Phosphonic acid compounds and their prodrugs, their preparation and use

Abstract

The present invention provides phosphonic acid compounds and their prodrugs, their preparation methods and uses. Specifically, the present invention provides compounds of formula (I) or formula (IA), and the compound of formula (IA) is a prodrug form of the compound of formula (I). Experiments have demonstrated that the phosphonic acid compounds of the present invention have good ENPP1 kinase inhibitory activity and can be used as a therapeutic agent for ENPP1-related diseases, and the phosphonic acid compounds have good metabolic stability in vivo. In addition, the phosphonate or amide prodrug compounds according to the present invention have high oral bioavailability, which overcomes the disadvantage that phosphonic acid drug compounds cannot be administered orally. JPEG2025503061000086.jpg46103

Description

[Technical field]

[0001] The present invention relates to the field of medicinal chemistry, in particular to phosphonic acid compounds and their prodrugs, their preparation methods and their use as ENPP1 inhibitors. [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 synthesis of cGAMP and increased 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

[0006] The present disclosure provides a compound of formula (I) or formula (IA), its pharma- ceutically acceptable salt, its pharmaceutical composition, and combinations thereof. The inventors have unexpectedly found that the phosphonic acid compounds of formula (I) are good ENPP1 inhibitors. The inventors have also unexpectedly found that the compounds of the present disclosure have good physical and chemical stability, good bioavailability, especially the phosphonic acid ester compounds. The phosphonic acid drug substance compounds of the present disclosure are excellent ENPP1 inhibitors with good activity and high selectivity, but are highly polar and not suitable for oral administration. On the other hand, the phosphonate or amide prodrug compounds of the present disclosure can be rapidly metabolized in vivo to produce the drug substance compounds. Therefore, the phosphonate or amide prodrug compound or its pharma- ceutically acceptable salt of the present disclosure is used as an active ingredient in a wide range of preparations, such as oral preparations, and since the active ingredient drug compound is rapidly generated after absorption into the body, the phosphonate or amide prodrug compound or its pharma- ceutically acceptable salt of the present disclosure is useful as a prodrug of the active ingredient compound. By preparing the phosphonic acid active ingredient compound into a phosphonate or amide prodrug compound, the physical and chemical properties of the drug substance are improved, the lipid solubility, oral administration and bioavailability of the drug are improved, and side effects are reduced, resulting in higher safety.

[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 a compound represented by formula (I) or formula (IA):

[0009] [ka] (However, X, X 1 , X 2 , X 3 , X 4 , X 5 , W 1 , W2 , Y., L. 1 , L 2 The variables, m, and ring A are each as defined herein. Included are stereoisomers, geometric isomers, tautomers, pharma- ceutically acceptable salts, solvates, or hydrates of this compound, which are useful for treating or preventing ENPP1-mediated diseases or disorders, particularly cancer, or infectious diseases or disorders.

[0010] 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.

[0011] The present disclosure further provides compositions comprising at least one compound of the present disclosure, selected from stereoisomers, geometric isomers, tautomers, pharma- ceutically acceptable salts, solvates, and hydrates thereof.

[0012] The present disclosure further provides pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the present disclosure, its stereoisomers, geometric isomers, tautomers, pharma- ceutically acceptable salts, solvates, and aqueous solutions, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0013] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the present disclosure, selected from stereoisomers, geometric isomers, tautomers, pharma- ceutically acceptable salts, solvates, and aqueous solutions thereof.

[0014] In another embodiment, the present disclosure provides combinations, particularly drug combinations, comprising a therapeutically effective amount of at least one compound of the present disclosure selected from stereoisomers, geometric isomers, tautomers, pharma- ceutically acceptable salts, solvates, and hydrates thereof, and one or more other therapeutic agents.

[0015] 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.

[0016] 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 compounds of the present disclosure can provide selective extracellular inhibition of ENPP1 activity, increasing the extracellular level of cGAMP and activating the stimulator of interferon genes (STING) pathway. For example, the use of the compounds of the present disclosure for enhancing STING-mediated responses in subjects, and the method of using the compounds of the present disclosure for regulating immune responses in subjects.

[0017] The compounds of the present disclosure may be used in therapy.

[0018] 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.

[0019] The present disclosure further relates to a method of inhibiting ENPP1 receptor activity in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of an ENPP1 inhibitor, such as a compound of the present disclosure, or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0020] 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 one or more compounds of the present disclosure, stereoisomers, geometric isomers, tautomers, pharma- ceutically acceptable salts, solvates, and hydrates thereof, and said second therapeutic agent is one or more other therapeutic agents.

[0021] 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 one or more compounds of the present disclosure, their stereoisomers, geometric isomers, tautomers, pharma- ceutically acceptable salts, solvates, and aqueous solutions.

[0022] 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.

[0023] 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.

[0024] The present disclosure also provides products comprising combination preparations of one or more of the disclosed compounds, their stereoisomers, geometric isomers, tautomers, pharma- ceutically acceptable salts, solvates and aqueous solutions, or pharmaceutical compositions thereof, as defined above, together with one or more other active agents, for simultaneous, separate or sequential use in anti-cancer therapy.

[0025] Implementation

[0026] Specifically, the present disclosure provides the following embodiments.

[0027] In one aspect, the present disclosure provides a compound represented by formula (I) or formula (IA):

[0028] [ka] (or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, JPEG2025503061000004.jpg413 is a single bond or a double bond, X 1 , N, CR 1 or a bond, X 2 , N, NR 2 or CR 2 and X 3 , N, NR 3 , -C(O) or CR 3 and X 4 , N, NR 4 , -C(O) or CR 4 and X 5 is N or CR 5 and X is N or CR 0 and However, X and X 5 is not N and is also X 1 , X 2 , X 3 , and X 4 At least one of is independently N or (where permitted) NR n where n=2, 3 or 4; R 0 , R 1 , R 3 , and R 5 are each independently hydrogen, halogen, CN, OR a , NO2, NR b R c , C1-C6 alkyl, and C1-C6 haloalkyl; R 2 and R 4are each independently hydrogen, halogen, CN, OR a , NO2, NR b R c , C1-C6 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted by halogen; Y is O, S, NR 6 or CR 7 R 8 where R 6 , R 7 , and R 8 are each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen; m is 1, 2 or 3; Ring A is C6~C 10 aryl and 5- to 10-membered heteroaryl, where ring A is optionally halogen, CN, OH, NO, NR b R c , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C 10 substituted one or more times with substituents independently selected from aryl and 5- to 10-membered heteroaryl, and C1-C3 haloalkyl; Here, R a , R b , and R c are each independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen; L 1 and L 2 are each independently NH or O, preferably L 1 and L 2 are both O, W 1 and W 2 are each independently hydrogen, C1 to C 10 Alkyl, C6-C 10Aryl, -CH2OC(O)R d , -CH2OC(O)OR d , -CH2C(CH3)2C(O)OR d , -CH(CH3)C(O)OR d , and -CH2C(CH3)2C(O)OR d wherein said alkyl is optionally substituted by halogen; R d is C2-C6 alkyl; In this specification, R n If listed, X 1 For R 1 , X 2 For R 2 , X 3 For R 3 , X 4 For R 4 Represents.)

[0029] In some specific embodiments, R 0 and R 5 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C6 alkyl, and C1-C6 alkoxy, wherein said alkyl and alkoxy are each optionally substituted with 0-3 halogen.

[0030] Preferably, R 0 and R 5 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, and C1-C4 alkoxy, wherein said alkyl and alkoxy are each optionally substituted with 0-3 halogens; More preferably, R 0 and R 5 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C3 alkyl, and C1-C3 alkoxy; Most preferably, R 0 and R 5 are each independently selected from hydrogen, halogen, OH, CN, methyl, ethyl, propyl, methoxy, and ethoxy.

[0031] In some specific embodiments, R 1 and R 3 are each independently selected from hydrogen, halogen, CN, OH, NH2, CF3, C1-C4 alkyl, and C1-C4 alkoxy.

[0032] Preferably, R 1 and R 3 are each independently selected from hydrogen, halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C3 alkoxy; More preferably, R 1 and R 3 are each independently selected from hydrogen, F, Cl, CN, OH, NH2, methyl, ethyl, propyl, methoxy, and ethoxy; Most preferably, R 1 is selected from hydrogen, F, and Cl; R 3 is selected from hydrogen, F, Cl, methoxy, and ethoxy.

[0033] In some specific embodiments, R 2 and R 4 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, -NHCH3, -N(CH3)2, C1-C4 alkyl, C3-C4 cycloalkyl, and C1-C4 alkoxy, wherein said alkyl, cycloalkyl, and alkoxy are each optionally substituted with 0-3 halogen.

[0034] Preferably, R 2 and R 4 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; More preferably, R 2 and R 4are each independently selected from hydrogen, F, Cl, CN, OH, NO, NH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 2,2-difluoromethyl, 1,2-difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl; Most preferably, R 2 and R 4 are each independently selected from hydrogen, F, Cl, OH, methyl, and ethyl.

[0035] In some specific embodiments, R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, and C1-C4 alkoxy.

[0036] Preferably, R 1 and R 3 are each independently selected from hydrogen, halogen, OH, and C1-C3 alkoxy; R 2 and R 4 are each independently selected from hydrogen, halogen, OH, and C1-C3 alkyl.

[0037] In some specific embodiments, X 1 , X 2 , X 3 , and X 4 At least one of is independently N or (where permitted) NR n where n=2, 3 or 4, for example X 1 is N, or X 2 N, and NR 2 Alternatively, X 3 N, and NR 3 or X 4 N, and NR 4 is selected from.

[0038] Preferably, X4 is N or NR 4 or X 2 is N or NR 2 and more preferably, X 4 is N, or X 2 is N.

[0039] In some specific embodiments, X 4 is N and X 3 is CR 3 and preferably, X 4 is N and X 3 is CR 3 And X 2 is CR 2 and more 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.

[0040] In some specific embodiments, X 2 is N and X 3 is CR 3 and preferably, X 2 is N and X 3 is CR 3 And X 1 is CR 1 and more preferably, X 2 is N and X 3 is CR 3 and X 1 is CR 1 And X 4 is CR 4 It is.

[0041] In some specific embodiments, X 4 is NR 4 and preferably, X 4 is NR 4 And X 3 is -C(O), more preferably, X 4 is NR 4and X 3 is -C(O) and X 2 is CR 2 and X 1 is CR 1 It is.

[0042] In some specific embodiments, X 3 is NR 3 and preferably, X 3 is NR 3 And X 4 is -C(O), more preferably, X 3 is NR 3 and X 4 is -C(O) and X 2 is CR 2 and X 1 is CR 1 It is.

[0043] In some specific embodiments, X 1 , X 2 , X 3 , and X 4 At least one of is independently N, for example X 1 is N, or X 2 is N, or X 3 is N, or X 4 is N, Preferably, X 3 is N, or X 4 is N, and more preferably, X 4 is N, More preferably, X 3 is N and X 4 is NR 4 or X 3 is N and X 2 is NR 2 It is.

[0044] In some specific embodiments, X 1 , X 2 , X 3 , and X 4 Exactly one of the is N, e.g. X 1 is N and X 2 is NR 2 or CR 2 and X 3 is NR 3 or CR 3 and X 4 is NR 4 or CR 4 or X 1 CR 1 or a bond, X 2 is N and X 3 is NR 3 or CR 3 and X 4 is NR 4 or CR 4 or X 1 CR 1 or a bond, X 3 is N and X 2 is NR 2 or CR 2 and X 4 is NR 4 or CR 4 or X 1 CR 1 or a bond, X 4 is N and X 2 is NR 2 or CR 2 and X 3 is NR 3 or CR 3 It is.

[0045] In some specific embodiments, X 1 , X 2 , X 3 , and X 4 At most one of, independently, is N or (where permitted) NR n where n=2, 3 or 4, for example X 1 is N and X 2 is CR 2 and X 3 is CR 3 and X 4 is CR4 or X 1 CR 1 or a bond, X 2 is N or NR 2 and X 3 is CR 3 and X 4 is CR 4 or X 1 CR 1 or a bond, X 3 is N or NR 3 and X 2 is CR 2 and X 4 is CR 4 or X 1 CR 1 or a bond, X 4 is N or NR 4 and X 2 is CR 2 and X 3 CR 3 It is.

[0046] Preferably, X 1 is N and X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 or X 1 CR 1 or a bond, X 2 is N and X 3 is CR 3 and X 4 is CR 4 or X 1 CR 1 or a bond, X 3 is N and X 2 is CR 2 and X 4 is CR 4 or X 1 CR 1or a bond, X 4 is N and X 2 is CR 2 and X 3 is CR 3 It is.

