6H), 0.62 - 0.54 (m, 1H), 0.49 (ddd, J = 12.6, 8.5, 4.2 Hz, 1H), 0.41 (td, J = 9.1, 4.7 Hz, 1H), 0.33 (dt, J = 9.2, 4.5 Hz, 1H).

[0462] Example 15 and Example 16: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3- methylazetidin-l-yl)-6-(cis-3-methylcyclobutyl)pyrazine-2-carboxamide and (S,E)-N-(l- cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-methylazetidin-l-yl)-6-(trans-3- methylcyclobutyl)pyrazine-2-carboxamide

[0463]

[0464] Step one: l,3-Dioxoisoindolin-2-yl-3-methylcyclobutane-l-carboxylate

[0465] To a solution of compound Cpd-15-1 (2.00 g, 17.5 mmol) and N-hydroxyphthalimide (3.14 g, 19.3 mmol) in dichloromethane (40 mL) was added 4-dimethylaminopyridine (107 mg, 876 μmol) at room temperature, followed by a solution of N,N'-dicyclohexylcarbodiimide (3.98 g, 19.3 mmol) in dichloromethane (6 mL) dropwise. The mixture was stirred at room temperature for 4 h. Water (40 mL) was added to dilute the mixture, which was extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 4: 1) to give compound Cpd-15-2 (3.40 g, 74.9% yield, white solid). LCMS calc. for C 14 H 13 NO4Na[M+Na] + :m / z = 282.3; Found: 282.2.

[0466] Step 2: 5-(3-methylazetidin-l-yl)-6-(3-methylcyclobutyl)pyrazine-2-carboxylic acid methyl ester

[0467] Bromine nickel hydrate (184 mg, 675 μmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (181 mg, 675 μmol) were dissolved in N,N-dimethylacetamide (10 mL) at room temperature, the system was cooled to 15 °C and stirred for 1 hour, then Cpd-15-2 (500 mg, 1.93 mmol), Cpd-9-3 (552 mg, 1.93 mmol) and zinc powder (630 mg, 9.64 mmol) were added. The system was warmed to 40 °C and stirred for 2 hours. The reaction solution was filtered, diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2), the organic layers were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase column chromatography (H20:CH3CN = 4: 1) to give compound Cpd-15-3 (150 mg, yield 28.3%, white solid). LCMS calc. for C 15 H 22 N3O2[M+H] + : m / z = 276.2; Found: 276.2.

[0468] Step 3: 5-(3-methylazetidin-l-yl)-6-(3-methylcyclobutyl)pyrazine-2-carboxylic acid

[0469] Cpd-15-3 (150 mg, 545 μmol) was dissolved in tetrahydrofuran (2 mL), water (1 mL) and methanol (1 mL) at room temperature, and lithium hydroxide (78.3 mg, 3.27 mmol) was added. The system was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 3-4 with 1 N hydrochloric acid and extracted with ethyl acetate (20 mL x 2), the organic layers were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give Cpd-15-4 (120 mg, yield 84.3%, white solid). LCMS calc. for C 14 H 20 N3O2[M+H] + : m / z = 262.2; Found: 262.2.

[0470] Step four: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-methylazetidin-l-yl)- 6-(cis-3-methylcyclobutyl)pyrazine-2-carboxamide and (S,E)-N-(1-cyclopropyl-3- (methylsulfonyl)allyl)-5-(3-methylazetidin-l-yl)-6-(trans-3-methylcyclobutyl)pyrazine- 2-carboxamide

[0471] To a solution of Cpd-15-4 (130 mg, 497 μmol) and INT-1 (207 mg, 597 μmol) in acetonitrile (3 mL) was added 2-chloro-l-methylpyridinium iodide (191 mg, 746 μmol) and triethylamine (151 mg, 1.49 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC and Chiral-HPLC to give Cpd-15 (20.0 mg, yield 9.61%, white solid) and Cpd-16 (23.1 mg, yield 11.1%, white solid). 21 H 31 N4O3S [M+H] + : m / z = 419.2; Found: 419.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.42 (d, J = 8.8 Hz, 1H), 6.95 (dd, J = 15.3, 5.8 Hz, 1H), 6.79 (dd, J = 15.3, 1.3 Hz, 1H), 4.30 (t, J = 8.4 Hz, 2H), 4.06 (dd, J = 14.7, 8.0 Hz, 1H), 3.80 - 3.72 (m, 2H), 3.71 - 3.60 (m, 1H), 3.02 (s, 3H), 2.83 - 2.72 (m, 1H), 2.66 (ddd, J = 11.8, 8.6, 6.6 Hz, 2H), 2.44 - 2.30 (m, 1H), 1.93 - 1.81 (m, 2H), 1.37 - 1.27 (m, 1H), 1.21 (dd, J = 13.5, 6.8 Hz, 6H), 0.58 (tt, J = 8.7, 4.5 Hz, 1H), 0.50 (ddd, J = 12.8, 8.7, 4.3 Hz, 1H), 0.41 (td, J = 9.0, 4.8 Hz, 1H), 0.34 (td, J = 9.0, 4.9 Hz, 1H). Cpd-16: LC-MS calc. for C21 H 31 N4O3S[M+H] + m / z = 419.2; Found: 419.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 6.95 (dd, J = 15.3, 5.7 Hz, 1H), 6.79 (dd, J = 15.3, 1.2 Hz, 1H), 4.31 (t, J = 8.4 Hz, 2H), 4.07 (dd, J = 14.2, 8.2 Hz, 1H), 3.76 (dd, J = 8.5, 5.8 Hz, 2H), 3.46 - 3.37 (m, 1H), 3.02 (s, 3H), 2.82 - 2.71 (m, 1H), 2.36 (dd, J = 9.1, 3.6 Hz, 3H), 2.01 (dt, J = 17.1, 8.5 Hz, 2H), 1.32 (qd, J = 8.4, 4.4 Hz, 1H), 1.23 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 5.7 Hz, 3H), 0.64 - 0.56 (m, 1H), 0.52 (ddd, J = 12.7, 8.6, 4.2 Hz, 1H), 0.42 (td, J = 8.9, 4.7 Hz, 1H), 0.35 (td, J = 9.1, 5.0 Hz, 1H).

[0472] Example 17 and Example 18: 6-((1R,5R)-Bicyclo[3.1.0]hexan-1-yl)-N-((S,E)-1- cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)pyrazine-2-carboxamide and 6- ((1S,5S)-Bicyclo[3.1.0]hexan-1-yl)-N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-5- (1,1-difluoroethyl)pyrazine-2-carboxamide

[0473]

[0474] Step one: 6-Chloro-5-(1,1-difluoroethyl)pyrazine-2-carboxylic acid

[0475] Lithium hydroxide (987 mg, 24.1 mmol) was added to a mixture of Cpd-5-1 (1.90 g, 8.03 mmol) in tetrahydrofuran (15 mL) and water (4 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was adjusted to pH 4 with 1 N aqueous hydrochloric acid solution, extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-17-1 (1.79 g, crude, yellow solid). LCMS calc. for C7H6ClF2N2O2[M+H] + : m / z = 223.0; Found: 223.0.

[0476] Step two: tert-Butyl 6-chloro-5-(1,1-difluoroethyl)pyrazine-2-carboxylate

[0477] A mixture of Cpd-17-1 (1.79 g, 8.04 mmol), di-tert-butyl dicarbonate (5.27 g, 24.1 mmol) and 4-dimethylaminopyridine (982 mg, 8.04 mmol) in tert-butanol (20 mL) was stirred at 60 °C for 2 h. The mixture was cooled to room temperature and poured into water (30 mL), extracted with ethyl acetate (30 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1) to give compound Cpd-17-2 (800 mg, yield 35.7%, yellow solid). LCMS calc. for C 11 H 13 ClF2N2O2Na[M+Na] + : m / z = 301.1; Found: 301.0.

[0478] Step three: tert-Butyl 6-(cyclopent-1-en-1-yl)-5-(1,1-difluoroethyl)pyrazine-2- carboxylate

[0479] To a mixture of Cpd-17-2 (2.00 g, 8.45 mmol) and 1-cyclopentenylboronic acid pinacol ester (1.64 g, 8.45 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added potassium phosphate (3.59 g, 16.9 mmol) and Pd(dppf)Cl2(928 mg, 1.27 mmol) at room temperature. The mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 10:1) to give compound Cpd-17-3 (1.87 g, 82.3% yield, yellow oil). LCMS calc. for C 16 H 21 F2N2O2[M+H] + :m / z = 311.2; Found: 311.3.

[0480] Step four: 6-(Bicyclo[3.1.0]hexan-1-yl)-5-(1,1-difluoroethyl)pyrazine-2-carboxylic acid tert-butyl ester

[0481] Sodium hydride (25.7 mg, 644 μmol, 60% content) was added to a solution of trimethylsulfoxonium iodide (141 mg, 644 μmol) in dimethylsulfoxide (2 mL) at room temperature. The mixture was stirred at room temperature for 0.5 h, then Cpd-17-3 (50.0 mg, 161 μmol) was added and stirred for 2 h. The reaction mixture was adjusted to pH 4 with 1 N hydrochloric acid solution, extracted with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-17-4 (43.0 mg, crude, yellow oil). LCMS calc. for C 17 H 22 F2N2O2Na[M+Na] + :m / z = 347.2; Found: 347.3.

[0482] Step five: 6-(Bicyclo[3.1.0]hexan-1-yl)-5-(1,1-difluoroethyl)pyrazine-2-carboxylic acid

[0483] Lithium hydroxide (38.6 mg, 1.61 mmol) was added to a solution of Cpd-17-4 (43.0 mg, 161 μmol) in tetrahydrofuran (2 mL) and water (1 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction was adjusted to pH 4 with 1 N hydrochloric acid solution and extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-17-5 (40.0 mg, crude, yellow oil). LCMS calc. for C 13 H 15 F2N2O2[M+H] + :m / z = 269.1 ; Found: 269.0.

