Poly(adp-ribose)glycohydrolase inhibitor and use thereof

Abstract

Disclosed are a PARG inhibitor, and a pharmaceutical composition and the use thereof. The compound is as shown in the following formula (I). The compound exhibits a high inhibitory activity against the PARG, has excellent efficacy, in-vitro / in-vivo pharmacokinetic properties and safety, and has broad clinical application prospects.

Description

A Poly-ADP Ribohydrolase Inhibitor and Its Application

[0001] This disclosure claims priority to Chinese Patent Application No. 202410916980.3, filed on July 10, 2024, entitled "A Poly-ADP Ribohydrolase Inhibitor and Its Application", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical chemistry. Specifically, this invention relates to a novel PARG inhibitor, its pharmaceutical composition, and its uses. Background Technology

[0003] Poly(ADP-ribose) riboglycosylation is a post-translational modification of proteins, primarily involving two types of enzymes: poly(ADP-ribose) polymerases (PARP) responsible for modification, and poly(ADP-ribose) glycohydrolases (PARG) responsible for demodification. PARP can be activated by DNA damage, and then converts ADP-ribose into NAD+. + Using PAR as a substrate, PARP forms a long chain of hundreds of ADP-ribose groups, namely a poly(ADP-ribose), PAR chain. Dependent on the PAR chain, PARP can recruit multiple interacting proteins to participate in DNA damage repair. PARP inhibitors are widely used clinically as anti-tumor drugs. PARG, on the other hand, is the reverse reaction enzyme of PARP, reversing the action of PARP enzymes by hydrolyzing PAR-ribose bonds after DNA damage. Numerous preclinical and clinical studies have shown that PARG is a key factor in the development of resistance to PARP inhibitors.

[0004] Studies have shown that PARG inhibitors primarily exhibit two anti-tumor mechanisms: 1) Synthetic lethality. PARG is involved in DNA replication and various DNA repair mechanisms, including single-strand break repair and replication fork restart. PARG inhibitors have demonstrated synthetic lethality in cells under high DNA replication stress, which is caused by low expression levels of genes involved in DNA replication and replication fork stabilization. Furthermore, PARG inactivation, depletion, or inhibition increases cellular sensitivity to DNA-damaging agents such as alkylating agents temozolomide and methyl mesylate. 2) Immune activation. PARG inhibitors are a strategy to enhance the visibility and sensitivity of tumor cells to the immune system. Because PARG inhibitors lead to the accumulation of DNA damage, tumor cells produce more mutations and neoantigens, making them more readily recognized and attacked by the immune system. In addition, PARG inhibitors can affect immune signaling pathways, such as inhibiting the PARation of ATM in the nucleus, promoting the formation of a complex between ATM and NEMO, activating the AKT signaling pathway, and enhancing cell survival and anti-apoptotic capabilities. Simultaneously, PARG inhibitors can also induce the expression of interferon signaling pathways and immune checkpoint molecules, enhancing the immune response.

[0005] Currently, there are no PARG inhibitor drugs on the market worldwide, and only four compounds have entered early clinical trial stages: IDE161 (Phase I, NCT05787587, structure not disclosed), ETX-19477 (Phase I, NCT06395519, structure not disclosed), XNW-29016 (Phase I / II, NCT06987500, structure not disclosed), and DAT-2645 (Phase I, NCT06614751, structure not disclosed). In preclinical animal models, IDE161, alone or in combination, has shown good anti-tumor effects against multiple PARP1-resistant xenograft models. Given the therapeutic potential of PARG inhibitors in cancer treatment and their early development stage, further in-depth research on PARG inhibitors is needed. Summary of the Invention

[0006] This invention provides a novel PARG inhibitor, its pharmaceutical composition, and its uses.

[0007] According to the purpose of this invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0008] in,

[0009] X 1 X 2 X 3 X 4 Each is independently selected from N, C and CR 4 , where R 4 H, halogen, substituted or unsubstituted C1-3 Alkyl group, wherein the substitution is performed by being substituted with one or more H atoms or halogens;

[0010] Y and Z are each independently selected from N, C, and CR. 5 , where R 5 H, halogen, substituted or unsubstituted C 1-3 Alkyl group, wherein the substitution is performed by being substituted with one or more H atoms or halogens;

[0011] This indicates that it can be a single bond or a double bond;

[0012] R 1 Selected from H, D, halogen, cyano, amino, hydroxyl and C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by one or more Q1 groups, wherein the Q1 groups are selected from H, D, halogens, amino groups, and hydroxyl groups;

[0013] R a R b Each is independently selected from H, D, halogen, cyano, amino, hydroxyl and C. 1-6 Alkyl, the C 1-6 The alkyl group is substituted by one or more Q2 groups selected from H, D, halogens, amino groups, and hydroxyl groups; or R. a and R b It is linked with the carbon atom it is attached to to form a C group. 3-8 cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl and 3-10 membered heterocyclic groups are replaced by one or more Q3 groups, wherein the Q3 groups are selected from H, D, halogens, amino groups, hydroxyl groups, and C. 1-6 alkyl;

[0014] R 2 Selected from H, D, halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is replaced by one or more Q4 groups selected from H, D, halogens, amino groups, and hydroxyl groups;

[0015] R 3 Selected from H, D, halogen, cyano, amino, hydroxyl and C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by one or more Q5 groups, wherein the Q5 groups are selected from H, D, halogens, amino groups, and hydroxyl groups;

[0016] Selected from 5-12 membered heterocyclic groups, wherein the 5-12 membered heterocyclic group is substituted by one or more Q6 groups, wherein the Q6 group is selected from H, D, halogen, amino, hydroxyl, C.1-6 Alkyl and C 3-8 cycloalkyl;

[0017] Selected from C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl and 3-10 membered heterocyclic groups are replaced by one or more Q7 groups, wherein the Q7 groups are selected from H, D, halogens, amino groups, hydroxyl groups, and C. 1-6 alkyl;

[0018] It is selected from 5-12-membered heteroaryl groups, wherein the 5-12-membered heteroaryl group is substituted by one or more Q8 groups, wherein the Q8 groups are selected from H, D, halogens, amino groups and hydroxyl groups.

[0019] The effects of the invention

[0020] The compound provided by this invention has strong inhibitory activity against PARG, and also has excellent pharmacodynamics, in vitro / in vivo pharmacokinetic properties and safety, showing great promise for clinical application. Detailed Implementation

[0021] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0022] On the one hand, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0023] in,

[0024] X 1 X 2 X 3 X 4 Each is independently selected from N, C and CR 4 , where R 4 H, halogen, substituted or unsubstituted C 1-3 Alkyl group, wherein the substitution is performed by being substituted with one or more H atoms or halogens;

[0025] Y and Z are each independently selected from N, C, and CR. 5 , where R 5 H, halogen, substituted or unsubstituted C 1-3 Alkyl group, wherein the substitution is performed by being substituted with one or more H atoms or halogens;

[0026] This indicates that it can be a single bond or a double bond;

[0027] R1 Selected from H, D, halogen, cyano, amino, hydroxyl and C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by one or more Q1 groups, wherein the Q1 groups are selected from H, D, halogens, amino groups, and hydroxyl groups;

[0028] R a R b Each is independently selected from H, D, halogen, cyano, amino, hydroxyl and C. 1-6 Alkyl, the C 1-6 The alkyl group is substituted by one or more Q2 groups selected from H, D, halogens, amino groups, and hydroxyl groups; or R. a and R b It is linked with the carbon atom it is attached to to form a C group. 3-8 cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl and 3-10 membered heterocyclic groups are replaced by one or more Q3 groups, wherein the Q3 groups are selected from H, D, halogens, amino groups, hydroxyl groups, and C. 1-6 alkyl;

[0029] R 2 Selected from H, D, halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is replaced by one or more Q4 groups selected from H, D, halogens, amino groups, and hydroxyl groups;

[0030] R 3 Selected from H, D, halogen, cyano, amino, hydroxyl and C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by one or more Q5 groups, wherein the Q5 groups are selected from H, D, halogens, amino groups, and hydroxyl groups;

[0031] Selected from 5-12 membered heterocyclic groups, wherein the 5-12 membered heterocyclic group is substituted by one or more Q6 groups, wherein the Q6 group is selected from H, D, halogen, amino, hydroxyl, C. 1-6 Alkyl and C 3-8 cycloalkyl;

[0032] Selected from C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl and 3-10 membered heterocyclic groups are replaced by one or more Q7 groups, wherein the Q7 groups are selected from H, D, halogens, amino groups, hydroxyl groups, and C. 1-6 alkyl;

[0033] It is selected from 5-12-membered heteroaryl groups, wherein the 5-12-membered heteroaryl group is substituted by one or more Q8 groups, wherein the Q8 groups are selected from H, D, halogens, amino groups and hydroxyl groups.

[0034] In some implementations, Y and Z are each independently selected from N and C.

[0035] In some embodiments, the compound has a structure as shown in formula (IA) or formula (IB).

[0036] Wherein, the R 1 R a R b R 2 R 3 , and As defined in any of the preceding implementations.

[0037] In some implementations, the X 1 X 2 X 3 and X 4 Each independently selected from CR 4 , where R 4 For H.

[0038] In some embodiments, the compound has a structure as shown in formula (IA-1), (IA-2), (IA-3), (IB-1), or (IB-2).

[0039] Wherein, the R 1 R a R b R 2 R 3 , and As defined in any of the preceding implementations.

[0040] In some implementations, the R 1 Selected from H, cyano and C 1-3 Alkyl, the C 1-3 The alkyl group is replaced by one or more Q1s, wherein the Q1s are selected from H, F, Cl and Br.

[0041] In some implementations, the R 1 Selected from H, -CN, -CH3, -CH2F and -CF3.

[0042] In some implementations, the R a and R b It is linked with the carbon atom it is attached to to form a C group.3-5 Cycloalkyl or 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group contains 1-2 heteroatoms selected from O, and the C 3-5 The cycloalkyl group and the 4-6 membered heterocyclic group are replaced by one or more Q3 groups, wherein the Q3 group is selected from H, F, Cl, Br and C. 1-3 alkyl.

[0043] In some implementations, the R a and R b It is linked together with the carbon atoms it is attached to to form

[0044] In some implementations, the R 2 Selected from H, cyano, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is replaced by one or more Q4 groups selected from H, F, Cl, and Br.

[0045] In some implementations, the R 2 Selected from -CN, -CHF2, -CF3, -O-CF3.

[0046] In some implementations, the R 3 Selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is replaced by one or more Q5 groups, wherein the Q5 groups are selected from H.

[0047] In some implementations, the R 3 Selected from H and -CH3.

[0048] In some implementations, the The heterocyclic group is selected from 6-8 membered heterocyclic groups, wherein the 6-8 membered heterocyclic group contains 1-3 heteroatoms selected from N and O, and the 6-8 membered heterocyclic group is substituted by one or more Q6, wherein the Q6 is selected from H and C. 1-3 alkyl.

[0049] In some implementations, the Selected from

[0050] In some implementations, the Selected from C 3-6 Cycloalkyl groups and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic group contains 1-2 heteroatoms selected from N and O, and the C 3-6 The cycloalkyl and 4-6 membered heterocyclic groups are replaced by one or more Q7 groups, wherein the Q7 groups are selected from H and C.1-3 alkyl.

[0051] In some implementations, the Selected from

[0052] In some implementations, the The aryl group is selected from 5-6-membered heteroaryl groups, wherein the 5-6-membered heteroaryl group contains 1-3 heteroatoms selected from N, O and S, and the 5-6-membered heteroaryl group is substituted by one or more Q8 atoms selected from H.

[0053] In some implementations, the Selected from

[0054] This invention provides a compound or a pharmaceutically acceptable salt thereof, said compound having one of the following structures:

[0055] On the other hand, the present invention provides a pharmaceutical composition comprising any of the preceding compounds or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

[0056] In some embodiments, the pharmaceutical composition is in the form of any one of an aqueous dispersant, liquid, gel, syrup, elixir, tincture, paste, suspension, aerosol, controlled-release agent, instant solvent, effervescent agent, lyophilized agent, tablet, powder, pill, sugar-coated pill, capsule, delayed-release agent, extended-release agent, pulsatile controlled-release agent, multi-microparticle agent, or immediate-release agent.

[0057] On the other hand, the present invention provides the use of any of the foregoing compounds or pharmaceutically acceptable salts thereof, or the foregoing pharmaceutical compositions, in the preparation of medicaments for treating and / or preventing PARG-related diseases.

[0058] In some implementations, the PARG-related diseases include cancer, autoimmune diseases, immunodeficiency diseases, viral infections, aging, and organ transplant rejection.

