Hydroxamic acid compounds having ENPP1 inhibitory activity and uses thereof

Abstract

The present disclosure relates to compounds of formula (I) having ENPP1 inhibitory activity, pharmaceutical compositions and uses thereof. The present disclosure particularly relates to compounds of formula (I), pharmaceutical compositions comprising these compounds, and methods of using these compounds for the prevention or treatment of diseases, particularly diseases or disorders mediated by abnormal ENPP1 activity. JPEG2024533433000116.jpg5331

Description

[Technical field]

[0001] The present disclosure relates to hydroxamic acid compounds, their use in inhibiting ENPP1, and methods of using said compounds in the prevention or treatment of disease. [Background technology]

[0002] As the body's first line of defense against pathogens, the body's immune system plays a key role in fighting tumor cells. STING (Stimulator of Interferon Gene), a 378-amino acid stimulator of interferon genes, plays a key role in immunity to tumor cells. STING is activated by binding to cGAMP (cyclic GMP-AMP synthase), which further recruits TANK-binding kinase 1 (TBK1), leading to phosphorylation of Interferon Regulatory Factor 3 (IRF3). Phosphorylated IRF3 produces type I interferon (IFN) and other cytokines, which work in conjunction with IFN to trigger an immune response of the body's adaptive immune system against tumor cells and infections.

[0003] Ectonucleotide pyrophosphatase / phosphodi-esterase 1 (ENPP1) is one of the seven enzymes in the ENPP family and is a type II transmembrane glycoprotein. Research has revealed that ENPP1 has high hydrolytic activity and can degrade many compounds, including phosphodiester bonds and pyrophosphate bonds, and ATP is one of the main targets of ENPP1. ENPP1 not only hydrolyzes ATP to AMP and PPi, but also hydrolyzes cGAMP, reducing the number of cGAMP in the human body and reducing STING activity. Therefore, ENPP1 activity inhibits the anti-tumor and anti-infectious disease immune responses of the human immune system via STING, and inhibition of ENPP1 activity contributes to the stabilization of cGAMP and the increase in STING activity, thereby improving the body's immune system's resistance to tumors and infections. Furthermore, ENPP1 was demonstrated to be more prominently expressed in human breast tumors than normal, which not only indicated that ENPP1 was a potential predictive marker for breast cancer, but also highlighted its potential and reliability as an anticancer drug target.

[0004] In addition to the prominent role of ENPP1 in tumors, studies have shown that the expression of ENPP1 is associated with many bacterial and viral infections, and therefore ENPP1 may be useful in treating infectious diseases.

[0005] Although cancer patients have multiple treatment options, there is a need for effective and safe therapeutic agents and their preferred application in combination therapy. Summary of the Invention [Problem to be solved by the invention]

[0006] The present disclosure provides a compound of formula (I), its pharma- ceutically acceptable salt, its pharmaceutical composition, and its combination.The present disclosure has surprisingly found that the compound of formula (I) is a good ENPP1 inhibitor.The present disclosure has also surprisingly found that the compound of the present disclosure has good physical and chemical stability, good bioavailability (e.g., low clearance rate) and good druggability.

[0007] The present disclosure further provides a method of treating, preventing, or ameliorating an ENPP1-mediated disease or disorder, comprising administering to an individual in need thereof an effective amount of an ENPP1 inhibitor.

[0008] Specifically, the present disclosure provides hydroxamic acid compounds of formula (I):

[0009] [ka]

[0010] However, X, X 1 , X 2 , X 3 , X 4 , X 5 and the variables of rings A, Y, and L are each as defined herein. Included are stereoisomers, geometric isomers, tautomers, pharma- ceutically acceptable salts, polymorphs, solvates, hydrates, or prodrugs of the compounds, which are useful for treating or preventing an ENPP1-mediated disease or disorder, particularly cancer, or an infectious disease or disorder.

[0011] The present disclosure also provides methods of preparing the compounds of the present disclosure, intermediates for preparing the compounds of the present disclosure, and methods for preparing said intermediates.

[0012] The present disclosure further provides compositions comprising at least one compound of the present disclosure or a pharma- ceutically acceptable salt thereof.

[0013] The present disclosure further provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0014] In one embodiment, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof.

[0015] In another embodiment, the present disclosure provides combinations, particularly drug combinations, comprising a therapeutically effective amount of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, and one or more other therapeutic agents.

[0016] The compounds of the present disclosure may be used alone, in combination with other compounds of the present disclosure, or in combination with one or more, preferably one or two, other substances, either simultaneously or sequentially.

[0017] The compounds of the present disclosure are ENPP1 inhibitors and can regulate STING activity in vivo, and can be used to treat or prevent ENPP1-mediated diseases or disorders, particularly cancer, or infectious diseases or disorders. Thus, the present disclosure provides selective extracellular inhibition of ENPP1 activity to increase extracellular levels of cGAMP and activate the stimulator of interferon genes (STING) pathway. For example, the use of the compounds of the present disclosure to enhance STING-mediated responses in subjects, and the method of using the compounds of the present disclosure to modulate immune responses in subjects.

[0018] The compounds of the present disclosure may be used in therapy.

[0019] The compounds of the present disclosure may be used in the preparation of a medicament or drug for the treatment or prevention of an ENPP1 mediated disease or disorder, in particular cancer, or an infection or disorder.

[0020] The present disclosure further relates to a method of inhibiting ENPP1 receptor activity in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of an ENPP1 inhibitor, such as a compound of the present disclosure or a pharma- ceutically acceptable salt thereof.

[0021] In one embodiment of the present disclosure, the present disclosure provides a method of treating or preventing an ENPP1 mediated disease or disorder, comprising administering to a patient in need thereof an effective amount of a first therapeutic agent and an optional second therapeutic agent, wherein said first therapeutic agent is a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, and said second therapeutic agent is one or more other therapeutic agents.

[0022] In another embodiment of the present disclosure, the present disclosure relates to a method of treating or preventing an ENPP1 mediated disease or disorder, such as cancer, or an infectious disease or condition, comprising administering to an individual a therapeutically effective amount of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof.

[0023] Preferred methods of the present disclosure treat certain cancers, including breast cancer, lung cancer, glioblastoma, brain and spinal cancer, head and neck cancer, skin cancer, reproductive system cancer, digestive system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcoma, midline carcinoma, and cancer of unknown primary.

[0024] Another preferred method of the present disclosure treats an ENPP1 mediated infection, including herpes simplex virus infection, vaccinia virus infection, adenovirus infection, human papillomavirus infection, hepatitis B virus infection, hepatitis D virus infection, human immunodeficiency virus infection, human cytomegalovirus infection, dengue virus infection, Ebola virus infection, Marburg virus infection, Zika virus infection, Listeria monocytogenes infection, Mycobacterium tuberculosis infection, Francisella novicida infection, Legionella pneumophila infection, Chlamydia trachomatis infection, Streptococcus pneumoniae infection, and Neisseria gonorrhoeae infection.

[0025] The present disclosure also provides a combination formulation, product or kit comprising the compound of the present disclosure defined above or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more other active agents, either simultaneously, separately or sequentially, for use in an anti-cancer therapy.

[0026] Implementation

[0027] Specifically, the present disclosure provides the following embodiments.

[0028] In one aspect, the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof:

[0029] [ka] however, JPEG2024533433000004.jpg414 is a single bond or a double bond, X is N or CR 0 and X 1 are N, O, S, and CR. 1 or a bond, X 2 are N, O, S, and NR 2 , or CR 2 and X 3 are N, O, S, and NR 3 , or CR 3 and X 4 are N, O, S, and NR 4 , or CR 4 and X 5 is N or CR 5 and Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, NR 6 , or CR 7 R 8 and L is a bond, NR a , -NR x -CHR y - or (CR9 R 10 ) m and m is 1 or 2; R 0 , R 5 are each independently hydrogen, halogen, CN, OH, NO2, NR b R c , C1-C6 alkyl, C3-C6 cycloalkyl, -SO2R a , -C(O)OR a , -C(O)NR b R c and C1-C6 alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; R 1 , R 2 are each independently hydrogen, halogen, CN, OH, NO2, NR b R c , C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; R 3 , R 4 are each independently hydrogen, halogen, CN, OH, NO2, NR b R c , =O, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; R 6 is selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen; R 7 , R 8 are each independently hydrogen, halogen, OH, CN, NO2, NR a, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; or R 7 and R 8 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with halogen, or N, NR a , O, and S(O) p forming a 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from R 9 , R 10 are each independently hydrogen, halogen, CN, OH, NO2, NR a R b , C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, carbon atoms and N, NR a , O, and S(O) p and 4- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxy, and CN; and each of which is substituted with 0 to 3 substituents independently selected from halogen, C1 to C4 alkyl, C3 to C6 cycloalkyl, and OR. a and is substituted with 0 to 3 substituents independently selected from or R 9 and R 10 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with halogen, or N, NR a , O, and S(O) p forming a 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from Ring A is C4~C 10cycloalkyl, 4- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, where Ring A is optionally selected from halogen, CN, OH, NO, NR b R c , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and C1-C3 haloalkyl; Or, L together with ring A forms a 5- to 10-membered partially saturated heterocycle containing at least one heteroatom selected from C4-C8 cycloalkyl, N, O, or S, a 6- to 10-membered aryl, or a 5- to 7-membered heteroaryl, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted one or more times with substituents independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy; or Y together with ring A forms a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl, wherein the heterocycle, aryl, and heteroaryl are optionally substituted one or more times with substituents independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy; R a , R b , R c are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and benzyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen; or R b and R c together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocycloalkyl optionally substituted with halogen; R x , R y are each independently selected from hydrogen and C1-C4 alkyl, or R x and R yform a 4- to 8-membered heterocycloalkyl together with the carbon and nitrogen atoms to which they are attached, and p is 1 or 2; X 1 ~X 4 Each is CR n Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, or CH2, where R n X 1 For R 1 , X 2 For R 2 , X 3 For R 3 , X 4 For R 4 It is.

[0030] In one particular embodiment of the present disclosure, X 1 is N, O, S, or CR 1 and preferably, X 1 is N or CR 1 It is.

[0031] In another particular embodiment of the present disclosure, X 1 is N.

[0032] In another particular embodiment of the present disclosure, X 1 CR 1 It is.

[0033] In another particular embodiment of the present disclosure, X 1 is a bond or CR 1 It is.

[0034] In another particular embodiment of the present disclosure, X 1 is a bond.

[0035] In some embodiments of the present disclosure, X 1 is CR 1 and Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, or CR 7 R 8and preferably, Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, or CH2.

[0036] In some other embodiments of the present disclosure, X 1 is CR 1 And X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 When Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, or CH2.

[0037] In this specification, R n As far as it is mentioned, X 1 For R 1 , X 2 For R 2 , X 3 For R 3 , X 4 For R 4 Represents.

[0038] In some further embodiments of the present disclosure, R 0 , R 5 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with 0-3 halogens. 0 , R 5 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with 0-3 halogens. More preferably, R 0 , R 5 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, and C1-C3 alkyl.

[0039] In some further embodiments of the present disclosure, R 1 is selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl, preferably selected from hydrogen, halogen, CN, OH, NH2, C1-C3 alkyl, more preferably R 1 is selected from hydrogen, halogen, CN, and OH.

[0040] In some further embodiments of the present disclosure, R 2 is selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl, preferably selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy, each of said alkyl, cycloalkyl, and alkoxy being optionally substituted with 0-3 halogens. More preferably, R 2 is selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy.

[0041] In some further embodiments of the present disclosure, R 3 , R 4 are each independently selected from hydrogen, halogen, CN, OH, NO, NH, C1-C4 alkyl, =O, C3-C6 cycloalkyl, and C1-C3 alkoxy, wherein the alkyl, cycloalkyl, and alkoxy are each optionally substituted with 0-3 halogens, and preferably R 3 , R 4 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, =O, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, and C1-C3 haloalkyl. More preferably, R 3 is selected from hydrogen, halogen, OH, ═O, C1-C3 alkyl, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C1-C3 haloalkyl.

[0042] In some embodiments of the present disclosure, R 3 , R 4 are each independently selected from =O.

[0043] In some particular embodiments, X 3 is -C(=O)- and X 4 is CH.

[0044] In other particular embodiments, X 4 is -C(=O)- and X 3 is CH.

[0045] In some further embodiments of the present disclosure, R 1 , R 2 , R 3 , R 4 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, and C1-C4 haloalkyl, preferably selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C1-C2 haloalkyl, more preferably selected from H, F, Cl, CN, OH, NO2, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 2,2-difluoromethyl, 1,2-difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl.

[0046] In some further embodiments of the present disclosure, R 1 is hydrogen or halogen, R 2 is selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy; R 3 is hydrogen, halogen, OH, =O, NR b R c , C1-C3 alkyl, and C1-C3 alkoxy; R 4is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C1-C4 haloalkyl, preferably R 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl.

[0047] In some further embodiments of the present disclosure, R 1 is hydrogen or halogen, R 2 is selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy; R 3 is selected from hydrogen, halogen, OH, ═O, C1-C3 alkyl, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy. 0 , R 5 are each independently selected from hydrogen, halogen, CN, and C1-C6 alkyl.

[0048] In some further embodiments of the present disclosure, R 0 is selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; R 1 is hydrogen or halogen, R 2 is selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy; R 3 is selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy; R 5 is selected from hydrogen, halogen, CN, and C1-C4 alkyl.

[0049] In some further embodiments of the present disclosure, R 1 is hydrogen or halogen, R 2 is selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy; R 3 is hydrogen, halogen, OH, =O, NRb R c , C1-C3 alkyl, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, and C1-C3 alkyl. 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl.

[0050] In some further embodiments of the present disclosure, R 1 is hydrogen or halogen, R 2 is selected from hydrogen, halogen, and C1-C3 alkoxy; R 3 is selected from hydrogen, halogen, OH, and C1-C3 alkoxy; R 4 is selected from hydrogen and halogen. 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl.

[0051] In some further embodiments of the present disclosure, R 1 is hydrogen or halogen, R 2 is selected from hydrogen, halogen, OH, and C1-C3 alkoxy; R 3 is selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, and C1-C3 alkoxy, preferably R 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl. More preferably, R 3 is selected from hydrogen, halogen, OH, and C1-C3 alkoxy.

[0052] In some further embodiments of the present disclosure, R 2 is selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy; R 3 is selected from hydrogen, OH, and halogen; R 4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, and C1-C3 haloalkyl, preferably R 5is selected from hydrogen, halogen, CN, and C1-C6 alkyl.

[0053] In one particular embodiment of the present disclosure, X is N or X 5 is N.

[0054] In another particular embodiment of the present disclosure, X 5 is N.

[0055] In another particular embodiment of the present disclosure, X is N.

[0056] In some embodiments of the present disclosure, Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, NR 6 , or CR 7 R 8 where R 6 is selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R 7 and R 8 are each independently selected from hydrogen, halogen, OH, CN, NO2, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy. Preferably, Y is O, NR 6 , or CR 7 R 8 It is.

[0057] In some embodiments of the present disclosure, Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, or CR 7 R 8 , preferably O, -C(=O)-, or CR 7 R 8 , more preferably O or CR 7 R 8 More preferably, R 7 , R 8 are each independently selected from hydrogen and C1-C3 alkyl.

[0058] In some embodiments of the present disclosure, Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, or CH2.

[0059] In some embodiments of the present disclosure, Y is NR 6 and R 6 is selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl. 6 is selected from hydrogen and C1-C3 alkyl.

[0060] In some embodiments of the present disclosure, Y together with ring A forms a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl, wherein the heterocycle, aryl, and heteroaryl are optionally substituted one or more times with substituents independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy; Y is NR 6 and R 6 is C1-C4 alkyl, and R 6 forms, together with the nitrogen atom to which it is attached and ring A, a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl; or Y is CR 7 R 8 And R 7 or R 8 together with the carbon atom to which it is attached and ring A, forms a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl.

[0061] In some embodiments of the present disclosure, Y together with ring A forms a 7- to 10-membered partially saturated bicyclic heterocycle, naphthyl, or a 7- to 10-membered bicyclic heteroaryl. Preferably, Y together with ring A forms dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydroindolyl, dihydrobenzothienyl, dihydrobenzothiazolyl, dihydrobenzopyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or tetrahydropyrido[3,4-b]pyrazinyl. More preferably, Y together with ring A forms dihydroindolyl.

[0062] In some embodiments of the present disclosure, Y is CR 7 R 8 where R 7 , R 8 are each independently selected from hydrogen, halogen, OH, CN, NO2, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy, preferably selected from hydrogen, and C1-C6 alkyl, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with 0-3 halogens.

[0063] In some other embodiments of the present disclosure, Y is CR 7 R 8 where R 7 and R 8 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with 0-3 halogens, or N, NR a , O, and S(O) p R a is selected from hydrogen, C1-C3 alkyl, and p is 1 or 2.

[0064] In some further embodiments of the present disclosure, Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, NR 6 , or CR 7 R 8 and R 6 is selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R 7 , R 8 are each independently selected from hydrogen and C1-C3 alkyl. More preferably, R 6 is selected from hydrogen, C1-C3 alkyl, R 7 , R 8 are each independently selected from hydrogen and C1-C3 alkyl; Preferably, Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, -NH-, -N(CH3)-, -N(ethyl)-, -N(propyl)-, -N(cyclopropyl)-, -N(cyclobutyl)-, -N(cyclopentyl)-, -CH2-, -CHF-, -CH(OH)-, -CH(CH3)-, -CH(OCH3)-, -CH(OEt)-, or -C(CH3)2-, and more preferably Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, -NH-, -N(CH3)-, -CH(CH3)-, or -CH2-.

[0065] In some embodiments of the present disclosure, Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, NH, or CH2, preferably Y is O, S, -S(=O)-, -S(=O)2-, NH, or CH2, more preferably Y is O, S, or NH.

[0066] In some further embodiments of the present disclosure, Y is O, NR 6 , or CR 7 R 8 and preferably, Y is O, NH, N(C 1~ C3 alkyl), CH2, CH(C 1~ C3 alkyl), or C(C 1~ C3 alkyl)(C 1~ C alkyl). More preferably, Y is O, NH, -NCH3, CH2, or -CHCH3.

[0067] In another particular embodiment of the present disclosure, Y is O.

[0068] In another particular embodiment of the present disclosure, Y is NH.

[0069] In some embodiments of the present disclosure, L is a bond, NR a , -NR x -CHR y -, CR 9 R 10 , or (CR 9 R 10)2. As something that can be understood, (CR 9 R 10 )2, for example, in -CH2-CH(CH3), two -CR 9 R 10 The units may be the same or different.

[0070] In some other embodiments, L is -NR x -CHR y - where R x , R y are each independently selected from hydrogen, C1-C4 alkyl, or R x and R y form a 4- to 8-membered heterocycloalkyl together with the carbon and nitrogen atoms to which they are attached. Preferably, a 4- to 6-membered heterocycloalkyl, for example,

[0071] [ka] Form.

[0072] In some embodiments of the present disclosure, R a is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and benzyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen. a is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C3-C6 halocycloalkyl, and benzyl. More preferably, R a is selected from hydrogen, C1-C3 alkyl, and benzyl.

[0073] In some embodiments of the present disclosure, R 9 , R 10 are each independently hydrogen, halogen, CN, OH, NH2, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, a carbon atom and N, NR a , O, and S(O) pand 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of hydrogen, halogen, OH, NH2, C1 to C8 alkyl, C3 to C8 cycloalkyl, C1 to C8 alkoxy, carbon atoms and N, NR a , O, and S(O) p and 4- to 8-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from:

[0074] In some further embodiments of the present disclosure, R 9 and R 10 together with the carbon atom to which they are attached, a C3-C6 cycloalkyl substituted with 0-3 halogens, or N, NR a , O, and S(O) p Preferably, R 9 and R 10 together with the carbon atom to which they are attached, C3-C6 cycloalkyl, or N, NR a , O, and S(O) p Form a 4- to 8-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from:

[0075] In one particular embodiment of the present disclosure, L is a bond.

[0076] In some embodiments of the present disclosure, L is a bond or (CR 9 R 10 ) m and m is 1 or 2. Preferably, L is CR 9 R 10 , or (CR 9 R 10 )2, more preferably L is CR 9 R 10 It is.

[0077] In some embodiments of the present disclosure, L is NR a , or (CR 9 R 10 ) mand m is 1 or 2. Preferably, L is NR a , or CR 9 R 10 and more preferably, L is NH or CR 9 R 10 It is.

[0078] In some embodiments of the present disclosure, L is NR a and R a is selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and cycloalkyl are each substituted with 0-3 halogens. a is selected from hydrogen and C1-C3 alkyl.

[0079] In some embodiments of the present disclosure, L is (CR 9 R 10 ) m and m is 1 or 2; R 9 , R 10 are each independently hydrogen, halogen, CN, OH, NO2, NH2, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, a carbon atom and N, NR a , O, and S(O) p and 1 to 2 heteroatoms selected from the group consisting of 4- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are each substituted with 0 to 3 substituents independently selected from halogen, hydroxy, and CN, and the aryl and heteroaryl are each independently selected from halogen, C1 to C4 alkyl, C3 to C6 cycloalkyl, OR a and is substituted with 0 to 3 substituents independently selected from Or R 9 and R 10together with the carbon atom to which they are attached form a C3-C6 cycloalkyl substituted with 0-3 halogens, or N, NR a , O, and S(O) p Form a 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from:

[0080] In some embodiments of the present disclosure, L is NH, or CR 9 R 10 and Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, NR 6 , or CR 7 R 8 and R 6 , R 7 , R 8 are each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, preferably R 6 , R 7 , R 8 are each independently selected from hydrogen, C1-C3 alkyl, and more preferably, L is CR 9 R 10 and R 6 , R 7 , R 8 are each independently selected from hydrogen and C1-C3 alkyl.

[0081] In one preferred embodiment of the present disclosure, wherein L is NR a , or CR 9 R 10 and Preferably, L is CR 9 R 10 where R 9 , R 10 are each independently selected from hydrogen, halogen, CN, OH, NO, NH, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy, 4- to 12-membered heterocycloalkyl containing carbon atoms and 1 to 2 heteroatoms selected from N, O, and S, or R 9 and R 10together with the carbon atom to which they are attached, are C3-C6 cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane) substituted with 0-3 halogens, or N, NR a , O, and S(O) p forming a 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from (e.g., oxetane, azetidine, thietane, tetrahydrofuran ring, pyrrolidine, tetrahydrothiophene ring, pyrazolidine, imidazolidine, thiazolidine, oxazolidine, piperidine ring, tetrahydropyran ring, piperazine ring, hexahydropyrimidine ring, oxazinane, pyridazinane, morpholine ring, thiomorpholine ring, thiophane, tetrahydropyran ring, thiane, oxepane, azepane, or thiepane); Or L is CR 9 R 10 where R 9 , R 10 are each independently selected from hydrogen, halogen, CN, OH, C1-C6 alkyl, and C1-C6 alkoxy, or R 9 and R 10 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane); Or, L is -CH2-, -CH(OH)-, -CHF-, -CH(CN)-, -CH(CH3)-, -CH(OCH3)-, -CH(OEt)-, -C(CH3)2-, - CH(CH(CH3)2)-, -CH(CH2CH(CH3)2)-, -C(CH2CH(CH3)2)2-, -C(CH(CH3)2)2-, -C(CH2CH3)2- and

[0082] [ka] is selected from.

[0083] Preferably, L is -CH2-, -CH(OH)-, -CHF-, -CH(CH3)-, -CH(OCH3)-, -CH(OEt)-, -C(CH3)2-, -CH(CH(CH3)2)-, -CH(CH2CH(CH3)2)-, -C(CH2CH(CH3)2)2-, -C(CH2CH3)2-,

[0084] [ka] is selected from.

[0085] In some other embodiments of the present disclosure, L is (CR 9 R 10 )2. Preferably, L is -CH2CH2-, -CH2CH(CH3)-, -CH(CH3)CH2-, -CH2CHF-, -CH2CH(OCH3)-.

[0086] In some embodiments of the present disclosure, ring A is selected from C4-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, and preferably ring A is optionally selected from halogen, CN, OH, NO2, NR b R c , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and C1-C3 haloalkyl, each of which may be substituted one or more times, for example once or twice, with a substituent independently selected from R b , R c are each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and cycloalkyl are each substituted with 0-3 halogens; or R b and R ctogether with the nitrogen atom to which they are attached form a 3- to 6-membered heterocycloalkyl substituted with 0-3 halogens. Further, ring A is optionally substituted one or more times, for example one or two times, with a substituent independently selected from halogen, CN, OH, NH2, C1-C4 alkyl, C1-C4 alkoxy, and C1-C3 haloalkyl. Still further, ring A is optionally substituted one or two times with a substituent independently selected from halogen, CN, C1-C4 alkyl, and C1-C4 alkoxy.

[0087] Preferably, ring A is optionally substituted one or more times, for example one or two times, with a substituent independently selected from F, Cl, CN, OH, NO2, NH2, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and C1-C3 haloalkyl; more preferably, ring A is optionally substituted one or more times, for example one or two times, with a substituent independently selected from F, Cl, CN, OH, NO2, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C3 alkoxy.

[0088] In one preferred embodiment of the present disclosure, ring A is an optionally substituted or unsubstituted cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, thiazolidine, pyrrole ring, furan ring, thiophene ring, pyrazole ring, thiazole ring, oxazole ring, imidazole ring, tetrahydrofuran ring, tetrahydrothiophene ring, pyran ring, pyrazine ring, tetrahydropyran ring, piperidine ring, hexahydropyrimidine, dihydrofuran ring, dihydrothiophene ring, dihydroimidazole ring, dihydropyrazole ring, dihydropyrrole ring, dihydroindole ring, dihydroisoindole ring, dihydropyran ring, dihydropyridine ring, dihydropiperazine ring, piperazine ring, benzene ring, pyridine ring, pyrimidine ring, naphthalene ring, quinoline ring, isoquinoline ring, indole ring, isoindole ring, indazole ring, or benzimidazole ring; Preferably, ring A is an optionally substituted or unsubstituted cyclopentane, cyclohexane, pyrrolidine, imidazolidine, pyrazole ring, pyrrole ring, imidazole ring, furan ring, thiophene ring, pyran ring, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyran ring, piperidine ring, pyrazine ring, piperazine ring, benzene ring, pyridine ring, pyrimidine ring, or naphthalene ring; More preferably, ring A is an optionally substituted or unsubstituted cyclopentane, cyclohexane, pyrrolidine, piperidine ring, pyrimidine ring, benzene ring, pyridine ring, piperazine ring, imidazole ring, pyrazole ring, or naphthalene ring; More preferably, ring A is a cyclopentane, cyclohexane, pyrrolidine, piperidine ring, pyrimidine ring, benzene ring, pyridine ring, piperazine ring, imidazole ring, tetrahydropyrrole ring, pyrazole ring, or naphthalene ring substituted once or twice with F, Cl, CN, OH, NO2, NH2, C1-C3 alkyl, or C1-C3 alkoxy.

[0089] In some embodiments of the present disclosure, ring A is optionally substituted one or more times, for example one or two times, with a substituent independently selected from halogen, CN, OH, NO2, NH2, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl, preferably ring A is optionally substituted one or more times, for example one or two times, with a substituent independently selected from F, Cl, CN, OH, NO2, NH2, C1-C3 alkyl, and C1-C3 alkoxy.

