JNK Inhibitor, Pharmaceutical Composition Thereof, and Use

Abstract

The present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, N-oxide or a pharmaceutically acceptable salt thereof, which can be used as a JNK inhibitor. Also provided are a method for preparing the compound represented by formula (I), a pharmaceutical composition comprising the compound represented by formula (I), and the use of the compound represented by formula (I) for preparing a medicament for treating a disease that can be treated by inhibiting JNK activity.

Description

Technical Field

[0001] The present invention relates to the field of drugs, and particularly to compounds capable of inhibiting JNK activity, pharmaceutical compositions thereof, and uses thereof. Background Art

[0002] Mitogen-activated protein kinases (MAPK) are one of the important pathways in the eukaryotic signal transduction network. The MAPK cascade consists of three classes of protein kinases MAP3K-MAP2K-MAPK, which transmit upstream signals to downstream responder molecules through sequential phosphorylation. In mammalian organisms, there are three major MAPK signal transduction pathways: extracellular signal-regulated kinase (ERK1 / 2), c-Jun N-terminal kinase (JNK), and p38 signal pathway. Among them, the ERK1 / 2 signal transduction pathway regulates cell growth and differentiation, and the JNK and p38 MAPK signal transduction pathways play important roles in stress responses such as inflammation and apoptosis. JNK is an important member of the MAPK family and can be activated by stress signals, so it is also known as stress-activated protein kinase (SAPK). JNK is involved in a wide range of biological processes, including embryonic development, cell apoptosis / survival, transformation of oncogene-expressing cells, angiogenesis, T cell activation, B cell proliferation, cytokine production, and the occurrence of inflammation, etc.

[0003] Currently, three distinct genes (JNK1, JNK2, and JNK3) have been identified, which encode 10 splice variants. JNK1 and JNK2 are expressed in a wide variety of tissues, while JNK3 is mainly expressed in neurons and to a lesser extent in the heart and testis. Members of the JNK family are activated by pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), as well as environmental stress. The activation of JNK is mediated by the dual phosphorylation of Thr-183 and Tyr-185 via its upstream kinases, MKK4 and MKK7. Studies have shown that MKK4 and MKK7 can be activated by different upstream kinases, including MEKK1 and MEKK4, depending on the external stimuli and cellular environment. The specificity of JNK signaling is achieved by forming JNK-specific signaling complexes using scaffold proteins called JNK-interacting proteins, which contain multiple components of the kinase cascade. By phosphorylating specific substrates, JNK has been shown to play important roles in inflammation, T cell function, apoptosis, and survival, including transcription factors such as c-Jun, members of the activator protein-1 (AP1) family, and ATF2, as well as non-transcription factors such as IRS-1 and Bcl-2. It is thought that the overactivation of JNK is an important mechanism in autoimmune, inflammatory, metabolic, neurological diseases, and cancer. Some studies have shown that the JNK signaling pathway is activated in pulmonary fibrosis and liver fibrosis, regulating cell inflammation, proliferation, differentiation, and apoptosis, which can be induced by TGF-β1.

[0004] Idiopathic interstitial pulmonary fibrosis (IPF) is a chronic, diffuse interstitial lung disease of unknown cause, characterized by typical pathological changes of usual interstitial pneumonia. Its histopathology and imaging mostly show the manifestations of usual interstitial pneumonia. Due to its complex pathogenesis, the disease progresses irreversibly, and early diagnosis is difficult. After diagnosis, the survival rate of patients decreases significantly over time. The 3-year survival rate is 50%, and the 5-year survival rate is only 20%, which is lower than that of most cancers (such as leukemia, breast cancer, colon cancer, uterine cancer, kidney cancer, etc.). It is called "cancer without being cancer".

[0005] Liver fibrosis is a common link in the progression of chronic liver diseases to liver cirrhosis. Previous related studies were limited to preventing the occurrence of fibrosis, delaying and even blocking the progression of fibrosis. However, in recent years, a number of experiments have suggested that whether eliminating pathogenic factors or applying effective anti-fibrotic drugs, liver fibrosis in patients and model animals may be partially or completely reversed, that is, liver fibrosis is reversible to a certain extent. However, the process of liver fibrosis reversal is very complex, and many signaling pathways such as the known MAPK / EKR signaling pathway and MAPK signaling pathways such as SAPK / JNK and MEK5, as well as non-MAPK signaling pathways such as PI3K / Akt and Notch, all play important roles in it.

[0006] At present, there is no drug on the market for treating diseases such as fibrotic diseases through the JNK inhibition pathway. Therefore, the development of new JNK inhibitor compounds is of positive significance for the treatment of the above diseases. Summary of the Invention

[0007] To improve the problems existing in the prior art, the present invention provides the following technical solutions:

[0008] A compound of formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, polymorph, N-oxide or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein, R1 and R2 are each independently selected from H, or the following groups which are unsubstituted or optionally substituted by one, two or more R a substituted: C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclic group, C 6-20 aryl, C 6-20 aryl-C 1-40 alkyl, 5-20 membered heteroaryl or 5-20 membered heteroaryl-C 1-40 alkyl; X, Y, and Z are the same or different and are each independently selected from (C=O)NH, (C=O)O, C=O, S(O)2, S=O, or the following groups which are unsubstituted or optionally substituted by one, two or more R b substituted: amino, C 1-40 alkylene, C 2-40 alkenylene, C 2-40 alkynylene, C 1-40 alkoxyalkylene, C 3-20 cycloalkylene, 3-20 membered heterocycloalkylene, C 6-20 arylene, C 6-20Aryl-C 1-40 alkylene, 5-20 membered heteroarylene or 5-20 membered heteroaryl-C 1-40 alkylene;

[0011] Each R a is independently selected from CN, halogen, OH, NH2, oxo(=O), NHC(O)R a1 , C(O)OR a2 , or an unsubstituted or optionally substituted by one, two or more R c substituted group: C 1-40 alkyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclic group or C 6-20 aryl;

[0012] Each R b is independently selected from CN, halogen, OH, NH2, COOH, NO2, oxo(=O), S(O)2CH3, C(O)NHCH2CH3, or an unsubstituted or optionally substituted by one, two or more R c substituted group: C 1-40 alkyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclic group, C 6-20 aryl or 5-20 membered heteroaryl;

[0013] Each R c is independently selected from CN, halogen, OH, NH2, oxo(=O), S(O)2CH3, C 1-40 alkyl, halo-C 1-40 alkyl, C 1-40 alkoxy or halo-C 1-40 alkoxy;

[0014] R a1 is selected from H, hydroxy, halogen, or an unsubstituted or optionally substituted by one, two or more R d substituted group: C 1-40 alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 1-40 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocyclic group, C 6-20 aryl or 5-20 membered heteroaryl;

[0015] R a2 is selected from H, or an unsubstituted or optionally substituted by one, two or more R d substituted group: C 1-40 alkyl, C 2-40 alkenyl, C2-40 alkynyl, C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6-20 aryl, or 5- to 20-membered heteroaryl;

[0016] Each R d is the same or different and is independently selected from CN, halogen, OH, NH2, oxo (=O), S(O)2CH3, C 1-40 alkyl, halo C 1-40 alkyl, C 1-40 alkoxy, or halo C 1-40 alkoxy.

[0017] According to an embodiment of the present invention, R1 and R2 are each independently selected from H, or an unsubstituted or optionally substituted by one, two or more R a substituted following groups: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-14 aryl, C 6-14 aryl-C 1-10 alkyl, 5- to 14-membered heteroaryl or 5- to 14-membered heteroaryl-C 1-10 alkyl;

[0018] X, Y, and Z are the same or different and are each independently selected from (C=O)NH, (C=O)O, C=O, S(O)2, S=O, or an unsubstituted or optionally substituted by one, two or more R b substituted following groups: amino, C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, C 1-10 alkoxyalkylene, C 3-10 cycloalkylene, 3- to 10-membered heterocycloalkylene, C 6-14 arylene, C 6-14 aryl-C 1-10 alkylene, 5- to 14-membered heteroarylene or 5- to 14-membered heteroaryl-C 1-10 alkylene;

[0019] Each R a is independently selected from CN, halogen, OH, NH2, oxo (=O), NHC(O)R a1 , C(O)OR a2 , or an unsubstituted or optionally substituted by one, two or more R c substituted following groups: C 1-10 alkyl, C 1-10 alkoxy, C3-10 cycloalkyl, 3- to 10-membered heterocyclic group, or C 6-14 aryl;

[0020] Each R b is independently selected from CN, halogen, OH, NH2, COOH, NO2, oxo(=O), S(O)2CH3, C(O)NHCH2CH3, or an unsubstituted or optionally substituted by one, two or more R c substituted group: C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl;

[0021] Each R c is independently selected from CN, halogen, OH, NH2, oxo(=O), S(O)2CH3, C 1-10 alkyl, halo C 1-10 alkyl, C 1-10 alkoxy or halo C 1-10 alkoxy;

[0022] R a1 is selected from H, hydroxy, halogen, or an unsubstituted or optionally substituted by one, two or more R d substituted group: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl;

[0023] R a2 is selected from H, or an unsubstituted or optionally substituted by one, two or more R d substituted group: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl;

[0024] Each R d is the same or different and is independently selected from CN, halogen, OH, NH2, oxo(=O), S(O)2CH3, C 1-10 alkyl, halo C 1-10 alkyl, C 1-10 alkoxy or halo C 1-10 alkoxy.