[0484] Step six: 6-((1R,5R)-Bicyclo[3.1.0]hexan-1-yl)-N-((S,E)-1-cyclopropyl-3- (methylsulfonyl)allyl)-5-(1,1-difluoroethyl)pyrazine-2-carboxamide and 6-((1S,5S)- bicyclo[3.1.0]hexan-1-yl)-N-((S,E)-1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1- difluoroethyl)pyrazine-2-carboxamide

[0485] To a solution of Cpd-17-5 (140 mg, 521 μmol) and INT-1 (217 mg, 626 μmol) in acetonitrile (5 mL) was added 2-chloro-1-methylpyridine iodide (200 mg, 782 μmol) and triethylamine (158 mg, 1.57 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 hour. The reaction was purified by Prep-HPLC and separated by Chiral-HPLC to give Cpd-17 (35.0 mg, yield 15.8%, white solid) and Cpd-18 (36.0 mg, yield 16.2%, white solid). Cpd-17: LCMS calc. for C 20 H 26 F2N3O3S[M+H] + :m / z = 426.2; Found: 426.4; 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.98 (d, J = 8.8 Hz, 1H), 7.08 - 6.56 (m, 2H), 4.08 (td, J = 14.4, 5.6 Hz, 1H), 3.02 (s, 3H), 2.21 - 1.87 (m, 7H), 1.82 - 1.70 (m, 2H), 1.50 - 1.28 (m, 2H), 1.06 - 0.92 (m, 2H), 0.67 - 0.58 (m, 1H), 0.57 - 0.50 (m, 1H), 0.49 - 0.43 (m, 1H), 0.39 - 0.34 (m, 1H). Cpd-18: LCMS calc. for C 20 H 26 F2N3O3S [M+H] + : m / z = 426.2; Found: 426.4; 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.97 (d, J = 8.4 Hz, 1H), 7.15 - 6.65 (m, 2H), 4.08 (td, J = 14.4, 5.6 Hz, 1H), 3.03 (s, 3H), 2.24 - 1.90 (m, 7H), 1.82 - 1.70 (m, 2H), 1.51 - 1.25 (m, 2H), 1.09 - 0.99 (m, 1H), 0.96 (t, J = 4.4 Hz, 1H), 0.68 - 0.57 (m, 1H), 0.56 - 0.49 (m, 1H), 0.48 - 0.43 (m, 1H), 0.39 - 0.33 (m, 1H).

[0486] Example 19: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-fluoro-3- methylazetidin-l-yl)-6-phenylpyrazine-2-carboxamide

[0487]

[0488] Step one: 5-amino-6-chloropyrazine-2-carboxylic acid methyl ester

[0489] A mixture of Cpd-19-1 (50.0 g, 327 mmol) and N-chlorosuccinimide (52.3 g, 392 mmol) in N,N-dimethylformamide (500 mL) was stirred at room temperature for 12 h under nitrogen. The reaction was concentrated under reduced pressure, the residue was diluted with ethyl acetate (1000 mL) and washed with saturated brine (500 mL x 2), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (PE:THF = 4:1) to give compound Cpd-19-2 (40.0 g, yield 65.3%, orange solid). LCMS calc. for C6H7ClN3O2[M+H] + : m / z = 188.0; Found: 188.1.

[0490] Step two: 5-amino-6-phenylpyrazine-2-carboxylic acid methyl ester

[0491] A mixture of Cpd-19-2 (20.0 g, 107 mmol), phenylboronic acid (15.6 g, 128 mmol), potassium phosphate (41.6 g, 266 mmol) and Pd(dppf)Cl2(6.97 g, 8.53 mmol) in dioxane (150 mL) and water (30 mL) was stirred at 95 °C for 3 h under nitrogen. The reaction was cooled to room temperature and extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (PE:THF = 3:1) to give compound Cpd-19-3 (9.00 g, yield 36.8%, yellow solid). LCMS calc. for C 12 H 12 N3O2[M+H] + : m / z = 230.1; Found: 230.2.

[0492] Step three: 5-bromo-6-phenylpyrazine-2-carboxylic acid methyl ester

[0493] To a solution of Cpd-19-3 (4.00 g, 17.5 mmol) in dichloromethane (50 mL) was added trimethylsilyl bromide (8.00 g, 52.5 mmol) at 0 °C, followed by the slow addition of tert-butyl nitrite (18.0 g, 175 mmol). The system was stirred at room temperature for 3 h. The system was concentrated, and the residue was purified by column chromatography on silica gel (PE:EA = 10:1) to give compound Cpd-19-4 (2.40 g, yield 47.2%, white solid). LCMS calc. for C 12 H 10 BrN2O2[M+H] +m / z = 293.0 / 295.0; Found: 293.1 / 295.1.

[0494] Step four: 5-(3-fluoro-3-methylazetidin-l-yl)-6-phenylpyrazine-2-carboxylic acid methyl ester

[0495] A solution of Cpd-19-4 (210 mg, 720 μmol), 3-fluoro-3-methylazetidine hydrochloride (180 mg, 1.43 mmol) and N,N-diisopropylethylamine (370 mg, 2.87 mmol) in tetrahydrofuran (8 mL) was stirred at 80 °C for 1 h. The reaction was cooled and concentrated, and the residue was purified by column chromatography on silica gel (PE:EA = 4: 1) to give compound Cpd-19-5 (125 mg, yield 57.9%, yellow oil). LCMS calc. for C 16 H 17 FN3O2[M+H] + m / z = 302.1; Found: 301.7.

[0496] Step five: 5-(3-fluoro-3-methylazetidin-l-yl)-6-phenylpyrazine-2-carboxylic acid

[0497] A solution of lithium hydroxide (19.9 mg, 830 μmol) in water (1.5 mL) was added to a mixture of Cpd-19-5 (125 mg, 410 μmol) in tetrahydrofuran (1.5 mL) and methanol (1.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was adjusted to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-19-6 (90.1 mg, crude, white solid). LCMS calc. for C 15 H 15 FN3O2[M+H] + m / z = 288.1; Found: 288.0.

[0498] Step six: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-fluoro-3- methylazetidin-l-yl)-6-phenylpyrazine-2-carboxamide

[0499] A mixture of Cpd-19-6 (90.1 mg, 314 pmol), INT-1 (79.6 mg, 380 pmol), triethylamine (159 mg, 1.57 mmol) and HATU (143 mg, 380 pmol) in N,N-dimethylformamide (6 mL) was stirred at room temperature for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give Cpd-19 (130 mg, yield 93.5%, white solid). LCMS calc. for C 22 H 26 FN4O3S [M+H] + : m / z = 445.2; Found: 445.4; 1 H NMR (400 MHz, DMSO-d6) d 8.71 (d, J = 8.8 Hz, 1H), 8.69 (s, 1H), 7.73-7.71 (m, 2H), 7.56-7.47 (m, 3H), 6.91 (dd, J = 14.8, 5.6 Hz, 1H), 6.79 (d, J = 15.2 Hz, 1H), 4.09-4.03 (m, 1H), 3.92-3.77 (m, 4H), 3.01 (s, 3H), 1.47 (d, J = 11.0 Hz, 3H), 1.33-1.24 (m, 1H), 0.61-0.55 (m, 1H), 0.52-0.30 (m, 3H).

[0500] Example 20: (S,E)-N-(1-cyclopropyl-3-((1-methylazetidin-3-yl)sulfonyl)allyl)-5-(1,1- difluoroethyl)-6-phenylpyrazine-2-carboxamide

[0501]

[0502] Step one: tert-butyl 3-(benzoylthio)azetidine-1-carboxylate

[0503] A mixture of Cpd-20-1 (1.00 g, 5.77 mmol), triphenylphosphine (3.79 g, 14.4 mmol), thiobenzoic acid (1.60 g, 11.6 mmol) and diisopropyl azodicarboxylate (2.33 g, 14.4 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE:EA = 5:1) to give compound Cpd-20-2 (1.63 g, yield 96.1%, colorless liquid). LCMS calc. for C 11H 12 NO3S[M-C4H8+H] + :m / z = 238.1 ; Found: 238.0.

[0504] Step two: tert-butyl 3-((diethoxyphosphoryl)methylthio)azetidine-1-carboxylate

[0505] To a solution of Cpd-20-2 (1.62 g, 5.52 mmol) in ethanol (10 mL) was added sodium ethoxide (10 mL, 20% in ethanol) at room temperature, and the system was stirred at room temperature for 1 h. Diethyl 1-chloromethylphosphonate (1.91 g, 11.1 mmol) was added, and the system was stirred at 50 °C for 2 h. The reaction was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH = 10:1) to give compound Cpd-20-3 (974 mg, 51.7% yield, white solid). LCMS calc. for C 13 H 26 NO5PSNa[M+Na] + :m / z = 362.1 ; Found: 362.1.

[0506] Step three: tert-butyl 3-(((diethoxyphosphoryl)methyl)sulfonyl)azetidine-1-carboxylate

[0507] To a solution of Cpd-20-3 (974 mg, 2.87 mmol) in dichloromethane (20 mL) was added m-chloroperoxybenzoic acid (1.75 g, 8.61 mmol, 85% content) at room temperature, and the system was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous sodium sulfite solution (20 mL) and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH = 10:1) to give compound Cpd-20-4 (886 mg, 83.1% yield, colorless liquid). LCMS calc. for C 13 H 27 NO7PS[M+H] + :m / z = 372.1 ; Found: 372.1.

[0508] Step four: tert-butyl (S,E)-3-((3-cyclopropyl-3-(5-(1,1-difluoroethyl)-6-phenylpyrazine-2- carboxamido)prop-1-en-1-yl)sulfonyl)azetidine-1-carboxylate

[0509] A solution of Cpd-20-4 (400 mg, 1.08 mmol), Cpd-12-11 (372 mg, 1.08 mmol), lithium chloride (54.8 mg, 1.29 mmol) and diisopropylethylamine (278 mg, 2.15 mmol) in acetonitrile (10 mL) was stirred at room temperature under argon overnight. The reaction was dropped into water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give compound Cpd-20-5 (592 mg, yield 97.7%, white solid). LCMS calc. for C 27 H 33 F2N4O5S [M+H] + : m / z = 563.2; Found: 563.1.

[0510] Step five: (S,E)-N-(3-(azetidin-3-ylsulfonyl)-1-cyclopropylallyl)-5-(1,1-difluoroethyl)-6- phenylpyrazine-2-carboxamide

[0511] To a solution of Cpd-20-5 (300 mg, 533 μmol) in dichloromethane (4 mL) was added hydrochloric acid (2 mL, 4N in dioxane) and the mixture was stirred at room temperature for 1 hour. It was concentrated under reduced pressure and the residue was co-evaporated with acetonitrile (40 mL) twice to give compound Cpd-20-6 (212 mg, yield 86.0%, white solid). LCMS calc. for C 22 H 25 F2N4O3S [M+H] + : m / z = 463.2; Found: 463.3.