[0047] In some specific embodiments, X and X 5 At most one of is N, e.g., X 5 is N and X is CR 0 or X 5 is CR 5 and X is N, or X 5 is CR 5 and X is CR 0 and for example,

[0048] [ka] teeth,

[0049] [ka] Preferably, X 5 is CR 5 and X is CR 0 It is.

[0050] In some specific embodiments, X 1 , X 2 , X 3 , and X 4 At least one of is independently N or (where permitted) NR n where n=2, 3 or 4, and X and X 5 At most one of is N, e.g.

[0051] [ka] teeth,

[0052] [ka] Preferably,

[0053] [ka] More preferably,

[0054] [ka]

[0055] In some specific embodiments, X 1 is N or CR 1 For example, the compound represented by formula (I) or formula (IA) is a compound represented by the following formula (II) or formula (II-A), respectively.

[0056] [ka] (In the formula, X 1 is N or CR 1 and X 2 is N or CR 2 and X 3 , N, NR 3 , -C(O) or CR 3 and X 4 , N, NR 4 , -C(O) or CR 4 and X 5 is N or CR 5 and X is N or CR 0 and However, X and X 5 is not N and is also X 1 , X 2 , X 3 , and X 4 At least one of is independently N or NR n where n=3 or 4; Y is O, S, NR 6 or CR 7 R8 and R 6 , R 7 , and R 8 are each independently selected from hydrogen and C1-C4 alkyl; R 0 and R 5 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, and C1-C4 alkoxy, wherein each said alkyl is optionally substituted with 0-3 halogens; R 1 and R 3 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, and C1-C4 alkoxy; R 2 and R 4 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, and C1-C4 alkyl; Ring A, m, L 1 , L 2 , W 1 , and W 2 The definition of is as above.)

[0057] In some specific embodiments, in Formula (II) or Formula (II-A), R 1 and R 3 are each independently selected from hydrogen, halogen, and C1-C3 alkoxy; R 2 , R 4 are each independently selected from hydrogen, halogen, OH, and C1-C3 alkyl; R 0 , R 5 are each independently selected from hydrogen, halogen, OH, CN, NO2, NH2, C1-C4 alkyl, and C1-C4 alkoxy.

[0058] In some specific embodiments, in Formula (II) or Formula (II-A), R 1 is hydrogen or halogen, R 3is selected from hydrogen, halogen, and C1-C3 alkoxy; R 2 is selected from hydrogen and halogen; R 4 is selected from hydrogen, halogen, and C1-C3 alkyl; R 0 and R 5 are each independently selected from hydrogen, halogen, CN, and C1-C4 alkyl.

[0059] In some specific embodiments, in Formula (II) or Formula (II-A), X 3 is -C(O) and X 4 is NR 4 And X 2 is CR 2 and X 1 is CR 1 or X 3 is NR 3 and X 4 is -C(O) and X 2 is CR 2 and X 1 is CR 1 and R 3 and R 4 are each independently selected from C1 to C3 alkyl.

[0060] In some specific embodiments, in formula (I), X 1 is a bond, and for example, the compound represented by formula (I) or formula (IA) is a compound represented by the following formula (III) or formula (III-A), respectively.

[0061] [ka] (In the formula, JPEG2025503061000013.jpg414 is a single bond or a double bond, X 2 , N, NR 2 or CR 2 and X 3, N, NR 3 or CR 3 and X 4 , N, NR 4 or CR 4 and X 5 is N or CR 5 and X is N or CR 0 and However, X and X 5 is not N and is also X 2 , X 3 , and X 4 At least one of the groups is N or NR n where n=2, 3 or 4; Y is O, S, NR 6 or CR 7 R 8 and R 6 , R 7 , and R 8 are each independently selected from hydrogen and C1-C4 alkyl; R 0 , R 5 are each independently selected from hydrogen, halogen, CN, C1-C6 alkyl, C1-C4 alkoxy, and C1-C6 haloalkyl; R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, and C1-C3 haloalkyl; Ring A, L 1 , L 2 , m, W 1 , and W 2 The definition of is as above.)

[0062] In some specific embodiments, in Formula (III) and Formula (III-A), R 0 is selected from hydrogen, halogen, and C1-C3 alkyl; R 2 is selected from hydrogen, halogen, and C1-C3 alkyl; R 3 is selected from hydrogen, R 4is selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 haloalkyl; R 5 is selected from hydrogen, halogen, CN, OH, C1-C4 alkoxy, and C1-C4 alkyl.

[0063] In some specific embodiments, in Formula (III) and Formula (III-A), X 2 , X 3 , and X 4 At least one of the groups is N or NR n where n=2, 3 or 4, for example X 2 is N or NR 2 or X 3 is N or NR 3 or X 4 is N or NR 4 It is.

[0064] Preferably, X 3 is N or NR 3 or X 4 is N or NR 4 It is.

[0065] In some specific embodiments, in formula (III) and formula (III-A), X 2 , X 3 , X 4 At least two of the are N or NR n and n=2, 3 or 4, for example: X 3 is N and X 4 is NR 4 and preferably, X 3 is N and X 4 is NR 4 And X 2 is CR 2 or X 3 is N and X 2 is NR 2 and preferably, X 3 is N and X 2is NR 2 And X 4 is CR 4 It is.

[0066] In some specific embodiments, X 4 is N, and for example, the compound represented by formula (I) or formula (IA) is a compound represented by the following formula (IV) or formula (IV-A), respectively.

[0067] [ka] (In the formula, JPEG2025503061000015.jpg414 is a single bond or a double bond, X 1 , N, CR 1 or a bond, X 2 , N, NR 2 or CR 2 and X 3 , N, NR 3 or CR 3 and X 5 is N or CR 5 and X is N or CR 0 where X and X 5 is not N at the same time, Y is O, S, NR 6 or CR 7 R 8 and R 6 , R 7 , and R 8 are each independently selected from hydrogen and C1-C4 alkyl; R 0 and R 5 are each independently selected from hydrogen, halogen, CN, C1-C6 alkyl, C1-C4 alkoxy, and C1-C6 haloalkyl; R 1 and R 3 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, and C1-C4 alkoxy; R 2is selected from hydrogen, halogen, OH, and C1-C3 alkyl; Ring A, L 1 , L 2 , m, W 1 , and W 2 The definition of is as above.)

[0068] In some specific embodiments, X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 Yes, X 4 is N, and for example, the compound represented by formula (I) or formula (IA) is a compound represented by the following formula (V) or formula (VA), respectively.

[0069] [ka] (In the formula, X 5 is N or CR 5 and X is N or CR 0 and X and X 5 is not N at the same time, Y is O, S, NR 6 or CR 7 R 8 and R 6 , R 7 , and R 8 are each independently selected from hydrogen and C1-C4 alkyl; R 0 and R 5 are each independently selected from hydrogen, halogen, CN, and C1-C6 alkyl; R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, and C1-C4 alkoxy; Ring A, L 1 , L 2 , m, W 1 , and W 2 The definition of is as above.)

[0070] In some specific embodiments, X 1 is CR 1 and X 2 is N and X 3 is CR 3 and X 4 is CR 4 For example, the compound represented by formula (I) or formula (IA) is a compound represented by the following formula (VI) or formula (VI-A), respectively.

[0071] [ka] (In the formula, X 5 is N or CR 5 and X is N or CR 0 and X and X 5 is not N at the same time, Y is O, S, NR 6 or CR 7 R 8 and R 6 , R 7 , and R 8 are each independently selected from hydrogen and C1-C4 alkyl; R 0 and R 5 are each independently selected from hydrogen, halogen, CN, and C1-C6 alkyl; R 1 and R 3 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, and C1-C4 alkoxy; R 4 is selected from hydrogen, halogen, and C1-C4 alkyl; Ring A, L 1 , L 2 , m, W 1 , and W 2 The definition of is as above.)

[0072] In some preferred embodiments, X 1 is CR 1 and X 2is CR 2 and X 3 is CR 3 and X 4 is N and X 5 is CR 5 and X is N. For example, the compound represented by formula (I) or formula (IA) is a compound represented by formula (VII) or formula (VII-A) below, respectively.

[0073] [ka] (Wherein, Y is O, S, NR 6 or CR 7 R 8 and R 6 , R 7 , and R 8 are each independently selected from hydrogen and C1-C4 alkyl; R 5 is selected from hydrogen, halogen, CN, and C1-C6 alkyl; R 1 and R 3 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, and C1-C4 alkoxy; R 2 is selected from hydrogen, halogen, and C1-C4 alkyl; Ring A, L 1 , L 2 , m, W 1 , and W 2 The definition of is as above.)

[0074] In some preferred embodiments, X 1 is CR 1 and X 2 is N and X 3 is CR 3 and X 4 is CR 4 And X 5 is CR 5 and X is CR 0For example, the compound represented by formula (I) or formula (IA) is a compound represented by formula (VIII) or formula (VIII-A) below, respectively.

[0075] [ka] (Wherein, Y is O, S, NR 6 or CR 7 R 8 and R 6 , R 7 , and R 8 are each independently selected from hydrogen and C1-C4 alkyl; R 0 and R 5 are each independently selected from hydrogen, halogen, CN, and C1-C6 alkyl; R 1 and R 3 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, and C1-C4 alkoxy; R 2 is selected from hydrogen, halogen, and C1-C4 alkyl; Ring A, L 1 , L 2 , m, W 1 , and W 2 The definition of is as above.)

[0076] In some preferred embodiments, X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and X 4 is N and X 5 is CR 5 and X is CR 0 For example, the compound represented by formula (I) or formula (IA) is a compound represented by formula (IX) or formula (IX-A) below, respectively.

[0077] [ka] (Wherein, Y is O, S, NR 6 or CR 7 R 8 and R 6 , R 7 , and R 8 are each independently selected from hydrogen and C1-C4 alkyl; R 0 and R 5 are each independently selected from hydrogen, halogen, CN, and C1-C6 alkyl; R 1 and R 3 are each independently selected from hydrogen, halogen, CN, OH, NO2, NH2, C1-C4 alkyl, and C1-C4 alkoxy; R 2 is selected from hydrogen, halogen, and C1-C4 alkyl; Ring A, L 1 , L 2 , m, W 1 , and W 2 The definition of is as above.)

[0078] In some specific embodiments, Y is O, S, NR 6 or CR 7 R 8 and R 6 , R 7 , and R 8 are each independently selected from hydrogen and C1-C4 alkyl, preferably R 6 , R 7 , and R 8 are each independently selected from hydrogen and C1-C3 alkyl.

[0079] In some specific embodiments, Y is O, NR 6 or CR 7 R 8 and preferably Y is NR 6 and R 6 is selected from hydrogen and C1-C4 alkyl, more preferably R 6 is selected from hydrogen and C1-C3 alkyl, or Preferably, Y is CR 7 R 8 and R 7 and R 8 are each independently selected from hydrogen and C1-C4 alkyl, more preferably R 7 and R 8 are each independently selected from hydrogen and C1-C3 alkyl; or Preferably, Y is O, S, -NH-, -N(CH3)-, -N(ethyl)-, -N(propyl)-, -CH2-, -CH(CH3)- or -C(CH3)2-; More preferably, Y is O, NH, N(CH3), CH(CH3) or CH2.

[0080] In some specific embodiments of the present disclosure, Y is O, S, NH, or CH2, preferably, Y is O, -NH-, or -CH2-, and more preferably, Y is O or -NH-.

[0081] In some further specific embodiments of the present disclosure, Y is O.

[0082] In some other specific embodiments of the present disclosure, Y is -NH-.

[0083] In some other specific embodiments of the present disclosure, Y is -CH2-.

[0084] In certain embodiments, ring A is an optionally substituted C-C 10 aryl and 5- to 10-membered heteroaryl, the substituents being halogen, CN, OH, NO2, NR b R c , C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, and C1 to C3 haloalkyl; R b and R care each independently selected from hydrogen, C1-C4 alkyl, and C3-C4 cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with halogen; Preferably, ring A is optionally substituted independently one or more times, for example one or two times, by a substituent selected from F, Cl, CN, OH, NO, NH, C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkyl, and C1-C3 haloalkyl; More preferably, ring A is optionally substituted independently one or more times, for example one or more times, by a substituent selected from F, Cl, CN, OH, NO, NH, C1-C3 alkyl, C1-C3 alkoxy, and C3-C4 cycloalkyl.