[0059] In some embodiments, the cancer is selected from bladder cancer, breast cancer, bone cancer, neuroblastoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, choriocarcinoma, multiple myeloma, basal cell carcinoma, teratoma, choroidal melanoma, seminoma, craniopharyngioma, plasmacytoma, papilloma, budding glioma, sarcoma (including but not limited to chondrosarcoma, histiosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma), melanoma, hemangioma, keloid, squamous cell carcinoma, astrocytoma, lymphoma (including but not limited to Hodgkin's lymphoma), and other types of cancer. Chigkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma, Hodgkin's disease, and central nervous system lymphoma), respiratory tract cancers (including but not limited to lung cancer, such as small cell and non-small cell lung cancer, as well as bronchial adenoma and thoracic pulmonary blastoma), head and neck cancers (including but not limited to head cancer, neck cancer, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer and / or oropharyngeal cancer, as well as lip and oral cavity cancer), breast cancers (including but not limited to invasive ductal carcinoma, lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma), and gastrointestinal cancers (including...). Including but not limited to anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, rectal cancer, stomach cancer, small bowel cancer, and salivary gland cancer), thyroid cancer, parathyroid cancer and its distant metastases, liver cancer (including but not limited to hepatocellular carcinoma, stem cell carcinoma with or without fibrolamellar structure, cholangiocarcinoma, and mixed hepatocellular cholangiocarcinoma), leukemia (including but not limited to acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and chorionic villus cell leukemia), and brain cancer (including but not limited to...). Brainstem and pituitary gliomas, medulloblastomas, cerebellar and cerebral astrocytomas, tympanomas, neuroectodermal tumors, and pineal adenomas; reproductive organ cancers (including but not limited to prostate cancer, testicular cancer, ovarian cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, and uterine sarcoma); urethral cancer; eye cancers (including but not limited to intraocular melanoma and retinoblastoma); skin cancers (including but not limited to Kaposi's sarcoma, squamous cell carcinoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer); renal parenchymal carcinoma; and other related cancers.

[0060] Terminology Explanation:

[0061] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0062] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 25 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. The substituents are preferably independently selected independently from one or more substituents selected from deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0063] The alkyl group described above is a residue derived from the parent atom by removing a hydrogen atom, namely a "alkylene group".

[0064] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.

[0065] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.

[0066] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0067] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between its rings, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0068] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0069] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0070] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferred

[0071] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0072] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), where alkyl and cycloalkyl are defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, they are preferably one or more of the following groups, independently selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0073] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but excluding the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0074] The term "spiroheterocyclic group" refers to a 5- to 20-membered non-aromatic polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom) between the rings, wherein the one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of shared spiro atoms between the rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0075] The term "fused heterocyclic group" refers to a 5- to 20-membered non-aromatic polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0076] The term "bridged heterocyclic group" refers to a 5- to 14-membered, non-aromatic polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0077] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0078] wait.

[0079] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0080] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0081] The aryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0082] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazole, thiadiazole, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0083] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0084] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0085] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0086] The term "hydroxyl group" refers to -OH.

[0087] The term "amino" refers to -NH2.

[0088] The term "cyano" refers to -CN.

[0089] The compounds disclosed herein contain their isotopic derivatives. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure disclosed herein, using "deuterium" or "tritium" instead of hydrogen, or using... 18 F-fluorine labeling ( 18 F isotopes) can be used instead of fluorine, or... 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of compounds disclosed herein refer to compounds in which each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to relevant literature. Commercially available deuteration starting materials can be used in the preparation of deuterated forms of compounds, or they can be synthesized using conventional techniques with deuteration reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and better metabolic stability can be achieved when deuterated at certain specific sites, resulting in certain therapeutic advantages.

[0090] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0091] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0092] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0093] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0094] "Pharmaceutically acceptable salt" refers to a salt of the compounds disclosed herein that is safe and effective in mammalian use and possesses the intended biological activity. The salt can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases as well as organic bases. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

[0095] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0096] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only and not as limitations.

[0097] The "room temperature" mentioned is not a specific temperature value, but refers to a temperature range of 10-30℃.

[0098] The synthetic processes disclosed herein can accommodate a wide range of functional groups, thus allowing the use of a variety of substituted starting materials. These processes generally provide the desired final compound at or near the end of the process, although in some cases it may be necessary to further convert the compound into its pharmaceutically acceptable salt.

[0099] The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art or obvious to those skilled in the art based on the teachings herein. Standard synthetic methods and procedures for preparing organic molecules, as well as functional group transformations and manipulations, are available from relevant scientific literature or from standard textbooks in the field. While not limited to any one or more sources, classic textbooks incorporated herein by reference include, such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, John.

[0100] The following description of synthetic methods is intended to illustrate, and not limit, a general procedure for preparing the compounds disclosed herein. Compounds of the invention having the forms described herein can be prepared from commercially available starting materials or starting materials that can be prepared using literature procedures, according to the procedures described in the following representative synthetic methods. Variables in each scheme (e.g., R1 and R2, etc., as defined herein) are as follows. Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may vary during the reaction procedures and synthetic schemes described herein. Those skilled in the art will recognize that it may be necessary to use protecting groups to protect certain groups from the effects of reaction conditions. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and methods for introducing and removing these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons: New York, 1999.

[0101] Preferred protecting groups include, but are not limited to:

[0102] For the hydroxyl moiety: TBS, benzyl, THP, Ac;

[0103] For carboxylic acids: benzoyl ester, methyl ester, ethyl ester, allyl ester;

[0104] For amines: Fmoc, Cbz, BOC, DMB, Ac, Bn, Tr, Ts, trifluoroacetyl, phthalimide, and phenylmethylamine;

[0105] For diols: Ac (×2), TBS (×2), or acetone when linked together;

[0106] For thiols: Ac;

[0107] For benzimidazole: SEM, benzyl, PMB, DMB;

[0108] For aldehydes: dialkyl acetals, such as dimethoxyethal or diethylacetyl.

[0109] In the reaction schemes described herein, a variety of stereoisomers can be produced. When a specific stereoisomer is not indicated, this should be understood to mean all possible stereoisomers that can be produced by the reaction. Those skilled in the art will recognize that the reaction can be optimized to preferentially obtain one isomer, or new schemes can be designed to produce a single isomer. If a mixture is produced, the isomers can be separated using techniques such as preparative thin-layer chromatography, preparative HPLC, preparative chiral HPLC, or preparative SFC.

[0110] The method of the present invention will be described below through specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0111] The units in the weight-volume percentages of this invention are well known to those skilled in the art, for example, referring to the weight of the solute in 100 ml of solution.

[0112] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0113] These embodiments are for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0114] 1 1H NMR spectroscopy was performed using a Bruker-400 or OXFORD-AS500 NMR spectrometer. Chemical shifts were expressed in parts per million (ppm), with tetramethylsilane as the internal standard. The coupling constant (J) was approximately 0.1 Hz. The abbreviations used are as follows: s, singlet; d, doublet; t, triplet; q, quartet; qu, quintet; m, multiplet; brs, broad peak. Mass spectrometry was performed using a Quattro Micro™ API triple quadrupole mass spectrometer.

[0115] Example 1

[0116] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-cyclopropylpiperazine-1-carboxamide (Compound 1)

[0117] 4-(cyclopropylcarbamoyl)piperazine-1-carboxylic acid benzyl ester

[0118] Triphosgene (485 mg, 1.63 mmol) was dissolved in DCM. Pyridine (430.9 mg, 5.448 mmol) was added at 0 °C. After 10 min, a DCM solution of cyclopropylamine (459 mg, 4.54 mmol) was added. After 2 h, a DCM solution of TEA (1.3 mL, 9.08 mmol) and benzyl piperazine-1-carboxylate (1.0 g, 4.54 mmol) was added, and the reaction was carried out at room temperature for 3 h. The reaction was monitored by TLC until complete. The reaction system was diluted with water, extracted with dichloromethane, and the organic solvent was removed by vacuum distillation of the organic phase. The residue was separated by rapid column chromatography (PE:EA = 1:1). 1.13 g of a pale yellow solid was given, with a yield of 82%.

[0119] MS-ESI: 304.16 [M+H] + .

[0120] N-Cyclopropylpiperazine-1-formamide

[0121] 4-(cyclopropylcarbamoyl)piperazine-1-carboxylic acid benzyl ester (500 mg, 1.65 mmol) was dissolved in MeOH (5 mL), and then 10% Pd / C (30 mg) was added to replace H2. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until completion. The mixture was filtered through diatomaceous earth, and the organic solvent was removed from the filtrate by vacuum distillation. 235 mg of a clear liquid was obtained, with a yield of 84%.

[0122] MS-ESI: 170.12 [M+H] + .

[0123] 4-Chloro-6-benzylthio-1H-indazole

[0124] 4-Chloro-6-bromo-1H-indazole (3.0 g, 12.96 mmol) and benzyl mercaptan (4.83 g, 38.88 mmol) were dissolved in 1,4-dioxane (20 mL). DIPEA (6.77 mL, 38.88 mmol), Xantphos (749.92 mg, 1.30 mmol), and Pd2(dba)3 (593 mg, 0.65 mmol) were added with stirring. After the addition was complete, N2 was purged, and the system temperature was raised to 100 °C for 4 h. The reaction was monitored by TLC until complete. The reaction system was diluted with water, extracted with ethyl acetate, and the organic phase was evaporated under reduced pressure to remove the solvent. The residue was separated by rapid column chromatography (PE:EA = 5:1). 3.4 g of the target product was obtained, with a yield of 96%.

[0125] 1H NMR (400MHz, DMSO-d6) δ13.32(s,1H),8.05(s,1H),7.40–7.34(m,3H),7.31-7.28(m,2H),7.25-7.21(m,1H),7.18-7.17(m,1H),4.34(s,2H).

[0126] MS-ESI: 275.2 [M+H] + .

[0127] 5-(difluoromethyl)-1,3,4-thiadiazole-2-amine

[0128] POCl3 (16.8 g, 109.8 mmol) was slowly added to a mixture of aminothiourea (5.0 g, 54.9 mmol) and difluoroacetic acid (10.5 g, 109.8 mmol) under ice bath conditions. After the addition was complete, stirring was continued for 10 min, and then the reaction was allowed to proceed at room temperature for 3 h. The reaction was monitored by TLC until complete. The system was then slowly added to ice water to adjust the pH to 6. The mixture was filtered, the filter cake was washed with water, and dried in an oven to constant weight. 4.9 g of the target product was obtained. The yield was 59%.

[0129] MS-ESI: 152.3 [M+H] + .

[0130] 2-Bromo-5-(difluoromethyl)-1,3,4-thiadiazole

[0131] 5-(difluoromethyl)-1,3,4-thiadiazol-2-amine (4.9 g, 32.5 mmol) was dissolved in 48% HBr (40 mL), and then water (33 mL) was added. The system was cooled to 0 °C, and then CuBr (870 mg, 6.2 mmol) was added. Subsequently, an aqueous solution of NaNO2 (2.7 g, 39 mmol) (85 mL) was added dropwise to the system. After the addition was complete, the mixture was allowed to rise naturally to room temperature and reacted overnight. The reaction was monitored by TLC until complete. The pH of the system was adjusted to 8 with a saturated NaHCO3 aqueous solution. Ethyl acetate was added to the system, the insoluble matter was filtered off, and the mixture was separated. The organic phase was dried, and the solvent was removed under reduced pressure. 5.7 g of the target product was obtained, with a yield of 81%.

[0132] MS-ESI: 214.9 / 216.9 [M+H] + .

[0133] 2-(6-benzylthio)-4-chloro-1H-indazol-1-yl)-5-difluoromethyl-1,3,4-thiadiazole

[0134] 4-Chloro-6-benzylthio-1H-indazole (3.4 g, 12.37 mmol) and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (3.99 g, 18.56 mmol) were dissolved in DMF (20 mL), and Cs₂CO₃ (4.03 g, 12.37 mmol) was added with stirring. After the addition was complete, N₂ was used to replace the solvent, and the system temperature was raised to 60 °C for 2 h. The reaction was confirmed to be complete by TLC. The reaction system was diluted with water, extracted with ethyl acetate, and the solvent was removed by vacuum evaporation of the organic phase. The residue was separated by rapid column chromatography (PE:EA = 5:1). 3.0 g of the target product was obtained, with a yield of 60%.

[0135] 1 H NMR (400MHz, CDCl3) δ8.47(s,1H),8.23(s,1H),7.46(s,1H),7.44(s,1H),7.35-7.32(m,2H),7.28-7.27(m,2H),7.00(t,J=52Hz,1H),4.32(s,2H).

[0136] MS-ESI: 409.01 [M+H] + .

[0137] 4-Chloro-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonyl chloride

[0138] 1.4 g (3.42 mmol) of 2-(6-benzylthio)-4-chloro-1H-indazol-1-yl)-5-difluoromethyl-1,3,4-thiadiazole was dissolved in MeCN (10 mL), and AcOH (1.85 mL) and H₂O (2.9 mL) were added with stirring. Then, 1,3-dichloro-5,5-dimethylhydantoin (1.01 g (5.14 mmol) was added at 0 °C. After the addition was complete, the reaction system was brought to room temperature and reacted for 2 h. The reaction was confirmed to be complete by TLC. The reaction system was diluted with water, extracted with dichloromethane, and the solvent was removed from the organic phase by vacuum evaporation. 1.0 g of the target product was obtained, with a yield of 80%.

[0139] MS-ESI: 385.9 [M+H] + .

[0140] 4-Chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide

[0141] 1-Amino-1-cyclopropyl cyanide hydrochloride (369.37 mg, 3.12 mmol), DMAP (15.86 mg, 0.13 mmol), and DIPEA (1.0 mL, 5.71 mmol) were dissolved in DCM (8 mL). 4-Chloro-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonyl chloride (1.0 g, 2.6 mmol) was added at 0 °C. After the addition was complete, the system was brought to room temperature and reacted for 4 h. The reaction was confirmed to be complete by TLC. The reaction mixture was diluted with water and extracted with ethyl acetate. The solvent was removed from the organic phase under reduced pressure, and the residue was separated by rapid column chromatography (PE:EA = 3:1). 300 mg of the target product was obtained, with a yield of 25%.

[0142] 1 H NMR (400MHz, CDCl3) δ9.12(s,1H),8.44(s,1H),7.96(s,1H),6.99(t,J=56Hz,1H),1.65-1.61(m,2H),1.48–1.44(m,2H).

[0143] MS-ESI: 409.01 [M+H] + .