[0025] According to an embodiment of the present invention, each of R1 and R2 is independently selected from H, or an unsubstituted or optionally substituted by one, two or more Rs a substituted with the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, C 6-14 aryl-C 1-6 alkyl, 5-14 membered heteroaryl or 5-14 membered heteroaryl-C 1-6 alkyl;

[0026] X, Y, and Z are the same or different and are each independently selected from (C=O)NH, (C=O)O, C=O, S(O)2, S=O, or an unsubstituted or optionally substituted by one, two or more Rs b substituted with the following groups: amino, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 alkoxyalkylene, C 3-10 cycloalkylene, 3-10 membered heterocycloalkylene, C 6-14 arylene, C 6-14 aryl-C 1-6 alkylene, 5-14 membered heteroarylene or 5-14 membered heteroaryl-C 1-6 alkylene;

[0027] Each R a is independently selected from CN, halogen, OH, NH2, oxo (=O), NHC(O)R a1 , C(O)OR a2 , or an unsubstituted or optionally substituted by one, two or more Rs c substituted with the following groups: C 1-6 alkyl or C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group or C 6-14 aryl;

[0028] Each R b is independently selected from CN, halogen, OH, NH2, COOH, NO2, oxo (=O), S(O)2CH3, C(O)NHCH2CH3, or an unsubstituted or optionally substituted by one, two or more Rs c substituted with the following groups: C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C6-14 an aryl or a 5- to 14-membered heteroaryl;

[0029] Each R c is independently selected from CN, halogen, OH, NH2, oxo (=O), S(O)2CH3, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halo C 1-6 alkoxy;

[0030] R a1 is selected from H, hydroxy, halogen, or the following groups which are unsubstituted or optionally substituted by one, two or more Rs d : C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, a 3- to 10-membered heterocyclic group, C 6-14 aryl or a 5- to 14-membered heteroaryl;

[0031] R a2 is selected from H, or the following groups which are unsubstituted or optionally substituted by one, two or more Rs d : C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, a 3- to 10-membered heterocyclic group, C 6-14 aryl or a 5- to 14-membered heteroaryl;

[0032] Each R d is the same or different and is independently selected from CN, halogen, OH, NH2, oxo (=O), S(O)2CH3, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halo C 1-6 alkoxy.

[0033] According to an embodiment of the present invention, R1 and R2 are each independently selected from H, or the following groups which are unsubstituted or optionally substituted by one, two or more Rs a : C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, a 3- to 7-membered heterocyclic group, phenyl, phenyl-C 1-6 alkyl, a 5- to 6-membered heteroaryl or a 5- to 6-membered heteroaryl-C 1-6 alkyl;

[0034] X, Y, and Z are the same or different and each independently selected from (C=O)NH, (C=O)O, C=O, S(O)2, S=O, or an unsubstituted or optionally substituted by one, two or more R b substituted groups as follows: amino, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 alkoxyalkylene, C 3-7 cycloalkylene, 3- to 7-membered heteroalkylene, phenylene, phenyl-C 1-6 alkylene, 5- to 6-membered heteroarylene or 5- to 6-membered heteroaryl-C 1-6 alkylene;

[0035] Each R a is independently selected from CN, halogen, OH, NH2, oxo (=O), NHC(O)R a1 , C(O)OR a2 , or an unsubstituted or optionally substituted by one, two or more R c substituted groups as follows: C 1-6 alkyl or C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group or phenyl;

[0036] Each R b is independently selected from CN, halogen, OH, NH2, COOH, NO2, oxo (=O), S(O)2CH3, C(O)NHCH2CH3, or an unsubstituted or optionally substituted by one, two or more R c substituted groups as follows: C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3- to 7-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl;

[0037] Each R c is independently selected from CN, halogen, OH, NH2, oxo (=O), S(O)2CH3, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy or halo-C 1-6 alkoxy;

[0038] R a1 is selected from H, hydroxy, halogen, or an unsubstituted or optionally substituted by one, two or more R d substituted groups as follows: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C3-10 a cycloalkyl group, a 3- to 7-membered heterocyclic group, a phenyl group or a 5- to 6-membered heteroaryl group;

[0039] R a2 selected from H, or an unsubstituted or optionally substituted by one, two or more Rs d substituted following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl group;

[0040] each R d is the same or different and is independently selected from CN, halogen, OH, NH2, oxo (=O), S(O)2CH3, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halo C 1-6 alkoxy.

[0041] According to an embodiment of the present invention, R1 and R2 are each independently selected from H, or an unsubstituted or optionally substituted by one, two or more Rs a substituted following groups: C 1-6 alkyl, C 3-7 cycloalkyl, phenyl;

[0042] X is selected from an unsubstituted or optionally substituted by one, two or more Rs b substituted following groups: C 1-6 alkylene, C 1-6 alkyleneoxy, phenylene;

[0043] Y is selected from (C=O)NH, (C=O)O, or an unsubstituted or optionally substituted by one, two or more Rs b substituted following groups: C 1-6 alkylene, C 1-6 alkyleneoxy, phenylene;

[0044] Z is selected from an unsubstituted or optionally substituted by one, two or more Rs b substituted following groups: C 1-6 alkylene, C 1-6 alkyleneoxy, phenylene;

[0045] each R a is independently selected from CN, halogen, OH, NH2, oxo (=O), or an unsubstituted or optionally substituted by one, two or more Rs c substituted following groups: C 1-6 alkyl or C 1-6 alkoxy;

[0046] Each R b is independently selected from CN, halogen, OH, oxo(=O), or an unsubstituted or optionally substituted by one, two or more R c substituted group as follows: C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl;

[0047] Each R c is independently selected from CN, halogen, OH, NH2, oxo(=O), C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halo C 1-6 alkoxy.

[0048] As an example, the compound of formula (I) can be selected from the compounds exemplified in Table 1 below and their pharmaceutically acceptable salts, racemates, stereoisomers, tautomers, isotope-labeled compounds, solvates, polymorphs or N-oxides:

[0049] Table 1

[0050]

[0051]

[0052]

[0053] The pharmaceutically acceptable salts of the compounds of the present invention can be acid addition salts or base addition salts. For example, the acid addition salts can be formed with the following inorganic acids or organic acids: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, tartaric acid, fumaric acid, citric acid, malic acid, oxalic acid, ascorbic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc., or the salts can be formed with sodium ions, potassium ions, calcium ions, ammonium ions, etc.

[0054] The present invention also provides a method for preparing the compound of formula (I), comprising the following steps 1)-3):

[0055]

[0056] Wherein, X, Y, Z, R1 and R2 independently have the definitions described above;

[0057] Step 1): Reacting compound 1 with compound 2 under the action of a base to obtain compound 3;

[0058] Step 2): Deprotecting compound 3 to obtain compound 4;

[0059] The above-mentioned deprotection conditions are known to those skilled in the art. For example, deprotection is carried out under the action of an acid, and the acid can be an organic acid or an inorganic acid, such as at least one selected from hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, propionic acid, sulfuric acid; and

[0060] Step 3): Compound 4 undergoes cyclization under the action of a base to obtain the compound shown in formula (I).

[0061] According to an embodiment of the present invention, the reaction conditions of step 1) can be conventionally selected. For example, the base can be selected from at least one of triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, or the basic condition can be provided by an excess of compound 1.

[0062] According to an embodiment of the present invention, the reaction of step 1) can be carried out in the presence or absence of a solvent. When a solvent is present, the solvent can be an organic solvent, and the organic solvent is preferably selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, acetone, dichloromethane;

[0063] According to an embodiment of the present invention, in step 1), the molar ratio of compound 1 to compound 2 can be 1:(0.5 - 20); the molar ratio of compound 1 to the base can be 1:(0.5 - 20); the weight-to-volume ratio of compound 1 to the organic solvent can be 1:(0 - 100) g / ml, preferably 1:(3 - 100) g / ml; the reaction can be carried out at 10°C to 150°C, preferably at 25°C to 120°C; the reaction time can be 1 to 24 h.

[0064] According to an embodiment of the present invention, the reaction of step 2) can be carried out in the presence or absence of a solvent. When a solvent is present, the solvent can be an organic solvent or a mixed solvent composed of water and an organic solvent, and the organic solvent is preferably selected from at least one of ethyl acetate, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, acetone, dichloromethane, and the volume ratio of water to the organic solvent is 0:100 to 100:0.

[0065] According to an embodiment of the present invention, in step 2), the molar ratio of compound 3 to the acid can be 1:(0.8 - 100); the weight-to-volume ratio of compound 3 to the solvent can be 1:(0 - 100) g / ml, preferably 1:(3 - 100) g / ml; the reaction can be carried out at -20°C to 150°C, preferably at 25°C to 120°C; the reaction time can be 1 to 24 h.

[0066] According to an embodiment of the present invention, the reaction conditions in step 3) can be conventionally selected. For example, the base can be selected from at least one of triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, and sodium hydroxide.