[0085] In some specific embodiments, Ring A is selected from an optionally substituted or unsubstituted pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, a thiazole ring, an oxazole ring, an imidazole ring, a pyran 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, or a benzimidazole ring; Preferably, ring A is an optionally substituted or unsubstituted pyrazole ring, pyrrole ring, imidazole ring, furan ring, thiophene ring, pyran ring, benzene ring, pyridine ring, pyrimidine ring or naphthalene ring; More preferably, ring A is an optionally substituted or unsubstituted pyrimidine ring, benzene ring, pyridine ring, imidazole ring, pyrazole ring or naphthalene ring; More preferably, ring A is a pyrimidine ring, a benzene ring, a pyridine ring, an imidazole ring, a pyrazole ring or a naphthalene ring substituted once or twice by F, Cl, CN, OH, NO2, NH2, C1-C3 alkyl or C1-C3 alkoxy.

[0086] In some specific embodiments, Ring A is selected from the following:

[0087] [ka] (In the formula, R 10 each is the same or different and is independently selected from halogen, CN, OH, NO, NH, C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 haloalkyl; and q is 0, 1, or 2; Preferably, R 10 are each independently selected from F, Cl, CN, C1-C3 alkyl, and C1-C3 alkoxy.

[0088] In certain embodiments, m is 1, 2 or 3; preferably, m is 1 or 2.

[0089] In certain embodiments, in formulas (IA)-(IX-A), W 1 and W 2 are each independently C1 to C 10 Alkyl, C6-C 10 Aryl, -CH2OC(O)R d , -CH2OC(O)OR d , -CH2C(CH3)2C(O)OR d , and -CH(CH3)C(O)OR d wherein said alkyl is optionally substituted by halogen; R d is C2-C6 alkyl, preferably R d is a C2-C4 alkyl, for example, R d is ethyl, tert-butyl, isobutyl or isopropyl.

[0090] Preferably, W 1 and W 2 are each independently C1-C6 alkyl, C6-C8 aryl, -CH2OC(O)R d , -CH2OC(O)OR d , and -CH(CH3)C(O)OR d Selected from R d is a C3-C4 alkyl, for example, R dis tert-butyl, isobutyl or isopropyl, More preferably, W 1 and W 2 are each independently phenyl, -CHOC(O)R d , -CH2OC(O)OR d , and -CH(CH3)C(O)OR d Selected from R d is a C3-C4 alkyl, for example, R d is tert-butyl, isobutyl or isopropyl, More preferably, W 1 and W 2 are each independently -CH2OC(O)R d , and -CH2OC(O)OR d is selected from More preferably, W 1 and W 2 are each independently -CH2OC(O)R d and L 1 , L 2 are both O, More preferably, W 1 and W 2 are each independently -CH2OC(O)OR d and L 1 and L 2 are both O.

[0091] In certain embodiments, in formulas (IA)-(IX-A),

[0092] [ka] teeth,

[0093] [ka]

[0094] [ka] teeth,

[0095] [ka]

[0096] In some specific embodiments, the compound of formula (I) is selected from the following compounds: [Table 1-1] [Table 1-2]

[0097] In some further particular embodiments, the compound of formula (IA) is selected from the following compounds: [Table 2]

[0098] In another aspect, the disclosure provides methods of preparing the compounds of the disclosure.

[0099] In certain embodiments, the compounds of formula (I) of the present disclosure are prepared by the following method.

[0100] The compound of general formula A2 and the compound of general formula A3 are reacted in the presence of cesium carbonate, Pd2dba3, and Xphos (when Y' in compound A2 is hydroxy) or DPBP (when Y' in compound A2 is amino) to produce the compound of general formula A4, which is then hydrolyzed by the action of TMSBr to produce the compound of formula I, as shown in the following reaction scheme:

[0101] [ka] (In the above reaction formula, Y' is a hydroxyl group or an amino group, R' is a C1-C6 alkyl group, X, X 1 , X 2 , X 3 , X 4, X 5 The definitions of Y, m, and ring A are as defined above.

[0102] In another aspect, the present disclosure further provides intermediates for preparing the compounds of the present disclosure, as well as methods for their preparation.

[0103] In certain embodiments, intermediate compound A3 is

[0104] [ka] and is synthesized by the following method:

[0105] [ka] (In the above reaction scheme, X 1 , X 2 , X 3 , and X 4 is as defined above, As shown in the above reaction scheme, the method includes the following steps: (1) Compound A in trimethyl orthoformate and 2,2-dimethyl-1,3-dioxane-4,6-dione 3-1 Add and react with A 3-2 Obtaining a compound, (2)A 3-2 The compound was dissolved in diphenyl ether and reacted to give A. 3-3 Obtaining a compound, (3)A 3-3 The compound is reacted with phosphorus oxychloride to obtain intermediate compound A3.

[0106] In another aspect, the present disclosure provides a composition comprising at least one compound of the present disclosure, selected from pharma- ceutically acceptable salts, stereoisomers, geometric isomers, tautomers, solvates, and hydrates thereof.

[0107] In one embodiment, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure, a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate, or hydrate thereof, and at least one pharma- ceutically acceptable carrier, diluent, or excipient.

[0108] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the present disclosure, its stereoisomers, geometric isomers, tautomers, pharma- ceutically acceptable salts, solvates and aqueous solutions, 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.

[0109] In another aspect, the present disclosure provides a drug combination product comprising at least one compound of the present disclosure, pharma- ceutically acceptable salts, stereoisomers, geometric isomers, tautomers, solvates, and hydrates thereof, and one or more other active agents.

[0110] In another aspect, the disclosure provides the use of a compound of Formula (I) or Formula (IA), or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate 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.

[0111] In one embodiment, the tumor or infection is caused by an alteration in the stimulator of interferon genes (STING).

[0112] In another embodiment, the disclosure provides the use of a compound of Formula (I) or Formula (IA), or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate 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.

[0113] In another embodiment, the present disclosure provides for the use of a compound of the present disclosure or a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate, or hydrate thereof, alone or optionally in combination with another compound of the present disclosure or a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate, or hydrate thereof, and / or at least one other therapeutic agent, in a therapy for treating an ENPP1 mediated disease or disorder.

[0114] In another embodiment, the present disclosure further provides the use of a compound of the present disclosure or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof in the preparation of a medicament, said medicament alone or, optionally in combination with another compound of the present disclosure or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, and / or at least one other therapeutic agent, for treating an ENPP1 mediated disease or disorder.

[0115] In another embodiment, the disclosure provides a combined formulation of a compound of the disclosure, or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, with one or more additional therapeutic agents for use in therapy.

[0116] In another embodiment, the present disclosure provides a combination of a compound of the present disclosure, or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof, with one or more additional therapeutic agents, used simultaneously or separately in a method of therapy.

[0117] In another embodiment, the present disclosure provides a combined formulation of a compound of the present disclosure or a stereoisomer, geometric isomer, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof with 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.

[0118] 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, solvate, and hydrate, or prodrug thereof, or a pharmaceutical composition comprising the same, to an individual in need thereof.

[0119] 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, or a stereoisomer, geometric isomer, tautomer, pharma-ceutically acceptable salt, solvate, or hydrate thereof, alone or optionally in combination with other compounds of the disclosure or a stereoisomer, geometric isomer, tautomer, pharma-ceutically acceptable salt, solvate, or hydrate thereof, and / or at least one other therapeutic agent.

[0120] 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 or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, and said second therapeutic agent is another compound of the disclosure or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, and / or at least one other therapeutic agent.

[0121] In some embodiments of the present disclosure, the ENPP1-mediated disease or disorder includes, but is not limited to, cancer, an infectious disease or disorder, particularly recurrent or refractory cancer, metastatic cancer, and the like.

[0122] In another embodiment, the ENPP1 mediated disease or disorder is recurrent or refractory cancer.

[0123] In another embodiment, the ENPP1 mediated disease or disorder is metastatic cancer.

[0124] In another embodiment, the cancer is a solid 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 tumors, germ cell tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcoma, midline carcinoma, and cancer of unknown primary.

[0125] In another embodiment, the cancer is a hematological malignancy, in particular leukemia, lymphoma, or myeloma.

[0126] 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.

[0127] The phosphonate or amide prodrug compounds of formula (IA) of the present disclosure are prodrug forms of biologically active compounds, specifically those that have a substituent W on one or more heteroatoms (N, O) of the active compound. 1 and W2 wherein the group W 1 Or W 2 may be metabolized or otherwise converted under certain conditions to produce the active compound (drug substance). The specific embodiments of the present disclosure are not intended to be limiting of the contents of the present disclosure, and the phosphonate or amide prodrug compounds of the present disclosure may increase the solubility of biologically active drug substances, thereby improving their oral bioavailability. Substituent W 1 and W 2 It has been found that is metabolized by phosphatases in the gastrointestinal tract to generate the potential active parent drug, which is then absorbed by the body.

[0128] Active compounds of the present disclosure have been discovered that have biological activity and 1 and W 2 When the compound is formulated in the form of a prodrug containing a group (i.e., the phosphonate or amide compound of formula (IA) described above), its lipid solubility and oral bioavailability are significantly improved. Such improved lipid solubility contributes to better absorption of the active ingredient in the intestinal tract.

[0129] In certain embodiments, the disclosed phosphonate compounds have an IC of 1 μM or less according to the EED Alphascreen binding, LC-MS, and / or ELISA assays disclosed herein. 50 value, more preferably 0.5 μM or less 50 value, more preferably 0.125 μM or less 50 value, most preferably 0.1 μM or less 50 In particular, naphthyridine-based phosphonic acid compounds having the above-mentioned properties are provided.

[0130] 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.

[0131] 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.

[0132] Explanation of terms

[0133] 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.

[0134] 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.

[0135] 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.

[0136] The base is a wavy line. JPEG2025503061000032.jpg412", the wavy line indicates the point of attachment of the group to the remainder of the molecule.

[0137] As used herein, " "JPEG2025503061000033.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 JPEG2025503061000034.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.

[0138] 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.

[0139] As used herein, "halogen" or "halogenated" means fluorine, chlorine, bromine and iodine. Preferred halogens as substituents are fluorine and chlorine.

[0140] As used herein, "alkyl" refers to a completely saturated, linear or branched monovalent hydrocarbon group. The alkyl group preferably has 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms. The number before the alkyl group represents the number of carbon atoms. For example, "C1 to C6 alkyl" represents an alkyl group having 1 to 6 carbon atoms, "C1 to C4 alkyl" represents an alkyl group having 1 to 4 carbon atoms, and "C1 to C3 alkyl" represents an alkyl group having 1 to 3 carbon atoms. Representative examples of alkyl groups 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, and n-decyl. This definition applies whether the term "alkyl" appears alone or as part of another group, such as haloalkyl, alkoxy, etc.

[0141] 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.

[0142] As used herein, "cycloalkyl" refers to a saturated or partially saturated non-aromatic carbocyclic ring, including monocyclic, bicyclic, or tricyclic rings, preferably having 3 to 12, more preferably 3 to 10, e.g., 3 to 8, 4 to 10, or 4 to 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, and the like. 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.

[0143] 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.

[0144] 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.

[0145] 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, e.g. 6 to 9, ring carbon atoms, with one or more fused rings, in which at least one ring is aromatic and the other rings (if present) may be aromatic or non-aromatic. Preferred aryls are those having 6 to 10 ring carbon atoms, i.e. C6 to C 10 Aryl, including monocyclic aryl (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 aryl include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl, dihydroindenyl, or anthracenyl, and the like.

[0146] 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.

[0147] 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.

[0148] 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).

[0149] 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.

[0150] 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.

[0151] 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.

[0152] Exemplary bicyclic heterocycles include indole, dihydroindole, benzothiazole, and the like.

[0153] 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.

[0154] 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.

[0155] As used herein, the term "-C(=O)" is carbonyl.

[0156] 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.

[0157] 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.

[0158] When any variable occurs more than once in any constituent or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, the group may be unsubstituted or substituted with up to 3 R, with R being 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., ring A is a C6-C 10 In the case of aryl and 6- to 10-membered aryl, these groups are unsubstituted or substituted with one or more, for example two, substituents independently selected from the given definition at each occurrence, which applies to the definitions of other similar scenarios as well.

[0159] 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.

[0160] Combinations of substituents and / or variables are permissible so long as such compositions result in stable compounds.

[0161] When a dashed ring is used for a ring structure, it means that the ring structure can be saturated, partially saturated, or unsaturated.

[0162] 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.