[0144] Compound 1

[0145] 4-Chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (100.00 mg, 0.24 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the addition of N-cyclopropylpiperazin-1-carboxamide (81.00 mg, 0.48 mmol), BINAP (14.46 mg, 0.24 mmol), Pd(OAc)₂ (5.22 mg, 0.24 mmol), and Cs₂CO₃ (151.26 mg, 0.46 mmol). After the addition was complete, N₂ was removed, and the system was heated to 100 °C and reacted overnight. The reaction was confirmed by TLC to be complete. The system was diluted with water, extracted with ethyl acetate, and the solvent was removed from the organic phase under reduced pressure. The residue was separated by rapid column chromatography (DCM:MeOH = 15:1). 40.2 mg of a white solid was obtained, with a yield of 30%.

[0146] 1H NMR (400MHz, CDCl3) δ8.77(s,1H),8.13(s,1H),7.24(d,J=1.39Hz,1H),7.01(t,J=56.0Hz,1H),5.07(s,1H),3.62(t,J=4 .56Hz,4H),3.34(s,4H),2.71–2.67(m,1H),1.66-1.63(m,2H),1.43–1.41(m,2H),0.76-0.71(m,2H),0.53–0.49(m,2H).

[0147] MS-ESI: 564.14 [M+H] + .

[0148] Example 2

[0149] 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-(1-methylcyclopropyl)piperazin-1-carboxamide (Compound 2)

[0150] 4-(1-Methylcyclopropylcarbamoyl)piperazine-1-carboxylic acid benzyl ester

[0151] Using 1-methylcyclopropylamine (322.14 mg, 4.54 mmol) as the starting material, the compound was synthesized using the same method as 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate. A white solid of 1.10 g was obtained, with a yield of 76%.

[0152] MS-ESI: 318.17 [M+H] + .

[0153] 4-(methyl(methylcyclopropyl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0154] Benzyl 4-(1-methylcyclopropylcarbamoyl)piperazine-1-carboxylate (500 mg, 1.65 mmol) was dissolved in tetrahydrofuran, and 60% NaH (79 mg, 3.30 mmol) was added at 0 °C. After 15 min, MeI (468.4 mg, 3.3 mmol) was added, and the reaction was carried out at room temperature for 12 h. The reaction was confirmed to be complete by TLC. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic solvent was removed by vacuum distillation of the organic phase. The residue was separated by rapid column chromatography (DCM:MeOH = 15:1). 365 mg of a white solid was given, with a yield of 70%.

[0155] MS-ESI: 318.67 [M+H] + .

[0156] N-Methyl-N-(methylcyclopropyl)piperazine-1-carboxamide

[0157] Using 4-(methyl(methylcyclopropyl)carbamoyl)piperazine-1-carboxylate (200 mg, 0.60 mmol) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. A white solid of 98.8 mg was obtained, with a yield of 83%.

[0158] MS-ESI: 198.15 [M+H] + .

[0159] Compound 2

[0160] The compound was synthesized from 4-chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (100 mg, 0.24 mmol) and N-methyl-N-(methylcyclopropyl)piperazine-1-carboxamide (95 mg, 0.48 mmol) using the same method as compound 1. A yellow solid of 28.2 mg was obtained, with a yield of 20%.

[0161] 1 H NMR (400MHz, CDCl3) δ8.79(s,1H),8.33(s,1H),7.27(s,1H),6.99(t,J=56.0Hz,1H),5.92(s,1H),3.52(q,J=4.0,4H),3.45( dd,J=6.0,2.8Hz,4H),2.89(s,3H),1.67–1.65(m,2H),1.48–1.44(m,2H),1.41(s,3H),0.78-0.75(m,2H),0.66–0.63(m,2H).

[0162] MS-ESI: 592.17 [M+H] + .

[0163] Example 3

[0164] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-cyclopropylpiperazine-1-carboxamide (compound 3)

[0165] 4-(cyclopropyl(methyl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0166] Using 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate (500.0 mg, 1.65 mmol) as a starting material, the synthesis method was the same as that for 4-(methyl(methylcyclopropyl)carbamoyl)piperazine-1-carboxylate. A white solid of 365.0 mg was obtained, with a yield of 70%.

[0167] MS-ESI: 318.67 [M+H] + .

[0168] N-Methyl-N-cyclopropylpiperazine-1-carboxamide

[0169] Using 4-(cyclopropyl(methyl)carbamoyl)piperazine-1-carboxylic acid benzyl ester (200.0 mg, 0.63 mmol) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. A white solid of 108.4 mg was obtained, with a yield of 93%.

[0170] MS-ESI: 184.14 [M+H] + .

[0171] Compound 3

[0172] 4-Chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (100 mg, 0.24 mmol) was dissolved in 1,4-dioxane (3 mL), followed by the addition of N-methyl-N-cyclopropylpiperazin-1-carboxamide (88 mg, 0.48 mmol), Ruphos-Pd-G3 (20 mg, 0.012 mmol), and Cs₂CO₃ (152 mg, 0.48 mmol). After the addition was complete, N₂ was substituted, and the system was heated to 100 °C and reacted overnight. The reaction was confirmed by TLC to be complete. The system was diluted with water, extracted with ethyl acetate, and the organic solvent was removed by vacuum distillation of the organic phase. The residue was separated by rapid column chromatography (DCM:MeOH = 15:1). 25.5 mg of a yellowish-brown solid was obtained, with a yield of 19%.

[0173] 1 H NMR (400MHz, CDCl3) δ8.79(s,1H),8.33(s,1H),7.29(s,1H),7.28(s,1H),6.99(t,J=56.0Hz,1H),3.65–3.62(m,4H),3.48–3 .45(m,4H),2.90(s,3H),2.67–2.64(m,1H),1.67–1.64(m,2H),1.48–1.43(m,2H),0.78(q,J=7.2Hz,2H),0.69–0.67(m,2H).

[0174] MS-ESI: 578.15 [M+H] + .

[0175] Example 4

[0176] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-cyclopentylpiperazine-1-carboxamide (compound 4)

[0177] 4-(cyclopentylcarbamoyl)piperazine-1-carboxylic acid benzyl ester

[0178] Using cyclopentylamine (381.36 mg, 4.54 mmol) as a starting material, the compound was synthesized using the same method as 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate. 1.08 g of a brown solid was obtained, with a yield of 72%.

[0179] MS-ESI: 332.19 [M+H] + .

[0180] 4-(cyclopentyl(methyl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0181] Using 4-(cyclopentylcarbamoyl)piperazine-1-carboxylate (500 mg, 1.51 mmol) as the starting material, the compound was synthesized using the same method as 4-(cyclopropyl(methyl)carbamoyl)piperazine-1-carboxylate. 391 mg of a brown powder was obtained, with a yield of 75%.

[0182] MS-ESI: 346.20 [M+H] + .

[0183] N-Methyl-N-cyclopentylpiperazine-1-carboxamide

[0184] Using 4-(cyclopentyl(methyl)carbamoyl)piperazine-1-carboxylate (200 mg, 0.58 mmol) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. 103.3 mg of a brown solid was obtained, with a yield of 84%.

[0185] MS-ESI: 212.16 [M+H] + .

[0186] Compound 4

[0187] The compound was synthesized from 4-chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (100 mg, 0.24 mmol) and N-methyl-N-cyclohexylpiperazine-1-carboxamide (101 mg, 0.48 mmol) using the same method as compound 3. A yellowish-white solid of 23.6 mg was obtained, with a yield of 16%.

[0188] 1 H NMR (400MHz, CDCl3) δ8.78(t,J=1.08Hz,1H),8.33(d,J=0.8Hz,1H),7.33(d,J=7.0Hz,1H),6.99(t,J=52.0Hz,1H),6.08(s,1H),3.49(dd,J= 16.2,5.8Hz,9H),2.79(s,3H),2.03(s,2H),1.99-1.92(m,2H),1.66– 1.63(m,4H),1.47–1.43(m,2H),1.41–1.37(m,2H),1.35–1.28(m,2H).

[0189] MS-ESI: 606.18 [M+H] + .

[0190] Example 5

[0191] 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-cyclohexylpiperazin-1-carboxamide (Compound 5)

[0192] 4-(cyclohexylcarbamoyl)piperazine-1-carboxylic acid benzyl ester

[0193] Using cyclohexylamine (445.33 mg, 4.54 mmol) as a starting material, the compound was synthesized using the same method as 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate. 1.23 g of a white solid was obtained, with a yield of 79%.

[0194] MS-ESI: 342.20 [M+H] + .

[0195] 4-(cyclohexyl(methyl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0196] Using 4-(cyclohexylcarbamoyl)piperazine-1-carboxylate (400 mg, 1.16 mmol) as the starting material, the compound was synthesized using the same method as 4-(cyclopropyl(methyl)carbamoyl)piperazine-1-carboxylate. 281 mg of a white powder was obtained, with a yield of 67%.

[0197] MS-ESI: 360.22 [M+H] + .

[0198] N-Methyl-N-cyclohexylpiperazine-1-carboxamide

[0199] Using 4-(cyclohexyl(methyl)carbamoyl)piperazine-1-carboxylate (200 mg, 0.55 mmol) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. 110.3 mg of a brown solid was obtained, with a yield of 87%.

[0200] MS-ESI: 226.18 [M+H] + .

[0201] Compound 5

[0202] The compound was synthesized from 4-chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (100 mg, 0.24 mmol) and N-methyl-N-cyclohexylpiperazine-1-carboxamide (108 mg, 0.48 mmol) using the same method as compound 3. A yellow solid of 32.2 mg was obtained, with a yield of 22%.

[0203] 1 H NMR (400MHz, CD3OD) δ8.72(s,1H),8.68(s,1H),7.29(s,1H),7.24(t,J=56.0Hz,1H),3.51(s,9H),2.83(s,3H),1.85( d,J=11.8Hz,2H),1.76–1.73(m,2H),1.62–1.59(m,2H),1.49(d,J=4.7Hz,2H),1.44–1.42(m,4H),1.18–1.177(m,2H).

[0204] MS-ESI: 620.20 [M+H] + .

[0205] Example 6

[0206] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxamide (compound 6)

[0207] 4-(3,4,5,6-tetrahydro-2H-carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0208] Using tetrahydropyran-4-amine (458.90 mg, 4.54 mmol) as a starting material, the compound was synthesized by the same method as benzyl 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate. 1.02 g of a pale yellow solid was obtained, with a yield of 65%.

[0209] MS-ESI: 348.18 [M+H] + .

[0210] 4-(methyl(3,4,5,6-tetrahydro-2H-pyran-4-yl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0211] Using 4-(3,4,5,6-tetrahydro-2H-carbamoyl)piperazine-1-carboxylate (400 mg, 1.15 mmol) as the starting material, the compound was synthesized using the same method as 4-(cyclopropyl(methyl)carbamoyl)piperazine-1-carboxylate. 320 mg of a white solid was obtained, with a yield of 77%.

[0212] MS-ESI: 362.20 [M+H] + .

[0213] N-Methyl-N-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazine-1-carboxamide

[0214] Using 4-(methyl(3,4,5,6-tetrahydro-2H-pyran-4-yl)carbamoyl)piperazine-1-carboxylate (200 mg, 0.55 mmol) as a starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. 103.6 mg of a white powder was obtained, with a yield of 82%.

[0215] MS-ESI: 228.16 [M+H] + .

[0216] Compound 6

[0217] The compound was synthesized from 4-chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (100 mg, 0.24 mmol) and N-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazine-1-carboxamide (109 mg, 0.48 mmol) using the same method as compound 1. 20.2 mg of a bright yellow solid was obtained, in 14% yield.

[0218] 1 H NMR (400MHz, CDCl3) δ8.81(s,1H),8.34(s,1H),7.28(s,1H),7.00(t,J=52.0Hz,1H),5.67(s,1 H),3.51–3.46(m,13H),2.84(s,3H),1.89–1.81(m,2H),1.72–1.65(m,4H),1.49–1.45(m,2H).

[0219] MS-ESI: 622.18 [M+H] + .

[0220] Example 7

[0221] 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-(1-methylpiperidin-4-yl)piperazin-1-carboxamide (Compound 7)

[0222] 4-((1-Methyltetrahydropyridin-4-yl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0223] Using tetrahydropyran-4-amine (517.56 mg, 4.54 mmol) as the starting material, the compound was synthesized by the same method as benzyl 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate. A yellow solid of 1.31 g was obtained, with a yield of 80%.

[0224] MS-ESI: 361.21 [M+H] + .

[0225] 4-(methyl(1-methylhexahydropyridin-4-yl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0226] Using 4-((1-methyltetrahydropyridin-4-yl)carbamoyl)piperazine-1-carboxylate (400 mg, 1.11 mmol) as the starting material, the compound was synthesized using the same method as 4-(cyclopropyl(methyl)carbamoyl)piperazine-1-carboxylate. 350 mg of a powdery white solid was obtained, with a yield of 84%.

[0227] MS-ESI: 375.23 [M+H] + .

[0228] N-Methyl-N-(1-methylhexahydropyridin-4-yl)piperazine-1-carboxamide

[0229] Using 4-(methyl(1-methylhexahydropyridin-4-yl)carbamoyl)piperazine-1-carboxylate (200 mg, 0.53 mmol) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. 100.5 mg of a powdery white solid was obtained, with a yield of 79%.

[0230] MS-ESI: 241.19 [M+H] + .

[0231] Compound 7

[0232] The compound was synthesized from 4-chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (100 mg, 0.24 mmol) and N-methyl-N-(1-methylhexahydropyridin-4-yl)piperazine-1-carboxamide (115 mg, 0.48 mmol) using the same method as compound 1. A yellow solid of 30.2 mg was obtained, in 20% yield.