[0067] According to an embodiment of the present invention, the reaction in step 3) can be carried out in the presence or absence of a solvent. When a solvent is present, the solvent can be an organic solvent, and the organic solvent is preferably selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, acetone, and dichloromethane.

[0068] According to an embodiment of the present invention, in step 3), the molar ratio of compound 4 to the base can be 1:(0.5 - 20); the weight-to-volume ratio of compound 4 to the organic solvent can be 1:(0 - 100) g / ml, preferably 1:(3 - 100) g / ml; the reaction can be carried out at 0°C to 150°C, preferably at 25°C to 120°C; and the reaction time can be 1 to 24 h.

[0069] Those skilled in the art should understand that the compound represented by formula (I), its racemate, stereoisomer, tautomer, and N-oxide can be used as raw materials or intermediates to prepare a pharmaceutically acceptable salt of the compound represented by formula (I), its racemate, stereoisomer, tautomer, and N-oxide. For this purpose, the present invention also provides the use of the compound represented by formula (I), its racemate, stereoisomer, tautomer, and N-oxide in the preparation of a pharmaceutically acceptable salt of the compound represented by formula (I), its racemate, stereoisomer, tautomer, and N-oxide.

[0070] The present invention also provides the use of at least one of the compound represented by formula I, its racemate, stereoisomer, tautomer, N-oxide, isotope-labeled compound, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt, or prodrug in the preparation of a drug, wherein the drug is an inhibitor of a protein kinase. The drug is used to treat, prevent, or improve a disease in an animal or a human, and the disease includes pulmonary fibrosis or liver fibrosis, etc. In addition, the compound is active against a protein kinase, especially JNK1 and / or JNK2. The methods provided herein include administering an effective amount of a compound of the present invention (including the compound represented by formula (I), its racemate, stereoisomer, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, the same hereinafter) to a subject in need thereof.

[0071] The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound represented by formula (I), its racemate, stereoisomer, tautomer, N-oxide, isotope-labeled substance, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug. The pharmaceutical composition may also optionally comprise pharmaceutically acceptable excipients, such as carriers, excipients. As an example, the excipients may be one or more selected from the following: disintegrants, glidants, lubricants, diluents or fillers, binders, colorants.

[0072] The present invention also provides a method for modulating the function of JNK kinase, which comprises administering an effective amount of one or more compounds of the present invention, or a pharmaceutical composition comprising the compound, to an individual in need thereof.

[0073] In yet another aspect, the present invention provides a method for inhibiting the kinase in a cell expressing the kinase, which comprises contacting the cell with an effective amount of a compound of the present invention. In one embodiment, the kinase is JNK1, JNK2 or a mutant or isoform thereof, or a combination thereof, and the compound is one or more compounds of formula (I), such as the compounds from Table 1.

[0074] In another aspect, provided herein is a method for treating or preventing a liver fibrosis disease such as non-alcoholic steatohepatitis, steatosis (i.e., fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma and liver fibrosis accompanied by long-term or repeated alcohol intake (alcoholic hepatitis), accompanied by infection (such as viral infection such as HCV), accompanied by liver transplantation or accompanied by drug-induced liver injury (such as acetaminophen toxicity), which comprises administering an effective amount of a compound of the present invention to a subject in need thereof. In some aspects, provided herein is a method for treating or preventing diabetes or metabolic syndrome that causes liver or lung fibrosis diseases such as non-alcoholic steatohepatitis, steatosis (i.e., fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis and hepatitis, which comprises administering an effective amount of a compound of the present invention to a subject in need thereof.

[0075] In another aspect, provided herein is a method for treating or preventing one or more disorders selected from idiopathic pulmonary fibrosis (IPF), systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection or lupus, which comprises administering an effective amount of a compound of the present invention to a subject in need thereof. In some such embodiments, the lupus is lupus erythematosus (e.g., discoid lupus erythematosus or cutaneous lupus erythematosus) or systemic lupus.

[0076] In another aspect, provided herein are methods for treating or preventing a disorder treatable or preventable by inhibiting JNK1 and / or JNK2, the methods comprising administering to a subject in need thereof an effective amount of a compound of the invention. Examples of such disorders include rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus; type II diabetes; obesity; atherosclerosis; restenosis after angioplasty; left ventricular hypertrophy; myocardial infarction; stroke; ischemic injury to the heart, lung, intestine, kidney, liver, pancreas, spleen and brain; acute or chronic organ transplant rejection; preservation of organs for transplantation; organ failure or limb defects (e.g., including but not limited to those caused by ischemia-reperfusion injury, trauma, systemic injury, motor vehicle accident, crush injury or transplant failure); graft-versus-host disease; endotoxin shock; multiple organ failure; psoriasis; burns caused by exposure to fire, chemicals or radiation; eczema; dermatitis; skin grafting; ischemia; ischemic disorders associated with surgical or traumatic injury (e.g., motor vehicle accident, gunshot wound or limb crush); epilepsy; Alzheimer's disease; Parkinson's disease; immune response to bacterial or viral infection; cachexia; angiogenic and proliferative diseases; solid tumors; and cancers of various tissues such as the colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, bladder, ovary or uterus.

[0077] In another aspect, provided herein are compounds of formula (I) for modulating JNK kinase function, comprising administering to an individual in need thereof an effective amount of one or more compounds of the invention, or a pharmaceutical composition comprising the compound.

[0078] In yet another aspect, the invention provides compounds of formula (I) for use in a method of inhibiting said kinase in a cell expressing the kinase, comprising contacting said cell with an effective amount of a compound of the invention. In one embodiment, the kinase is JNK1, JNK2 or a mutant or isoform thereof, or a combination thereof, and the compound is one or more compounds of formula (I), such as a compound from Table 1.

[0079] In yet another aspect, the present invention provides a compound of formula (I) for use in a method of treating or preventing a liver fibrosis disease such as non-alcoholic steatohepatitis, steatosis (i.e., fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, and liver fibrosis in the presence of long-term or repeated alcohol intake (alcoholic hepatitis), in the presence of an infection (e.g., a viral infection such as HCV), in the presence of a liver transplant, or in the presence of drug-induced liver injury (e.g., acetaminophen toxicity), the method comprising administering to a subject in need thereof an effective amount of a compound of the invention. In some aspects, provided herein is a method of treating or preventing diabetes or metabolic syndrome that leads to a liver or lung fibrosis disease such as non-alcoholic steatohepatitis, steatosis (i.e., fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, and hepatitis, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.

[0080] In yet another aspect, the present invention provides a compound of formula (I) for use in a method of treating or preventing one or more disorders selected from idiopathic pulmonary fibrosis (IPF), systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection, or lupus, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention. In some such embodiments, the lupus is lupus erythematosus (e.g., discoid lupus erythematosus or cutaneous lupus erythematosus) or systemic lupus.

[0081] In yet another aspect, the present invention provides compounds of formula (I) for use in a method of treating or preventing a disorder treatable or preventable by inhibiting JNK1 and / or JNK2, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention. Examples of such disorders include rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; allergic bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus; type II diabetes; obesity; atherosclerosis; restenosis after angioplasty; left ventricular hypertrophy; myocardial infarction; stroke; ischemic injury to the heart, lung, intestine, kidney, liver, pancreas, spleen and brain; acute or chronic organ transplant rejection; preservation of organs for transplantation; organ failure or limb defects (e.g., including but not limited to those caused by ischemia-reperfusion injury, trauma, systemic injury, car accident, crush injury or transplant failure); graft-versus-host disease; endotoxin shock; multiple organ failure; psoriasis; burns caused by exposure to fire, chemicals or radiation; eczema; dermatitis; skin grafting; ischemia; ischemic disorders associated with surgical or traumatic injury (e.g., vehicle accident, gunshot wound or limb crush); epilepsy; Alzheimer's disease; Parkinson's disease; immune response to bacterial or viral infection; cachexia; angiogenic and proliferative diseases; solid tumors; and cancers of various tissues such as colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, bladder, ovary or uterus.

[0082] Beneficial effects

[0083] The compounds of formula (I) provided by the present invention have excellent JNK inhibitory activity, and have good safety and metabolic stability. In addition, the preparation method of the compounds of formula (I) of the present invention is simple and easy to purify, and thus has good application prospects.

[0084] Term definitions and explanations

[0085] Unless otherwise specified, the definitions of groups and terms recited in the specification and claims of the present application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should fall within the scope described in the specification of the present application.

[0086] For the numerical ranges recited in the description and claims of the present application, when the numerical range is defined as "integer", it should be understood that the two endpoints of the range and each integer within the range are recited. For example, "integers from 0 to 10" should be understood to recite each of the integers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. When the numerical range is defined as "number", it should be understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "numbers from 0 to 10" should be understood to recite not only each of the integers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively.

[0087] Unless otherwise specified, when the term "compound of the present invention" or "the compound of the present invention" is used herein, it is intended to cover the triazole derivatives represented by formula (I), their racemates, stereoisomers, tautomers, N-oxides or their pharmaceutically acceptable salts.

[0088] The term "halogen" refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I can be described as "halogen" in the present specification.