[0090] In some embodiments of the present disclosure, Ring A is selected from:

[0091] [ka] However, R 11may be the same or different and are independently selected from halogen, CN, OH, NO2, NH2, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkyl, and q is 0, 1, or 2. Preferably, R 11 is selected from F, Cl, CN, C1-C4 alkyl, or C1-C4 alkoxy; R a is selected from hydrogen and C1-C4 alkyl, and q is 0, 1, or 2.

[0092] In some embodiments of the present disclosure, L together with ring A forms a 5- to 10-membered partially saturated heterocycle containing at least one heteroatom selected from C4-C8 cycloalkyl, N, O, or S, a 6- to 10-membered aryl, or a 5- to 7-membered heteroaryl, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted one or more times with a substituent independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy. Preferably, the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted one or more times with a substituent independently selected from halogen, C1-C3 alkyl, and C1-C3 alkoxy.

[0093] In some embodiments of the present disclosure, L together with ring A forms a 5- to 10-membered partially saturated heterocycle containing at least one heteroatom selected from N, O, or S, a 6- to 10-membered aryl, or a 5- to 7-membered heteroaryl, wherein the heterocycle, aryl, and heteroaryl are optionally substituted once or twice with substituents independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy.

[0094] In some embodiments of the present disclosure, L, together with ring A, is an optionally substituted or unsubstituted dihydrobenzofuran ring, dihydroisobenzofuran ring, dihydrobenzothiophene ring, dihydroindole ring, dihydroisoindole ring, dihydrobenzimidazole ring, dihydrobenzoxazole ring, dihydrobenzothiazole ring, dihydrobenzopyran ring, dihydroisobenzopyran ring, tetrahydroquinoline ring, tetrahydroisoquinoline ring, 2,3-dihydro-1H -pyrrolo[2,3-b]pyridine ring, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine ring, tetrahydropyrido[3,4-b]pyrazine ring, dihydroindene ring, tetrahydronaphthalene ring, 2,3-dihydrofura[2,3-b]pyridine ring, 2,3-dihydrofura[3,2-b]pyridine ring, each of which is preferably optionally substituted one or more times with a substituent independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy.

[0095] More preferably, L together with ring A forms an optionally substituted or unsubstituted dihydrobenzofuran ring, dihydroisobenzofuran ring, dihydroindole ring, dihydroisoindole ring, dihydrobenzopyran ring, dihydroisobenzopyran ring, tetrahydroquinoline ring, tetrahydroisoquinoline ring, dihydroindene ring, tetrahydronaphthalene ring, 2,3-dihydrofura[2,3-b]pyridine ring, or 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring, each of which is further preferably optionally substituted one or more times with a substituent independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy.

[0096] In one preferred embodiment of the present disclosure, L together with ring A forms a 5- to 10-membered partially saturated heterocycle containing at least one heteroatom selected from the following N, O, or S, a 6- to 10-membered aryl, or a 5- to 7-membered heteroaryl:

[0097] [ka] wherein M and T may be the same or different and each independently represents N or C; R 11 may be the same or different and are independently selected from halogen, CN, OH, NH, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl, and q is 0, 1, or 2. Preferably, R 11 is selected from F, Cl, CN, C1-C3 alkyl, or C1-C3 alkoxy; and q is 0, 1, or 2.

[0098] In one preferred embodiment of the present disclosure, Y together with ring A forms a group selected from:

[0099] [ka] However, each M1 is independently N, CH, or C(C 1~ C4 alkyl). Preferably, Y is NR 6 and R 6 is C1-C4 alkyl, and R 6 together with the nitrogen atom to which it is attached and ring A, form a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl, wherein said heterocycle, aryl, and heteroaryl are optionally substituted one or more times with substituents independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy.

[0100] Furthermore, Y together with ring A forms a group selected from the following:

[0101] [ka]

[0102] The present disclosure further provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof:

[0103] [ka] however, JPEG2024533433000013.jpg414 is a single bond or a double bond, X is N or CR 0 and X 1 are N, O, S, and CR. 1 or a bond, X 2 are N, O, S, and NR 2 , or CR 2 and X 3 are N, O, S, and NR 3 , or CR 3 and X 4 are N, O, S, and NR 4 , or CR 4 and X 5 is N or CR 5 and Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, NR 6 , or CR 7 R 8 and L is a bond, NR a , -NR x -CHR y - or (CR 9 R 10 ) m and m is 1 or 2; R 0 , R 5 are each independently hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, -SO2R a , -C(O)OR a , -C(O)NR b R c and C1-C4 alkoxy, wherein said alkyl, cycloalkyl, alkoxy are each optionally substituted with halogen; R 1 , R 2are each independently selected from H, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R 3 , R 4 are each independently selected from H, halogen, CN, OH, NO2, NH2, =O, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; R 6 is selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl; R 7 , R 8 are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy; R 9 , R 10 are each independently hydrogen, halogen, CN, OH, NH2, NO2, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, a carbon atom and 1N, NR a , O, and S(O) p and 4- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, each of which is substituted with 0 to 3 substituents independently selected from halogen, OH, and CN; and each of which is substituted with 0 to 3 substituents independently selected from halogen, C1 to C4 alkyl, C3 to C6 cycloalkyl, and OR. a and is substituted with 0 to 3 substituents independently selected from Or R 9 and R 10 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with halogen, or N, NR a , O, and S(O) p forming a 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from Ring A is selected from C4-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, where Ring A is optionally selected from halogen, CN, OH, NO2, NR b R c , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, and C1-C3 haloalkyl; Or, L together with ring A forms a 5- to 10-membered partially saturated heterocycle containing at least one heteroatom selected from C4-C8 cycloalkyl, N, O, or S, a 6- to 10-membered aryl, or a 5- to 7-membered heteroaryl, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted one or more times with substituents independently selected from halogen, C1-C3 alkyl, and C1-C3 alkoxy; or Y together with ring A forms a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl, wherein the heterocycle, aryl, and heteroaryl are optionally substituted one or more times with substituents independently selected from halogen, C1-C4 alkyl, and C1-C4 alkoxy; R a , R b , R c are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and benzyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen, or R b and R c together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocycloalkyl optionally substituted with halogen; R x , R y are each independently selected from hydrogen and C1-C4 alkyl, or R x and R yform a 4- to 8-membered heterocycloalkyl together with the carbon and nitrogen atoms to which they are attached, and p is 1 or 2; X 1 ~X 4 Each is CR n Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, or CH2, where R n X 1 For R 1 , X 2 For R 2 , X 3 For R 3 , X 4 For R 4 It is.

[0104] In one particular embodiment of the present disclosure, R 1 is hydrogen or a halogen, R 2 is selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy; R 3 is hydrogen, halogen, OH, NR b R c , ═O, C1-C3 alkyl, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C1-C4 haloalkyl; R 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl.

[0105] In another particular embodiment of the present disclosure, R 1 is hydrogen or a halogen, R 2 is selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy; R 3 is selected from hydrogen, halogen, OH, ═O, C1-C3 alkyl, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, and C1-C4 haloalkyl; R 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl; R 6 , R 7 , R 8 are each independently selected from hydrogen and C1-C3 alkyl.

[0106] In another particular embodiment of the present disclosure, X 1 , X 2 , X 3 , X 4 At least one of N, O, S and NR n (if present), where R n X 1 For R 1 , X 2 For R 2 , X 3 For R 3 , X 4 For R 4 It is.

[0107] In another particular embodiment of the present disclosure, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 At least one of is independently N and NR n (if present), where R n X 1 For R 1 , X 2 For R 2 , X 3 For R 3 , X 4 For R 4 Specifically, the present disclosure provides a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof:

[0108] [ka] however, X 1 , X 2 , X 3 , X 4 At least one of is independently N or NR n is selected from the group consisting of X 1 , X 2 , X 3 , X 4 At least X of 1 is N, or at least X 2 is N or NR 2 or at least X 3 is N or NR 3 or at least X 4 is N or NR 4 and X 5 , X, Y, A, and L are each defined as in formula (I).

[0109] In one particular embodiment of the present disclosure, X 1 , X 2 , X 3 , X 4 At least one of is independently N or NR n and R 1 is hydrogen or a halogen, R 2 is selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy; R 3 is hydrogen, halogen, OH, =O, NR b R c , C1-C3 alkyl, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, and C1-C3 alkyl; R 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl; R a is selected from hydrogen, C1-C3 alkyl, Preferably, R 6, R 7 , R 8 are each independently selected from hydrogen and C1-C3 alkyl.

[0110] In one preferred embodiment of the present disclosure, X 1 , X 2 , X 3 , X 4 At least one of is independently N or NR n and R 1 is hydrogen or a halogen, R 2 is selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy; R 3 is selected from hydrogen, halogen, OH, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, and C1-C3 alkoxy; R 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl; R a is selected from hydrogen and C1-C3 alkyl.

[0111] In another particular embodiment of the present disclosure, X 1 , X 2 , X 3 , X 4 is independently selected from N. Specifically, the present disclosure provides compounds of formula (Ia1), (Ia2), (Ia3), or (Ia4), or a pharma- ceutically acceptable salt thereof:

[0112] [ka] However, X 1 , X 2 , X 3 , X 4 is independently selected from N; The other variables are as defined in formula (I).

[0113] In one particular embodiment of the present disclosure, X 1 is N or CR 1 Preferably, X 1 is N or CR 1 And X 2 , X 3 , X 4 At least one of is independently N and NR n is selected from.

[0114] In one particular embodiment of the present disclosure, X 1 is N. Preferably, X 1 is N and X 3 is CR 3 It is.

[0115] In another particular embodiment of the present disclosure, X 2 is N or NR 2 Preferably, X 2 is N, more preferably X 2 is N and X 3 is CR 3 and more preferably, X 2 is N and X 3 is CR 3 And X 4 is CR 4 and most preferably, X 2 is N and X 3 is CR 3 and X 4 is CR 4 And X 1 is CR 1 It is.

[0116] In another particular embodiment of the present disclosure, X 3 is N or NR 3 Preferably, X 3 is N, more preferably X 3 is N and X 4 is CR 4 and more preferably, X 3 is N and X 4 is CR4 And X 2 is CR 2 and most preferably, X 3 is N, X 4 is CR 4 and X 2 is CR 2 And X 1 is CR 1 It is.

[0117] In another particular embodiment of the present disclosure, X 4 is N or NR 4 Preferably, X 4 is N, more preferably X 4 is N and X 3 is CR 3 and more preferably, X 4 is N and X 3 is CR 3 And X 2 is CR 2 and most preferably, X 4 is N and X 3 is CR 3 and X 2 is CR 2 And X 1 is CR 1 It is.

[0118] In one particular embodiment of the present disclosure, X 1 , X 2 , X 3 , X 4 Only one of the groups is independently N and NR n where R n X 1 For R 1 , X 2 For R 2 , X 3 For R 3 , X 4 For R 4 In some particular embodiments, X 1 is N and X 2 is CR 2 and X 3 is CR3 and X 4 is CR 4 It is.

[0119] In other particular embodiments, X 2 is N, O, S, or NR 2 And X 1 is a bond or CR 1 and X 3 is CR 3 and X 4 is CR 4 and preferably, X 2 is N or NR 2 And X 1 is a bond or CR 1 and X 3 is CR 3 and X 4 is CR 4 It is.

[0120] In other particular embodiments, X 3 is N, O, S, or NR 3 And X 1 is a bond or CR 1 and X 2 is CR 2 and X 4 is CR 4 and preferably, X 3 is N or NR 3 And X 1 is a bond or CR 1 and X 2 is CR 2 and X 4 is CR 4 It is.

[0121] In other particular embodiments, X 4 is N, O, S, or NR 4 And X 1 is a bond or CR 1 and X 2 is CR 2 and X 3 is CR 3 and preferably, X 4is N or NR 4 And X 1 is a bond or CR 1 and X 2 is CR 2 and X 3 is CR 3 It is.

[0122] In another particular embodiment of the present disclosure, X 1 , X 2 , X 3 , X 4 at least two of are independently N and NR n is selected from.

[0123] In some particular embodiments, X 1 is N and X 2 is N or NR 2 It is.

[0124] In other particular embodiments, X 1 is N and X 3 is N or NR 3 It is.

[0125] In other particular embodiments, X 1 is N and X 4 is N or NR 4 It is.

[0126] In other particular embodiments, X 2 is N or NR 2 And X 3 is N or NR 3 It is.

[0127] In other particular embodiments, X 2 is N or NR 2 And X 4 is N or NR 4 It is.

[0128] In other particular embodiments, X 3 is N or NR 3 And X4 is N or NR 4 It is.

[0129] In other particular embodiments, X 2 is N or NR 2 And X 3 is N or NR 3 and X 4 is N or NR 4 It is.

[0130] In one particular embodiment of the present disclosure, X 3 is NR 3 And X 4 is carbonyl -C(=O)-. Preferably, X 3 is NH and X 4 is -C(=O)-.

[0131] In one particular embodiment of the present disclosure, X 4 is NR 4 And X 3 is carbonyl -C(=O)-. Preferably, X 4 is NH and X 3 is -C(=O)-.

[0132] In another particular embodiment of the present disclosure, X 1 is a bond, and specifically, the present disclosure provides a compound of formula (Ib), or a pharma- ceutically acceptable salt thereof:

[0133] [ka] however, X 2 , X 3 , X 4 , X 5 , X, Y, A, and L are each defined as in formula (I).

[0134] In one particular embodiment of the present disclosure, X 1 is a bond, and R 2is selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy; R 3 is selected from hydrogen, OH, and halogen; R 4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, and C1-C3 haloalkyl; R 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl; R 6 is selected from hydrogen, C1-C3 alkyl, R 7 , R 8 are each independently selected from hydrogen and C1-C3 alkyl. In one particular embodiment of the present disclosure, X 1 is a bond and X 2 , X 3 , X 4 At least one of is independently N, O, S, or NR n is selected from the group consisting of X 1 If is a bond, then X 2 , X 3 , X 4 At least X of 2 is N, O, S, or NR 2 or at least X 3 is N, O, S, or NR 3 or at least X 4 is N, O, S, or NR 4 It is.

[0135] In one particular embodiment of the present disclosure, X 1 is a bond and X 2 , X 3 , X 4 At least one of is independently N or NR n is selected from the group consisting of X 1 If is a bond, then X 2 , X 3 , X 4 At least X of 2 is N or NR 2or at least X 3 is N or NR 3 or at least X 4 is N or NR 4 It is.

[0136] In some particular embodiments, X 1 If is a bond, then X 2 is N, O, S, or NR 2 and preferably, X 1 is a bond and X 2 is N or NR 2 It is.

[0137] In other particular embodiments, X 1 If is a bond, then X 3 is N, O, S, or NR 3 and preferably, X 1 is a bond, and X 3 is N or NR 3 and more preferably, X 1 is a bond, and X 3 is N.

[0138] In other particular embodiments, X 1 If is a bond, then X 4 is N, O, S, or NR 4 and preferably, X 1 is a bond and X 4 is N, O, or NR 4 and more preferably, X 1 is a bond, and X 4 is NR 4 It is.

[0139] In one preferred embodiment of the present disclosure, X 1 is a bond and X 3 N, R 2 is selected from hydrogen, halogen, and C1-C3 alkyl; R 4is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C4 cycloalkyl, and C1-C3 haloalkyl; R 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl.

[0140] In another particular embodiment of the present disclosure, X 1 If is a bond, then X 2 , X 3 , X 4 At least two of are independently N, O, S, or NR n Preferably, X 1 is a bond, and X 2 , X 3 , X 4 At least two of are independently N or NR n is selected from.

[0141] In some particular embodiments, X 1 If is a bond, then X 2 , X 3 , X 4 one of which is N, and at least one of the remaining is independently N, O, S, or NR n is selected from.

[0142] In another particular embodiment of the present disclosure, X 1 If is a bond, then X 2 , X 3 , X 4 are all independently N, O, S, and NR n Preferably, X 1 is a bond, and X 2 , X 3 , X 4 are all independently N and NR n is selected from.

[0143] In some particular embodiments, X 1 is a bond, and X 2 is N, O, S, or NR 2 And X 3is N or NR 3 Preferably, X 1 is a bond and X 2 is O or NR 2 and X 3 is N. More preferably, X 1 is a bond, and X 2 is NR 2 and X 3 is N and X 4 is CR 4 It is.

[0144] In other particular embodiments, X 1 is a bond, and X 3 is N, O, S, or NR 3 And X 4 is N or NR 4 Preferably, X 1 is a bond and X 3 is N and X 4 is NR 4 More preferably, X 1 is a bond, and X 3 is N and X 4 is NR 4 And X 2 is CR 2 It is.

[0145] In other particular embodiments, X 1 is a bond, and X 2 is N, O, S, or NR 2 And X 4 is N, O, S, or NR 4 Preferably, X 1 is a bond, and X 2 is O or N, and X 4 is N, O, S, or NR 4 More preferably, X 1 is a bond and X 2 is N and X 4 is S, N, or NR 4 It is.

[0146] In other particular embodiments, X1 is a bond, and X 3 is N and X 4 is N or NR 4 or X 2 is N, O, or NR 2 Preferably, X 1 is a bond, and X 3 is N and X 4 is NR 4 and more preferably, X 1 is a bond, and X 3 is N and X 4 is NR 4 And X 2 is CR 2 and Or, X 1 is a bond, and X 3 is N and X 2 is O or NR 2 and preferably, X 1 is a bond, and X 3 is N and X 2 is O or NR 2 And X 4 is CR 4 It is.

[0147] In another particular embodiment of the present disclosure, X 1 If is a bond, then X 2 , X 3 , X 4 are all independently N and NR n is selected from the group consisting of X 1 is a bond, and X 2 is N or NR 2 And X 3 is N or NR 3 and X 4 is N or NR 4 Preferably, X 1 is a bond and X 2 is N and X 3 is N and X 4 is NR 4 It is.

[0148] In another particular embodiment of the present disclosure, X 1 is CR 1 Specifically, the present disclosure provides a compound of formula (Ic), or a pharma- ceutically acceptable salt thereof:

[0149] [ka] R 1 , X 2 , X 3 , X 4 , X 5 , X, Y, A, and L are each defined as in formula (I).

[0150] In one particular embodiment of the present disclosure, X 1 is CR 1 And X 2 , X 3 , X 4 At least one of is independently N and NR n is selected from the group consisting of X 1 is CR 1 And X 2 , X 3 , X 4 At least X of 2 is N or NR 2 or at least X 3 is N or NR 3 or at least X 4 is N or NR 4 It is.

[0151] In some particular embodiments, X 1 CR 1 If X 2 is N or NR 2 Preferably, X 1 CR 1 and X 2 is N or NR 2 If X 3 is CR 3 More preferably, X 1 is CR 1 and X2 is N and X 3 is CR 3 It is.

[0152] In other particular embodiments, X 1 CR 1 If X 3 is N or NR 3 Preferably, X 1 is CR 1 and X 3 is N.

[0153] In other particular embodiments, X 1 CR 1 and X 3 is N or NR 3 If X 2 is CR 2 Preferably, X 1 CR 1 and X 3 is N or NR 3 If X 2 is CR 2 and X 4 is CR 4 More preferably, X 1 is CR 1 and X 3 is N and X 2 is CR 2 and X 4 is CR 4 It is.

[0154] In other particular embodiments, X 1 CR 1 If X 4 is N or NR 4 Preferably, X 1 CR 1 and X 4 is N or NR 4 If X 3 is CR 3 and more preferably, X 1 CR 1 If X 3 is CR 3 and X4 is N.

[0155] In another particular embodiment of the present disclosure, X 1 is CR 1 And X 2 , X 3 , X 4 All are CR n That is, X 1 is CR 1 And X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 Specifically, the present disclosure provides a compound of formula (Id), or a pharma- ceutically acceptable salt thereof:

[0156] [ka] wherein Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, or CH2; R 1 , R 2 , R 3 , R 4 , X 5 The variables X, A, and L are each as defined in formula (I).

[0157] In one particularly preferred embodiment of the present disclosure, X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 and Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, or CH2, and R 1 is hydrogen or a halogen, R 2 is selected from hydrogen, halogen, OH, and C1-C3 alkoxy; R 3is selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, and C1-C3 alkoxy; R 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl; Preferably, R 6 , R 7 , R 8 are each independently selected from hydrogen and C1-C3 alkyl.

[0158] In some particular embodiments, Y is O, S, -S(=O)-, -S(=O)2-, or -C(=O)-.

[0159] In other specific embodiments, Y is O, S, -S(=O)-, or -S(=O)2-.

[0160] In some particular embodiments, Y is O or CH2.

[0161] In another particular embodiment of the present disclosure, X 1 is CR 1 And X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 and Y is O, S, -S(=O)-, -S(=O)2-, -C(=O)-, or CH2, and R 1 is hydrogen or a halogen, R 2 is selected from hydrogen, halogen, OH, and C1-C3 alkoxy; R 3 is selected from hydrogen, halogen, OH, C1-C3 alkyl, and C1-C3 alkoxy; R 4 is selected from hydrogen, halogen, and C1-C3 alkoxy; R 5is selected from hydrogen, halogen, CN, and C1-C6 alkyl; R 6 is selected from hydrogen, C1-C3 alkyl, R 7 , R 8 are each independently selected from hydrogen, C1-C3 alkyl, and preferably, Y is O or CH2.

[0162] In one particularly preferred embodiment of the present disclosure, the present disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof,

[0163] [ka] teeth,

[0164] [ka] is selected from.

[0165] Preferably,

[0166] [ka] is selected from.

[0167] More preferably,

[0168] [ka] is selected from.

[0169] In one preferred embodiment of the present disclosure, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein X 1 is a bond or CR 1 Specifically, the present disclosure provides the following compounds (Ie1), (Ie2), (Ie3), (Ie4), (Ie5), (Ie6), or pharma- ceutically acceptable salts thereof:

[0170] [ka] However, X 2 , R 3 , R 4 , R 5 , X, Y, A, and L variables are each as defined in formula (I).

[0171] Preferably, L is NR a , or (CR 9 R 10 ) m and m is 1 or 2. More preferably, L is CR 9 R 10 It is.

[0172] In one embodiment of the present disclosure, the compound of formula (I) is selected from the following example compounds: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0173] In another aspect, the disclosure provides methods of preparing the compounds of the disclosure.

[0174] In one embodiment, the present disclosure further provides intermediates for preparing the compounds of the present disclosure, as well as methods for their preparation.

[0175] In another aspect, the present disclosure provides a composition comprising at least one compound of the present disclosure or a pharma- ceutically acceptable salt thereof.

[0176] In one embodiment, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier, diluent, or excipient.

[0177] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the present disclosure, or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, crystalline form, solvate, hydrate, or prodrug thereof, and at least one pharma- ceutically acceptable carrier, diluent, or excipient. In some embodiments of the pharmaceutical composition, the pharmaceutical composition is formulated for any suitable route of administration, such as intravenous, intramuscular, oral, rectal, inhalation, nasal, topical, ocular, or otic administration. In other embodiments of the pharmaceutical composition, the pharmaceutical composition is a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, solution, emulsion, ointment, eye drop, or ear drop.

[0178] In another aspect, the present disclosure provides a drug combination product comprising at least one compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, and one or more other active agents.

[0179] In another aspect, the disclosure provides the use of a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, crystal form, solvate, hydrate, or prodrug thereof, in the preparation of a medicament for preventing, treating, or ameliorating a disorder or disease in a patient caused by a tumor or an infectious disease.

[0180] In one embodiment, the tumor or infection is caused by an alteration in the stimulator of interferon genes (STING).

[0181] In another embodiment, the disclosure provides the use of a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, crystal form, solvate, hydrate, or prodrug thereof, in the preparation of a medicament for preventing, treating, or ameliorating an ENPP1 mediated disease or disorder, such as cancer, or an infectious disease, or a symptom.

[0182] In another embodiment, the present disclosure provides compounds of the present disclosure for use in therapy, either alone or, optionally, in combination with other compounds of the present disclosure, and / or at least one other therapeutic agent, to treat an ENPP1-mediated disease or disorder.

[0183] In another embodiment, the present disclosure further provides the use of a compound of the present disclosure in the preparation of a medicament, said medicament alone or, optionally, in combination with other compounds of the present disclosure, and / or at least one other therapeutic agent, for treating an ENPP1 mediated disease or disorder.

[0184] In another embodiment, the disclosure provides a combined formulation of a compound of the disclosure and one or more additional therapeutic agents for use in therapy.

[0185] In another embodiment, the disclosure provides a combination of a compound of the disclosure with one or more additional therapeutic agents, used simultaneously or separately in a method of therapy.

[0186] In another embodiment, the present disclosure provides a combined preparation of a compound of the present disclosure and one or more additional therapeutic agents for simultaneous, separate or sequential use in treating an ENPP1-mediated disease or disorder. The compound may be administered as a pharmaceutical composition as described herein.

[0187] In another aspect, the disclosure provides a method of treating or preventing an ENPP1 mediated disease or disorder, comprising administering a therapeutically effective amount of a compound of the disclosure, or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, crystalline form, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition comprising same, to an individual in need thereof.

[0188] In one embodiment, the disclosure provides a method of treating an ENPP1 mediated disease or disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the disclosure, alone or optionally in combination with other compounds of the disclosure and / or at least one other therapeutic agent.

[0189] In another embodiment, the disclosure provides a method of treating an ENPP1 mediated disease or disorder, comprising administering to a patient in need thereof therapeutically effective amounts of a first therapeutic agent and a second therapeutic agent, wherein said first therapeutic agent is a compound of the disclosure and said second therapeutic agent is another compound of the disclosure and / or at least one other therapeutic agent.

[0190] In some embodiments of the present disclosure, the ENPP1-mediated disease or disorder includes, but is not limited to, a tumor, an infection, or a disorder, particularly a cancer, such as a recurrent cancer, a refractory cancer, or a metastatic cancer.

[0191] In another embodiment, the ENPP1 mediated disease or disorder is recurrent or refractory cancer.

[0192] In another embodiment, the ENPP1 mediated disease or disorder is metastatic cancer.

[0193] In another embodiment, the ENPP1 mediated disease or disorder is a tumor, particularly a solid tumor, such as breast cancer, lung cancer, glioblastoma, brain and spinal cancer, head and neck cancer, skin cancer, reproductive system cancer, digestive system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline carcinoma, and cancer of unknown primary origin.

[0194] In another embodiment, the ENPP1 mediated disease or disorder is a tumor, particularly a hematological malignancy, in particular a leukemia, lymphoma, or myeloma.

[0195] In another embodiment, the ENPP1 mediated disease or disorder is an infectious disease or disorder, including, but not limited to, herpes simplex virus infection, vaccinia virus infection, adenovirus infection, human papillomavirus infection, hepatitis B virus infection, hepatitis D virus infection, human immunodeficiency virus infection, human cytomegalovirus infection, dengue virus infection, Ebola virus infection, Marburg virus infection, Zika virus infection, Listeria monocytogenes infection, Mycobacterium tuberculosis infection, Francisella novicida infection, Legionella pneumophila infection, Chlamydia trachomatis infection, Streptococcus pneumoniae infection, and Neisseria gonorrhoeae infection.

[0196] In certain embodiments, compounds of the present disclosure have an IC of 5 μM or less according to the EED Alphascreen binding, LC-MS, and / or ELISA assays disclosed herein. 50 IC value, preferably 1 μM or less 50 value, more preferably 0.5 μM or less 50 IC value of 0.125 μM or less, more preferably 50 value, most preferably 0.1 μM or less 50 It has a value.

