A compound with selective inhibitory effect on JAK2, its use and medicine

Abstract

The present invention provides a compound having a selective inhibitory effect on JAK2, its use and medicine, and belongs to the field of medical technology. The compound of the present invention is a compound shown in formula I, a salt thereof, a stereoisomer thereof or a crystalline form thereof. The compound of the present invention has a high selective inhibitory effect on JAK2, and has good in vivo pharmacokinetic properties and good drugability. Therefore, the compound of the present invention can be used to prepare a JAK2 inhibitor for preventing and / or treating diseases related to JAK2, and has a good application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a compound having a selective inhibitory effect on JAK2, a use thereof and a medicine thereof. Background Art

[0002] Janus kinase 2 (JAK2) is an intracellular non-receptor tyrosine kinase that belongs to the JAK kinase family (JAK1, JAK2, JAK3 and TYK2). The JAK family is regulated by a variety of cytokines, including interleukins, interferons, erythropoietin, thrombopoietin and growth hormone. The four subtypes of the JAK family are highly homologous and contain seven homologous domains (JH1-7). Among them, JH1 is located in the carbon-terminal region and belongs to the typical tyrosine kinase domain. JH2 is also called the pseudokinase domain, which has an ATP binding site but almost no catalytic activity. However, the JH2 domain has a regulatory function on the kinase activity of JH1. Mutations in JH2 can cause overactivation of JAK proteins, leading to a variety of diseases and cancers, such as JAK2 V617F Mutation. The N-terminus of JAK2 contains a domain composed of four-point-one, ezrin, radixin, and moesin, called FERM (JH5-JH7) and Src homology 2 domain (SH2; JH4). The FERM domain is required for association with the erythropoietin receptor (EPOR) and affects the activity of the kinase domain. The function of the SH2 domain is still unknown, but it is generally believed that it structurally regulates the binding of JAK2 to cytokine receptors.

[0003] Among the four JAK isoforms, JAK2 is involved in hematopoiesis and mediates signal transduction of the immune system, and is essential for the growth and progression of hematological malignancies, especially for myeloproliferative neoplasms. In addition, activated JAK2 fusion proteins have also been reported in chronic myeloid leukemia, acute myeloid leukemia (AML), and acute lymphoblastic leukemia. In myeloproliferative neoplasms, after cytokine binding to the receptor, JAK2 is recruited by the cytokine receptor and leads to phosphorylation of two tyrosine residues in the JH1 domain, and the protein tyrosine kinase is activated. Subsequently, JH1 catalyzes the phosphorylation of tyrosine residues in the SH2 domain of STATs. Then, the JH1 domain catalyzes the phosphorylation of the STAT molecule itself. Phosphorylated STATs form dimers, which leads to phosphorylation of downstream signaling pathways such as phosphoinositide 3-kinase (PI3K), RAS, and STAT3 / 5, and subsequently mediates other related pathways. At the same time, STAT heterodimers and homodimers translocate to the cell nucleus and bind to homologous DNA sequences in the promoter regions of genes that control cell proliferation and apoptosis, inducing cell proliferation. V617FIn the case of mutations, the JAK / STAT pathway can be constitutively activated, leading to the occurrence of MPNs. V617F Mutation is also an important reason for the poor prognosis of patients, so JAK2 is an important target for the treatment of myeloproliferative neoplasms.

[0004] Since the discovery of JAK2 in 2005 V617F Since mutations can continuously activate the JAK-STAT pathway and lead to MPNs, JAK2 inhibitors have made great progress. A large number of drugs for myeloproliferative neoplasms (MPNs) are in the clinical research stage, such as Lestaurtinib (CEP701), Pacritinib, Momelotinib (CYT-387), Gandotinib (LY2784544), BMS-911543, Ilginatinib, Ruxolitinib, Fedratinib and Zotiraciclib. Among them, Ruxolitinib and Fedratinib were approved by the FDA in 2011 and 2019, respectively. Their main targets are JAK1 / 2 and JAK2 / FLT3. The side effects of the former are mainly platelet abnormalities, while the latter has the risk of Wernicke's encephalopathy (WE). Therefore, both drugs have been warned by the FDA black box. Except for BMS-911543 and Ilginatinib, the rest of the clinical or research drugs have different degrees of inhibitory activity against other subtypes of the JAK family. JAK3 is only expressed in hematopoietic cells, bone marrow and lymphocytes. The activity against JAK1 / 3 in MPNs may lead to a series of side effects such as bone marrow suppression and immune function suppression. In addition, according to clinical needs, MPNs patients need long-term medication, so safety and selectivity are the focus of attention when developing new JAK2 inhibitors. Summary of the invention

[0005] The object of the present invention is to provide a compound having a selective inhibitory effect on JAK2, its use and medicine.

[0006] The present invention provides a compound represented by formula I, a salt thereof, a stereoisomer thereof or a crystal form thereof:

[0007]

[0008] Formula I

[0009] in,

[0010] linker is selected from ;

[0011] n is an integer selected from 1 to 6;

[0012] m is an integer selected from 0 to 3;

[0013] Each R3 and R4 are independently selected from hydrogen, C1~C6 alkyl; or R3 and R4 on the same carbon atom are connected to form a C3~C 10 Cycloalkyl;

[0014] R2 is selected from hydrogen, C1~C6 alkyl;

[0015] X is selected from CH or N;

[0016] When X is selected from CH, R1 is selected from -NR5R6; R5 is selected from hydrogen, C1~C6 alkyl; R6 is selected from hydrogen, substituted or unsubstituted groups: C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8, C3~C 10 Cycloalkyl, C6~C 12 Aryl, 3- to 10-membered heterocyclic group, 5- to 12-membered heteroaryl group;

[0017] When X is selected from N, R1 is selected from hydrogen, substituted or unsubstituted groups: C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8, C3~C 10 Cycloalkyl, C6~C 12 Aryl, 3- to 10-membered heterocyclic group, 5- to 12-membered heteroaryl group;

[0018] R7 and R8 are independently selected from hydrogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C3~C 10 Cycloalkyl, 3-10 membered heterocyclic group;

[0019] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8 are selected from the group consisting of C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, halogen, hydroxyl, carboxyl, cyano, C3~C 10 Cycloalkyl, 3-10 membered heterocyclic group, -C(O)R 10 ;

[0020] The substituents of the cycloalkyl, aryl, heterocyclic and heteroaryl groups are selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, carboxyl and cyano;

[0021] R 10 Selected from hydrogen, C1~C6 alkyl.

[0022] Furthermore, the compound is as shown in Formula II:

[0023]

[0024] Formula II

[0025] in,

[0026] linker is selected from , , , , , ;

[0027] X is selected from CH or N;

[0028] When X is selected from CH, R1 is selected from -NR5R6; R5 is selected from hydrogen, C1~C6 alkyl; R6 is selected from hydrogen, substituted or unsubstituted groups: C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8, C3~C 10 Cycloalkyl, C6~C 12 Aryl, 3- to 10-membered heterocyclic group, 5- to 12-membered heteroaryl group;

[0029] When X is selected from N, R1 is selected from hydrogen, substituted or unsubstituted groups: C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8, C3~C 10 Cycloalkyl, C6~C 12 Aryl, 3- to 10-membered heterocyclic group, 5- to 12-membered heteroaryl group;

[0030] R7 and R8 are independently selected from hydrogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C3~C 10 Cycloalkyl, 3-10 membered heterocyclic group;

[0031] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8 are selected from the group consisting of C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, halogen, hydroxyl, carboxyl, cyano, C3~C 10 Cycloalkyl, 3-10 membered heterocyclic group, -C(O)R 10 ;

[0032] The substituents of the cycloalkyl, aryl, heterocyclic and heteroaryl groups are selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, carboxyl and cyano;

[0033] R 10 Selected from hydrogen, C1~C6 alkyl.

[0034] Further,

[0035] linker is selected from , , , , , ;

[0036] X is selected from CH or N;

[0037] When X is selected from CH, R1 is selected from -NR5R6; R5 is selected from hydrogen, C1~C6 alkyl; R6 is selected from hydrogen, substituted or unsubstituted groups: C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8, C3~C6 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl;

[0038] When X is selected from N, R1 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8, C3~C6 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl;

[0039] R7 and R8 are independently selected from hydrogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C3~C6 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl;

[0040] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8 are selected from the group consisting of C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, halogen, hydroxyl, carboxyl, cyano, C3~C6 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl, -C(O)R 10 ;

[0041] The substituents of the cycloalkyl, morpholinyl, pyrrolidinyl and piperidinyl are selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, carboxyl and cyano;

[0042] R 10 Selected from hydrogen, C1~C6 alkyl.

[0043] Furthermore, the compound is as shown in Formula III-A:

[0044]

[0045] Formula III-A

[0046] in,

[0047] linker is selected from , , , , , ;

[0048] R5 is selected from hydrogen, C1~C6 alkyl;

[0049] R6 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8, C3~C5 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl;

[0050] R7 and R8 are independently selected from hydrogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C3~C5 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl;

[0051] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8 are selected from the group consisting of C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, halogen, hydroxyl, carboxyl, cyano, C3~C5 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl, -C(O)R 10 ;

[0052] The substituents of the cycloalkyl, morpholinyl, pyrrolidinyl and piperidinyl are selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, carboxyl and cyano;

[0053] R 10 Selected from hydrogen, C1~C6 alkyl.

[0054] Furthermore, the compound is as shown in Formula III-B:

[0055]

[0056] Formula III-B

[0057] in,

[0058] linker is selected from , , , , , ;

[0059] R1 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8, C3~C5 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl;

[0060] R7 and R8 are independently selected from hydrogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C3~C5 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl;

[0061] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8 are selected from the group consisting of C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, halogen, hydroxyl, carboxyl, cyano, C3~C5 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl, -C(O)R 10 ;

[0062] The substituents of the cycloalkyl, morpholinyl, pyrrolidinyl and piperidinyl are selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, carboxyl and cyano;

[0063] R 10 Selected from hydrogen, C1~C6 alkyl.

[0064] Furthermore, the compound is as shown in Formula IV:

[0065]

[0066] Formula IV

[0067] in,

[0068] linker is selected from , , , , , ;

[0069] R6 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8, C3~C5 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl;

[0070] R7 and R8 are independently selected from hydrogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C3~C5 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl;

[0071] The substituents of the alkyl, alkenyl, alkynyl, alkoxy, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)(O)R7, -S(O)R7, -S(O)(O)NR7R8 are selected from the group consisting of C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, halogen, hydroxyl, carboxyl, cyano, C3~C5 cycloalkyl, morpholinyl, pyrrolidinyl, piperidinyl, -C(O)R 10 ;

[0072] The substituents of the cycloalkyl, morpholinyl, pyrrolidinyl and piperidinyl are selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, carboxyl and cyano;

[0073] R 10 Selected from hydrogen, C1~C6 alkyl.

[0074] Furthermore, the compound is selected from one of the following compounds:

[0075]

[0076]

[0077] .

[0078] The present invention also provides the use of the aforementioned compound, its salt, its stereoisomer or its crystal form in the preparation of a JAK2 inhibitor or a drug for preventing and / or treating a disease associated with JAK2.

[0079] Furthermore, the JAK2-related diseases are immune diseases, inflammatory-related diseases, solid tumors, and hematological tumors;

[0080] The solid tumor is selected from lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma, ovarian cancer, breast cancer, prostate cancer, bladder cancer, kidney cancer, esophageal cancer, cervical cancer, pancreatic cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, thyroid cancer, brain cancer, lymphoma, epidermal transition hyperplasia, psoriasis, prostate cancer, or a combination thereof;

[0081] The blood tumor is selected from acute myeloid leukemia, chronic myeloid leukemia, myeloma, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated cell leukemia, myelodysplastic syndrome, myelodysplasia, myelofibrosis, multiple myeloma, spinal cord sarcoma, or a combination thereof;

[0082] The inflammatory-related disease is selected from inflammatory bowel disease, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome, postoperative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngitis, gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis;

[0083] The immune disease is selected from psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylarthritis, polymyositis, dermatomyositis, periarteritis nodosa, mixed connective tissue disease, scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, Addison's disease, abnormal immune response, arthritis, dermatitis, and radiation dermatitis.

[0084] The present invention also provides a medicine, which is a preparation prepared by using the aforementioned compound, its salt, its stereoisomer or its crystal form as an active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients.

[0085] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0086] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0087] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0088] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a ~C b Alkyl refers to any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, C6 alkyl; "C1-C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, C6 alkoxy.

[0089] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of carbon atoms. For example, C1~C6 alkyl refers to an alkyl group with 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl, etc.

[0090] "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group can be straight-chain or branched.

[0091] "Alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. Alkynyl groups can be straight or branched.

[0092] "Halogen" is fluorine, chlorine, bromine or iodine.

[0093] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic ring (including fused rings, spiro rings or bridged rings) without a conjugated π electron system, such as but not limited to: , , , , , , , , , , , wait.

[0094] "Heterocycloalkyl" refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom, wherein the heteroatom is O, N or S, and is a saturated or unsaturated monocyclic or polycyclic ring (including fused rings, spiro rings or bridged rings) without a conjugated π electron system, such as but not limited to: , , , , , , , , , , , , , , , , wait.

[0095] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused ring, spirocyclic or bridged ring) with a conjugated π electron system, such as but not limited to: phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N or S. At the same time, the point of connection to the parent must be on a carbon atom on the ring with a conjugated π electron system, such as but not limited to , , , wait.

[0096] "Heteroaryl" refers to an aromatic group in which at least one carbon atom on the ring of the conjugated π-electron system is replaced by a heteroatom, wherein the heteroatom is O, N or S, such as but not limited to thienyl, furyl, isothiazolyl and the like.

[0097] The "salt" described in the present invention is a pharmaceutically acceptable salt, including acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, teasulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, p-toluenesulfonate, quaternary ammonium salt or succinate, etc.

[0098] The present invention has achieved the following beneficial effects:

[0099] The present invention provides a compound with a highly selective inhibitory effect on JAK2, and the compound also has good in vivo pharmacokinetic properties and good drugability. Therefore, the compound of the present invention can be used to prepare JAK2 inhibitors for preventing and / or treating diseases related to JAK2, and has good application prospects.

[0100] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0101] The above contents of the present invention are further described in detail below through specific implementation methods in the form of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0102] Figure 1 The graph shows the inhibitory activity of the compounds of the present invention on different kinases.

[0103] Figure 2 The figure shows the selectivity of the preferred compound 15au among 206 kinases.

[0104] Figure 3The results of compound 15au in vivo treatment of myelofibrosis are shown in Figure 1: A is a graph showing the ratio of 15au inhibiting spleen enlargement; B is a graph showing the weight change curve of mice during the drug administration process; C is a graph showing the change in spleen index of mice after treatment with 15au; and D is a graph showing the spleen of mice after being sacrificed. DETAILED DESCRIPTION

[0105] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0106] The present invention uses 4-pyrazole-2-aminopyrimidine as a parent core, and performs structural modification and synthesis on the linker part, pyrazole part, pyrimidine part and solvent region in the molecular structure. First, the hydrophilic end of the benzene ring is constructed, and 2-fluoro-5-nitrophenol (1) and a secondary amine derivative undergo a nucleophilic reaction to obtain phenol intermediates 2a-b. The phenol intermediates react with different halides under alkaline conditions to obtain nitro intermediates 3a-f. 2-Fluoro-5-nitrobenzaldehyde and a secondary amine derivative undergo a nucleophilic reaction to obtain aldehyde intermediates 5a-b. The aldehyde intermediates are reduced with sodium borohydride to obtain benzyl alcohol derivatives 6a-b. The benzyl alcohol derivatives react with different halides under alkaline conditions to obtain nitro intermediates 7a-b. Pyrazole borate (8) and 2,4-dichloro-5-methylpyrimidine undergo a Suzuki reaction to obtain intermediate 9. Intermediate 9 is deprotected by THP in dioxane hydrochloride to obtain the corresponding intermediate 10. Intermediate 10 reacts with the previously constructed benzene ring intermediate (3a-f, 7a-b) under alkaline conditions to produce intermediate 11a-h. Intermediate 11a-h is reduced by iron powder and ammonium chloride to produce amine compounds 12a-h. Amine compounds 12a-h undergo intramolecular cyclization through Buchwarld coupling to produce macrocyclic compounds 13a-h. Macrocyclic compounds 13a-h are deprotected from Boc under acidic conditions and then undergo nucleophilic reaction to obtain the target compounds.