[0089] The term "C 1-40 alkyl" should be understood to preferably represent a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1 to 40 carbon atoms, preferably C 1-10 alkyl and C 1-6 alkyl. "C 1-10 alkyl" should be understood to preferably represent a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. "C 1-6 alkyl" should be understood to preferably represent a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl groups are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc. or their isomers. In particular, the group has 1, 2, 3, 4, 5, or 6 carbon atoms (i.e., C 1-6 alkyl), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, and more particularly, the group has 1, 2, or 3 carbon atoms (i.e., C 1-3(alkyl), such as methyl, ethyl, n-propyl or isopropyl.

[0090] The term "C 1-40 alkoxy" refers to the group -OR, where R is a substituted or unsubstituted C 1-40 alkyl, and where "C 1-40 alkyl" has the definition given above. Similarly, the term "C 1-10 alkoxy" refers to the group -OC 1-10 alkyl, "C 1-6 alkoxy" refers to the group -OC 1-6 alkyl, "C 1-3 alkoxy" refers to the group -OC 1-3 alkyl, where "C 1-10 alkyl", "C 1-6 alkyl" and "C 1-3 alkyl" have the definitions given above. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.

[0091] The term "C 2-40 alkenyl" should be understood to preferably denote a straight-chain or branched monovalent hydrocarbon group that contains one or more double bonds and has 2 to 40 carbon atoms, preferably "C 2-10 alkenyl". "C 2-10 alkenyl" should be understood to preferably denote a straight-chain or branched monovalent hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C 2-3(alkenyl). It should be understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0092] The term "C" 2-40 alkynyl" should be understood to mean a straight-chain or branched monovalent hydrocarbon group that contains one or more triple bonds and has 2 to 40 carbon atoms, preferably "C" 2-10 alkynyl". The term "C" 2-10 alkynyl" should be understood to preferably mean a straight-chain or branched monovalent hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms,, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., "C" 2-6 alkynyl"), having 2 or 3 carbon atoms ("C" 2-3"-alkynyl"). The alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0093] The term "C 3-20 cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which may be a spiro or bridged ring and which has 3 to 20 carbon atoms, preferably "C 3-10 cycloalkyl". For example, the term "C 3-10 cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which may be a spiro or bridged ring and which has 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C 3-10 cycloalkyl may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decahydronaphthalene ring. For example, the term "C 3-6 cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which may be a spiro or bridged ring and which has 3, 4, 5 or 6 carbon atoms. The C 3-6 cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.0]butyl, spiropentyl, spiro[2.3]hexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl or bicyclo[3.1.0]hexyl.

[0094] The term "3-20 membered heterocyclic group" means a monovalent group of a 3 to 20 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, which non-aromatic ring system may be saturated or contain one or more double bonds, and which may be monocyclic, bicyclic, spiro or bridged, wherein each ring heteroatom is independently selected from N, O, S, B, P and Si. The "3-20 membered heterocyclic group" may be, for example, a "3-10 membered heterocyclic group", a "3-7 membered heterocyclic group" or a "5-6 membered heterocyclic group". The term "3-10 membered heterocyclic group" means a monovalent group of a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, which non-aromatic ring system may be monocyclic, bicyclic, spiro or bridged, wherein each ring heteroatom is independently selected from N, O, S, B, P and Si, preferably comprising 1-3 heteroatoms selected from N, O and S. The term "3-7 membered heterocyclic group" means a monovalent group of a 3 to 7 non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, which non-aromatic ring system may be monocyclic, bicyclic, spiro or bridged, wherein each ring heteroatom is independently selected from N, O, S, B, P and Si, preferably comprising 1-3 heteroatoms selected from N, O and S. The term "5-6 membered heterocyclic group" means a monovalent group of a 5 to 6 non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, which non-aromatic ring system is usually monocyclic, wherein each ring heteroatom is independently selected from N, O, S, B, P and Si, preferably comprising 1-3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the remainder of the molecule through any one of the carbon atoms or a nitrogen atom (if present). Whether or not the heterocyclic group is preceded by "substituted", each atom of the heterocyclic group is independently optionally substituted, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents include but are not limited to hydroxy, amino, oxo, halogen, cyano, nitro, C 1-40 alkyl, C 2-40 alkenyl, C2- 40Alkynyl and the like. In particular, the heterocyclic group may include, but is not limited to: 3-membered rings such as aziridinyl, oxiranyl and thiiranyl; 4-membered rings such as azetidinyl, oxetanyl and thietanyl; 5-membered rings such as dihydrofuryl, tetrahydrofuryl, dihydrothienyl, tetrahydrothienyl, dioxolanyl, pyrrolidinyl, dihydropyrrolyl, imidazolidinyl, pyrazolidinyl, pyrroline, dioxolane, oxathiolanyl, disulfuranyl, oxazolidin-2-one, triazolinyl, oxadiazolinyl and thiadiazolinyl; or 6-membered rings such as dihydropyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, dihydropyridyl, thianyl, dithianyl, thiomorpholinyl, piperazinyl, dithiane, dioxane and trithianyl; or 7-membered rings such as diazepanyl, azepanyl, oxepanyl and thiepanyl. Bicyclic heterocyclic groups, for example but not limited to 5,5-membered rings such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or 5,6-membered bicyclic rings such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. Rings containing nitrogen atoms may be partially unsaturated, i.e., it may contain one or more double bonds, for example but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or, it may be benzo-fused, for example but not limited to dihydroisoquinolinyl.

[0095] The term "C 6-20 aryl" should preferably be understood to represent a monocyclic, bicyclic or tricyclic hydrocarbon ring that is monovalent, aromatic or partially aromatic and has 6 to 20 carbon atoms, preferably "C 6-14 aryl". The term "C 6-14 aryl" should preferably be understood to represent a monocyclic, bicyclic or tricyclic hydrocarbon ring that is monovalent, aromatic or partially aromatic and has 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C 6-14 aryl"), especially a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl.

[0096] The term "5-20 membered heteroaryl" should be understood to include a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5 to 20 ring atoms and containing 1-5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" should be understood to include a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and containing 1-5, preferably 1-3 heteroatoms independently selected from N, O and S and, additionally in each case, may be benzo-fused. The term "5-6 membered heteroaryl" should be understood to be a monovalent monocyclic aromatic ring system having 5 or 6 ring atoms, containing 1-3 heteroatoms independently selected from N, O and S, and which in each case may be benzo-fused. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0097] Unless otherwise specified, heterocyclic group, heteroaryl or heteroarylene includes all its possible isomeric forms, such as its position isomers. Thus, for some illustrative and non-limiting examples, pyridyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylidene, pyridin-3-yl, pyridin-3-ylidene, pyridin-4-yl and pyridin-4-ylidene; thienyl or thienylene includes thien-2-yl, thien-2-ylidene, thien-3-yl and thien-3-ylidene.

[0098] The above definition of the term "alkyl", such as "C 1-40 alkyl", also applies to other terms containing "C 1-40 alkyl", such as the terms "C 1-40 alkylene", "C 1-40 alkoxy", "C 1-40 alkylsilyl" and "C 1-40 alkylsilyloxy", etc. Similarly, the above definitions of the terms "C 2-40 alkenyl", "C 2-40 alkynyl", "C 3-20 cycloalkyl", "C 5-20"cycloalkenyl", "3-20 membered heterocyclic group", "C 6-20 The definitions of "aryl" and "5-20 membered heteroaryl" correspondingly apply equally to other terms containing them, such as the term "C 2-40 alkenyloxy", "C 2-40 alkynyloxy", "C 3-20 cycloalkyloxy", "3-20 membered heterocyclic group", "3-20 membered heterocyclic oxy group", "C 6-20 aryloxy", "C 6-20 arylalkyl", and "5-20 membered heteroarylalkyl", etc.

[0099] The term "sub*yl" should be understood to represent the corresponding divalent group, where two positions of hydrogen in the substituent are replaced, such as "C 1-40 alkylene" should be understood to represent a divalent hydrocarbon group. Similarly, the above definitions correspondingly apply equally to other "sub*yl", such as the terms "C 2-40 alkenylene", "C 2-40 alkynylene", "C 1-40 alkoxy", "C 3-20 cycloalkylene", "3-20 membered subheterocyclic group", "C 6-20 arylene", and other terms containing it, such as "5-20 membered subheteroaryl", "5-20 membered heteroaryl-C 1-40 alkylene", etc.

[0100] In any method for preparing the compounds of the present invention, it may be necessary and / or desirable to protect any sensitive or reactive groups on any relevant molecule. This can be achieved by conventional protecting groups, such as those described in textbooks or reference books in the art. The protecting groups can be removed using methods known in the art at a convenient subsequent stage. Those skilled in the art will recognize that depending on the specific protecting group, other reagents can be used for this deprotection step, including but not limited to Pd / C, Pd(OH)2, PdCl2, Pd(OAc)2 / Et3SiH, Raney nickel, appropriately selected acids, appropriately selected bases, fluorides, and the like.

[0101] The target compound can be separated according to known methods, such as by extraction, filtration, or column chromatography.

[0102] Depending on their molecular structure, the compounds of the present invention may be chiral and thus may exist in various enantiomeric forms. These compounds may thus exist in racemic or optically active form. The compounds of the present invention or their intermediates may be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in synthesis in such form. In the case of a racemic amine, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (such as N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can also be advantageously carried out with the aid of an optically active resolving agent such as dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile.