[0197] It should be understood that within the scope of the present disclosure, the technical features defined in the technical solution of the present disclosure and each technical feature specifically described below (for example, in the examples) may be combined with each other to form a novel or preferred technical solution. Due to space limitations, we will not repeat each one here. It is also understood that each element of the embodiment is an independent embodiment in itself.

[0198] Other features of the present disclosure will become apparent in the above description of exemplary embodiments, which are given to illustrate the present disclosure without intending to limit the same.

[0199] Explanation of terms

[0200] In this disclosure, the terms used in this disclosure have the following defined meanings unless expressly explained otherwise. Terms not expressly defined in this disclosure have the general meanings commonly understood by those of ordinary skill in the art.

[0201] As used in the context of this disclosure (particularly in the context of the claims), the terms "a," "an," "the," and similar terms are understood to include the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0202] A short side ("-") that is not between two letters or symbols represents a point of attachment of a substituent. For example, -O(C 1~ C alkyl) indicates that the group is linked to the remainder of the molecule via an oxygen atom. However, the "-" may be omitted if the point of attachment of a substituent such as halogen, hydroxy, etc. is obvious to one of ordinary skill in the art.

[0203] The base is a wavy line. JPEG2024533433000034.jpg412", a wavy line indicates the point of attachment of the group to the remainder of the molecule.

[0204] As used herein, " "JPEG2024533433000035.jpg314" means a single bond or a double bond. Those skilled in the art will recognize that depending on the circumstances, such as the valence of the relevant ring atoms and the linked groups, It is within the ability of one of ordinary skill in the art to determine whether JPEG2024533433000036.jpg314 represents a single or double bond. Those skilled in the art will appreciate that the ring involved may be saturated, partially saturated, or aromatic.

[0205] As used herein, "heteroatom" refers to a nitrogen (N), oxygen (O) or sulfur (S) atom, particularly nitrogen or oxygen, which may be substituted or unsubstituted, including their oxidized forms. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S-, -S(O)- and -S(O)2, where R is hydrogen, C1-C4 alkyl or a nitrogen protecting group (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, t-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). Unsatisfied heteroatoms are assumed to have sufficient hydrogen atoms to fill the bonds, unless otherwise stated.

[0206] As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine. Preferred halogens as substituents are fluorine and chlorine.

[0207] As used herein, "alkyl" refers to a fully saturated, linear or branched monovalent hydrocarbon group. The alkyl group preferably has 1 to 20 carbon atoms, more preferably 1 to 16, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The number before the alkyl group indicates the number of carbon atoms. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, "C1-C4 alkyl" refers to an alkyl group having 1 to 4 carbon atoms, and "C1-C3 alkyl" refers to an alkyl group having 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. This definition applies whether the term "alkyl" appears by itself or as part of another group, such as a haloalkyl, alkoxy, etc.

[0208] As used herein, "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing at least one double bond. Alkenyl preferably has 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. The number before alkenyl indicates the number of carbon atoms. Representative examples of alkenyl include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isoprenyl, hexenyl, heptenyl, octenyl, and the like.

[0209] As used herein, "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing at least one triple bond. Alkynyl preferably has 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. The number before alkynyl represents the number of carbon atoms. Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, isopentenyl, hexynyl, heptynyl, octynyl, and the like.

[0210] As used herein, "alkoxy" refers to an alkyl linked through an oxygen bridge, as defined herein, i.e., an alkyl-O- group, where the number before the alkoxy represents the number of carbon atoms. For example, "C 1~ "C6 alkoxy" means alkoxy having 1 to 6 carbon atoms, i.e., -OC 1~6 Represents alkyl, and "C 1~ "C4 alkoxy" means alkoxy having 1 to 4 carbon atoms, i.e., -OC 1~4 Represents alkyl, and "C 1~ "C3 alkoxy" means alkoxy having 1 to 3 carbon atoms, i.e., -OC 1~3 It represents an alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. The alkoxy preferably has about 1 to 6 carbon atoms, or about 1 to 4 carbon atoms, etc.

[0211] As used herein, "cycloalkyl" refers to a saturated or partially saturated non-aromatic carbocyclic ring, including monocyclic, bicyclic, or tricyclic rings, preferably having 3-12, more preferably 3-10, e.g., 3-8, 3-7, 3-6, 4-10, or 4-8 ring carbon atoms. "C3-C8 cycloalkyl" is intended to include C3, C4, C5, C6, C7, and C8 cycloalkyl groups, and "C3-C6 cycloalkyl" is intended to include C3, C4, C5, and C6 cycloalkyl groups, and by analogy therewith. Exemplary monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl. Exemplary bicyclic cycloalkyls include bornyl, tetrahydronaphthyl, decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, and the like. Exemplary tricyclic cycloalkyls include adamantyl, and the like.

[0212] As used herein, "haloalkyl" refers to an alkyl as defined herein in which one or more hydrogen atoms, e.g., 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, e.g., 1, 2, or 3 hydrogen atoms, are replaced by halogen, and when one or more hydrogen atoms are replaced by halogen atoms, said halogen atoms may be the same or different from each other. For example, "C1-C4 haloalkyl" is intended to include C1, C2, C3, and C4 haloalkyl groups, and "C1-C3 haloalkyl" is intended to include C1, C2, and C3 haloalkyl groups. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1,1-difluoroethyl, 1,1,-difluoropropyl, and 1,1,1-trifluoropropyl. Examples of haloalkyl also include "fluoroalkyl," which is intended to include alkyl as defined herein in which one or more hydrogen atoms are replaced by fluorine atoms. Here, the "haloalkyl" preferably refers to an alkyl group in which up to three hydrogen atoms have been replaced with halogen.

[0213] As used herein, "haloalkoxy" refers to a haloalkyl as defined above with a specific number of carbon atoms linked through an oxygen bridge, where one or more hydrogen atoms, for example 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, for example 1, 2, or 3 hydrogen atoms, are replaced by halogen. For example, "C1-C6 haloalkoxy" or "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, and 2,2,2-trifluoroethoxy. Examples of haloalkoxy also include "fluoroalkoxy".

[0214] As used herein, "aryl" refers to a monocyclic, bicyclic or tricyclic carbocyclic hydrocarbon group having 6 to 20, preferably 6 to 14, more preferably 6 to 12, most preferably 6 to 10, for example 6 to 9 ring carbon atoms, with one or more fused rings, where at least one ring is an aromatic ring and the other rings (if present) may be aromatic or non-aromatic. Preferred aryls are aryls having 6 to 10 ring carbon atoms, i.e., 6- to 10-membered aryls, including monocyclic aryls (e.g., phenyl) or fused bicyclic ring systems in which one ring is aromatic and the other ring is aromatic (e.g., naphthyl, biphenyl) or non-aromatic (e.g., indane, tetralin). Non-limiting examples of aryls include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl, dihydroindenyl or anthracenyl.

[0215] As used herein, "heteroaryl" refers to a 5-14 membered, preferably 5-10 membered, more preferably 5-7 membered or 5-6 membered aromatic ring system containing 1-8, preferably 1-4, more preferably 1-3, and even more preferably 1 or 2 heteroatoms selected from N, O, or S, including a monocyclic, bicyclic or fused polycyclic ring, with the remaining ring atoms being carbon atoms. Heteroaryl is preferably a 5-10 membered heteroaryl, more preferably a 5-7 membered heteroaryl or a 5-6 membered heteroaryl, each containing 1, 2, or 3 heteroatoms selected from N, O, or S. Examples of heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, 2H-chromene, benzopyranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl, 1H-benzo[d][1,2,3]triazolyl, and the like.

[0216] As used herein, "heterocycloalkyl" means cycloalkyl, as defined herein, except that one or more of the ring carbons may be heterocyclic, e.g., -O-, -N=, -NR-, -S-, -S(=O)-, and -S(=O)-. 2- wherein R is hydrogen, C 1~4It is an alkyl or nitrogen protecting group (e.g., benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxybenzyl, p-methoxyphenyl, 3,4-dimethyloxybenzyl, etc.). Preferably, the heterocycloalkyl is a monocyclic, bicyclic, or tricyclic saturated and partially unsaturated non-aromatic ring having 3 to 20 ring atoms, such as 3 to 12 ring atoms, such as 3 to 8 ring atoms, such as 3 to 6 ring atoms. More preferably, the heterocycloalkyl includes 4- to 12-membered heterocycloalkyl, preferably 4- to 8-membered heterocycloalkyl, more preferably 4- to 7-membered, 4- to 6-membered, or 4- to 5-membered heterocycloalkyl, containing 1, 2, or 3 heteroatoms selected from N, O, or S, the heteroatoms being substituted or unsubstituted, for example substituted by C1 to C4 alkyl. For example, examples of heterocycloalkyl include oxiranyl, aziridinyl, azetidinyl, oxetanyl, azolidinyl (pyrrolidinyl), tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolidinyl-2-one, imidazolonyl, piperidinyl (hexahydropyridinyl), N-methylpiperidinyl, tetrahydropi These include, but are not limited to, pyrazinyl, oxazinyl, 1,3-oxazinyl, hexahydropyrimidinyl, piperazinyl, piperidinylone, 1,4-dioxa-8-aza-spiro[4.5]decan-8-yl, morpholino, thiomorpholino, sulfanomorpholino, sulfonomorpholino, octahydropyrro[3,2-b]pyrrolyl, and the like.

[0217] As used herein, "partially saturated heterocycle" means a partially hydrogenated non-aromatic ring, which can exist as a monocycle or bicycle (including fused rings). Unless otherwise specified, the partially saturated heterocycle usually contains at least one, for example 1 to 3, preferably 1 or 2 heteroatoms selected from N, O, or S, such as -O-, -N=, -NR-, or -S- (wherein R is hydrogen, C 1~4 Partially saturated heterocycles include, for example, dihydropyrrolyl, dihydrofuryl, dihydroxazolyl, dihydropyridyl, imidazolinyl, 1H-dihydroimidazolyl, 2H-pyranyl, 2H-chromenyl, dihydroxazinyl, and the like groups. Partially saturated heterocycles further include heterocycles having fused aryl or heteroaryl rings, preferably having 9 to 10 ring members (e.g., dihydrobenzofuryl, dihydroisobenzofuranyl, dihydroindolyl (or 2,3-dihydroindolyl), dihydrobenzothienyl, dihydrobenzothiazolyl, dihydrobenzopyranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydropyrido[3,4-b]pyrazinyl, and the like).

[0218] As used herein, "partially or fully saturated heterocycle" means a partially or fully hydrogenated non-aromatic ring, which can exist as a monocycle, bicycle (including fused rings), or spirocycle. Unless otherwise specified, the heterocycle is usually a 3- to 12-membered ring, preferably a 5- to 10-membered ring, containing 1 to 3, preferably 1 or 2 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. When the term "partially or fully saturated heterocycle" is used, it is intended to include "heterocycloalkyl" and "partially saturated heterocycle". Examples of spirocycles include 2,6-diazaspiro[3.3]heptyl, 3-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, and the like.

[0219] As used herein, "heterocycle" refers to a fully saturated or unsaturated, aromatic or non-aromatic cyclic group, which is intended to include "heterocycloalkyl", "partially or fully saturated heterocycle", "partially saturated heterocycle", "fully saturated heterocycle" and "heteroaryl". For example, it is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 15-membered tricyclic ring system containing at least one heteroatom on a ring containing at least one carbon atom. The heteroatom-containing ring of the heterocycle can contain 1 to 6, preferably 1, 2 or 3, heteroatoms selected from nitrogen, oxygen or sulfur atoms, and the nitrogen and sulfur atoms may be optionally oxidized. Preferably, the heterocycle is a 4- to 7-membered monocyclic heterocycle.

[0220] Exemplary monocyclic heterocycles include pyrrolidine, pyrrole, pyrazole, oxetane, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, thiazole, thiadiazole, thiazolidine, isothiazole, isothiazolidine, furan, tetrahydrofuran, thiophene, piperidine, piperazine, 2-oxopiperazine, 2-oxopiperidine, 2-oxopyrrolidine, 4-piperidone, pyridine, pyrazine, pyrimidine, pyridazine, tetrahydropyran, morpholine, thiomorpholino-S-monoxide, thiomorpholino-S,S-dioxide, 1,3-dioxolane, and tetrahydro-1,1-dioxothiophene, 1,1,4-trioxo-1,2,5-thiadiazolidine-2-, and the like.

[0221] Exemplary bicyclic heterocycles include indole, dihydroindole, benzothiazole, and the like.

[0222] As used herein, a "heterocyclic group" refers to a group formed by the loss of one or more hydrogen atoms from a heterocycle as defined above. The heterocyclic group may be linked at a heteroatom or a carbon atom.

[0223] As used herein, "carbocycle" refers to a saturated or unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon group having 3 to 12 carbon atoms. The carbocycle preferably has 3 to 8, e.g., 3 to 7, or 4 to 7 ring carbon atoms. Exemplary monocyclic carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, and the like. Exemplary dicycloalkanes include tetralin, decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, and the like. Exemplary tricyclic hydrocarbon groups include adamantyl, and the like.

[0224] As used herein, the term "-C(=O)" is a carbonyl, "-S(=O)" is a sulfoxide group, and "-S(=O)2" is a sulfone group. "=O" is an oxo, i.e., an oxygen atom is connected to another atom through a double bond.

[0225] As used herein, groups such as alkyl, alkenyl, alkoxy, carbocycle, cycloalkyl, heteroaryl, heterocycle, heterocyclic group, carbonyl, sulfonyl, sulfinyl, etc., may be substituted with substituents including, but not limited to, OH, Boc, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group; NRR', C(O)R, SOR, C(O)NRR', or C(O)OR, where R and R' are each independently selected from H and substituted or unsubstituted alkyl.

[0226] As used herein, "optionally", "optionally", or "optionally" means that the event described below may or may not occur, and the description includes the event occurring and the event not occurring. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined herein. "Optionally substituted with halogen" includes "substituted with halogen" and "not substituted with halogen", e.g., substituted with 0-3 halogens. Those skilled in the art will understand that for any group containing one or more substituents, the group does not include any substitution pattern that is spatially impractical, chemically imprecise, synthetically impossible, and / or inherently unstable.

[0227] When any variable occurs multiple times in any structure or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, when a group is indicated to be substituted by 0-3 R, this group may be unsubstituted or substituted by up to 3 R, where R is independently selected from the definition of R at each occurrence. For example, the single or multiple substitutions applied to the definition of ring A, i.e., when ring A is C4-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 6-membered heteroaryl, these groups are unsubstituted or substituted by one or more, e.g., two, substituents independently selected from the given definition at each occurrence. This applies to the definitions of other similar scenarios as well.

[0228] When a bond of a substituent is shown to pass through a bond connecting two atoms in a ring, the substituent may be bonded to any atom on the ring. When a substituent is recited but the atom of the substituent that is bonded to the remainder of the compound of the formula below is not specified, the substituent may be bonded through any atom in the substituent.

[0229] Combinations of substituents and / or variables are permissible so long as such compositions result in stable compounds.

[0230] When a dashed ring is used for a ring structure, it means that the ring structure can be saturated, partially saturated, or unsaturated.

[0231] As used herein, the terms "substituted", "substituted" or "substituted by" mean that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group of substituents, provided that the normal valence of the given atom is not exceeded. When a substituent is oxo (=O), two hydrogen atoms on a single atom are replaced by oxygen. There are no oxo substituents in aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is substituted with a carbonyl group or a double bond, it is preferred that the carbonyl group or double bond is part of the ring (i.e., within the ring). Such combinations are only permissible if the combination of substituents and / or variables results in a chemically precise and stable compound. A chemically precise and stable compound means that the compound is sufficiently stable that it can be separated from a reaction mixture, the chemical structure of the compound can be determined, and then it can be prepared into a formulation that has at least practical utility. For example, if no substituents are explicitly recited, the terms "substituted," "substituted," or "substituted by" as used herein mean that one or more hydrogen atoms on a given atom or group are independently replaced with one or more, e.g., 1, 2, 3, or 4, substituents. When an atom or group is substituted with multiple substituents, the substituents may be the same or different.

[0232] The terms "pharmaceutical acceptable" or "medically acceptable" include a substance or composition that must be chemically / toxicologically compatible with other ingredients, formulations in which it is contained, and / or mammals treated therewith.

[0233] Unless otherwise indicated, the term "disclosed compound" or "compound of the disclosure" means a compound of formula (I) or subformulas thereof, such as formulas (Ia), (Ia1), (Ia2), (Ia3), (Ia4), (Ib), (Ic), (Id), (Ie1), (Ie2), (Ie3), (Ie4), (Ie5), and (Ie6), as defined herein, or a pharma- ceutically acceptable salt thereof, and includes one or more of all isomers, such as stereoisomers (including diastereomers, enantiomers, and racemates), geometric isomers, conformational isomers (including rotamers and atropisomers), tautomers, internal isomeric addition products, prodrugs, and isotopically labeled compounds (including deuterium substitutions) and inherently formed moieties (e.g., polycrystalline forms, solvates, and / or hydrates). When moieties capable of forming salts are present, salts, particularly pharma- ceutically acceptable salts, are also included.The presence of tautomers or isomeric internal addition products can be identified by those skilled in the art using tools such as NMR.The compounds of formula (I) of the present disclosure can easily form tautomers and isomeric internal addition products as described herein.

[0234] When formula (I) is referred to in this specification, this designation also includes subformulas such as formulas (Ia), (Ia1), (Ia2), (Ia3), (Ia4), (Ib), (Ic), (Id), (Ie1), (Ie2), (Ie3), (Ie4), (Ie5), and (Ie6).

[0235] Those of skill in the art will recognize that compounds of the present disclosure may contain chiral centers and may therefore exist in different heteromorphic forms. As used herein, "isomers" refer to compounds that have the same molecular formula but differ in the arrangement and configuration of their atoms.

[0236] As used herein, "enantiomers" refer to a pair of stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term refers to a racemic mixture. When describing the stereochemistry of the compounds of this disclosure, the conventional RS system is used to identify single stereoisomers of known relative and absolute configurations with two chiral centers (e.g., (1S,2S)). Single stereoisomers of known relative configuration but unknown absolute configuration are indicated with an asterisk (e.g., (1R * ,2R * )) is added, with racemates with two letters (e.g., (1RS,2RS)) being a racemic mixture of (1R,2R) and (1S,2S), and (1RS,2SR) being a racemic mixture of (1R,2S) and (1S,2R). "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified by the Cahn-Ingold-Prelog RS system. If the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be described by R or S. Resolved compounds with unknown absolute configuration may be specified as (+) or (-) based on the direction (dextrorotatory or levorotatory) they rotate plane polarized light at the wavelength of the sodium D line. Resolved compounds may also be defined by the retention times of the corresponding enantiomers / diastereomers via chiral HPLC.

[0237] Some of the compounds described herein contain one or more asymmetric centers or axes and can therefore give rise to enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- in terms of absolute stereochemistry.

[0238] Geometric isomers can occur when a compound contains a double bond or other feature that gives the molecule a certain amount of structural rigidity. When a compound contains a double bond, the substituent may be in the E or Z configuration. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.

[0239] Conformational isomers are isomers that differ by rotation about one or more bonds. Rotamers are conformational isomers that differ by rotation about only a single bond.

[0240] "Atropisomer" refers to a structural isomer based on axial or planar chirality resulting from restricted rotation within a molecule.

[0241] Unless otherwise indicated, the compounds of the present disclosure are intended to include all such possible isomers, including racemic mixtures, optically active forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0242] The compounds of the present disclosure can be separated into optically active or racemic forms. Optically active forms can be prepared by resolving racemic forms or by synthesis from optically active starting materials. All methods for preparing the compounds of the present disclosure and intermediates prepared herein are considered to be part of this disclosure. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods such as chromatography or fractional crystallization.

[0243] The final products of the present disclosure may be obtained in free (neutral) or salt form, depending on the conditions of the process. Both the free and salt forms of these final products are within the scope of the present disclosure. If desired, one form of the compound may be converted to the other form. Free alkalis or acids may be converted to salts. Salts may be converted to free compounds or to other salts. Mixtures of isomeric compounds of the present disclosure may be separated into individual isomers.

[0244] Pharmaceutically acceptable salts are preferred, however, other salts are considered within the scope of the disclosure since they may be useful, for example, in separation or purification steps, or can be used during preparation.

[0245] As used herein, "pharmaceutical acceptable" and "pharmaceutical acceptable" can be used interchangeably and mean capable of being used to prepare pharmaceutical compositions that are generally safe, non-toxic, and biologically and otherwise undesirable, including acceptable for veterinary and human pharmaceutical use.

[0246] As used herein, "pharmaceutically acceptable salt" and "pharmaceutically acceptable salt" refer to salts that maintain the biological effectiveness and performance of the compounds of the present disclosure, which are not biologically or otherwise undesirable. Non-limiting examples of such salts include non-toxic inorganic or organic alkali or acid addition salts of the compounds of the present disclosure. In many cases, the compounds of the present disclosure are capable of forming acid salts and / or alkali salts due to the presence of amino and / or carboxyl or similar groups. Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, hydroxyacetic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable alkali addition salts may be formed using inorganic and organic alkalis. Inorganic alkalis from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Organic alkalis from which salts can be derived include, for example, primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, alkaline ion exchange resins, etc., and particularly, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Pharmaceutically acceptable salts can be synthesized from parent compounds (alkaline or acidic moieties) by conventional chemical methods. Generally, the salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate alkali (e.g., hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free alkali form of the compound with a stoichiometric amount of an appropriate acid.Such reactions are usually carried out in water, an organic solvent, or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Other suitable salts are described in Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing Company, Easton, Pa., (1985), incorporated herein by reference.

[0247] As used herein, "pharmaceutical acceptable excipients" include any and all of the following: solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption retardants, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, similar substances, and combinations thereof, which are well known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, 1990, pp. 1289-1329, incorporated herein by reference). Except insofar as conventional carriers are incompatible with the active ingredients, their use in therapeutic or pharmaceutical compositions is contemplated.

[0248] As used herein, "solvate" refers to a physical association of a compound of the present disclosure with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, the solvate can be separated, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. The solvent molecules in the solvate may be present in an ordered and / or non-ordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of the solvent molecules. "Solvate" includes solvates that are separable from the solution phase. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are known to those skilled in the art.

[0249] As used herein, "crystalline polymorphism" refers to crystalline forms that have the same chemical structure / composition but have different spatial arrangements of molecules and / or ions that form the crystal.The compounds of the present disclosure can be provided as amorphous solids or crystalline solids.Lyophilization can be used to provide the solids of the compounds of the present disclosure.

[0250] As used herein, "prodrug" refers to a chemically modified active or inactive compound that, after administration to an individual, is converted through in vivo physiological action (e.g., hydrolysis, neo-metabolism, etc.) to a compound of the present disclosure. The suitability and techniques for the manufacture and use of prodrugs are well known to those of skill in the art.

[0251] Any formula given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure described in the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g., 2 H (i.e. D), 3 H (i.e. T), 11 C. 13 C. 14 C. 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 125 I. The present disclosure includes different isotopically labeled compounds as defined herein, for example, radioisotopes, e.g. 3 H, 13 C, and 14 Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution measurements, and radiation treatment of patients. In particular, 18 F or 18 F-labeled compounds are particularly desirable for use in PET or SPECT studies. Isotopically labeled compounds of the present disclosure can generally be prepared by carrying out the methods described in the flows or examples and preparations below, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0252] In addition, the heavier isotopes, especially deuterium (i.e. 2 Substitution with H or D) can also provide some therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, or improved therapeutic index. It is understood that the above deuterium can be considered as a substituent of the compounds of the present disclosure. The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. The "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a given isotope.

[0253] Isotopically labeled compounds of the present disclosure can be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, typically by substituting an appropriate isotopically labeled reagent for another unlabeled reagent used. Such compounds have a variety of potential applications as standards and reagents for measuring the ability of potential drug compounds to bind to target proteins or receptors, or for imaging of compounds of the present disclosure binding to biological receptors in vivo or in vitro.

[0254] As used herein, a "therapeutically effective amount" of a compound of the present disclosure refers to an amount of a compound of the present disclosure that may elicit a biological or medical response in an individual, ameliorate symptoms, slow or delay the progression of a disease, or prevent a disease, etc. A "therapeutically effective amount" may be determined by the attending physician or veterinarian and will vary depending on factors such as the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, and the judgment of the attending physician or veterinary practitioner.

[0255] As used herein, "individual" refers to an animal. Preferably, the animal is a mammal. An individual also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the individual is a human.

[0256] As used herein, "inhibition" refers to the reduction or prevention of a particular disease, symptom, condition, or disorder, or a significant decrease in the baseline activity of a biological activity or process.

[0257] As used herein, in one embodiment, the term "treating" any disease or condition means ameliorating the disease or condition (i.e., arresting or slowing the progression of the disease or at least one clinical symptom thereof). In another embodiment, "treatment" means improving at least one physical parameter, which may not be discernible by the patient. In another embodiment, "treatment" means modulating the disease or condition physically (e.g., stable perceptible symptoms), physiologically (e.g., stable physical parameters), or both.

[0258] As used herein, "prophylaxis" refers to the administration of one or more drug substances, particularly the compounds of the present disclosure and / or pharma- ceutically acceptable salts thereof, to an individual predisposed to a disease in question to prevent the individual from acquiring the disease in question.

[0259] When chemical reactions are referred to, "treating," "contacting," and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction that produces the indicated and / or desired product does not necessarily result directly from the combination of the two reagents initially added, i.e., one or more intermediates produced may be present in the mixture and ultimately result in the production of the indicated and / or desired product.

[0260] In general, the term "about" is used herein to adjust a given numerical value to be 20%, such as 10%, such as 5% higher or lower than the numerical value in question.

[0261] Any technical and scientific terms used herein that are not specifically defined have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0262] effect

[0263] The hydroxamic acid compound of the present disclosure is an ENPP1 inhibitor compound, which has high selectivity and inhibitory activity against ENPP1, few side effects, high drug resistance, high bioavailability, and high clinical application value. The compound of the present disclosure is useful in various applications requiring inhibition of ENPP1.

[0264] The compounds of the present disclosure are useful for treating, preventing, or ameliorating an ENPP1-mediated disease or disorder, such as an ENPP1-mediated tumor (eg, cancer), infection, or disorder, particularly recurrent, refractory, or metastatic cancer.

[0265] In particular, the compounds of the present disclosure are useful for the treatment, prevention, or amelioration of solid tumors selected from, for example, breast cancer, lung cancer, glioblastoma, brain and spinal cancer, head and neck cancer, skin cancer, reproductive system cancer, digestive system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcoma, midline carcinoma, and cancer of unknown primary.

[0266] The compounds of the present disclosure are also useful for treating, preventing, or ameliorating a hematological malignancy selected from, for example, leukemia, lymphoma, or myeloma.

[0267] Additionally, the compounds of the present disclosure are also useful for treating, preventing, or ameliorating an infection or condition selected from, for example, herpes simplex virus infection, vaccinia virus infection, adenovirus infection, human papilloma virus infection, hepatitis B virus infection, hepatitis D virus infection, human immunodeficiency virus infection, human cytomegalovirus infection, dengue virus infection, Ebola virus infection, Marburg virus infection, Zika virus infection, Listeria monocytogenes infection, Mycobacterium tuberculosis infection, Francisella novicida infection, Legionella pneumophila infection, Chlamydia trachomatis infection, Streptococcus pneumoniae infection, and Neisseria gonorrhoeae infection, particularly an ENPP1 mediated infection or condition.