[0107] Scheme 1: Construction of intermediates 3a-f

[0108]

[0109]

[0110]

[0111] Reaction reagents and conditions: (a) potassium carbonate, secondary amine, acetonitrile, 80°C, 4h; (b) sodium hydroxide, halide, N,N-dimethylformamide, 60°C, 2h.

[0112] Scheme 2: Construction of intermediates 7a-b

[0113]

[0114]

[0115] Reaction reagents and conditions: (a) potassium carbonate, secondary amine, acetonitrile, 80°C, 4h; (b) sodium borohydride, tetrahydrofuran, 0°C, 2h; (c) sodium hydroxide, halide, N,N-dimethylformamide, 60°C, 2h.

[0116] Scheme 3: Synthesis of the final product

[0117]

[0118] Reaction reagents and conditions: (a) 2,4-dichloropyrimidine derivative, potassium carbonate, DPPF palladium dichloride, dioxane / water, 90℃, 4h; (b) hydrochloric acid / dioxane, dichloromethane, room temperature, 2h; (c) sodium hydroxide, N,N-dimethylformamide, 60℃, 2h; (d) reduced iron powder, ammonium chloride, methanol / water (4:1, volume ratio), 90℃, 4h; (e) Pd2Dba3, Cs2CO3, 4,5-bis(diphenylphosphino-9,9-dimethylxanthene), dioxane, 100℃, N2, 10h; (f) hydrochloric acid / dioxane, dichloromethane, room temperature, 2h; (g) potassium carbonate, acetonitrile, halide, 80℃, 4h; (h) aldehyde derivative, methanol, sodium cyanoborohydride, acetic acid, room temperature, 2h; (i) Dichloromethane, triethylamine, acid chloride, room temperature, 2h.

[0119] Example 1. Synthesis of the compounds of the present invention

[0120] Tert-butyl (1-(2-hydroxy-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (2a)

[0121] Compound 1 (3.0 g, 19.1 mmol, 1.0 equivalent), tert-butyl methyl (piperidin-4-yl) carbamate (5.3 g, 24.8 mmol, 1.3 equivalent), and potassium carbonate (6.6 g, 47.8 mmol, 2.5 equivalent) were dissolved in acetonitrile (100 mL) and heated at 80°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by FlashMaster Personal+ column (DCM: MeOH = 90:10) to obtain 6.2 g of the target product with a yield of 92%. 1 H NMR (400 MHz, DMSO- d6) δ 10.29 (s, 1H), 7.67 (dd, J = 8.9, 2.7 Hz,1H), 7.62 (d, J = 2.7 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 3.86 – 3.76 (m, 2H), 2.79 – 2.67 (m, 5H), 1.80 (qd, J = 12.2, 3.9 Hz, 2H), 1.62 (d, J = 12.0 Hz, 2H),1.41 (s, 9H).

[0122] Tert-butyl 4-(2-hydroxy-4-nitrophenyl)piperazine-1-carboxylate (2b)

[0123] The synthesis of intermediate 2b was the same as 2a, except that tert-butylpiperazinecarboxylate was used instead of tert-butylmethyl(piperidin-4-yl)carbamate in 90% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 10.40 (s, 1H),7.68 (dd, J = 8.8, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H),3.47 (t, J = 4.9 Hz, 4H), 3.16 (dd, J = 6.2, 3.8 Hz, 4H), 1.43 (s, 10H).

[0124] Tert-butyl (1-(2-(3-chloropropyloxy)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (3a)

[0125] 2a (6.2 g, 17.6 mmol, 1.0 eq.) and sodium hydroxide (1.1 g, 26.5 mmol, 1.5 eq.) were dissolved in N,N-dimethylformamide (80 mL), and then 1,3-dichloropropane (5.5 g, 44.0 mmol, 2.5 eq.) was added, and the mixture was heated at 60°C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate, and the extract was further extracted with ethyl acetate (50 mL×3). The organic layers were combined and concentrated under reduced pressure, and the residue was purified by FlashMaster Personal+ column (PE:EA =4:1) to obtain 6.2 g of the target product with a yield of 83%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.83 (dd, J = 8.9, 2.6 Hz, 1H), 7.70 (d, J =2.6 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 4.22 (td, J = 6.0, 3.7 Hz, 2H), 4.07 –3.69 (m, 5H), 2.84 – 2.75 (m, 2H), 2.71 (s, 3H), 2.29 (dp, J = 29.8, 6.2 Hz,2H), 1.81 (dt, J = 21.8, 11.2 Hz, 2H), 1.65 (d, J = 12.1 Hz, 2H), 1.42 (s, 9H).

[0126] tert-Butyl(1-(2-((1-(chloromethyl)cyclopropyl)methoxy)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate) (3b)

[0127] The synthesis method of intermediate 3b was the same as that of 3a, except that 1,1-bis(chloromethyl)cyclopropane was used instead of 1,3-dichloropropane, with a yield of 75%. 1 H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 8.8, 2.5 Hz, 1H),7.69 (d, J = 2.5 Hz, 1H), 6.89 (d, J= 8.8 Hz, 1H), 4.06 (s, 2H), 3.78 (dp, J =12.5, 2.2 Hz, 2H), 3.58 (s, 2H), 2.80 (d, J = 11.4 Hz, 5H), 2.43 (s, 1H), 1.94– 1.82 (m, 2H), 1.80 – 1.73 (m, 2H), 1.48 (s, 10H), 0.98 – 0.94 (m, 2H),0.86– 0.82 (m, 2H).

[0128] tert-Butyl(1-(2-(3-chloro-2-methylpropoxy)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate) (3c)

[0129] The synthesis method of intermediate 3c is the same as 3a, except that 1,3-dichloro-2-methylpropane is used instead of 1,3-dichloropropane. The yield is 70%. 1 H NMR (400 MHz, CDCl3) δ 7.86 (dt, J = 8.9, 2.2 Hz, 1H), 7.72(t, J = 2.6 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 4.07 (d, J = 6.0 Hz, 2H), 3.86 –3.64 (m, 4H), 2.79 (s, 5H), 2.46 (dq, J = 12.1, 5.8 Hz, 1H), 2.01 – 1.81 (m,3H),1.81 – 1.72 (m, 2H), 1.48 (s, 10H), 1.21 (d, J = 6.9 Hz, 3H).

[0130] tert-Butyl(1-(2-(4-chlorobutoxy)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate) (3d)

[0131] The synthesis method of intermediate 3d is the same as 3a, except that 1,4-dichlorobutane is used instead of 1,3-dichloropropane. Yield 83%. 1 H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 8.8, 2.5 Hz, 1H), 7.70 (d, J=2.5 Hz, 1H), 6.96 (d, J = 20.3 Hz, 1H), 4.20 (s, 1H), 4.13 (t, J = 5.6 Hz, 2H),3.75 (dq, J = 11.9, 2.2 Hz, 2H), 3.66 (t, J = 5.9 Hz, 2H), 2.86 (s, 2H), 2.79 (s,3H), 2.10 – 2.00(m, 4H), 1.96 (dd, J = 13.2, 10.0 Hz, 2H), 1.82 – 1.74 (m, 2H), 1.48 (s, 9H).

[0132] (1-(2-((5-chloropentyl)oxy)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate) (3e)

[0133] The synthesis of intermediate 3e was the same as 3a, except that 1,5-dichloropentane was used instead of 1,3-dichloropropane. Yield 85%. 1 H NMR (400 MHz, CDCl3) δ 7.89 – 7.80 (m, 1H), 7.69 (d, J = 2.5 Hz,1H), 6.92 (d, J = 7.6 Hz, 1H), 4.40 – 3.96 (m, 3H), 3.77 (d, J = 12.1 Hz, 2H),3.60 (t, J = 6.4 Hz, 2H), 2.81 (d, J = 19.8 Hz, 5H), 2.01 – 1.84 (m, 6H), 1.81 –1.67 (m, 4H), 1.48 (s, 9H).

[0134] Tert-butyl 4-(2-(4-chlorobutoxy)-4-nitrophenyl)piperazine-1-carboxylate (3f)

[0135] The synthesis method of intermediate 3f is the same as that of 3a, except that intermediate 2b is used instead of 2a, and 1,4-dichlorobutane is used instead of 1,3-dichloropropane. Yield 80%. 1 H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 8.8, 2.5 Hz,1H), 7.70 (d,J = 2.5 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.13 (t, J = 5.7 Hz, 2H),3.65 (t, J = 5.9 Hz, 1H), 3.61 (t, J = 5.1 Hz, 4H), 3.51 (t, J = 6.1 Hz, 1H), 3.18(t, J = 5.0 Hz, 4H), 2.16 – 1.97 (m, 4H), 1.49 (s, 9H).

[0136] Tert-butyl (1-(2-formyl-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (5a)

[0137] Intermediate 4 (8.0 g, 47.3 mmol, 1.0 equiv) was dissolved in acetonitrile (100 mL), potassium carbonate (16.3 g, 11.8 mmol, 2.5 equiv) was added, and then tert-butyl methyl (piperidin-4-yl) carbamate (13.1 g, 61.5 mmol, 1.3 equiv) was added. The mixture was heated at 80 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with ethyl acetate. The mixture was extracted with ethyl acetate 3 times (150 mL×3). The organic layers were combined and concentrated under reduced pressure, and the residue was purified by FlashMaster Personal+ chromatography (PE:EA = 5:1) to obtain the target product 15.5 g with a yield of 90%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.01 (s, 1H), 8.48 (d, J = 2.9 Hz, 1H), 8.28 (dd, J = 9.2, 2.9 Hz, 1H), 7.30 (d, J = 9.3 Hz, 1H), 4.03(p, J = 7.1 Hz, 1H), 3.63 (dq, J = 13.0, 2.3 Hz, 2H), 3.21 (td, J = 12.7, 2.3 Hz,2H), 2.72 (s, 3H), 1.92 (qd, J= 12.3, 3.9 Hz, 2H), 1.67 (d, J = 12.2 Hz, 2H),1.42 (s, 9H).

[0138] Tert-butyl 4-(2-formyl-4-nitrophenyl)piperazine-1-carboxylate (5b)

[0139] The synthesis of 5b was similar to that of 5a except that the intermediate N-Boc piperazine was used instead of tert-butyl methyl (piperidin-4-yl) carbamate. 1 H NMR (400 MHz, DMSO- d 6) δ 10.19 (d, J = 0.6 Hz, 1H), 8.45(d, J = 1.4 Hz, 1H), 8.11 (dd, J = 7.5, 1.7 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 3.63(t, J = 7.2 Hz, 4H), 3.19 (dt, J = 12.2, 6.9 Hz, 2H), 3.06 (dt, J = 12.5, 7.1 Hz, 2H), 1.45 (s, 9H).

[0140] Tert-butyl (1-(2-(hydroxymethyl)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (6a)

[0141] 5a (15 g, 41.3 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (100 mL), and sodium borohydride (1.7 g, 45.4 mmol, 1.1 equivalent) was slowly added at 0°C for 2 h. After the reaction was completed, the mixture was cooled to room temperature and water (200 mL) was slowly added. The mixture was extracted with ethyl acetate. The mixture was extracted with ethyl acetate 3 times (150 mL×3). The organic layers were combined and concentrated under reduced pressure, and the residue was not further purified to obtain 14.4 g of the target product with a yield of 96%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.32 (d, J = 2.8 Hz, 1H), 8.07 (dd, J = 8.9, 2.9 Hz, 1H),7.16 (d, J= 8.9 Hz, 1H), 5.53 (s, 1H), 4.59 – 4.48 (m, 2H), 3.96 (s, 1H), 3.32 – 3.22 (m, 2H), 2.89 – 2.78 (m, 2H), 2.74 (s, 3H), 1.85 (qd, J = 12.1, 3.7 Hz,2H), 1.65 (d, J = 12.0 Hz, 2H), 1.42 (s, 9H).

[0142] Tert-butyl 4-(2-(hydroxymethyl)-4-nitrophenyl)piperazine-1-carboxylate (6b)

[0143] The synthesis of 6b was similar to that of 6a, except that intermediate 5b was used instead of 5a. 1 H NMR (400 MHz, DMSO- d 6) δ 8.06 (dd, J = 7.5, 1.7 Hz, 1H), 7.96 (q, J = 1.0 Hz, 1H), 6.93 (d, J =7.5 Hz, 1H), 4.99 (t, J = 6.7 Hz, 1H), 4.64 (dd, J = 6.7, 1.1 Hz, 2H), 3.63 (t, J =7.1 Hz, 4H), 3.07 (qt, J = 12.5, 7.0 Hz, 4H), 1.45 (s, 9H).

[0144] tert-Butyl (1-(2-((3-chloropropoxy)methyl)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate) (7a)

[0145] The synthesis method of intermediate 7a is the same as that of 3a, except that intermediate 6a is used instead of 2a. Yield: 82%. 1 HNMR (400 MHz, CDCl3) δ 8.32 (d, J = 2.8 Hz, 1H), 8.11 (dd, J = 8.9, 2.8 Hz, 1H),7.06 (d, J = 8.9 Hz, 1H), 4.55 (s, 2H), 4.33 – 3.95 (m, 1H), 3.70 (dt,J = 7.6,6.1 Hz, 4H), 3.34 (dp, J = 12.2, 2.3 Hz, 2H), 2.94 – 2.84 (m, 2H), 2.82 (s,3H), 2.10 (p, J = 6.0 Hz, 2H), 1.91 (qd, J = 12.1, 3.9 Hz, 2H), 1.83 – 1.75 (m,2H), 1.49 (s, 9H).

[0146] Tert-butyl 4-(2-((3-chloropropoxy)methyl)-4-nitrophenyl)piperazine-1-carboxylate (7b)

[0147] The synthesis method of intermediate 7b is the same as 3a, except that intermediate 6b is used instead of 2a. The intermediate is directly used for the next step after LCMS confirmation. m / z = 414.2

[0148] 2-Chloro-5-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine (9)

[0149] 1-(tetrahydro-2 H -pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -pyrazole (10.0 g, 35.9 mmol, 1.3 equiv.), 2,4-dichloro-5-methylpyrimidine (4.5 g, 27.6 mmol, 1.0 equiv.) and potassium carbonate (9.5 g, 69.0 mmol, 2.5 equiv.) were dissolved in a solution of dioxane / water (140 mL, volume ratio of 7: 3), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.0 g, 2.8 mmol, 0.1 equiv.) was added. Under argon atmosphere, the reactants were heated to 90 ° C in a closed three-necked flask. After reacting for 4 hours, they were cooled to room temperature and concentrated under reduced pressure. The residue was purified by FlashMaster Personal+ chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 5.2 g of the target product with a yield of 67%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.77 (d, J = 0.8 Hz, 1H),7.71 (s, 1H), 6.83 (s, 1H), 5.79 – 5.73 (m, 1H), 3.70 (dtd, J= 11.4, 3.8, 1.4Hz, 1H), 3.43 – 3.37 (m, 1H), 2.29 (d, J = 0.7 Hz, 4H), 2.00 – 1.91 (m, 2H), 1.59 (dddd, J = 11.6, 9.2, 6.8, 4.1 Hz, 1H), 1.46 (dh, J = 8.0, 3.7 Hz, 2H).

[0150] 2-Chloro-5-methyl-4-(1H-pyrazol-4-yl)pyrimidine (10)

[0151] Compound 9 (5.1 g, 18.3 mmol, 1.0 equivalent) was dissolved in dichloromethane (50 mL), and then hydrochloric acid / dioxane solution (4M, 20 mL) was added at room temperature and reacted for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a residue without further purification to obtain 3.5 g of the target product with a yield of 99%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.59(s, 1H), 7.87 (s, 1H), 6.95 (s, 1H).

[0152] Tert-butyl (1-(2-(3-(4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propoxy)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (11a)

[0153] The synthesis method of intermediate 11a is the same as that of 3a, except that intermediate 10 is used to replace 2a, and 3a is used to replace 1,3-dichloropropane. The yield is 86%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.52 (dd, J = 2.7, 0.8 Hz, 2H), 8.13(d, J = 0.7 Hz, 1H), 7.81 (dd, J = 8.9, 2.6 Hz, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.02(d, J = 8.9 Hz, 1H), 4.45 (t, J = 6.9 Hz, 2H), 4.13 (t, J = 6.0 Hz, 2H), 3.76 (d,J =12.2 Hz, 2H), 2.84 – 2.75 (m, 2H), 2.71 (s, 3H), 2.41 – 2.31 (m, 5H),1.82 (q, J = 11.9 Hz, 2H), 1.66 (d, J = 11.9 Hz, 2H), 1.41 (s, 9H).