[0163] Unless otherwise indicated, the term "disclosed compound" or "compound of the disclosure" refers to a compound of formula (I) or subformulas thereof, such as formulas (II) and (III), 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 intrinsically formed moieties (e.g., polycrystalline forms, solvates and / or hydrates). In cases where moieties capable of forming salts are present, salts, particularly pharma- ceutically acceptable salts, are also included. The presence of tautomers or internal isomeric addition products can be identified by one of skill in the art using tools such as NMR. Compounds of formula (I) of the disclosure can readily form tautomers and internal isomeric addition products as described herein.

[0164] When formula (I) is mentioned in this specification, the expression also includes its subformulae, such as formulae (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX), unless the context requires otherwise. When formula (IA) is mentioned in this specification, the expression also includes its subformulae, such as formulae (II-A), (III-A), (IV-A), (VA), (VI-A), (VII-A), (VIII-A), and (IX-A), unless the context requires otherwise.

[0165] Those skilled in the art will recognize that the compounds of the present disclosure may contain chiral centers, and in this case may exist in different heteromorphic forms.Therefore, the compounds of the present invention may exist in the form of individual stereoisomers (e.g., enantiomers, diastereomers) and mixtures in any ratio, for example in the form of racemates, and may also exist in the form of their tautomers and geometric isomers, if necessary.As used herein, "stereoisomers" refer to compounds that have the same molecular formula but have different atomic arrangements and configurations.

[0166] Stereoisomers include enantiomers, diastereomers, and conformers. As used herein, "enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term is used to refer to a racemic mixture.

[0167] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Mixtures of diastereomers can be separated using high resolution analytical methods such as electrophoresis or chromatography such as HPLC. As used herein, "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that has no optical activity. A racemic mixture can be used in its own form or separated into individual isomers. Resolution can provide stereochemically pure compounds or mixtures enriched in one or more isomers.

[0168] As used herein, "tautomers" or "tautomeric forms" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via rearrangement of some of the bonding electrons.

[0169] As used herein, "geometric isomers" are isomers resulting from the inability to freely rotate about double bonds or single bonds of ring carbon atoms, also called cis-trans isomers, where the substituents are located on the same side of a plane are cis isomers and the substituents are located on opposite sides of a plane are trans isomers. When a compound contains double bonds, the substituents can be in the E or Z conformation.

[0170] 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.

[0171] "Conformers" are isomers that differ by rotation about one or more bonds. "Rotational isomers" are conformers that differ by rotation about only a single bond. "Atropisomers" refer to structural isomers based on axial or planar chirality resulting from restricted rotation within a molecule.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] As used herein, "pharmaceutical acceptable" and "pharmaceutical tolerable" may be used interchangeably and include a substance or composition that must be chemically / toxicologically compatible with other ingredients, formulations contained therein, and / or mammals treated therewith.

[0177] As used herein, "pharmaceutically acceptable salts" and "pharmaceutically acceptable salts" refer to salts that retain the biological effectiveness and performance of the compounds of the present disclosure, which salts 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. Non-limiting examples of salts include acid addition salts of compounds of the present disclosure with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfites, carbonates, bicarbonates, nitric acid, phosphoric acid, and the like, and acid addition salts of compounds of the present disclosure with organic acids, such as, 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, stearic acid, and the like, as well as pharma- ceutically acceptable base addition salts of compounds of the present disclosure with inorganic and organic bases, from which derived salts can be prepared. Inorganic bases include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., and particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts, and organic bases of the salts derived therefrom 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. Conventional chemical methods can be used to synthesize pharmaceutically acceptable salts from parent compounds (alkaline or acidic moieties). In general, the salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate alkali (e.g., hydroxide, carbonate, bicarbonate, 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, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable.

[0178] As used herein, "pharmaceutical composition" means a compound of the present disclosure in a form suitable for oral or parenteral administration, or at least one pharma- ceutically acceptable excipient thereof.

[0179] As used herein, "pharmaceutically acceptable excipients" includes any and all of solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, which are well known to those skilled in the art. Except insofar as conventional carriers are incompatible with the active ingredient, their use in the therapeutic or pharmaceutical compositions is contemplated.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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 3 H), 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.

[0191] 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.

[0192] 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.

[0193] 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.

[0194] effect

[0195] The phosphonic 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] Pharmaceutical Compositions and Administration

[0201] 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.

[0202] 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.

[0203] The compounds of the present disclosure may be formulated into syrups, infusion or injection solutions, sprays, tablets, capsules, troches, liposomes, suppositories, and the like.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] Drug Combinations

[0212] 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.

[0213] 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.

[0214] In one embodiment, the disclosure provides a pharmaceutical composition comprising a compound having either Formula (I) or Formula (IA), or a pharma- ceutically acceptable salt thereof, and one or more other active agents. Optionally, the pharmaceutical composition may include a pharma- ceutically acceptable excipient as described above.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] General synthesis method

[0219] 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.

[0220] 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.

[0221] Flow 1

[0222] [ka] In the above reaction formula, Y' is hydroxy, Y'' is C1-C4 alkoxy, and X 1 , X 2 , X 3 , X 4 The definitions of , Y, and ring A are as defined above.

[0223] The compound of general formula A2 can be prepared by the following synthesis method: Add raw material A1, diethyl phosphate, and cesium carbonate to dimethylformamide, react at room temperature overnight, add water to the reaction solution to quench, extract with dichloromethane, wash the organic phase with saturated sodium chloride solution, concentrate under reduced pressure, and pass the residue through a silica gel column to obtain the compound of general formula A2.

[0224] The compound of general formula A4 can be prepared by the following synthesis method. Raw materials A2 and A3, cesium carbonate, Pd2dba3, and Xphos are added to dioxane, and reacted overnight under nitrogen protection at 100°C with stirring. The reaction solution is cooled to room temperature, filtered and concentrated, and the residue is purified by high-performance liquid reverse phase preparative column to obtain the compound of general formula A4.

[0225] The compound of general formula A5 can be prepared by the following synthesis method: Add raw material A4 and trimethylsilyl bromide to acetonitrile, react at room temperature for 16 hours, then concentrate, separate and purify using a high-performance liquid reverse phase preparative column to obtain the compound of general formula I.

[0226] In another embodiment, compound A3 of the present disclosure can be synthesized according to the following general synthetic scheme.

[0227] Flow 2

[0228] [ka] The compound of general formula A3 can be prepared by the following synthesis method: Trimethyl orthoformate and 2,2-dimethyl-1,3-dioxane-4,6-dione are reacted at 100° C. for 2 hours to obtain compound A 3-1 The reaction is continued at this temperature for 2 hours. The reaction is cooled to room temperature to precipitate a solid, and the solid is collected by filtration. 3-2 Obtain the compound A 3-2 The compound was dissolved in diphenyl ether and reacted at 230° C. for 1 hour. The reaction solution was cooled to room temperature, petroleum ether was added to precipitate a solid, and the solid was collected by filtration. 3-3 Compound A was obtained. 3-3 The compound and phosphorus oxychloride are reacted at 100°C for 1 hour, cooled to room temperature, excess phosphorus oxychloride is removed, ice water is added to the residue, and the pH is adjusted to 8 with aqueous ammonia. Extraction is performed with dichloromethane, and the organic phase is washed successively with water and saturated sodium chloride solution, dried, filtered, concentrated, and purified by silica gel column to obtain the compound of general formula A3. [Brief description of the drawings]

[0229] [Figure 1] 1 is a pharmacokinetic curve graph of active ingredient Compound 1 in plasma when prodrug Compound 7 (50 mg / kg) was orally administered to mice.

[0230] [Diagram 2] 1 is a graph showing the pharmacokinetic curve of active ingredient Compound 1 in plasma when prodrug Compound 8 (50 mg / kg) was orally administered to mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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).

[0235] 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.

[0236] 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.

[0237] Working Example

[0238] 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.

[0239] 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. 13C 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.

[0240] [Table 3]

[0241] Synthesis of key intermediates

[0242] Intermediate 1a: 5-chloro-2-methoxy-1,8-naphthyridine

[0243] [ka]

[0244] Step 1: Synthesis of 5-(((6-methoxypyridin-2-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0245] 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%. 1H-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).

[0246] Step 2: Synthesis of 7-methoxy-1,8-naphthyridin-4(1H)-one

[0247] 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%. 1 H-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).

[0248] Step 3: Synthesis of 5-chloro-2-methoxy-1,8-naphthyridine

[0249] 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).

[0250] Intermediate 2a: 4-chloro-6-chloro-7-methoxyquinoline

[0251] [ka]

[0252] Step 1: Synthesis of 5-((((4-chloro-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0253] 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).

[0254] Step 2: Synthesis of 6-chloro-7-methoxyquinolin-4(1H)-one

[0255] 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).

[0256] Step 3: Synthesis of 4-chloro-6-chloro-7-methoxyquinoline

[0257] 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).

[0258] Intermediate 3a: 4-Chloro-7-methoxy-pyrido[2,3-d]pyrimidine

[0259] [ka]

[0260] Step 1: Synthesis of 2-amino-6-methoxynicotinic acid

[0261] Compound 3a-1 (5.0 g, 29.0 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 h. 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 3a-2 (2.0 g, white solid) in a yield of 40%. LCMS (ESI): m / z 169.0 [M+H] + ;RT=1.10min(3min).

[0262] Step 2: Synthesis of 7-methoxypyrido[2,3-d]pyrimidine-4-phenol

[0263] Compound 3a-2 (1.0 g, 6.0 mmol), formamidine acetate (624 mg, 17.8 mmol), and ethylene glycol monomethyl 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 h. The reaction solution was concentrated and purified with (DCM:methanol=10:1) to give compound 3a-3 (200 mg, white solid) in a 20% yield. LCMS (ESI): m / z 177.9 [M+H] + ;RT=1.502min(3min).

[0264] Step 3: Synthesis of 4-chloro-7-methoxypyrido[2,3-d]pyrimidine

[0265] Compound 3a-3 (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 h. 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 give compound 3a (200 mg, white solid) in 90% yield. LCMS (ESI): m / z 339.7 [M+H] + ;RT=1.521min(3min).

[0266] Intermediate 4a: 4-Chloro-7-methoxy-2-methylpyrido[2,3-d]pyrimidine

[0267] [ka]

[0268] Step 1: Synthesis of methyl 6-methoxy-2-((4-methoxybenzyl)amino)nicotinate

[0269] At room temperature, 4a-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 4a-2 (7 g, colorless liquid), with a yield of 92%. LCMS (ESI): m / z 303.1 [M+H] + ;RT=1.98min(3min).

[0270] Step 2: Synthesis of methyl 2-amino-6-methoxynicotinate

[0271] Compound 4a-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 4a-3 (3.5 g, colorless liquid), with a yield of 80%. LCMS (ESI): m / z 183.1 [M+H] + ;RT=1.42min(3min).

[0272] Step 3: Synthesis of 2-acetamido-6-methoxymethyl nicotinate

[0273] Compound 4a-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 for 16 hours at room temperature. 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 4a-4 (1.0 g, white solid). The yield was 45%. LCMS (ESI): m / z 224.8 [M+H] + ;RT=1.541min(3min).

[0274] Step 4: Synthesis of 7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one

[0275] Compound 4a-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 4a-5 (200 mg, white solid), with a yield of 21%. LCMS (ESI): m / z 191.8 [M+H] + ;RT=1.715min(3min).

[0276] Step 5: Synthesis of 4-chloro-7-methoxy-2-methylpyrido[2,3-d]pyrimidine

[0277] Compound 4a-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 4a (210 mg, white solid), with a yield of 90%. LCMS (ESI): m / z 209.8 [M+H] + ;RT=2.44min(5min).

[0278] Intermediate 5a: 7-Chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine

[0279] [ka]

[0280] Step 1: Synthesis of methyl 4-amino-1-methyl-1H-pyrazole-5-formate

[0281] Compound 5a-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 5a-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).

[0282] Step 2: Synthesis of 1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol

[0283] Compound 5a-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 5a-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).

[0284] Step 3: Synthesis of 7-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine

[0285] Compound 5a-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 5a (1.20 g, white solid), with a yield of 82.4%. LCMS (ESI): m / z 169.0 [M+H] + ;RT=1.20min(2.00min).

[0286] Intermediate 6a: 4-Chloro-7-methoxy-1,6-naphthyridine

[0287] [ka]

[0288] Step 1: Synthesis of 3-bromo-2-methoxypyridin-4-amine

[0289] Compound 6a-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 6a-2 (1.4 g, yellow solid), with a yield of 88%. LCMS (ESI): m / z 203.0 [M+H] + ;RT=0.967min(2.50min).