[0233] 1 H NMR (400MHz, CDCl3) δ8.94(s,1H),8.46(s,1H),7.77(s,1H),7.01(t,J=52.0Hz,1H),3.48(s,1H),3. 34–3.32(m,6H),3.14–3.11(m,10H),2.70(s,3H),2.43(s,3H),2.28–2.25(m,2H),2.01–2.00(m,2H).

[0234] MS-ESI: 635.21 [M+H] + .

[0235] Example 8

[0236] Preparation of 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-1H-indazol-4-yl)-N-methyl-N-cyclopropylpiperazine-1-carboxamide (compound 8)

[0237] 4-Fluoro-6-(benzylthio)-1H-indazole

[0238] The synthesis of this compound was the same as that of 4-chloro-6-benzylthio-1H-indazole, using 4.0 g (18.5 mmol) as the starting material. 4.33 g of a yellow powder was obtained, with a yield of 62%.

[0239] 1 H NMR (400MHz, CDCl3) δ8.06(s,1H),7.34–7.26(m,5H),7.14(s,1H),6.80(s,1H),5.29(s,1H).

[0240] MS-ESI: 259.07 [M+H] + .

[0241] 2-(6-(benzylthio)-4-fluoro-1H-indazol-1-yl)-5-(difluoromethyl)-1,3,4-thiadiazole

[0242] Using 4-fluoro-6-(benzylthio)-1H-indazole (4.33 g, 9.28 mmol) as the starting material, this compound was synthesized using the same method as 2-(6-benzylthio)-4-chloro-1H-indazole-1-yl)-5-difluoromethyl-1,3,4-thiadiazole. 3.5 g of a pale yellow product was obtained, with a yield of 95%.

[0243] 1 H NMR (400MHz, CDCl3) δ8.37 (s, 1H), 8.23 ​​(s, 1H), 7.62–7.59 (m, 5H), 6.99 (t, J = 56Hz, 1H), 6.95 (s, 1H).

[0244] MS-ESI: 393.04 [M+H] + .

[0245] 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazole-6-sulfonyl chloride

[0246] Using 2-(6-(benzylthio)-4-fluoro-1H-indazol-1-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (1.8 g, 5.0 mmol) as a starting material, this compound was synthesized using the same method as 4-chloro-1-(5-difluoromethyl)-1,3,4-thiadiazole-2-yl)-1H-indazol-6-sulfonyl chloride. A yellowish-brown liquid was obtained in 1.2 g, with a yield of 67%.

[0247] MS-ESI: 368.94 [M+H] + .

[0248] 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide

[0249] Using 1-methyl-cyclopropylamine hydrochloride (708 mg, 6.0 mmol) and 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazole-6-sulfonyl chloride (1.96 g, 5.0 mmol) as starting materials, this compound was synthesized using the same method as 4-chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide. A white powder product of 387.7 mg was obtained, with a yield of 19%.

[0250] 1 H NMR(400MHz, CDCl3)δ9.01(s,1H),8.44(s,1H),7.63–7.55(m,1H),7.01(t,J=56Hz,2H ),5.11(s,1H),5.01(s,1H),1.29–1.28(m,3H),0.86–0.82(m,2H),0.57–0.54(m,2H).

[0251] MS-ESI: 404.04 [M+H] + .

[0252] Compound 8

[0253] 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (50 mg, 0.124 mmol) was dissolved in DMSO (5 mL), and N-methyl-N-cyclopropylpiperazine-1-carboxamide (45.4 mg, 0.248 mmol) and DIPEA (0.11 mL, 0.62 mmol) were added. The reaction was carried out at 130 °C for 3 h. The reaction was confirmed to be complete by TLC. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic solvent was removed by vacuum distillation of the organic phase. The residue was separated by rapid column chromatography (DCM:MeOH = 30:1). 31.96 mg of a pale yellow powder product was obtained, with a yield of 46%.

[0254] 1 H NMR (400MHz, CDCl3) δ8.70(s,1H),8.28(s,1H),7.21(d,J=1.34Hz,1H),6.98(t,J=52.0Hz,1H),5.97(s,1H),5.01(s,1H), 3.64–3.62(m,4H),3.42–3.39(m,4H),1.88(s,3H),1.23(s,3H),0.84–0.81(m,2H),0.76–0.72(m,2H),0.51–0.47(m,4H).

[0255] MS-ESI: 567.17 [M+H] + .

[0256] Example 9

[0257] Preparation of 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-1H-indazol-4-yl)-N-methyl-N-cyclopentylpiperazine-1-carboxamide (compound 9)

[0258] Compound 9

[0259] The compound was synthesized from 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (50.00 mg, 0.12 mmol) and N-methyl-N-cyclopentylpiperazine-1-carboxamide (52.4 mg, 0.24 mmol) using the same method as compound 8. 20.02 mg of a pale yellow solid was obtained, in 28% yield.

[0260] 1H NMR (400MHz, CDCl3) δ8.72(s,1H),8.32(s,1H),7.24(s,J=1.2Hz,1H),7.00(t,J=52.0Hz,1H),5.02(s,1H),4.23(t,J=8.08Hz,1H),3.50(q,J=3. 9,3.4Hz,4H),3.43(q,J=4.3,3.6Hz,4H),2.79(s,3H),1.62–1.59(m,4H ),1.33–1.30(m,4H),1.27(s,3H),0.88–0.85(m,2H),0.54–0.52(m,2H).

[0261] MS-ESI: 595.20 [M+H] + .

[0262] Example 10

[0263] Preparation of 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-1H-indazol-4-yl)-N-methyl-N-cyclohexylpiperazine-1-carboxamide (compound 10)

[0264] Compound 10

[0265] The same method was used to synthesize compound 8, starting with 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (50.0 mg, 0.12 mmol) and N-methyl-N-cyclohexylpiperazine-1-carboxamide (55.8 mg, 0.24 mmol). 35.69 mg of a pale yellow solid was obtained, with a yield of 49%.

[0266] 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),8.32(s,1H),7.24(d,J=1.28Hz,1H),7.00(t,J=5 2.0Hz,1H),5.04(s,1H),3.70–3.64(m,1H),3.47–7.44(m,8H),2.80(s,3H),1.84(d ,J=12.8Hz,2H),1.75(d,J=12.0Hz,2H),1.68(d,J=13.0Hz,2H),1.49(dd,J=12.2,3 .3Hz,2H),1.44–1.38(m,2H),1.27(s,3H),0.86(t,J=6.1Hz,2H),0.55–0.51(m,2H).

[0267] MS-ESI: 609.22 [M+H] + .

[0268] Example 11

[0269] Preparation of 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-1H-indazol-4-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxamide (compound 11)

[0270] Compound 11

[0271] The same method was used to synthesize compound 8, starting with 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (50.0 mg, 0.12 mmol) and N-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazine-1-carboxamide (56.3 mg, 0.24 mmol). 20.0 mg of a pale yellow solid was obtained, in 27% yield.

[0272] 1 H NMR (400MHz, DMSO-d6) δ8.58(s,1H),8.18(s,1H),7.08(d,J=7.5Hz,1H),6.82(t,J=52.0Hz,1H),5.20(s,1H),3.94(d,J=5.8Hz,1H),3.3 8–3.29(m,12H),2.72(s,3H),1.71(td,J=12.2,4.3Hz,2H),1.54(d,J=12.0Hz,2H),1.08(s,3H),73(t,J=5.6Hz,2H),0.42–0.35(m,2H).

[0273] MS-ESI: 611.20 [M+H] + .

[0274] Example 12

[0275] Preparation of 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-1H-indazol-4-yl)-N-methyl-N-(1-methylpiperidin-4-yl)piperazin-1-carboxamide (compound 12)

[0276] Compound 12

[0277] The compound was synthesized from 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (50.0 mg, 0.12 mmol) and N-methyl-N-(1-methylhexahydropyridin-4-yl)piperazine-1-carboxamide (59.6 mg, 0.24 mmol) using the same method as compound 8. A pale yellow solid of 16.61 mg was obtained, in 22% yield.

[0278] 1 H NMR (400MHz, CDCl3) δ8.94(s,1H),8.46(s,1H),7.77(s,1H),7.01(t,J=52Hz,1H),3.48(s,1H),3.34–3.32(m, 6H),3.14–3.11(m,10H),2.70(s,3H),2.43(s,3H),2.28–2.25(m,2H),2.01–2.00(m,2H),1.68(d,J=12Hz,3H).

[0279] MS-ESI: 624.23 [M+H] + .

[0280] Example 13

[0281] Preparation of 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)imidazo[1,2-a]pyridin-8-yl)-N-methyl-N-cyclopropylpiperazine-1-carboxamide (compound 13)

[0282] 2-(2,2-difluoroacetyl)hydrazino-1-carboxylic acid benzyl ester

[0283] Benzyl hydrazinocarbamate (10.0 g, 60.16 mmol) was dissolved in DCM (50 mL). TEA (12.5 mL, 90.24 mmol) was added under ice-water bath conditions. After 20 min, 2,2-difluoroacetic anhydride (7.8 mL, 66.2 mmol) was added dropwise under ice-water bath conditions. The reaction was allowed to proceed at room temperature for 1 h after the addition was complete. The reaction was monitored by TLC until complete. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography. 14.5 g of the target product was obtained as a white solid, with a yield of 99%.

[0284] 1H NMR (400MHz, DMSO-d6) δ10.75(s,1H),9.53(s,1H),7.49–7.23(m,5H),6.37(t,J=52.0Hz,1H),5.11(s,2H).

[0285] MS-ESI: 243.3 [MH] - .

[0286] 2,2-Difluoroacetylhydrazine

[0287] Benzyl 2-(2,2-difluoroacetyl)hydrazino-1-carboxylate (14.5 g, 59.4 mmol) was dissolved in methanol (50 mL), and 10% Pd / C (1.57 g) was added. Hydrogen gas was purged three times, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until complete. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure. 6.2 g of the target product was obtained, with a yield of 94%.

[0288] ethyl 8-fluoro-6-bromo-imidazo[1,2-a]pyridine-3-carboxylate

[0289] 10.0 g (52 mmol) of 3-fluoro-5-bromo-pyridin-2-amine was dissolved in 40 mL of ethanol, and 11.8 g (78 mmol) of ethyl 2-chloro-2-formyl acetate was added. The mixture was purged with nitrogen three times and heated overnight at 80 °C. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by rapid column chromatography. 4.3 g of the target product was given as a white solid, in 29% yield.

[0290] 1 H NMR (400MHz, CDCl3) δ9.32 (s, 1H), 8.26 (s, 1H), 7.28 (s, 1H), 4.43 (q, J = 8.0Hz, 2H), 1.43 (t, J = 4.0Hz, 3H).

[0291] 8-Fluoro-6-benzylthioimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

[0292] Ethyl 8-fluoro-6-bromoimidazolo[1,2-a]pyridine-3-carboxylate (4.3 g, 14.98 mmol) was dissolved in 1,4-dioxane (30 mL), followed by the addition of DIPEA (5.8 g, 44.94 mmol), Xantphos (865 mg, 1.5 mmol), and Pd2(dba)3 (686 mg, 0.75 mmol). The mixture was purged with nitrogen three times. Benzyl mercaptan (2.6 mL, 22.47 mmol) was then added using a syringe, and the reaction was carried out at 100 °C for 3 h. The reaction was monitored by TLC until complete. The system was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was removed from the organic phase under reduced pressure, and the residue was purified by rapid column chromatography. 3.9 g of the target product was given as an orange solid, in 79% yield.

[0293] MS-ESI: 331.0 [M+H] + .

[0294] 8-Fluoro-6-(benzylthio)imidazo[1,2-a]pyridine-3-carboxylic acid

[0295] Ethyl 8-fluoro-6-(benzylthio)imidazo[1,2-a]pyridine-3-carboxylate (3.9 g, 11.8 mmol) was dissolved in a methanol:water mixture of 3:1 (30 mL:10 mL), followed by the addition of THF (15 mL) to aid dissolution, and then LiOH·H₂O (2.48 g, 59 mmol). After the addition was complete, the reaction was heated at 50 °C for 3 h. The reaction was monitored by TLC until complete. The solvent was removed under reduced pressure, the pH was adjusted to approximately 3–4, a small amount of water was added for dilution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and used directly in the next step. 3.1 g of the target product was obtained as a yellow solid, with a yield of 88%.

[0296] 8-Fluoro-6-(benzylthio)imidazo[1,2-a]pyridine-3-carboxyl chloride

[0297] 3.1 g (10.32 mmol) of 8-fluoro-6-(benzylthio)imidazo[1,2-a]pyridine-3-carboxylic acid was dissolved in 20 mL of dichloromethane. Then, 1.3 mL (15.48 mmol) of oxaloyl chloride and 2 drops of DMF were added under ice-water bath. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. The reaction was monitored by TLC until complete. The solvent was removed from the system under reduced pressure and the solution was used directly in the next step.

[0298] 8-Fluoro-6-(benzylthio)-N'-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3-carboxylhydrazine

[0299] 10.32 mmol of 8-fluoro-6-(benzylthio)imidazo[1,2-a]pyridine-3-carboxyl chloride was dissolved in 30 mL of DCM, and DIPEA (4.0 g, 30.96 mmol) was added. Then, at -60 °C, a THF (3 mL) solution of 1.15 g, 10.32 mmol of 2,2-difluoroacetylhydrazine was added. After the addition was complete, the system was brought to room temperature and reacted overnight. The reaction was monitored by TLC until complete, and water was added to the system. The mixture was extracted with dichloromethane. The solvent was removed from the organic phase under reduced pressure, and the residue was purified by rapid column chromatography. 2.7 g of the target product was given as a yellow solid, in 67% yield.