[0154] tert-Butyl (1-(2-((1-((4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)methyl)cyclopropyl)methoxy)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (11b)

[0155] The synthesis method of intermediate 11b is the same as that of 3a, except that intermediate 10 is used to replace 2a and 3b is used to replace 1,3-dichloropropane. Yield 80%. 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 0.8 Hz, 1H), 8.23 ​​(s, 1H), 8.05 (s, 1H), 7.85 (dd, J = 8.9, 2.5 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.03 (s,1H), 4.34 (s, 2H), 3.86 (d, J = 18.7 Hz, 4H), 3.01 – 2.88 (m, 2H), 2.80 (s, 3H), 2.38 (s, 3H), 2.01 (t, J = 10.8 Hz, 2H), 1.88 – 1.79 (m, 2H), 1.49 (s, 10H), 0.94 (t, J = 3.3 Hz, 2H), 0.88 – 0.82 (m, 2H).

[0156] Tert-butyl (1-(2-(3-(4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropyloxy)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (11c)

[0157] The synthesis method of intermediate 11c is the same as that of 3a, except that intermediate 10 is used to replace 2a and 3c is used to replace 1,3-dichloropropane. Yield 87%. 1H NMR (400 MHz, CDCl3) δ 8.36 (t, J = 3.3 Hz, 1H), 8.33 (d, J =2.7 Hz, 1H), 8.15 – 8.08 (m, 1H), 7.05 (dd, J = 8.9, 2.5 Hz, 1H), 6.02 – 5.91(m, 1H),5.38 – 5.22 (m, 1H), 4.59 – 4.52 (m, 2H), 3.70 (dt, J = 8.1, 6.1 Hz,3H), 3.65 – 3.57 (m, 4H), 3.02 (dd, J = 14.2, 9.2 Hz, 4H), 2.13 – 2.06 (m, 1H), 1.49 (s, 9H).

[0158] Tert-butyl(1-(2-(4-(4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)butoxy)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamic acid (11d)

[0159] The synthesis method of intermediate 11d is the same as that of 3a, except that intermediate 10 is used to replace 2a and 3d is used to replace 1,3-dichloropropane. Yield 88%. 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 0.8 Hz, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.83 (dd, J = 8.8, 2.5 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 4.32 (t, J = 6.9 Hz, 2H), 4.10 (t, J = 6.2 Hz, 2H), 3.78 – 3.69 (m, 2H), 3.00 – 2.80 (m,2H), 2.77 (s, 3H), 2.44 (d, J = 0.7 Hz, 3H), 2.20 (dq, J = 8.9, 6.9 Hz, 2H), 2.02– 1.87 (m, 4H), 1.83 – 1.74 (m, 2H), 1.48 (s, 9H).

[0160] Tert-butyl (1-(2-((5-(4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)pentyl)oxy)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (11e)

[0161] The synthesis method of intermediate 11e is the same as that of 3a, except that intermediate 10 is used to replace 2a and 3e is used to replace 1,3-dichloropropane. Yield 86%. 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.17 (s, 1H), 8.06 (s,1H), 7.83 (dd, J = 8.8, 2.5 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 6.91 (s, 1H), 4.25(t, J = 7.0 Hz, 2H), 4.07 (t, J = 6.4 Hz, 2H), 3.75 (dt, J = 12.1, 2.3 Hz, 2H), 2.78 (s, 5H), 2.45 (s, 3H), 2.06 (p, J = 7.2 Hz, 2H), 2.00 – 1.93 (m, 2H), 1.92– 1.83 (m, 2H), 1.75 (dd, J = 12.9, 4.2 Hz, 2H), 1.62 – 1.52 (m, 2H), 1.48 (s,9H).

[0162] Tert-butyl (1-(2-((3-(4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propoxy)methyl)-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (11f)

[0163] The synthesis method of intermediate 11f is the same as that of 3a, except that intermediate 10 is used to replace 2a and 7a is used to replace 1,3-dichloropropane. Yield 89%. 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 0.8 Hz, 1H), 8.31 (d, J =2.8 Hz, 1H), 8.13 (s, 1H), 8.11 – 8.07 (m, 2H), 7.09 (d, J= 8.9 Hz, 1H), 4.55(s, 2H), 4.37 (t, J = 6.7 Hz, 2H), 3.59 (t, J = 5.8 Hz, 2H), 3.32 (d, J = 12.0 Hz,2H), 2.91 (t, J = 10.7 Hz, 2H), 2.80 (s, 3H), 2.42 (d, J = 0.7 Hz, 3H), 2.29 (p, J = 6.3 Hz, 2H), 2.16 (d, J = 11.3 Hz, 1H), 1.93 (tt, J = 12.1, 6.3 Hz, 2H), 1.82 –1.74 (m, 2H), 1.48 (s, 10H).

[0164] Tert-butyl 4-(2-(4-(4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)butoxy)-4-nitrophenyl)piperazine-1-carboxylate (11 g)

[0165] The synthesis method of intermediate 11g is the same as that of 3a, except that intermediate 10 is used to replace 2a and 3f is used to replace 1,3-dichloropropane. Yield 90%. 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 0.9 Hz, 1H), 8.19 (d, J =0.7 Hz, 1H), 8.07 (d, J = 0.6 Hz, 1H), 7.83 (dd, J = 8.8, 2.5 Hz, 1H), 7.67 (d, J =2.5 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 4.31 (t, J = 6.8 Hz, 2H), 4.08 (t, J = 6.2Hz, 2H), 3.64 – 3.56 (m, 4H), 3.19 (t, J = 5.0 Hz, 4H), 2.44 (d, J= 0.7 Hz, 3H), 2.23 – 2.14 (m, 2H), 1.96 – 1.89 (m, 2H), 1.49 (s, 9H).

[0166] Tert-butyl 4-(2-((3-(4-(5-chloro-2-methylpyrimidin-4-yl)-1 H -pyrazol-1-yl)propoxy)methyl)-4-nitrophenyl)piperazine-1-carboxylate (11h)

[0167] The synthesis method of intermediate 11h is the same as that of 3a, except that intermediate 10 is used to replace 2a, and 7b is used to replace 1,3-dichloropropane. The intermediate is directly subjected to the next step after confirmation by LCMS. m / z = 572.3

[0168] Tert-butyl (1-(4-amino-2-(3-(4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propoxy)phenyl)piperidin-4-yl)(methyl)carbamate (12a)

[0169] 11a (3.0 g, 5.1 mmol, 1.0 equivalent) was dissolved in methanol / water (50 mL, volume ratio 4:1), and reduced iron powder (2.8 g, 50.0 mmol, 10.0 equivalent) and ammonium chloride (2.8 g, 50.0 mmol, 10.0 equivalent) were added. The reaction mixture was heated at 90 °C for 4 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate (50 mL*2), and the organic phases were combined and concentrated under reduced pressure to obtain a residue. Without further purification, 2.7 g of the target product was obtained with a yield of 95%. 1 H NMR (400 MHz, DMSO -d 6 ) δ 8.50 (d, J = 6.2 Hz, 2H), 8.13 (s, 1H), 6.64(d, J = 8.3 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 6.09 (dd, J = 8.3, 1.9 Hz, 1H), 4.68(s, 2H), 4.45 (t, J = 6.7 Hz, 2H), 3.86 (t, J = 5.8 Hz, 2H), 3.24 (d, J = 11.1 Hz,2H), 2.69 (s, 3H), 2.52 (dd, J= 14.4, 6.3 Hz, 3H), 2.30 (dd, J = 13.1, 6.7 Hz,2H), 1.80 (d, J = 10.3 Hz, 2H), 1.59 (s, 2H), 1.40 (s, 10H).

[0170] Tert-butyl (Z)-methyl (1-(5'-methylspiro[cyclopropane-1,7'-5-oxo-3-aza-2(4,2)-pyrimidine-1(4,1)-pyrazol-4(1,3)-benzocyclooctane]-4'-yl)piperidin-4-yl)carbamate (12b)

[0171] The synthesis method of intermediate 12b is the same as that of 12a, except that intermediate 11b is used to replace 11a. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 546.4

[0172] Tert-butyl (Z)-(1-(2,5,7-trimethyl-1 1 H-5-Oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazol-4(1,3)-benzocyclooctan-4,4'-yl)piperidin-4-yl)(methyl)carbamate (12c)

[0173] The synthesis method of intermediate 12c is the same as that of 12a, except that intermediate 11c is used to replace 11a. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 534.5

[0174] Tert-butyl (1-(4-amino-2-(4-(4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)butoxy)phenyl)piperidin-4-yl)(methyl)carbamate (12d)

[0175] The synthesis method of intermediate 12d was the same as that of 12a, except that intermediate 11d was used instead of 11a. Yield: 92%. 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 0.5 Hz, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 6.76 (s, 1H), 6.28 – 6.18 (m, 2H), 4.31 (t, J = 6.9 Hz, 2H), 3.99 (d, J= 5.2 Hz,2H), 3.38 (s, 2H), 2.76 (s, 3H), 2.60 (s, 1H), 2.44 (s, 3H), 2.22 – 2.13 (m,2H), 1.90 (d, J = 7.8 Hz, 4H), 1.71 (s, 2H), 1.60 (d, J = 16.8 Hz, 2H), 1.47 (s,9H).

[0176] tert-Butyl (Z)-methyl (1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecane-4 4 -yl)piperidin-4-yl)carbamate (12e)

[0177] The synthesis method of intermediate 12e is the same as that of 12a, except that intermediate 11e is used to replace 11a. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 548.4

[0178] tert-Butyl (Z)-methyl (1-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclopenta ... 4 -yl)piperidin-4-yl)carbamate (12f)

[0179] The synthesis method of intermediate 12f is the same as that of 12a, except that intermediate 11f is used to replace 11a. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 534.5

[0180] Tert-butyl (Z)-4-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclopenta ... 4 -yl)piperazine-1-carboxylate (12 g)

[0181] The synthesis method of intermediate 12g is the same as that of 12a, except that intermediate 11g is used to replace 11a. The intermediate is directly used for the next step after LCMS confirmation. m / z = 506.3

[0182] Tert-butyl (Z)-4-(2 5 -methyl-1 1H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclopenta ... 4 -yl)piperazine-1-carboxylate (12h)

[0183] The synthesis method of intermediate 12h is the same as that of 12a, except that intermediate 11h is used to replace 11a. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 506.3

[0184] tert-butyl (Z)-methyl (1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)piperidin-4-yl)carbamate (13a)

[0185] 12a (2.6 g, 4.7 mmol, 1.0 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (272 mg, 0.47 mmol, 0.1 eq.) and cesium carbonate (4.5 g, 11.8 mmol, 2.5 eq.) were dissolved in dioxane (100 mL), and Pd2Dba3 (214 mg, 0.23 mmol, 0.05 eq.) was added. The mixture was heated to 100 °C in a sealed three-necked flask under nitrogen atmosphere. The reaction lasted for 10 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by FlashMaster Personal+ chromatograph (PE:EA = 3:1) to obtain 1.1 g of the target product with a yield of 47%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.21 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 8.14(d, J = 2.4 Hz, 1H), 7.85 (s, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.4, 2.3Hz, 1H), 4.25 – 4.16 (m, 2H), 4.10 – 3.98 (m, 2H), 2.44 (d, J = 7.3 Hz, 4H),2.39 (t, J = 11.3 Hz, 3H), 2.32 (s, 3H), 2.30 (s, 3H), 1.72 (d,J = 12.0 Hz, 2H),1.47 (s, 9H).

[0186] Tert-butyl (Z)-methyl (1-(5'-methylspiro[cyclopropane-1,7'-5-oxo-3-aza-2(4,2)-pyrimidine-1(4,1)-pyrazol-4(1,3)-benzocyclooctane]-4'-yl)piperidin-4-yl)carbamate (13b)

[0187] The synthesis method of intermediate 13b is the same as that of 13a, except that intermediate 12b is used to replace 12a. Yield 42%. 1 H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.80 (s,1H), 7.03 (d, J = 22.9 Hz, 1H), 6.88 (s, 1H), 6.51 (dd, J = 8.4, 2.3 Hz, 1H), 4.35 (s, 2H), 4.12 (p, J = 7.2 Hz, 3H), 3.40 (d, J = 11.3 Hz, 2H), 2.81 (s, 3H), 2.62 (d, J = 59.9 Hz, 2H), 2.39 (d, J = 8.0 Hz, 3H), 2.02 – 1.81 (m, 2H), 1.73(d, J = 9.9 Hz, 2H), 1.49 (s, 9H), 1.05 (t, J = 5.4 Hz, 2H), 0.73 (s, 2H).

[0188] Tert-butyl (Z)-(1-(2 5 ,7-dimethyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctahedral-4 4 -yl)piperidin-4-yl)(methyl)carbamate (13c)

[0189] The synthesis method of intermediate 13c is the same as that of 13a, except that intermediate 12c is used to replace 12a. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 534.4

[0190] tert-butyl (Z)-methyl (1-(25 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-yl)carbamate (13d)

[0191] The synthesis method of intermediate 13d was the same as that of 13a, except that intermediate 12d was used instead of 12a. Yield 50%. 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.48 (s, 1H), 8.20 (s, 1H), 7.82 (s,1H), 7.05 (s, 1H), 6.95 (d, J = 41.9 Hz, 1H), 6.50 (dd, J = 8.5, 2.4 Hz, 1H),4.37 (t, J = 7.4 Hz, 2H), 4.33 – 4.25 (m, 2H), 4.24 – 3.86 (m, 1H), 3.49 (d, J =11.4 Hz, 2H), 2.80 (s, 3H), 2.60 (d, J = 51.6 Hz, 2H), 2.38 (s, 3H), 2.06 –1.87 (m, 6H), 1.73 (d, J = 10.0 Hz, 2H), 1.48 (s, 9H).

[0192] tert-butyl (Z)-methyl (1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecane-4 4 -yl)piperidin-4-yl)carbamate (13e)

[0193] The synthesis method of intermediate 13e was the same as that of 13a, except that intermediate 12e was used to replace 12a. Yield: 53%. 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 7.1 Hz, 2H), 8.19 (s, 1H), 7.88 (s, 1H), 7.10 (s, 1H), 6.95 (d, J = 37.6 Hz, 1H), 6.47 (dd, J= 8.4, 2.4 Hz, 1H), 4.32 –4.26 (m, 2H), 4.23 – 3.93 (m, 3H), 3.53 (dd, J = 13.1, 7.1 Hz, 2H), 2.82 (d, J =17.1 Hz, 3H), 2.67 (s, 2H), 2.37 (d, J = 10.3 Hz, 3H), 2.06 – 1.87 (m, 6H), 1.73 (d, J = 10.0 Hz, 2H), 1.48 (s, 9H), 1.32 – 1.22 (m, 2H).

[0194] tert-butyl (Z)-methyl (1-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-yl)carbamate (13f)

[0195] The synthesis method of intermediate 13f was the same as that of 13a, except that intermediate 12f was used to replace 12a. Yield: 62%. 1 H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 9.01 (d, J = 2.5 Hz, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.36 (s, 1H), 7.00 (t, J = 6.5 Hz, 1H), 6.81 (dd, J = 8.5, 2.7 Hz,1H), 4.72 (s, 2H), 4.50 – 4.38 (m, 2H), 4.26 – 3.98 (m, 1H), 3.98 – 3.93(m,2H), 3.04 (d, J = 11.8 Hz, 2H), 2.86 – 2.72 (m, 5H), 2.42 – 2.27 (m, 5H), 1.87(dt, J = 9.9, 7.8 Hz, 2H), 1.76 – 1.69 (m, 2H), 1.49 (s, 9H).

[0196] Tert-butyl (Z)-4-(2 5 -methyl-1 1H-5-Oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacyclic-4,4'-yl)piperazine-1-carboxylate (13 g)

[0197] The synthesis method of intermediate 13g is the same as that of 13a, except that intermediate 12g is used to replace 12a. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 507.3

[0198] Tert-butyl (Z)-4-(2 5 -methyl-1 1 H-6-Oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacyclic-4,4'-yl)piperazine-1-carboxylate (13h)

[0199] The synthesis method of intermediate 13h is the same as that of 13a, except that intermediate 12h is used to replace 12a. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 507.3

[0200] (Z)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)piperidin-4-amine (14a)

[0201] The synthesis method of intermediate 14a is the same as that of 10, except that intermediate 13a is used to replace 9. Yield 97%. 1 HNMR (400 MHz, DMSO- d 6 ) δ 9.23 (d, J = 20.9 Hz, 1H), 8.75 (s, 1H), 8.25 (d, J =10.2 Hz, 1H), 8.13 (t, J = 5.3 Hz, 1H), 7.86 (s, 1H), 6.76 (d, J = 8.5 Hz, 1H),6.60 (dd, J = 8.4, 2.2 Hz, 1H), 4.30 – 4.14 (m, 2H), 4.01 (dd, J = 18.2, 10.3 Hz,2H), 3.26 (d, J = 11.6 Hz, 3H), 2.56 (d, J= 11.3 Hz, 1H), 2.42 – 2.24 (m, 11H), 1.86 (d, J = 10.0 Hz, 2H), 1.40 – 1.33 (m, 2H).