[0512] Step six: (S,E)-N-(1-cyclopropyl-3-((1-methylazetidin-3-yl)sulfonyl)allyl)-5-(1,1-difluoroethyl)- 6-phenylpyrazine-2-carboxamide

[0513] A mixture of Cpd-20-6 (150 mg, 324 pmol), sodium cyanoborohydride (40.8 mg, 649 pmol), diisopropylethylamine (126 mg, 973 pmol) and aqueous formaldehyde (0.5 mL, 37% content) in methanol (4 mL) was stirred at room temperature for 2 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by pre-HPLC and Chiral-HPLC to give compound Cpd-20 (12.3 mg, yield 7.97%, white solid). LCMS calc. for C 23 H 27 F2N4O3S [M+H] + : m / z = 477.2; Found: 477.3; 1 H NMR (400 MHz, DMSO-d6) δ 9.27 - 9.17 (m, 2H), 7.67 - 7.58 (m, 2H), 7.57 - 7.47 (m, 3H), 6.94 (dd, J = 15.2, 6.0 Hz, 1H), 6.81 - 6.70 (m, 1H), 4.16 - 3.99 (m, 2H), 3.43 (t, J = 8.0 Hz, 2H), 3.27 - 3.17 (m, 2H), 2.18 (s, 3H), 2.01 (t, J = 19.2 Hz, 3H), 1.33 - 1.23 (m, 1H), 0.61 - 0.30 (m, 4H).

[0514] Example 21: (S,E)-N-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(3- methylazetidin-l-yl)-6-phenylpyrazine-2-carboxamide

[0515]

[0516] Step one: Diethyl (fluoro(methylsulfonyl)methyl)phosphonate

[0517] Potassium hexamethyldisilazide (54.3 mL, 54.3 mmol, 1 M in tetrahydrofuran) was added dropwise to a solution of INT-1-4 (10.0 g, 43.4 mmol) in tetrahydrofuran (120 mL) at -60 °C under nitrogen. The mixture was stirred at -60 °C for 0.5 h. A solution of l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (23.1 g, 65.1 mmol) in N,N-dimethylformamide (80 mL) was added to the above reaction mixture and slowly raised to 0 °C. The mixture was stirred at 0 °C for 3 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give compound Cpd-21-1 (5.00 g, yield 46.3%, yellow oil). 1 H NMR (400 MHz, DMSO-d6) δ 6.41 (dd J = 42.9, 6.9 Hz, 1H), 4.27-4.14 (m 4H), 3.19 (s, 3H), 1.30-1.24 (m 6H).

[0518] Step two: (S,E)-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)carbamic acid tert-butyl ester

[0519] A solution of Cpd-21-1 (4.00 g, 20.1 mmol), INT-1-3 (4.98 g, 20.1 mmol) and potassium carbonate (6.94 g, 50.1 mmol) in tetrahydrofuran (80 mL) was stirred at 35 °C for 1 h under nitrogen. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to give compound Cpd-21-2 (2.00 g, yield 33.9%, colorless oil). LCMS calc. for C 12 H 21 FNO4S [M+H] + : m / z = 294.1; Found: 294.2.

[0520] Step three: (S,E)-l-cyclopropyl-3-fluoro-3-(methylsulfonyl)prop-2-en-l-amine p-toluenesulfonic acid salt

[0521] A solution of Cpd-21-2 (1.10 g, 3.75 mmol) and p-toluenesulfonic acid monohydrate (855 mg, 4.50 mmol) in acetonitrile (20 mL) was stirred at 50 °C for 16 h. The reaction was cooled to room temperature, the filter cake was collected by filtration to give compound Cpd-21-3 (1.30 g, 94.8% yield, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 3H), 7.48 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.26 (dd, J = 33.3, 9.3 Hz, 1H), 3.57 (t, J = 9.5 Hz, 1H), 3.31 (s, 3H), 2.29 (s, 3H), 1.21 - 1.12 (m, 1H), 0.69 - 0.54 (m, 3H), 0.36 - 0.31 (m, 1H).

[0522] Step Four: (S,E)-N-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(3- methylazetidin-l-yl)-6-phenylpyrazine-2-carboxamide

[0523] A solution of Cpd-21-3 (207 mg, 1.07 mmol), Cpd-9-5 (144 mg, 530 μmol), N,N- diisopropylethylamine (242 mg, 1.87 mmol) and HATU (407 mg, 1.07 mmol) in N,N- dimethylformamide (4 mL) was stirred at room temperature for 1 h. The system was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with water (50 mL x 2), dried over sodium sulfate, concentrated by filtration, the residue was purified by preparative purification and Chiral-HPLC to give compound Cpd-21 (86.2 mg, 36.3%, white solid). LCMS calc. for C 22 H 26 FN4O3S [M+H] + : m / z = 445.2; Found: 445.3; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 9.2 Hz, 1H), 8.63 (s, 1H), 7.70 - 7.62 (m, 2H), 7.57 - 7.40 (m, 3H), 6.54 (dd, J = 34.8, 9.2 Hz, 1H), 4.33 (q, J = 9.2 Hz, 1H), 3.84 (dd, J = 12.0, 5.2 Hz, 2H), 3.29 (s, 2H), 3.24 (s, 3H), 2.69 - 2.57 (m, 1H), 1.37 - 1.27 (m, 1H), 1.09 (d, J = 6.8 Hz, 3H), 0.57 - 0.22 (m, 4H).

[0524] Example 22: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3- methylazetidin-l-yl)-4-phenylpyrimidine-2-carboxamide

[0525]

[0526] Step one: 5-fluoro-4-phenylpyrimidine-2-carboxylic acid methyl ester

[0527] To a mixture of compound Cpd-22-1 (1.01 g, 6.47 mmol), phenylboronic acid (1.18 g, 9.70 mmol), silver nitrate (1.10 g, 6.47 mmol) and potassium persulfate (8.74 g, 32.4 mmol) in dichloromethane (30 mL) and water (30 mL) was added trifluoroacetic acid (740 mg, 6.47 mol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography (PE:EA = 1:3) to give compound Cpd-22-2 (680 mg, yield 45.3%, yellow solid). LCMS calc. for C 12 H 10 FN2O2[M+H] + : m / z = 233.1 ; Found: 232.9.

[0528] Step two: 5-(3-methylazetidin-l-yl)-4-phenylpyrimidine-2-carboxylic acid methyl ester

[0529] To a solution of compound Cpd-22-2 (348 mg, 1.50 mmol) and 3-methylazetidine hydrochloride (193 mg, 1.80 mmol) in THF (15 mL) was added N,N- diisopropylethylamine (581 mg, 4.50 mmol) at room temperature. The mixture was stirred in a sealed tube at 80 °C for 16 h. The mixture was cooled and concentrated. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 1:1) to give compound Cpd-22-3 (200 mg, yield 47.1%, yellow solid). LCMS calc. for C 16 H 18 N3O2[M+H] + : m / z = 284.1 ; Found: 284.0.

[0530] Step three: 5-(3-methylazetidin-l-yl)-4-phenylpyrimidine-2-carboxylic acid

[0531] To a solution of compound Cpd-22-3 (80.0 mg, 283 μmol) in tetrahydrofuran (1 mL), water (1 mL) and methanol (1 mL) was added lithium hydroxide (13.5 mg, 563 μmol) at room temperature. The mixture was stirred at room temperature for 1 h. The pH was adjusted to 5-6 by adding 1 N HC1 and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-22-4 (75.0 mg, yield 98.6%, white solid) which was used directly in the next step. LCMS calc. for C 15 H 16 N3O2[M+H] + : m / z = 270.1 ; Found: 270.0.

[0532] Step four: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-methylazetidin-l-yl)-4- phenylpyrimidine-2-carboxamide

[0533] To a solution of compound Cpd-22-4 (75.0 mg, 279 pmol), INT-1 (70.8 mg, 336 pmol), N,N-diisopropylethylamine (108 mg, 837 pmol) in N,N-dimethylformamide (2 mL) was added HATU (138 mg, 363 pmol) at room temperature. The mixture was stirred at room temperature for 1 h. Water (50 mL) was added to the reaction mixture, which was extracted with ethyl acetate (50 mL x 2), the combined organic phase was washed with water (50 mL x 2), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by Prep-HPLC to give compound Cpd-22 (59.5 mg, yield 50.1%, white solid). LCMS calc. for C 22 H 27 N4O3S [M+H] + : m / z = 427.2; Found: 427.2; 1 H NMR (400 MHz, DMSO-d6) d 8.88 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H), 7.66 (dd, J = 7.9, 1.4 Hz, 2H), 7.56 - 7.45 (m, 3H), 6.90 (dd, J = 15.2, 5.5 Hz, 1H), 6.79 (dd, J = 15.3, 1.0 Hz, 1H), 4.11 - 3.98 (m, 1H), 3.81 (td, J = 7.9, 1.6 Hz, 2H), 3.27 - 3.19 (m, 2H), 3.01 (m, 3H), 2.72 - 2.62 (m, 1H), 1.30 - 1.23 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H), 0.62 - 0.53 (m, 1H), 0.53 - 0.45 (m, 1H), 0.45 - 0.38 (m, 1H), 0.38 - 0.29 (m, 1H).

[0534] Example 23: (S,E)-N-(l-cyclopropyl-3-(methyl-d3)allyl)-5-(3-fluoro-3-(methyl-d3)azetidin-l-yl)-6-phenylpyrazine-2-carboxamide

[0535]

[0536] Step one: 3-hydroxy-3-(methyl-d3)azetidine-1-carboxylic acid tert-butyl ester

[0537] Under argon protection at -78°C, (methyl-d3)magnesium iodide (49.5 mL, 49.5 mmol, 1 M tetrahydrofuran solution) was slowly added dropwise to a tetrahydrofuran (180 mL) solution of Cpd-23-1 (7.70 g, 45.0 mmol). The system was stirred at -78°C for 2 hours, quenched with saturated ammonium chloride aqueous solution (180 mL), and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue purified by silica gel column chromatography (PE:EA = 3:1) to give compound Cpd-23-2 (7.86 g, 91.8% yield, white solid). LCMScalc. for C9H 14 D3NO3Na[M+Na] + :m / z=213.1;Found:213.1.

[0538] Step 2: tert-butyl 3-fluoro-3-(methyl-d3)azacyclobutane-1-carboxylate

[0539] Diethylaminosulfur trifluoride (3.86 g, 224 mmol) was slowly added dropwise to a solution of Cpd-23-2 (3.80 g, 20.0 mmol) in dichloromethane (50 mL) at -78 °C under argon protection. The system was stirred at -78 °C for 1 hour, then transferred to room temperature and stirred for 16 hours. The pH of the reaction mixture was adjusted to neutral with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (100 mL × 2). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give Cpd-23-3 (3.80 g, 99.0% yield, white solid). LCMS calc. for C5H6D3FNO2[M-C4H8+H] + :m / z=137.1;Found:137.1.