[0268] Pharmaceutical Compositions and Administration

[0269] The compounds of the present disclosure may be administered to an individual in the form of a pharmaceutical composition, which may optionally contain one or more pharma- ceutically acceptable excipients.

[0270] The compounds of the present disclosure can be administered by various known routes, including oral, rectal, intragastric, intracranial, and parenteral administration, such as intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar routes of administration.In particular, oral, intranasal, and parenteral administration are preferred.Different pharmaceutical formulations are required depending on the route of administration, and some of these routes of administration may require the application of protective coatings to pharmaceutical formulations, for example, to prevent the degradation of the compounds of the present disclosure in the digestive tract.

[0271] The compounds of the present disclosure may be formulated into syrups, infusion or injection solutions, sprays, tablets, capsules, troches, liposomes, suppositories, and the like.

[0272] Particularly preferred pharmaceutical forms for administering the compounds of the present disclosure are suitable for injection use, including sterile aqueous solutions or dispersions and sterile powders for extemporaneous preparation of sterile injection solutions or dispersions. In either case, the final solution or dispersion form must be sterile and fluid. Typically, such solutions or dispersions contain a solvent or dispersion medium, including, for example, a biocompatible buffer, ethanol, or a polyhydric alcohol, such as glycerin, propylene glycol, polyethylene glycol, or suitable mixtures thereof, a surfactant, or an aqueous water-buffer solution, such as vegetable oil. The compounds of the present disclosure can also be formulated into liposomes, particularly liposomes for parenteral administration. Liposomes offer the advantage of increased circulation half-life (even compared to free drug) and extended and more uniform release of the encapsulated drug.

[0273] Sterilization of infusion and injection solutions can be achieved by techniques recognized by those skilled in the art, including, but not limited to, the addition of preservatives such as antibacterial or antifungal agents, such as parabens, trichloro-t-butanol, phenol, sorbic acid, thimerosal, etc. In addition, infusion and injection solutions can contain isotonic agents, such as sugars and salts, especially sodium chloride.

[0274] The preparation of sterile injection solution containing one or more of the compounds of the present disclosure can be achieved by incorporating the required amount of each compound in a suitable solvent with various components as required above, and then sterilizing.To obtain sterile powder, the above solution can be vacuum dried or freeze-dried as required.The preferred diluent of the present disclosure is water, physiologically acceptable buffer, physiologically acceptable buffered salt solution or salt solution.Preferred carrier is cocoa butter and vitebesole.

[0275] The excipients that can be used with various pharmaceutical forms of the compounds of the present disclosure can be selected from the following non-limiting list: a) binders, such as lactose, mannitol, crystalline sorbitol, hydrogen phosphate, sugar, microcrystalline cellulose, carboxymethylcellulose, hydroxyethylcellulose and / or polyvinylpyrrolidone; b) lubricants, such as magnesium stearate, talc powder, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oils, leucine, glycerides, and sodium stearyl fumarate; c) disintegrants, such as cross-linked carboxymethylcellulose, sodium methylcellulose, agar, bentonite, alginic acid, carboxymethylcellulose and / or polyvinylpyrrolidone. Other suitable pharma-ceutically acceptable carriers and their preparation are well known in the art and are described, for example, in Remington: The Science and Practice of Pharmacy 1995, edited by EW Martin, Mack Publishing Company, 19th Edition, Easton, Vincent Vanuatu.

[0276] In one embodiment, the formulation is for oral administration and comprises one, more or all of pregelatinized starch, talc powder, polyvinylpyrrolidone K30, cross-linked sodium carboxymethylcellulose, sodium stearyl fumarate, gelatin, titanium dioxide, sorbitol, monosodium citrate, xanthan gum, titanium dioxide, flavoring agents, sodium benzoate, and sodium saccharin.

[0277] In one embodiment, the compounds of the present disclosure are administered in a dry powder inhaler or in the form of a spray from a pressurized container, pump, nebulizer, or atomizer with a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, e.g., 1,1,1,2-tetrafluoroethane (HFA 134A™) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA™), carbon dioxide, or other suitable gas. The pressurized container, pump, nebulizer, or atomizer may contain a solution or suspension of the compounds of the present disclosure, for example, in ethanol and the propellant, and may also contain a lubricant, such as sorbitan trioleate.

[0278] A typical dose range of the compounds of the present disclosure is 0.001-1000 mg active ingredient / kg body weight / day. The dose can be administered once or in multiple doses per day. The appropriate dose is determined by the attending physician based on the type and severity of the disease to be treated, the individual's health condition and medical history, concomitant drugs, the specific compound to be administered, the route of administration, etc. If necessary, the dose of the compounds of the present disclosure may exceed this dose range.

[0279] Drug Combinations

[0280] The compounds of the present disclosure may be used for the uses described herein alone or in combination with one or more other active agents or therapies that may have or produce the same or different pharmacological effect. The compounds of the present disclosure may be administered simultaneously with, prior to, or subsequent to the other active agents or therapies.

[0281] When the compound of the present disclosure is administered in combination with other active agents, the dose of the other active agent administered in combination will vary depending on factors such as the coadministered drug, the disease to be treated, the general health of the patient, and the physician's or veterinarian's judgment. The compound of the present disclosure can be administered simultaneously, separately, or sequentially by the same or different administration route as the other active agent in combination. They may be included in the same pharmaceutical composition or in a single form, for example, a combination product in the form of a cartridge. They may be prepared and / or compounded by the same or different manufacturers. Furthermore, the compound of the present disclosure and the other active agent may be added to the combination therapy (i) before sending the combination product to the physician (e.g., in the case of a cartridge containing the compound of the present disclosure and an additional drug), (ii) by the physician himself (or under the physician's guidance) immediately before administration, or (iii) by the patient himself, for example, during the sequential administration of the compound of the present disclosure and the other active agent.

[0282] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt thereof and one or more other active agents. Optionally, the pharmaceutical composition may comprise a pharma- ceutically acceptable excipient as described above.

[0283] In one embodiment, the disclosure provides a cartridge comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In one embodiment, the cartridge comprises a device for separately holding the compositions, such as a container, separate bottles, or separate foil bags. An example of such a cartridge is a blister pack, typically used for packaging tablets, capsules, etc.

[0284] The cartridges of the present disclosure can administer a variety of dosage forms, e.g., oral and parenteral dosage forms, for interval administration of individual compositions at different doses or for incremental administration of individual compositions relative to one another. To improve compliance, the cartridges of the present disclosure typically include instructions for use.

[0285] In the combination therapy of the present disclosure, the compound of the present disclosure and the other therapeutic agent may be prepared and / or coordinated by the same or different manufacturers. Furthermore, the compound of the present disclosure and the other therapeutic agent may be introduced together into the combination therapy (i) prior to sending the combination product to the physician (e.g., in the case of a cartridge containing the compound of the present disclosure and the other therapeutic agent), (ii) immediately prior to administration by the physician himself (or under the physician's guidance), or (iii) by the patient himself, e.g., during administration of the compound of the present disclosure and the other active agent in a sequential order.

[0286] General synthesis method

[0287] The compounds of the present disclosure can be prepared by various methods, including the methods described below, the methods described in the Examples, or methods similar thereto. A suitable general synthesis scheme is shown below. Suitable reaction conditions for each reaction step are known to those skilled in the art. The starting materials can be obtained commercially or prepared by the methods below, methods similar to those shown below, or methods known in the art. Each variable in the general formula has the same meaning as above, unless otherwise specified.

[0288] In one embodiment, the compounds of the present disclosure can be synthesized according to a general synthetic scheme in which the variables are as defined herein and the specific reaction conditions are the same as in the examples.

[0289] Flow 1

[0290] [ka]

[0291] The compound of general formula A2 can be prepared by the following synthesis method. Trimethyl orthoformate and 2,2-dimethyl-1,3-dioxane-4,6-dione are reacted with stirring at 100°C for 2 hours, and then the compound of general formula A1 is added and reacted at this temperature for another 2 hours. The reaction solution is cooled to room temperature to precipitate a solid, and the solid is collected by filtration to obtain the compound of general formula A2.

[0292] The compound of general formula A3 can be prepared by the following synthesis method: dissolve the compound of general formula A2 in diphenyl ether, react with stirring at 230°C for 1 hour, cool the reaction solution to room temperature, add petroleum ether to precipitate a solid, filter, and collect the solid to obtain the compound of general formula A3.

[0293] The compound of general formula A4 can be prepared by the following synthesis method: The compound of general formula A3 is reacted with phosphorus oxychloride at 100℃ for 1 hour, then cooled to room temperature, excess phosphorus oxychloride is removed to obtain a residue, ice water is added to the residue, pH is adjusted to 8 with ammonia water, extracted with dichloromethane, the organic phase is washed with water and saturated saline solution in sequence, dried, filtered, and concentrated to obtain a crude product, which is purified by silica gel column to obtain the compound of general formula A4.

[0294] The compound of general formula A6 can be prepared by the following synthetic methods: in one case, the compound of general formula A4 and the compound of general formula A5 undergo nucleophilic substitution reaction under the condition of DIEA, potassium carbonate or hydrochloric acid to produce the compound of general formula A6; in another case, the compound of general formula A4 and the compound of general formula A5 undergo coupling reaction under the condition of palladium catalyst to obtain the compound of general formula A6.

[0295] The compound of formula A7 can be prepared by the following synthesis method: The compound of formula A6 and sodium hydroxide are hydrolyzed in a suitable amount of solvent to obtain the compound of formula A7.

[0296] The compound of general formula A8 can be prepared by the following synthetic method: The compound of general formula A7 and hydroxylamine are subjected to a condensation reaction in the presence of a condensing agent HATU to obtain the compound of general formula A8. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0297] In this application, when a chemical name and a structural formula conflict, the structural formula shall control unless the context indicates that the chemical name, rather than the structural formula, is correct.

[0298] As will be apparent to those skilled in the art, for simplicity, not all hydrogen atoms in the structural formulas of some of the compounds described herein are explicitly shown. When a carbon or nitrogen atom in a compound has an open valence, this indicates the presence of an unshown hydrogen.

[0299] The compounds of the present disclosure can be prepared in various ways known to those skilled in the art of organic synthesis, following the methods, reaction flows, and examples described herein. The compounds of the present disclosure can be synthesized by combining the methods described below with synthetic methods known in the art of organic chemistry, or by using variations that would be understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in a solvent or solvent mixture that is suitable for the reagents and materials used and for the conversion to be made. Those skilled in the art of organic synthesis can understand that the functional groups present on the molecule must be consistent with the desired conversion. This may require judgment to change the order of synthetic steps or to select a particular operational flow over others in order to obtain the desired compound of the present disclosure.

[0300] The present disclosure will be further described below with reference to specific examples. It should be understood that these examples are only used to illustrate the present disclosure and are not used to limit the scope of the present disclosure. Experimental methods without specific conditions described in the following examples usually follow normal conditions or conditions suggested by the manufacturer. Unless otherwise specified, percentages and parts are weight percent, weight parts, or volume percent (for liquids).

[0301] For illustrative purposes, the reaction flows shown below provide potential routes and key intermediates for synthesizing the compounds of the present disclosure. For more detailed descriptions of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that the compounds of the present disclosure may be synthesized by other synthetic routes. Although specific raw materials and reagents are shown in the flows and discussed below, other raw materials and reagents can be easily substituted to provide various derivatives and / or reaction conditions. Additionally, most of the compounds produced by the methods below may be further modified using conventional chemistry well known to those skilled in the art based on the present disclosure.

[0302] In the preparation of compounds of the present disclosure, protection of the terminal functional groups of intermediates may be necessary. The need for such protection will depend on the nature of the distal functional group and the conditions of the preparation method. The need for such protection can be readily determined by one skilled in the art.

[0303] The experimental materials and reagents used in the following examples are commercially available unless otherwise specified. The raw materials are generally available from commercial sources or can be readily prepared using methods well known to those skilled in the art.

[0304] In each example, the experimental equipment is described, for example, 1 H NMR was recorded on a Varian Mercury-300 or Varian Mercury-400 nuclear magnetic resonance instrument. 13 C NMR was recorded on a Varian Mercury-400, Varian Mercury-500, or Varian Mercury-600 nuclear magnetic resonance spectrometer, and chemical shifts are expressed in δ (ppm). Mass spectrometry was recorded on a Finnigan / MAT-95 (EI), Finnigan LCQ / DECA, and Micromass Ultra Q-TOF (ESI) mass spectrometer. Silica gel used for separation by reversed-phase preparative HPLC was 200–300 mesh.

[0305] [Table 2]

[0306] Synthesis of key intermediates

[0307] Intermediate 1a: 5-chloro-2-methoxy-1,8-naphthyridine

[0308] [ka]

[0309] Step 1: Synthesis of 5-(((6-methoxypyridin-2-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0310] Compound 2,2-dimethyl-1,3-dioxane-4,6-dione (12.7 g, 88.61 mmol) was added to a one-neck flask (250 mL) containing trimethyl orthoformate (100 mL). The mixture was stirred at 100° C. for 2 hours, and then compound 1a-1 (5.0 g, 40.28 mmol) was added and the reaction was continued at this temperature for 2 hours. The reaction solution was cooled to room temperature to precipitate a solid, which was filtered and collected to obtain compound 1a-2 (10 g, yellow solid), with a yield of 89%. 1 H-NMR (400MHz, CDCl3-d): δ9.30(d,J=13.6Hz,1H),7.63-7.59(m,1H),6.63-6.57(m,2H),3.99(s,3H),1.76(s,6H).

[0311] Step 2: Synthesis of 7-methoxy-1,8-naphthyridin-4(1H)-one

[0312] 1a-2 (5 g, 17.98 mmol) was added to a one-neck flask (250 mL) containing diphenyl ether (50 mL) and reacted at 230° C. for 1 hour with stirring. The reaction solution was then cooled to room temperature, and petroleum ether was added to precipitate a solid. The solid was collected by filtration to obtain compound 1a-3 (2.9 g, yellow solid) in a yield of 94%. 1H-NMR (400MHz, CDCl3-d): δ11.97(s,1H),8.30(d,J=8.8Hz,1H),7.78-7.75(m,1H),6.79(d,J=8.8Hz,1H),6.05-6.03(m,1H),3.96(s,3H).

[0313] Step 3: Synthesis of 5-chloro-2-methoxy-1,8-naphthyridine

[0314] Compound 1a-3 (500 mg, 2.84 mmol) and phosphorus oxychloride 10 mL were added in sequence to a one-neck flask (100 mL), and the mixture was reacted at 100 ° C for 1 hour. The reaction solution was then cooled to room temperature, and excess phosphorus oxychloride was removed. Ice water was added to the residue, and the pH was adjusted to 8 with aqueous ammonia. The mixture was extracted with dichloromethane, and the organic phase was washed with water and saturated aqueous sodium chloride in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by a silica gel column (PE:EA = 5:1) to obtain compound 1a (400 mg, white solid), with a yield of 73%. LCMS (ESI): m / z 195.1 [M + H] + ;RT=1.137min(6.00min).

[0315] Intermediate 2a: 4-chloro-6-chloro-7-methoxyquinoline

[0316] [ka]

[0317] Step 1: Synthesis of 5-((((4-chloro-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0318] Compound 2a-1 (3.00 g, 21.3 mmol) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4.75 g, 25.6 mmol) were added to a one-neck flask containing IPA (50 mL), and the mixture was stirred at 70° C. for 2 hours to react, cooled to room temperature, filtered, and the solid was washed with methanol and dried to obtain compound 2a-2 (5.80 g, yellow solid), with a yield of 92.3%. LCMS (ESI): m / z 256.1 [M-40+H] + ;RT=1.08min(2.00min).

[0319] Step 2: Synthesis of 6-chloro-7-methoxyquinolin-4(1H)-one

[0320] Compound 2a-2 (5.80 g, 19.7 mmol) was added to a one-neck flask containing diphenyl ether (100 mL) and stirred at 200° C. for 2 hours. After cooling to room temperature, the reaction solution was poured into petroleum ether, filtered, and the filter cake was slurried with chloroform to give compound 2a-3 (2.80 g, gray solid), with a yield of 73.6%. LCMS (ESI): m / z 194.0 [M+H] + ;RT=1.08min(2.00min).

[0321] Step 3: Synthesis of 4-chloro-6-chloro-7-methoxyquinoline

[0322] Compound 2a-3 (1.00 g, 5.18 mmol) and phosphorus oxychloride (2 mL) were added to a one-neck flask containing DIEA (7 mL), and the mixture was stirred at 100° C. for 1 hour to react. The reaction solution was poured into ice water, extracted with dichloromethane, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography plate to obtain compound 2a (950 mg, white solid), with a yield of 86.9%. LCMS (ESI): m / z 212.0 [M+H] + ;RT=1.15min(2.00min).

[0323] Intermediate 3a: 4-Chloro-7-methoxy-1,6-naphthyridine

[0324] [ka]

[0325] Step 1: Synthesis of 3-bromo-2-methoxypyridin-4-amine

[0326] Compound 3a-1 (1.0 g, 8.06 mmol) was added to a one-neck flask (100 mL) containing anhydrous acetonitrile (10 mL). After cooling to 0°C, NBS (1.44 g, 8.06 mmol) was slowly added thereto, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated saline in that order, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by column (PE:EA=8:1) to obtain compound 3a-2 (1.4 g, yellow solid), with a yield of 88%. LCMS (ESI): m / z 203.0 [M+H] + ;RT=0.967min(2.50min).

[0327] Step 2: Synthesis of 5-(((3-bromo-2-methoxypyridin-4-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0328] 2,2-Dimethyl-1,3-dioxane-4,6-dione (709 mg, 4.92 mmol) was added to a one-neck flask (100 mL) containing HC(OMe)3 (10 mL) and the mixture was stirred at 100° C. for 2 hours to react, and compound 3a-2 (500 mg, 2.46 mmol) was added and the reaction was continued for 2 hours. After the reaction solution was cooled to room temperature, petroleum ether was added to precipitate a solid, which was filtered and collected to obtain compound 3a-3 (679 mg, white solid), with a yield of 77%. LCMS (ESI): m / z 357.0359.0 [M+H] + ;RT=1.517min(2.50min).

[0329] Step 3: Synthesis of 8-bromo-7-methoxy-1,6-naphthyridin-4-ol

[0330] Compound 3a-3 (3.0 g, 8.40 mmol) was added to a one-neck flask (100 mL) containing diphenyl ether (20 mL) and stirred at 230° C. for 1 hour to react. The reaction solution was then cooled to room temperature, diluted with petroleum ether, filtered, and the filter cake was collected to obtain compound 3a-4 (2.27 g, brown solid), with a yield of 100%. LCMS (ESI): m / z 255.0257.0 [M+H] + ;RT=0.957min(2.50min).

[0331] Step 4: Synthesis of 7-methoxy-1,6-naphthyridin-4-ol

[0332] Compound 3a-4 (2.0 g, 7.84 mmol), ammonium formate (980 mg, 15.68 mmol) and palladium carbon (300 mg, wt%: 10%) were added in sequence to a one-neck flask (50 mL) containing methanol (10 mL), and the mixture was stirred at 60° C. for 1 hour to react. The reaction solution was filtered, and the filtrate was concentrated, diluted with ethyl acetate, washed with water and saturated saline solution in sequence, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 3a-5 (1.4 g, yellow solid), with a yield of 100%. LCMS (ESI): m / z 177.1 [M+H] + ;RT=0.757min(2.50min).

[0333] Step 5: Synthesis of 4-chloro-7-methoxy-1,6-naphthyridine

[0334] Compound 3a-5 (900 mg, 0.644 mmol) and DIEA (1.7 mL, 5.62 mmol) were added in a three-neck flask (100 mL) containing anhydrous acetonitrile (10 mL) in sequence, and cooled to 0 ° C under nitrogen protection, and then phosphorus oxychloride (0.9 mL, 5.62 mmol) was slowly added dropwise thereto, and stirred at 70 ° C for 30 minutes. The reaction solution was then cooled to room temperature, adjusted to pH = 8 with saturated sodium bicarbonate, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated saline in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column (PE:EA = 10:1) to obtain compound 3a (1.0 g, yellow solid), with a yield of 100%. LCMS (ESI): m / z 195.1 [M + H] + ;RT=1.287min(2.50min).

[0335] Intermediate 4a: 8-Chloro-3-methoxy-1,5-naphthyridine

[0336] [ka]

[0337] Step 1: Synthesis of 5-((5-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0338] 2,2-Dimethyl-1,3-dioxane-4,6-dione (4.64 g, 16.11 mmol) was added to a one-neck flask (250 mL), followed by trimethyl orthoformate (100 mL). Stirred at 105° C. for 2 hours. Compound 4a-1 (4 g, 16.11 mmol) was then added, and the mixture was kept at 105° C. and stirred overnight. Petroleum ether was added to dilute the mixture at room temperature, followed by filtration and washing the filter cake with petroleum ether to obtain crude product 4a-2 (7 g, yellow solid) as a filter cake. LCMS (ESI): m / z 279.1 [MH] - ;RT=0.891min(2.50min).

[0339] Step 2: Synthesis of 7-methoxy-1,5-naphthyridin-4(1H)-one

[0340] Compound 4a-2 (5 g, 17.97 mmol) was placed in a three-neck flask (250 mL), diphenyl ether (100 mL) was added, and the mixture was stirred under nitrogen protection for 1 hour. A large amount of n-hexane was added at room temperature to dilute the mixture, and the mixture was filtered. The filter cake was washed with n-hexane to obtain crude product 4a-3 (2.5 g, gray solid) as a filter cake.

[0341] Step 3: Synthesis of 8-chloro-3-methoxy-1,5-naphthyridine

[0342] Compound 4a-3 (3.50 g, 19.87 mmol) was placed in a three-neck flask (250 mL), phosphorus oxychloride (70 mL) was added, and the mixture was stirred at 110° C. for 12 hours. The mixture was cooled to room temperature, the solvent was removed, and then dichloromethane and a small amount of water were added. The pH was adjusted to 9-10 with sodium bicarbonate, and then extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed. The crude product was purified by normal phase column (PE / EA=3:1) to obtain compound 4a (2.70 g, yellow solid). The yield was 70%. LCMS (ESI): m / z 195.1 [M+H] + ;RT=1.271min(2.50min).

[0343] Intermediate 5a: 4-chloro-8-chloro-7-methoxyquinoline

[0344] [ka]

[0345] Step 1: Synthesis of 5-(((2-chloro-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0346] Compound 5a-1 (500 mg, 3.50 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (655 mg, 4.55 mmol), trimethoxymethane (725 mg, 4.9 mmol), and acetonitrile (10 mL) were added to a dry one-neck flask (50 mL) at room temperature, and the mixture was heated to 85° C. and reacted overnight. The reaction solution was concentrated under reduced pressure. The residue was slurried in n-pentane and dried to obtain crude product 5a-2 (1 g, white solid). LCMS (ESI): m / z 296.1 [M+H] + ;RT=6.324min(15.00min).

[0347] Step 2: Synthesis of 8-chloro-7-methoxyquinolin-4(1H)-one

[0348] Compound 5a-2 (1 g, crude) and diphenyl ether (10 g) were added sequentially to a dry one-neck flask (50 mL) at room temperature, and the mixture was heated to 200° C. and reacted for 2 hours. The mixture was concentrated under reduced pressure, and the residue was slurried in n-pentane and dried to obtain compound 5a-3 (600 mg, brown solid), with a yield of 91.70%. LCMS (ESI): m / z 194.0 [M+H] + ;RT=0.94min(3.00min).

[0349] Step 3: Synthesis of 4-chloro-8-chloro-7-methoxyquinoline

[0350] Compound 5a-3 (600 mg, 3.11 mmol), acetonitrile (20 mL), DIEA (1.5 mL), and phosphorus oxychloride (3 mL) were added to a dry one-neck flask (50 mL) at room temperature, and then the mixture was heated to 80° C. and reacted overnight. The reaction solution was poured into ice water, adjusted to alkaline with saturated sodium bicarbonate solution, and extracted with ethyl acetate (30 mL). The organic phase was washed with brine, dried over sodium sulfate, suction filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (PE:EA=1:1) to obtain compound 5a (350 mg, yellow solid), with a yield of 53.4%. LCMS (ESI): m / z 212.0 [M+H] + ;RT=1.51min(3.00min).

[0351] Intermediate 6a: 4-chloro-7-methoxyquinoline-3-carbonitrile

[0352] [ka]

[0353] Step 1: Synthesis of (E)-2-(((dimethylamino)methylene)amino)-4-methoxybenzoic acid methyl ester

[0354] Compound 6a-1 (3 g, 17.9 mmol) was added to a one-neck flask (250 mL) containing DMF-DMA (30 mL) and stirred at 105° C. for 4 hours. After cooling, the mixture was concentrated to give crude product 6a-2 (5.0 g, yellow solid). LCMS (ESI): m / z 237.1 [M+H] + ;RT=0.792min(2.50min).

[0355] Step 2: Synthesis of 7-methoxy-4-oxo-3,4-dihydroquinoline-3-carbonitrile

[0356] At -78°C, n-butyllithium (13.7mL, 34.3mmol) was added dropwise over 10 minutes to a three-neck flask containing anhydrous THF (40mL). Acetonitrile (1.46g, 35.5mmol) was added dropwise over half an hour, and when a white solid precipitated, a THF solution (10mL) of compound 6a-2 (3.0g, 12.7mmol) was added dropwise. The reaction was allowed to proceed for 40 minutes, quenched with acetic acid (3mL), concentrated, filtered with water, and the filter cake was dried to give crude product 6a-3 (1.6g, yellow solid), with a yield of 24%. LCMS (ESI): m / z 201.1 [M+H] + ;RT=1.032min(2.50min).

[0357] Step 3: Synthesis of 4-chloro-7-methoxyquinoline-3-carbonitrile

[0358] Compound 6a-3 (1.1 g, 5.5 mmol) was added to a one-neck flask (100 mL) containing POCl3 (15 mL) and stirred at 100 °C for 1.5 hours. After cooling, the solvent was removed, ethyl acetate and water were added at room temperature, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The organic phase was washed with sodium chloride, dried over anhydrous sodium sulfate, and filtered. Purification was performed by prep-TCL (PE:EA = 5:1) to obtain crude product 6a (500 mg, yellow solid), with a yield of 42%. LCMS (ESI): m / z 219.1 [M + H] + ;RT=1.662min(2.50min).

[0359] Intermediate 7a: 4-chloro-7-methoxy-2-methylpyrido[2,3-d]pyrimidine

[0360] [ka]

[0361] Step 1: Synthesis of methyl 6-methoxy-2-((4-methoxybenzyl)amino)nicotinate

[0362] At room temperature, 7a-1 (5.0 g, 24.9 mmol), PMBNH2 (4.1 g, 29.9 mmol), potassium carbonate (6.87 g, 49.8 mmol), and DMF (20 mL) were added sequentially to a dry one-neck flask (100 mL). The mixture was heated to 80° C. and reacted for 16 hours. The mixture was cooled to room temperature, extracted with ethyl acetate and water, and the organic phase was washed with brine, concentrated, and purified by (PE / EA=2 / 1) to obtain compound 7a-2 (7 g, colorless liquid), with a yield of 92%. LCMS (ESI): m / z 303.1 [M+H] + ;RT=1.98min(3min).