[0202] (Z)-N-methyl-1-(5'-methylspiro[cyclopropane-1,7'-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazol-4(1,3)-benzocyclooctacyclic]-4'-yl)piperidin-4-amine (14b)

[0203] The synthesis method of intermediate 14b is the same as that of 10, except that intermediate 13b is used to replace 9. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 446.3

[0204] (Z)-1-(2 5 ,7-dimethyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)-N-methylpiperidin-4-amine (14c)

[0205] The synthesis method of intermediate 14c was the same as that of 10, except that intermediate 13c was used to replace 9. Yield 95%. 1 HNMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.16 (s, 1H), 7.96 (d, J = 2.3 Hz, 1H),7.75 (s, 1H), 6.87 – 6.78 (m, 2H), 6.53 (dd, J = 8.3, 2.3 Hz, 1H), 4.30 – 4.17(m, 2H), 3.92 (dd, J = 14.1, 12.4 Hz, 1H), 3.74 (dd, J = 12.0, 8.8 Hz, 1H), 3.43(d, J = 11.7 Hz, 2H), 2.70 – 2.60 (m, 2H), 2.60 – 2.43 (m, 5H), 2.36 (s, 3H), 2.02 (dd, J = 9.9, 3.7 Hz, 2H), 1.38 (d, J = 6.6 Hz, 3H).

[0206] (Z)-N-methyl-1-(25 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclopenta ... 4 -yl)piperidin-4-amine (14d)

[0207] The synthesis method of intermediate 14d is the same as that of 10, except that intermediate 13d is used to replace 9. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 434.3

[0208] (Z)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecane-4 4 -yl)piperidin-4-amine (14e)

[0209] The synthesis method of intermediate 14e is the same as that of 10, except that intermediate 13e is used to replace 9. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 448.3

[0210] (Z)-N-methyl-1-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclopenta ... 4 4-(2-(4-(2-piperidin-4-amine))

[0211] The synthesis method of intermediate 14f is the same as that of 10, except that intermediate 13f is used to replace 9. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 434.3

[0212] (Z)- 2 5 -Methyl-4 4 -(piperazin-1-yl)-1 1 H-5-Oxy-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclopentacyclic (14g)

[0213] The synthesis method of intermediate 14g is the same as that of 10, except that intermediate 13g is used to replace 9. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 406.4

[0214] (Z)- 2 5 -Methyl-4 4 '-(piperazin-1-yl)-1 1H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclopentacyclic (14h)

[0215] The synthesis method of intermediate 14h is the same as that of 10, except that intermediate 13h is used to replace 9. The intermediate was directly subjected to the next step after confirmation by LCMS. m / z = 406.4

[0216] (Z)-2-(Methyl(1-(2,5-methyl-11H-5-oxo-3-nitrogen-2(4,2)-pyrimidin-1(4,1)-pyrazol-4(1,3)-benzocyclooctan-44-yl)piperidin-4-yl)amino)ethanol (15a)

[0217] 14a (100 mg, 0.24 mmol, 1.0 eq.), 2-iodoethanol (62 mg, 0.36 mmol, 1.5 eq.), and potassium carbonate (83 mg, 0.6 mmol, 2.5 eq.) were dissolved in 50 mL of acetonitrile and heated at 80°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by FlashMaster Personal+ column (DCM: MeOH = 9: 1) to obtain 74 mg of the target product with a yield of 67%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.27 (d, J = 3.0 Hz, 1H), 8.77 (s, 1H), 8.40 – 8.13 (m, 2H), 7.88 (s,1H), 6.79 (d, J = 8.6 Hz, 1H), 6.63 (dd, J = 8.4, 2.3 Hz, 1H), 5.32 (dt, J = 34.9,4.9 Hz, 1H), 4.34 – 4.15 (m, 2H), 4.14 – 3.94 (m, 2H), 3.90 – 3.75 (m, 2H), 3.64 – 3.35 (m, 4H), 2.81 (d, J = 4.7 Hz, 3H), 2.59 (s, 2H), 2.41 (s, 2H), 2.32(s, 3H), 2.30 – 2.11 (m, 1H), 2.11 – 1.90 (m, 2H), 1.90 – 1.63(m, 2H).

[0218] (Z)-N,N-dimethyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)piperidin-4-amine (15b)

[0219] 14a (100 mg, 0.24 mmol, 1.0 equivalent), paraformaldehyde (11 mg, 0.36 mmol, 1.5 equivalent) and acetic acid (14 mg, 0.24 mmol, 1.0 equivalent) were dissolved in 50 mL of methanol (MeOH), and NaBH3CN (20 mg, 0.31 mmol, 1.3 equivalent) was added at room temperature and reacted for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by FlashMaster Personal+ column (DCM: MeOH = 9: 1) to obtain 88 mg of the target product with a yield of 85%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.21 (s, 1H), 8.76 (s, 1H), 8.24 (s, 1H), 8.16(d, J = 2.3 Hz, 1H), 7.86 (s, 1H), 6.81 – 6.73 (m, 1H), 6.61 (dd, J = 8.4, 2.3Hz, 1H), 4.29 – 4.15 (m, 2H), 4.10 – 3.96 (m, 2H), 3.35 (s, 2H), 2.39 (d, J =8.0 Hz, 2H), 2.31 (s, 3H), 2.21 (s, 5H), 2.17 – 2.11(m, 1H), 1.88 – 1.75 (m,2H), 1.52 (qd, J = 11.9, 3.9 Hz, 2H), 1.32 – 1.15 (m, 6H).

[0220] (Z)-N-ethyl-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)piperidin-4-amine (15c)

[0221] The synthesis method of intermediate 15c is the same as that of 15a, except that 2-bromoethane is used instead of 2-iodoethanol. The yield is 75%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.20 (s, 1H), 8.75 (s, 1H), 8.23 ​​(s, 1H), 8.15(d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.60 (dd, J = 8.4, 2.3Hz, 1H), 4.30 – 4.14 (m, 2H), 4.10 – 3.94 (m, 2H), 2.50 – 2.44(m, 7H), 2.40(t, J = 11.3 Hz, 3H), 2.30 (s, 3H), 2.18 (s, 3H), 1.73 (d, J = 12.0 Hz, 2H), 1.56(qd, J = 11.8, 3.6 Hz, 2H), 0.98 (t, J = 7.0 Hz, 3H).

[0222] (Z)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)-N-propylpiperidin-4-amine (15d)

[0223] The synthesis method of intermediate 15d is the same as that of 15b, except that n-propionaldehyde is used instead of paraformaldehyde. The yield is 80%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.22 (s, 1H), 8.75 (s, 1H), 8.24 (s, 1H), 8.17(d, J = 2.3 Hz, 1H), 7.86 (s, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.61 (dd, J= 8.5, 2.3Hz, 1H), 4.31 – 4.12 (m, 2H), 4.10 – 3.92 (m, 2H), 3.49 – 3.36(m, 4H), 2.81 –2.51 (m, 4H), 2.38 (ddd, J = 14.4, 13.6, 8.8 Hz, 4H), 2.31 (s, 3H), 1.93 – 1.75(m, 2H), 1.64 (d, J = 12.0 Hz, 2H), 1.50 (s, 2H), 0.88 (t, J = 7.4 Hz, 3H).

[0224] (Z)-N-butyl-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)piperidin-4-amine (15e)

[0225] The synthesis method of intermediate 15e is the same as that of 15b, except that n-butyraldehyde is used instead of paraformaldehyde. The yield is 88%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.26 (s, 1H), 8.76 (s, 1H), 8.25 (s, 1H), 8.22(d, J = 2.3 Hz, 1H), 7.87 (s, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.62 (dd, J = 8.5, 2.3Hz, 1H), 4.27 – 4.18 (m, 2H), 4.08 – 3.97 (m, 2H), 3.41 (d, J = 11.5 Hz, 2H),2.67 (d, J = 7.0 Hz, 2H), 2.57 (t, J = 11.4 Hz, 3H), 2.44 – 2.36 (m, 2H), 2.31(s, 3H), 2.02 (dd, J = 11.5, 6.5 Hz, 2H), 1.86 – 1.73 (m, 2H), 1.62 (d, J= 15.4Hz, 2H), 1.36 – 1.33 (m, 2H), 1.24 (dd, J = 9.8, 3.6 Hz, 2H), 0.93 (t, J = 7.4Hz, 3H).

[0226] (Z)-N-(cyclopropylmethyl)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)piperidin-4-amine (15f)

[0227] The synthesis method of intermediate 15f is the same as that of 15b, except that cyclopropylcarboxaldehyde is used instead of paraformaldehyde. The yield is 83%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.98 (d, J = 13.0 Hz, 1H), 8.52 (s, 1H), 8.00(s, 1H), 7.93 (dd, J = 13.9, 8.2 Hz, 1H), 7.62 (s, 1H), 6.53 (d, J = 8.5 Hz, 1H),6.37 (dd, J = 8.4, 2.1 Hz, 1H), 4.02 – 3.93 (m, 2H), 3.82 – 3.75 (m, 2H), 3.20 (s, 4H), 2.42 (d, J = 22.6 Hz, 2H), 2.31 (d, J = 7.1 Hz, 4H), 2.16 (s, 2H), 2.07(s, 3H), 1.63 (s, 2H), 1.44 (dd, J = 20.4, 11.5 Hz, 2H), 0.72 (s, 1H), 0.32 (d, J = 6.8 Hz, 2H), 0.00 (d, J = 4.0 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 172.35,160.79, 158.19, 157.25, 150.18, 137.63, 137.48, 135.47, 122.90, 118.79,115.87, 112.56,108.07, 64.32, 61.39, 57.98, 50.57, 47.61, 37.12, 29.09,27.63, 21.54, 14.67, 4.45.

[0228] (Z)-N-isopropyl-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)piperidin-4-amine (15g)

[0229] The synthesis method of intermediate 15g is the same as that of 15b, except that acetone is used instead of paraformaldehyde. Yield: 83%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.27 (s, 1H), 8.77 (s, 1H), 8.26 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.88 (s, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.4, 2.3Hz, 1H), 4.23 (t, J = 5.7 Hz, 2H), 4.04 (t, J = 8.0 Hz, 2H), 3.77 (s, 1H), 3.42(s, 2H), 2.68 (d, J = 4.5 Hz, 3H), 2.60 (q, J = 11.1 Hz, 3H), 2.41 (s, 2H), 2.32(s, 3H), 2.12 (s, 2H), 1.80 (s, 2H), 1.32 (d, J = 6.4 Hz, 3H), 1.25 – 1.21 (m,3H).

[0230] (Z)-N-methyl-1-(2 5 -methyl-1 1H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)-N-(2-methylallyl)piperidin-4-amine (15h)

[0231] The synthesis method of intermediate 15h is the same as that of 15a, except that 3-bromo-2-methyl-1-propene is used instead of 2-iodoethanol. The yield is 80%. 1 H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.18 (s, 1H), 8.13 (d, J =2.0 Hz, 1H), 7.77 (s, 1H), 7.01 (d, J = 10.9 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H),6.53 (dd, J = 8.4, 2.3 Hz, 1H), 5.00 (s, 2H), 4.33 – 4.26 (m, 2H), 4.22 – 4.14(m, 2H), 3.55 – 3.48 (m, 2H), 3.17 (s, 2H), 2.61 (t, J = 11.2 Hz, 2H), 2.53 –2.46 (m, 2H), 2.45 – 2.27 (m, 6H), 2.11 – 1.68 (m, 8H). 13 C NMR (101 MHz, CDCl3)δ 160.35, 157.73, 157.47, 149.79, 137.51, 136.35, 135.30, 123.24, 118.53,116.34, 112.68, 109.05, 63.87, 60.78, 60.06, 51.07, 47.51,37.34, 28.95,27.60, 21.09, 14.78.

[0232] (Z)-N-(cyclobutylmethyl)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)piperidin-4-amine (15i)

[0233] The synthesis method of intermediate 15i is the same as that of 15a, except that bromomethylcyclobutane is used instead of 2-iodoethanol. The yield is 78%.1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.18 – 8.08 (m, 2H), 7.71 (s,1H), 6.92 (d, J = 10.0 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.45 (dd, J = 8.4, 2.3Hz, 1H), 4.26 – 4.21 (m, 2H), 4.12 – 4.07 (m, 2H), 3.50 (d, J = 11.5 Hz, 2H), 3.15 (s, 2H), 2.64 (s, 3H), 2.37 (d, J = 9.7 Hz, 3H), 2.31 (s, 3H), 2.21 (d, J =7.6 Hz, 3H), 1.97 (d, J = 8.0 Hz, 4H), 1.79 (s, 4H), 0.80 (d, J = 11.0 Hz, 2H).

[0234] (Z)-N,N-Dimethyl-1-(5'-methylspiro[cyclopropane-1,7'-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazol-4(1,3)-benzocyclooctane]-4'-yl)piperidin-4-amine (15j)

[0235] The synthesis method of intermediate 15j is the same as that of 15b, except that intermediate 14b is used instead of 14a. The yield is 87%. 1 H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.80 (s, 1H), 6.91 (s, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 8.3 Hz, 1H), 4.35(s, 2H), 4.10 (s, 2H), 3.41 (d, J = 11.1 Hz, 2H), 2.59 (t, J = 11.5 Hz, 2H), 2.38(d, J = 8.3 Hz, 9H), 2.34 (s, 1H), 1.96 (d,J = 11.6 Hz, 2H), 1.72 (dd, J = 22.7,11.1 Hz, 2H), 1.06 (s, 2H), 0.69 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.31,157.71, 157.60, 150.78, 137.60,137.43, 136.53, 136.23, 122.84, 118.57,116.28, 112.36, 108.52, 65.65, 62.47, 57.15, 50.85, 41.55, 28.88, 19.61,15.29, 14.83, 8.66.

[0236] (Z)-2-(Methyl(1-(5'-methylspiro[cyclopropane-1,7'-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazol-4(1,3)-benzocyclooctane]-4'-yl)piperidin-4-yl)amino)ethanol (15k)

[0237] The synthesis method of intermediate 15k was the same as that of 15a, except that intermediate 14b was used instead of 14a. The yield was 74%. 1 H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.19 (s,1H), 7.80 (s, 1H), 6.94 (s, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.50 (dd, J = 8.4, 2.3Hz, 1H), 4.34 (s, 2H), 4.11 (s, 2H), 3.77 (dd, J = 11.4, 6.7 Hz, 2H), 3.43 (d, J = 11.7 Hz, 2H), 2.88 (s, 3H), 2.62 (t, J = 11.1 Hz, 2H), 2.55 (s, 3H), 2.38 (s,3H), 2.02 (d, J = 11.0 Hz, 2H), 1.85 (tt, J = 11.9, 5.8 Hz, 2H), 1.03 (t, J= 5.4Hz, 2H), 0.72 (t, J = 5.4 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.34, 157.59,150.80, 137.62, 136.71, 136.59, 136.44, 122.90, 118.88, 116.38,112.11,107.88, 65.51, 62.79, 57.45, 57.07, 55.67, 50.75, 37.40, 29.71, 27.76, 19.63,14.82, 8.65.

[0238] (Z)-N-methyl-1-(5'-methylspiro[cyclopropane-1,7'-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane]-4'-yl)-N-propylpiperidin-4-amine (15l)

[0239] The synthesis method of intermediate 151 is the same as that of 15d, except that intermediate 14b is used instead of 14a. The yield is 88%. 1 H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.19 (s,1H), 7.80 (s, 1H), 6.88 – 6.77 (m, 2H), 6.50 (dd, J = 8.4, 2.2 Hz, 1H), 4.34(s, 2H), 4.12 (s, 2H), 3.47 (t, J = 9.2 Hz, 2H), 3.06 (s, 1H), 2.83 (s, 2H), 2.71 – 2.57 (m, 5H), 2.38 (s, 3H), 2.19 (d, J = 23.0 Hz, 2H), 1.90 (dd, J = 22.1,10.3 Hz, 4H), 1.01 (t, J = 7.3 Hz, 5H), 0.73 (t, J = 5.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 160.47, 160.38, 157.54, 150.84, 137.62,136.95, 136.52, 136.41,122.92, 119.01, 116.47, 112.02, 107.69, 67.27, 65.50, 57.24, 57.04, 55.25,50.43, 29.71, 19.64, 14.81, 11.53, 8.65, 2.73, 1.86.