[0540] Step 3: 3-Fluoro-3-(methyl-d3)azacyclobutane hydrochloride

[0541] Hydrochloric acid (19.8 mL, 79.1 mmol, 4N ethyl acetate solution) was added to a solution of Cpd-23-3 (3.80 g, 19.8 mmol) in 20 mL of dichloromethane under ice bath conditions, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to give compound Cpd-23-4 (2.45 g, 96.4% yield, white solid). LCMS calc. for C4H6D3FN[M+H] + :m / z=93.1;Found:92.9.

[0542] Step four: 5-(3-fluoro-3-(methyl-d3)azetidin-l-yl)-6-phenylpyrazine-2-carboxylic acid methyl ester

[0543] A mixture of Cpd-19-4 (1.02 g, 3.50 mmol), Cpd-23-4 (0.49 g, 3.85 mmol) and diisopropylethylamine (1.81 g, 14.0 mmol) in tetrahydrofuran (10 mL) was stirred at 80 °C for 3 h. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (PE:EA = 3: 1) to give compound Cpd-23-5 (1.05 g, yield 98.7%, white solid). LCMS calc. for C 16 H 13 D3FN3O2Na [M+Na] + : m / z = 327.1; Found: 327.1.

[0544] Step five: 5-(3-fluoro-3-(methyl-d3)azetidin-l-yl)-6-phenylpyrazine-2-carboxylic acid

[0545] A solution of lithium hydroxide (170 mg, 6.90 mmol) in water (10 mL) was added to a mixture of Cpd-23-5 (1.05 g, 3.45 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL). The mixture was stirred at room temperature for 1 h. The reaction was concentrated, diluted with water (30 mL), adjusted to pH 5-6 with 1 N hydrochloric acid and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-23-6 (960 mg, crude, white solid). Used directly in the next step. LCMS calc. for C 15 H 12 D3FN3O2 [M+H] + : m / z = 291.1; Found: 291.5.

[0546] Step six: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-fluoro-3-(methyl-d3)azetidin-l-yl)-6-phenylpyrazine-2-carboxamide

[0547] A mixture of Cpd-23-6 (960 mg, 3.31 mmol), INT-1 (770 mg, 3.64 mmol), diisopropylethylamine (1.07 g, 8.27 mmol) and HATU (1.38 g, 3.64 mmol) in N,N-dimethylformamide (25 mL) was stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give Cpd-23 (919 mg, yield 62.1%, white solid). LCMS calc. for C 22 H 23 D3FN4O3S [M+H] + : m / z = 448.2; Found: 447.9; 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 8.9 Hz, 1H), 8.68 (s, 1H), 7.75-7.69 (m, 2H), 7.57-7.46 (m, 3H), 6.90 (dd, J = 15.2, 5.7 Hz, 1H), 6.78 (dd, J = 15.3, 1.0 Hz, 1H), 4.11-3.98 (m, 1H), 3.96-3.74 (m, 4H), 3.01 (s, 3H), 1.34-1.22 (m, 1H), 0.65-0.53 (m, 1H), 0.53-0.39 (m, 2H), 0.38-0.27 (m, 1H).

[0548] Example 24: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-fluoro-3- methylazetidin-1-yl)-6-(phenyl-d5)pyrazine-2-carboxamide

[0549]

[0550] Step one: 5-(3-fluoro-3-methylazetidin-1-yl)pyrazine-2-carboxylic acid methyl ester

[0551] A mixture of Cpd-9-1 (3.00 g, 17.4 mmol), 3-fluoro-3-methylazetidine hydrochloride (2.40 g, 19.1 mmol) and N,N-diisopropylethylamine (6.74 g, 52.2 mmol) in tetrahydrofuran (40 mL) was stirred at 80 °C for 1 h. The mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 1:1) to give compound Cpd-24-1 (3.90 g, yield 99.6%, white solid). LCMS calc. for C 10 H13 FN3O2[M+H] + m / z = 226.1 ; Found: 226.0.

[0552] Step two: 6-bromo-5-(3-fluoro-3-methylazetidin-l-yl)pyrazine-2-carboxylic acid methyl ester

[0553] A solution of Cpd-24-1 (3.90 g, 17.3 mmol) and N-bromosuccinimide (6.16 g, 34.6 mmol) in tetrahydrofuran (80 mL) was stirred at 75 °C for 6 hours. The reaction was cooled and concentrated, and the residue was purified by column chromatography on silica gel (PE:EA = 2:1) to give compound Cpd-24-2 (4.30 g, yield 81.7%, yellow oil). LCMS calc. for C 10 H 12 BrFN3O2[M+H] + m / z = 304.0 / 306.0; Found: 303.9 / 305.9.

[0554] Step three: 5-(3-fluoro-3-methylazetidin-l-yl)-6-(phenyl-d5)pyrazine-2-carboxylic acid methyl ester

[0555] A mixture of Cpd-24-2 (4.30 g, 14.1 mmol), (phenyl-d5)boronic acid (2.15 g, 17.0 mmol), potassium phosphate (6.00 g, 28.3 mmol) and Pd(dppf)Cl2(1.15 g, 1.41 mmol) in toluene (50 mL) and water (12 mL) was stirred at 80 °C for 4 hours under argon protection. The reaction was cooled to room temperature and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 1:1) to give compound Cpd-24-3 (3.90 g, yield 90.0%, yellow solid). LCMS calc. for C 16 H 12 D5FN3O2[M+H] + m / z = 307.2; Found: 307.0.

[0556] Step four: 5-(3-fluoro-3-methylazetidin-l-yl)-6-(phenyl-d5)pyrazine-2-carboxylic acid

[0557] To a solution of Cpd-24-3 (3.90 g, 12.7 mmol) in tetrahydrofuran (25 mL) and methanol (25 mL) was added a solution of lithium hydroxide (610 mg, 25.5 mmol) in water (25 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction was adjusted to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-24-4 (3.70 g, crude, yellow solid) which was used directly in the next step. LCMS calc. for C 15 H 10 D5FN3O2[M+H] + : m / z = 293.1 ; Found: 293.2.

[0558] Step five: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-fluoro-3- methylazetidin-l-yl)-6-(phenyl-d5)pyrazine-2-carboxamide

[0559] A mixture of Cpd-24-4 (2.00 g, 6.85 mmol), INT-1 (1.59 g, 7.53 mmol), HATU (3.12 g, 8.21 mmol) and triethylamine (3.46 g, 34.2 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give Cpd-24 (510 mg, yield 16.1%, white solid). LCMS calc. for C 22 H 21 D5FN4O3S[M+H] + : m / z = 450.2; Found: 450.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 8.8 Hz, 1H), 8.68 (s, 1H), 6.90 (dd, J = 15.2, 6.0 Hz, 1H), 6.78 (d, J = 15.2 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.91 - 3.76 (m, 4H), 3.01 (s, 3H), 1.47 (d, J = 22.0 Hz, 3H), 1.32 - 1.23 (m, 1H), 0.61 - 0.54 (m, 1H), 0.51 - 0.35 (m, 2H), 0.34 - 0.30 (m, 1H).

[0560] Example 25: (S,E)-N-(l-cyclopropyl-3-(methyl-d3)allyl)-5-(3-fluoro-3-(methyl- d3)azetidin-l-yl)-6-(phenyl-d5)pyrazine-2-carboxamide

[0561]

[0562] Step one: 5-(3-fluoro-3-(methyl-d3)azetidin-l-yl)pyrazine-2-carboxylic acid methyl ester

[0563] A solution of Cpd-9-1 (1.20 g, 6.95 mmol), Cpd-23-4 (980 mg, 7.65 mmol) and N,N- diisopropylethylamine (2.70 g, 20.9 mmol) in tetrahydrofuran (30 mL) was stirred at 80 °C for 16 h. The system was cooled and concentrated, the residue was purified by silica gel column chromatography (PE:EA = 1:1) to give compound Cpd-25-1 (1.50 g, yield 94.5%, yellow solid). LCMS calc. for C 10 H 10 D3FN3O2[M+H] + : m / z = 229.1; Found: 229.0.

[0564] Step two: 6-bromo-5-(3-fluoro-3-(methyl-d3)azetidin-l-yl)pyrazine-2-carboxylic acid methyl ester

[0565] A solution of Cpd-25-1 (1.50 g, 6.57 mmol) and N-bromosuccinimide (1.52 g, 8.54 mmol) in acetonitrile (30 mL) was stirred at 75 °C for 1 h. The system was cooled and concentrated, the residue was purified by silica gel column chromatography (PE:EA = 4:1) to give compound Cpd-25-2 (1.80 g, yield 89.2%, yellow oil). LCMS calc. for C 10 H9BrD3FN3O2[M+H] + : m / z = 307.0 / 309.0; Found: 307.0 / 308.8.

[0566] Step three: 5-(3-fluoro-3-(methyl-d3)azetidin-l-yl)-6-(phenyl-d5)pyrazine-2-carboxylic acid methyl ester

[0567] A mixture of Cpd-25-2 (1.80 g, 5.86 mmol), (phenyl-d5)boronic acid (820 mg, 6.45 mmol), potassium phosphate (2.49 g, 11.7 mmol) and Pd(dppf)Cl2(480 mg, 590 umol) in toluene (25 mL) and water (5 mL) was stirred at 95 °C for 2 h under argon. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (50 mL x 2), the combined organic layers were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 3:1) to give compound Cpd-25-3 (1.80 g, 99.3% yield, yellow oil). LCMS calc. for C 16 H9D8FN3O2[M+H] + : m / z = 310.2; Found: 309.8.

[0568] Step four: 5-(3-fluoro-3-(methyl-d3)azetidin-l-yl)-6-(phenyl-d5)pyrazine-2-carboxylic acid

[0569] To a solution of Cpd-25-3 (1.80 g, 5.82 mmol) in tetrahydrofuran (12 mL) and methanol (12 mL) was added a solution of lithium hydroxide (280 mg, 11.6 mmol) in water (12 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH 2 with 1 N hydrochloric acid and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give compound Cpd-25-4 (1.70 g, crude, white solid), which was used directly in the next step. LCMS calc. for C 15 H7D8FN3O2[M+H] + : m / z = 296.2; Found: 296.4.