[0300] MS-ESI: 317.0 [M+H] + .

[0301] 2-(6-(benzylthio)-8-fluoroimidazole[1,2-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole

[0302] 2.7 g (6.85 mmol) of 8-fluoro-6-(benzylthio)-N'-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3-carboxylhydrazide was dissolved in toluene (30 mL), and Lawson's reagent (3.0 g, 7.54 mmol) was added. The mixture was heated at 110 °C overnight after the addition was complete. The reaction was monitored by TLC until complete. Water was added to the system, and the mixture was extracted with ethyl acetate. The solvent was removed from the organic phase under reduced pressure, and the residue was purified by rapid column chromatography. 2.0 g of the target product was given as a white solid, in 74% yield.

[0303] 1 H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 8.57 (s, 1H), 7.67 (t, J = 52.0Hz, 1H), 7.70 (s, 1 H),7.33(d,J=8.0Hz,2H),7.27(t,J=8.0Hz,2H),7.18(t,J=8.0Hz,1H),4.30(s,2H).

[0304] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-fluoro-imidazo[1,2-a]pyridine-6-sulfonyl chloride

[0305] Using 2-(6-(benzylthio)-8-fluoroimidazolo[1,2-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (400 mg, 1.02 mmol) as a starting material, the same synthesis method as 4-chloro-1-(5-difluoromethyl)-1,3,4-thiadiazole-2-yl)-1H-indazole-6-sulfonyl chloride was used to obtain a yellowish-brown liquid, which was directly used in the next step.

[0306] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-fluoro-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide

[0307] Using methylcyclopropylamine hydrochloride (241.5 mg, 2.24 mmol) and 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-fluoro-imidazo[1,2-a]pyridine-6-sulfonyl chloride (1.02 mmol) as starting materials, the target product was synthesized using the same method as 4-chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide. 160 mg of the target product was obtained as a white solid, in 39% yield.

[0308] 1 H NMR (400MHz, DMSO-d6) δ9.88(d,J=1.0Hz,1H),8.78(s,1H),8.59(s,1H),7.72(t,J=52Hz, 1H),7.69(dd,J=12.0,4.0Hz,1H),1.18(s,3H),0.72(q,J=4.0Hz,2H),0.54–0.40(m,2H).

[0309] Compound 13

[0310] 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-fluoro-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (70 mg, 0.17 mmol) was dissolved in DMF (3 mL), followed by the sequential addition of DIPEA (112 mg, 0.87 mmol) and N-methyl-N-cyclopropylpiperazine-1-carboxamide (64 mg, 0.35 mmol). The mixture was heated at 130 °C overnight after the addition was complete. The reaction was monitored by TLC until complete. Water was added to the system, and the mixture was extracted with ethyl acetate. The solvent was removed from the organic phase under reduced pressure, and the residue was purified by rapid column chromatography. 40 mg of the target product was obtained as a white solid, in 42% yield.

[0311] 1H NMR (400MHz, DMSO-d6) δ9.66(d,J=1.0Hz,1H),8.60(s,1H),8.39(s,1H),7.68(t,J=52.0Hz,1H),7.00(d,J=1.0Hz,1H),3. 60(d,J=4.0Hz,5H),2.78(s,3H),1.13(s,3H),0.88-0.80(m,1H),0.72-0.67(m,2H),0.59-0.54(m,2H),0.47-0.40(m,2H).

[0312] MS-ESI: 567.2 [M+H] + .

[0313] Example 14

[0314] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridin-8-yl)-N-methyl-N-cyclopropylpiperazine-1-carboxamide (compound 14)

[0315] N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-fluoroimidazo[1,2-a]pyridine-6-sulfonamide

[0316] Using 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-fluoro-imidazo[1,2-a]pyridine-6-sulfonyl chloride (2.54 mmol) and cyanocyclopropylamine hydrochloride (660 mg, 5.59 mmol) as starting materials, the target product was synthesized using the same method as 4-chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide. 480 mg of the target product was obtained as a white solid, in 42% yield.

[0317] 1 H NMR(400MHz,DMSO-d6)δ9.98(d,J=1.0Hz,1H),8.82(s,1H),8.34(s,1H),7.75( dd,J=8.0Hz,1H),7.72(t,J=52.0Hz,1H),1.51–1.46(m,2H),1.41–1.35(m,2H).

[0318] Compound 14

[0319] The target product was synthesized from N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-fluoroimidazole[1,2-a]pyridine-6-sulfonamide (50 mg, 0.12 mmol) and N-methyl-N-cyclopropylpiperazine-1-carboxamide (44 mg, 0.24 mmol) using the same method as compound 8. 18 mg of the target product was obtained as a yellow solid, in 27% yield.

[0320] 1 H NMR (400MHz, DMSO-d6) δ9.75(d,J=1.0Hz,1H),9.44(s,1H),8.64(s,1H),7.69(t,J=52.0Hz,1H),7.00(d,J=1.0Hz,1H),3.66-3.63(m ,4H),3.48-3.39(m,4H),2.78(s,3H),2.68-3.65(m,1H),1.49-1.45(m,2H),1.39-1.36(m,2H),0.70-0.68(m,2H),0.58-0.56(m,2H).

[0321] MS-ESI: 578.3 [M+H] + .

[0322] Example 15

[0323] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridin-8-yl)-N-methyl-N-cyclobutylpiperazine-1-carboxamide (compound 15)

[0324] 4-(cyclobutylcarbamoyl)piperazine-1-carboxylic acid benzyl ester

[0325] Using cyclobutylamine (1.0 g, 14.02 mmol) and benzyl piperazine-1-carboxylate (3.1 g, 14.02 mmol) as starting materials, the same method as for 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate was used to synthesize the target product. 3.2 g of the target product was obtained as a yellow solid, with a yield of 73%.

[0326] 1 H NMR(400MHz, CDCl3)δ7.26(m,5H),5.20(s,1H),5.05(s,1H),4.10–3.97(m,1H),3.46 –3.38(m,4H),3.13–3.08(m,4H),2.67(s,3H),2.07–1.96(m,4H),1.64–1.47(m,2H).

[0327] 4-(cyclobutyl(methyl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0328] Using 3.2 g (10.09 mmol) of 4-(cyclobutylcarbamoyl)piperazine-1-carboxylate as a starting material, the same method as for 4-(methyl(methylcyclopropyl)carbamoyl)piperazine-1-carboxylate was used to synthesize the target product. 3.3 g of the target product was obtained as a yellow liquid, with a yield of 99%.

[0329] 1 H NMR (400MHz, CDCl3) δ7.30–7.20(m,5H),5.20(s,1H),5.05(s,1H),4.14–3.94(m,1H),3 .46–3.38(m,4H),3.13–3.08(m,4H),2.67(s,3H),2.05-1.98(m,4H),1.64–1.49(m,2H).

[0330] N-Methyl-N-cyclobutylpiperazine-1-carboxamide

[0331] Using 3.3 g (9.96 mmol) of 4-(cyclobutyl(methyl)carbamoyl)piperazine-1-carboxylate as a starting material, the same method as that used for N-cyclopropylpiperazine-1-carboxamide was employed. 1.5 g of the target product was obtained as a gray, viscous liquid, with a yield of 77%.

[0332] 1 H NMR (400MHz, DMSO-d6) δ4.11–3.96(m,1H),3.03–2.96(m,4H),2.75–2.57(m,7H),2.11–1.95(m,4H),1.66–1.46(m,2H).

[0333] Compound 15

[0334] The target product was synthesized from N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-fluoroimidazo[1,2-a]pyridine-6-sulfonamide (100 mg, 0.24 mmol) and N-methyl-N-cyclobutylpiperazine-1-carboxamide (94 mg, 0.48 mmol) using the same method as compound 8. 15 mg of the target product was obtained as a yellow solid, in 11% yield.

[0335] 1H NMR (400MHz, DMSO-d6) δ9.75(d,J=1.0Hz,1H),9.43(s,1H),8.65(s,1H),7.70(t,J=52.0Hz,1H),7.02(d,J=1.0Hz,1H),4.22-4.13(m ,1H),3.70-3.60(m,4H),3.36-3.34(m,4H),2.75(s,3H),2.10-2.01(m,4H),1.63-1.57(m,2H),1.51-1.39(m,2H),1.42-1.34(m,2H).

[0336] MS-ESI: 592.2 [M+H] + .

[0337] Example 16

[0338] Preparation of 4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-(N-(1-methylcyclopropyl)aminosulfonyl)imidazo[1,2-a]pyridin-8-yl}-N-methyl-N-cyclopentylpiperazin-1-carboxamide (compound 16)

[0339] Compound 16

[0340] The target product was synthesized from 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-fluoro-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (70 mg, 0.17 mmol) and N-methyl-N-cyclopentylpiperazine-1-carboxamide (73 mg, 0.35 mmol) using the same method as compound 13. 35 mg of the target product was obtained as a yellow solid in 35% yield.

[0341] 1 H NMR (400MHz, CDCl3) δ9.89(d,J=1.0Hz,1H),8.16(s,1H),8.07(s,1H),7.09(t,J=52.0Hz,1H),6.98(d,J=1.0Hz,1H),4.24 -4.19(m,1H),3.71–3.60(m,4H),3.53 -3.51(m,4H),2.78(s,3H),1.86-1.70(m,6H),1.37-1.33(m,5H),0.97–0.81(m,2H),0.61–0.54(m,2H).

[0342] MS-ESI: 595.3 [M+H] + .

[0343] Example 17

[0344] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)imidazo[1,2-a]pyridin-8-yl)-N-methyl-N-cyclopentylpiperazine-1-carboxamide (compound 17)

[0345] Compound 17

[0346] The target product was synthesized from N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-fluoroimidazole[1,2-a]pyridine-6-sulfonamide (150 mg, 0.36 mmol) and N-methyl-N-cyclopentylpiperazine-1-carboxamide (153 mg, 0.72 mmol) using the same method as compound 8. 36 mg of the target product was obtained as a yellow solid, in 17% yield.

[0347] 1 H NMR (400MHz, CDCl3) δ9.98(d,J=1.0Hz,1H),8.17(s,1H),7.09(t,J=52.0Hz,1H),7.04(d,J=1.0Hz,1H),4.27-4.07( m,1H),3.71-3.66(m,4H),3.56-3.49(m,4H),2.78(s,3H),1.77-1.62(m,5H),1.62-1.53(m,5H),1.50-1.48(m,2H).

[0348] MS-ESI: 606.4 [M+H] + .

[0349] Example 18

[0350] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-cyclobutylpiperazine-1-carboxamide (compound 18)

[0351] 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide

[0352] Using 1-amino-cyclopropyl cyanide hydrochloride (369.37 mg, 3.12 mmol) and 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazole-6-sulfonyl chloride (958 mg, 2.6 mmol) as starting materials, this compound was synthesized using the same method as 4-chloro-N-1-cyanocyclopropyl-1-(5-difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide. 226 mg of a white powder product was obtained, with a yield of 21%.

[0353] 1 H NMR (400MHz, CD3OD) δ9.05(s,1H),8.72(s,1H),7.67(d,J=8.9Hz,1H),7.28(t,J=53.4Hz,1H),1.50–1.46(m,2H),1.46–1.42(m,2H).

[0354] MS-ESI: 413.1 [MH] - .

[0355] Compound 18

[0356] Using 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (100 mg, 0.242 mmol) and N-methyl-N-cyclobutylpiperazine-1-carboxamide (95 mg, 0.484 mmol) as starting materials, the same method as compound 8 was used for synthesis. 119 mg of a pale yellow powder was obtained, with a yield of 84%.

[0357] 1 H NMR (400MHz, CDCl3) δ8.77(s,1H),8.33(s,1H),7.28(s,1H),6.99(t,J=52.0Hz,1H),6.14(s,1H),4.25-4.16(m, 1H),3.52–3.49(m,4H),3.47–3.45(m,4H),2.83(s,3H),2.21-2.13(m,4H),1.74-1.62(m,4H),1.47-1.44(m,2H).

[0358] MS-ESI: 592.4 [M+H] + .

[0359] Example 19

[0360] Preparation of 4-(6-(N-(1-methylcyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-cyclobutylpiperazine-1-carboxamide (compound 19)

[0361] Compound 19

[0362] The target product was synthesized from 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (100 mg, 0.248 mmol) and N-methyl-N-cyclobutylpiperazine-1-carboxamide (98 mg, 0.496 mmol) using the same method as compound 8. 80 mg of the target product was obtained as a yellow solid, in 56% yield.

[0363] 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),8.32(s,1H),7.25(s,3H),7.00(t,J=52.0Hz,1H),4.24-4.14(m,1H),3.54-3.49 (m,4H),3.45–3.43(m,4H),2.85(s,3H),2.22-2.13(m,4H),1.25(s,3H),0.90–0.85(m,4H),0.53(t,J=4.0Hz,2H).

[0364] MS-ESI: 579.4 [MH] - .

[0365] Example 20

[0366] Preparation of (2S,6S)-4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-cyclopropyl-2,6-dimethylpiperazine-1-carboxamide (compound 20)

[0367] (3S,5S)-3,5-dimethylpiperazine-1-carboxylic acid benzyl ester

[0368] (2S,6S)-2,6-dimethylpiperazine dihydrochloride (1.0 g, 5.34 mmol) was dissolved in DCM (10 mL), and TEA (1.1 g, 10.87 mmol) was added. Then, Cbz-Cl (910 mg, 5.34 mmol) was added dropwise under ice bath conditions, and the reaction was carried out at room temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction solution was quenched with water, extracted with DCM, and the organic phase was dried over anhydrous Mg2SO4. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (DCM / MeOH = 100:1 → 15:1). 820 mg of a white solid was given, with a yield of 62%.