[0240] (Z)-N-(Cyclopropylmethyl)-N-methyl-1-(5'-methylspiro[cyclopropane-1,7'-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazol-4(1,3)-benzocyclooctane]-4'-yl)piperidin-4-amine (15m)

[0241] The synthesis of intermediate 15m was the same as that of 15f, except that intermediate 14b was used instead of 14a. The yield was 80%. 1 H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.18 (s,1H), 7.80 (s, 1H), 6.86 (s, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.50 (dd, J = 8.4, 2.3Hz, 1H), 4.34 (s, 2H), 4.10 (s, 2H), 3.41 (d, J = 11.6 Hz, 2H), 2.70 (s, 1H), 2.58 (t, J = 11.0 Hz, 2H), 2.51 (d, J = 21.1 Hz, 5H), 2.37 (s, 3H), 1.93 (d, J =11.0 Hz, 2H), 1.76 (dt, J = 12.1, 8.7 Hz, 3H), 1.05 (t, J = 5.4 Hz, 2H), 0.98 (s,1H), 0.70 (t, J = 5.4 Hz, 2H), 0.59 (d, J = 7.6 Hz, 2H), 0.18 (d, J= 4.7 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.31, 157.66, 157.57, 150.76, 137.59,136.50,136.27, 123.22, 122.85, 118.63, 116.29, 112.23, 108.24, 65.60, 61.08, 58.62,57.12, 51.14, 37.81, 28.28, 19.63, 14.82, 8.67, 4.17.

[0242] (Z)-N-allyl-N-methyl-1-(5'-methylspiro[cyclopropane-1,7'-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazol-4(1,3)-benzocyclooctane]-4'-yl)piperidin-4-amine (15n)

[0243] The synthesis method of intermediate 15n is the same as that of 15a, except that intermediate 14b is used instead of 14a, and propylene bromide is used instead of 2-iodoethanol. The yield is 81%. 1 H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.31 (d, J = 1.7Hz, 1H), 8.18 (s, 1H), 7.80 (s, 1H), 6.88 – 6.75 (m, 2H), 6.50 (dd, J = 8.4, 2.3Hz, 1H), 6.05 (s, 1H), 5.31 (d, J = 16.8 Hz, 2H), 4.34 (s, 2H), 4.11 (s, 2H), 3.43 (d, J = 11.1 Hz, 2H), 3.35 (s, 2H), 2.79 (s, 1H), 2.60 (t, J = 11.0 Hz, 2H),2.56 – 2.40 (m, 3H), 2.38 (s, 3H), 2.02 (d, J = 11.0 Hz, 2H), 1.83 (d, J = 10.0Hz, 2H), 1.04 (t, J = 5.4 Hz, 2H), 0.71 (t, J = 5.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 160.36, 157.62, 157.58, 150.79, 137.61, 137.14, 136.52, 136.47,122.88, 118.76, 117.25, 116.37, 112.18, 108.13, 108.09, 72.71, 67.50,65.58,65.53, 57.10, 56.84, 50.80, 22.75, 19.63, 14.82, 8.66.

[0244] (Z)-N-isobutyl-N-methyl-1-(5'-methylspiro[cyclopropane-1,7'-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazol-4(1,3)-benzocyclooctane]-4'-yl)piperidin-4-amine (15o)

[0245] The synthesis of intermediate 15o was the same as that of 15a, except that intermediate 14b was used instead of 14a, and isobutane bromide was used instead of 2-iodoethanol. The yield was 80%. 1 H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.33 (d, J =2.1 Hz, 1H), 8.18 (s, 1H), 7.80 (s, 1H), 6.92 (s, 1H), 6.81 (d, J = 8.4 Hz,1H), 6.50 (dd, J = 8.4, 2.3 Hz, 1H), 4.35 (s, 2H), 4.11 (s, 2H), 3.41 (d, J =11.7 Hz, 2H), 2.66 (d, J = 24.0 Hz, 1H), 2.59 (t, J = 11.1 Hz, 2H), 2.44 (s, 3H), 2.38 (s, 5H), 1.93 (s, 2H), 1.87 – 1.73(m, 3H), 1.05 (t, J = 5.4 Hz, 2H), 0.98(d, J = 6.5 Hz, 6H), 0.72 (t, J = 5.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 160.32,157.63, 157.59, 150.78, 137.60, 136.48, 131.90, 131.10, 122.90, 118.76,116.31, 112.10, 107.90, 65.53, 61.99, 61.56, 57.12,51.09, 38.67, 29.73,27.81, 26.18, 21.05, 19.64, 14.82, 8.66.

[0246] (Z)-1-(2 5 ,7-dimethyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)-N-isobutyl-N-methylpiperidin-4-amine (15p)

[0247] The synthesis of intermediate 15p was the same as that of 15a, except that intermediate 14c was used instead of 14a, and isobutane bromide was used instead of 2-iodoethanol. The yield was 72%. 1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 23.5 Hz, 1H), 7.76 (s, 1H), 6.83 (d, J = 8.2 Hz, 2H), 6.52 (dd, J =8.3, 2.3 Hz, 1H), 4.33 – 4.20 (m, 2H), 3.94 (dd, J = 14.1, 12.4 Hz, 1H), 3.74(dd, J = 12.1, 9.0 Hz, 1H), 3.52 (dd, J = 33.2, 11.2 Hz, 2H), 2.61 (dt, J = 23.3,11.1 Hz, 4H), 2.39 (d, J = 19.8 Hz, 7H), 1.91 (dd, J = 56.6, 24.9 Hz, 6H), 1.39(d, J = 6.6 Hz, 3H), 0.92 (dd, J = 38.9, 5.9 Hz, 6H).13 C NMR (101 MHz, CDCl3) δ160.37, 157.77, 157.56, 149.78, 144.57, 141.14, 137.34, 135.71, 123.24,120.42,118.41, 116.34, 112.63, 69.58, 61.50, 53.96, 50.95, 50.04, 38.63,34.87, 21.05, 19.25, 16.82, 14.76, 7.66.

[0248] (Z)-N-(1-(2 5 ,7-dimethyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)piperidin-4-yl)-N-methylpiperidine-1-carboxamide (15q)

[0249] 14c (100 mg, 0.23 mmol, 1.0 equivalent), pyrrolidine-1-carboxylic acid chloride (40 mg, 0.30 mmol, 1.3 equivalent), and triethylamine (58 mg, 0.58 mmol, 2.5 equivalent) were dissolved in dichloromethane (50 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by FlashMaster Personal+ column (dichloromethane: methanol = 9:1) to obtain 103 mg of the target product with a yield of 85%. 1 H NMR (400 MHz, CDCl3) δ 8.65(s, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 6.87 (d, J = 8.3 Hz, 1H),6.57 (dd, J = 8.4, 2.2 Hz, 1H), 4.34 – 4.20 (m, 2H), 3.95 (dd, J = 14.0, 12.4 Hz,1H), 3.84 (dd, J = 15.9, 7.8 Hz, 1H), 3.75 (dd, J = 12.0, 8.9 Hz, 1H), 3.55 (d, J =11.8 Hz, 1H), 3.45 (d, J= 13.3 Hz, 1H), 2.94 (s, 4H), 2.87 – 2.68 (m, 4H), 2.68 – 2.51 (m, 2H), 2.37 (s, 3H), 2.05 (dd, J = 30.0, 18.3 Hz, 2H), 1.95 –1.69 (m, 6H), 1.39 (d, J = 6.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 163.88, 159.89,157.91, 157.58, 149.69,137.42, 136.33, 136.06, 123.25, 118.65, 116.32,112.84, 108.96, 69.40, 54.59, 53.87, 52.10, 51.14, 50.00, 34.87, 30.83,29.62, 25.63, 16.73, 14.74.

[0250] (Z)-1-(1-(2 5 ,7-dimethyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)piperidin-4-yl)-1,3,3-trimethylurea (15r)

[0251] The synthesis of intermediate 15r was the same as that of 15q, except that N,N-dimethylformyl chloride was used instead of pyrrolidine-1-carboxylic acid chloride. The yield was 88%. 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.76 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 6.52 (dd, J =8.3, 2.2 Hz, 1H), 4.28 (dd, J = 18.4, 8.0 Hz, 2H), 3.99 – 3.90 (m, 1H), 3.82 –3.71 (m, 2H), 3.56 (d, J = 12.0 Hz, 1H), 3.48 – 3.42 (m, 1H), 2.80 (d, J= 11.4Hz, 10H), 2.63 (d, J = 11.3 Hz, 2H), 2.37 (s, 3H), 2.09 – 1.96 (m, 2H), 1.81(d, J = 11.2 Hz, 2H), 1.39 (d, J = 6.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.75,160.37, 157.72, 157.55, 149.72, 137.64, 137.35, 135.68, 126.75, 123.26,116.36, 112.59, 109.43, 108.94, 69.52, 53.95, 51.98, 42.95, 38.88, 34.85,31.23, 29.49, 16.78, 14.76.

[0252] (Z)-N-(cyclopropylmethyl)-1-(2 5 ,7-dimethyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)-N-methylpiperidin-4-amine (15s)

[0253] The synthesis method of intermediate 15s was the same as that of 15a, except that intermediate 14c was used instead of 14a, and bromomethylcyclopropane was used instead of 2-iodoethanol. The yield was 80%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.79 (s, 1H), 8.46 (s, 1H), 8.17 (d, J = 1.5 Hz, 1H), 7.70 (d, J = 1.4 Hz, 1H), 7.30 (dd, J = 7.6, 1.6 Hz,1H), 6.88 (d, J = 1.5 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 4.00 (dd, J = 7.0, 2.0 Hz,2H), 3.83 (dd, J = 12.5, 7.1 Hz, 1H), 3.78 – 3.73 (m, 1H), 3.60 (dt,J = 12.2,7.1 Hz, 2H), 3.32 (dt, J = 12.3, 7.1 Hz, 2H), 2.74 (pq, J = 7.1, 1.5 Hz, 1H),2.56 (d, J = 0.6 Hz, 3H), 2.39 (dd, J = 12.4, 7.0 Hz, 1H), 2.33 – 2.23 (m, 5H), 1.85 (dq, J = 12.2, 7.0 Hz, 2H), 1.78 – 1.63 (m, 3H), 1.38 (d, J = 6.9 Hz, 4H),1.15 (d, J = 6.8 Hz, 3H).

[0254] (Z)-N-allyl-1-(2 5 ,7-dimethyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)-N-methylpiperidin-4-amine (15t)

[0255] The synthesis method of intermediate 15t is the same as that of 15a, except that intermediate 14c is used instead of 14a, and propylene bromide is used instead of 2-iodoethanol. The yield is 80%. 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.17 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.75 (s, 1H), 6.99 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H),6.52 (dd, J = 8.4, 2.4 Hz, 1H), 5.97 (ddt, J = 16.8, 10.0, 6.6 Hz, 1H), 5.33 –5.16 (m, 2H), 4.32 – 4.18 (m, 2H), 3.93 (dd, J = 14.2, 12.2 Hz, 1H), 3.74 (dd, J = 12.1, 8.8 Hz, 1H), 3.57 – 3.47 (m, 2H), 3.25 (d,J = 6.6 Hz, 2H), 2.60 (dtd, J =25.9, 11.8, 2.7 Hz, 4H), 2.37 (d, J = 3.2 Hz, 6H), 1.95 (d, J = 12.2 Hz, 2H),1.84 (ttd, J = 11.9, 8.5, 4.5 Hz, 2H), 1.39 (d, J = 6.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.32, 157.84, 157.57, 149.79, 138.32, 137.33, 136.18, 135.74,123.21, 118.31, 116.29, 112.79,109.47, 69.68, 60.62, 57.01, 53.95, 51.57,50.96, 37.20, 34.86, 28.26, 28.11, 16.81, 14.76.

[0256] (Z)-1-(2 5 ,7-dimethyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclooctane-4 4 -yl)-N-methyl-N-(2-methylbutyl)piperidin-4-amine (15u)

[0257] The synthesis method of intermediate 15u is the same as that of 15a, except that intermediate 14c is used instead of 14a, and 1-bromo-2-methylbutane is used instead of 2-iodoethanol. The yield is 72%. 1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.21 –8.14 (m, 1H), 8.08 (s, 1H), 7.76 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.76 (s,1H), 6.51 (dd, J = 8.4, 2.4 Hz, 1H), 4.32 – 4.21 (m, 2H), 3.94 (dd, J = 14.2,12.2 Hz, 1H), 3.74 (dd, J= 12.2, 8.9 Hz, 1H), 3.53 (dd, J = 35.1, 11.4 Hz, 2H),2.63 (dd, J = 43.9, 11.0 Hz, 4H), 2.37 (s, 3H), 1.86 (s, 4H), 1.59 (s, 6H), 1.39 (d, J = 6.6 Hz, 3H), 1.31 (s, 1H), 0.98 (s, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13 CNMR (101 MHz, CDCl3) δ 159.95, 158.04, 157.34, 151.55, 138.55, 136.11,132.48, 122.17, 118.65, 116.55,110.91, 105.85, 68.75, 65.87, 60.11, 51.23,50.72, 38.83, 27.80, 27.75, 27.43, 21.21, 17.90, 16.21, 15.29, 11.36.

[0258] (Z)-2-(methyl(1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-yl)amino)ethanol (15v)

[0259] The synthesis of intermediate 15v was the same as that of 15a, except that intermediate 14d was used instead of 14a. The yield was 70%. 1 H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.23 ​​–8.15 (m, 1H), 7.82 (s, 1H), 6.88 (s, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.50 (dd, J =8.4, 2.5 Hz, 1H), 4.35 (t, J = 7.5 Hz, 2H), 4.30 (t, J = 5.0 Hz, 2H), 3.72 (s,2H), 3.52 (d,J = 11.5 Hz, 2H), 2.78 (d, J = 27.9 Hz, 3H), 2.63 – 2.55 (m, 2H), 2.48 (s, 3H), 2.38 (s, 3H), 1.99 (d, J = 30.2 Hz, 6H), 1.86 (td, J = 12.1, 8.4 Hz, 3H).

[0260] (Z)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)-N-propylpiperidin-4-amine (15w)

[0261] The synthesis of intermediate 15w was the same as that of 15d, except that intermediate 14d was used instead of 14a. The yield was 76%. 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.19 (s,1H), 7.81 (s, 1H), 7.05 (s, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.51 (dd, J = 8.5, 2.5Hz, 1H), 4.36 (t, J = 7.5 Hz, 2H), 4.29 (dd, J = 6.6, 3.8 Hz, 2H), 3.54 – 3.47(m, 2H), 2.54 (ddt, J = 23.5, 10.0, 5.1 Hz, 5H), 2.36 (d, J = 6.8 Hz, 6H), 2.10 –1.96 (m, 4H), 1.89 (d, J = 11.9 Hz, 2H), 1.79 (qd, J = 11.9, 3.8 Hz, 2H), 1.55(h, J = 7.3 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.89,158.00, 157.37, 151.49, 137.95, 137.73, 136.22, 133.32, 122.59, 118.57,116.51, 112.19, 109.54, 69.65, 61.13, 55.72, 51.16, 50.88, 37.84, 28.23,26.77, 24.75, 20.69, 15.41, 11.94.

[0262] (Z)-N-isobutyl-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-amine (15x)

[0263] The synthesis of intermediate 15x was similar to that of 15o, except that intermediate 14d was used instead of 14b. The yield was 77%. 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.19 (s,1H), 7.81 (s, 1H), 7.06 (d, J = 1.7 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.51 (dd, J = 8.5, 2.5 Hz, 1H), 4.36 (t, J = 7.4 Hz, 2H), 4.29 (dd, J = 6.7, 3.7 Hz, 2H),3.53 – 3.46 (m, 2H), 2.55 (td, J = 11.6, 2.5 Hz, 3H), 2.35 (d, J = 17.5 Hz, 6H),2.29 – 2.19 (m, 2H), 2.09 – 1.97 (m, 4H), 1.77 (qd, J = 11.3, 3.5 Hz, 5H), 0.92(d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 159.86, 157.99, 157.39, 151.49,137.95, 137.82, 136.19, 133.33, 122.60, 118.58, 116.49, 112.13, 109.33,69.61, 61.79, 61.64, 51.31,50.89, 38.83, 28.10, 26.74, 26.50, 24.76, 21.00,15.40.