[0103] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides since nitrogen requires an available lone pair of electrons for oxidation to the oxide; those skilled in the art will identify the nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These methods for the preparation of N-oxides have been widely described and reviewed in the literature.

[0104] Pharmaceutically acceptable salts can be, for example, acid addition salts of the compounds of the present invention having sufficient basicity with a nitrogen atom in the chain or ring, such as acid addition salts formed with the following inorganic acids: for example, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or bisulfates, or acid addition salts formed with the following organic acids: for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, amidosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

[0105] In addition, another suitable pharmaceutically acceptable salt of the compounds of the present invention having sufficient acidity is an alkali metal salt (such as a sodium salt or a potassium salt), an alkaline earth metal salt (such as a calcium salt or a magnesium salt), an ammonium salt, or a salt formed with an organic base providing a physiologically acceptable cation, such as a salt formed with the following substances: sodium ion, potassium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol. As an example, the pharmaceutically acceptable salts include salts formed by the group -COOH with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol; when 1, 2 or 3 of M1, M2, M3 in the present invention are H, the pharmaceutically acceptable salts of the present invention include, for example, salts formed by -OP(O)(OM1)(OM2), -P(O)(OM1)(OM2), -OS(O)2OM3, -S(O)2OM3 with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol.

[0106] In addition, the basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate; long-chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, etc. As examples, pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate or meglumine salt, etc.

[0107] Since the compounds of the present invention may have multiple salt-forming sites, the "pharmaceutically acceptable salts" include not only the salts formed at one salt-forming site of the compounds of the present invention, but also the salts formed at two, three or all of the salt-forming sites. For this reason, the molar ratio of the compound of formula (I) to the acid radical ion (anion) or the cation of the base required for salt formation in the "pharmaceutically acceptable salts" can vary within a relatively wide range, for example, it can be 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0108] According to the present invention, pharmaceutically acceptable anions include anions selected from those generated by the ionization of inorganic acids or organic acids. The "inorganic acids" include but are not limited to hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid. The "organic acids" include but are not limited to formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, amidosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfate or thiocyanic acid.

[0109] The term "ionization-generated anion" includes all possible anion forms generated by ionization of the inorganic and organic acids, such as different anions that can be generated through primary ionization, secondary ionization, or tertiary ionization. As an example, phosphoric acid can generate dihydrogen phosphate through primary ionization, hydrogen phosphate through secondary ionization, or phosphate through tertiary ionization; sulfuric acid can generate hydrogen sulfate through primary ionization or sulfate through secondary ionization. The compounds of formula (I) of the present invention can share a polyvalent anion generated through multiple-stage ionization by multiple molecules. All possible generated anions are covered within the scope of the anions of the present invention.

[0110] The term "tautomer" refers to functional group isomers generated due to the rapid movement of an atom in a molecule between two positions. The compounds of the present invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Prototrophic tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium form, and a mixture is usually produced when attempting to isolate a single tautomer, and its physicochemical properties are consistent with those of a mixture of compounds. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0111] The term "effective amount" or "therapeutically effective amount" refers to the amount of the compound of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount can vary depending on factors such as the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be readily determined by those of ordinary skill in the art. The specific dose will vary depending on factors such as the particular compound selected, the dosing regimen followed, whether co-administered with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system employed.

[0112] The term "excipient" refers to pharmaceutically inert ingredients. Examples of types of excipients include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents, etc. Excipients can enhance the handling characteristics of pharmaceutical formulations, that is, make the formulations more suitable for direct compression by increasing fluidity and / or adhesiveness. Examples of typical pharmaceutically acceptable carriers suitable for the above-mentioned formulations are: saccharides, such as lactose, sucrose, mannitol, and sorbitol; starches, such as corn starch, tapioca starch, and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal salts of stearic acid, such as magnesium stearate and calcium stearate; stearic acid; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; nonionic, cationic, and anionic surfactants; ethylene glycol polymers; fatty alcohols; and hydrolyzed cereal solids, as well as other non-toxic and compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants, etc., which are excipients commonly used in pharmaceutical formulations. Detailed implementation manners

[0113] The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only for illustrative explanation of the present invention and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0114] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products or can be prepared by known methods.

[0115] Nouns and representative reagents

[0116] The nouns used in the following specific experimental descriptions represent (unless otherwise specified) the following reagents:

[0117] TEA: Triethylamine; DIEA: Diisopropylethylamine; DCM: Dichloromethane; THF: Tetrahydrofuran; EA: Ethyl acetate; MeOH: Methanol; MeCN: Acetonitrile.

[0118] <Preparation Example>

[0119] Example 1: Preparation of 2,11-diaza-1(2,4)-pyrimidinecycloundecane-1 5 -carboxamide (L001)

[0120]

[0121] 1.1 Preparation of compound tert-butyl (8-aminooctyl)carbamate (L001-2)

[0122] 1,8 - Octanediamine (2 g, 13.86 mmol) and DIEA (537 mg, 4.16 mmol) were dissolved in DCM (50 mL). A solution of (Boc)₂O (106 mg, 4.85 mmol) in DCM (20 mL) was slowly added dropwise to the solution. After the addition was complete, the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the pH of the reaction solution was adjusted to 3 - 4, and the mixture was extracted with water (50 mL × 3). The aqueous phases were combined, and then the pH of the aqueous phase was adjusted to 9 - 10, followed by extraction with DCM (50 mL × 3). The organic phases were collected, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain 600 mg of a white solid product, which was the title compound L001 - 2, with a yield of 12%, LC - MS [M + H] + : 245.0.

[0123] 1.2 Preparation of compound tert - butyl (8 - ((5 - carbamoyl - 2 - chloropyrimidin - 4 - yl)amino)octyl)carbamate (L001 - 3)

[0124] L001 - 2 (600 mg, 2.45 mmol) was dissolved in tetrahydrofuran (20 mL), and DIEA (635 mg, 4.91 mmol) and 2,4 - dichloropyrimidine - 5 - carboxamide (471 mg, 2.45 mmol) were added. The reaction mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was evaporated to dryness to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0 - 50%) to obtain 400 mg of a white solid, which was the title compound L001 - 3, with a yield of 37%, LC - MS [M + H] + : 399.8.

[0125] 1.3 Preparation of compound 4 - ((8 - aminooctyl)amino)-2 - chloropyrimidine - 5 - carboxamide (L001 - 4)

[0126] L001 - 3 (400 mg, 1 mmol) was dissolved in ethyl acetate (10 mL), and HCl / EA (4N, 5 mL) was added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was evaporated to dryness to obtain 400 mg of a crude product, in which the purity of the title compound L001 - 4 was 60%, and the yield was 86%. LC - MS [M + H] + : 299.8.

[0127] 1.4 Preparation of compound 2,11 - diaza - 1(2,4)-pyrimidinecycloundecane - 1 5 - carboxamide (L001)

[0128] L001-4 (300 mg, 1 mmol) was dissolved in tetrahydrofuran (200 mL), DIEA (853 mg, 6.6 mmol) was added, the temperature was raised to 70 °C, and the mixture was stirred overnight. After the reaction was completed, the reaction solution was concentrated in vacuo and purified by preparative chromatography to obtain 17 mg of a white solid, which was the title compound L001, yield: 4%, LC-MS [M+H] + : 264.0.

[0129] 1 1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.31 (s, 1H), 7.55 (brs, 1H), 7.18 (s, 1H), 6.93 (brs, 1H), 3.49–3.39 (m, 2H), 3.35–3.25 (m, 2H), 1.66–1.56 (m, 4H), 1.49 (s, 4H), 1.24 (s, 4H).

[0130] Example 2: Preparation of 2,10-diaza-1(2,4)-pyrimidylcyclodecane-1 5 -carboxamide (L002)

[0131]

[0132] 2.1 Preparation of tert-butyl (7-aminoheptyl)carbamate (L002-2)

[0133] L002-1 (2.0 g, 15.36 mmol) and (Boc)2O (0.67 g, 3.07 mmol) were dissolved in DCM (100 mL), and the reaction solution was reacted at room temperature for 4 h. TLC (DCM:MeOH = 10:1) showed that the reaction was completed. The reaction solution was added dropwise to DCM (100 mL) and water (50 mL), the aqueous phase was extracted with DCM (100 mL * 3), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (DCM:MeOH = 20:1, adding 1% ammonia water) to obtain 0.6 g of a colorless liquid, which was the title compound L002-2.

[0134] 2.2 Preparation of tert-butyl (7-((5-carbamoyl-2-chloropyrimidin-4-yl)amino)heptyl)carbamate (L002-3)

[0135] L002-2 (0.60 g, 2.60 mmol), 2,4-dichloropyrimidine-5-carboxamide (0.53 g, 2.73 mmol) and TEA (0.39 g, 3.91 mmol) were dissolved in THF (20 mL), and the reaction mixture was stirred at room temperature for 4 h. TLC (DCM:MeOH = 10:1) showed the reaction was complete. The reaction mixture was added dropwise to EA (150 mL) and water (50 mL), and the aqueous phase was extracted with EA (150 mL × 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 0.80 g of a white solid, which was the title compound L002-3. LC-MS [M+H] + := 387.4.