[0290] Step 2: Synthesis of 5-(((3-bromo-2-methoxypyridin-4-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0291] 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 6a-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 6a-3 (679 mg, white solid), with a yield of 77%. LCMS (ESI): m / z 357.0359.0 [M+H] + ;RT=1.517min(2.50min).

[0292] Step 3: Synthesis of 8-bromo-7-methoxy-1,6-naphthyridin-4-ol

[0293] Compound 6a-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 6a-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).

[0294] Step 4: Synthesis of 7-methoxy-1,6-naphthyridin-4-ol

[0295] Compound 6a-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 6a-5 (1.4 g, yellow solid), with a yield of 100%. LCMS (ESI): m / z 177.1 [M+H] + ;RT=0.757min(2.50min).

[0296] Step 5: Synthesis of 4-chloro-7-methoxy-1,6-naphthyridine

[0297] Compound 6a-5 (900 mg, 0.644 mmol) and DIEA (1.7 mL, 5.62 mmol) were added to 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 6a (1.0 g, yellow solid), with a yield of 100%. LCMS (ESI): m / z 195.1 [M + H] + ;RT=1.287min(2.50min).

[0298] Intermediate 7a: 8-Chloro-3-methoxy-1,5-naphthyridine

[0299] [ka]

[0300] Step 1: Synthesis of 5-((5-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0301] 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 7a-1 (4 g, 16.11 mmol) was then added, and the mixture was kept at 105° C. and stirred overnight. After dilution with petroleum ether at room temperature, the mixture was filtered, and the filter cake was washed with petroleum ether to obtain crude product 7a-2 (7 g, yellow solid) as a filter cake. LCMS (ESI): m / z 279.1 [MH] - ;RT=0.891min(2.50min).

[0302] Step 2: Synthesis of 7-methoxy-1,5-naphthyridin-4(1H)-one

[0303] Compound 7a-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 7a-3 (2.5 g, gray solid) as a filter cake.

[0304] Step 3: Synthesis of 8-chloro-3-methoxy-1,5-naphthyridine

[0305] Compound 7a-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 give compound 7a (2.70 g, yellow solid). The yield was 70%. LCMS (ESI): m / z 195.1 [M+H] + ;RT=1.271min(2.50min).

[0306] Intermediate 8a: 5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one

[0307] [ka]

[0308] Step 1: Synthesis of N-(4-chloropyridin-2-yl)pivaloylindanedionamide

[0309] Compound 8a-1 (1.28 g, 10.0 mmol), triethylamine (1.31 g, 13.0 mmol), pyridine (15 mL) and dichloromethane (15 mL) were added in sequence to a dry 100 mL one-neck flask at room temperature. Then, tert-pentanoyl chloride (1.32 g, 11.0 mmol) was added dropwise in an ice bath, and the reaction was stirred overnight. The mixture was concentrated under reduced pressure, and the residue was purified by a silica gel column (PE:EA=10:1) to obtain product 8a-2 (1.85 g, powdery solid) in a yield of 87.00%. 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).

[0310] Step 2: Synthesis of N-(4-chloro-3-formylpyridin-2-yl)pivaloylindanedionamide

[0311] Compound 8a-2 (5.7 g, 26.9 mmol) and tetrahydrofuran (70 mL) were added in sequence to a dry 250 mL three-neck flask at room temperature. Under nitrogen protection, n-butyllithium (27 mL, 2.5 M tetrahydrofuran) was added dropwise at -78 °C, and the reaction solution was stirred at -78 °C for 0.5 h. A solution of N,N-dimethylformamide in tetrahydrofuran (30 mL) was added and stirred at -78 °C for 1 h. The temperature was raised to room temperature, and a saturated ammonium chloride solution (200 mL) was added and reacted at room temperature for 30 minutes. The reaction solution was extracted three times with EA (100 mL), and the organic phase was washed once 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 product 8a-3 (2 g, yellow oil) in a yield of 31.00%. LCMS(ESI):m / z240.8[M+H] + ;RT=1.768min(3.00min).

[0312] Step 3: Synthesis of tert-butyl 3-(4-chloro-2-pyridonamidopyridin-3-yl)-3-hydroxypropionate

[0313] Compound 8a-3 (2.28 g, 9.5 mmol) and tetrahydrofuran (40 mL) were added to a dry 250 mL three-neck flask at room temperature. Under nitrogen protection, lithium diisopropylamide (10.5 mL, 2 M tetrahydrofuran) was added dropwise at -78 °C, and the reaction solution was stirred at -78 °C for 0.5 h. Further, tert-butyl acetate dissolved in tetrahydrofuran (20 mL) was added, and stirring was continued at -78 °C for 1 h. The temperature was raised to room temperature, water (40 mL) was added, and the mixture was extracted with EA (50 mL). The organic phase was washed with saturated brine (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 obtain product 8a-4 (2.2 g, yellow solid) in a yield of 65.00%. LCMS (ESI): m / z 356.7 [M + H] + ;RT=1.871min(3.00min).

[0314] Step 4: Synthesis of 5-chloro-1,8-naphthyridin-2(1H)-one

[0315] Compound 8a-4 (1.9 g, 5.34 mmol) and 3M hydrochloric acid (20 mL) were added to a dry 50 mL single-neck flask at room temperature, and the mixture was reacted at 100° C. for 8 h. The reaction solution was cooled, filtered, washed with saturated sodium bicarbonate solution (5 mL) and water (5 mL), and dried to give product 8a-5 (440 mg, white solid) in a yield of 46.00%. LCMS (ESI): m / z 181.0 [M+H] + ;RT=1.20min(3.00min).

[0316] Step 5: Synthesis of 5-chloro-1-methyl-1,8-naphthyridin-2(1H)-one

[0317] Compound 8a-5 (100 mg, 0.56 mmol), methyl iodide (102 mg, 0.72 mmol), potassium carbonate (154 mg, 1.12 mmol), and DMF (3 mL) were added sequentially to a dry 25 mL one-neck flask at room temperature. The reaction solution was stirred at room temperature overnight. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EA (20 mL). The organic phase was washed with saturated brine (10 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 product 8a (100 mg, white solid) in 92.60% yield. LCMS (ESI): m / z 194.8 [M+H] + ;RT=1.621min(3.00min).

[0318] Intermediate 9a: Synthesis of 4-chloro-7-methyl-1,7-naphthyridin-8-(7H)-one

[0319] [ka]

[0320] Step 1: Synthesis of 2,2-dimethyl-5-(((2-oxo-1,2-dihydropyridin-3-yl)amino)methylene)-1,3-dioxa-4,6-dione

[0321] 2,2-Dimethyl-1,3-dioxane-4,6-dione (2.36 g, 16.35 mmol) was added to a 100 mL single-neck flask containing 20 mL of trimethyl orthoformate, and the mixture was stirred at 105° C. under nitrogen protection for 2 h. Compound 9a-1 (1.5 g, 13.62 mmol) was then added and the reaction was continued at this temperature for 2 h. After cooling to room temperature, a solid precipitated out, which was collected by filtration to give product 9a-2 (3.9 g, pale off-white solid) in 100% yield. LCMS (ESI): m / z 263.1 [MH] - ;RT=0.931min(2.50min).

[0322] Step 2: Synthesis of 2,2-dimethyl-5-(((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)methylene)-1,3-dioxa-4,6-dione

[0323] 9a-2 (1.5 g, 5.68 mmol) and anhydrous potassium carbonate (4.32 g, 31.22 mmol) were added in sequence to a 100 mL three-neck flask containing 30 mL of DMF at room temperature, and after cooling to 0°C, methyl iodide (0.35 ml, 5.68 mmol) was slowly added dropwise thereto. The mixture was stirred overnight at room temperature, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol=20:1) to obtain 9a-3 (700 mg, yellow solid). LCMS (ESI): m / z 277.1 [MH] + ;RT=0.831min(2.50min).

[0324] Step 3: Synthesis of 7-methyl-1,7-dihydro-1,7-naphthyridine-4,8-dione

[0325] 9a-3 (6.0 g, 21.58 mmol) was added to a 250 mL one-neck flask containing 100 mL of diphenyl ether and stirred at 230° C. for 2 h. After cooling to room temperature, the mixture was filtered and the filter cake was collected to give 9a-4 (3.1 g, maroon solid) in 82% yield. LCMS ESI): m / z 177.1 [M+H] + ;RT=0.617min(2.50min).

[0326] Step 4: Synthesis of 4-chloro-7-methyl-1,7-naphthyridin-8-(7H)-one

[0327] 9a-4 (3.1 g, 17.6 mmol) was added to a 100 mL single-neck flask containing 30 mL of phosphorus oxychloride and stirred at 100° C. under nitrogen protection for 1 h. After cooling, phosphorus oxychloride was removed, crushed ice was added at 0° C., the pH was adjusted to 8 with saturated sodium bicarbonate, extracted with dichloromethane, the organic phase was washed with water and saturated sodium chloride in succession, dried over anhydrous sodium sulfate, filtered and concentrated to give product 9a (2.1 g, maroon solid). LCMS (ESI): m / z 195.1 [M+H] - ;RT=0.937min(2.50min).

[0328] Example 1: Synthesis of Compound 1

[0329] [ka]

[0330] Step 1: Synthesis of (4-methoxybenzyl)diethylphosphonate

[0331] Compound 1-1 (2.0 g, 12.8 mmol), diethyl phosphate (2.7 g, 19.2 mmol), cesium carbonate (8.4 g, 25.6 mmol) and dimethylformamide (60 mL) were added to a single-neck flask containing 100 mL of methanol. The mixture was allowed to react at room temperature overnight. Water was added to the reaction solution for quenching, and the mixture was extracted with dichloromethane. The organic phase was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified using a silica gel column (PE:EA=5:1) to obtain compound 1-2 (2.5 g, oil). LCMS (ESI): m / z 259.0 [M+H] + ;RT=1.452min(2.50min).

[0332] Step 2: Synthesis of (4-hydroxybenzyl)diethylphosphonate

[0333] Compound 1-2 (200 mg, 0.8 mmol) was added to a three-neck flask containing dry dichloromethane (3 mL), and 1.0 M boron tribromide dichloromethane solution (3.2 mL, 3.2 mmol) was added dropwise under argon protection at -78 ° C. After completion of the dropwise addition, the reaction mixture was warmed to 0 ° C and stirred for 1 h. The reaction mixture was quenched with saturated sodium chloride, extracted with dichloromethane, and the organic phase was washed with saturated saline. It was concentrated under reduced pressure, and the residue was purified by a silica gel column (PE:EA = 1:1) to obtain compound 1-3 (100 mg, white solid). 1 H-NMR (400MHz, CDCl3-d): δ7.05-7.02(m,2H),6.63(d,J=8.4Hz,2H),4.06-4.00(m,4H),3.05(d,J=21.2Hz,2H),1.28-1.25(m,6H).

[0334] Step 3: Synthesis of (4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)benzyl)diethylphosphonate

[0335] Compound 1-3 (100 mg, 0.4 mmol), compound 1a (78 mg, 0.4 mmol), cesium carbonate (261 mg, 0.8 mmol), Pd2dba3 (catalytic amount) and Xphos (catalytic amount) were added to a single-neck flask containing 3 mL of dioxane. The mixture was stirred at 100°C under nitrogen protection and reacted overnight. The reaction solution was cooled to room temperature, filtered and concentrated, and the residue was purified by Prep-HPLC to obtain compound 1-4 (21 mg, off-white solid) in a yield of 13.0%. LCMS (ESI): m / z 403.15 [M+H] + ;RT=2.323min(6.00min). 1 H-NMR(400MHz,MeOD-d4):δ8.62(d,J=8.8Hz,2H),7.48(dd,J=8.4,2.4Hz,2H),7.22(d,J=8.4Hz,2H) ,7.11(d,J=8.8Hz,1H),6.59(d,J=6.4Hz,1H),4.20-4.00(m,7H),3.35(s,2H),1.29(t,J=7.2Hz,6H).

[0336] Step 4: Synthesis of (4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)benzyl)phosphonic acid

[0337] Compound 1-4 (75 mg, 0.19 mmol) and trimethylsilyl bromide (0.12 mL, 0.93 mmol) were added to a single-neck flask containing acetonitrile (5 mL), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated, separated and purified using a high-performance reversed-phase liquid preparative column to obtain compound 1 (5.15 mg, white solid) in 7.98% yield. LCMS (ESI): m / z 347.00 [M+H] + ;RT=3.262min(6.00min). 1 H-NMR(400MHz,MeOD-d4):δ8.83-8.77(m,2H),7.56(d,J=5.6Hz,2H),7.39(d,J=9.2H z,1H),7.30(d,J=6.0Hz,2H),6.99(d,J=9.2Hz,1H),4.22(s,3H),3.24-3.16(m,2H).