[0264] (Z)-N,N-dimethyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-amine (15y)

[0265] The synthesis method of intermediate 15y was the same as that of 15b, except that intermediate 14d was used instead of 14a. The yield was 77%. 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.23 ​​–8.15 (m, 1H), 7.81 (s, 1H), 6.98 (s, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.51 (dd, J =8.5, 2.5 Hz, 1H), 4.36 (t, J = 7.6 Hz, 2H), 4.32 – 4.26 (m, 2H), 3.54 – 3.48(m, 2H), 2.58 (td, J = 11.8, 2.2 Hz, 2H), 2.39 (d, J = 10.5 Hz, 10H), 2.11 – 2.03(m, 2H), 1.99 (ddd, J = 20.2, 8.7, 4.9 Hz, 4H), 1.77 (qd, J = 12.0, 3.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 159.90, 157.98, 157.37, 151.52, 137.95, 137.58,136.28, 133.31, 122.58, 118.58,116.55, 112.21, 109.58, 69.68, 62.43, 50.88,50.74, 41.35, 28.53, 26.77, 24.74, 15.41.

[0266] (Z)-N-methyl-N-(1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-yl)cyclopropanecarboxamide (15z)

[0267] The synthesis of intermediate 15z was the same as that of 15q, except that intermediate 14d was used instead of 14c, and cyclopropanecarbonyl chloride was used instead of pyrrolidine-1-carboxylic acid chloride. The yield was 87%. 1 H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.46(d, J = 2.8 Hz, 1H), 8.19 (s, 1H), 7.81 (s, 1H), 7.46 (d, J = 15.4 Hz, 1H), 6.97– 6.81 (m, 1H), 6.51 (dd, J = 8.4, 2.6 Hz, 1H), 4.60 (dt, J = 11.1, 3.6 Hz, 1H),4.36 (d, J = 7.8 Hz, 2H), 4.29 (t, J = 4.7 Hz, 2H), 3.58 – 3.42 (m, 3H), 3.09 (s, 2H), 2.96 – 2.87 (m, 1H), 2.70 (dt, J = 21.9, 11.6 Hz, 2H), 2.37 (s, 3H), 2.07 –1.94 (m, 5H), 1.87 – 1.67 (m, 3H), 1.07 – 0.95 (m, 2H), 0.78 (dt, J = 8.0, 3.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 173.33, 159.74, 157.96, 157.42, 151.62,137.98, 136.80, 133.35, 122.62, 118.98, 118.67, 116.49, 111.94, 108.43,69.63, 65.85, 51.15,30.69, 29.72, 29.24, 26.69, 24.78, 15.39, 11.83, 7.62.

[0268] (Z)-N-methyl-N-(1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-yl)piperidine-1-carboxamide (15aa)

[0269] The synthesis of intermediate 15aa was the same as that of 15q, except that intermediate 14d was used instead of 14c, and piperidine-1-carboxylic acid chloride was used instead of pyrrolidine-1-carboxylic acid chloride. The yield was 88%. 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H),8.45 (d, J = 2.4 Hz, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 7.27 (s, 1H), 7.02 – 6.76(m, 1H), 6.51 (dd, J = 8.5, 2.5 Hz, 1H), 4.36 (t, J = 7.4 Hz, 2H), 4.29 (t, J = 5.0Hz, 2H), 3.78 (tt, J = 12.1, 3.9 Hz, 1H), 3.49 (dt, J = 11.0, 2.7 Hz, 2H), 3.15(t, J = 4.6 Hz, 4H), 2.80 (s, 3H), 2.72 (d, J = 13.5 Hz, 2H), 2.37 (s, 3H), 2.02(h, J = 6.9, 5.6 Hz, 6H), 1.82 – 1.75 (m, 2H), 1.59 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 165.30, 159.83, 157.97, 157.39, 151.61, 137.97, 136.73, 133.33,122.62, 118.94, 116.55, 111.98,108.72, 69.66, 54.79, 51.37, 50.89, 48.09,47.93, 31.41, 29.39, 26.70, 25.76, 24.77, 15.40.

[0270] (Z)-N-allyl-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-amine (15ab)

[0271] The synthesis of intermediate 15ab was the same as that of 15q, except that intermediate 14d was used instead of 14c, and 3-butenoyl chloride was used instead of pyrrolidine-1-carboxylic acid chloride. The yield was 90%. 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.45(d, J = 2.5 Hz, 1H), 8.19 (s, 1H), 7.82 (s, 1H), 6.92 (s, 1H), 6.82 (d, J = 8.4Hz, 1H), 6.50 (dd, J = 8.5, 2.5 Hz, 1H), 6.08 (s, 1H), 5.33 (d, J = 15.1 Hz, 2H),4.35 (t, J = 7.5 Hz, 2H), 4.32 – 4.26 (m, 2H), 3.53 (d, J = 11.3 Hz, 2H), 3.39(s, 2H), 2.87 (s, 1H), 2.60 (td, J = 11.9, 2.3 Hz, 2H), 2.48 (s, 3H), 2.38 (s, 3H), 2.11 – 1.97 (m, 6H), 1.95 – 1.84 (m, 2H). 13C NMR (101 MHz, CDCl3) δ159.94, 158.05, 157.93, 157.38, 152.16,151.63, 137.98, 136.98, 136.62,133.29, 122.60, 118.75, 116.66, 111.97, 108.87, 69.67, 65.86, 60.97, 56.77,50.91, 50.63, 36.60, 26.72, 24.75, 15.39.

[0272] (Z)-N-methyl-N-(1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-yl)pyrrolidine-1-carboxamide (15ac)

[0273] The synthesis of intermediate 15ac was the same as that of 15q, except that intermediate 14d was used instead of 14c. The yield was 91%. 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.49 (s, 1H), 8.20 (s, 1H), 7.82(s, 1H), 7.10 (s, 1H), 6.51 (dd, J = 8.5, 2.4 Hz, 1H), 4.37 (t, J = 7.5 Hz, 2H),4.30 (t, J = 5.1 Hz, 2H), 3.87 (s, 1H), 3.54 – 3.48 (m, 2H), 3.39 – 3.33 (m, 4H), 2.79 (s, 5H), 2.38 (s, 3H), 2.18 – 1.95 (m, 6H), 1.87 – 1.76 (m, 6H). 13CNMR (101 MHz, CDCl3) δ 163.59, 159.89, 157.91, 157.42, 151.71,141.69, 138.02,133.33, 122.99, 122.63, 116.69, 111.91, 108.59, 108.46, 69.72, 51.55, 50.90,48.59, 30.85, 26.67, 25.61, 25.31, 24.99, 24.78, 15.39.

[0274] (Z)-2-(methyl(1-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-yl)amino)ethanol (15ad)

[0275] The synthesis of intermediate 15ad was the same as that of 15a, except that intermediate 14f was used instead of 14a. The yield was 80%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.52 (s, 1H), 9.28 (s, 1H), 8.99 (d, J = 2.3 Hz,1H), 8.24 (s, 1H), 7.90 (s, 1H), 7.04 – 6.94 (m, 2H), 4.61 (s, 2H), 4.45 –4.36 (m, 2H), 4.31 (s, 1H), 3.91 (t, J = 4.8 Hz, 2H), 3.46 (d, J = 5.1 Hz, 2H),2.95 (d, J = 11.1 Hz, 2H), 2.65 – 2.57 (m, 2H), 2.53 (d, J = 6.5 Hz, 2H), 2.46 –2.39 (m, 1H), 2.31 (s, 3H), 2.23 (d, J = 17.7 Hz, 5H), 1.76 (d, J = 10.9 Hz, 2H),1.60 (td, J = 11.9, 3.7 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6) δ 160.59, 158.45,156.64, 144.46, 137.68, 137.36, 134.89, 132.64, 122.46, 120.07, 119.08,118.28, 115.51, 71.95, 69.37, 61.19, 59.99,56.06, 53.22, 52.81, 38.68, 29.88,28.84, 16.02.

[0276] (Z)-N-methyl-1-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)-N-propylpiperidin-4-amine (15ae)

[0277] The synthesis of intermediate 15ae was the same as that of 15d, except that intermediate 14f was used instead of 14a. The yield was 87%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.42 (s, 1H), 9.18 (s, 1H), 8.89 (d, J = 2.2 Hz,1H), 8.14 (s, 1H), 7.79 (s, 1H), 6.92 – 6.83 (m, 2H), 4.51 (s, 2H), 4.35 –4.22 (m, 2H), 3.80 (t, J = 4.8 Hz, 2H), 2.85 (d, J = 11.1 Hz, 2H), 2.55 – 2.47(m, 2H),2.32 (q, J = 10.1, 7.3 Hz, 3H), 2.21 (s, 3H), 2.11 (d, J = 9.0 Hz, 5H),1.66 (dd, J = 11.5, 3.9 Hz, 2H), 1.50 (qd, J = 12.0, 3.7 Hz, 2H), 1.33 (h, J = 7.4Hz, 2H), 0.76 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 160.59, 158.45,156.64, 144.43, 137.68, 137.38, 134.89, 132.65, 122.46, 120.08, 119.08,118.29, 115.51, 71.95, 69.36, 60.83, 55.50,53.20, 52.80, 37.93, 29.88, 28.75,20.78, 16.02, 12.23.

[0278] (Z)-N-isobutyl-N-methyl-1-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-amine (15af)

[0279] The synthesis of intermediate 15af was similar to that of 15o, except that intermediate 14f was used instead of 14b. The yield was 80%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.52 (s, 1H), 9.27 (s, 1H), 8.99 (d, J = 2.3 Hz,1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.03 – 6.93 (m, 2H), 4.61 (s, 2H), 4.45 –4.33 (m, 2H), 3.91 (t, J = 4.7 Hz, 2H), 2.95 (d, J = 11.3 Hz, 2H), 2.67 – 2.56(m, 2H),2.31 (s, 4H), 2.18 (d, J = 22.5 Hz, 7H), 1.78 – 1.65 (m, 3H), 1.59 (qd, J = 12.0, 3.8 Hz, 2H), 0.87 (d, J = 6.5 Hz, 6H). 13 C NMR (101 MHz, DMSO- d6) δ160.59, 158.45, 156.64, 144.49, 137.68,137.37, 134.88, 132.66, 122.46,120.06, 119.08, 118.28, 115.51, 71.94, 69.36, 61.88, 61.36, 53.35, 52.80,38.74, 29.87, 28.72, 26.53, 21.18, 16.02.

[0280] (Z)-N-methyl-N-(1-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-yl)pyrrolidine-1-carboxamide (15ag)

[0281] The synthesis of intermediate 15aq was the same as that of 15q, except that intermediate 14f was used instead of 14c. The yield was 84%. 1 H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.93 (d, J = 2.7 Hz, 1H), 8.07 (s,1H), 7.76 (s, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.74 (dd, J = 8.5, 2.7 Hz, 1H), 4.65(s, 2H), 4.42 – 4.32 (m, 2H), 3.92 – 3.84 (m, 2H), 3.73 (tt, J = 11.9, 4.0 Hz,1H), 3.33 – 3.27 (m, 4H), 2.97 (dp, J = 11.7, 2.1 Hz, 2H), 2.76 – 2.67 (m, 5H), 2.30 (s, 3H), 2.28 – 2.22 (m, 2H), 1.87 (qd, J = 12.0, 3.9 Hz, 2H), 1.79 – 1.68(m, 6H). 13C NMR (101 MHz, CDCl3) δ 162.58, 158.10, 156.63, 156.59, 144.02,136.63, 135.36, 134.68, 131.82, 121.71, 119.65, 118.29,117.14, 115.03, 70.87,68.74, 53.53, 52.24, 51.60, 47.56, 29.89, 28.98, 28.87, 24.58, 15.09.

[0282] (Z)-N-(cyclopropylmethyl)-N-methyl-1-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-amine (15ah)

[0283] The synthesis of intermediate 15ah was the same as that of 15f, except that intermediate 14f was used instead of 14a. The yield was 85%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.50 (s, 1H), 9.31 (s, 1H), 9.01 (d, J = 2.1 Hz,1H), 8.24 (s, 1H), 7.90 (s, 1H), 7.00 (d, J = 3.3 Hz, 2H), 4.62 (s, 2H), 4.48 –4.28 (m, 2H), 3.90 (t, J = 4.7 Hz, 2H), 3.02 (d, J = 11.5 Hz, 2H), 2.92 (s, 1H), 2.69 (q, J = 13.9, 11.4 Hz, 4H), 2.31 (s, 3H), 2.21 (p, J = 4.1 Hz, 2H), 2.09 –1.92 (m, 2H), 1.87 – 1.66 (m, 2H), 1.06 (s, 1H), 0.63 (d, J = 7.8 Hz, 2H), 0.33(d, J = 11.6 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6) δ 160.63, 158.43, 156.64,137.76, 137.71, 134.90, 134.84, 132.79, 122.45, 120.08, 119.33, 118.31,115.62, 71.95, 69.34, 67.20, 60.75, 52.78, 52.16, 36.72, 29.86, 16.02, 4.57,-4.19, -8.54.

[0284] (Z)-N-allyl-N-methyl-1-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-amine (15ai)

[0285] The synthesis of intermediate 15ai was similar to that of 15n, except that intermediate 14f was used instead of 14b. The yield was 80%. 1 H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 9.03 (d, J = 2.7 Hz, 1H), 8.16 (s,1H), 7.83 (s, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.88 (s, 1H), 6.79 (dd, J = 8.5, 2.8Hz, 1H), 6.03 (s, 1H), 5.31 (d, J = 16.2 Hz, 2H), 4.71 (s, 2H), 4.49 – 4.39 (m,2H), 4.00 – 3.90 (m, 2H), 3.40 (d, J = 43.3 Hz, 2H), 3.09 (d, J = 11.7 Hz, 2H),2.70 (dd, J = 12.7, 10.4 Hz, 3H), 2.45 (s, 3H), 2.39 – 2.27 (m, 5H), 2.02 (s, 2H), 1.83 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 159.96, 157.90, 157.27, 156.36,137.61, 136.69, 135.52, 133.06, 122.77, 120.70,119.56, 119.28, 117.99,116.22, 104.97, 73.08, 71.93, 69.75, 58.97, 52.65, 39.12, 38.11, 30.00,16.10, 0.04.

[0286] (Z)-N,N-dimethyl-1-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononacan-4 4 -yl)piperidin-4-amine (15aj)

[0287] The synthesis of intermediate 15aj was similar to that of 15b, except that intermediate 14f was used instead of 14a in 82% yield. 1 H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 9.03 (d, J = 2.7 Hz, 1H), 8.18 –8.13 (m, 1H), 7.83 (s, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.93 (s, 1H), 6.79 (dd, J =8.5, 2.8 Hz, 1H), 4.71 (s, 2H), 4.48 – 4.40 (m, 2H), 3.98 – 3.90 (m, 2H), 3.08 (d, J = 11.7 Hz, 2H), 2.71 (td, J = 12.0, 2.1 Hz, 2H), 2.49 (s, 7H), 2.37(s, 3H), 2.32 (q, J = 5.0 Hz, 2H), 2.02 (d, J = 12.5 Hz, 2H), 1.76 (tt, J = 13.6,6.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 159.91, 158.61, 157.90, 157.30, 137.60,136.68, 135.55, 133.06, 127.68, 122.77, 120.69, 119.26, 118.00, 116.20,71.93, 69.75, 52.66,52.61, 41.34, 30.01, 28.72, 16.10, 0.04.

[0288] (Z)-2-(methyl(1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-yl)amino)ethanol (15ak)

[0289] The synthesis of intermediate 15ak was the same as that of 15a, except that intermediate 14e was used instead of 14a. The yield was 76%. 1 H NMR (400 MHz, CDCl3) δ 8.40 – 8.30 (m, 2H), 8.19 (s, 1H), 7.88 (s, 1H), 6.97 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.46 (dd, J = 8.4, 2.4 Hz, 1H), 4.34 –4.26 (m, 2H), 4.15 – 4.08 (m, 2H), 3.78 – 3.71 (m, 2H), 3.55 (d, J = 11.2 Hz,2H), 2.85 (d, J = 6.1 Hz, 3H), 2.60 (td, J = 11.8, 2.4 Hz, 2H), 2.52 (s, 3H), 2.38 (s, 3H), 2.05 – 1.83 (m, 8H), 1.28 (dd, J = 14.0, 6.6 Hz, 2H). 13C NMR (101MHz, CDCl3) δ 159.97, 158.02, 157.35, 151.60, 138.57, 136.47, 134.73, 132.45,122.16, 118.78, 116.67, 110.82,105.59, 68.82, 62.71, 57.52, 55.56, 50.78,50.70, 37.32, 27.76, 27.69, 27.41, 21.12, 16.21.