[0136] 2.3 Preparation of 4-((7-aminoheptyl)amino)-2-chloropyrimidine-5-carboxamide (L002-4)

[0137] L002-3 (0.80 g, 2.07 mmol) was dissolved in EA (10 mL), and then HCl / EA (4N, 20 mL) was added. The reaction mixture was stirred at room temperature for 3 h. TLC (DCM:MeOH = 10:1) showed the reaction was complete. The reaction mixture was concentrated to give 0.70 g of a white solid, which was the title compound L002-4. LC-MS [M+H] + : 286.1.

[0138] 2.4 Preparation of 2,10-diaza-1(2,4)-pyrimidinylcyclodecane-1 5 -carboxamide (L002)

[0139] L002-4 (0.7 g, 2.45 mmol) and TEA (0.74 g, 7.35 mmol) were dissolved in THF (350 mL), and the reaction mixture was stirred at room temperature for 48 h. TLC (DCM:MeOH = 10:1) showed that only about 20% of the starting material had reacted. The reaction mixture was directly evaporated to dryness and separated by prep-HPLC using the H2O / MeCN system. After lyophilization, 23 mg of a white solid was obtained, which was the title compound L002 with a purity of 99.10%. LC-MS [M+H] + : 250.2.

[0140] 11H NMR (400 MHz, DMSO) δ 9.04 (t, J = 6.2 Hz, 1H), 8.33 (s, 1H), 7.55 (s, 1H), 7.23 (t, J = 6.2 Hz, 1H), 6.95 (s, 1H), 3.31 (s, 4H), 1.51 (d, J = 4.0 Hz, 2H), 1.45–1.36 (m, 4H), 1.21 (m, 4H).

[0141] Example 3: Preparation of 6-oxa-2,10-diaza-1(2,4)-pyrimidinylcyclodecane-1 5 -carboxamide (L003)

[0142]

[0143] 3.1 Preparation of tert-butyl ((3-(3-aminopropoxy)propyl)carbamate (L003-2)

[0144] 2,2'-oxybis(ethylamine) (750 mg, 5.7 mmol) and DIEA (220 mg, 1.7 mmol) were dissolved in DCM (50 mL). A solution of (Boc)2O (433 mg, 2 mmol) in DCM (20 mL) was slowly added dropwise to the solution. After the addition was complete, the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the pH was adjusted to 3 - 4 with dilute hydrochloric acid, and the mixture was extracted with water (50 mL × 3). The aqueous phases were combined, then the pH of the aqueous phase was adjusted to 9 - 10, and then extracted with DCM (50 mL × 3). The organic phases were collected, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain 250 mg of a white solid product, which was the title compound L003-2, yield: 19%.

[0145] 3.2 Preparation of tert-butyl ((3-(3-((5-carbamoyl-2-chloropyrimidin-4-yl)amino)propoxy)propyl)carbamate (L003-3)

[0146] Compound L003-2 (250 mg, 1.15 mmol) was dissolved in tetrahydrofuran (20 mL), and DIEA (446 mg, 3.45 mmol) and 2,4-dichloropyrimidine-5-carboxamide (220 mg, 1.15 mmol) were added. The reaction mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was evaporated to dryness to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0 - 50%) to obtain 300 mg of a white solid, which was the title compound L003-3, yield: 60%. LC-MS [M + H] + : 388.0.

[0147] 3.3 Preparation of 4-((3-(3-aminopropoxy)propyl)amino)-2-chloropyrimidine-5-carboxamide (L003-4)

[0148] Compound L003-3 (250 mg, 0.64 mmol) was dissolved in ethyl acetate (10 mL), and HCl / EA (4N, 5 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was evaporated to dryness to obtain 250 mg of the crude product. The purity of the title compound L003-4 was 60%, and the yield was 81%. LC-MS [M+H] + : 287.9.

[0149] 3.4 Preparation of 6-oxa-2,10-diaza-1(2,4)-pyrimidinylcyclodecane-1 5 -carboxamide (L003)

[0150] Compound L003-4 (250 mg, 0.86 mmol) was dissolved in acetonitrile (200 mL), and DIEA (853 mg, 6.6 mmol) was added. The temperature was raised to 70 °C and stirred overnight. After the reaction was completed, the reaction solution was evaporated to dryness and purified by preparative chromatography to obtain 20.9 mg of a white solid, which was the title compound L003. The yield was 11%, and LC-MS [M+H] + : 252.0.

[0151] 1 H NMR (400 MHz, DMSO) δ 8.70 (t, J = 6.5 Hz, 1H), 8.33 (s, 1H), 7.52 (brs, 1H), 7.08 (t, J = 6.3 Hz, 1H), 6.92 (brs, 1H), 4.25 - 3.40 (m, 4H), 3.25 - 2.90 (m, 4H), 1.62–1.48 (m, 4H).

[0152] Example 4 Preparation of 2,9-diaza-1(2,4)-pyrimidinylcyclononane-1 5 -carboxamide (L004)

[0153]

[0154] 4.1 Preparation of tert-butyl ((6-((5-carbamoyl-2-chloropyrimidin-4-yl)amino)hexyl)carbamate (L004-2)

[0155] L004-1 (0.5 g, 2.31 mmol), 2,4-dichloropyrimidine-5-carboxamide (0.46 g, 2.43 mmol) and TEA (0.35 g, 3.47 mmol) were dissolved in THF (20 mL), and the reaction mixture was stirred at room temperature for 4 h. TLC (DCM:MeOH = 10:1) showed the completion of the reaction. The reaction mixture was added dropwise to EA (100 mL) and water (50 mL). The aqueous phase was extracted with EA (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 0.75 g of a white solid, which was the title compound L004-2. LC-MS [M+H] + : 372.2.

[0156] Preparation of 4-((6-aminohexyl)amino)-2-chloropyrimidine-5-carboxamide (L004-3)

[0157] L004-2 (0.75 g, 2.02 mmol) was dissolved in EA (10 mL), and then HCl / EA (4N, 20 mL) was added. The reaction mixture was stirred at room temperature for 3 h. TLC (DCM:MeOH = 10:1) showed the completion of the reaction. The reaction mixture was concentrated to obtain 0.53 g of a crude white solid containing the title compound L004-3. LC-MS [M+H] + : 272.1.

[0158] 4.3 Preparation of 2,9-diaza-1(2,4)-pyrimidinylcyclononan-1 5 -carboxamide (L004)

[0159] L004-3 (0.4 g, 1.47 mmol) and TEA (0.45 g, 4.42 mmol) were dissolved in THF (200 mL), and the reaction mixture was stirred at room temperature for 48 h. TLC (DCM:MeOH = 10:1) showed that only about 30% of the starting material had reacted. The reaction mixture was directly evaporated to dryness to obtain 0.3 g of a crude product. The crude product was directly separated by prep-HPLC using the H2O / MeCN system, and after lyophilization, 100 mg of a white solid was obtained. The purity of the product was not sufficient. After purification, the product was further separated by prep-TLC, and after lyophilization, 45 mg of a white solid was obtained, which was the title compound L004 (purity 100.00%). LC-MS [M+H] + : 236.2.

[0160] 11H NMR (400 MHz, DMSO) δ (t, J = 5.2 Hz, 1H), 8.45 (t, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.02 (s, 1H), 7.56 (s, 1H), 3.50 (d, J = 4.0 Hz, 2H), 1.63–1.44 (m, 8H), 1.32 (s, 2H).

[0161] Example 5: Preparation of 5,8-dioxy-2,11-diaza-1(2,4)-pyrimidyl cycloundecane-1 5 -carboxamide (L005)

[0162]

[0163] 5.1 Preparation of compound tert-butyl ((2-(2-aminoethoxy)ethoxy)carbamate) (L005-2)

[0164] 2,2'-(ethane-1,2-diylbis(oxy))bis(ethan-1-amine) (L005-1) (2.0 g, 13.49 mmol) and DIEA (523 mg, 4.05 mmol) were dissolved in DCM (50 mL). A solution of (Boc)2O (1.03 g, 4.72 mmol) in DCM (20 mL) was slowly added dropwise to the solution. After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 3 - 4, and it was extracted with water (50 mL * 3). The aqueous phases were combined, then the pH of the aqueous phase was adjusted to 9 - 10, and it was extracted with DCM (50 mL * 3). The organic phases were collected, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain 500 mg of a white solid product, which was the title compound L005-2, yield: 12%, LC-MS [M + H] + : 249.0.

[0165] 5.2 Preparation of compound tert-butyl (2-(2-(2-((5-carbamoyl-2-chloropyrimidin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamate (L005-3)

[0166] L005-2 (400 mg, 1.61 mmol) was dissolved in tetrahydrofuran (20 mL), and DIEA (416 mg, 3.22 mmol) and 2,4-dichloropyrimidine-5-carboxamide (231 mg, 1.2 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was evaporated to dryness to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0 - 50%) to obtain 300 mg of a white solid, which was the title compound L005-3, yield: 42%, LC-MS [M + H] + : 403.8.