[0369] 1 H NMR (400MHz, CDCl3) δ7.39-7.29(m,5H),5.13(q,J=12.0Hz,2H),3.83(dd,J=44.0,12.0Hz,2H),3.50-3.45(m,4H),1.36(d,J=4.0Hz,6H).

[0370] (3S,5S)-4-(cyclopropylcarbamoyl)-3,5-dimethylpiperazine-1-carboxylic acid benzyl ester

[0371] Using cyclopropylamine (314 mg, 5.5 mmol) and (3S,5S)-3,5-dimethylpiperazine-1-carboxylate (820 mg, 3.3 mmol) as starting materials, the same method as for 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate was used to synthesize the target product. 260 mg of the target product was obtained, with a yield of 24%.

[0372] MS-ESI: 332.2 [M+H] + .

[0373] (3S,5S)-4-(cyclopropyl(methyl)carbamoyl)-3,5-dimethylpiperazine-1-carboxylic acid benzyl ester

[0374] Using (3S,5S)-4-(cyclopropylcarbamoyl)-3,5-dimethylpiperazine-1-carboxylate (260 mg, 0.754 mmol) as the starting material, the same method as for 4-(methyl(methylcyclopropyl)carbamoyl)piperazine-1-carboxylate benzyl ester was synthesized. 170 mg of the target product was obtained, with a yield of 65%.

[0375] 1H NMR (400MHz, CDCl3) δ7.34(m,5H),5.14(q,J=12.4Hz,2H),3.57(dd,J=13.0,3.2Hz,4H),3.29( s,2H),2.90(s,3H),2.58(m,1H),1.09(d,J=7.6Hz,6H),0.83(m,1H),0.66(m,2H),0.52(m,1H).

[0376] (2S,6S)-N-methyl-N-cyclopropyl-2,6-dimethylpiperazine-1-carboxamide

[0377] Using (3S,5S)-4-(cyclopropyl(methyl)carbamoyl)-3,5-dimethylpiperazine-1-carboxylate (160 mg, 0.46 mmol) as the starting material, the same method as that used for N-cyclopropylpiperazine-1-carboxamide was employed. 95 mg of the target product was obtained, with a yield of 98%.

[0378] 1 H NMR (400MHz, CDCl3) δ3.41 (pd, J=6.3, 3.6Hz, 2H), 2.95 (dd, J=12.5, 3.7Hz, 2H), 2.9 0(s,3H),2.58(m,3H),1.09(d,J=6.3Hz,6H),0.85(m,1H),0.66(m,2H),0.49(m,1H).

[0379] Compound 20

[0380] Using 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (45 mg, 0.11 mmol) and (2S,6S)-N-methyl-N-cyclopropyl-2,6-dimethylpiperazine-1-carboxamide (45 mg, 0.213 mmol) as starting materials, the same method as compound 8 was used for synthesis. 40 mg of the target product was obtained in 60% yield.

[0381] 1H NMR (400MHz, CDCl3) δ8.72(s,1H),8.31(s,1H),7.25(d,J=1.4Hz,1H),6.99(t,J=53.6Hz,1H),6.25(s,1H),3.89(m,2H),3.53(dd,J=12.0,3. 5Hz,2H),3.28(dd,J=11.9,6.2Hz,2H),2.95(s,3H),2.64(m,1H),1.45(m,2H),1.30(d,J=6.3Hz,6H),1.26(m,2H),0.87(m,2H),0.72(m,2H).

[0382] MS-ESI: 604.2 [MH] - .

[0383] Example 21

[0384] Preparation of (2S,6S)-4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-cyclobutyl-2,6-dimethylpiperazine-1-carboxamide (compound 21)

[0385] (3S,5S)-4-(cyclobutylcarbamoyl)-3,5-dimethylpiperazine-1-carboxylic acid benzyl ester

[0386] Using cyclobutamine (500 mg, 7.04 mmol) and (3S,5S)-3,5-dimethylpiperazine-1-carboxylate (1.75 g, 7.04 mmol) as starting materials, the same method as for 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate was used for synthesis. 1.7 g of a yellow solid was obtained, with a yield of 71%.

[0387] 1 H NMR (400MHz, CDCl3) δ7.37-7.34(m,5H),5.21-5.13(m,2H),4.35-4.29(m,1H),4.07-3.99(m,2H), 3.78-3.56(m,4H),2.38-2.32(m,2H),1.83-1.76(m,2H),1.71-1.65(m,2H),1.27(d,J=8.0Hz,6H).

[0388] (3S,5S)-4-(cyclobutyl(methyl)carbamoyl)-3,5-dimethylpiperazine-1-carboxylic acid benzyl ester

[0389] Using (3S,5S)-4-(cyclobutylcarbamoyl)-3,5-dimethylpiperazine-1-carboxylate (730 mg, 2.12 mmol) as a starting material, the synthesis method was the same as that for 4-(methyl(methylcyclopropyl)carbamoyl)piperazine-1-carboxylate. A yellow liquid of 738 mg was obtained, with a yield of 97%.

[0390] 1 H NMR (400MHz, CDCl3) δ7.36-7.31(m,5H),5.18-5.11(m,2H),4.47-4.39(m,1H),3.60-3.56( m,2H),3.39-3.26(m,4H),2.85(s,3H),2.14-2.08(m,4H),1.69-1.61(m,2H),1.07(s,6H).

[0391] (2S,6S)-N-methyl-N-cyclobutyl-2,6-dimethylpiperazine-1-carboxamide

[0392] Using (3S,5S)-4-(cyclobutyl(methyl)carbamoyl)-3,5-dimethylpiperazine-1-carboxylate (738 mg, 2.06 mmol) as the starting material, the same method as that used for N-cyclopropylpiperazine-1-carboxamide was employed. 410 mg of the target product was obtained, with a yield of 89%.

[0393] 1 H NMR (400MHz, CDCl3) δ4.45-4.38(m,1H),3.33-3.26(m,2H),2.96(dd,J=12.0,4.0Hz,2H),2.85(s ,3H),2.59(dd,J=12.0,4.0Hz,2H),2.13-2.06(m,4H),1.67-1.55(m,2H),1.06(d,J=8.0Hz,6H).

[0394] Compound 21

[0395] Using 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (50 mg, 0.12 mmol) and (2S,6S)-N-methyl-N-cyclobutyl-2,6-dimethylpiperazine-1-carboxamide (56 mg, 0.25 mmol) as starting materials, the same method as compound 8 was used for synthesis. 63 mg of a yellow powder solid was obtained, with a yield of 87%.

[0396] 1H NMR (400MHz, CDCl3): δ8.76(d,J=1.0Hz,1H),8.32(d,J=1.0Hz,1H),7.27(d,J=1 .0Hz,1H),6.99(t,JF-H=52.0Hz,1H),5.85(s,1H),4.53-4.44(m,1H),3.72-3.68 (m,2H),3.49(dd,J=12.0,4.0Hz,2H),3.25(dd,J=12.0,6.0Hz,2H),2.91(s,3H) ,2.19-2.13(m,4H),1.71-1.62(m,4H),1.49-1.45(m,2H),1.29(d,J=6.0Hz,6H).

[0397] MS-ESI): 620.2 [M+H] + .

[0398] Example 22

[0399] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-ethyl-N-cyclopropylpiperazine-1-carboxamide (compound 22)

[0400] 4-(cyclopropyl(ethyl)carbamoyl)-piperazine-1-carboxylic acid benzyl ester

[0401] Using 4-(cyclopropylcarbamoyl)-piperazine-1-carboxylate (2.0 g, 6.59 mmol) and iodoethane (2.05 g, 13.18 mmol) as starting materials, the same method as for 4-(cyclopropyl(methyl)carbamoyl)-piperazine-1-carboxylate was used for synthesis. 450 mg of the target product was obtained, with a yield of 21%.

[0402] 1 H NMR (400MHz, CDCl3) δ7.34(m,5H),5.14(s,2H),3.50(dd,J=6.2,4.1Hz,4H),3.31(m,4H),3.26(dd, J=14.4,7.2Hz,2H),2.59(dt,J=10.2,3.3Hz,1H),1.16(t,J=7.2Hz,3H),0.75(m,2H),0.59(m,2H).

[0403] N-Ethyl-N-cyclopropylpiperazine-1-carboxamide

[0404] Using 4-(cyclopropyl(ethyl)carbamoyl)-piperazine-1-carboxylate (450 mg, 1.36 mmol) as the starting material, the same method as that used for N-cyclopropylpiperazine-1-carboxamide was employed. 250 mg of the target product was obtained, with a yield of 93%.

[0405] MS-ESI: 198.2 [M+H] + .

[0406] Compound 22

[0407] Using 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (50 mg, 0.12 mmol) and N-ethyl-N-cyclopropylpiperazine-1-carboxamide (47 mg, 0.24 mmol) as starting materials, the same method as compound 8 was used for synthesis. 42 mg of the target product was obtained, with a yield of 59%.

[0408] 1 H NMR (400MHz, CDCl3) δ8.78 (s, 1H), 8.33 (d, J = 1.0Hz, 1H), 7.28 (d, J = 1.4Hz, 1H), 6.99(t,J=53.6Hz,1H),6.01(s,1H),3.64(t,J=5.0Hz,4H),3.47(dd,J=6.2,3.6 Hz,5H),3.33(q,J=7.1Hz,3H),2.65(m,1H),1.65(dd,J=8.7,5.5Hz,3H),1.46(d d,J=8.7,5.5Hz,2H),1.21(t,J=7.1Hz,4H),0.81(q,J=6.7Hz,3H),0.66(m,2H).

[0409] MS-ESI: 590.2 [MH] - .

[0410] Example 23

[0411] Preparation of 4-(6-(N-(1-methylcyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-n-propyl-N-cyclopropylpiperazine-1-carboxamide (compound 23)

[0412] 4-(cyclopropyl(n-propyl)carbamoyl)-piperazine-1-carboxylic acid benzyl ester

[0413] Using 4-(cyclopropylcarbamoyl)-piperazine-1-carboxylate (2.0 g, 6.59 mmol) and 1-iodopropane (2.05 g, 13.18 mmol) as starting materials, the same method as for 4-(cyclopropyl(methyl)carbamoyl)-piperazine-1-carboxylate was used for synthesis. 450 mg of the target product was obtained, with a yield of 21%.

[0414] 1 H NMR (400MHz, CDCl3) δ7.34(m,5H),5.14(s,2H),3.51(m,4H),3.32(m,4H),3.19(m,2 H),2.57(m,1H),1.62(m,2H),0.88(dd,J=8.8,6.0Hz,3H),0.75(m,2H),0.60(m,2H).

[0415] N-n-propyl-N-cyclopropylpiperazine-1-carboxamide

[0416] Using 4-(cyclopropyl(n-butyl)carbamoyl)-piperazine-1-carboxylate (120 mg, 0.347 mmol) as the starting material, the same method as N-cyclopropylpiperazine-1-carboxamide was used for synthesis. 73 mg of the target product was obtained, with a yield of 99%.

[0417] MS-ESI: 212.2 [M+H] + .

[0418] Compound 23

[0419] Using 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (50 mg, 0.12 mmol) and N-n-propyl-N-cyclopropylpiperazine-1-carboxamide (51 mg, 0.24 mmol) as starting materials, the same method as compound 8 was used for synthesis. 46 mg of the target product was obtained, with a yield of 63%.

[0420] 1H NMR (400MHz, CDCl3) δ8.78(s,1H),8.33(d,J=0.9Hz,1H),7.28(d,J=1.4Hz,1H),6.99(t,J=53.6Hz,1H),5.97(s,1H),3.64(t,J=5.0Hz,4H),3.47(m, 4H),3.25(t,J=7.2Hz,2H),2.64(ddd,J=10.4,6.8,3.9Hz,1H),1.65(m,5H ),1.46(q,J=5.5Hz,3H),0.93(t,J=7.4Hz,3H),0.81(m,3H),0.67(m,2H).

[0421] MS-ESI: 604.2 [MH] - .

[0422] Example 24

[0423] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-isobutyl-N-cyclopropylpiperazine-1-carboxamide (compound 24)

[0424] N-Cyclopropylisobutylamine

[0425] Isobutyraldehyde (3.0 g, 41.0 mmol) and cyclopropylamine (2.4 g, 41.0 mmol) were dissolved in DCM (30 mL), and the mixture was stirred at room temperature for 1 h. Then, a DCM solution of NaBH(OAc)3 (17.3 g, 82.0 mmol) (10 mL) was added dropwise under ice bath. After the addition was complete, the mixture was brought to room temperature and reacted for 4 h. The reaction was monitored by TLC until complete. The reaction was quenched with saturated NaHCO3 solution. The organic layer was separated, washed with water, dried over anhydrous MgSO4, and concentrated under reduced pressure. 2.01 g of crude product was obtained and used directly in the next step, with a yield of 43%.

[0426] 4-(cyclopropyl(isobutyl)carbamoyl)-piperazine-1-carboxylic acid benzyl ester

[0427] Using N-cyclopropyl isobutylamine (1.0 g, 6.71 mmol) and benzyl piperazine-1-carboxylate (1.47 g, 6.71 mmol) as starting materials, the same method as for 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate was used to synthesize the product. 410 mg of a yellow solid was obtained, with a yield of 17%.