[0338] Examples 2 to 6: Synthesis of Compounds 2 to 6

[0339] The synthesis method was the same as that of compound 1 in Example 1. As the raw material, the starting compound 1-1 in Example 1 was changed to 4-chloromethyl-2-fluoro-1-methoxybenzene, 4-chloromethyl-2,6-difluoro-1-methoxybenzene, 4-chloromethyl-5-fluoro-1-methoxybenzene, 4-chloromethyl-3,5-difluoro-1-methoxybenzene, and 4-chloromethyl-2,6-difluoro-1-methoxybenzene, respectively. The structural formula of the compound in each example is shown in the above table. The data of the compounds in Examples 2 to 6 are shown below. [Table 4]

[0340] Example 7: Synthesis of Compound 7

[0341] [ka]

[0342] Step 1: Synthesis of (4-(benzyloxy)benzyl)diethylphosphonate

[0343] Compound 7-1 (3.0 g, 12.92 mmol) was added to a 100 mL one-neck flask, and triethyl phosphite (20 mL) was added at room temperature. The mixture was stirred at 150° C. under nitrogen protection for 6 h. The mixture was concentrated and purified by silica gel column (PE:EA=1:1) to give compound 7-2 (4.18 g, yellow oil) in 97% yield. LCMS (ESI): m / z 357.1 [M+Na] + ;RT=1.441min(2.50min).

[0344] Step 2: Synthesis of (4-(benzyloxy)benzyl)phosphonic acid

[0345] Compound 7-2 (4.80 g, 14.35 mmol) was added to a 250 mL single-neck flask containing chloroform (50 mL). Trimethylsilyl bromide (20 mL) was added at room temperature, and the mixture was stirred at room temperature overnight, quenched with ethanol, diluted with dichloromethane, and concentrated under reduced pressure. The mixture was slurried with PE:EA=5:1 (50 mL), filtered, and the filter cake was washed with (PE:EA=4:1, 10 mL), and purified to give compound 7-3 (2.80 g, white solid) in 70% yield. 1 H NMR (400MHz, DMSO-d6): δ7.44-7.30(m,5H),7.15-7.12(m,2H),6.91-6.90(d,J=8.4Hz,2H),5.06(s,2H),2.86(d,J=21.6Hz,2H).

[0346] Step 3: Synthesis of ((4-(benzyloxy)benzyl)(methylene)-15 phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropionic acid)

[0347] Compound 7-3 (200 mg, 0.72 mmol), N-methylpyrrolidone (5 mL), chloromethyl pivalate (0.62 mL, 4.31 mmol) and N,N-diisopropylethylamine (0.71 mL, 4.31 mmol) were added to a dry 25 mL one-neck flask at room temperature. The mixture was reacted at 75° C. for 16 h. After the reaction was completed, the mixture was poured into 20 mL of water and extracted with ethyl acetate. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography column (PE:EA=1:1) to obtain compound 7-4 (320 mg, yellow oil) in a yield of 87.89%. 1 H-NMR (400MHz, CDCl3): δ7.43-7.30(m,5H),7.20(dd,J=2.8Hz,8.8Hz,2H),6.92(d, J=8.4Hz,2H),5.62-5.56(m,4H),5.04(s,2H),3.17(d,J=21.6Hz,2H),1.21(s,18H).

[0348] Step 4: Synthesis of ((4-hydroxybenzyl)(methylene)-15-phosphoryl)bis(oxy)bis(methylene)bis(2,2-dimethylpropionic acid)

[0349] Compound 7-4 (480 mg, 0.95 mmol), ethyl acetate (30 mL), and palladium / carbon catalyst (48 mg) were added sequentially to a dry 100 mL one-neck flask at room temperature. The reaction was allowed to proceed at room temperature for 1.5 h. After filtration, the filtrate was concentrated under reduced pressure to give 7-5 (390 mg, colorless oil) in a yield of 98.84%. 1 H-NMR (400MHz, CDCl3-d): δ7.05(dd,J=2.8Hz,8.4Hz,2H),6.96(s,1H),6.65(d,J=8.0Hz,2H),5.64-5.58(m,4H),3.15(d,J=21.6Hz,2H),1.22(s,18H).

[0350] Step 5: Synthesis of (((4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)benzyl)(methylene)-15-phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropionic acid)

[0351] Compound 7-5 (86 mg, 0.21 mmol), toluene (5 mL), compound 1a (40 mg, 0.21 mmol), potassium phosphate (87 mg, 0.41 mmol), Xphos (9 mg, 0.02 mmol) and Pd2dba3 (19 mg, 0.02 mmol) were added in sequence to a dry 25 mL one-neck flask at room temperature. The mixture was heated to 100°C under nitrogen protection and reacted for 16 h. The reaction solution was filtered and concentrated, and then purified by prep-HPLC to obtain compound 7 (8.5 mg, colorless oil) in a yield of 7.20%. LCMS (ESI): m / z 575.25 [M+H] + ;RT=4.181min(6.00min). 1 H-NMR(400MHz,DMSO-d6):δ8.71(d,J=5.6Hz,1H),8.58(d,J=8.8Hz,1H),7.42(d,J=7.2Hz,2H),7.26(d,J=8.0Hz,2H) ,7.17(d,J=8.8Hz,1H),6.57(d,J=5.6Hz,1H),5.64-5.57(m,4H),4.05(s,3H),3.45(d,J=21.6Hz,2H),1.17(s,18H).

[0352] Examples 8 and 9: Synthesis of Compounds 8 and 9

[0353] [ka]

[0354] Compounds 8 and 9 were synthesized with reference to the synthesis method of Example 7.

[0355] Compound 8:LCMS(ESI):m / z579.0[M+H] + ;RT=3.957min(6.00min). 1H-NMR(400MHz,DMSO-d6):δ8.70(d,J=5.6Hz,1H),8.57(d,J=8.8Hz,1H),7.42-7.40(m,2H),7.26(d,J=8.8Hz,2H),7.17(d,J=8.8 Hz,1H),6.57(d,J=5.6Hz,1H),5.61-5.56(m,4H),4.85-4.82(m,2H),4.05(s,3H),3.50(d,J=22.4Hz,2H),1.25(d,J=6.4Hz,12H).

[0356] Compound 9:LCMS(ESI):m / z615.5[M+H] + .

[0357] Example 10: Synthesis of Compound 10

[0358] [ka]

[0359] Step 1: Synthesis of diethyl (4-nitrobenzyl)phosphonate

[0360] At room temperature, p-nitrobenzyl bromide (2.5 g, 11.6 mmol), triethyl phosphite (4.8 g, 34.9 mmol), and toluene (30 mL) were added in sequence to a dry 100 mL one-neck flask, heated to 100° C. and allowed to stand overnight, and the reaction solution was concentrated under reduced pressure. The residue was purified using a silica gel column (PE:EA=1:1) to obtain compound 10-2 (2.5 g, yellow solid) in a yield of 81.00%. 1 H-NMR (600MHz, CDCl3):8.19-8.18(m,2H),7.48-7.46(m,2H),4.07-4.04(m,4H),3.25(d,J=22.2Hz,2H),1.27(t,J=7.2Hz,6H).

[0361] Step 2: Synthesis of diethyl (4-aminobenzyl)phosphonate

[0362] Compound 10-2 (4 g, 14.6 mmol), 10% palladium on carbon (400 mg), and ethanol (30 mL) were added to a dry 100 mL one-neck flask at room temperature in that order, and the mixture was stirred overnight under hydrogen gas protection, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column (EA) to give product 10-3 (3 g, yellow solid) in 84.00% yield. LCMS (ESI): m / z 244.1 [M+H] + ;RT=1.10min(3.00min).

[0363] Step 3: Synthesis of diethyl (4-((7-methoxy-1,8-naphthyridin-4-yl)amino)benzyl)phosphonate

[0364] Compound 10-3 (130 mg, 0.53 mmol), compound 1a (104 mg, 0.53 mmol), Pd2dba3 (48 mg, 0.053 mmol), Xphos (33 mg, 0.053 mmol), potassium carbonate (345 mg, 1.06 mmol), and dioxane (10 mL) were added sequentially to a dry 50 mL one-neck flask at room temperature. The mixture was heated to 100° C. under nitrogen protection and stirred overnight. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane:methanol=30:1) to give product 10-4 (150 mg, yellow solid) in 7.0% yield. LCMS (ESI): m / z 402.1 [M+H] + ;RT=1.19min(3.00min).

[0365] Step 4: Synthesis of (4-((7-methoxy-1,8-naphthyridin-4-yl)amino)benzyl)phosphonic acid

[0366] Compound 10-4 (150 mg, 0.37 mmol) and chloroform (5 mL) were added to a 25 mL three-neck flask, and trimethylsilyl bromide (1 M dichloromethane solution) (0.37 mL, 0.37 mmol) was added dropwise in an ice bath under nitrogen protection, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated, separated and purified using a high-performance liquid reverse phase preparative column to obtain compound 10 (30 mg, white solid). LCMS (ESI): m / z 345.9 [M+H] +;RT=3.26min(5.00min). 1 H-NMR(400MHz,DMSO-d6):9.02(d,J=9.2Hz,1H),8.32(d,J=7.2Hz,1H),7.46-7.38(m, 4H),7.30(d,J=9.2Hz,1H),6.79(d,J=7.2Hz,1H),4.10(s,3H),3.10(d,J=21.6Hz,2H).

[0367] Example 11: Synthesis of Compound 11

[0368] [ka]

[0369] Step 1: Synthesis of 4-bromomethylbenzyl diethyl phosphite

[0370] 1,4-Di(bromomethyl)benzene (1g, 3.8mmol), triethyl phosphite (318mg, 1.9mmol), and N,N-dimethylformamide (2mL) were added to a dry 50mL single-neck flask in sequence at room temperature. The reaction was carried out in a microwave at 150°C for 2 minutes. Water (10mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20mL). The organic phases were combined, washed with water (10mL), washed with brine (10mL), dried, and concentrated under reduced pressure. The residue was purified by a silica gel column (PE:EA=20:1) to obtain product 11-2 (800mg, yellow oil) in 66% yield. LCMS (ESI): m / z 322.9 [M+H] + ;RT=1.55min(3.00min).

[0371] Step 2: Synthesis of (4-((4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)methyl)benzyl)diethylphosphonate

[0372] Compound 11-2 (1.1 g, 3.44 mmol), bis(pinacolato)diboron (1.31 g, 5.16 mmol), potassium acetate (842 mg, 8.59 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (catalytic amount) were added in sequence at room temperature to a 100 mL three-neck flask containing 15 mL of dioxane. The reaction was carried out at 100° C. for 10 h in a nitrogen environment, filtered, and the filtrate was concentrated under reduced pressure. The crude product of the residue was purified by column (PE:EA=3:1) to obtain compound 11-3 (520 mg, yellow oil) in a yield of 38.1%. LCMS (ESI): m / z 369.2 [M+H] + ;RT=1.047min(2.50min).

[0373] Step 3: Synthesis of (4-((7-methoxy-1,8-naphthyridin-4-yl)methyl)benzyl)diethylphosphonate

[0374] Compound 11-3 (420 mg, 1.14 mmol), 5-chloro-2-methoxy-1,8-naphthyridine (221 mg, 1.14 mmol), potassium carbonate (394 mg, 2.85 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (catalytic amount) were added to a 50 mL three-neck flask containing 9 mL of dioxane and 3 mL of water. The reaction was carried out at 100° C. under nitrogen protection for 3 h. After cooling, the reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phase was washed twice with saturated sodium chloride, dried and filtered. After concentration under reduced pressure, the mixture was purified by prep-TLC (PE / EA=2 / 1) to obtain compound 11-4 (430 mg, yellow oil) in a yield of 76.1%. LCMS (ESI): m / z 401.0 [M+H] + ;RT=1.024min(2.50min).