[0363] Step 2: Synthesis of methyl 2-amino-6-methoxynicotinate

[0364] Compound 7a-2 (7 g, 24 mmol), dichloromethane (5 mL), and TFA (5 mL) were added to a dry one-neck flask (100 mL) at room temperature and reacted at room temperature for 16 hours. The mixture was concentrated, the residue was diluted with dichloromethane, washed with aqueous sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain compound 7a-3 (3.5 g, colorless liquid), with a yield of 80%. LCMS (ESI): m / z 183.1 [M+H] + ;RT=1.42min(3min).

[0365] Step 3: Synthesis of 2-acetamido-6-methoxymethyl nicotinate

[0366] Compound 7a-3 (2.0 g, 11.0 mmol), DIEA (7.1 g, 55.0 mmol), DMAP (134 mg, 1.1 mmol), dichloromethane (20 mL) and acetyl chloride (1.7 g, 22.0 mmol) were added in sequence to a dry one-neck flask (50 mL) at room temperature. The reaction was allowed to proceed at room temperature for 16 hours. The mixture was concentrated, and the residue was extracted with ethyl acetate and water. The organic phase was concentrated and purified by (PE / EA=10 / 1-1 / 1) to obtain compound 7a-4 (1.0 g, white solid). The yield was 45%. LCMS (ESI): m / z 224.8 [M+H] + ;RT=1.541min(3min).

[0367] Step 4: Synthesis of 7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one

[0368] Compound 7a-4 (1.0 g, 4.46 mmol), anhydrous methanol (10 mL), and aqueous ammonia (20 mL) were added to a dry one-neck flask (50 mL) at room temperature. The mixture was allowed to react at room temperature for 16 hours. The mixture was concentrated, and the residue was extracted with ethyl acetate and water. The organic phase was concentrated, and the residue was slurried with a small amount of ethyl acetate and filtered to obtain compound 7a-5 (200 mg, white solid), with a yield of 21%. LCMS (ESI): m / z 191.8 [M+H] + ;RT=1.715min(3min).

[0369] Step 5: Synthesis of 4-chloro-7-methoxy-2-methylpyrido[2,3-d]pyrimidine

[0370] Compound 7a-5 (200 mg, 1.05 mmol) and phosphorus oxychloride (10 mL) were added sequentially to a dry one-neck flask (50 mL) at room temperature. The mixture was heated to 100° C. and reacted for 16 hours. The mixture was concentrated, and the residue was adjusted to pH=9 with aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic phase was dried, concentrated, and filtered to obtain compound 7a (210 mg, white solid), with a yield of 90%. LCMS (ESI): m / z 209.8 [M+H] + ;RT=2.44min(5min).

[0371] Intermediate 8a: 7-Chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine

[0372] [ka]

[0373] Step 1: Synthesis of methyl 4-amino-1-methyl-1H-pyrazole-5-formate

[0374] Compound 8a-1 (2 g, 10.8 mmol) and palladium carbon (400 mg) were added to a one-neck flask containing methanol (30 mL), and the mixture was reacted by stirring at room temperature for 3 hours under hydrogen gas pressure (15 psi). The mixture was filtered and the filtrate was concentrated to obtain compound 8a-2 (1.6 g, white solid), with a yield of 95.6%. LCMS (ESI): m / z 156.1 [M+H] + ;RT=0.94min(2.00min).

[0375] Step 2: Synthesis of 1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol

[0376] Compound 8a-2 (1.6 g, 10.3 mmol) and formamidine acetate (1.29 g, 12.4 mmol) were added to a one-neck flask containing n-butanol (15 mL) and DIEA (15 mL), and the mixture was stirred at 110° C. for 6 hours to react. The reaction solution was cooled to room temperature, filtered, and the solid was washed with ethyl ether to obtain compound 8a-3 (1.30 g, white solid), with a yield of 84.1%. LCMS (ESI): m / z 151.2 [M+H] + ;RT=0.623min(2.00min).

[0377] Step 3: Synthesis of 7-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine

[0378] Compound 8a-3 (1.30 g, 8.67 mmol) and DMF (0.5 mL) were added to a one-neck flask containing thionyl chloride (20 mL), and the mixture was stirred at 90° C. for 2 hours to react. Thionyl chloride was removed, and dichloromethane and water were added to separate the layers. The aqueous phase was extracted with dichloromethane, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain compound 8a (1.20 g, white solid), with a yield of 82.4%. LCMS (ESI): m / z 169.0 [M+H] + ;RT=1.20min(2.00min).

[0379] Intermediate 9a: 4-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine

[0380] [ka]

[0381] Step 1: Synthesis of 5-(((1,3-dimethyl-1H-pyrazol-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0382] 2,2-Dimethyl-1,3-dioxane-4,6-dione (2.33 g, 16.19 mmol) was added to a one-neck flask (100 mL) containing trimethyl orthoformate (30 mL) and reacted at 100° C. for 2 hours, and then compound 9a-1 (1.5 g, 13.5 mmol) was added thereto and stirred at 100° C. for 2 hours. The reaction solution was cooled to room temperature, diluted with petroleum ether, filtered, and the solid was collected to obtain compound 9a-2 (2.6 g, yellow solid), with a yield of 74%. LCMS (ESI): m / z 264.1 [MH] + ;RT=1.004min(2.50min).

[0383] Step 2: Synthesis of 1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-ol

[0384] Compound 9a-2 (2.6 g, 9.81 mmol) was added to a one-neck flask (100 mL) containing diphenyl ether (50 mL), and the mixture was stirred at 230 ° C for 2 hours to react. The reaction solution was cooled to room temperature, and then petroleum ether (100 mL) was added, filtered, and the solid was collected. The solid was purified by a silica gel column (DCM:methanol = 15:1) to obtain compound 9a-3 (0.8 g, white solid), with a yield of 50%. LCMS (ESI): m / z 164.2 [M + H] + ;RT=0.680min(2.50min).

[0385] Step 3: Synthesis of 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine

[0386] 9a-3 (0.7 g, 4.30 mmol) was added to a one-neck flask (100 mL) containing POCl3 (10 mL), and the reaction solution was stirred at 100° C. for 2 hours. The reaction solution was concentrated, adjusted to pH=8 using saturated aqueous sodium bicarbonate solution in an ice bath, extracted with dichloromethane, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 9a (700 mg, gray solid), with a yield of 91%. LCMS (ESI): m / z 182.1 [M+H] +;RT=1.540min(2.50min).

[0387] Intermediate 10a: 2-(4-amino-2-methylphenyl)methyl acetate

[0388] [ka]

[0389] Step 1: Synthesis of 2-(2-bromo-4-nitrophenyl)diethyl malonate

[0390] Under nitrogen protection, sodium hydride (0.50 g, 2.27 mmol) and DMF (10 mL) were sequentially placed in a three-neck flask (100 mL), and diethyl malonate (0.47 mg, 2.95 mmol) was slowly added dropwise at 0°C and stirred for 30 minutes. Next, compound 10a-1 (0.5 g, 2.27 mmol) was slowly added dropwise. The mixture was warmed to room temperature and stirred for 12 hours. 1 mol / L hydrochloric acid was added at room temperature to adjust the pH to 5-6, and then extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain crude product 10a-2 (0.9 g, yellow oil). LCMS (ESI): m / z 359.9 [MH] - ;RT=1.040min(2.50min).

[0391] Step 2: Synthesis of 2-(2-bromo-4-nitrobenzene)acetic acid

[0392] Compound 10a-2 (0.9 g, 2.49 mmol) and sodium hydroxide (0.4 g, 9.99 mmol) were added in sequence to a one-neck flask (100 mL) containing methanol (6 mL) and water (6 mL) at room temperature, and the mixture was allowed to react at room temperature for 12 hours. The solvent was removed, and a 2 mol / L aqueous hydrochloric acid solution was added to adjust the pH to 3-4, and a solid was precipitated and filtered. The filter cake was washed with a small amount of dichloromethane to obtain crude product 10a-3 (600 mg, yellow oil). LCMS (ESI): m / z 257.9 [MH] - ;RT=1.384min(2.50min).

[0393] Step 3: Synthesis of 2-(2-bromo-4-nitrobenzene)methyl acetate

[0394] 4 mL of thionyl chloride was slowly added to a one-neck flask (100 mL) containing anhydrous methanol (10 mL) at 0° C. and stirred for 10 minutes. Next, compound 10a-3 (170 mg, 0.56 mmol) was added to the one-neck flask, warmed to room temperature, and stirred for 12 hours. Concentration gave crude product 10a-4 (150 mg, yellow solid). LCMS (ESI): m / z 273.2, 275.2 [M+H] + ;RT=1.369min(2.50min).

[0395] Step 4: Synthesis of 2-(2-methyl-4-nitrobenzene) methyl acetate

[0396] Compound 10a-4 (150 mg, 0.48 mmol) was placed in a 100 mL three-neck flask, and 1,4-dioxane and water mixture (9 mL, 10 / 1), MeBF3K (99 mg, 0.27 mmol), potassium carbonate (275 mg, 2.27 mmol) and PdCl2dppf (45 mg, 0.02 mmol) were added. The mixture was stirred at 80° C. for 8 hours. Ethyl acetate and water were added for extraction. The organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The crude product was purified by prep-TCL (PE / EA=5:1) to give compound 10a-5 (165 mg, off-white solid). The yield was 97%. LCMS (ESI): m / z 210.2 [M+H] + ;RT=1.456min(2.50min).

[0397] Step 5: Synthesis of 2-(4-amino-2-methylphenyl)methyl acetate

[0398] Compound 10a-5 (160 mg, 0.76 mmol) was added to a one-neck flask (100 mL) containing 3 mL of methanol, followed by the addition of palladium on carbon (16 mg) and stirring at 30° C. for 12 hours under hydrogen gas protection. Filtration through diatomaceous earth, washing with methanol, and removal of the organic phase gave crude 10a (130 mg, off-white solid). LCMS (ESI): m / z 180.2 [M+H] + ;RT=0.756min(2.50min).

[0399] Intermediate 11a: 2-(4-amino-2-fluorophenyl)methylpropionate

[0400] [ka]

[0401] Step 1: Synthesis of 2-(2-chloro-4-nitrophenyl)-2-methyldiethyl malonate

[0402] Compound 11a-1 (1 g, 6.23 mmol) was added to a one-neck flask (100 mL) containing DMF (15 mL), followed by the addition of 2-methyldiethyl malonate (1.3 g, 7.55 mmol) and sodium hydroxide (377 mg, 9.43 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by normal phase column (PE:EA=60:1) to obtain compound 11a-2 (2.0 g, yellow oil). The yield was 100%. LCMS (ESI): m / z 314.1 [M+H] + ;RT=1.832min(2.50min).

[0403] Step 2: Synthesis of 2-(2-chloro-4-nitrophenyl)propionic acid

[0404] Compound 11a-2 (2 g, 6.04 mmol) was added to a one-neck flask (100 mL) containing glacial acetic acid (7.5 mL) and water (5 mL) at room temperature, and then concentrated sulfuric acid (2 mL) was slowly added. The mixture was allowed to react at 130°C overnight. The solvent was removed, 20 mL of water was added, the pH was adjusted to 11-12, extracted with ethyl acetate, the aqueous phase was retained, the pH of the aqueous phase was adjusted to 3-4, extracted with ethyl acetate, the organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain compound 11a-3 (1 g, colorless oil). The yield was 73.4%. 1 HNMR (400MHz, CDCl3): δ8.06-8.03(m,1H),7.97-7.94(m,1H),7.55-7.51(m,1H),4.16-4.11(m,1H),1.59(d,J=7.2Hz,3H).

[0405] Step 3: Synthesis of 2-(2-chloro-4-nitrophenyl)methylpropionate

[0406] Compound 11a-3 (1.0 g, 5.49 mmol) was added to a one-neck flask (100 mL) containing methanol (15 mL), and then concentrated hydrochloric acid (0.2 mL) was added and stirred at 75° C. for 3 hours. The reaction solution was directly concentrated to obtain crude compound 11a-4 (1.0 g, colorless oil). LCMS (ESI): m / z 226.1 [MH] - ;RT=1.672min(2.50min).

[0407] Step 4: Synthesis of 2-(4-amino-2-fluorophenyl)methylpropionate

[0408] Compound 11a-4 (1.0 g, 4.4 mmol) and palladium carbon catalyst (100 mg) were added in sequence to a one-neck flask (100 mL) containing methanol (20 mL) at room temperature, and the mixture was reacted at room temperature for 2 hours under hydrogen gas. The mixture was filtered and concentrated to obtain crude compound 11a (900 mg, colorless oil). LCMS (ESI): m / z 239.2 [M+H+41] + ;RT=1.309min(2.50min).

[0409] Intermediate 12a: 6-amino-2,3-dihydrobenzofuran-3-formate ethyl ester

[0410] [ka]

[0411] Step 1: Synthesis of ethyl 6-bromobenzofuran-3-formate

[0412] Compound 12a-1 (8 g, 40 mmol) and tetrafluoroborate ethyl ether solution (0.6 mL) were added to a one-neck flask (250 mL) containing dichloromethane (40 mL), and then a solution of ethyl diazoacetate (9.2 g, 8 mmol) in dichloromethane (10 mL) was added dropwise and stirred at room temperature for 1 hour. The mixture was concentrated to remove the solvent, and concentrated sulfuric acid (4 mL) was added and stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with dichloromethane, and the organic phases were combined. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude product was purified by column (PE:EA=3:1) to obtain compound 12a-2 (7.1 g, white solid), with a yield of 66%. 1 H-NMR (400MHz, CDCl3): δ8.21(s,1H),7.92(d,J=8.0Hz,1H),7.71(d,J=1.6H z,1H),7.48(dd,J=8.4,1.6Hz,1H),4.45-4.36(m,2H),1.42(t,J=8.0Hz,3H).

[0413] Step 2: Synthesis of ethyl 6-(diphenylmethyleneamino)benzofuran-3-formate

[0414] 12a-2 (2.70 g, 10.0 mmol), benzophenone imine (2.72 g, 10.0 mmol), cesium carbonate (6.52 g, 20.0 mmol), BIANP (623 mg, 1.0 mmol) and Pd2dba3 (916 mg, 1.0 mmol) were added in sequence to a one-neck flask (100 mL) containing 1,4-dioxane (50 mL), and the mixture was reacted at 100° C. for 16 hours under nitrogen protection. After removing the solvent, the mixture was purified by column (PE / EA=1 / 1) to obtain compound 12a-3 (3.40 mg, yellow solid), with a yield of 92%. LCMS (ESI): m / z 370.3 [M+H] + ;RT=1.64min(2.50min).

[0415] Step 3: Synthesis of ethyl 6-aminobenzofuran-3-formate

[0416] 12a-3 (3.40 g, 9.21 mmol) and 4N hydrochloric acid (25 mL) were added to a one-neck flask (250 mL) containing THF (50 mL) and stirred at room temperature for 3 hours. After removing the solvent, the aqueous phase was washed with ethyl acetate and the pH was adjusted to 8 with sodium bicarbonate solution. Further extraction with EA was performed, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 12a-4 (1.70 g, yellow solid), with a yield of 90%. LCMS (ESI): m / z 306.0 [M+H] + ;RT=1.476min(2.50min).

[0417] Step 4: Synthesis of ethyl 6-amino-2,3-dihydrobenzofuran-3-formate

[0418] Compound 12a-4 (1.3 g, 6.34 mmol) and magnesium turnings (1.54 g, 63.40 mmol) were added to a one-neck flask (250 mL) containing methanol (100 mL), and the mixture was stirred at room temperature for 4 hours to react. Ethyl acetate was added, and the mixture was concentrated. The crude product obtained was purified by column (PE / EA=1 / 1) to obtain compound 12a (1.1 g, yellow oil), with a yield of 84%. LCMS (ESI): m / z 208.2 [M+H] +;RT=1.18min(2.50min).

[0419] Intermediate 13a: Ethyl 2-(6-aminopyridin-3-yl)-2-methylpropionate

[0420] [ka]

[0421] Step 1: Synthesis of ethyl 2-methyl-2-(6-nitropyridin-3-yl)propionate

[0422] Compound 13a-1 (1.5 g, 7.14 mmol) was dissolved in DMF (15 mL), sodium hydride (857 mg, 21.42 mmol) was added in batches at 0 ° C., and the mixture was stirred for half an hour while keeping at 0 ° C., and then methyl iodide (3.04 g, 21.42 mmol) was slowly added dropwise, and after the addition was completed, the mixture was stirred at room temperature for 3 hours. The mixture was quenched by pouring into water, extracted with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by (PE / EA=10 / 1) to obtain compound 13a-2 (1.0 g, yellow oily liquid), with a yield of 59%. LCMS (ESI): m / z 239.1 [M+H] + ;RT=1.56min(3min).

[0423] Step 2: Synthesis of ethyl 2-(6-aminopyridin-3-yl)-2-methylpropionate

[0424] Compound 13a-2 (1 g, 4.2 mmol), anhydrous methanol (15 mL), and 10% palladium on carbon (200 mg) were added to a dry one-neck flask (50 mL) at room temperature, and the mixture was reacted overnight at room temperature under hydrogen gas protection. The reaction mixture was filtered under reduced pressure, and the filtrate was concentrated to give compound 13a (600 mg, yellow oily liquid), with a yield of 68.7%. LCMS (ESI): m / z 209.1 [M+H] + ;RT=0.99min(3min).

[0425] Intermediate 14a: 4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-formate methyl

[0426] [ka]

[0427] Step 1: Synthesis of methyl 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-formate

[0428] 14a-1 (5 g, 27.78 mmol) was added to a three-neck flask containing 20 mL of N-methylpyrrolidone, and sodium hydride (2.8 g, 69.45 mmol) was added under ice bath. The reaction was allowed to proceed for half an hour at 0°C, and 1-bromo-2-(2-bromoethoxy)ethane (7.1 g, 30.56 mmol) was added and the reaction was allowed to proceed for 1 hour at room temperature. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and subjected to column chromatography (EA:PE=1:3) to obtain compound 14a-2 (2.1 g, colorless oil). 1 HNMR(400MHz, CDCl3-d): δ7.27(d,J=8Hz,2H),6.88(d,J=8.8Hz,2H),3.97-3.91(m,2H ),3.84(s,3H),3.67(s,3H),3.61-3.40(m,2H),2.52-2.49(m,2H),1.99-1.93(m,2H).

[0429] Step 2: Synthesis of methyl 4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-formate

[0430] Compound 14a-2 (1 g, 4 mmol) was added to a three-neck flask containing 15 mL of dichloromethane, and boron tribromide (5 g, 20 mmol) was added under ice bath, and the mixture was reacted at room temperature for 2 hours. The reaction solution was poured into water, extracted with dichloromethane, and the organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain crude product 14a (900 mg, colorless oil). 1H-NMR(400MHz,DMSO-d6):δ9.40(s,1H),7.15(d,J=8.4Hz,2H),6.73(d,J=8.8Hz,2H),3 .80-3.76(m,2H),3.58(s,3H),3.40-3.35(m,2H),2.36-2.32(m,2H),1.84-1.77(m,2H).

[0431] Intermediate 15a: 6-Hydroxy-1-methyl-1,2,3,4-tetrahydronaphthalene-1-formic acid

[0432] [ka]

[0433] Step 1: Synthesis of methyl 6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene-1-formate

[0434] Sodium hydride (270 mg, 6.81 mmol) and DMF (20 mL) were added to a dry 50 mL three-neck flask at 0° C. in sequence. Under nitrogen protection, a solution of compound 15a-1 (500 mg, 2.27 mmol) and methyl iodide (0.42 mL, 6.81 mmol) in DMF (10 mL) was added at 0° C. The mixture was stirred at 0° C. for 30 minutes and further stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by a preparative plate (PE:EA=20:1) to give compound 15a-2 (500 mg, yellow oil), with a yield of 94.01%. LCMS (ESI): m / z 235.2 [MH] - ;RT=1.567min(2.50min).

[0435] Step 2: Synthesis of methyl 6-hydroxy-1-methyl-1,2,3,4-tetrahydronaphthalene-1-formate

[0436] Aluminium trichloride (1420 mg, 10.67 mmol), dichloromethane (30 mL) and compound 15a-2 (500 mg, 2.13 mmol) were added to a dry 100 mL three-neck flask at 0° C. in sequence. The mixture was stirred at 0° C. for 10 minutes, and then ethyl mercaptan (0.79 mL, 10.67 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with dichloromethane. The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 15a-3 (430 mg, yellow oil), with a yield of 91.48%. LCMS (ESI): m / z 221.2 [M+H] + ;RT=1.506min(2.50min).

[0437] Step 3: Synthesis of 6-hydroxy-1-methyl-1,2,3,4-tetrahydronaphthalene-1-formic acid

[0438] Compound 15a-3 (380 mg, 1.73 mmol), 1,4-dioxane (24 mL), water (8 mL) and potassium t-butoxide (968 mg, 8.63 mmol) were added sequentially to a dry 25 mL one-neck flask at room temperature. The mixture was heated to 60° C. and reacted for 24 hours. The reaction solution was adjusted to pH 4 with 1 mol / L aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic phase was collected, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain product 15a (350 mg, white solid), with a yield of 98.37%. LCMS (ESI): m / z 205.2 [MH] - ;RT=1.258min(2.50min).

[0439] Intermediate 16a: 2-(indol-5-yl)methyl acetate

[0440] [ka]

[0441] Step 1: Synthesis of 5-(2-(t-butoxy)-2-oxyethyl)indole-1-formic acid t-butyl ester

[0442] Lithium bistrimethylsilylamide (2.5mL, 2.50mmol), palladium(II) acetate (catalytic amount) and tri-t-butylphosphine (catalytic amount) were placed in a 100mL three-neck flask, and then 5mL of anhydrous toluene was added under nitrogen protection. Acetic acid t-butyl ester (269mg, 2.32mmol) was slowly added dropwise at -10℃ and stirred for 20 minutes. Next, 16a-1 (300g, 1.01mmol) was added dropwise, and after the addition was completed, the temperature was raised to 80℃ and reacted for 2 hours. Extraction was performed by adding ethyl acetate and water at room temperature. The organic phase was washed with salt water, dried over anhydrous sodium sulfate, concentrated, and then purified by column (PE:EA=10:1) to obtain 16a-2 (180mg, yellow oil). The yield was 54%. 1 HNMR (400MHz, CDCl3): δ7.65-7.44(m,1H),7.05-7.03(m,1H),3.99-3.96(m,2H),3.44(s,2H),3.08-3.05(m,2H),1.56(s,9H),1.47(s,9H).

[0443] Step 2: Synthesis of 2-(indol-5-yl)methyl acetate

[0444] A 50 mL one-neck flask was charged with 16a-2 (160 mg, 0.48 mmol), 5 mL of methanol, and 3 drops of concentrated sulfuric acid. The mixture was stirred at 70° C. overnight. After cooling to room temperature, the solvent was removed, water and ethyl acetate were added, and the pH was adjusted to 9 with aqueous sodium bicarbonate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed to give 16a (90 mg, yellow oil). LCMS (ESI): m / z 192.2 [MH] - ;RT=0.645min(2.50min).

[0445] Intermediate 17a: 3-(4-methoxyphenyl)tetrahydrofuran-3-formic acid

[0446] [ka]

[0447] Step 1: Synthesis of 3-(4-methoxyphenyl)tetrahydrofuran-3-ol

[0448] Under nitrogen protection, n-butyllithium (8.7ml, 13.48mmol, 1.6N) was slowly added dropwise to a 100mL three-neck flask containing p-bromoanisole (2.82g, 14.6mmol) in anhydrous THF (25mL) at -78℃. After reacting for 30 minutes, a THF solution of compound 17a-1 (1.0g, 11.23mmol) was slowly added dropwise, stirred at -78℃ for 10 minutes, and warmed to room temperature. The reaction solution was quenched with a saturated ammonium chloride solution, diluted with water, washed and extracted with ethyl acetate and water. The organic phase was washed with sodium chloride, dried over anhydrous sodium sulfate, and filtered. The mixture was purified using a silica gel column (PE:EA=1:1) to obtain compound 17a-2 (2.0g, white solid). The yield was 92%. 1 HNMR (400MHz, CDCl3): δ7.41-7.38(m,2H),6.92-6.88(m,2H),4.22-4.07(m,2H),3.99- 3.95(m,1H),3.86(d,J=9.2Hz,1H),3.81(s,3H),2.42-2.35(m,1H),2.27-2.16(m,1H).

[0449] Step 2: Synthesis of 2-(3-(4-methoxyphenyl)tetrahydrofuran-3-yl)-5-methylfuran

[0450] Compound 17a-2 (200 mg, 1.03 mmol), 2-methylfuran (422 mg, 5.1 mmol), lithium bis(trifluoromethanesulfonyl)amide (33 mg, 0.11 mmol) and tetrabutylammonium hexafluorophosphate (22 mg, 0.062 mmol) were added in sequence to a 50 mL one-neck flask containing 5 mL of anhydrous toluene, and reacted at 60 ° C. for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was washed with sodium chloride, dried over anhydrous sodium sulfate, and filtered. Purification was performed by prep-TLC (PE:EA = 15:1) to obtain compound 17a-3 (220 mg, yellow oil). The yield was 83%. 1 HNMR (400MHz, CDCl3): δ7.19-7.15(m,2H),6.86-6.82(m,2H),5.99(d,J=3.2Hz,1H),5.87-5.86(m,1H),4.35(d,J=8 .4Hz,1H),4.12(d,J=8.4Hz,1H),4.02-3.97(m,2H),3.78(s,3H),2.72-2.66(m,1H),2.42-2.35(m,1H),2.22(s,3H).

[0451] Step 3: Synthesis of 3-(4-methoxyphenyl)tetrahydrofuran-3-formic acid

[0452] Compound 17a-3 (220 mg, 0.85 mmol), sodium periodate (422 mg, 5.1 mmol) and ruthenium trichloride (catalytic amount) were added to a 50 mL one-neck flask containing 8 mL of mixed solvent (n-heptane: EA: water = 1: 1: 2) at 0 ° C. in order, and reacted overnight at room temperature under nitrogen protection, diluted with water, extracted with ethyl acetate, washed with sodium chloride, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain compound 17a (200 mg, yellow solid). 1HNMR(400MHz,DMSO-d6):δ12.51(brs,1H),7.23-7.21(m,2H),6.91-6.89(m,2H),4.50(d,J=8.0Hz ,1H),3.86-3.76(m,2H),3.73(s,3H),3.68(d,J=8.4Hz,1H),2.84-2.78(m,1H),2.15-2.08(m,1H).

[0453] Intermediate 18a: 6-Hydroxy-1,2,3,4-tetrahydronaphthalene-1-formate methyl ester

[0454] [ka]

[0455] Step 1: Synthesis of 6-methoxy-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate

[0456] Compound 18a-1 (500 mg, 2.84 mmol) and anhydrous THF (10 mL) were added to a dry 50 mL one-neck flask at room temperature. Under nitrogen protection, the mixture was cooled to -78 ° C., lithium bistrimethylsilylamide (4.26 mL, 4.26 mmol) was slowly added dropwise, and after the addition was completed, the mixture was reacted for 1 hour. Next, N-phenylbis(trifluoromethanesulfonimide) (2030 mg, 5.67 mmol) was added, and the mixture was reacted for 2 hours at -78 ° C. 20 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The crude product was purified by column chromatography (PE:EA = 50:1) to obtain compound 18a-2 (800 mg, yellow solid), with a yield of 91.46%. 1 H-NMR (400MHz, CDCl3): δ7.42-7.38(m,1H),6.78-6.73(m,2H),5.86(t,J=4.8Hz,1H),3.81(s,3H),2.83(t,J=8.0Hz,2H),2.50-2.45(m,2H).