[0428] 1H NMR (400MHz, CDCl3) δ7.33(m,5H),5.14(s,2H),3.51(m,4H),3.19(m,5H),3.05(d,J=7.4Hz,1H),2.57(m, 1H), 2.01 (dt, J = 13.7, 4.3Hz, 1H), 1.12 (t, J = 7.1Hz, 4H), 0.88 (d, J = 6.6Hz, 3H), 0.75 (m, 1H), 0.61 (m, 1H).

[0429] N-Isobutyl-N-cyclopropylpiperazine-1-carboxamide

[0430] Using 4-(cyclopropyl(isobutyl)carbamoyl)-piperazine-1-carboxylate (410 mg, 1.14 mmol) as the starting material, the same method as that used for N-cyclopropylpiperazine-1-carboxamide was employed. 106 mg of the target product was obtained, with a yield of 41%.

[0431] MS-ESI: 226.2 [M+H] + .

[0432] Compound 24

[0433] Using 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (92 mg, 0.22 mmol) and N-isobutyl-N-cyclopropylpiperazine-1-carboxamide (100 mg, 0.44 mmol) as starting materials, the same method as compound 8 was used for synthesis. 75 mg of the target product was obtained, with a yield of 55%.

[0434] 1 H NMR (400MHz, CDCl3) δ8.82 (s, 1H), 8.33 (s, 1H), 7.28 (d, J = 1.4Hz, 1H), 7.00 ( t,J=53.6Hz,1H),5.68(s,1H),3.71(t,J=5.0Hz,3H),3.49(m,4H),3.31(q,J =7.1Hz,1H),3.13(d,J=7.4Hz,2H),1.67(q,J=5.6Hz,2H),1.48(q,J=5.6Hz, 3H), 1.19 (t, J = 7.1Hz, 2H), 0.93 (d, J = 6.6Hz, 5H), 0.87 (m, 4H), 0.72 (m, 2H).

[0435] MS-ESI: 618.2 [MH] - .

[0436] Example 25

[0437] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-isopropyl-N-cyclopropylpiperazine-1-carboxamide (compound 25)

[0438] N-Isopropylcyclopropylamine

[0439] Cyclopropylamine (320 mg, 5.7 mmol) and 2-bromopropane (700 mg, 5.7 mmol) were added to a sealed tube, and the reaction was carried out overnight at 70 °C. The next day, the system was cooled, water was added, and the mixture was extracted with DCM. The organic phase was dried over anhydrous MgSO4. The starting material was removed by atmospheric distillation, and the residue was used for the next reaction step.

[0440] 4-(cyclopropyl(isopropyl)carbamoyl)-piperazine-1-carboxylic acid benzyl ester

[0441] Using N-isopropylcyclopropylamine (the product of the previous step) and benzyl piperazine-1-carboxylate (220 mg, 1.0 mmol) as starting materials, the compound was synthesized using the same method as 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate. 100 mg of the target product was obtained, with a yield of 29%.

[0442] 1 H NMR (400MHz, CDCl3) δ7.40-7.29(m,5H),5.14(s,2H),3.79(p,J=8.0Hz,1H),3.55-3.45(m,4H), 3.25-3.15(m,4H),2.41–2.28(m,1H),1.30–1.22(m,6H),0.76-0.70(m,2H),0.65–0.53(m,2H).

[0443] N-Cyclopropyl-N-(propyl-2-yl)piperazine-1-carboxamide

[0444] Using 4-(cyclopropyl(isopropyl)carbamoyl)piperazine-1-carboxylic acid benzyl ester (95 mg) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. 110.3 mg of a brown solid was obtained, with a yield of 99%.

[0445] 1H NMR (400MHz, CDCl3) δ3.79-3.67(m,1H),3.32–3.27(m,4H),2.86-2.81(m,4H), 2.40–2.31(m,1H),1.24(d,J=8.0Hz,6H),0.74-0.68(m,4H),0.60–0.48(m,4H).

[0446] Compound 25

[0447] The target product was synthesized from 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (47 mg, 0.1 mmol) and N-isopropyl-N-cyclopropylpiperazine-1-carboxamide (46 mg, 0.2 mmol) using the same method as compound 8. 36 mg of the target product was obtained in 60% yield.

[0448] 1 H NMR (400MHz, CDCl3) δ8.79(s,1H),8.33(s,1H),7.26(s,6H),7.00(t,J=52.0Hz,1H),5.89(s,1H),3.89(p,J=8.0Hz,1H),3.60- 3.70(m,4H),3.50-3.40(m,4H),2.52-2.39(m,1H),1.70-1.62(m,2H),1.50-1.43(m,2H),0.84-0.78(m,2H),0.69-0.62(m,2H).

[0449] MS-ESI: 606.4 [M+H] + .

[0450] Example 26

[0451] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N,N-dicyclopropylpiperazine-1-carboxamide (compound 26)

[0452] 4-(dicyclopropylcarbamoyl)piperazine-1-carboxylic acid benzyl ester

[0453] Using dicyclopropylamine (94 mg, 0.97 mmol) and benzyl piperazine-1-carboxylate (214 mg, 0.97 mmol) as starting materials, the compound was synthesized using the same method as 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate benzyl ester. 100 mg of the target product was obtained, with a yield of 30%.

[0454] 1 H NMR (400MHz, CDCl3) δ7.40–7.29(m,5H),5.14(s,2H),3.55–3.46(m,4H),3.27- 3.21(m,4H),2.55(tt,J=8.0,4.0Hz,2H),0.78-0.71(m,4H),0.66-0.61(m,4H).

[0455] N,N-Dicyclopropylpiperazine-1-carboxamide

[0456] Using 4-(dicyclopropylcarbamoyl)piperazine-1-carboxylate (95 mg) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. 57 mg of the target product was obtained, with a yield of 99%.

[0457] MS-ESI: 210.2 [M+H] + .

[0458] Compound 26

[0459] The target product was synthesized from 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (50 mg, 0.12 mmol) and N,N-dicyclopropylpiperazine-1-carboxamide (52 mg, 0.25 mmol) using the same method as compound 8. 35 mg of the target product was obtained, with a yield of 48%.

[0460] 1 H NMR (400MHz, CDCl3) δ8.78 (s, 1H), 8.32 (s, 1H), 7.26 (d, J = 2.0Hz 1H),6.99(t,J=52.0Hz,1H),6.37(s,1H),3.68(t,J=4.0Hz,4H),3.45(t,J=4.0Hz,4H),2.6 2–2.57(m,2H),1.70–1.62(m,2H),1.49–1.40(m,2H),0.83-0.77(m,4H),0.72-0.67(m,4H).

[0461] MS-ESI: 604.2 [M+H] + .

[0462] Example 27

[0463] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-(5-(cyclopropylethynyl)-2-fluorophenyl)piperazine-1-carboxamide (compound 27)

[0464] 4-(cyclopropylethynyl)-1-fluoro-2-nitrobenzene

[0465] 4-Bromo-1-fluoro-2-nitrobenzene (500 mg, 2.3 mmol), cuprous iodide (44 mg, 0.2 mmol), palladium dichloride bis(triphenylphosphine) (159 mg, 0.2 mmol), DIPEA (1.47 g, 11.3 mmol), and ethynylcyclopropane (225 mg, 3.4 mmol) were dissolved in THF (20 mL), and nitrogen was used to replace the atmosphere. After the addition was complete, the mixture was reacted at 40 °C for 4 h. Water was added to the system, and the mixture was extracted with ethyl acetate. The solvent was removed from the organic phase under reduced pressure, and the residue was purified by rapid column chromatography (PE:EA = 80:1) to give 291 mg of the target product, with a yield of 63%.

[0466] 1 H NMR (400MHz, CDCl3) δ8.03(dd,J=8.0,4.0Hz,1H),7.60–7.56(m,1H),7.21–7.16(m,1H),1.47–1.41(m,1H),0.96–0.86(m,2H),0.86–0.77(m,2H).

[0467] 5-(cyclopropylethynyl)-2-fluoroaniline

[0468] 4-(cyclopropylethynyl)-1-fluoro-2-nitrobenzene (400 mg, 1.95 mmol), iron powder (328 mg, 5.8 mmol), and ammonium chloride (1.03 g, 19.5 mmol) were dissolved in 9 mL of EtOH:H₂O (2:1). After the addition was complete, the mixture was reacted overnight at 50 °C. The reaction was monitored by TLC until complete. The system was filtered through diatomaceous earth, and water was added. The mixture was extracted with ethyl acetate. The solvent was removed by vacuum extraction of the organic phase, and the residue was purified by rapid column chromatography (PE:EA = 80:1). 184 mg of the target product was obtained, with a yield of 54%.

[0469] 1H NMR (400MHz, CDCl3) δ6.90–6.85(m,1H),6.83–6.81(m,1H),6.75–6.72(m,1H),1.44–1.38(m,1H),0.87–0.81(m,2H),0.79–0.74(m,2H).

[0470] MS-ESI: 176.1 [M+H] + .

[0471] (5-(cyclopropylethynyl)-2-fluorophenyl)carbamate

[0472] 5-(cyclopropylethynyl)-2-fluoroaniline (1.0 g, 5.7 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of phenyl chloroformate (981 mg, 6.27 mmol) and pyridine (1.35 g, 17.1 mmol). The reaction was allowed to proceed at room temperature for 3 h after the addition was complete. The reaction was monitored by TLC until complete. Water was added to the system, and the mixture was extracted with ethyl acetate. The solvent was removed from the organic phase under reduced pressure, and the residue was purified by rapid column chromatography (PE:EA = 10:1). 1.43 g of the target product was obtained, with a yield of 85%.

[0473] 1 H NMR(400MHz, DMSO-d6)δ7.69(d,J=8.0Hz,1H),7.43(t,J=8.0Hz,2H),7.30–7.11(m ,5H),6.77–6.72(m,1H),1.56–1.44(m,1H),0.91–0.81(m,2H),0.74–0.65(m,2H).

[0474] 4-(5-(cyclopropylethynyl)-2-fluorophenyl)carbamoylpiperazine-1-carboxylic acid tert-butyl ester

[0475] (5-(cyclopropylethynyl)-2-fluorophenyl)carbamate (100 mg, 0.308 mmol) and piperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.308 mmol) were dissolved in DMF (3 mL). DIPEA (100 mg, 0.775 mmol) was then added and the mixture was stirred at room temperature. After the reaction was complete as monitored by TLC, the reaction mixture was diluted with water (15 mL), extracted with EA (20 mL), and the organic phase was washed three times with water (5 mL). The organic phase was collected and purified by rapid column chromatography (PE:EA = 3:1). 115 mg of the target compound was obtained, with a yield of 96%.

[0476] 1H NMR(400MHz, CDCl3)δ8.13(dd,J=8.0,4.0,1H),7.04–6.88(m,2H),6.51(d, J=4.0,1H),3.50(s,8H),1.48(s,9H),1.44–1.36(m,1H),0.89–0.72(m,4H).

[0477] N-(5-(cyclopropylethynyl)-2-fluorophenyl)piperazine-1-carboxamide hydrochloride

[0478] 4-((5-(cyclopropylethynyl)-2-fluorophenyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester (115 mg, 0.297 mmol) was dissolved in DCM (2 mL), and 4.0 M hydrochloric acid / 1,4-dioxane (2 mL) was added. The reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed as monitored by TLC, the system was concentrated and used directly for the next reaction.

[0479] 1 H NMR(400MHz, DMSO-d6)δ9.17(s,2H),8.63(s,1H),7.48(dd,J=8.0,2.0Hz,1H),7.20–7.06(m, 2H),3.69–3.63(m,4H),3.11(s,4H),1.53–1.49(m,1H),0.91–0.84(m,2H),0.74–0.68(m,2H).

[0480] Compound 27

[0481] Using 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (45 mg, 0.11 mmol) and N-(5-(cyclopropylethynyl)-2-fluorophenyl)piperazine-1-carboxamide (63 mg, 0.22 mmol) as starting materials, the reaction temperature was 100 °C, and the synthesis method was similar to that of compound 8. 25 mg of the target product was obtained, with a yield of 33%.

[0482] 1H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.99(s,1H),8.49(d,J=12.0Hz,2H),7.76–7.45(m,2H),7.21–7.07(m,3H),3.74(s ,4H),3.53–3.50(m,4H),1.53–1.50(m,1H),1.46–1.41(m,2H),1.35–1.30(m,2H),0.90–0.85(m,2H),0.75–0.68(m,2H).

[0483] MS-ESI: 682.6 [M+H] + .

[0484] Example 28

[0485] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-(4-fluorophenyl)piperazine-1-carboxamide (compound 28)

[0486] 4-((4-fluorophenyl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0487] Using 4-fluoroaniline (52 mg, 0.47 mmol) and benzyl piperazine-1-carboxylate (103 mg, 0.47 mmol) as starting materials, the compound was synthesized using the same method as 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate. 96 mg of the target product was obtained, with a yield of 57%.

[0488] 1 H NMR (400MHz, CDCl3) δ7.42–7.30(m,5H),7.29-7.24(m,1H),7.00–6.91(m,2H),5.15(s,2H),3.61–3.42(m,8H).

[0489] N-(4-Fluorophenyl)piperazine-1-carboxamide

[0490] Using 4-((4-fluorophenyl)carbamoyl)piperazine-1-carboxylate (90 mg, 0.25 mmol) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. 55 mg of the target product was obtained, with a yield of 99%.