[0375] Step 4: Synthesis of (4-((7-methoxy-1,8-naphthyridin-4-yl)methyl)benzyl)phosphonic acid

[0376] Compound 11-4 (100 mg, 0.25 mmol) and trimethylsilyl bromide (191 mg, 1.25 mmol) were added in sequence to a 50 mL single-neck flask containing 6 mL of chloroform at room temperature, and the mixture was allowed to react overnight at room temperature. The reaction solution was quenched with methanol, concentrated, and purified by prep-HPLC (trifluoroacetic acid system) to obtain compound 11 (45.0 mg, white solid) in a yield of 52.3%. LCMS (ESI): m / z 344.9 [M+H] + ;RT=3.305min(6.00min). 1 H NMR(400MHz,DMSO-d6):δ8.92(d,J=5.2Hz,1H),8.69(d,J=9.2Hz,1H),7.51(d,J=4.8Hz,1 H),7.27(d,J=9.2Hz,1H),7.18(s,4H),4.52(s,2H),4.06(s,3H),2.90(d,J=21.6Hz,2H).

[0377] Examples 12 to 56, 58 to 69: Synthesis of Compounds 12 to 56, 58 to 69

[0378] Compounds 12 to 56 and 58 to 69 were synthesized with reference to the synthesis methods of compounds 1, 7, 10, and 11, respectively, and the data of each compound are shown below. [Table 5] [Table 6]

[0379] Example 57: Synthesis of Compound 57

[0380] [ka]

[0381] Step 1: Synthesis of isopropyl((4-(benzyloxy)benzyl)(phenoxy)phosphoryl)-L-alanine ester

[0382] Compound 57-1 (700 mg, 2.52 mmol) and N,N-dimethylformamide (catalytic amount) were added to a 50 mL three-neck flask containing 10 mL of anhydrous dichloromethane, heated to 40° C., and under nitrogen protection, a solution of oxalyl chloride (0.47 mL, 5.54 mmol) in anhydrous dichloromethane was slowly added dropwise thereto, and the mixture was reacted at this temperature with stirring for 3 h. The temperature was then lowered to 30° C. and reacted overnight. The acid chloride solution prepared was slowly added dropwise to a dry tetrahydrofuran solution containing phenol (592 mg, 6.3 mmol) and triethylamine (636 mg, 6.3 mmol) under ice bath, and stirred at room temperature for 2 h. This step was repeated, and further added dropwise to a dry tetrahydrofuran solution of L-alanine isopropyl ester (464 mg, 2.77 mmol) and triethylamine (390 mg, 3.02 mmol), and reacted at room temperature overnight. The reaction solution was filtered and concentrated to obtain a crude product, which was purified by column (PE:EA=1:1) to obtain compound 57-2 (140 mg, yellow solid) in a yield of 11.9%. LCMS (ESI): m / z 468.2 [M+H] + ;RT=1.296min(2.50min).

[0383] Step 2: Synthesis of isopropyl((4-hydroxybenzyl)(phenoxy)phosphoryl)-L-alanine ester

[0384] Compound 57-2 (0.14 g, 0.30 mmol) and 10% wet palladium on carbon (14 mg) were added in sequence to a 50 mL one-neck flask containing 10 mL of ethyl acetate, and the mixture was reacted at room temperature for 2 h under hydrogen gas protection. After filtration, the filtrate was concentrated to give compound 57-3 (130 mg, yellow oil) with a purity of 60%. LCMS (ESI): m / z 378.1 [M+H] + ;RT=1.179min(2.50min).

[0385] Step 3: Synthesis of isopropyl((4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)benzyl)(phenoxy)phosphoryl)-L-alanine ester

[0386] Compound 57-3 (65 mg, 0.17 mmol), 1a (35 mg, 0.17 mmol), anhydrous potassium phosphate (73 mg, 0.34 mmol), Pd2dba3 (catalytic amount), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (catalytic amount) were added in sequence to a 50 mL three-neck flask containing 6 mL of anhydrous toluene, and the mixture was reacted overnight at 100°C under argon protection. The reaction solution was filtered, and the filtrate was concentrated and purified by Prep-HPLC (formic acid system), to obtain compound 57 (9.75 mg, white solid) in a yield of 5.3%. LCMS (ESI): m / z 536.1 [M+H] + ;RT=3.821min(6.00min). 1 H-NMR(400MHz,MeOH-d4):δ8.61(d,J=5.6Hz,2H),7.56-7.53(m,2H),7.34-7.31(m,2H),7.24-7.09(m,6H), 6.63-6.59(m,1H),4.95-4.90(m,1H),4.12(s,3H),3.88-3.86(m,1H),3.51-3.40(m,2H),1.22-1.15(m,9H).

[0387] Biological Examples

[0388] Evaluation of ENPP1 inhibitory activity of compounds

[0389] Testing the ENPP1 Inhibitory Activity of Compounds of the Present Disclosure in the Detection of Substrate 2',3'-cGAMP

[0390] 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).

[0391] 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)

[0392] Testing Method:

[0393] 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.

[0394] 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 from the final concentration, and 5 nL was transferred to a 384-well reaction plate using Echo550 for measurement. 5 nL of 100% DMSO was transferred to the smallest well and largest hole.

[0395] 3.2x protein solution 20 μM was prepared in the 1x reaction solution.

[0396] 4.2x substrate solution 40 μM was prepared in the 1x reaction solution.

[0397] 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.

[0398] 6. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes.

[0399] 7. 2.5 μL of 2× 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.

[0400] 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.

[0401] 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.

[0402] 10. The test results were detected and recorded using a multi-function microplate reader (2104EnVision).

[0403] Data analysis

[0404] The inhibition rate was calculated by the following formula: % Inhibition = (Maximum signal - Compound signal) / (Maximum signal - Minimum signal) x 100 Here, "minimum signal" is the average value of the negative control wells and "maximum signal" is the average value of the positive control wells.

[0405] Fitting Dose-Response Curve:

[0406] 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.

[0407] The fitting formula is Y=bottom+(top-bottom) / (1+10^((logIC 50 -X) * HillSlope).

[0408] [ka]

[0409] [Table 7]

[0410] As can be seen from Table 1, the ENPP1 kinase inhibitory activity of the disclosed phosphonic acid compounds, especially naphthyridine phosphonic acid compounds, is comparable to that of the positive compound STF32, and is significantly superior to that of the literature compound STF22 (STF22 was obtained from the literature Cell Chemical Biology 2020(27), 1347-1358). According to literature reports, STF32 is metabolically unstable in the mouse body, has a short half-life after injection, and has a short T 1 / 2 The phosphonic acid compound of the present disclosure has significantly improved metabolic stability in vivo, and T 1 / 2 The effective life span is 3 to 5 hours, and the prodrug has high oral bioavailability, which overcomes the drawback that phosphonic acid compounds cannot be administered orally.

[0411] Experimental example 2: Experiment to test pharmacokinetics in mice

[0412] 1. For each administration method, nine healthy ICR male mice weighing 30-35g were prepared and randomly divided into three groups of three mice each (M1, M2, M3). The test compound was administered intragastricly (50mg / kg) and intravenously (1mg / kg). 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.

[0413] 2. Blood Collection Time Points and Sample Processing

[0414] 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.

[0415] 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.

[0416] 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.

[0417] 3. Sample testing and data analysis

[0418] 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).

[0419] 4. Experimental Results

[0420] In an oral administration experiment of prodrug compounds 7 and 8 to mice, the blood concentrations of prodrug compounds 7 and 8 and their active ingredient (drug substance compound 1) in plasma were detected using LC-MS / MS. As a result, the blood concentrations of the active ingredient (drug substance compound 1) in the plasma of mice after 5 minutes were 2941 ng / mL and 2432 ng / mL, respectively. This indicates that after oral administration of prodrug compounds 7 and 8, prodrug compounds 7 and 8 are rapidly converted (within 5 minutes) to drug substance compound 1 in the plasma of mice.

[0421] Specifically, the pharmacokinetics of active ingredient 1 detected in mouse plasma after oral administration of prodrug compounds 7 and 8 (50 mg / kg) to mice are shown in Figures 1 and 2. Here, M1, M2, and M3 are the numbers of the animal groups, respectively. From Figures 1 and 2, it can be seen that compounds 7, 8 and compound 1 of the present disclosure have good pharmacokinetic properties. After administration of compounds 7 and 8 to mice, the pharmacokinetic properties (clearance rate, AUC and bioavailability, etc.) of compound 1 monitored were similar to those of compound 1 administered alone. This indicates that compounds 7 and 8 are converted to drug substance compound 1 in mice, and compound 1 exerts pharmaceutical activity. Preparation of compound 1 into prodrug compound 7 or 8 does not affect the pharmacological activity of the compound itself. This indicates that compound 1 of the present disclosure has a remarkable inhibitory effect on diseases associated with ENPP1 expression, such as disorders and diseases caused by tumors or infections.

[0422] [Table 8]

[0423] * After the compounds of Examples 7 and 8 were orally administered, the active ingredient Compound 1 was converted from Compounds 7 and 8 in the plasma.

[0424] As can be seen from Table 2, when the phosphonate or amide prodrug compounds of the present disclosure were orally administered to mice as in Examples 7 and 8, only the active ingredient, Compound 1, was detected in the plasma after 5 min. Compared with prodrug compounds 7 and 8, the raw drug compound 1 of the present disclosure had a higher AUC 0-tThe results show a significant improvement in the absorption rate of the phosphonate or amide prodrugs of the present disclosure. Phosphonate-based drug substances containing free phosphate groups are not suitable for absorption in the gastrointestinal tract or oral administration due to excessive polarity, poor lipophilicity, and low oral bioavailability. This problem can be solved by converting the phosphate group into a phosphonate diester or amide derivative, for example, esters such as compounds 7 and 8 obtained by esterification of compound 1 have improved lipophilicity and are hydrolyzed in the body to form compounds that exert pharmacological effects and have oral bioavailability of 10% to 17%. Compared with compound 1, the phosphonate form improves the lipophilicity, oral administration, and bioavailability of the drug, reduces side effects, and makes it safer.

[0425] Example 3: Experiments testing pharmacokinetics in rats

[0426] 1. For each administration method, six male SD rats aged 6 to 8 weeks were selected and the test compound was administered intragastrically (5 mg / kg) and intravenously (1 mg / kg). Before the test, the rats were fasted for 12 hours and allowed to drink water freely. Food was uniformly added 4 hours after administration.

[0427] 2. Blood Collection Time Points and Sample Processing

[0428] 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.

[0429] 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.

[0430] Plasma collection and processing: At the above-mentioned set time points, 150-200 μL of blood was collected from the rat's jugular plexus or appropriate site, placed in an EDTA-K2 test tube, centrifuged at 3500 rpm for 10 min, and the plasma was separated and frozen in a -20℃ refrigerator.

[0431] 3. Sample testing and data analysis

[0432] 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).

[0433] 4. Experimental Results

[0434] In an experiment in which the prodrug compound 7 was administered intravenously and orally to rats, the plasma concentration of the drug substance compound 1 (active ingredient) was detected using LC-MS / MS. The results are shown in Table 3.

[0435] Example 4: Experiments testing pharmacokinetics in dogs

[0436] 1. Six beagle dogs aged 0.5 to 1.5 years were selected for each administration method, and the test compound was administered intragastrically (2 mg / kg) and intravenously (1 mg / kg). They were fasted for 12 hours before the test and allowed to drink water freely. Food was uniformly added 4 hours after administration.

[0437] 2. Blood Collection Time Points and Sample Processing

[0438] Intravenous and intragastric administration: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Blood was continuously collected from three animals at each time point. Plasma collection and processing: 1000μL of blood was collected from the jugular plexus or an appropriate site of beagle dogs at the above set time points, placed in EDTA-K2 test tubes, centrifuged at 3500rpm for 10min, plasma was separated, and frozen in a refrigerator at -20℃.

[0439] 3. Sample testing and data analysis

[0440] Compound concentrations in beagle dog plasma were measured using LC / MS / MS. Pharmacokinetic parameters after administration were calculated using the noncompartmental model of Phoenix8.3 software (Pharsight, USA).

[0441] 4. Experimental Results

[0442] In an experiment in which prodrug compound 7 was administered intravenously and orally to beagle dogs, the plasma concentration of drug substance compound 1 (active ingredient) was detected using LC-MS / MS. The results are shown in Table 3.

[0443] [Table 9]

[0444] * After administration of the compound of Example 7, the active ingredient compound 1 converted from compound 7 is detected in plasma. Rats are given an oral dose of prodrug compound 7 (5 mg / kg) and an intravenous injection of active compound 1 (1 mg / kg), and beagle dogs are given an oral dose of prodrug compound 7 (2 mg / kg) and an intravenous injection of active compound 1 (1 mg / kg).