[0570] Step five: (S,E)-N-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-fluoro-3-(methyl-d3)azetidin-l-yl)-6-(phenyl-d5)pyrazine-2-carboxamide

[0571] A mixture of Cpd-25-4 (1.70 g, 5.76 mmol), INT-1 (1.22 g, 5.76 mmol), HATU (2.63 g, 6.91 mmol) and triethylamine (2.91 g, 28.8 mmol) in N,N-dimethylformamide (15 mL) was stirred at room temperature for 2 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give Cpd-25 (1.15 g, 44.3% yield, white solid). LCMS calc. for C 22 H 18 D8FN4O3S [M+H] + : m / z = 453.2; Found: 453.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 8.8 Hz, 1H), 8.68 (s, 1H), 6.90 (dd, J = 15.2, 5.6 Hz, 1H), 6.78 (dd, J = 15.2, 0.8 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.91 - 3.76 (m, 4H), 3.01 (s, 3H), 1.33 - 1.23 (m, 1H), 0.61 - 0.54 (m, 1H), 0.51 - 0.39 (m, 2H), 0.35 - 0.29 (m, 1H).

[0572] Biological evaluation

[0573] I. Bioactivity test: DNA unwinding fluorescence assay of WRN helicase

[0574] The fluorescence (FI)-based WRN helicase assay was used to detect the inhibitory effect of compounds on WRN helicase. The recombinant His-tagged WRN (517-1238) used in the assay was expressed in insect cells and purified to 90% purity by Ni-NTA column; the fluorescently labeled ssDNA was synthesized by GenScript with the specific sequence of 5'-TTT TTT TTT TTT TTT TTT TTT TTT TTTTTT CGT ACC CGA TGT GTT CGT TC-3'; 5'-GAA CGA ACA CAT CGG GTA CG TTT TTT TTTTTT TTT TTT TTT TTT TTT TTT-3'; after annealing, a dsDNA substrate was formed for experimental determination. The capturing strand ssDNA was synthesized by GenScript with the specific sequence of: 5'-GAACGAACACATCGGGTACG-3'.

[0575] Compounds were gradient diluted in 384PP Plate Compound Dilution Plate using DMSO, 0.15 μΐ of compound was transferred to 384 reaction microplate (Corning 4514) using Echo, ensuring a final DMSO content of 1% (duplicates). 5 μΐ of WRN (517-1238) enzyme solution (containing 0.2 mM ATP) was added to each well of the 384 reaction microplate, after centrifugation for 1 min, incubated for 240 min at 25°C. Wells containing 1% DMSO and enzyme were used as high control, wells containing the same content of DMSO and buffer were used as low control. 5 μΐ of a mixture containing dsDNA solution and Capture stand ssDNA solution was added to each well, after centrifugation for 1 min, 5 μΐ of ATP solution was added, incubated for 30 min at 25°C. (Reagent final concentration: 5 nM WRN (517-1238), 100 nM dsDNA and 1 μΜ Capture strand ssDNA, 4 mM ATP). The fluorescence intensity signal (Ex: 620 nm and Em: 685 nm) was read on a BMG (CLARIO Star Plus acu) microplate reader. The percentage of inhibition of the compound treated wells was normalized between the high control and the low control (% inhibition = (FI reading high control - FI reading compound) / (FI reading high control - FI reading low control) * 100). IC50 curves were then fitted and analyzed by XLfit 5.5.0, IC 50 is the compound concentration corresponding to 50% inhibition on the curve.

[0576] Table 1. Results of the DNA unwinding fluorescence assay of WRN helicase

[0577]

[0578]

[0579] Note 1 : Ref. 1 is selected from WO2024010782A1,

[0580] Note 2: A means IC 50 > 1.0 μΜ, B means 0.5 μΜ < IC 50 ≤ 1.0 μΜ, C means 0.1 μΜ < IC 50 ≤ 0.5 μΜ, D means 0.02 μΜ < IC 50 ≤ 0.1 μΜ, E means IC 50 ≤ 0.02 μΜ.

[0581] The above data show that the compounds of the present application have good inhibitory activity against WRN helicase function.

[0582] II. Cell activity test: Proliferation inhibition activity test of SW48 cells

[0583] The anti-proliferative effect of compounds on human colon carcinoma cell lines was evaluated by ATP quantification, which is well correlated with the number of viable cells. Cell line SW48 (ATCC, CCL-231) was cultured in DMEM (Gibco, 11965118) medium supplemented with 10% (v / v) fetal bovine serum (Gibco, 10099141C). The cell line was cultured according to the standard instructions of the American Type Culture Collection. The cell line was identified by short tandem repeat profiling.

[0584] In the proliferation test, 4000 SW48 cells were seeded in 200 μL medium per well in a 96-well clear bottom black TC-treated plate (Corning, 3603) and incubated overnight in medium to recover. Compounds were added in increasing concentration gradient, DMSO treatment as positive control. After 5 days of treatment, the microplate was equilibrated to room temperature for 30 minutes and the number of viable cells was measured by adding CellTiter-Glo reagent (Promega, G7573). Chemiluminescent readings were measured on a Spark (Tecan). The % growth rate (%G) of each well was obtained from the formula, when T > V0, %G = (T - V0) / V0) * 100; when T < V0, %G = (T - V0) / (V - V0)) * 100; V0is the cell viability at the time of addition of the compound treatment; V and T represent the cell viability of vehicle control and compound treatment at the time of the last measurement, respectively. 100%, 0% and -100% represent no cell proliferation inhibition effect, complete blockage of cell proliferation and complete cell killing, respectively. The %G according to the growth rate was then fitted to a four-parameter nonlinear curve using the program GraphPad 10 software to calculate the half-growth inhibition concentration GI 50 .

[0585] Table 2. Results of the proliferation inhibition activity test of SW48 cells

[0586]

[0587]

[0588] Note 1: Ref. 1 is selected from WO2024010782A1,

[0589] Note 2: A means GI 50 > 5 μM, B means 0.5 μM50 ≤5 μM, C means 0.05 μM < GI 50 ≤0.5 μM, D means 0.01 μM < GI 50 ≤0.05 μM, E means 0.002 μM < GI 50 ≤0.01 μM, F means GI 50 ≤0.002 μM.

[0590] The above data show that the compounds of the present application have good inhibitory activity on the proliferation of SW48 cells.

[0591] III. Human plasma stability experiment

[0592] Experimental procedure

[0593] 1. Preheat the buffer containing 0.05 M sodium phosphate and 0.07 M sodium chloride to pH 7.4.

[0594] 2. Preparation of plasma:

[0595] 2.1 Thaw the frozen plasma quickly at 37 °C.

[0596] 2.2 Check and record the pH value of the plasma. Only use the plasma with pH value in the range of 7.4 to 8.0.

[0597] 2.3 Keep the plasma on ice until use.

[0598] 3. Preparation of test compound and reference compound solutions:

[0599] 3.1 Preparation of 0.5 mM test compound solution A: add 10 μL of 10 mM test compound stock solution to 190 μL of DMSO.

[0600] 3.2 Preparation of 0.02 mM test compound solution B: add 40 μL of the above solution A to 960 μL of 0.05 M sodium phosphate buffer containing 0.5% BSA.

[0601] 4. Preheat the plasma and solution B (see step 3.2) at 37 °C for 5 minutes.

[0602] 5. Add 10 μL of preheated test compound solution B to the wells designated for all time points (5, 15, 30, 45, 60 minutes) on the reaction plate.

[0603] 6. At 0 minute, immediately add 400 μL of acetonitrile containing internal standard to the 0 minute reaction plate, then add 90 μL of plasma.

[0604] 7. Add 90 μL of preheated plasma to the wells designated for time points (0, 5, 15, 30, 45, 60 minutes) on the reaction plate and start timing.

[0605] 8. At 5, 15, 30, 45, 60 minutes, add 400 μL of acetonitrile containing internal standard to the corresponding wells on the reaction plate to terminate the reaction.

[0606] 9. After termination of the reaction, vortex the samples for 10 minutes (600 rpm) and centrifuge the samples at 5594 g for 15 minutes on a centrifuge (Thermo Multifuge ulti).

[0607] 10. Take 50 μL of the supernatant from the centrifuged samples and transfer to a 96-well sample plate to which 120 μL of water has been added, mix, and finally send the samples for LC-MS / MS analysis.

[0608] Table 3: Stability of compounds in human plasma

[0609] Compound No. T 1 / 2 (min)]]> Cpd-19 92 Ref. 1 55

[0610] The above data show that the compounds of the present application have good stability in human plasma, and are superior to the reference compounds.

[0611] IV. In vivo pharmacokinetic study in mice

[0612] 1. Purpose of the experiment: to test the pharmacokinetics of the compounds in CD-1 mice.

[0613] 2. Experimental instruments and materials:

[0614] Animals: CD-1 mice (male)

[0615] Instruments:

[0616]

[0617] Reagents:

[0618]

[0619] Solvents:

[0620] 10% NMP + 15% Kolliphor EL + 1% Tween-20 + 74% (20% HP-β-CD)

[0621] 3. Experimental method:

[0622] 6 male mice. Fasting treatment was performed in the evening one day before dosing, and free access to water. The mice were allowed free access to food and water during the experiment, and dosing was performed by intravenous injection or gavage. The animals were observed after dosing and abnormal behavior was recorded. Blood samples were taken from the orbital sinus at 0.0833, 0.25, 1, 2, 4, 8 and 24 hours after intravenous injection, and at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after gavage. Plasma samples of 20 μL were taken, and 250 μL acetonitrile (containing dexamethasone as an internal standard) was added to precipitate the proteins. The samples were centrifuged at 4000 rpm for 20 minutes at 4°C, and 180 μL supernatant was mixed with 180 μL water containing 0.1% formic acid. 10 μL of the sample was used for LC-MS / MS detection.

[0623] 4. Data processing method and results:

[0624] The standard curve was established using the internal standard method. The theoretical standard curve concentration was the abscissa, and the peak area ratio was the ordinate (peak area of test compound / peak area of internal standard). The linear regression method (weighting factor 1 / X2) was used, and R 2 >0.9900. The unknown samples were calculated by the standard curve. The pharmacokinetic parameters were calculated by the non-compartment analysis model of WinNonlin 8.2 software, and were presented in the report. The parameters included Clint, C max max, and AUC, etc.

[0625] Table 4: Pharmacokinetic parameters of the compound in CD-1 mice

[0626]

[0627] The above data show that the compound of the present application has a lower clearance rate and a higher oral exposure in mice, and is superior to the reference compound.