[0457] Step 2: Synthesis of methyl 6-methoxy-3,4-dihydronaphthalene-1-formate

[0458] Compound 18a-2 (700 mg, 2.27 mmol), methanol (20 mL), triethylamine (1.58 mL, 11.35 mmol) and PdCl2dppf (830 mg, 1.14 mmol) were added to a 50 mL one-neck flask at room temperature. The mixture was purged with carbon monoxide three times and reacted at 90 °C for 16 hours with stirring. The mixture was concentrated under reduced pressure. The crude product was purified by a separation plate (PE:EA = 20:1) to obtain compound 18a-3 (300 mg, yellow oil), with a yield of 60.53%. 1 H-NMR (400MHz, CDCl3): δ7.74(d,J=8.4Hz,1H),7.03(t,J=4.8Hz,1H),6.77-6. 71(m,2H),3.83(s,3H),3.81(s,3H),2.74(t,J=8.0Hz,2H),2.40-2.35(m,2H).

[0459] Step 3: Synthesis of methyl 6-methoxy-1,2,3,4-tetrahydronaphthalene-1-formate

[0460] Compound 18a-3 (300 mg, 1.37 mmol), methanol (10 mL) and palladium carbon catalyst (30 mg) were added to a dry 50 mL one-neck flask at room temperature. The atmosphere was replaced with hydrogen gas three times and the reaction was carried out by stirring at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain compound 18a-4 (240 mg, yellow oil), with a yield of 79.27%. 1 H-NMR (400MHz, CDCl3): δ7.08(d,J=8.8Hz,1H),6.72-6.70(m,1H),6.63(d,J=2.4Hz,1H),3.79-3.7 7(m,4H),3.71(s,3H),2.85-2.71(m,2H),2.16-2.10(m,1H),2.02-1.92(m,2H),1.78-1.72(m,1H).

[0461] Step 4: Synthesis of methyl 6-hydroxy-1,2,3,4-tetrahydronaphthalene-1-formate

[0462] Aluminum trichloride (726 mg, 5.45 mmol), dichloromethane (15 mL) and compound 18a-4 (240 mg, 1.09 mmol) were added to a 50 mL three-neck flask at 0° C. in sequence. The mixture was stirred at 0° C. for 10 minutes, and then ethyl mercaptan (0.40 mL, 5.45 mmol) was added and the mixture was reacted at room temperature for 2 hours. The mixture was poured into water and extracted with dichloromethane. The organic phase was collected, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 18a (210 mg, yellow oil), with a yield of 93.45%. 1 H-NMR (400MHz, CDCl3): δ7.01(d,J=8.4Hz,1H),6.61-6.58(m,1H),6.54(d,J=2.4Hz,1H),5.02( s,1H),3.78-3.75(m,1H),3.71(s,3H),2.81-2.64(m,2H),2.15-1.88(m,3H),1.77-1.68(m,1H).

[0463] Intermediate 19a: Methyl 2-(4-hydroxyphenyl)-3-methylbutyrate

[0464] [ka]

[0465] Step 1: Synthesis of methyl 2-(4-methoxyphenyl)-3-methylbutyrate

[0466] In a dry 100 mL single-neck flask, potassium t-butoxide-THF (1.0 M, 8.25 mL, 8.25 mmol), THF (20 mL), compound 19a-1 (1.00 g, 5.50 mmol) and iodoisopropane (1.50 g, 8.25 mmol) were added successively at 0° C. The reaction was allowed to proceed at room temperature for 2 hours. The mixture was poured into 50 mL of water and extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography column (PE:EA=5:1) to give compound 19a-2 (0.86 g, yellow solid), with a yield of 69.70%.1 H-NMR (400MHz, CDCl3-d): δ9.60(d,J=8.4Hz,2H),9.20(d,J=8.4Hz,2H),6.15(s,3H),6.00(s ,3H),5.46(d,J=10.8Hz,1H),4.68-4.62(m,1H),3.38(d,J=6.4Hz,3H),3.04(d,J=8.8Hz,3H).

[0467] Step 2: Synthesis of methyl 2-(4-hydroxyphenyl)-3-methylbutyrate Aluminum trichloride (2.58 g, 19.34 mmol), DCM (100 mL), and compound 19a-2 (0.86 g, 3.87 mmol) were added to a 100 mL three-neck flask at 0° C. in sequence. The mixture was stirred at 0° C. for 10 minutes. Ethyl mercaptan (1.43 mL, 19.34 mmol) was added at 0° C. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was poured into 100 mL of water and extracted with ethyl acetate. The organic phase was collected, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography column (PE:EA=3:1) to give compound 19a (0.68 g, yellow oil), with a yield of 84.40%. LCMS (ESI): m / z 209.2 [M+H] + ;RT=1.571min(2.50min).

[0468] Intermediate 20a: 4-(4-methoxyphenyl)oxepane-4-formic acid

[0469] [ka]

[0470] Step 1: Synthesis of 4-(4-methoxyphenyl)oxepan-4-ol

[0471] 1-Bromo-4-methoxybenzene (5.9g, 31.6mmol) was added to a 250mL three-neck flask containing 60mL of THF at room temperature, followed by n-butyllithium (14.7mL, 26.3mmol) at -78℃. After half an hour of reaction, compound 20a-1 (3g, 36.8mmol) was added and reacted at -78℃ for 2 hours. The reaction solution was quenched with saturated ammonium chloride, diluted with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated saline, and concentrated to obtain crude product 20a-2 (4.2g, colorless oil). The yield was 71.9%. 1 HNMR(400MHz,CDCl3):δ7.42-7.40(m,2H),6.88-6.86(m,2H),3.94-3.88(m ,2H),3.80(s,3H),3.75-3.67(m,2H),2.29-2.12(m,4H),1.93-1.88(m,2H).

[0472] Step 2: Synthesis of 4-(4-methoxyphenyl)-4-(5-methylfuran-2-yl)oxepane

[0473] 20a-2 (4.2 g, 18.9 mmol), 2-methylfuran (7.76 g, 94.6 mmol), lithium bistrifluoromethanesulfonimide (597 mg, 2.08 mmol) and tetrabutylammonium hexafluorophosphate (366 mg, 0.95 mmol) were added to a 100 mL one-neck flask containing 50 mL of toluene, and the mixture was reacted at 40° C. for 2 hours. After filtration and concentration of the filtrate, the compound 20a-3 (4.7 g, colorless oil) was obtained by column chromatography. The yield was 86.9%. 1 HNMR (400MHz, CDCl3): δ7.09-7.06(m,2H),6.82-6.80(m,2H),5.97-5.90(m ,2H),3.76-3.71(m,7H),2.40-2.29(m,4H),2.23(s,3H),1.75-1.72(m,2H).

[0474] Step 3: Synthesis of 4-(4-methoxyphenyl)oxepane-4-formic acid

[0475] 20a-3 (4.7 g, 16.4 mmol) was added to a 2000 mL one-neck flask containing a mixed solvent of 200 mL n-heptane, 200 mL ethyl acetate, and 400 mL water at room temperature, and sodium periodate (24.6 g, 115 mmol) was added in an ice bath. After stirring for 5 minutes, ruthenium trichloride (catalytic amount) was added. The reaction solution was filtered, diluted with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain crude product 20a (2.6 g, yellow oil). LCMS (ESI): m / z 251.1 [M+H] + ;RT=1.064min(2.50min).

[0476] Intermediate 21a: 3-(4-methoxyphenyl)-8-oxabicyclo[3.2.1]octane-3-formic acid

[0477] [ka]

[0478] Referring to the synthesis method of intermediate 20a, 8-oxabicyclo[3.2.1]octan-3-one was used as the starting material. 1 HNMR(400MHz,DMSO-d6):δ12.21-12.17(m,1H),7.40(d,J=8.8Hz,2H),6.88(d,J=8.8Hz,2H),4.33-4 .29(m,2H),3.74(s,1H),2.73-2.68(m,2H),1.96-1.92(m,2H),1.69-1.66(m,2H),1.20-1.17(m,2H).

[0479] Intermediate 22a:

[0480] [ka]

[0481] Step 1: 3-(1-methoxy-1-oxopropan-2-yl)pyrrolidine-1-formic acid t-butyl ester

[0482] Under nitrogen protection, 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-formic acid t-butyl ester (500 mg, 2.05 mmol) and THF (5 mL) were added to a 100 mL three-neck flask in this order, and lithium diisopropylamide (2 M, 3 mL) was added dropwise at -78°C. After reacting for 1 hour, a THF solution (5 mL) of methyl iodide (1.75 g, 12.3 mmol) was added. The reaction was allowed to proceed at room temperature for 1 hour, and the reaction solution was quenched with a saturated ammonium chloride solution, diluted with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product 22a-1 (150 mg, yellow solid).

[0483] Step 2: 3-(1-methoxy-2-methyl-1-oxopropan-2-yl)pyrrolidine-1-formic acid t-butyl ester

[0484] Under nitrogen protection, 22a-1 (150 mg, 0.58 mmol) and THF (3 mL) were added to a 50 mL three-neck flask in this order, and lithium diisopropylamide (2 M, 0.88 mL) was added dropwise at -78 ° C., and the mixture was reacted for 1 hour, after which a THF solution of methyl iodide (123 mg, 0.87 mmol) was added. The mixture was reacted at room temperature for 1 hour, and the reaction solution was quenched with a saturated ammonium chloride solution, diluted with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 22a-2 (105 mg, transparent oil). 1 HNMR(400MHz,DMSO-d6):δ3.68(d,J=6.0Hz,3H),3.55-3.36(m,2H),3.26-3.20(m,1H ),3.10-2.99(m,1H),2.45-2.37(m,1H),1.87-1.81(m,1H),1.46(s,9H),1.19(s,6H).

[0485] Step 3: 2-Methyl-2-(pyrrolidin-3-yl)methylpropionate hydrochloride

[0486] Compound 22a-2 (800 mg, 2.95 mmol) and TFA (2 mL) were added in sequence to a 50 mL one-neck flask containing 6 mL of dichloromethane at room temperature. The mixture was reacted at room temperature for 4 hours, adjusted to pH=9, diluted with water, extracted with dichloromethane, and the organic phase was washed with water and saturated saline in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 22a (500 mg, yellow oil).

[0487] Example 1 Preparation of Compound 1

[0488] [ka]

[0489] Step 1: Synthesis of 2-amino-6-methoxynicotinic acid

[0490] 2-Amino-6-chloronicotinic acid (5 g, 29 mmol), sodium methoxide (15.7 g, 290 mmol), and methanol (50 mL) were added sequentially to a dry one-neck flask (100 mL) at room temperature. The mixture was heated to 80° C. and reacted for 48 hours. The mixture was cooled to room temperature, filtered under reduced pressure, and the filter cake was washed with methanol and dried in vacuum to obtain compound 1-1 (2 g, white solid), with a yield of 40%. LCMS (ESI): m / z 169.0 [M+H] + ;RT=1.10min(3min).

[0491] Step 2: Synthesis of 7-methoxypyrido[2,3-d]pyrimidine-4-phenol

[0492] 1-1 (1 g, 6 mmol), formamidine acetate (624 mg, 17.8 mmol), and ethylene glycol methyl ether (10 mL) were added to a dry one-neck flask (50 mL) in that order at room temperature. The mixture was heated to 100° C. and reacted for 18 hours. The reaction solution was concentrated, and the residue was purified by a silica gel column (DCM:methanol=10:1) to obtain compound 1-2 (200 mg, white solid), with a yield of 20%. LCMS (ESI): m / z 177.9 [M+H] +;RT=1.502min(3min).

[0493] Step 3: Synthesis of 4-chloro-7-methoxypyrido[2,3-d]pyrimidine

[0494] 1-2 (200 mg, 1.13 mmol) and phosphorus oxychloride (10 mL) were added successively to a dry one-neck flask (50 mL) at room temperature. The mixture was heated to 100° C. and reacted for 16 hours. The reaction solution was concentrated, and the residue was alkalized to pH 9 with sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried over sodium sulfate and concentrated to obtain compound 1-3 (200 mg, white solid), with a yield of 90%. LCMS (ESI): m / z 339.7 [M+H] + ;RT=1.521min(3min).

[0495] Step 4: Synthesis of ethyl 2-(4-((7-methoxypyrido[2,3-d]pyrimidin-4-yl)amino)phenyl)acetate

[0496] 1-3 (200 mg, 1.02 mmol) and ethyl 2-(4-aminophenyl)acetate (275 mg, 1.54 mmol) were added sequentially to a dry one-neck flask (50 mL) at room temperature. The mixture was heated to 80° C. and reacted for 16 hours. The reaction solution was extracted with ethyl acetate and water, and the organic phase was washed with saturated saline, dried over sodium sulfate, concentrated, and purified by (PE:EA=10:1-1:1) to obtain compound 1-4 (100 mg, white solid), with a yield of 29%. LCMS (ESI): m / z 339.1 [M+H] + ;RT=1.33min(3min).

[0497] Step 5: Synthesis of N-hydroxy-2-(4-((7-methoxypyrido[2,3-d]pyrimidin-4-yl)amino)phenyl)acetamide

[0498] 1-4 (100 mg, 0.30 mmol), 50% aqueous hydroxylamine solution (1 mL), methanol (2 mL), THF (2 mL), and sodium hydroxide (60 mg, 1.5 mmol) were added to a dry one-neck flask (50 mL) in that order at room temperature. The reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was acidified to pH 7 with 1 M dilute hydrochloric acid, concentrated, and the precipitated solid was washed with methanol and dried to obtain compound 1 (20 mg, white solid), with a yield of 20%. LCMS (ESI): m / z 326.1 [M+H] + ;RT=0.92min(3min). 1 HNMR(400MHz,DMSO-d6):δ10.67(s,1H),9.90(s,1H),8.33-8.62(m,2H),8.61(m,1H) ,7.70-7.69(m,2H),7.28-7.26(m,2H),7.12-7.11(m,1H),4.01(s,2H),3.28(s,2H).

[0499] Example 2 Preparation of Compound 2

[0500] [ka]

[0501] Step 1: Synthesis of 2-(4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)methyl acetate

[0502] 1a-3 (0.5 g, 2.84 mmol), BOP reagent (2.51 g, 5.68 mmol) and anhydrous cesium carbonate (3.7 g, 11.36 mmol) were added in sequence to a one-neck flask (100 mL) containing anhydrous DMF (20 mL). After stirring at room temperature for 1 hour, 2-(4-hydroxyphenyl)methyl acetate (940 mg, 5.68 mmol) and anhydrous cesium carbonate (3.7 g, 11.36 mmol) were added. After reacting at 70° C. for 6 hours, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column (EA / PE=2 / 1) to obtain compound 2-1 (280 mg, yellow solid), with a yield of 30%. LCMS (ESI): m / z 325.2 [M+H] +;RT=1.307min(2.50min).

[0503] Step 2: Synthesis of 2-(4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)acetic acid

[0504] 2-1 (280 mg, 0.864 mmol) and lithium hydroxide (42 mg, 1.73 mmol) were added in sequence to a one-neck flask (50 mL) containing 5 mL of a mixed solvent (THF / water = 3 / 1), and the mixture was allowed to react at room temperature overnight with stirring. After concentrating the reaction solution, the pH was adjusted to 4 with 1N hydrochloric acid to precipitate a solid, which was then filtered and collected to obtain compound 2-2 (200 mg, yellow solid), with a yield of 75%. LCMS (ESI): m / z 311.1 [M+H] + ;RT=0.96min(2.50min).

[0505] Step 3: Synthesis of 2-(4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acetamide

[0506] 2-2 (200 mg, 0.644 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (114 mg, 0.966 mmol), and DIEA (250 mg, 1.93 mmol) were added in sequence to a one-neck flask (100 mL) containing anhydrous DMF (8 mL). After stirring uniformly, HATU (490 mg, 1.29 mmol) was slowly added thereto and stirred at room temperature for 1 hour to react. The reaction solution was concentrated and purified by prep-TLC (dichloromethane:methanol=20:1) to obtain compound 2-3 (200 mg, yellow solid), with a yield of 76%. LCMS (ESI): m / z 410.2 [M+H] + ;RT=1.237min(2.50min).

[0507] Step 4: Synthesis of N-hydroxy-2-(4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)acetamide

[0508] 2-3 (200 mg, 0.49 mmol) and TsOH (252 mg, 1.47 mmol) were added in sequence to a one-neck flask (50 mL) containing acetonitrile (5 mL), and the mixture was stirred at room temperature for 2 hours to react. The reaction solution was concentrated, and the crude product was separated and purified by reverse phase fractionation to obtain compound 2 (30 mg, white solid), with a yield of 19%. LCMS (ESI): m / z 326.0 [M+H] + ;RT=3.245min(6.00min). 1 H-NMR(400MHz,DMSO-d6):δ8.69(d,J=6.4Hz,1H),8.58(d,J=8.8Hz,1H),7.41(d,J=8.4Hz,2H) ,7.24(d,J=8.8Hz,2H),7.15(d,J=9.2Hz,1H),6.54(d,J=5.2Hz,1H),4.04(s,3H),3.35(s,2H).

[0509] Example 3 Preparation of Compound 3

[0510] [ka]

[0511] Step 1: Synthesis of 4-((7-methoxyquinolin-4-yl)oxy)benzoic acid methyl ester

[0512] 4-Chloro-7-methoxyquinoline (100 mg, 0.52 mmol), methylparaben (95 mg, 0.62 mmol), potassium carbonate (143 mg, 1.04 mmol), and DMF (5 mL) were added to a dry one-neck flask (50 mL) in sequence at room temperature, and the mixture was heated to 130° C. and reacted overnight. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column (PE:EA=3:1) to obtain compound 3-1 (90 mg, pale yellow solid), with a yield of 56.00%. LCMS (ESI): m / z 310.1 [M+H] + ;RT=1.81min(3.00min).

[0513] Step 2: Synthesis of 4-((7-methoxyquinolin-4-yl)oxy)benzeneformic acid

[0514] 3-1 (90 mg, 0.29 mmol), THF (3 mL), water (1 mL), and lithium hydroxide monohydrate (36 mg, 0.67 mmol) were added sequentially to a dry one-neck flask (25 mL) at room temperature. The reaction was allowed to proceed and stirred at room temperature overnight. The reaction solution was adjusted to pH 6 with 1 M dilute hydrochloric acid, THF was removed under reduced pressure, filtered, and the filter cake was washed with water and dried to obtain compound 3-2 (70 mg, pale yellow solid), with a yield of 81.39%. LCMS (ESI): m / z 296.1 [M+H] + ;RT=1.39min(3.00min).

[0515] Step 3: Synthesis of N-hydroxy-4-((7-methoxyquinolin-4-yl)oxy)benzamide

[0516] 3-2 (30 mg, 0.10 mmol), DIEA (39 mg, 0.30 mmol), HATU (57 mg, 0.15 mmol) and DMF (3 mL) were added to a dry one-neck flask (25 mL) in sequence at room temperature. The reaction mixture was stirred at room temperature for 10 min. 50% aqueous hydroxylamine solution (7 mg, 0.20 mmol) was added and the reaction mixture was stirred for 2 h. The residue was concentrated and purified by high performance reverse phase liquid preparative column to give compound 3 (11 mg, milky white solid) in 35.48% yield. LCMS (ESI): m / z 310.7 [M+H] + ;RT=3.199min(15.00min). 1 H-NMR(400MHz,DMSO-d6):δ11.27(s,1H),9.08(s,1H),8.67-8.66(m,1H),8.16-8.14(m, 1H),7.90-6.88(m,2H),7.43(s,1H),7.34-7.28(m,3H),7.61-7.60(m,1H),3.94(s,3H).

[0517] Example 4 Preparation of Compound 4

[0518] [ka]

[0519] Step 1: Synthesis of ethyl 2-(4-(((7-methoxyquinolin-4-yl)amino)phenyl)acetate

[0520] 4-Chloro-7-methoxyquinoline (1.50 g, 10.33 mmol) was added to a one-neck flask (100 mL) containing IPA (10 mL), followed by ethyl 2-(4-aminophenyl)acetate (1.39 mg, 10.33 mmol) and concentrated hydrochloric acid (1.95 mL, 30.99 mmol), and stirred at 90 °C under nitrogen protection for 1.5 h. After cooling, sodium bicarbonate was added at room temperature to adjust the pH to 9-10, followed by slurrying with petroleum ether-dichloromethane (10:1, 100 mL), filtering, and washing the filter cake with petroleum ether to obtain crude product 4-1 (2.0 g, yellow solid), yield 58%. LCMS (ESI): m / z 337.0 [M+H] + ;RT=1.120min(2.50min).

[0521] Step 2: Synthesis of 2-(4-((7-methoxyquinolin-4-yl)amino)phenyl)acetic acid

[0522] 4-1 (700 mg, 2.08 mmol) and lithium hydroxide (98 mg, 4.14 mmol) were added in sequence to a one-neck flask (100 mL) containing a mixed solution of THF (12 mL) and water (4 mL) at room temperature, and the mixture was allowed to react at room temperature for 16 hours. The solvent was removed, and the pH was adjusted to 3-4 by adding a 1 mol / L aqueous hydrochloric acid solution. The aqueous phase was freeze-dried to obtain crude product 4-2 (700 mg, white solid). LCMS (ESI): m / z 309.1 [M+H] + ;RT=0.762min(2.50min).

[0523] Step 3: Synthesis of 2-(4-((7-methoxyquinolin-4-yl)amino)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acetamide

[0524] 4-2 (200 mg, 0.65 mmol) was added to a one-neck flask (100 mL) containing DMF (5 mL), followed by batchwise addition of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (92 mg, 0.78 mmol), TEA (132 mg, 1.30 mmol) and HATU (370 mg, 0.97 mmol). The mixture was stirred at room temperature for 3 hours. Ethyl acetate and water were added at room temperature for washing and extraction. The organic phase was washed with sodium chloride, dried over anhydrous sodium sulfate and filtered. Purification was carried out by prep-TCL (dichloromethane:methanol=20:1) to give compound 4-3 (200 mg, white solid), with a yield of 76%. LCMS (ESI): m / z 408.2 [M+H] + ;RT=1.137min(2.50min).

[0525] Step 4: Synthesis of N-hydroxy-2-(4-(((7-methoxyquinolin-4-yl)amino)phenyl)acetamide

[0526] 4-3 (100 mg, 0.25 mmol) and TsOH (94 mg, 0.49 mmol) were added sequentially to a one-neck flask (50 mL) containing acetonitrile (10 mL) at room temperature, and the reaction was allowed to proceed for 3 hours at room temperature. The reaction solution was purified by prep-HPLC (formic acid system) to obtain compound 4 (43 mg, white solid), with a yield of 53%. LCMS (ESI): m / z 324.0 [M+H] + ;RT=3.155min(6.00min). 1 HNMR(400MHz,MeOD-d4):δ8.43(d,J=9.2Hz,1H),8.24(d,J=7.2Hz,1H),7.41-7 .39(m,3H),7.24-7.23(m,3H),6.76(d,J=7.2Hz,1H),4.02(s,3H),3.50(s,2H).

[0527] Examples 5 to 17 Compounds 5 to 17 were synthesized according to the methods described in Examples 1 to 4, respectively, and the structural formula of the compound of each Example is shown in the above table.

[0528] [Table 3]

[0529] Example 18 Preparation of Compound 18

[0530] [ka]

[0531] Step 1: Synthesis of N-(4-chloropyridin-2-yl)pivalamide

[0532] 4-Chloropyridin-2-amine (12.8 g, 100 mmol), triethylamine (13.1 g, 130 mmol), pyridine (15 mL) and dichloromethane (15 mL) were added to a dry one-neck flask (100 mL) at room temperature in that order, and pivaloyl chloride (13.2 g, 110 mmol) was added dropwise under ice bath conditions. After the addition was completed, the mixture was reacted and stirred overnight. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column (PE / EA=10 / 1) to obtain compound 18-1 (18.5 g, powder-colored solid), with a yield of 87%. 1 H-NMR (400MHz, CDCl3):8.36-8.35(m,1H),8.16-8.14(m,1H),8.10(s,1H),7.05-7.03(m,1H),1.30(s,9H).

[0533] Step 2: Synthesis of N-(4-chloro-3-formylpyridin-2-yl)pivalamide

[0534] 18-1 (11.4 g, 53.8 mmol) and THF (70 mL) were added to a dry three-neck flask (250 mL) at room temperature. Under nitrogen protection, n-butyllithium (54 mL, 2.5 M THF) was added dropwise at -78 °C, and the reaction solution was stirred at -78 °C for half an hour. A solution of DMF (4.0 g, 54.0 mmol) in THF (30 mL) was added to the above reaction solution, and stirring was continued at -78 °C for 1 hour. The reaction solution was warmed to room temperature, and a saturated ammonium chloride solution (200 mL) was added, and the reaction was allowed to proceed at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column (PE / EA=3 / 1) to obtain compound 18-2 (4 g, yellow oil), with a yield of 31.00%. LCMS(ESI):m / z240.8[M+H] + ;RT=1.768min(3.00min).

[0535] Step 3: Synthesis of 3-(4-chloro-2-pivalamidoaminopyridin-3-yl)-3-hydroxypropionic acid t-butyl ester

[0536] 18-2 (2.28 g, 9.5 mmol) and THF (40 mL) were added to a dry three-neck flask (250 mL) at room temperature. Under nitrogen protection, LDA (10.5 mL, 2M THF) was added dropwise at -78 °C, and the reaction solution was stirred at -78 °C for half an hour. A solution of acetic acid t-butyl ester (1.1 g, 9.5 mmol) in THF (20 mL) was added to the above reaction solution, and stirring was continued at -78 °C for 1 hour. The temperature was raised to room temperature, water (40 mL) was added, and extraction was performed with ethyl acetate (50 mL), and the organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (PE / EA=2 / 1) to obtain compound 18-3 (2.2 g, yellow solid), with a yield of 65%. LCMS (ESI): m / z 356.7 [M+H] + ;RT=1.871min(3.00min).

[0537] Step 4: Synthesis of 5-chloro-1,8-naphthyridin-2(1H)-one

[0538] 18-3 (1.9 g, 5.34 mmol) and 3M hydrochloric acid (20 mL) were added to a dry one-neck flask (50 mL) at room temperature and reacted at 100° C. for 8 hours. The reaction solution was cooled, filtered, washed with saturated sodium bicarbonate solution (5 mL) and water (5 mL), and dried to obtain compound 18-4 (440 mg, white solid), with a yield of 46.00%. LCMS (ESI): m / z 181.0 [M+H] + ;RT=1.20min(3.00min).