[0445] The results of pharmacokinetic studies in SD rats and beagle dogs indicate that the intravenous injection of active compound 1 has a low clearance rate and a long half-life in vivo. When orally administered, prodrug compound 7 is rapidly metabolized in the body to active compound 1, demonstrating high oral bioavailability.

[0446] In summary, the phosphonate or amide prodrug compounds of the present disclosure have no biological activity by themselves, but can be converted into active phosphonate compounds through in vivo metabolism after IV or PO administration. Phosphonate drug substances have high inhibitory activity against ENPP1, but are not suitable for oral administration due to their high polarity, while phosphonate or amide prodrug compounds can not only increase the solubility of the drug and improve the administration route, but also increase the stability of the drug and improve the oral bioavailability of the drug.

[0447] The phosphonate or amide (IA) compounds of the present disclosure can be used as prodrugs of the phosphonic acid (I) compounds. The compounds of formula (I) have been shown to be ENPP1 inhibitors, and therefore the compounds of the present disclosure can be used to treat ENPP1-related diseases and are useful for providing compounds as therapeutic agents for ENPP1-related diseases.

Claims

1. A compound represented by formula (I) or formula (IA), or a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate or hydrate thereof. 【Chemistry 1】 (In the formula, 【change】 is a single bond or a double bond, X １ , N, CR １ or a bond, X ２ , N, NR ２ Or CR ２ and X ３ , N, NR ３ , —C(O) or CR ３ and X ４ , N, NR ４ , —C(O) or CR ４ and X ５ is N or CR ５ and X is N or CR ０ and However, X and X ５ is not N and is also X １ , X ２ , X ３ , and X ４ At least one of is independently N or NR ｎ where n=2, 3 or 4; R ０ , R １ , R ３ , and R ５ are each independently hydrogen, halogen, CN, OR ａ , NO ２ , N.R. ｂ R ｃ , C １ ~C ６ Alkyl, and C １ ~C ６ haloalkyl; R ２ and R ４ are each independently hydrogen, halogen, CN, OR ａ , NO ２ , N.R. ｂ R ｃ , and C １ ~C ６ alkyl, wherein said alkyl is optionally substituted by halogen; Y is O, S, NR ６ Or CR ７ R ８ where R ６ , R ７ , and R ８ are each independently hydrogen and C １ ~C ４ alkyl, m is 1, 2 or 3; Ring A is C ６ ~C １０ aryl and 5- to 10-membered heteroaryl, where 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, and C １ ~C ３ substituted one or more times with substituents independently selected from haloalkyl; Here, R ａ , R ｂ , and R ｃ each independently represents hydrogen and C optionally substituted with halogen １ ~C ４ alkyl, L １ and L ２ are each independently NH or O, preferably L １ and L ２ are both O, W １ and W ２ Each independently represents an unsubstituted or halogen-substituted C ６ ~C １０ Aryl, -CH ２ O.C.(O)R ｄ , -CH ２ O.C. (O) O.R. ｄ , -CH ２ C (CH ３ ) ２ C(O)OR ｄ , -CH(CH ３ ) C(O)OR ｄ , and -CH ２ C (CH ３ ) ２ C(O)OR ｄ where R ｄ is C ２ ~C ６ It is alkyl. 【Request 2】 【Chemistry 2】 teeth, 【Chemistry 3】 Preferably, 【Chemistry 4】 teeth, 【Chemistry 5】 More preferably, 【Chemistry 6】 teeth, 【Chemistry 7】 is selected from More preferably, 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 Preferably, 【Chemistry 11】 teeth, 【Chemistry 12】 wherein each substituent is as defined in claim 1; or a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate or hydrate thereof.

3. The compound represented by formula (I) or formula (IA) according to claim 1 or 2, which is a compound represented by formula (II) or formula (II-A), respectively, or a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate or hydrate thereof. 【Chemistry 13】 (wherein, in formula (II) or (II-A), X １ is N or CR １ and X ２ is N or CR ２ and X ３ , N, NR ３ , —C(O) or CR ３ and X ４ , N, NR ４ , —C(O) or CR ４ and X ５ is N or CR ５ and X is N or CR ０ and However, X and X ５ is not N and is also X １ , X ２ , X ３ , and X ４ At least one of is independently N or NR ｎ where n=3 or 4; R ０ and R ５ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , C １ ~C ６ Alkyl, and C １ ~C ４ alkoxy, wherein each said alkyl is optionally substituted with 0 to 3 halogens; R １ and R ３ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , and C １ ~C ４ alkoxy; R ２ and R ４ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , and C １ ~C ４ alkyl, Y is O, S, NR ６ Or CR ７ R ８ where R ６ , R ７ , and R ８ are each independently hydrogen and C １ ~C ４ alkyl, Ring A, m, L １ , L ２ , W １ , and W ２ The definitions are as set forth in claim 1.

4. The compound represented by formula (I) or formula (IA) according to claim 1 or 2, which is a compound represented by formula (III) or formula (III-A), respectively, or a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate, or hydrate thereof. 【Chemistry 14】 (wherein, in formula (III) or (III-A), 【change】 is a single bond or a double bond, X ２ , N, NR ２ Or CR ２ And X ３ , N, NR ３ Or CR ３ And X ４ , N, NR ４ Or CR ４ and X ５ is N or CR ５ and X is N or CR ０ and However, X and X ５ is not N and is also X ２ , X ３ , and X ４ At least one of is independently N or NR ｎ where n=2, 3 or 4; R ０ and R ５ are each independently hydrogen, halogen, CN, C １ ~C ６ Alkyl, C １ ~C ４ Alkoxy, and C １ ~C ６ haloalkyl; R ２ , R ３ , and R ４ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , C １ ~C ４ Alkyl, and C １ ~C ３ haloalkyl; Y is O, S, NR ６ Or CR ７ R ８ where R ６ , R ７ , and R ８ are each independently hydrogen and C １ ~C ４ alkyl, Ring A, m, L １ , L ２ , W １ , and W ２ The definitions are as set forth in claim 1.

5. The compound represented by formula (I) or formula (IA) according to claim 1 or 2, which is a compound represented by formula (IV) or formula (IV-A), respectively, or a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate, or hydrate thereof. 【Chemistry 15】 (wherein, in formula (IV) or (IV-A), 【change】 is a single bond or a double bond, X １ , N, CR １ or a bond, X ２ , N, NR ２ Or CR ２ And X ３ , N, NR ３ Or CR ３ and X ５ is N or CR ５ and X is N or CR ０ where X and X ５ is not N at the same time, R ０ and R ５ are each independently hydrogen, halogen, CN, C １ ~C ６ Alkyl, C １ ~C ４ Alkoxy, and C １ ~C ６ haloalkyl; R １ and R ３ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , C １ ~C ４ Alkyl, and C １ ~C ４ alkoxy; R ２ is hydrogen, halogen, OH, and C １ ~C ３ alkyl, Y is O, S, NR ６ Or CR ７ R ８ where R ６ , R ７ , and R ８ are each independently hydrogen and C １ ~C ４ alkyl, Ring A, m, L １ , L ２ , W １ , and W ２ The definitions are as set forth in claim 1.

6. The compound represented by formula (I) or formula (IA) is a compound represented by formula (V) or formula (VA), respectively; or The compound represented by formula (I) or formula (IA) is a compound represented by formula (VI) or formula (VI-A), respectively; or The compound represented by formula (I) or formula (IA) is a compound represented by formula (VII) or formula (VII-A), respectively; or The compound represented by formula (I) or formula (IA) is a compound represented by formula (VIII) or formula (VIII-A), respectively; or The compound represented by formula (I) or formula (IA) according to claim 1 or 2, which is a compound represented by formula (IX) or formula (IX-A), respectively, or a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate, or hydrate thereof. 【Chemistry 16】 (wherein, in formula (V) or (VA), X ５ is N or CR ５ and X is N or CR ０ and X and X ５ is not N at the same time, R ０ and R ５ are each independently hydrogen, halogen, CN, and C １ ~C ６ alkyl, R １ , R ２ , and R ３ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , C １ ~C ４ Alkyl, and C １ ~C ４ alkoxy; Y is O, S, NR ６ Or CR ７ R ８ where R ６ , R ７ , and R ８ are each independently hydrogen and C １ ~C ４ alkyl, Ring A, L １ , L ２ , m, W １ , and W ２ The definitions are as set forth in claim 1. 【Chemistry 17】 (wherein, in formula (VI) or (VI-A), X ５ is N or CR ５ and X is N or CR ０ and X and X ５ is not N at the same time, R ０ and R ５ are each independently hydrogen, halogen, CN, and C １ ~C ６ alkyl, R １ and R ３ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , and C １ ~C ４ alkoxy; R ４ is hydrogen, halogen, and C １ ~C ４ alkyl, Y is O, S, NR ６ Or CR ７ R ８ where R ６ , R ７ , and R ８ are each independently hydrogen and C １ ~C ４ alkyl, Ring A, L １ , L ２ , m, W １ , and W ２ The definitions are as set forth in claim 1. 【Chemistry 18】 (wherein, in formula (VII) or (VII-A), Y is O, S, NR ６ Or CR ７ R ８ where R ６ , R ７ , and R ８ are each independently hydrogen and C １ ~C ４ alkyl, R ５ is hydrogen, halogen, CN, and C １ ~C ６ alkyl, R １ and R ３ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , and C １ ~C ４ alkoxy; R ２ is hydrogen, halogen, and C １ ~C ４ alkyl, Ring A, L １ , L ２ , m, W １ , and W ２ The definitions are as set forth in claim 1. 【Chemistry 19】 (wherein, in formula (VIII) or (VIII-A), Y is O, S, NR ６ Or CR ７ R ８ where R ６ , R ７ , and R ８ are each independently hydrogen and C １ ~C ４ alkyl, R ０ and R ５ are each independently hydrogen, halogen, CN, and C １ ~C ６ alkyl, R １ and R ３ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , and C １ ~C ４ alkoxy; R ２ is hydrogen, halogen, and C １ ~C ４ alkyl, Ring A, L １ , L ２ , m, W １ , and W ２ The definitions are as set forth in claim 1. 【Chemistry 20】 (wherein, in formula (IX) or (IX-A), Y is O, S, NR ６ Or CR ７ R ８ and R ６ , R ７ , and R ８ are each independently hydrogen and C １ ~C ４ alkyl, R ０ and R ５ are each independently hydrogen, halogen, CN, and C １ ~C ６ alkyl, R １ and R ３ are each independently hydrogen, halogen, CN, OH, NO ２ , N.H. ２ , C １ ~C ４ Alkyl, and C １ ~C ４ alkoxy; R ２ is hydrogen, halogen, and C １ ~C ４ alkyl, Ring A, L １ , L ２ , m, W １ , and W ２ The definitions are as set forth in claim 1.

7. The compound of formula (I) is selected from the following compounds: 【Table 1-1】 【Table 1-2】 The compound of formula (IA) is selected from the following compounds: 【Table 2】 A compound of formula (I) or formula (IA) according to claim 1, or a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate or hydrate thereof.

8. A pharmaceutical composition comprising one or more of the compounds of formula (I) or formula (IA) according to any one of claims 1 to 7, or pharma- ceutically acceptable salts, stereoisomers, geometric isomers, tautomers, solvates or hydrates thereof as an active ingredient, and optionally a pharma- ceutically acceptable carrier, diluent or excipient.

9. Use of a compound of formula (I) or formula (IA) as defined in any one of claims 1 to 7, a pharma- ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate or hydrate thereof, or a pharmaceutical composition as defined in claim 8, in the preparation of a medicament for preventing, treating or alleviating a disorder or disease in a patient caused by an ENPP1 mediated disease or disorder.

10. A method for treating or preventing an ENPP1 mediated disease or disorder, comprising administering to an individual in need thereof a therapeutically effective amount of one or more of the compounds of formula (I) or formula (IA) according to any one of claims 1 to 7, or a pharma-ceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate or hydrate thereof, or the pharmaceutical composition according to claim 8.

11. the ENPP1 mediated disease or disorder is cancer, or an infectious disease or disorder; More preferably, the cancer is selected from recurrent or refractory cancer, metastatic cancer, 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 tumor, germ cell tumor, malignant neuroendocrine tumor, malignant rhabdoid tumor, soft tissue sarcoma, midline carcinoma, and solid tumor of unknown primary cancer, or hematological malignancy, in particular leukemia, lymphoma, or myeloma, More preferably, the infectious disease or disorder is 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, Neisseria gonorrhoeae infection.

Images