[0628] Five. In vivo pharmacodynamic experiment of Cpd-1 in SW48 human colon cancer xenograft mouse model

[0629] 1. Purpose of the experiment: to test the in vivo pharmacodynamic activity of the compound in the SW48 human colon cancer subcutaneous xenograft model of BALB / c Nude female mice.

[0630] 2. Experimental materials:

[0631] Animals: 6-8 week old female BALB / c Nude mice;

[0632] Reagents:

[0633]

[0634]

[0635] Cpd-1 solvent: 10% NMP+15% Kolliphor EL+1% Tween-20+74% (20% HP-β-CD)

[0636] 3. Experimental Design:

[0637] Cell culture: SW48 cells were cultured in medium containing L-15 + 10% FBS + 1% P / S; the cells were cultured in an incubator at 37°C and 5% carbon dioxide.

[0638] Tumor modeling and grouping: SW48 cells were digested and collected, counted, and resuspended in a mixture of equal proportions of culture medium and Matrigel (Matrigel, Corning Biocoat 356234) to reach 1*102 7 Cells / mL concentration, at 1*10 6 Cells per mouse (100 μL) were transplanted subcutaneously into the right anterior shoulder and back of mice. Following inoculation, based on tumor growth, the average tumor volume in mice reached 119.43 ± 2.73 mm. 3 Students were randomly assigned to groups. The day on which medication began was designated Day 0.

[0639] 4. Experimental Design: The grouping and administration information for this pharmacodynamic experiment are shown in Table 5. Mice in group G1 were administered the solvent control (10% NMP + 15% KolliphorEL + 1% Tween-20 + 74% (20% HP-β-CD)) orally once daily. Mice in groups G2 and G3 were administered Cpd-1 orally once daily at doses of 5 mg / kg and 20 mg / kg, respectively, for a total of 21 days.

[0640] Table 5. In vivo pharmacodynamic design of SW48 xenograft mouse model

[0641]

[0642] 5. Experimental observation and result judgment:

[0643] Experimental observation: After cell inoculation, the mice's condition, mobility, food intake, and water consumption were closely monitored daily. Any deaths, abnormal behavior, or disease symptoms were immediately reported and recorded to determine appropriate intervention. After grouping the mice, their body weight was measured twice weekly. Tumor volume was measured twice weekly using calipers. The formula for calculating tumor volume was TV = 0.5 * length * width * width.

[0644] Data processing: Tumor volume inhibition rate TGI (%): The calculation formula of TGI (%) is as follows: TGI (%) = [1 - (the average tumor volume at the end of administration of a certain treatment group - the average tumor volume at the beginning of administration of the treatment group) / (the average tumor volume at the end of treatment of the vehicle control group - the average tumor volume at the beginning of treatment of the vehicle control group)] x 100%.

[0645] Statistical analysis: The results of tumor volume and animal body weight are expressed as Mean ± SEM. The tumor volumes of different groups were statistically compared and analyzed. All statistical analyses were completed in GraphPad Prism 8.0. According to the tumor volumes of different groups, t-test was used for analysis of significant difference with the vehicle group as control, where p≥0.05 was no significant difference, p<0.05 was significant difference, and p<0.001 was extremely significant difference.

[0646] 6. Experimental results:

[0647] The tumor growth curves of the control group and each experimental group in the pharmacodynamic evaluation experiment of the SW48 human colon cancer xenograft tumor model in mice are shown in Figure 1 , and the relative body weight changes of mice are shown in Figure 2 . The average tumor volume, tumor volume inhibition rate TGI (%) and comparison results of animals in each group at the end of the experiment are shown in Table 6.

[0648] At the end of the experiment (20 days after grouping), the average tumor volume of mice in the vehicle control group (G1) was 1386.90 mm 3 , the average tumor volume of mice in the 5 mg / kg Cpd-1 treatment group (G2) was 995.75 mm 3 (TGI was 30.86%, and the p value was 0.0132), and the average tumor volume of mice in the 20 mg / kg Cpd-1 treatment group G3 was 214.07 mm 3 (TGI was 92.53%, and the p value was <0.0001). The above results show that Cpd-1 exhibits significant SW48 transplanted tumor growth inhibition activity in mice at each test dose, and has a dose-dependent relationship.

[0649] Table 6. In vivo pharmacodynamic experiment results of SW48 xenograft tumor mouse model

[0650]

[0651] Six. In vivo pharmacodynamic experiment of Cpd-19 in SW48 human colon cancer xenograft tumor mouse model

[0652] 1. Experimental purpose: To test the in vivo pharmacodynamic activity of the compound in the BALB / c Nude female mouse SW48 human colon cancer subcutaneous xenograft tumor model.

[0653] 2. Experimental materials:

[0654] Animals: 5-6-week-old female BALB / c Nude mice;

[0655] Reagents:

[0656]

[0657] Cpd-19 vehicle: 5% DMSO + 10% Solutol + 85% PBS buffer (0.01M)

[0658] 3. Experimental scheme:

[0659] Cell culture: The SW48 cell line was cultured in L-15 + 10% FBS + 1% P / S medium; the cells were cultured in a incubator at a temperature of 37°C and a carbon dioxide concentration of 5%.

[0660] Tumor modeling and grouping: SW48 cells were digested and collected, resuspended in an equal proportion of mixed medium and Matrigel (Corning Biocoat 356234) to a concentration of 1*10 7 cells / mL, and transplanted in the right front subcutaneous position of the mouse shoulder and back at a concentration of 1*10 6 cells / mouse (volume 100 μL). After inoculation, the mice were randomly grouped according to the tumor growth, and the average tumor volume of the mice reached 144.24 ± 1.08 mm 3 on the 28th day. The day of the first administration was marked as Day 0.

[0661] 4. Experimental design: The grouping and administration information of the pharmacodynamic experiment is shown in Table 7. The G1 group of mice was orally administered with the vehicle control (5% DMSO + 10% Solutol + 85% PBS buffer (0.01M)) once a day, the G2 and G3 groups of mice were orally administered with Cpd-19 at doses of 5 mg / kg and 20 mg / kg once a day, respectively, for a total of 28 days.

[0662] Table 7. In vivo pharmacodynamic experimental design of SW48 xenograft tumor mouse model

[0663]

[0664] 5. Experimental observation and result judgment:

[0665] Experimental observation: After inoculation of cells, the state, activity, food intake and water intake of mice were observed daily. If death, abnormal behavior and disease symptoms were found, they were immediately reported and recorded to determine whether they needed to be treated. After grouping, the body weight of mice was measured twice a week. The tumor volume was measured twice a week using a vernier caliper, and the tumor volume calculation formula was TV = 0.5 * length * width * width.

[0666] Data processing: Tumor volume inhibition rate TGI (%): The calculation formula of TGI (%) is as follows: TGI (%) = [1 - (average tumor volume at the end of administration of a certain treatment group - average tumor volume at the start of administration of the treatment group) / (average tumor volume at the end of treatment of the vehicle control group - average tumor volume at the start of treatment of the vehicle control group)] * 100%.

[0667] Statistical analysis: The results of tumor volume and animal body weight are expressed as Mean (average) ± SEM (standard error of the mean). The tumor volumes of different groups were statistically compared and analyzed. All statistical analyses were completed in GraphPad Prism 8.0. According to the tumor volumes of different groups, the vehicle group was used as a control to analyze the significant differences using t-test, where p≥0.05 was not significantly different, p<0.05 was significantly different, and p<0.001 was extremely significantly different.

[0668] 6. Experimental results:

[0669] The tumor growth curves of the control group and each experimental group in the pharmacodynamic evaluation experiment of the SW48 human colon cancer xenograft tumor model in mice are shown in Figure 3 , and the relative body weight changes of mice are shown in Figure 4 . The average tumor volume, tumor volume inhibition rate TGI (%) and comparison results of animals in each group at the end of the experiment are shown in Table 8.

[0670] At the end of the experiment (27 days after grouping), the average tumor volume of mice in the vehicle control group (G1) was 2589.85 mm 3 , the average tumor volume of mice in the 5 mg / kg Cpd-19 treatment group (G2) was 1743.53 mm 3 (TGI was 34.61%, and the p value was 0.0073), and the average tumor volume of mice in the 20 mg / kg Cpd-19 treatment group (G3) was 41.74 mm 3 (TGI was 104.19%, and the p value was <0.0001). The above results show that Cpd-19 exhibits good activity in inhibiting the growth of SW48 transplanted tumors in mice at various tested doses, and has a dose-dependent relationship.

[0671] Table 8. In vivo pharmacodynamic experiment results of SW48 xenograft tumor mouse model

[0672]

Claims

1. A compound of formula (IA), its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof: in, Y is selected from CR 0 or N; R 0 is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, -NR x0 R y0 ; R x0 and R y0 are each independently selected from hydrogen, Ci-C6alkyl, haloCi-C6alkyl; R 1 is -(CR 11 R 12 ) m R 13 , m is 0, 1, 2 or 3; each R 11 and R 12 is independently hydrogen, C1-C6alkyl, halogen, halogenated C1-C6alkyl; R 13 is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8cycloalkenyl, unsubstituted or substituted benzo C3-C6cycloalkyl, unsubstituted or substituted benzo 3-8 membered heterocyclyl; the substitution in R 13 is by one or more substituents selected from Group A; Group A substituents include: oxo (=0), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl unsubstituted or substituted by one or more substituents selected from Group A1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR a1 R a2 , -CONR a1 R a2 , -NR a1 C(O)R a2 ; Group A1substituents include: deuterium, halogen, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, cyano, hydroxyl, carboxyl, -NR a3 R a4 , -CONR a3 R a4 , -NR a3 C(O)R a4 ; R 2 is -NR x R y ; -CONR x R y ; -NR x C(O)R y ; -R 9 ; -OR 10 ; R 9 and R 10 are selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl; the substitution in R 9 and R 10 means substituted with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR b1 R b2 , -CONR b1 R b2 , -NR b1 C(O)R b2 ; R 3 is hydrogen or CrC6alkyl; R 4 is hydrogen, unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 5-6 membered heterocyclyl; R 4 substituted in R c1 c2 c1 c2 c1 c2 ;​​​​​ R 5 is hydrogen or deuterium; R 6 is hydrogen or CrC6alkyl; or R 3 and R 6 with the atom to which they are attached together form a 4-6 membered heterocyclyl containing one N atom; R 7 is hydrogen, C1-C6alkyl or halogen; R 8 is hydrogen, unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; the substitution in R 8 is by one or more substituents selected from Group D; Group D substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy-substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR d1 R d2 , -CONR d1 R d2 , -NR d1 C(O)R d2 ; X 1 is N or CR 14 , X 2 is N or CR 15 , and at least one of X 1 and X 2 is N; R 14 and R 15 each independently is selected from hydrogen, C1-C6alkyl, halogen or halogenated C1-C6alkyl; R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R x , R y are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, halogenated Ci-C6alkyl, C3-C6cycloalkyl; With S atoms and R 7 Connected separately express It can be a geometric isomer of (Z) or (E); This indicates the connection point of the group with other locations; The *-marked C atom can be a chiral carbon atom or a non-chiral carbon atom; when the *-marked C atom is a chiral carbon atom, the configuration of the chiral carbon atom is S configuration or R configuration; The heteroatoms in the 3-8 membered heterocyclic group, 4-6 membered heterocyclic group, 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, and 5-10 membered heteroaryl group are independently selected from 1, 2, 3, or 4 of N, O, and S.

2. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) has the following structure: in, R 0 is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, -NR x0 R y0 ; R x0 and R y0 are each independently selected from hydrogen, Ci-C6alkyl, haloCi-C6alkyl; R 1 is -(CR 11 R 12 ) m R 13 , m is 0, 1, 2 or 3; each R 11 and R 12 is independently hydrogen, C1-C6alkyl, halogen, halogenated C1-C6alkyl; R 13 is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8cycloalkenyl, unsubstituted or substituted benzo C3-C6cycloalkyl, unsubstituted or substituted benzo 3-8 membered heterocyclyl; the substitution in R 13 is by one or more substituents selected from Group A; Group A substituents include: oxo (=0), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl unsubstituted or substituted by one or more substituents selected from Group A1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR a1 R a2 , -CONR a1 R a2 , -NR a1 C(O)R a2 ; Group A1substituents include: deuterium, halogen, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, cyano, hydroxyl, carboxyl, -NR a3 R a4 , -CONR a3 R a4 , -NR a3 C(O)R a4 ; R 2 is -NR x R y , -CONR x R y , -NR x C(O)R y ; R 9 , -OR 10 ; R 9 and R 10 are selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl; the substitution in R 9 and R 10 means substituted with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR b1 R b2 , -CONR b1 R b2 , -NR b1 C(O)R b2 ; R 3 is hydrogen or CrC6alkyl; R 4 is hydrogen, unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 5-6 membered heterocyclyl; R 4 substituted in R c1 c2 c1 c2 c1 c2 ;​​​​​ R 5 is hydrogen or deuterium; R 6 is hydrogen or CrC6alkyl; or R 3 and R 6 with the atom to which they are attached together form a 4-6 membered heterocyclyl containing one N atom; R 7 is hydrogen, C1-C6alkyl or halogen; R 8 is hydrogen, unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 8 substituted as described in group D; group D substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, Ci-C6alkyl, deuterated Ci-C6alkyl, halogenated Ci-C6alkyl, Ci-C6alkoxy substituted Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, halogenated Ci-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR d1 R d2 , -CONR d1 R d2 , -NR d1 C(O)R d2 ; X 1 is N or CR 14 , X 2 is N or CR 15 , and at least one of X 1 and X 2 is N; R 14 and R 15 each independently is selected from hydrogen, C1-C6alkyl, halogen or halogenated C1-C6alkyl; R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R x , R y each independently is selected from hydrogen, Ci-C6alkyl, halogenated Ci-C6alkyl, C3-C6cycloalkyl; With S atoms and R 7 Connected separately express It can be a geometric isomer of (Z) or (E); This indicates the connection point of the group with other locations; The *-marked C atom can be a chiral carbon atom or a non-chiral carbon atom; when the *-marked C atom is a chiral carbon atom, the configuration of the chiral carbon atom is S configuration or R configuration; The heteroatoms in the 3-8 membered heterocyclic group, 4-6 membered heterocyclic group, 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, and 5-10 membered heteroaryl group are independently selected from 1, 2, 3, or 4 of N, O, and S.

3. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, Y is selected from CR 0 or N; R 0 is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, -NR x0 R y0 ; R x0 and R y0 are each independently selected from hydrogen, Ci-C6alkyl, haloCi-C6alkyl; R 1 R 13 ; R 13 is unsubstituted or substituted C3-C8 cycloalkyl, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-C8 cycloalkenyl, unsubstituted or substituted benzo C3-C6 cycloalkyl, unsubstituted or substituted benzo 3-8 membered heterocyclyl; the substitution in R 13 is by one or more substituents selected from Group A; Group A substituents include: oxo (=0), deuterium, halogen, hydroxyl, cyano, carboxyl, unsubstituted or substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR a1 R a2 , -CONR a1 R a2 , -NR a1 C(O)R a2 ; Group A1 substituents include: deuterium, halogen, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxyl, carboxyl, NR a3 R a4 , -CONR a3 R a4 , -NR a3 C(O)R a4 ; R 2 is -NR x R y ; -CONR x R y ; -NR x C(O)R y ; -R 9 ; -OR 10 ; R 9 and R 10 are selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted C6-C10aryl, unsubstituted or substituted 3-8 membered heterocyclyl, unsubstituted or substituted 5-10 membered heteroaryl; the substitution in R 9 and R 10 means substituted with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR b1 R b2 , -CONR b1 R b2 , -NR b1 C(O)R b2 ; R 3 is hydrogen; R 4 is hydrogen, unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 5-6 membered heterocyclyl; R 4 substituted in R c1 c2 c1 c2 c1 c2 ;​​​​​ R 5 is hydrogen or deuterium; R 6 is hydrogen; or R 3 and R 6 with the atom to which they are attached together form a 4-6 membered heterocyclyl containing one N atom; R 7 is hydrogen or halogen; R 8 is hydrogen, unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; the substitution in R 8 is by one or more substituents selected from Group D; Group D substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, Ci-C6alkyl, deuterated Ci-C6alkyl, halogenated Ci-C6alkyl, Ci-C6alkoxy-substituted Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, halogenated Ci-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR d1 R d2 , -CONR d1 R d2 , -NR d1 C(O)R d2 ; X 1 is N or CR 14 , X 2 is N or CR 15 , and at least one of X 1 and X 2 is N; R 14 and R 15 each independently is selected from hydrogen, C1-C6alkyl, halogen or halogenated C1-C6alkyl; R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R x , R y are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, halogenated Ci-C6alkyl, C3-C6cycloalkyl; With S atoms and R 7 Connected separately express It can be a geometric isomer of (Z) or (E); This indicates the connection point of the group with other locations; The *-marked C atom can be a chiral carbon atom or a non-chiral carbon atom; when the *-marked C atom is a chiral carbon atom, the configuration of the chiral carbon atom is S configuration or R configuration; The heteroatoms in the 3-8 membered heterocyclic group, 4-6 membered heterocyclic group, 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, and 5-10 membered heteroaryl group are independently selected from 1, 2, 3, or 4 of N, O, and S.

4. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, Y is selected from CR 0 or N; R 0 is hydrogen, C1-C2alkyl, haloC1-C2alkyl, -NR x0 R y0 ; R x0 and R y0 are each independently selected from hydrogen, C1-C2alkyl; R 1 R 13 ; R 13 is unsubstituted or substituted C3-C8cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 4-6 membered heterocyclyl, unsubstituted or substituted 5-6 membered heteroaryl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted benzo C3-C4cycloalkyl; the substitution in R 13 is by one or more substituents selected from group A; group A substituents include: oxo (=0), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl unsubstituted or substituted by one or more substituents selected from group A1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halo C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR a1 R a2 , -CONR a1 R a2 , -NR a1 C(O)R a2 ; group A1 substituents include: deuterium, halogen, C1-C6alkoxy, halo C1-C6alkoxy, C3-C6cycloalkyl, cyano, hydroxyl, carboxyl, -NR a3 R a4 , -CONR a3 R a4 , -NR a3 C(O)R a4 ; R 2 is -NR x R y ; -CONR x R y ; -NR x C(O)R y ; -R 9 ; -OR 10 ; R 9 and R 10 are selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted 4-6 membered heterocyclyl, unsubstituted or substituted 5-6 membered heteroaryl; the substitution in R 9 and R 10 means substituted with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR b1 R b2 ; -CONR b1 R b2 ; -NR b1 C(O)R b2 ; R 3 is hydrogen; R 4 is hydrogen, unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 4 substituted in R c1 is substituted by one or more substituents selected from Group C; Group C substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, Ci-C6alkyl, deuterated Ci-C6alkyl, halogenated Ci-C6alkyl, Ci-C6alkoxy-substituted Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, halogenated Ci-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR c2 , -CONR c1 , -NR c2 , -NR c1 C(O)R c2 ; R 5 is hydrogen or deuterium; R 6 is hydrogen; or R 3 and R 6 with the atom to which they are attached together form a 4-6 membered heterocyclyl containing one N atom; R 7 is hydrogen or halogen; R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4-6 membered heterocyclic group; R 8 The substitution mentioned herein refers to substitution by one or more substituents selected from group D; group D substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR d1 R d2 -CONR d1 R d2 -NR d1 C(O)R d2 ; X 1 is N or CR 14 , X 2 is N or CR 15 , and at least one of X 1 and X 2 is N; R 14 and R 15 each independently is selected from hydrogen, C1-C6alkyl, halogen or halogenated C1-C6alkyl; R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R x , R y are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, halogenated Ci-C6alkyl, C3-C6cycloalkyl; With S atoms and R 7 Connected separately express It can be a geometric isomer of (Z) or (E); This indicates the connection point of the group with other locations; The *-marked C atom can be a chiral carbon atom or a non-chiral carbon atom; when the *-marked C atom is a chiral carbon atom, the configuration of the chiral carbon atom is S configuration or R configuration; The heteroatoms in the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

5. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, Y is selected from CR 0 or N; R 0 is hydrogen, methyl or -NH2; R 1 For R 13 ;R 13 The following are unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl, unsubstituted or substituted benzocyclopropyl, unsubstituted or substituted benzocyclobutyl, unsubstituted or substituted six-membered heterocyclic group, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted No substitution or substitution No substitution or substitution No substitution or substitution R 13 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, unsubstituted or substituted by one or more substituents selected from group A1, namely C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, -NR a1 R a2 -CONR a1 R a2 -NR a1 C(O)R a2 Group A1 substituents include: deuterium, halogen, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, hydroxyl, carboxyl, -NR a3 R a4 -CONR a3 R a4 -NR a3 C(O)R a4 ; R 2 is -NR x R y , -CONR x R y , -NR x C(O)R y , -R 9 , -OR 10 ; R 9 and R 10 are selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted C2-C6alkenyl, unsubstituted or substituted C2-C6alkynyl, unsubstituted or substituted 4-6 membered heterocyclyl; the substitution in R 9 and R 10 means substituted with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, halogenated C1-C6alkyl, C1-C6alkoxy substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, halogenated C1-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR b1 R b2 , -CONR b1 R b2 , -NR b1 C(O)R b2 ; R 3 is hydrogen; R 4 is hydrogen, unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl; R 4 substituted as described in R c1 is hydrogen, unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl; R c2 , -CONR c1 R c2 , -NR c1 C(O)R c2 ; R 5 is hydrogen or deuterium; R 6 is hydrogen; or R 3 and R 6 with the atom to which they are attached together form a 4-6 membered heterocyclyl containing one N atom; R 7 is hydrogen or halogen; R 8 is hydrogen, unsubstituted or substituted Ci-C6alkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; the substitution in R 8 is by one or more substituents selected from Group D; Group D substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, Ci-C6alkyl, deuterated Ci-C6alkyl, halogenated Ci-C6alkyl, Ci-C6alkoxy-substituted Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, halogenated Ci-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, -NR d1 R d2 , -CONR d1 R d2 , -NR d1 C(O)R d2 ; X 1 is N or CR 14 , X 2 is N or CR 15 , and at least one of X 1 and X 2 is N; R 14 and R 15 each independently is selected from hydrogen, C1-C6alkyl, halogen or halogenated C1-C6alkyl; R a1 , R a2 , R a3 , R a4 , R b1 , R b2 , R c1 , R c2 , R d1 , R d2 , R x , R y are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, halogenated Ci-C6alkyl, C3-C6cycloalkyl; With S atoms and R 7 Connected separately express It can be a geometric isomer of (Z) or (E); This indicates the connection point of the group with other locations; The *-marked C atom can be a chiral carbon atom or a non-chiral carbon atom; when the *-marked C atom is a chiral carbon atom, the configuration of the chiral carbon atom is S configuration or R configuration; The heteroatoms in the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are independently selected from 1, 2, 3 or 4 of N, O and S.

6. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 0 is hydrogen, C1-C2alkyl, haloC1-C2alkyl, -NR x0 R y0 ; R x0 and R y0 are each independently selected from hydrogen, C1-C2alkyl; preferably, R 0 is hydrogen, methyl or -NH2.

7. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 1 For R 13 ;R 13 Selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl, unsubstituted or substituted benzocyclopropyl, unsubstituted or substituted benzocyclobutyl, unsubstituted or substituted six-membered heterocyclic group, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted cyclopentenyl, unsubstituted or substituted No substitution or substitution No substitution or substitution No substitution or substitution R 13 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

8. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 1 For R 13 ;R 13 Selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution R 13 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

9. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 1 Selected from the following structure:

10. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 2 is -NR x R y ; -CONR x R y ; -NR x C(O)R y ; -R 9 ; R 9 is selected from unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted 4-6 membered heterocyclyl; the substitution in R 9 is substitution with one or more substituents selected from Group B; Group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6alkyl, deuterated C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl; R x , R y are each independently selected from hydrogen or C1-C6alkyl, C3-C6cycloalkyl.

11. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 2 For -NR x R y or -R 9 ;R 9 Selected from unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted. R 9 The substitution mentioned herein refers to substitution by one or more substituents selected from group B; group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; R x R y Each is independently selected from hydrogen or C1-C6 alkyl or C3-C6 cycloalkyl.

12. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 2 Methyl, ethyl, tert-butyl, 13. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 4 substituted or unsubstituted C1-C6alkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 4 substituted or unsubstituted C1-C6alkyl, unsubstituted or substituted C3-C6cycloalkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R c1 R c2 , -CONR c1 R c2 , -NR c1 C(O)R c2 ; R c1 , R c2 each independently is selected from hydrogen or Ci-C6-alkyl, C3-C6-cycloalkyl.

14. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 4 It is an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted cyclopropyl group, or an unsubstituted or substituted cyclobutyl group; R 4 The substitution mentioned herein refers to being replaced by one or more substituents selected from group C; group C substituents include: halogen, hydroxyl, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy.

15. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 8 R is unsubstituted or substituted C1-C6alkyl, unsubstituted or substituted 4-6 membered heterocyclyl; R 8 The substituents in R are 1 or more substituents selected from Group D; Group D substituents include: deuterium, halogen, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkoxy, amino, -N(CH3)2.

16. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 8 For methyl, ethyl, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, 17. The compound of formula (IA) as claimed in any one of claims 1-16, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (IA) has a structure as shown in formula (II) or formula (III): in, p is 1 or 2; X 1 , X 2 , R 1 , R 2 , R 4 , R 7 and R 8 are as defined in the respective claim.

18. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (IA) has a structure as shown in formula (IV), (V), (VI) or (VII): in, X 1 is N or CH; X 2 is N or CH; and X 1 and X 2 at least one of which is N; R 13 It can be an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C3-C8 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-8 membered heterocyclic group, an unsubstituted or substituted 5-10 membered heteroaryl, an unsubstituted or substituted C3-C8 cycloalkenyl, an unsubstituted or substituted benzo[3-C6] cycloalkyl, or an unsubstituted or substituted benzo[3-8] membered heterocyclic group; R 13 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3; n is 0, 1, or 2; R 4a It can be halogen, hydroxyl, cyano, C1-C6 alkyl, deuterated C1-C6 alkyl, or halo-C1-C6 alkyl; R 2 For -NR x R y -CONR x R y -NR x C(O)R y -R 9 ;R 9 Selected from unsubstituted or substituted C1-C6 alkyl groups, and unsubstituted or substituted 4-6 membered heterocyclic groups; R 9 The substitution mentioned herein refers to substitution by one or more substituents selected from group B; group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; R x R y Each is independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

19. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (IA) has the following structure: in, R 13 It can be an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C3-C8 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-8 membered heterocyclic group, an unsubstituted or substituted 5-10 membered heteroaryl, an unsubstituted or substituted C3-C8 cycloalkenyl, an unsubstituted or substituted benzo[3-C6] cycloalkyl, or an unsubstituted or substituted benzo[3-8] membered heterocyclic group; R 13 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

20. The compound of formula (IA) as claimed in claim 19, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 13 Selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution R 13 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3.

21. The compound of formula (IA) as claimed in claim 19, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, R 13 Selected from the following structure:

22. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (IA) has the following structure: X 2 For N or CH; R 0 It is hydrogen or amino; R 4 It is cyclopropyl or cyclobutyl; R 1 Selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution R 1 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3; R 2 For -NR x R y or -R 9 ;R 9 Selected from unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted. R 9 The substitution mentioned herein refers to substitution by one or more substituents selected from group B; group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; R x R y Each is independently selected from hydrogen or C1-C6 alkyl or C3-C6 cycloalkyl; R 8 It is an unsubstituted or substituted C1-C6 alkyl group, or an unsubstituted or substituted 4-6 membered heterocyclic group; R 8 The substitution mentioned herein refers to being replaced by one or more substituents selected from group D; group D substituents include: deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, amino, -N(CH3)2.

23. The compound of formula (IA) as claimed in claim 22, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that: X 2 Let N be the number of people in the group. R 0 It is hydrogen or amino; R 4 It is cyclopropyl or cyclobutyl; R 1 Selected from R 2 Methyl, ethyl, tert-butyl, R 8 For methyl, ethyl, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, 24. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (IA) has the following structure: R 7 It is a halogen; R 13 It can be an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C3-C8 cycloalkyl, an unsubstituted or substituted C6-C10 aryl, an unsubstituted or substituted 3-8 membered heterocyclic group, an unsubstituted or substituted 5-10 membered heteroaryl, an unsubstituted or substituted C3-C8 cycloalkenyl, an unsubstituted or substituted benzo[3-C6] cycloalkyl, or an unsubstituted or substituted benzo[3-8] membered heterocyclic group; R 13 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3; Preferably, R 7 It is a halogen; R 13 Selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution R 13 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3; Preferably, R 7 It is a halogen; R 13 Selected from the following structure:

25. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (IA) has the following structure: R 4 It is cyclopropyl or cyclobutyl; R 1 Selected from unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted phenyl, unsubstituted or substituted No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution No substitution or substitution R 1 The substitution mentioned herein refers to substitution by one or more substituents selected from group A; group A substituents include: oxo (=O), deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, NH2, -CONH2, -NHC(O)CH3; R 2 For -NR x R y or -R 9 ;R 9 Selected from unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted. R 9 The substitution mentioned herein refers to substitution by one or more substituents selected from group B; group B substituents include: deuterium, halogen, hydroxyl, cyano, carboxyl, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl; R x R y Each is independently selected from hydrogen or C1-C6 alkyl or C3-C6 cycloalkyl; R 8 It is an unsubstituted or substituted C1-C6 alkyl group, or an unsubstituted or substituted 4-6 membered heterocyclic group; R 8 The substitution mentioned herein refers to being replaced by one or more substituents selected from group D; group D substituents include: deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, amino, -N(CH3)2.

26. The compound of formula (IA) as claimed in claim 25, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that: X 2 Let N be the number of people in the group. R 0 It is hydrogen or amino; R 4 It is cyclopropyl or cyclobutyl; R 1 Selected from R 2 Methyl, ethyl, tert-butyl, R 8 For methyl, ethyl, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, 27. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, The compounds represented by formula (IA) are selected from the following compounds:

28. The compound of formula (IA) as claimed in claim 1, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, characterized in that, The compounds represented by formula (IA) are selected from the following compounds:

29. A pharmaceutical composition comprising a compound of formula (IA) as claimed in any one of claims 1-28, an isotopic label thereof, an enantiomer, a diastereomer, a transisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

30. The use of a compound of formula (IA) as described in any one of claims 1-28, its isotopic label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof in the preparation of a WRN inhibitor or medicament; said medicament being a medicament for treating and / or preventing disease by inhibiting WRN.

31. The use of a compound of formula (IA) as claimed in any one of claims 1-28, its isotopic label, enantiomer, diastereomer, transisomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer.

32. A method for treating and / or preventing cancer, characterized in that, The compound, its isotope label, enantiomer, diastereomer, transisomer, or pharmaceutically acceptable salt thereof, is administered to the patient in a therapeutically effective amount as described in any one of claims 1-28, of formula (IA).

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