[0290] (Z)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)-N-propylpiperidin-4-amine (15al)

[0291] The synthesis method of intermediate 15al was the same as that of 15d, except that intermediate 14e was used instead of 14a. The yield was 83%. 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.18 (d, J =0.8 Hz, 1H), 7.91 – 7.85 (m, 1H), 7.00 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.46(dd, J = 8.4, 2.5 Hz, 1H), 4.33 – 4.26 (m, 2H), 4.17 – 4.09 (m, 2H), 3.55 (d, J =11.3 Hz, 2H), 2.77 – 2.68 (m, 1H), 2.65 – 2.56 (m, 4H), 2.46 (s, 3H), 2.38(s, 3H), 2.00 (q, J = 6.5 Hz, 2H), 1.93 (dd, J = 9.6, 5.3 Hz, 4H), 1.89 – 1.80(m, 2H), 1.67 – 1.56 (m, 2H), 1.30 (p, J = 7.2 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H).13 C NMR (101 MHz, CDCl3) δ 159.95, 158.02, 157.35, 151.61, 138.55, 136.59,136.37, 132.46, 122.15, 118.77,116.61, 110.94, 105.87, 68.82, 61.75, 55.66,50.86, 50.72, 37.55, 27.81, 27.74, 27.42, 21.19, 20.10, 16.21, 11.76.

[0292] (Z)-N-methyl-N-(1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-yl)pyrrolidine-1-carboxamide (15am)

[0293] The synthesis of intermediate 15am was similar to that of 15q, except that intermediate 14e was used instead of 14c. The yield was 88%. 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 6.9 Hz, 2H), 8.19 (s, 1H), 7.88 (s,1H), 7.12 (s, 1H), 6.93 (s, 1H), 6.47 (dd, J = 8.5, 2.4 Hz, 1H), 4.35 – 4.24(m, 2H), 4.19 – 4.07 (m, 2H), 3.87 (s, 1H), 3.59 – 3.49 (m, 2H), 3.42 – 3.30(m, 4H), 2.79 (s, 5H), 2.38 (s, 3H), 1.98 (dp, J = 30.7, 7.9, 7.3 Hz, 6H), 1.88– 1.74 (m, 6H), 1.33 – 1.22 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 163.61, 159.91,158.00, 157.37, 151.59,149.70, 138.59, 136.49, 132.53, 122.15, 116.64,110.85, 105.40, 68.81, 54.20, 51.44, 50.65, 48.59, 30.80, 29.34, 27.70,27.41, 25.61, 21.05, 16.21.

[0294] (Z)-N-(cyclopropylmethyl)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-amine (15an)

[0295] The synthesis of intermediate 15an was similar to that of 15f, except that intermediate 14e was used instead of 14a. The yield was 82%. 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.18 (s,1H), 7.88 (s, 1H), 6.99 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.46 (dd, J = 8.4, 2.4Hz, 1H), 4.34 – 4.26 (m, 2H), 4.17 – 4.08 (m, 2H), 3.55 (d, J = 11.3 Hz, 2H),2.89 (t, J = 11.6 Hz, 1H), 2.65 – 2.59 (m, 4H), 2.57 (s, 3H), 2.54 (s,1H), 2.38(s, 3H), 2.07 – 1.82 (m, 8H), 1.29 (p, J = 6.9 Hz, 2H), 1.04 – 0.95 (m, 1H), 0.71 – 0.64 (m, 2H), 0.29 – 0.22 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 159.96,158.01, 157.35, 151.62, 138.56,136.47, 136.37, 132.46, 122.14, 118.80,116.65, 110.91, 105.78, 68.83, 61.67, 58.60, 50.74, 50.71, 37.31, 27.79,27.53, 27.41, 21.16, 16.21, 8.16, 4.46.

[0296] (Z)-N-allyl-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-amine (15ao)

[0297] The synthesis of intermediate 15ao was similar to that of 15n, except that intermediate 14e was used instead of 14b. The yield was 80%. 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.18 (s,1H), 7.88 (s, 1H), 7.00 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.47 (dd, J = 8.4, 2.5Hz, 1H), 6.07 – 5.90 (m, 1H), 5.32 – 5.17 (m, 2H), 4.33 – 4.25 (m, 2H), 4.17– 4.09 (m, 2H), 3.53 (dt, J = 11.6, 3.1 Hz, 2H), 3.26 (d, J = 6.3 Hz, 2H), 2.70(s, 1H), 2.58 (td, J = 11.8, 2.4 Hz, 2H), 2.38 (s, 6H), 1.93 (dddd, J = 43.9,23.7, 12.4, 5.4 Hz, 8H), 1.31 (p, J = 7.1 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ159.96, 158.04, 157.33, 155.94, 151.60,138.54, 136.86, 136.24, 132.41,122.17, 118.68, 116.57, 110.97, 106.05, 68.84, 60.70, 56.98, 50.93, 50.75,37.07, 27.96, 27.85, 27.42, 21.26, 16.22.

[0298] (Z)-N-methyl-N-(1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-yl)cyclopropanecarboxamide (15ap)

[0299] The synthesis of intermediate 15ap was similar to that of 15z, except that intermediate 14e was used instead of 14d. The yield was 78%. 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 11.8 Hz, 2H), 8.19 (s, 1H), 7.88 (s,1H), 7.10 (s, 1H), 6.87 (d, J = 9.6 Hz, 1H), 6.47 (dd, J = 8.3, 2.8 Hz, 1H), 4.35– 4.24 (m, 2H), 4.13 (q, J = 7.9, 6.5 Hz, 2H), 3.62 – 3.46 (m, 2H), 3.09 (s,2H), 2.70 (d, J = 12.9 Hz, 2H), 2.38 (s, 3H), 2.23 – 2.07(m, 1H), 1.99 (dq, J =28.1, 7.6, 7.2 Hz, 6H), 1.85 – 1.65 (m, 4H), 1.36 – 1.25 (m, 2H), 1.22 (q, J =6.7 Hz, 1H), 1.01 (dq, J = 7.8, 4.2 Hz, 2H), 0.78 (dt, J = 8.0, 3.3 Hz, 2H).13 CNMR (101 MHz, CDCl3) δ 173.34, 159.93, 158.04, 157.35, 151.51,138.58, 136.52,132.54, 122.17, 118.71, 116.60, 110.81, 105.51, 105.24, 68.71, 51.13, 50.65,30.65, 29.70, 29.23, 27.68, 27.42, 21.03, 16.21, 11.83, 7.61.

[0300] (Z) -2 5 -Methyl-4 4 -(4-methylpiperazin-1-yl)-1 1 H-5-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15aq)

[0301] The synthesis of intermediate 15aq was the same as that of 15b, except that intermediate 14g was used instead of 14a. The yield was 83%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.43 (d, J = 2.5 Hz, 1H), 8.18 (s,1H), 7.81 (s, 1H), 7.14 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.52 (dd, J = 8.4, 2.5Hz, 1H), 4.40 – 4.26 (m, 4H), 3.11 (s, 4H), 2.70 (s,4H), 2.39 (d, J = 16.9 Hz, 6H), 2.06 – 1.94 (m, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 154.99, 153.16, 152.73,146.91, 133.24, 132.15, 131.82, 128.60, 117.85, 113.95, 111.82, 107.51,104.53, 64.94, 50.63, 46.14, 45.68,41.14, 21.98, 20.00, 10.65.

[0302] (Z)-2-(4-(2 5 -methyl-1 1 H-5-Oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline-44-yl)piperazin-1-yl)ethanol (15ar)

[0303] The synthesis of intermediate 15ar was the same as that of 15a, except that intermediate 14g was used instead of 14a. The yield was 65%. 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.38 (d, J = 2.5 Hz, 1H), 8.12 (d, J =0.8 Hz, 1H), 7.74 (s, 1H), 6.97 (s, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.45 (dd, J =8.5, 2.5 Hz, 1H), 4.31 – 4.18 (m, 4H), 3.64 (t, J = 5.3 Hz, 2H), 3.04 (s, 4H), 2.72 (d, J = 5.5 Hz, 4H), 2.62 (t, J = 5.3 Hz, 2H), 2.31 (s, 3H), 2.00 – 1.89 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 158.89, 156.93, 156.36, 150.59, 136.96, 135.78,135.59, 132.29, 121.59, 117.54,115.59, 111.13, 108.09, 68.65, 58.51, 56.55,52.31, 49.85, 49.56, 25.69, 23.73, 14.36.

[0304] (Z) -2 5 -Methyl-4 4 -(4-propylpiperazin-1-yl)-1 1 H-5-Oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15as)

[0305] The synthesis of intermediate 15as was the same as that of 15d, except that intermediate 14g was used instead of 14a. The yield was 81%.1 H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.19 (s,1H), 7.81 (s, 1H), 7.35 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.53 (dd, J = 8.5, 2.5Hz, 1H), 4.40 – 4.25 (m, 4H), 3.09 (d, J = 5.9 Hz, 4H), 2.67 (s, 4H), 2.43 –2.33 (m, 5H), 2.10 – 1.94 (m, 4H), 1.59 (dt, J = 15.5, 7.5 Hz, 2H), 0.94 (t, J =7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.06, 153.28, 152.64, 146.77,133.21,132.50, 131.68, 128.60, 117.86, 113.69, 111.72, 107.57, 104.80, 64.90,56.03, 48.85, 46.12, 45.95, 21.99, 20.00, 15.19, 10.66, 7.25.

[0306] (Z) -4 4 -(4-isobutylpiperazin-1-yl)-2 5 -methyl-1 1 H-5-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15at)

[0307] The synthesis of intermediate 15at was similar to that of 15o, except that intermediate 14g was used instead of 14b. The yield was 65%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.43 (d, J = 2.5 Hz, 1H), 8.19 (s,1H), 7.81 (s, 1H), 7.01 (s, 1H), 6.85 (d, J= 8.4 Hz, 1H), 6.51 (dd, J = 8.5, 2.5Hz, 1H), 4.40 – 4.26 (m, 4H), 3.15 (s, 4H), 2.72 (s,4H), 2.37 (s, 3H), 2.34 –2.20 (m, 2H), 2.09 – 1.96 (m, 4H), 1.91 (t, J = 6.2 Hz, 1H), 0.97 (d, J = 6.5 Hz,6H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.17, 153.23, 152.63, 146.84, 133.23,132.14, 131.75, 128.59, 117.87, 113.88, 111.84, 107.45, 104.44, 64.90, 61.88,49.06, 46.13, 45.46, 21.97, 20.43, 20.01, 16.36, 10.64.

[0308] (Z) -4 4 -(4-(cyclopropylmethyl)piperazin-1-yl)-2 5 -methyl-1 1 H-5-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15au)

[0309] The synthesis of intermediate 15au was the same as that of 15f, except that intermediate 14g was used instead of 14a. The yield was 68%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.55 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.18 (s,1H), 7.80 (s, 1H), 7.25 – 7.20 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.52 (dd, J =8.4, 2.4 Hz, 1H), 4.34 (t, J = 7.5 Hz, 2H), 4.28 (dd, J= 6.4, 3.9 Hz, 2H), 3.11(s, 4H), 2.77 (s, 4H), 2.37 (d, J = 6.7 Hz, 5H), 2.08 – 1.94 (m, 4H), 0.96 –0.87 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.30, 153.48, 152.90, 147.07,133.46,132.66, 131.96, 128.84, 118.10, 114.02, 112.00, 107.75, 104.83, 65.13,59.26, 49.07, 46.36, 46.08, 22.21, 20.24, 10.89, 3.65, -0.50.

[0310] (Z) -4 4 -(4-allylpiperazin-1-yl)-2 5 -methyl-1 1 H-5-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15av)

[0311] The synthesis of intermediate 15av was similar to that of 15n, except that intermediate 14g was used instead of 14b. The yield was 71%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.27 (d, J = 2.0 Hz, 1H), 8.63 (d, J = 2.0 Hz,1H), 8.43 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H),6.77 (dd, J = 8.6, 2.1 Hz, 1H), 6.73 – 6.67 (m, 1H), 5.85 (tdd, J = 16.7, 7.1,3.5 Hz, 1H), 5.18 (dd, J = 25.3, 13.7 Hz, 2H), 4.36 – 4.19 (m, 4H), 2.99 (d, J=6.5 Hz, 2H), 2.90 (s, 4H), 2.46 (s, 4H), 2.32 (s, 3H), 1.91 (d, J = 7.7 Hz,2H), 1.73 (h, J = 7.0, 6.5 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 160.33, 158.49,157.28, 151.88, 138.10, 137.46, 136.57, 136.06, 134.47, 122.04,118.46,117.97, 116.08, 112.31, 108.51, 69.88, 61.51, 53.47, 50.87, 50.44, 26.65,25.04, 15.21.

[0312] (Z) -2 5 -Methyl-4 4 -(4-methylpiperazin-1-yl)-1 1 H-6-Oxy-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15aw)

[0313] The synthesis of intermediate 15aw was the same as that of 15b, except that intermediate 14h was used instead of 14a. The yield was 80%. 1 H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 9.03 (d, J = 2.7 Hz, 1H), 8.16 (s,1H), 7.83 (s, 1H), 7.21 (d, J = 4.0 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.82 (dd, J = 8.5, 2.7 Hz, 1H), 4.72 (s, 2H), 4.49 – 4.39 (m, 2H), 3.98 – 3.88 (m, 2H), 2.92 (t, J = 4.8 Hz, 4H), 2.61 (s, 4H), 2.38 (d, J = 8.8 Hz, 6H), 2.35 – 2.28 (m,2H). 13C NMR (101 MHz, CDCl3) δ 159.86, 157.95, 157.26, 144.36, 137.58,136.79,135.55, 133.04, 122.79, 120.68, 119.47, 118.13, 116.11, 71.88, 69.76, 55.64,52.68, 52.60, 46.09, 30.01, 16.11.

[0314] (Z)-2-(4-(2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline-4 4 -yl)piperazin-1-yl)ethanol (15ax)

[0315] The synthesis of intermediate 15ax was the same as that of 15a, except that intermediate 14h was used instead of 14a. The yield was 67%. 1 H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 8.90 (d, J = 2.7 Hz, 1H), 8.02 (s,1H), 7.73 (s, 1H), 7.20 (s, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.77 (dd, J = 8.5, 2.7Hz, 1H), 4.61 (s, 2H), 4.36 – 4.29 (m, 2H), 3.83 (t, J = 4.9 Hz, 2H), 3.61 (t, J = 5.3 Hz, 2H), 2.84 (t, J = 4.8 Hz, 4H), 2.75 – 2.50 (m, 6H), 2.27 (s, 3H), 2.25 – 2.18 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.46, 157.65, 157.46, 144.19,137.58,136.69, 135.71, 132.88, 122.68, 120.72, 119.40, 118.29, 116.11, 71.81,69.70, 59.80, 57.81, 53.61, 52.58, 52.47, 29.87, 16.01.

[0316] (Z) -2 5 -Methyl-4 4 -(4-propylpiperazin-1-yl)-1 1 H-6-Oxy-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15ay)

[0317] The synthesis of intermediate 15ay was the same as that of 15d, except that intermediate 14h was used instead of 14a. The yield was 82%. 1 H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 9.04 (d, J = 2.7 Hz, 1H), 8.16 (d, J =0.8 Hz, 1H), 7.83 (d, J = 0.7 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.98 (s, 1H), 6.81 (dd, J = 8.5, 2.8 Hz, 1H), 4.71 (s, 2H), 4.49 – 4.40 (m, 2H), 3.98 – 3.89 (m, 2H), 3.02 (s, 4H), 2.78 (s, 4H), 2.54 (s, 2H), 2.41 – 2.36 (m, 3H),2.35 –2.28 (m, 2H), 1.69 (s, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ159.96, 157.90, 157.24, 150.96, 137.61, 136.29, 135.51, 133.06, 122.80,120.62, 119.71, 118.18, 116.24, 77.23, 71.91, 69.76, 53.50,52.58, 52.16,51.93, 30.00, 16.09, 11.84.