[0167] 5.3 Preparation of Compound 4-((2-(2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-chloropyrimidine-5-carboxamide (L005-4))

[0168] L005-3 (300 mg, 0.72 mmol) was dissolved in ethyl acetate (10 mL), and HCl / EA (4N, 5 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness to obtain 300 mg of the crude product. The purity of the title compound L005-4 was 60%, and the yield was 86%. LC-MS [M+H] + : 303.9.

[0169] 5.4 Preparation of Compound 5,8-Dioxo-2,11-diaza-1(2,4)-pyrimidinylcycloundecane-1 5 -carboxamide (L005)

[0170] L005-4 (200 mg, 0.63 mmol) was dissolved in tetrahydrofuran (200 mL), and DIEA (853 mg, 6.6 mmol) was added. The temperature was raised to 70 °C and stirred overnight. After the reaction was completed, the reaction solution was concentrated to dryness and purified by preparative chromatography to obtain 25.1 mg of a white solid, which was the title compound L005. The yield was 14%, and LC-MS [M+H] + : 268.0.

[0171] 1 H NMR (400 MHz, MeOD) δ 8.27 (s, 1H), 3.83–3.77 (m, 6H), 3.73–3.67 (m, 6H).

[0172] Example 6 Preparation of Compound 2,12-Diaza-1(2,4)-pyrimidinylcyclododecane-1 5 -carboxamide (L006)

[0173]

[0174] 6.1 Preparation of Compound (9-Aminononyl)carbamic Acid tert-Butyl Ester (L006-2)

[0175] The weighed L006-1 (2.0 g, 12.635 mmol) was dissolved in 50 mL of DCM, and TEA (2.56 g, 25.270 mmol) was added. The mixture was stirred at room temperature for 10 min, and Boc anhydride (552 mg, 2.527 mmol) was added dropwise. After the addition was complete, the reaction was carried out at room temperature overnight. TLC monitoring of the reaction solution showed that the raw material was not completely reacted and a new spot appeared. The reaction solution was concentrated, triturated with silica gel, and purified by column chromatography (DCM:MeOH = 10:1) to obtain 500 mg of the product, which was a white solid and was the title compound L006-2.

[0176] 6.2 Preparation of tert-butyl (9-((5-carbamoyl-4-chloropyrimidin-2-yl)amino)nonyl)carbamate (L006-3)

[0177] Weighed L006-2 (500 mg, 1.935 mmol), 2,4-dichloropyrimidine-5-carboxamide (372 mg, 1.935 mmol), and TEA (588 mg, 5.805 mmol) were successively added to 20 mL of THF, and the reaction was carried out overnight at room temperature. TLC monitoring showed that there was a little unreacted raw material L006 and a new spot was generated. The reaction solution was added with water and extracted with EA. The organic phase was washed with 0.1 M HCl and concentrated to dryness to obtain 800 mg of the product, which was a white solid and was the title compound L006-3.

[0178] 6.3 Preparation of 2-((9-aminononyl)amino)-4-chloropyrimidine-5-carboxamide (L006-4)

[0179] L006-3 (800 mg, 1.933 mmol) was dissolved in 20 mL of EA, and HCl / EA (4N, 20 mL) was added. The mixture was stirred at room temperature for 1 h, and a solid precipitated. TLC monitoring showed that there was a little unreacted raw material. The reaction solution was directly filtered, and the filter cake was washed twice with EA and concentrated to dryness to obtain 530 mg of the product, which was a pale yellow solid and was the title compound L006-4.

[0180] 6.4 Preparation of 2,12-diaza-1(2,4)-pyrimidinylcyclododecane-1 5 -carboxamide (L006)

[0181] L006-4 (300 mg, 0.956 mmol) was dissolved in 300 mL of THF, and TEA (484 mg, 4.780 mmol) was added. The reaction was carried out overnight at 70 °C. LC-MS showed that the product was formed. The reaction solution was concentrated to dryness and purified by Prep-HPLC to obtain 51.7 mg of a white solid, which was the title compound L006. LC-MS: [M+H] + : 278.2.

[0182] 1 H NMR (400 MHz, dmso) δ 9.19 (t, J = 6.2 Hz, 1H), 8.31 (s, 1H), 7.53 (s, 1H), 7.33 (t, J = 6.2 Hz, 1H), 6.98 (s, 1H), 3.39–3.35 (m, 2H), 3.21 (dd, J = 10.7, 5.5 Hz, 2H), 1.52 (s, 4H), 1.36 (s, 10H).

[0183] The preparations of Examples 7-17 were carried out with reference to the methods of Examples 1-6.

[0184]

[0185]

[0186]

[0187] <Biological Activity Test>

[0188] Kinase Activity Screening

[0189] JNK1 activity screening. The JNK1 activity was detected by using a 96-well (Cisbio, 66PL96025) time-resolved fluorescence assay. The JNK1 assay was run in the following assay buffer: 10 mM MgCl2 (Sigma, M1028), 1 mM MnCl2 (Sigma, M1787), 1 mM DTT (Sigma, D0632), and 1X Enzymatic buffer / kinase (Cisbio, 62EZBFDC). Using the assay buffer, first transfer 3 μl of 0.1 ng / μl JNK1 kinase (Carna Biosciences, 04-163) into a 96-well microplate, and then transfer 4 μl of the appropriately diluted compound with 2.5% DMSO content, and incubate at room temperature for 0.5 h. To initiate the reaction, also using the assay buffer, after mixing 0.003 μM ATP (Aladdin, A7699) and 30 μM substrate ATF2-GST fusion (Cisbio, 64CUS000AFPEB) together, add 3 μl of the mixture into the microplate and continue to incubate at room temperature for 2.5 h. Then prepare a mixture of 5 μg / ml MAb Anti GST-XL665 (Cisbio, 61GSTXLA) and 0.045 μg / ml PAb Anti-phospho ATF2-K (Cisbio, 61P12KAZ) using HTRF detection buffer (Gibco, 62SDBRDD), and transfer 10 μl of the mixture to terminate the reaction. After incubating for about 12 h, read the plate on a Perkin-Elmer Envision reader.

[0190] Cell Evaluation Method

[0191] 1. RAW264.7 Phosphorylated c-jun Whole Cell Assay. RAW264.7 (ATCC TIB-71) cells were purchased from BeNa Culture Collection and maintained in high-glucose DMEM medium (Gibco) containing 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Gibco). All cells were cultured at 37°C in 95% air and 5% CO2. Cells were seeded at a density of 2×10 5 cells per well into 120 μl of cell culture medium in a 96-well plate. The compound stock solution (15 mM) was serially diluted in DMSO (Sigma), further diluted in growth medium, and then 15 μl of the 10× concentrated solution was added to the wells, mixed, and incubated with the cells for 30 min. The concentration of compound vehicle (DMSO) in all wells was 0.2%. After 30 min, the cells were activated with 25 ng / ml lipopolysaccharide (Sigma). Lipopolysaccharide was added to the growth medium as a 10× concentrated solution and added at a volume of 15 μl per well. The cell plates were incubated for 1 hour, and then all the culture medium was discarded. The protein level of c-jun phosphorylated at serine 63 was measured using a Whole Cell Lysis Kit - Phospho-c-Jun (Ser63) Sandwich ELISA Kit (CST, 7145C) according to the manufacturer's instructions.

[0192] 2. Jurkat T Cell IL-2 Production Assay. Jurkat T cells (clone E6-1) were purchased from China Center for Type Culture Collection and maintained in RPMI 1640 (Gibco) containing 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Gibco). All cells were cultured at 37°C in 95% air and 5% CO2. Cells were seeded at a density of 1×10 5 ​Cells were seeded at a density of [number of cells] into 120 μl of cell culture medium in a 96-well plate. The compound stock solution (15 mM) was serially diluted in DMSO (Sigma), further diluted in growth medium, and then 15 μl of the 10× concentrated solution was added to the wells, mixed, and incubated with the cells for 30 min. The concentration of the compound vehicle (DMSO) in all wells was 0.2%. After 30 min, the cells were activated with PMA (phorbol 12-myristate 13-acetate; final concentration 50 ng / ml) (Sigma) and PHA (phytohemagglutinin; final concentration 1 μg / ml) (Sigma). PMA and PHA were prepared as 10× concentrated solutions in growth medium and added at a volume of 15 μl per well. The cell plates were incubated for 6 hours. The cells were pelleted using a microplate centrifuge (Xiangyi), and the cell supernatants were collected and stored at -20°C. The amount of IL-2 in the supernatants was measured using a Human IL-2 ValukineTM ELISA Kit (R&D Systems, VAL110) according to the manufacturer's instructions.

[0193] Each of the compounds in Table 2 below was tested enzymatically and cell-based in the JNK1 biochemical assay, and the compounds of the present invention were found to have good activity. In the enzymatic assay, an IC 50 lower than 100 nM was designated as activity level A, an IC 50 between 100 nM and 500 nM was designated as activity level B, and an IC 50 between 500 nM and 1 μM was designated as activity level C. In the cell-based assay, an IC 50 lower than 100 nM was designated as activity level A, an IC 50 between 100 nM and 500 nM was designated as activity level B, and an IC 50 between 500 nM and 1 μM was designated as activity level C.