[0539] Step 5: Synthesis of 5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one

[0540] 18-4 (150 mg, 0.84 mmol), methyl iodide (153 mg, 1.08 mmol), potassium carbonate (231 mg, 1.58 mmol), and DMF (3 mL) were added to a dry one-neck flask (25 mL) in sequence at room temperature, and the mixture was stirred at room temperature overnight. Water (10 mL) and ethyl acetate (20 mL) were added for extraction, and the organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column (PE:EA=2:1) ​​to give compound 18-5 (150 mg, white solid), with a yield of 92.60%. LCMS (ESI): m / z 194.8 [M+H] + ;RT=1.621min(3.00min).

[0541] Step 6: Synthesis of 2-(4-((8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)acetic acid

[0542] 18-5 (110 mg, 0.57 mmol), ethyl 4-aminophenylacetate (101 mg, 0.57 mmol), Pd2(dba)3 (52 mg, 0.057 mmol), x-PHOS (54 mg, 0.11 mmol), sodium t-butoxide (109 mg, 1.14 mmol), and dioxane (5 mL) were added to a dry one-neck flask (50 mL) at room temperature. The mixture was heated to 100 °C under nitrogen protection and stirred overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (DCM:MeOH = 40:1) to give compound 18-6 (70 mg, yellow solid), with a yield of 40.00%. LCMS (ESI): m / z 309.7 [M + H] + ;RT=1.433min(3.00min).

[0543] Step 7: Synthesis of N-hydroxy-2-(4-((8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)acetamide

[0544] 18-6 (70 mg, 0.23 mmol), DIEA (89 mg, 0.69 mmol), HATU (131 mg, 0.34 mmol) and DMF (3 mL) were added to a dry one-neck flask (25 mL) in sequence at room temperature. The reaction mixture was stirred at room temperature for 10 min. 50% aqueous hydroxylamine solution (30 mg, 0.45 mmol) was added and stirred for 1 h. The reaction mixture was concentrated, and the residue was purified by high-performance reversed-phase liquid preparative column (gradient elution with 0.1% formic acid / acetonitrile / water) to give compound 18 (15 mg, yellow solid), with a yield of 20.00%. LCMS (ESI): m / z 325.0 [M+H] + ;RT=3.16min(15.00min). 1 HNMR(400MHz,DMSO-d6):10.66(s,1H),9.04(s,1H),8.84(s,1H),8.34-8.32(m,1H),8.17-8. 16(m,1H),7.31-7.22(m,4H),6.69-6.68(m,1H),6.59-6.57(m,1H),3.63(s,3H),3.29(s,2H).

[0545] Example 19 Preparation of Compound 141

[0546] [ka]

[0547] Step 1: Synthesis of 2-(4-(((t-butyldimethylsilyl)oxy)methyl)phenyl)methyl acetate

[0548] 2-(4-(hydroxymethyl)phenyl)methyl acetate (4g, 22.22mmol) and imidazole (3.02g, 44.44mmol) were dissolved in DMF (25mL), and a solution of TBSCl (4.03g, 26.67mmol) in DMF (10mL) was slowly added dropwise in a nitrogen and ice bath, and after the addition was completed, the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was washed with water, a dilute aqueous solution of hydrochloric acid (1M), and a saturated aqueous solution of sodium chloride. The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (EA:PE=1:20) to obtain compound 141-1 (5.3g, 18.03mmol) as a colorless oil, with a yield of 81%. 1 HNMR(400MHz,DMSO-d6)δ7.20-7.12(m,4H),4.61(s,2H),3.58(s,2H),3.53(s,3H),0.86-0.78(m,9H),0.03-0.05(m,6H).

[0549] Step 2: Synthesis of methyl 1-(4-(((t-butyldimethylsilyl)oxy)methyl)phenyl)cyclopentane-1-formate

[0550] Compound 141-1 (2 g, 6.80 mmol) was dissolved in DMF (20 mL), NaH (680 mg, 17 mmol) was added under ice-salt bath, 1,4-dibromobutane (1.47 g, 6.8 mmol) was added dropwise, and after the dropwise addition, the mixture was stirred at room temperature for 3 hours. Water was slowly added dropwise to the reaction solution to quench it, and then it was extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (EA:PE=1:20) to obtain compound 141-2 (1.1 g, 3.16 mmol) as a colorless oil, with a yield of 46%. 1 HNMR(600MHz,DMSO-d6)δ7.23-7.16(m,4H),4.60(s,2H),3.46(s,3H),2.47-2.43(m,2H),1 .77(ddd,J=12.4,8.2,6.0Hz,2H),1.64-1.50(m,4H),0.84-0.81(m,9H),0.02-0.01(m,6H).

[0551] Step 3: Synthesis of methyl 1-(4-(hydroxymethyl)phenyl)cyclopentane-1-formate

[0552] Compound 141-2 (500 mg, 1.436 mmol) was dissolved in methanol (10 mL), HCl / MeOH (2 mL, 4 M) was added at 0° C., the mixture was stirred at 0° C. for 1 h, concentrated under reduced pressure, the solvent and excess hydrochloric acid were removed, and the mixture was dried in vacuum to obtain compound 141-3 (336 mg, 1.436 mmol), with a yield of 100%. LCMS (ESI): m / z 235.1 [M+H] + ;RT=1.54min(3min)

[0553] Step 4: Synthesis of methyl 1-(4-(bromomethyl)phenyl)cyclopentane-1-formate

[0554] Compound 141-3 (500 mg, 2.14 mmol) was dissolved in dichloromethane (15 mL), PBr3 (577 mg, 2.14 mmol) was slowly added dropwise at 0 °C, and the mixture was stirred in an ice bath for 2 hours. The reaction mixture was quenched by adding water, the aqueous phase was extracted with dichloromethane, the organic phase was concentrated, and purified by column chromatography (EA:PE = 1:20) to give compound 141-4 (530 mg, 1.78 mmol) as a colorless oil in a yield of 83%. 1 HNMR(400MHz,DMSO-d6)δ7.44-7.37(m,2H),7.36-7.28(m,2H),4.69(s,12H)3.55(s,3H),2.58-2.51(m,2H),1.86(m,2H),1.74-1.53(m,4H).

[0555] Step 5: Synthesis of methyl 1-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)cyclopentane-1-formate

[0556] 141-4 (500 mg, 1.69 mmol), bis(pinacolato)diboron (858 mg, 3.38 mmol), tetrakistriphenylphosphinepalladium (195 mg, 0.169 mmol), potassium carbonate (700 mg, 5.07 mmol), and dioxane (25 mL) were added to a 50 mL one-neck flask, and the mixture was heated to 100 °C under argon gas protection and stirred for 4 hours. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography (MeOH:DCM = 1:10) to obtain compound 141-5 (350 mg, 1.017 mmol) as a white solid in a 60% yield. 1 HNMR(400MHz,DMSO-d6)δ7.23-7.17(m,2H),7.09(m,2H),3.58(s,3H),2.5 4-2.50(m,2H),2.20(s,2H),1.86(m,2H),1.74-1.62(m,4H),1.22(s,12H).

[0557] Step 6: Synthesis of methyl 1-(4-((7-methoxy-1,8-naphthyridin-4-yl)methyl)phenyl)cyclopentane-1-formate

[0558] Compound 141-5 (480 mg, 1.395 mmol), 1a (271 mg, 1.395 mmol), PdCl2dppf (102 mg, 0.140 mmol), potassium carbonate (578 mg, 4.185 mmol), dioxane / water (15 mL / 5 mL) were added to a 50 mL one-neck flask, and the mixture was heated to 100 ° C. under argon gas protection and stirred for 8 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (EA:PE = 1:2) to obtain compound 141-6 (80 mg, 0.212 mmol) as a yellow oil, with a yield of 15.2%. LCMS (ESI): m / z 377.1 [M + H] + ;RT=1.85min(3.0min).

[0559] Step 7: Synthesis of N-hydroxy-1-(4-((7-methoxy-1,8-naphthyridin-4-yl)methyl)phenyl)cyclopentane-1-formamide

[0560] 141-6 (80 mg, 0.265 mmol) was added to a 10 mL one-neck flask, methanol / THF (1 mL / 1 mL) was added, and the mixture was stirred. 50% hydroxylamine aqueous solution (0.5 mL) and sodium hydroxide (21 mg, 0.53 mmol) were added in sequence, and the mixture was reacted at room temperature for 8 hours. The pH was adjusted to 7-8 with 1 M dilute hydrochloric acid, and the mixture was purified by reverse phase column (acetonitrile:water (1‰HCOOH) = 35:65) to obtain compound 141 (30 mg, 0.0796 mmol) as a white solid, with a yield of 30%. LCMS (ESI): m / z 378.2 [M+H] + ;RT=1.39min(3.0min). 1HNMR(400MHz,DMSO-d6)δ10.38(s,1H),8.82(d,J=4.6Hz,1H),8.62-8.51(m,2H),8.14(s,1H),7.28(m,3 H),7.18(m,2H),7.12(d,J=9.0Hz,1H),4.41(s,2H),4.01(s,3H),2.46(s,2H),1.73(m,2H),1.57(m,4H).

[0561] Example 20 Preparation of Compound 194

[0562] [ka]

[0563] Step 1: Synthesis of 5-amino-3-methylisoxazole-4-carbonitrile

[0564] Hydroxylamine hydrochloride (2.55 g, 36.72 mmol) was dissolved in 25 mL of sodium hydroxide solution (1.50 M), 50 mL of ethanol was added, and (1-ethoxyethylidene)malononitrile (5.00 g, 36.72 mmol) was added slowly with stirring. The mixture was heated to 50° C. for 30 minutes, and then reacted at room temperature overnight. The solvent was removed, filtered, and the solid was collected, washed with fresh water, and dried to give compound 194-1 (3.75 g, white solid), with a yield of 82.85%. LCMS (ESI): m / z 124.3 [M+H] + ;RT=0.897min(2.50min). 1 H-NMR (400MHz, DMSO-d6): δ8.33(s,2H),2.13(s,3H).

[0565] Step 2: Synthesis of 5-amino-3-methylisoxazole-4-formamide

[0566] Compound 194-1 (3.6 g, 29.24 mmol) was dissolved in 100 mL of water and 100 mL of ethanol, and sodium hydroxide (9.36 g, 233.93 mmol) was slowly added to the solution, and the mixture was reacted at 100° C. for 3 hours. The ethanol was removed, the reaction solution was diluted with water, adjusted to pH=8, and extracted with ethyl acetate. The organic phase was collected, dried, and filtered to obtain compound 194-2 (1.07 g, white solid), with a yield of 25.90%. LCMS (ESI): m / z 142.3 [M+H] + ;RT=0.557min(2.50min).

[0567] Step 3: Synthesis of 3-methylisoxazol[5,4-d]pyrimidin-4-ol

[0568] Compound 194-2 (1 g, 7.09 mmol) and triethyl orthoformate (2.1 g, 14.17 mmol) were dissolved in 20 mL of acetic anhydride, and the mixture was heated at 120° C. and reacted for 3 hours. The mixture was cooled to room temperature, diluted with ice water, adjusted to pH=8 with NaOH (2M), extracted with ethyl acetate, and the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified to obtain compound 194-3 (260 mg, white solid), with a yield of 24.30%. LCMS (ESI): m / z 152.2 [M+H] + ;RT=0.827min(2.50min). 1 H-NMR (400MHz, CDCl3): δ11.38(s,1H),8.17(s,1H),2.63(s,3H).

[0569] Step 4: Synthesis of 4-chloro-3-methylisoxazole and [5,4-d]pyrimidine

[0570] Compound 194-3 (260 mg, 1.72 mmol) was dissolved in 10 mL of phosphorus oxychloride and stirred at 90° C. for 2 hours. After cooling to room temperature and removing the solvent, the mixture was diluted with ice water and adjusted to pH=8 with 2M sodium hydroxide solution. Extracted with ethyl acetate, the organic phase was collected, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC (PE:EA=3:1) to give compound 194-4 (227 mg, brown solid), with a yield of 77.90%. LCMS (ESI): m / z 170.2 [M+H] + ;RT=1.337min(2.50min).

[0571] Step 5: Synthesis of 2-methyl-2-(4-((3-methylisoxazole[5,4-d]pyrimidin-4-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propionamide

[0572] Compound 194-4 (50 mg, 0.29 mmol), 2-(4-hydroxyphenyl)-2-methyl-N-((tetrahydro-2H-pyran-2-yl)oxy)propionamide (99 mg, 0.35 mmol), and cesium carbonate (192 mg, 0.59 mmol) were dissolved in 3 mL of DMF and reacted at 80° C. for 2 hours. Cooled to room temperature, filtered, extracted with ethyl acetate, the organic phase was collected, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC (PE:EA=1:1) to obtain compound 194-5 (92 mg, transparent oil), with a yield of 75.65%. LCMS (ESI): m / z 411.1 [MH] - ;RT=1.571min(2.50min).

[0573] Step 6: Synthesis of N-hydroxy-2-methyl-2-(4-((3-methylisoxazole[5,4-d]pyrimidin-4-yl)oxy)phenyl)propanamide

[0574] Compound 194-5 (65 mg, 0.16 mmol) and TFA (1 mL) were dissolved in 3 mL of anhydrous dichloromethane and stirred at room temperature for 2 hours. Extraction was performed with ethyl acetate, and the organic phase was collected, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-HPLC (FA) to give compound 194, yield 30.92%. LCMS (ESI): m / z 328.95 [M+H] + ;RT=3.933min(6min). 1 H-NMR (400MHz, DMSO-d6): δ10.42(s,1H),8.71(s,1H),8.70(s,1H),7.44(d,J=8.4Hz,2H),7.28(d,J=8.8Hz,2H),2.68(s,3H),1.49(s,6H).

[0575] Example 21 Preparation of Compound 195

[0576] [ka]

[0577] Step 1: (7-Methoxy-1,8-naphthyridin-4-yl)methanol

[0578] Compound 1a (808 mg, 4.2 mmol), potassium fluoride (732 mg, 12.6 mmol) and (tributyl)methanol (1.6 g, 5 mmol) were added to a 50 mL three-neck flask containing 10 mL of dioxane at room temperature, and then PdCl2dppf (307 mg, 0.42 mmol) was added and reacted overnight at 100 ° C., filtered, and the filtrate was concentrated and purified by column chromatography (EA:PE = 1:2) to obtain compound 1a-4 (200 mg, yellow solid). LCMS (ESI): m / z 191.1 [M + H] + ;RT=0.307min(2.50min).

[0579] Step 2: 7-Methoxy-1,8-naphthyridine-4-formaldehyde

[0580] Compound 1a-4 (90 mg, 0.26 mmol) and Dess-Martin periodinane (535 mg, 1.26 mmol) were added sequentially to a 50 mL single-neck flask containing 7 mL of dichloromethane at room temperature, and the mixture was allowed to react at room temperature for 3 hours. The reaction solution was diluted with water and extracted with dichloromethane. The organic phase was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 1a-5 (180 mg, white solid) in a yield of 90.9%. 1 HNMR (400MHz, DMSO-d6): δ10.41(s,1H),9.25-9.23(m,2H),7.73(d,J=4.0Hz,1H),7.17(d,J=9.2Hz,1H),4.19(s,3H).

[0581] Step 3: 2-(1-((7-methoxy-1,8-naphthyridin-4-yl)methyl)pyrrolidin-3-yl)-2-methyl methylpropionate

[0582] Compound 1a-5 (60 mg, 0.33 mmol), compound 22a (82 mg, 0.48 mmol) and sodium cyanoborohydride (42 mg, 0.66 mmol) were added in sequence to a 50 mL one-neck flask containing 1,2-dichloroethane (3 mL), and the mixture was reacted at room temperature for 2 hours, diluted with water, extracted with dichloromethane, the organic phase was washed with water and saturated saline solution in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by concentrated column chromatography (PE:EA=4:1) to obtain compound 195-1 (105 mg, transparent oil). LCMS (ESI): m / z 344.1 [M+H] + ;RT=0.880min(2.50min)

[0583] Step 4: 2-(1-((7-methoxy-1,8-naphthyridin-4-yl)methyl)pyrrolidin-3-yl)-2-methylpropionic acid

[0584] Compound 195-1 (80 mg, 0.23 mmol) and lithium hydroxide (11 mg, 0.47 mmol) were added in sequence to a 50 mL one-neck flask containing 1,4-dioxane / water (3:1, 3 mL) at room temperature. The reaction was carried out at 80° C. for 10 hours, the pH was adjusted to 5 with an aqueous hydrochloric acid solution (1 M), the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed with water and saturated saline solution in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude product 195-2 (50 mg, white solid). LCMS (ESI): m / z 320.2 [M+H] + ;RT=0.807min(2.50min).

[0585] Step 5: 2-(1-((7-methoxy-1,8-naphthyridin-4-yl)methyl)pyrrolidin-3-yl)-2-methyl-N-((tetrahydro-2H-pyran-2-yl)oxy)propionamide

[0586] Compound 195-2 (60 mg, 0.18 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (26 mg, 0.22 mmol), diisopropylethylamine (46 mg, 0.36 mmol) and HATU (102 mg, 0.27 mmol) were added to a one-neck flask containing 15 mL of DMF, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, concentrated, and purified by chromatography plate (EA) to obtain compound 195-3 (30 mg, white solid), with a yield of 38.4%. LCMS (ESI): m / z 429.2 [M+H] + ;RT=0.360min(2.50min).

[0587] Step 6: N-hydroxy-2-(1-((7-methoxy-1,8-naphthyridin-4-yl)methyl)pyrrolidin-3-yl)-2-methylpropionamide 2 mL of dichloromethane, 195-3 (40 mg, 0.09 mmol) and TFA (0.6 mL) were added to a one-neck flask and stirred at room temperature for 3 hours. The solvent was removed and the crude product was purified by reverse phase column (formic acid) to obtain compound 195 (8.5 mg, white solid), with a yield of 26.4%. LCMS (ESI): m / z 345.05 [M+H] + ;RT=1.978min(6.00min). 1 HNMR(400MHz,DMSO-d6):δ10.41(s,1H),8.91(s,1H),8.69-8.61(m,2H),7.53(s,1H),7.19(d, J=7.6Hz,1H),4.04(s,3H),3.34(s,2H),2.51(s,4H),1.79-1.63(m,3H),1.03(d,J=6.0Hz,6H).

[0588] Example 22 Preparation of Compound 196

[0589] [ka]

[0590] Step 1: Synthesis of (4-(benzyloxy)phenyl)-L-proline methyl ester

[0591] 1-(benzyloxy)-4-bromobenzene (500 mg, 1.9 mmol), (S)-5-oxopyrrolidine-2-formic acid (549 mg, 4.8 mmol), cuprous iodide (72 mg, 0.38 mmol), potassium phosphate (1.6 g, 7.6 mmol), and dimethyl sulfoxide (10 mL) were added in sequence to a dry 50 mL one-neck flask, and the mixture was heated to 100 ° C under nitrogen protection and left overnight. DMF (10 mL) and methyl iodide (1.3 g, 9.5 mmol) were added, and the mixture was heated to 60 ° C and reacted for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column (PE:EA = 1:10) to obtain compound 196-1 (350 mg, yellow solid), with a yield of 59.0%. LCMS(ESI):m / z312.1[M+H]+ ;RT=1.94min(3.00min).

[0592] Step 2: Synthesis of (4-hydroxyphenyl)-L-proline methyl ester

[0593] 196-1 (350 mg, 1.1 mmol), 10% palladium on carbon (35 mg), and methanol (10 mL) were added to a dry 50 mL one-neck flask at room temperature, and the mixture was stirred at room temperature for 2 hours under hydrogen gas protection. The filtrate was concentrated to give compound 196-2 (220 mg, yellow solid), with a yield of 88.0%. LCMS (ESI): m / z 222.1 [M+H] + ;RT=1.36min(3.00min).

[0594] Step 3: Synthesis of (4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)-L-proline methyl ester

[0595] 196-2 (220 mg, 1 mmol), 5-chloro-2-methoxy-1,8-naphthyridine (194 mg, 1 mmol), potassium carbonate (276 mg, 2 mmol), and DMF (5 mL) were added to a dry 50 mL one-neck flask at room temperature, heated to 100 ° C. and stirred overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (PE:EA = 1:1) to give compound 196-3 (100 mg, yellow oil), the yield was 26.0%. LCMS (ESI): m / z 380.1 [M + H] + ;RT=1.66min(3.00min).

[0596] Step 4: Synthesis of (S)-N-hydroxy-1-(4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)pyrrolidine-2-formamide

[0597] 196-3 (100 mg, 0.26 mmol), THF (1 mL), methanol (1 mL), 50% aqueous hydroxylamine solution (0.5 mL), and sodium hydroxide (21 mg, 0.52 mmol) were added sequentially to a dry 25 mL one-neck flask at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH=8 with 1M dilute hydrochloric acid, and the residue was purified by high-performance reversed-phase liquid preparative column (0.1% formic acid) and dried to obtain compound 196 (17 mg, yellow solid), with a yield of 17%. LCMS (ESI): m / z 381.1 [M+H] + ;RT=4.27min(15.00min). 1 H-NMR(400MHz,DMSO-d6):δ10.70(s,1H),8.70(s,1H),8.68-8.59(m,2H),7.15-7.12(m,3H),6.61-6.59(m,2H),6 .45-6.44(m,1H),4.05-3.98(m,4H),3.58-3.55(m,1H),3.23-3.19(m,1H),2.08-2.00(m,1H),1.99-1.96(m,3H).

[0598] Examples 23-207: Compounds 19-140, 142-193, and 197-207 were synthesized according to the methods described in Examples 1-4 and 18-22, respectively, and the structural formulas of the compounds of each Example are shown in the above table.

[0599] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15] [Table 4-16] [Table 4-17]

[0600] Example 208 Preparation of Compounds 208 and 209

[0601] [ka]

[0602] Step: Compound 131 was resolved to give compound 208 (isomer 1) and compound 209 (isomer 2).

[0603] Compound 131 (92 mg) was separated by chiral column. Column model number CHIRALCELOZ-H (OZH0CE-RJ014), 0.46 cmI.D. x 25 cmL, mobile phase: Hexane / EtOH / TFA / DEA = 50 / 50 / 0.1 / 0.05. Compound 208 (20 mg) and compound 209 (22 mg) were obtained.

[0604] Compound 208: Peak appearance time 9.688min;ee%>99,LCMS(ESI):m / z382.20[M+H] + ; 1 HNMR(400MHz,DMSO-d6):δ10.80(s,1H),8.97(s,1H),8.79-8.80(m,1H),8.65(d,J=9.2Hz,1H),7.53(d,J=8.8Hz,2H),7.36(d,J=8.8Hz,2H) ,7.24(d,J=9.2Hz,1H),6.66(d,J=5.6Hz,1H),4.58(d,J=8.8Hz,1H),4.04(s,3H),3.94-3.86(m,3H),2.97-2.59(m,1H),2.32-2.27(m,1H).

[0605] Compound 209: Peak appearance time 14.023min;ee%>99,LCMS(ESI):m / z382.20[M+H] + ; 1 HNMR(600MHz,DMSO-d6):δ10.73(s,1H),8.97(s,1H),8.74(d,J=3.6Hz,1H),8.61(d,J=5.6Hz,1H),7.48-7.46(m,2H),7.32(d,J=8.8Hz,2H) ,7.21(d,J=6.0Hz,1H),6.63(d,J=4.0Hz,1H),4.50(d,J=5.6Hz,1H),4.07(s,3H),3.87-3.78(m,3H),2.90-2.86(m,1H),2.23-2.18(m,1H).

[0606] Example 209 Preparation of Compounds 210 and 211

[0607] [ka]

[0608] Step: Compound 165 was resolved to give compound 210 (isomer 1) and compound 211 (isomer 2).

[0609] Compound 165 (420 mg) was separated by chiral column. Column model number: DAICEL CHIRALPAK (registered trademark) OZ, 250 x 25 mm 10 μm, mobile phase: methanol (+0.1% 7.0 mol / L ammonia·methanol). Compound 210 (101.74 mg) and compound 211 (117.52 mg) were obtained.

[0610] Compound 210: Peak appearance time 4.478min;ee%>86,LCMS(ESI):m / z382.00[M+H] + ;(DMSO-d6):δ10.38(s,1H),8.71-8.67(m,2H),8.58(d,J=9.2Hz,1H),7.35(d,J=8.8Hz,2H),7.25(d,J=8.8Hz,2H) ,6.53(d,J=5.2Hz,1H),4.04(s,3H),2.74-2.67(m,1H),1.41(s,3H),0.91(d,J=6.4Hz,3H),0.56(d,J=6.8Hz,3H);

[0611] Compound 211: Peak appearance time 5.364min;ee%>97,LCMS(ESI):m / z382.00[M+H] + ;(DMSO-d6):δ10.38(s,1H),8.71-8.68(m,2H),8.58(d,J=8.8Hz,1H),7.55(d,J=8.8Hz,2H),7.25(d,J=8.8Hz,2H),7.15(d,J =8.8Hz,1H),6.53(d,J=5.2Hz,1H),4.04(s,3H),2.74-2.67(m,1H),1.41(s,3H),0.91(d,J=6.8Hz,3H),0.56(d,J=7.2Hz,3H).

[0612] Example 210 Preparation of Compounds 212 and 213

[0613] [ka]

[0614] Step: Compound 130 was resolved to give compound 212 (isomer 1) and compound 213 (isomer 2).

[0615] Compound 130 (100 mg) was separated using a chiral column. Column model number: DAI CEL CHIRALPAK (registered trademark) IG, 250 x 25 mm 10 μm, mobile phase: methanol (+0.1% 7.0 mol / L ammonia·methanol). Compound 212 (18.03 mg) and compound 213 (24.55 mg) were obtained.

[0616] Compound 212: Peak appearance time 4.970min;ee%>99,LCMS(ESI):m / z368.05[M+H] + ;(MeOD-d4):δ8.63-8.60(m,2H),7.54(d,J=8.4Hz,2H),7.20(d,J=8.4Hz,2H),7.10(d,J=9.2Hz,1H),6.56(d,J= 1.6Hz,1H),4.12(s,3H),2.90(d,J=10.0Hz,1H),2.43-2.37(m,1H),1.07(d,J=6.4Hz,3H),0.77(d,J=6.8Hz,3H);

[0617] Compound 213: Peak appearance time 5.665 min; ee%>99, LCMS (ESI): m / z 368.00 [M+H] + ;(MeOD-d4):δ8.63-8.60(m,2H),7.54(d,J=8.8Hz,2H),7.20(d,J=8.4Hz,2H),7.10(d,J=8.8Hz,1H),6.57(d,J= 5.6Hz,1H),4.12(s,3H),2.90(d,J=11.2Hz,1H),2.43-2.37(m,1H),1.07(d,J=6.4Hz,3H),0.77(d,J=6.8Hz,3H).

[0618] Example 211 Preparation of Compounds 214 and 215

[0619] [ka]

[0620] Step: Compound 177 was resolved to give compound 214 (isomer 1) and compound 215 (isomer 2).

[0621] Compound 177 (500 mg) was separated by chiral column. Column model number: DAICEL CHIRALPAK (registered trademark) OM, 250 x 25 mm 10 μm, mobile phase: methanol (+0.1% 7.0 mol / l ammonia·methanol). Compound 214 (112 mg) and compound 215 (232 mg) were obtained.