[0491] Compound 28

[0492] Using 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (45 mg, 0.11 mmol) and N-(4-fluorophenyl)piperazine-1-carboxamide (49 mg, 0.22 mmol) as starting materials, the same method as compound 8 was used for synthesis. 35 mg of the target product was obtained, with a yield of 52%.

[0493] 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),9.00(s,1H),8.70(s,1H),8.50(s,1H),7.61(t,J=52.0Hz,1H),7.51–7.45(m,2H),7.19(s 1H),7.14–7.05(m,2H),3.52(t,J=4.0Hz,4H),3.52(t,J=4.0Hz,4H),1.49–1.42(m,2H),1.42–1.28(m,2H).

[0494] MS-ESI: 618.9 [M+H] + .

[0495] Example 29

[0496] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-(4-methoxyphenyl)piperazine-1-carboxamide (compound 29)

[0497] 4-((4-methoxyphenyl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0498] Using 4-methoxyaniline (400 mg, 3.25 mmol) and benzyl piperazine-1-carboxylate (715 mg, 3.25 mmol) as starting materials, the compound was synthesized using the same method as 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate. 850 mg of the target product was obtained, with a yield of 71%.

[0499] 1 H NMR(400MHz, CDCl3) δ7.35(m,5H),7.23(d,J=9.0Hz,2H),6.84(d,J=9.0Hz,2H), 6.24(s,1H),5.16(s,2H),3.78(s,3H),3.58(m,4H),3.48(dd,J=6.6,3.7Hz,4H).

[0500] N-(4-Methoxyphenyl)piperazine-1-carboxamide

[0501] Using 4-((4-fluorophenyl)carbamoyl)piperazine-1-carboxylate (850 mg, 2.3 mmol) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. 360 mg of the target product was obtained, with a yield of 67%.

[0502] Compound 29

[0503] The target product was synthesized from 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (50 mg, 0.12 mmol) and N-(4-methoxyphenyl)piperazine-1-carboxamide (56 mg, 0.24 mmol) using the same method as compound 8. 25 mg of the target product was obtained, with a yield of 33%.

[0504] 1 H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.99(d,J=0.9Hz,1H),8.50(d,J=2.7Hz,2H),7.61(t,J=53.1Hz,1H),7.37(m,2H),7.19(d,J= 1.3Hz,1H),6.84(m,2H),3.73(m,4H),3.71(s,4H),3.51(t,J=5.1Hz,4H),1.45(dd,J=8.5,5.3Hz,2H),1.32(dd,J=8.6,5.3Hz,2H).

[0505] MS-ESI: 628.1 [MH] - .

[0506] Example 30

[0507] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-phenylpiperazine-1-carboxamide (compound 30)

[0508] 4-(phenylcarbamoyl)piperazine-1-carboxylic acid benzyl ester

[0509] Using aniline (255 mg, 2.74 mmol) and benzyl piperazine-1-carboxylate (603 mg, 2.74 mmol) as starting materials, the compound was synthesized using the same method as 4-(cyclopropylcarbamoyl)piperazine-1-carboxylate. 800 mg of the target product was obtained, with a yield of 86%.

[0510] 1 H NMR (400MHz, CDCl3) δ7.41-7.26(m,10H),5.16(s,2H),3.61-3.54(m,4H),3.52-3.47(m,4H).

[0511] N-Phenyloprazine-1-formamide

[0512] Using 4-((4-fluorophenyl)carbamoyl)piperazine-1-carboxylate (800 mg, 2.36 mmol) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. 479 mg of the target product was obtained, with a yield of 99%.

[0513] MS-ESI: 206.1 [M+H] + .

[0514] Compound 30

[0515] Using 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (50 mg, 0.12 mmol) and N-phenylpiperazine-1-carboxamide (49 mg, 0.24 mmol) as starting materials, the same method as compound 8 was used for synthesis. 20 mg of the target product was obtained, with a yield of 28%.

[0516] 1 H NMR(400MHz, DMSO-d6)δ9.00(s,1H),8.67(s,1H),8.50(s,1H),7.74(t,J=52.0Hz,1H),7.53–7.46(m,2H),7.33–7.22(m,2H), 7.19(d,J=4.0Hz,1H),6.98-6.92(m,1H),3.76(t,J=4.0Hz,4H),3.52(t,J=4.0Hz,4H),1.53–1.41(m,2H),1.38–1.29(m,2H).

[0517] MS-ESI: 600.4 [M+H] + .

[0518] Example 31

[0519] Preparation of 4-(6-(N-(1-cyanocyclopropyl)aminosulfonyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methyl-N-phenylpiperazin-1-carboxamide (compound 31)

[0520] 4-(phenyl(methyl)carbamoyl)piperazine-1-carboxylic acid benzyl ester

[0521] Using 4-(phenyl)carbamoyl)piperazine-1-carboxylate (360 mg, 1.06 mmol) as the starting material, the same synthesis method as for 4-(methyl(methylcyclopropyl)carbamoyl)piperazine-1-carboxylate was employed. 371 mg of the target product was obtained, with a yield of 99%.

[0522] MS-ESI: 376.2 [M+Na] + .

[0523] N-Methyl-N-phenylpiperazine-1-carboxamide

[0524] Using 4-((4-fluorophenyl)carbamoyl)piperazine-1-carboxylate (371 mg, 1.05 mmol) as the starting material, the compound was synthesized using the same method as N-cyclopropylpiperazine-1-carboxamide. 230 mg of the target product was obtained, with a yield of 100%.

[0525] 1 H NMR (400MHz, CDCl3) δ7.37-7.28(m,3H),7.13-7.06(m,2H),3.21(s,3H),3.17(t,J=4.0Hz 4H),2.65(t,J=4.0Hz,4H).

[0526] Compound 31

[0527] The target product was synthesized from 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-cyanocyclopropyl)-1H-indazole-6-sulfonamide (50 mg, 0.12 mmol) and N-methyl-N-phenylpiperazine-1-carboxamide (53 mg, 0.24 mmol) using the same method as compound 8. 42 mg of the target product was obtained, with a yield of 57%.

[0528] 1H NMR (400MHz, CDCl3) δ8.72(s,1H),8.23(s,1H),7.38(t,J=8.0Hz,2H),7.21–7.13(m,4H),6.98(t,J=5 2.0Hz,1H),6.17(s,1H),3.48–3.45(m,4H),3.30-3.25(m,7H),1.67–1.59(m,2H),1.51–1.39(m,2H).

[0529] MS-ESI: 614.4 [M+H] + .

[0530] Example 1

[0531] Assay for PARG enzyme inhibitory activity

[0532] TR-FRET test

[0533] Operating steps:

[0534] 1) The compound was serially diluted with DMSO in a dilution plate. The initial concentration of the compound was 1000 nM, and it was diluted 3 times to obtain 10 concentrations.

[0535] 2) Transfer the compound to a 384 reaction plate using an Echo, in duplicate wells, 100 nL per well.

[0536] 3) Add 2.5 μL of PARG enzyme solution to each well of the reaction plate and incubate at room temperature (25°C) for 15 minutes.

[0537] 4) Add 2.5 μL of PARP1-PARylation enzyme solution to each well of the reaction plate.

[0538] 5) Centrifuge at 1000 rpm for 60 seconds, and react at room temperature for 60 minutes.

[0539] 6) Add 5 μL of His-Tb & SA-XL665 mixture to a 384 reaction plate.

[0540] 7) Centrifuge at 1000 rpm for 60 seconds, and react at room temperature for 60 minutes.

[0541] 8) Use a BMG microplate reader to read the ratio at 665 / 615nm.

[0542] Calculate IC based on test results 50 .

[0543] IC 50 Size is divided into four levels: ++++, IC 50 <10nM; +++, IC 50 10-100nM; ++, IC50 100-200nM; +, IC 50 >200nM.

[0544] Compound IC of the present invention 50 As shown in Table 1 below.

[0545] Table 1. Results of the assay for the inhibitory effect of the compounds on PARG enzyme.

[0546] As can be seen from the above activity data, most of the compounds of the present invention have strong inhibitory activity against PARG.

[0547] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, X 1 X 2 X 3 X 4 Each is independently selected from N, C and CR 4 , where R 4 H, halogen, substituted or unsubstituted C 1-3 Alkyl group, wherein the substitution is performed by being substituted with one or more H atoms or halogens; Y and Z are each independently selected from N, C, and CR. 5 , where R 5 H, halogen, substituted or unsubstituted C 1-3 Alkyl group, wherein the substitution is performed by being substituted with one or more H atoms or halogens; This indicates that it can be a single bond or a double bond; R 1 Selected from H, D, halogen, cyano, amino, hydroxyl and C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by one or more Q1 groups, wherein the Q1 groups are selected from H, D, halogens, amino groups, and hydroxyl groups; R a R b Each is independently selected from H, D, halogen, cyano, amino, hydroxyl and C. 1-6 Alkyl, the C 1-6 The alkyl group is substituted by one or more Q2 groups selected from H, D, halogens, amino groups, and hydroxyl groups; or R. a and R b It is linked with the carbon atom it is attached to to form a C group. 3-8 cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl and 3-10 membered heterocyclic groups are replaced by one or more Q3 groups, wherein the Q3 groups are selected from H, D, halogens, amino groups, hydroxyl groups, and C. 1-6 alkyl; R 2 Selected from H, D, halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is replaced by one or more Q4 groups selected from H, D, halogens, amino groups, and hydroxyl groups; R 3 Selected from H, D, halogen, cyano, amino, hydroxyl and C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by one or more Q5 groups, wherein the Q5 groups are selected from H, D, halogens, amino groups, and hydroxyl groups; Selected from 5-12 membered heterocyclic groups, wherein the 5-12 membered heterocyclic group is substituted by one or more Q6 groups, wherein the Q6 group is selected from H, D, halogen, amino, hydroxyl, C. 1-6 Alkyl and C 3-8 cycloalkyl; Selected from C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the C 3-8 The cycloalkyl and 3-10 membered heterocyclic groups are replaced by one or more Q7 groups, wherein the Q7 groups are selected from H, D, halogens, amino groups, hydroxyl groups, and C. 1-6 alkyl; It is selected from 5-12-membered heteroaryl groups, wherein the 5-12-membered heteroaryl group is substituted by one or more Q8 groups, wherein the Q8 groups are selected from H, D, halogens, amino groups and hydroxyl groups.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Y and Z are each independently selected from N and C.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound has a structure as shown in formula (IA) or formula (IB). Wherein, the R 1 R a R b R 2 R 3 , As defined in claim 1.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The X 1 X 2 X 3 and X 4 Each independently selected from CR 4 , where R 4 For H.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound has a structure as shown in formula (IA-1), (IA-2), (IA-3), (IB-1), or (IB-2). Wherein, the R 1 R a R b R 2 R 3 , As defined in claim 1.

6. The compound of formula (I) according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 Selected from H, cyano and C 1-3 Alkyl, the C 1-3 The alkyl group is replaced by one or more Q1s, wherein the Q1s are selected from H, F, Cl and Br.

7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 Selected from H, -CN, -CH3, -CH2F and -CF3.

8. The compound of formula (I) according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, characterized in that, The R a and R b It is linked with the carbon atom it is attached to to form a C group. 3-5 Cycloalkyl or 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group contains 1-2 heteroatoms selected from O, and the C 3-5 The cycloalkyl group and the 4-6 membered heterocyclic group are replaced by one or more Q3 groups, wherein the Q3 group is selected from H, F, Cl, Br and C. 1-3 alkyl.

9. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, characterized in that, The R a and R b It is linked together with the carbon atoms it is attached to to form 10. The compound of formula (I) according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, characterized in that, The R 2 Selected from H, cyano, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is replaced by one or more Q4 groups selected from H, F, Cl, and Br.

11. The compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof, characterized in that, The R 2 Selected from -CN, -CHF2, -CF3, -O-CF3.

12. The compound of formula (I) according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, characterized in that, The R 3 Selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is replaced by one or more Q5 groups, wherein the Q5 groups are selected from H.

13. The compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt thereof, characterized in that, The R 3 Selected from H and -CH3.

14. The compound of formula (I) according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, characterized in that, The The heterocyclic group is selected from 6-8 membered heterocyclic groups, wherein the 6-8 membered heterocyclic group contains 1-3 heteroatoms selected from N and O, and the 6-8 membered heterocyclic group is substituted by one or more Q6, wherein the Q6 is selected from H and C. 1-3 alkyl.

15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, characterized in that, The Selected from 16. The compound of formula (I) according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, characterized in that, The Selected from C 3-6 Cycloalkyl groups and 4-6 membered heterocyclic groups, wherein the 4-6 membered heterocyclic group contains 1-2 heteroatoms selected from N and O, and the C 3-6 The cycloalkyl and 4-6 membered heterocyclic groups are replaced by one or more Q7 groups, wherein the Q7 groups are selected from H and C. 1-3 alkyl.

17. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, characterized in that, The Selected from 18. The compound of formula (I) according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, characterized in that, The The aryl group is selected from 5-6-membered heteroaryl groups, wherein the 5-6-membered heteroaryl group contains 1-3 heteroatoms selected from N, O and S, and the 5-6-membered heteroaryl group is substituted by one or more Q8 atoms selected from H.

19. The compound of formula (I) according to claim 18, or a pharmaceutically acceptable salt thereof, characterized in that, The Selected from 20. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound has one of the following structures:

21. A pharmaceutical composition comprising a compound as described in any one of claims 1-20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. The use of any compound of claims 1-20 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21, in the preparation of a medicament for treating and / or preventing PARG-related diseases.

23. The application according to claim 22, characterized in that, The PARG-related diseases include cancer, autoimmune diseases, immunodeficiency diseases, viral infections, aging, and organ transplant rejection.

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