[0194] Table 2

[0195]

[0196]

[0197] As described above, the embodiments of the present invention have been described. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein, R1 and R2 are each independently selected from H, or an unsubstituted or optionally substituted by one, two or more R a substituted with the following groups: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl, C 6-14 aryl-C 1-10 alkyl, 5- to 14-membered heteroaryl or 5- to 14-membered heteroaryl-C 1-10 alkyl; X is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene or C 1-6 alkoxy; Y is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene or C 1-6 alkoxy; Z is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene or C 1-6 alkoxy; Each R a is independently selected from CN, halogen, OH, NH2, oxo, NHC(O)R a1 , C(O)OR a2 , or an unsubstituted or optionally substituted by one, two or more R c substituted group: C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group or C 6-14 aryl; Each R b is independently selected from CN, halogen, OH, NH2, COOH, NO2, oxo, S(O)2CH3, C(O)NHCH2CH3, or an unsubstituted or optionally substituted by one, two or more R c substituted group as follows: C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl; Each R c is independently selected from CN, halogen, OH, NH2, oxo, S(O)2CH3, C 1-10 alkyl, halo C 1-10 alkyl, C 1-10 alkoxy or halo C 1-10 alkoxy; R a1 selected from H, hydroxy, halogen, or an unsubstituted or optionally substituted by one, two or more R d substituted with the following groups: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl; R a2 selected from H, or an unsubstituted or optionally substituted by one, two or more R d substituted with the following groups: C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl; Each R d is the same or different and is independently selected from CN, halogen, OH, NH2, oxo, S(O)2CH3, C 1-10 alkyl, halo C 1-10 alkyl, C 1-10 alkoxy or halo C 1-10 alkoxy.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R1 and R2 are each independently selected from H, or an unsubstituted or optionally substituted by one, two or more R a substituted with the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl, C 6-14 aryl-C 1-6 alkyl, 5- to 14-membered heteroaryl or 5- to 14-membered heteroaryl-C 1-6 alkyl; X is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene or C 1-6 alkoxy; Y is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene or C 1-6 alkoxy; Z is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene; Each R a is independently selected from CN, halogen, OH, NH2, oxo, NHC(O)R a1 , C(O)OR a2 , or an unsubstituted or optionally substituted by one, two or more R c substituted group: C 1-6 alkyl or C 1-6 alkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclic group or C 6-14 aryl; Each R b is independently selected from CN, halogen, OH, NH2, COOH, NO2, oxo, S(O)2CH3, C(O)NHCH2CH3, or an unsubstituted or optionally substituted by one, two or more R c substituted group as follows: C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl; Each R c is independently selected from CN, halogen, OH, NH2, oxo, S(O)2CH3, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halo C 1-6 alkoxy; R a1 selected from H, hydroxy, halogen, or an unsubstituted or optionally substituted by one, two or more R d substituted with the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl; R a2 selected from H, or an unsubstituted or optionally substituted by one, two or more R d substituted with the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 10-membered heterocyclic group, C 6-14 aryl or 5- to 14-membered heteroaryl; Each R d is the same or different and each independently selected from CN, halogen, OH, NH2, oxo, S(O)2CH3, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halo C 1-6 alkoxy.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 and R2 are each independently selected from H, or an unsubstituted or optionally substituted by one, two or more R a substituted with the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, phenyl, phenyl-C 1-6 alkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl-C 1-6 alkyl; X is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene or C 1-6 alkoxy; Y is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene or C 1-6 alkoxy; Z is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene; Each R a is independently selected from CN, halogen, OH, NH2, oxo, NHC(O)R a1 , C(O)OR a2 , or an unsubstituted or optionally substituted by one, two or more R c substituted group as follows: C 1-6 alkyl or C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocyclic group or phenyl; Each R b is independently selected from CN, halogen, OH, NH2, COOH, NO2, oxo, S(O)2CH3, C(O)NHCH2CH3, or an unsubstituted or optionally substituted by one, two or more R c substituted group as follows: C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl; Each R c is independently selected from CN, halogen, OH, NH2, oxo, S(O)2CH3, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halo C 1-6 alkoxy; R a1 selected from H, hydroxy, halogen, or an unsubstituted or optionally substituted by one, two or more R d substituted with the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 3-7-membered heterocyclic group, phenyl or 5-6-membered heteroaryl; R a2 selected from H, or an unsubstituted or optionally substituted by one, two or more R d substituted with the following groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 7-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl; Each R d is the same or different and each independently selected from CN, halogen, OH, NH2, oxo, S(O)2CH3, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halo C 1-6 alkoxy.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 and R2 are each independently selected from H, or an unsubstituted or optionally substituted by one, two or more R a substituted with the following groups: C 1-6 alkyl, C 3-7 cycloalkyl, phenyl; X is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene or C 1-6 alkoxy; Y is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene or C 1-6 alkoxy; Z is selected from unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-6 alkylene; Each R a is independently selected from CN, halogen, OH, NH2, oxo, or an unsubstituted or optionally substituted by one, two or more R c substituted with the following groups: C 1-6 alkyl or C 1-6 alkoxy; Each R b is independently selected from CN, halogen, OH, oxo, or an unsubstituted or optionally substituted by one, two or more R c substituted following groups: C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl; Each R c is independently selected from CN, halogen, OH, NH2, oxo, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy or halo C 1-6 alkoxy.

5. The compound or a pharmaceutically acceptable salt thereof is selected from the following structures:

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is an acid addition salt or a base addition salt, and the acid addition salt or the base addition salt is an acid addition salt formed with the following inorganic acids or organic acids: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, tartaric acid, fumaric acid, citric acid, malic acid, oxalic acid, ascorbic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or a salt formed with sodium ion, potassium ion, calcium ion, ammonium ion.

7. A process for preparing the compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, characterized in that, Comprising the following steps 1)-3): Wherein, X, Y, Z, R1 and R2 independently have the definitions described in any one of claims 1-6; Step 1): Compound 1 reacts with Compound 2 under the action of a base to obtain Compound 3; Step 2): Compound 3 is deprotected to obtain Compound 4; Step 3): Compound 4 is cyclized under the action of a base to obtain the compound of formula (I); And / or, the base in step 1) is selected from at least one of triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, or the basic condition is provided by an excessive amount of Compound 1; And / or, the reaction in step 1) is carried out in the presence or absence of a solvent; when a solvent is present, the solvent is an organic solvent, and the organic solvent is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, acetone, dichloromethane; And / or, in step 1), the molar ratio of Compound 1 to Compound 2 is 1:(0.5~20); And / or, in step 1), the molar ratio of Compound 1 to the base is 1:(0.5~20); And / or, in step 1), the weight-volume ratio of Compound 1 to the organic solvent is 1:(0~100) g / mL; And / or, in step 1), the reaction is carried out at 10°C~150°C; And / or, in step 1), the reaction time is 1~24 h; And / or, in step 2), deprotection is carried out under the action of an acid, and the acid is selected from at least one of hydrochloric acid, trifluoroacetic acid, formic acid, acetic acid, propionic acid, sulfuric acid; And / or, the reaction in step 2) is carried out in the presence or absence of a solvent; when a solvent is present, the solvent is an organic solvent or a mixed solvent composed of water and an organic solvent, and the organic solvent is selected from at least one of ethyl acetate, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, acetone, dichloromethane, and the volume ratio of water to the organic solvent is 0:100~100:0; And / or, in step 2), the molar ratio of compound 3 to the acid is 1:(0.8 - 100); And / or, in step 2), the weight - volume ratio of compound 3 to the solvent is 1:(0 - 100) g / mL; And / or, in step 2), the reaction is carried out at - 20°C to 150°C; And / or, in step 2), the reaction time is 1 - 24 h; And / or, the base in step 3) is selected from at least one of triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium tert - butoxide, sodium tert - butoxide, potassium hydroxide, and sodium hydroxide; And / or, the reaction in step 3) is carried out in the presence or absence of a solvent; when a solvent is present, the solvent is an organic solvent, and the organic solvent is selected from at least one of methanol, ethanol, isopropanol, tert - butanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, acetone, and dichloromethane; And / or, in step 3), the molar ratio of compound 4 to the base is 1:(0.5 - 20); And / or, in step 3), the weight - volume ratio of compound 4 to the organic solvent is 1:(0 - 100) g / mL; And / or, in step 3), the reaction is carried out at 0°C to 150°C; And / or, in step 3), the reaction time is 1 - 24 h.

8. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 - 6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

9. The pharmaceutical composition according to claim 8, wherein The excipients are selected from one or more of the following: disintegrants, glidants, lubricants, diluents, fillers, binders, or colorants.

10. Use of the compound according to any one of claims 1 - 6 or a pharmaceutically acceptable salt thereof for the preparation of a kinase JNK1 inhibitor, wherein the kinase JNK1 inhibitor is used for the prevention and / or treatment of fibrotic diseases.

11. The use according to claim 10, wherein The fibrotic diseases are selected from liver fibrotic diseases and lung fibrotic diseases.

12. The use according to claim 10, wherein The fibrotic diseases are selected from non - alcoholic steatohepatitis, cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, liver fibrosis accompanied by long - term or repeated alcohol intake, accompanied by infection, accompanied by liver transplantation, or accompanied by drug - induced liver injury, and idiopathic pulmonary fibrosis.

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