[0622] Compound 214: Peak appearance time 2.174min; ee%>99, LCMS(ESI): m / z367.20[M+H] + ;(DMSO-d6):δ10.65(s,1H),9.44(d,J=20.4Hz,2H),8.83(s,1H),8.43(d,J=2.4Hz,1H),7.40(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),7. 00(s,1H),6.67(d,J=4.0Hz,1H),3.97(s,3H),2.84(d,J=10.8Hz,1H),2.33-2.08(m,1H),0.97(d,J=6.4Hz,3H),0.687(d,J=6.8Hz,3H);

[0623] Compound 215: Peak appearance time 7.057min;ee%>99,LCMS(ESI):m / z367.10[M+H] + ;(DMSO-d6):δ10.70(s,1H),9.66(s,2H),8.86(s,1H),8.43(d,J=6.8Hz,1H),7.51(d,J=8.4Hz,2H),7.41(d,J=8.4Hz,2H),7.08(s ,1H),6.23(d,J=7.2Hz,1H),4.04(s,3H),2.90(d,J=10.4Hz,1H),2.34-2.25(m,1H),0.98(d,J=6.8Hz,3H),0.68(d,J=6.8Hz,3H).

[0624] Biological Examples

[0625] Evaluation of ENPP1 inhibitory activity of compounds

[0626] Testing the ENPP1 Inhibitory Activity of Compounds of the Present Disclosure in the Detection of Substrate 2',3'-cGAMP

[0627] Experimental objective: According to the established experimental method, the inhibitory IC of the compound of the present application against ENPP1 using 2',3'-cGAMP as a substrate was 50 was detected. STF-32 was used as a positive control compound (STF-32 is derived from the literature Cell Chemical Biology 2020(27), 1347-1358).

[0628] Experimental Reagents: hENPP1-ECD-His (ChemPartner, cat. 202103121201), AMP-Glo™ Assay Kit (Promega, cat. V5011), DMSO (Sigma, cat. D8418-1L), 384-well white plates (PerkinElmer, cat. 6007290), 2'3'-cGAMP (MCE, cat. HY-100564A)

[0629] Testing Method:

[0630] Preparation of 1.1× reaction solution: 50 mM Tris-HCl (pH 7.5), 10 mM NaCl, 0.5 mM CaCl2, 1 μM ZnCl2, 0.01% Twain-20, 0.01% BSA.

[0631] 2. Preparation of compound concentration gradient: The test compound was dissolved in DMSO (dimethyl sulfoxide) to a starting concentration of 10 μM, diluted 3-fold, and tested in 10 concentrations in a single well or in duplicate wells. The concentration of the positive control compound STF-32 during testing started at 1 μM, and was diluted 3-fold to 10 concentrations in a duplicate well for each concentration. In a 384-well plate, the solution was diluted 1000-fold (1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15 nM) at the final concentration of each compound, and 5 nL was transferred to a 384-well reaction plate using Echo550 for measurement. 5 nL of 100% DMSO was transferred to the minimum well (substrate only, no enzyme, minimum signal value) and maximum well (substrate, enzyme, no inhibitor, maximum signal value).

[0632] 3.2× hENPP1-ECD-His protein solution 20 nM was prepared in 1× reaction solution.

[0633] 4.2x 2'3'-cGAMP substrate solution 40 μM was prepared in 1x reaction solution.

[0634] 5. To each compound well and the largest well of the reaction plate was added 2.5 μL of 2× protein solution and to the smallest well was added 2.5 μL of 1× reaction solution.

[0635] 6. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes.

[0636] 7. 2.5 μL of 2×2′3′-cGAMP substrate solution was added to each well of the reaction plate, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes.

[0637] 8. 5 μL of R1 solution (from AMP-Glo™ Kit) was added to each well of the reaction plate, centrifuged at 1000 rpm for 1 min, and incubated at room temperature for 120 min.

[0638] 9. 10 μL of R2 solution (from AMP-Glo™ Kit) was added to each well of the reaction plate, centrifuged at 1000 rpm for 1 min, and incubated at room temperature for 30 min.

[0639] 10. The test results were detected and recorded using a multi-function microplate reader (2104EnVision).

[0640] Data analysis

[0641] The inhibition rate was calculated by the following formula:

[0642] % Inhibition = (Maximum signal - Compound signal) / (Maximum signal - Minimum signal) x 100

[0643] Here, "minimum signal" is the average value of the negative control wells and "maximum signal" is the average value of the positive control wells.

[0644] Fitting Dose-Response Curve:

[0645] The IC of inhibition of enzyme activity by compounds of the present disclosure was calculated using log(inhibitor) vs. response-variable slope fitting dose-response curves in the analysis software GraphPad Prism 5, with log concentration on the X-axis and percentage inhibition on the Y-axis. 50 obtained.

[0646] The fitting formula is Y=bottom+(top-bottom) / (1+10^((logIC 50 -X) * HillSlope) (where the bottom and top are the minimum and maximum values ​​of the fitting, respectively).

[0647] In this experiment, the IC value of ENPP1 inhibition by sulfonamide compound Ex58 (see WO2019 / 046778A1) and compounds A-1 and A-2 reported in a public literature was 50The values ​​were also detected under the same detection conditions. As shown in Table 1, the hydroxamic acid compounds of the present disclosure exhibit good inhibitory activity against ENPP1 kinase.

[0648] [ka]

[0649] (Table 1) [Table 5-1] [Table 5-2]

[0650] As can be seen from Table 1, the hydroxamic acid compounds of the present disclosure are excellent ENPP1 inhibitors, with IC values ​​of 5 μM or less. 50 IC value, preferably 1 μM or less 50 value, more preferably 0.5 μM or less 50 IC value of 0.125 μM or less, more preferably 50 value, most preferably 0.1 μM or less 50 The dihydroxamic acid compounds of the present disclosure have significantly superior ENPP1 inhibitory activity to compound A-2.

[0651] Preliminary pharmacokinetic study

[0652] 1. Six healthy ICR male mice weighing 30-35 g were prepared and randomly divided into two groups of three mice each, and the test compound was administered intragastrically (5 mg / kg) and intravenously (1 mg / kg) to each group.

[0653] Before the test, the animals were fasted for 12 h and allowed to drink water ad libitum. Food was consistently introduced 4 h after administration.

[0654] 2. Blood Collection Time Points and Sample Processing

[0655] Intragastric administration: 0.25 h, 0.5 h, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 6.0 h, 8.0 h, and 24 h after administration.

[0656] Intravenous administration: 5 min, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24 h after administration.

[0657] Blood was collected consecutively from three animals at each time point. Plasma collection and processing: At the above-mentioned time points, 30-40 μL of venous blood was collected from the retroocular plexus of the mice, placed in EDTA-K2 tubes, and centrifuged at 3500 rpm for 10 min to separate the plasma, which was then frozen in a -20°C refrigerator.

[0658] 3. Sample testing and data analysis

[0659] Compound concentrations in rat plasma were measured using LC / MS / MS. Pharmacokinetic parameters after administration were calculated using the noncompartmental model of Phoenix8.3 software (Pharsight, USA).

[0660] 4. Experimental Results

[0661] The compounds of the present invention have high oral bioavailability, which is more than 20%, as shown in Examples 2 and 110. Thus, the hydroxamic acid compounds of the present disclosure are clearly more advantageous in oral absorption than known phosphoric acid compounds. The pK data of some compounds are shown in Table 2.

[0662] (Table 2) [Table 6]

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 however, 【change】 is a single bond or a double bond, X is N or CR ０ and X １ is N, O, S, CR １ , or a bond, X ２ is N, O, S, NR ２ , or CR ２ and X ３ is N, O, S, NR ３ , or CR ３ and X ４ is N, O, S, NR ４ , or CR ４ and X ５ is N or CR ５ and Y is O, S, -S(=O)-, -S(=O) ２ -, -C(=O)-, NR ６ , or CR ７ R ８ and L is a bond, NR ａ , -NR ｘ -CHR ｙ - or (CR ９ R １０ ) ｍ and m is 1 or 2; R ０ , R ５ are each independently hydrogen, halogen, CN, OH, NO ２ , N.R. ｂ R ｃ , C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, —SO ２ R ａ , -C(O)OR ａ , —C(O)NR ｂ R ｃ , and C １ ~C ６ alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; R １ , R ２ are each independently hydrogen, halogen, CN, OH, NO ２ , N.R. ｂ R ｃ , C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, and C １ ~C ４ alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; R ３ , R ４ are each independently hydrogen, halogen, CN, OH, NO ２ , N.R. ｂ R ｃ , =O,C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, and C １ ~C ４ alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; R ６ is hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen; R ７ , R ８ are each independently hydrogen, halogen, OH, CN, NO ２ , N.R. ａ , C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, and C １ ~C ６ alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; or R ７ and R ８ together with the carbon atom to which they are attached, optionally substituted with halogen. ３ ~C ６ forming a cycloalkyl or N, NR ａ , O, and S(O) ｐ forming a 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from R ９ , R １０ are each independently hydrogen, halogen, CN, OH, NO ２ , N.R. ａ R ｂ , C １ ~C ８ Alkyl, C ３ ~C ８ Cycloalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Alkoxy, carbon atom and N, NR ａ , O, and S(O) ｐ and 1 to 2 heteroatoms selected from: wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are each substituted with 0 to 3 substituents independently selected from halogen, hydroxy, and CN; and wherein said aryl and heteroaryl are each substituted with 0 to 3 substituents independently selected from halogen, C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, and OR ａ and is substituted by 0 to 3 substituents independently selected from Or, R ９ and R １０ together with the carbon atom to which they are attached, optionally substituted with halogen. ３ ~C ６ forming a cycloalkyl or N, NR ａ , O, and S(O) ｐ forming a 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from Ring A is C ４ ~C １０ cycloalkyl, 4- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein Ring A is optionally selected from halogen, CN, OH, NO ２ , N.R. ｂ R ｃ , C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C ３ ~C ６ cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and C １ ~C ３ substituted one or more times with substituents independently selected from haloalkyl; Or, L, together with ring A, is C ４ ~C ８ forming a 5- to 10-membered partially saturated heterocycle containing at least one heteroatom selected from cycloalkyl, N, O, or S, a 6- to 10-membered aryl, or a 5- to 7-membered heteroaryl, wherein said cycloalkyl, heterocycle, aryl, and heteroaryl are optionally selected from halogen, C １ ~C ４ Alkyl, C １ ~C ４ substituted one or more times with substituents independently selected from alkoxy; Y together with ring A forms a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl, wherein the heterocycle, aryl, and heteroaryl are optionally selected from the group consisting of halogen, C １ ~C ４ Alkyl, C １ ~C ４ substituted one or more times with substituents independently selected from alkoxy; R ａ , R ｂ , R ｃ are each independently hydrogen, C １ ~C ４ Alkyl, C ３ ~C ６ cycloalkyl, and benzyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocycloalkyl optionally substituted with halogen; R ｘ , R ｙ are each independently hydrogen, and C １ ~C ４ alkyl, or R ｘ and R ｙ form a 4- to 8-membered heterocycloalkyl together with the carbon and nitrogen atoms to which they are attached, and p is 1 or 2; X １ ~X ４ are CR respectively ｎ When Y is O, S, -S(=O)-, -S(=O) ２ -, -C(=O)-, or CH ２ where R ｎ is X １ R １ , X ２ R ２ , X ３ R ３ , X ４ R ４ is.

2. A compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 however, 【change】 is a single bond or a double bond, X is N or CR ０ and X １ is N, O, S, CR １ , or a bond, X ２ is N, O, S, NR ２ , or CR ２ and X ３ is N, O, S, NR ３ , or CR ３ and X ４ is N, O, S, NR ４ , or CR ４ and X ５ is N or CR ５ and Y is O, S, -S(=O)-, -S(=O) ２ -, -C(=O)-, NR ６ , or CR ７ R ８ and L is a bond, NR ａ , or (CR ９ R １０ ) ｍ and m is 1 or 2; R ０ , R ５ are each independently hydrogen, halogen, CN, OH, NO ２ , N.R. ｂ R ｃ , C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, —SO ２ R ａ , -C(O)OR ａ , —C(O)NR ｂ R ｃ , and C １ ~C ６ alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; R １ , R ２ are each independently hydrogen, halogen, CN, OH, NO ２ , N.R. ｂ R ｃ , C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, and C １ ~C ４ alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; R ３ , R ４ are each independently hydrogen, halogen, CN, OH, NO ２ , N.R. ｂ R ｃ , =O,C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, and C １ ~C ４ alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; R ６ is hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen; R ７ , R ８ are each independently hydrogen, halogen, OH, CN, NO ２ , N.R. ａ , C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, and C １ ~C ６ alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with halogen; or R ７ and R ８ together with the carbon atom to which they are attached, optionally substituted with halogen. ３ ~C ６ forming a cycloalkyl or N, NR ａ , O, and S(O) ｐ forming a 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from R ９ , R １０ are each independently hydrogen, halogen, CN, OH, NO ２ , N.R. ａ R ｂ , C １ ~C ８ Alkyl, C ３ ~C ８ Cycloalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Alkoxy, carbon atom and N, NR ａ , O, and S(O) ｐ and 1 to 2 heteroatoms selected from: wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are each substituted with 0 to 3 substituents independently selected from halogen, hydroxy, and CN; and wherein said aryl and heteroaryl are each substituted with 0 to 3 substituents independently selected from halogen, C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, and OR ａ and is substituted by 0 to 3 substituents independently selected from Or, R ９ and R １０ together with the carbon atom to which they are attached, optionally substituted with halogen. ３ ~C ６ forming a cycloalkyl or N, NR ａ , O, and S(O) ｐ forming a 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from Ring A is C ４ ~C １０ cycloalkyl, 4- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein Ring A is optionally selected from halogen, CN, OH, NO ２ , N.R. ｂ R ｃ , C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C ３ ~C ６ cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and C １ ~C ３ substituted one or more times with substituents independently selected from haloalkyl; Or, L, together with ring A, forms C ４ ~C ８ forming a 5- to 10-membered partially saturated heterocycle containing at least one heteroatom selected from cycloalkyl, N, O, or S, a 6- to 10-membered aryl, or a 5- to 7-membered heteroaryl, wherein said cycloalkyl, heterocycle, aryl, and heteroaryl are optionally selected from halogen, C １ ~C ４ Alkyl, C １ ~C ４ substituted one or more times with substituents independently selected from alkoxy; R ａ , R ｂ , R ｃ are each independently hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen, or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocycloalkyl optionally substituted with halogen, and p is 1 or 2; X １ ~X ４ are CR respectively ｎ When Y is O, S, -S(=O)-, -S(=O) ２ -, -C(=O)-, or CH ２ where R ｎ is X １ R １ , X ２ R ２ , X ３ R ３ , X ４ R ４ is.

3. R ０ , R ５ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, —SO ２ R ａ , -C(O)OR ａ , —C(O)NR ｂ R ｃ , and C １ ~C ４ alkoxy, wherein said alkyl, cycloalkyl, alkoxy are each optionally substituted with halogen, preferably R ０ , R ５ are each independently hydrogen, CN, halogen, and C １ ~C ４ alkyl, R １ , R ２ are each independently H, halogen, CN, OH, NO ２ , N.H. ２ , C １ ~C ４ Alkyl, C １ ~C ３ Alkoxy, and C １ ~C ３ haloalkyl, preferably H, halogen, C １ ~C ４ Alkyl, and C １ ~C ３ alkoxy; R ３ , R ４ are each independently H, halogen, CN, OH, NO ２ , N.H. ２ , =O,C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ３ haloalkyl, preferably H, halogen, OH, ═O, C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ３ Alkoxy, and C １ ~C ３ haloalkyl; R ６ is hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, preferably hydrogen, and C １ ~C ４ alkyl, R ７ , R ８ are each independently hydrogen, C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, and C １ ~C ４ Alkoxy is preferably selected from hydrogen and C １ ~C ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

4. X １ , X ２ , X ３ , X ４ At least one of is independently N, O, S, and NR ｎ (when present), preferably selected from X １ , X ２ , X ３ , X ４ At least one of is independently N and NR ｎ (if present), where R ｎ is X ２ R ２ , X ３ R ３ , X ４ R ４ and R １ is hydrogen or halogen, R ２ is hydrogen, halogen, C １ ~C ３ Alkyl, and C １ ~C ３ alkoxy; R ３ is hydrogen, halogen, OH, ═O, NR ｂ R ｃ , C １ ~C ３ Alkyl, and C １ ~C ３ alkoxy; R ４ is hydrogen, halogen, and C １ ~C ３ alkyl, R ５ is hydrogen, halogen, CN, and C １ ~C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

5. X １ , X ２ , X ３ , X ４ At least one of is independently selected from N, or X １ , X ２ , X ３ , X ４ and only one of the groups is independently N and NR ｎ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from: (when present).

6. X ２ is N or NR ２ and preferably, X ２ is N, more preferably X ２ is N and X ３ is CR ３ and more preferably, X ２ is N and X ３ is CR ３ and X ４ is CR ４ and most preferably, X ２ is N and X ３ is CR ３ and X ４ is CR ４ and X １ is CR １ 2. The compound of claim 1, wherein:

7. X ４ is N or NR ４ and preferably, X ４ is N, more preferably X ４ is N and X ３ is CR ３ and more preferably, X ４ is N and X ３ is CR ３ and X ２ is CR ２ and most preferably, X ４ is N and X ３ is CR ３ and X ２ is CR ２ and X １ is CR １ 2. The compound of claim 1, wherein:

8. X １ is a bond, R ２ is hydrogen, halogen, C １ ~C ３ Alkyl, and C １ ~C ３ alkoxy; R ３ is selected from hydrogen, OH, and halogen; R ４ is hydrogen, halogen, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C ３ ~C ４ Cycloalkyl, and C １ ~C ３ haloalkyl; R ５ is hydrogen, halogen, CN, and C １ ~C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

9. X １ is a bond, X ２ , X ３ , X ４ at least two of which are independently N and NR ｎ is selected from For example, X １ is a bond, and X ３ is N and X ４ is NR ４ and preferably, X １ is a bond, and X ３ is N and X ４ is NR ４ and X ２ is CR ２ and Or, For example, X １ is a bond, and X ３ is N and X ２ is NR ２ and preferably, X １ is a bond, and X ３ is N and X ２ is NR ２ and X ４ is CR ４ 2. The compound of claim 1, wherein:

10. X １ is CR １ and X ２ is CR ２ and X ３ is CR ３ and X ４ is CR ４ and Y is O, S, -S(=O)-, -S(=O) ２ -, -C(=O)-, or CH ２ and R １ is hydrogen or halogen, R ２ is hydrogen, halogen, OH, and C １ ~C ３ alkoxy; R ３ is hydrogen, halogen, OH, C １ ~C ３ Alkyl, and C １ ~C ３ alkoxy; R ４ is hydrogen, halogen, and C １ ~C ３ alkoxy; R ５ is hydrogen, halogen, CN, and C １ ~C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

11. 【Chemical 3】 teeth, 【Chemistry 4-1】 【Chemistry 4-2】 is selected from Preferably, 【Chemistry 5】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

12. Y is O, NR ６ , or CR ７ R ８ and preferably O, NH, N(C １～ C ３ alkyl), CH ２ , CH(C １～ C ３ alkyl), or C(C １～ C ３ alkyl) (C １～ C ３ alkyl), or Y is O, S, -S(=O)-, -S(=O) ２ -, -C(=O)-, -NH-, -N(CH ３ )-, -N(ethyl)-, -N(propyl)-, -N(cyclopropyl)-, -N(cyclobutyl)-, -N(cyclopentyl)-, -CH ２ -, -CHF-, -CH(OH)-, -CH(CH ３ )-,-CH(OCH ３ )-, -CH(OEt)-, or -C(CH ３ ) ２ -or- Y is O, S, -S(=O)-, -S(=O) ２ -, -C(=O)-, -NH-, -N(CH ３ ) -, -CH(CH ３ ) - or -CH ２ The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

13. L is a bond, NR ａ , -NR ｘ -CHR ｙ -, CR ９ R １０ , or (CR ９ R １０ ) ２ where R ａ is hydrogen, C １ ~C ４ Alkyl, C ３ ~C ６ cycloalkyl, and benzyl, preferably hydrogen, C １ ~C ３ alkyl, and benzyl; R ｘ , R ｙ are each independently hydrogen and C １ ~C ４ alkyl, or R ｘ and R ｙ form a 4- to 8-membered heterocycloalkyl together with the carbon and nitrogen atoms to which they are attached, and R ９ , R １０ are each independently hydrogen, halogen, OH, NH ２ , C １ ~C ８ Alkyl, C ３ ~C ８ Cycloalkyl, C １ ~C ８ Alkoxy, carbon atom and N, NR ａ , O, and S(O) ｐ and 4- to 8-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from R ９ and R １０ are C together with the carbon atoms to which they are attached. ３ ~C ６ cycloalkyl, or N, NR ａ , O, and S(O) ｐ forming a 4- to 8-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from Or, L is CR ９ R １０ where R ９ and R １０ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, and C １ ~C ６ alkoxy, 4- to 7-membered heterocycloalkyl containing carbon atoms and 1 to 2 heteroatoms selected from N, O, and S, or R ９ and R １０ are C substituted with 0 to 3 halogens together with the carbon atom to which they are attached. ３ ~C ６ cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane), or N, NR ａ , O, and S(O) ｐ forming a 4- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from (e.g., oxetane, azetidine, thietane, tetrahydrofuran ring, pyrrolidine, tetrahydrothiophene ring, pyrazolidine, imidazolidine, thiazolidine, oxazolidine, piperidine ring, tetrahydropyran ring, piperazine ring, hexahydropyrimidine ring, oxazinane, pyridazinane, morpholine ring, thiomorpholine ring, thiophane, tetrahydropyran ring, thiane, oxepane, azepane, or thiepane); Or, L is CR ９ R １０ where R ９ and R １０ are each independently hydrogen, halogen, CN, OH, C １ ~C ６ Alkyl, and C １ ~C ６ alkoxy, or R ９ and R １０ are C together with the carbon atoms to which they are attached. ３ ~C ６ forming a cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane); or, L is -CH ２ -, -CH(OH)-, -CHF-, -CH(CH ３ ), -CH(OCH ３ ), -CH(OEt)-, -C(CH ３ ) ２ -, -CH(CH(CH ３ )) ２ -, -CH(CH ２ CH(CH ３ )) ２ -, -C(CH ２ CH(CH ３ )) ２ )) ２ -, -C(CH ２ CH ３ )) ２ -, 【Chemistry 6】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

14. Ring A is C ４ ~C １０ and wherein the ring A is selected from cycloalkyl, 4- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl, and the ring A is optionally selected from halogen, CN, OH, NH ２ , C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, and C １ ~C ３ and substituted by substituents independently selected from haloalkyl, preferably halogen, CN, C １ ~C ４ Alkyl, and C １ ~C ４ Optionally substituted one or more times with substituents selected from alkoxy; or Ring A is selected from cyclopentane, cyclohexane, pyrazolidine, imidazolidine, a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, a tetrahydrofuran ring, pyrrolidine, a tetrahydrothiophene ring, a pyran ring, a tetrahydropyran ring, a piperidine ring, a hexahydropyrimidine, a piperazine ring, a benzene ring, a pyridine ring, a pyrimidine ring, a naphthalene ring, a quinoline ring, an isoquinoline ring, an indole ring, an isoindole ring, an indazole ring, and a benzimidazole ring, and is preferably selected from cyclopentane, cyclohexane, pyrrolidine, a pyrrole ring, a piperidine ring, a pyrimidine ring, a benzene ring, a pyridine ring, a piperazine ring, an imidazole ring, a pyrazole ring, and a naphthalene ring, wherein Ring A optionally represents a halogen atom, CN, OH, NO ２ , N.H. ２ , C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, and C １ ~C ３ and ring A is optionally substituted one or more times, for example one or two times, with substituents independently selected from haloalkyl, and preferably ring A is optionally substituted one or more times, for example one or two times, with substituents independently selected from haloalkyl, for example one or more times, with F, Cl, CN, OH, NO ２ , N.H. ２ , C １ ~C ３ Alkyl, and C １ ~C ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted one or more times, for example one or two times, with substituents independently selected from alkoxy.

15. The compound of claim 1, wherein ring A is selected from the following: 【Chemistry 7】 However, R １１ may be the same or different and independently represent halogen, CN, OH, NO ２ , N.H. ２ , C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, and C １ ~C ３ haloalkyl, preferably F, Cl, CN, C １ ~C ３ Alkyl, and C １ ~C ３ alkoxy; and q is 0, 1, or 2.

16. L together with ring A forms a dihydrobenzofuran ring, a dihydroisobenzofuran ring, a dihydrobenzothiophene ring, a dihydroindole ring, a dihydroisoindole ring, a dihydrobenzimidazole ring, a dihydrobenzoxazole ring, a dihydrobenzothiazole ring, a dihydrobenzopyran ring, a dihydroisobenzopyran ring, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring, a 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine ring, a tetrahydropyrido[3,4-b]pyrazine ring, a dihydroindene ring, a tetrahydronaphthalene ring, a 2,3-dihydrofura[2,3-b]pyridine ring, or a 2,3-dihydrofura[3,2-b]pyridine ring, each of which optionally represents a halogen, C １ ~C ４ Alkyl, C １ ~C ４ substituted one or more times with substituents independently selected from alkoxy; Preferably, L together with ring A forms a dihydrobenzofuran ring, a dihydroisobenzofuran ring, a dihydroindole ring, a dihydroisoindole ring, a dihydrobenzopyran ring, a dihydroisobenzopyran ring, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, a dihydroindene ring, a tetrahydronaphthalene ring, a 2,3-dihydrofura[2,3-b]pyridine ring, or a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring, each of which optionally contains halogen, C １ ~C ４ Alkyl, C １ ~C ４ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted one or more times with substituents independently selected from alkoxy.

17. Y together with ring A forms a 7- to 10-membered partially saturated bicyclic heterocycle, naphthyl, or a 7- to 10-membered bicyclic heteroaryl, wherein the heterocycle, aryl, and heteroaryl are optionally selected from the group consisting of halogen, C １ ~C ４ Alkyl, C １ ~C ４ substituted one or more times with substituents independently selected from alkoxy; Preferably, Y together with ring A is 【Chemistry 8】 However, M １ are each independently N, CH, or C(C １～ C ４ alkyl), More preferably, Y together with ring A is 【Chemistry 9】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which forms a group selected from:

18. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

20. 20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing an ENPP1-mediated disease or disorder.

21. 21. The use of claim 20, wherein the ENPP1-mediated disease or disorder is a solid tumor, e.g., selected from breast cancer, lung cancer, glioblastoma, brain and spinal cancer, head and neck cancer, skin cancer, reproductive system cancer, digestive system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, thyroid cancer, cardiac tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline carcinoma, and cancer of unknown primary.

22. 21. The use of claim 20, wherein the ENPP1-mediated disease or disorder is a hematological malignancy, for example selected from leukemia, lymphoma, or myeloma.

23. The use of claim 20, wherein the ENPP1-mediated disease or disorder is an infectious disease, for example, selected from herpes simplex virus infection, vaccinia virus infection, adenovirus infection, human papillomavirus infection, hepatitis B virus infection, hepatitis D virus infection, human immunodeficiency virus infection, human cytomegalovirus infection, dengue virus infection, Ebola virus infection, Marburg virus infection, Zika virus infection, Listeria monocytogenes infection, Mycobacterium tuberculosis infection, Francisella novicida infection, Legionella pneumophila infection, Chlamydia trachomatis infection, Streptococcus pneumoniae infection, and Neisseria gonorrhoeae infection.

24. 19. A drug combination product comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and one or more other active agents.

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