[0318] (Z) -4 4 -(4-isobutylpiperazin-1-yl)-2 5 -methyl-1 1 H-6-Oxy-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15az)

[0319] The synthesis of intermediate 15az was similar to that of 15o, except that intermediate 14h was used instead of 14b. The yield was 77%. 1 H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 9.00 (d, J = 2.6 Hz, 1H), 8.12 (s,1H), 7.83 (s, 1H), 7.43 (s, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.83 (dd, J = 8.5, 2.7Hz, 1H), 4.72 (s, 2H), 4.49 – 4.39 (m, 2H), 3.98 – 3.85 (m, 2H), 2.89 (t, J =4.8 Hz, 4H), 2.56 (s, 4H), 2.37 (s, 3H), 2.35 – 2.28 (m, 2H), 2.18 (d, J = 7.3Hz, 2H), 1.83 (hept, J = 6.8 Hz, 1H), 0.93 (d, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 159.30, 157.77, 157.57, 144.77, 137.60, 136.47, 135.69, 132.91,122.74, 120.65, 119.33, 118.22, 115.98, 71.86, 69.79, 67.01, 54.09,52.84,52.64, 30.01, 25.41, 21.01, 16.10.

[0320] (Z) -4 4 -(4-(cyclopropylmethyl)piperazin-1-yl)-2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15aaa)

[0321] The synthesis of intermediate 15aaa was the same as that of 15f, except that intermediate 14h was used instead of 14a. The yield was 80%. 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 9.04 (d, J = 2.7 Hz, 1H), 8.16 (s,1H), 7.83 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 6.82 (dd, J = 8.5, 2.7Hz, 1H), 4.72 (s, 2H), 4.53 – 4.38 (m, 2H), 4.01 – 3.87 (m, 2H), 2.99 (s,4H), 2.80 (s, 4H), 2.44 (d, J = 6.7 Hz, 2H), 2.37 (s, 3H), 2.36 – 2.28 (m, 2H), 1.00 (s, 1H), 0.66 – 0.56 (m, 2H), 0.21 (t, J = 5.0 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.93, 157.91, 157.23, 137.59, 136.84,135.52, 133.05, 122.79,120.61, 119.60, 118.15, 116.18, 71.89, 69.76, 63.62, 53.63, 52.59, 52.33,30.01, 16.10, 15.29, 4.12.

[0322] (Z) -4 4 -(4-allylpiperazin-1-yl)-2 5 -methyl-1 1 H-6-Oxy-3-nitro-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15aab)

[0323] The synthesis of intermediate 15aab was the same as that of 15n, except that intermediate 14h was used instead of 14b. The yield was 77%. 1 H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 9.03 (d, J = 2.7 Hz, 1H), 8.16 (d, J =0.8 Hz, 1H), 7.83 (s, 1H), 7.04 (d, J= 8.6 Hz, 2H), 6.81 (dd, J = 8.5, 2.7 Hz,1H), 5.96 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 5.32 – 5.18 (m, 2H), 4.71 (s, 2H), 4.48 – 4.39 (m, 2H), 4.00 – 3.88 (m, 2H), 3.16 (d, J = 6.7 Hz, 2H), 2.96 (t, J =4.8 Hz, 4H), 2.69 (s, 4H), 2.37 (s, 3H), 2.35 – 2.27 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.90, 159.32, 157.91, 157.25, 144.25,137.59, 136.83, 135.53,133.95, 133.04, 122.79, 120.67, 119.54, 118.15, 116.17, 71.89, 69.76, 61.69,53.47, 52.59, 52.48, 30.01, 16.10.

[0324] (Z) -2 5- Methyl-4 4 -(4-(2-methylbutyl)piperazin-1-yl)-1 1 H-6-Oxy-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclononazoline (15aac)

[0325] The synthesis of intermediate 15aac was similar to that of 15u, except that intermediate 14h was used instead of 14c. The yield was 63%. 1 H NMR (400 MHz, DMSO- d 6) δ 9.61 (s, 1H), 9.02 (d, J = 2.7 Hz, 1H), 8.16 (d, J = 0.8 Hz, 1H), 7.83 (d, J = 0.6 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.93 (s, 1H), 6.80 (dd, J= 8.5, 2.7 Hz, 1H), 4.72 (s, 2H), 4.47 – 4.41 (m, 2H), 3.97 – 3.91 (m, 2H), 2.92 (s, 4H), 2.62 (d, J = 26.9 Hz, 4H), 2.37 (s, 3H), 2.35 – 2.29 (m,2H), 1.70 – 1.46 (m, 4H), 1.20 – 1.10 (m, 1H), 0.93 (q, J = 7.3 Hz, 6H). 13 C NMR(101 MHz, CDCl3)δ 159.97, 157.95, 157.28, 143.11, 137.62, 135.59, 133.69,133.04, 122.83, 121.21, 120.68, 118.16, 116.20, 71.93, 69.82, 54.15, 52.66,31.92, 30.06, 27.90, 18.01, 16.14, 14.23, 11.41, 0.05.

[0326] (Z)-N,N-dimethyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-amine (15aad)

[0327] The synthesis of intermediate 15aad was the same as that of 15b, except that intermediate 14e was used instead of 14a. The yield was 86%. 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.18 (s,1H), 7.88 (s, 1H), 7.01 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.47 (dd, J = 8.4, 2.5Hz, 1H), 4.35 – 4.26 (m, 2H), 4.20 – 4.10 (m, 2H), 3.51 (t, J = 9.8 Hz, 2H),2.58 (td, J= 11.8, 2.3 Hz, 2H), 2.38 (d, J = 5.6 Hz, 10H), 2.06 – 1.89 (m, 6H), 1.78 (td, J = 12.0, 3.8 Hz, 2H), 1.33 (p, J = 7.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3)δ 159.94, 158.04, 157.34, 151.61, 138.53, 137.05, 136.16, 132.40, 122.17,118.63, 116.53, 111.05, 106.27, 68.85, 62.45, 50.81, 50.77, 41.43,28.53,27.89, 27.42, 21.33, 16.22.

[0328] (Z)-N-isobutyl-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-amine (15aae)

[0329] The synthesis of intermediate 15aae was similar to that of 15o, except that intermediate 14e was used instead of 14b. The yield was 63%. 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.18 (s,1H), 7.88 (s, 1H), 6.97 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.46 (dd, J = 8.4, 2.4Hz, 1H), 4.33 – 4.25 (m, 2H), 4.17 – 4.08 (m, 2H), 3.55 – 3.48 (m, 2H), 2.56(t, J = 10.8 Hz, 3H), 2.38 (s, 8H), 2.01 (p, J = 7.0 Hz, 2H), 1.93 (q, J= 7.7 Hz,2H), 1.88 – 1.57 (m, 6H), 1.29 (td, J = 13.4, 12.2, 6.1 Hz, 2H), 0.93 (d, J = 6.4Hz, 6H).

[0330] (Z)-1,1,3-trimethyl-3-(1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-yl)urea (15aaf)

[0331] The synthesis of intermediate 15aaf was similar to that of 15r, except that intermediate 14e was used instead of 14c. The yield was 83%. 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.19 (s,1H), 7.88 (s, 1H), 7.27 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.47 (dd, J = 8.5, 2.4Hz, 1H), 4.34 – 4.25 (m, 2H), 4.13 (t, J = 7.7 Hz, 2H), 3.75 (tt, J = 12.2, 4.0Hz, 1H), 3.56 – 3.49 (m, 2H), 2.79 (d, J = 13.5 Hz, 9H), 2.67 (t, J = 11.5 Hz, 2H), 2.37 (s, 3H), 2.07 – 1.91 (m, 6H), 1.84 – 1.75 (m, 2H), 1.28 (p, J = 6.7Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 165.73, 159.88, 158.08, 157.34, 151.52,138.56, 136.74, 136.36, 132.51, 122.17, 118.78, 116.51, 110.89, 105.59,68.74, 55.00, 51.24,50.67, 38.89, 31.22, 29.48, 27.73, 27.42, 21.12, 16.21.

[0332] (Z)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)-N-(2-methylbutyl)piperidin-4-amine (15aag)

[0333] The synthesis of intermediate 15aag was the same as that of 15u, except that intermediate 14e was used instead of 14c. The yield was 58%. H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 8.18 (s,1H), 7.88 (s, 1H), 6.94 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.46 (dd, J = 8.4, 2.5Hz, 1H), 4.33 – 4.27 (m, 2H), 4.17 – 4.11 (m, 2H), 3.52 (d, J = 11.2 Hz, 2H),2.56 (t, J = 11.5 Hz, 3H), 2.38 (s, 9H), 2.02 (q, J = 6.5, 5.9 Hz, 2H), 1.94 (t, J = 7.7 Hz, 2H), 1.82 (s, 4H), 1.63 (s, 4H), 1.36 – 1.29(m, 2H), 0.92 (d, J = 7.3Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.96, 158.04, 157.33, 151.55, 138.54,132.47, 122.17, 118.64, 116.55, 110.90, 105.83, 68.75, 51.27, 50.72, 38.82,27.75, 27.43, 21.21, 21.01, 17.90, 16.21, 11.36.

[0334] (Z)-N-butyl-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-amine (15aah)

[0335] The synthesis of intermediate 15aah was similar to that of 15e, except that intermediate 14e was used instead of 14a. The yield was 84%. 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.1 Hz, 2H), 8.19 (s, 1H), 7.88 (s,1H), 7.15 (s, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.46 (dd, J = 8.4, 2.4 Hz, 1H), 4.33– 4.26 (m, 2H), 4.14 – 4.06 (m, 2H), 3.62 – 3.54 (m, 2H), 3.24 (ddd, J = 12.3,8.7, 3.6 Hz, 1H), 3.01 – 2.93 (m, 2H), 2.74 – 2.59 (m, 5H), 2.38 (s, 3H), 2.27(d, J = 11.7 Hz, 2H), 2.01 (ddd, J = 12.2, 7.4, 4.9 Hz, 4H), 1.96 – 1.82 (m, 4H), 1.42 (h, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H), 0.98 (d, J = 7.4 Hz, 3H). 13C NMR(101 MHz, CDCl3) δ 159.91, 157.98, 157.37, 151.62, 138.58, 136.90, 135.50,132.50, 122.10, 118.98, 116.74, 110.82,105.36, 68.82, 62.56, 53.30, 50.64,50.19, 36.89, 27.68, 27.39, 26.84, 26.75, 20.98, 20.42, 16.20, 13.63.

[0336] (Z)-N-(2-fluoro-2-methylpropyl)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-amine (15aai)

[0337] The synthesis of intermediate 15aai was the same as that of 15a, except that intermediate 14e was used instead of 14a, and 1-chloro-2-fluoro-2-methylpropane was used instead of 2-iodoethanol. The yield was 75%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.79 (s,1H), 8.47 (s, 1H), 8.17 (d, J = 1.5 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.30 (dd, J = 7.5, 1.5 Hz, 1H), 6.91 – 6.82 (m, 2H), 4.01 – 3.93 (m, 2H), 3.77 (t, J = 7.1Hz, 2H), 3.62 (dt, J = 12.4, 7.1 Hz, 2H), 3.38 – 3.26 (m, 3H), 3.21 (s, 1H), 2.76 (pq, J = 6.9, 1.4 Hz, 1H), 2.56 (d, J = 0.6 Hz, 3H), 2.34 (d, J = 1.5 Hz, 3H), 1.94 – 1.73 (m, 6H), 1.71 – 1.64 (m, 7H), 1.60 (s, 3H).

[0338] (Z)-1-(methyl(1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-yl)amino)aceton-2-one (15aaj)

[0339] The synthesis of intermediate 15aaj was the same as that of 15a, except that intermediate 14e was used instead of 14a, and bromoacetone was used instead of 2-iodoethanol. The yield was 76%. 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.32 (d, J =2.4 Hz, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.21 (s, 1H), 6.85 (d, J = 8.5 Hz,1H), 6.47 (dd, J = 8.5, 2.5 Hz, 1H), 4.34 – 4.23 (m, 2H), 4.20 – 4.08 (m, 2H), 3.50 (dd, J = 9.2, 5.7 Hz, 2H), 3.30 (s, 2H), 2.61 – 2.49(m, 3H), 2.36 (d, J =7.0 Hz, 6H), 2.18 (s, 3H), 2.01 (q, J = 6.4 Hz, 2H), 1.96 – 1.82 (m, 4H), 1.73(qd, J = 12.0, 3.8 Hz, 2H), 1.33 – 1.26 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ208.87, 159.81, 158.03, 157.40, 151.54, 138.54, 137.01, 136.19, 132.47,122.16,118.62, 116.49, 110.99, 105.95, 68.77, 63.92, 61.35, 51.08, 50.71,39.31, 28.64, 27.82, 27.42, 27.39, 21.23, 16.21.

[0340] (Z)-N-methyl-1-(25 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)-N-(2-methylallyl)piperidin-4-amine (15aak)

[0341] The synthesis method of intermediate 15aak was the same as that of 15a, except that intermediate 14e was used instead of 14a, and 3-chloro-2-methylpropene was used instead of 2-iodoethanol. The yield was 80%. 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.31(d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.18 (s, 1H), 6.86 (d, J = 8.5Hz, 1H), 6.47 (dd, J = 8.4, 2.5 Hz, 1H), 4.89 (d, J = 17.0 Hz, 2H), 4.36 – 4.24(m, 2H), 4.18 – 4.08 (m, 2H), 3.60 – 3.42 (m, 2H), 3.04 (s, 2H), 2.56 (td, J =11.3, 3.0 Hz, 3H), 2.37 (s, 3H), 2.27 (s, 3H), 2.01 (q, J = 6.4, 5.9 Hz, 2H),1.94 (q, J = 8.6, 7.6 Hz, 2H), 1.86 (dd, J = 15.0, 5.4 Hz, 2H), 1.82 (s, 1H), 1.81 (s, 4H), 1.32 (q, J = 7.2 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 159.89,158.08, 157.35, 151.54, 138.54, 137.18, 136.11, 132.46, 122.18, 118.62,116.47, 110.99, 106.04, 68.76, 60.52, 60.41, 51.24, 50.73, 37.56, 27.99,27.84, 27.43, 21.27, 20.72, 16.22.

[0342] (Z)-N-(cyclobutylmethyl)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-amine (15aal)

[0343] The synthesis method of intermediate 15aal was the same as that of 15a, except that intermediate 14e was used instead of 14a, and 3-bromomethylcyclobutane was used instead of 2-iodoethanol. The yield was 67%. 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.32(d, J = 2.4 Hz, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.41 (s, 1H), 6.84 (d, J = 8.5Hz, 1H), 6.49 (dd, J = 8.4, 2.4 Hz, 1H), 4.32 – 4.25 (m, 2H), 4.14 – 4.08 (m,2H), 3.54 (dd, J = 9.3, 6.5 Hz, 2H), 2.92 (tt, J = 11.9, 3.8 Hz, 1H), 2.87 – 2.73(m, 3H), 2.60 (td, J = 11.8, 2.2 Hz, 2H), 2.51 (s, 3H), 2.37 (s, 3H), 2.22 –2.14 (m, 2H), 2.07 (d, J= 3.7 Hz, 2H), 2.03 – 1.98 (m, 2H), 1.97 – 1.80 (m,6H), 1.80 – 1.70 (m, 2H), 1.31 – 1.24 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ159.53, 157.90, 157.58, 151.55, 138.58,136.56, 136.13, 132.55, 122.09,118.84, 116.56, 110.97, 105.55, 68.78, 61.86, 58.85, 50.67, 50.60, 37.04,32.53, 27.84, 27.72, 27.40, 27.00, 21.07, 18.67,16.20.

[0344] (Z)-N-(2-butyl)-N-methyl-1-(2 5 -methyl-1 1 H-5-oxo-3-nitrogen-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzocyclodecazane-4 4 -yl)piperidin-4-amine (15aam)

[0345] The synthesis of intermediate 15aam was the same as that of 15a, except that intermediate 14e was used instead of 14a, and 2-bromobutane was used instead of 2-iodoethanol. The yield was 59%. 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.2 Hz, 2H),8.19 (s, 1H), 7.89 (s, 1H), 7.00 (s, 1H), 6.91 (s, 1H), 6.47(dd, J = 8.4, 2.4Hz, 1H), 4.78 (q, J = 6.3 Hz, 1H), 4.35 – 4.26 (m, 2H), 4.17 – 4.10 (m, 2H), 3.50 (dd, J = 17.2, 9.2 Hz, 2H), 2.84 (s, 3H), 2.69 (s, 1H), 2.38 (s, 3H), 1.98(dt, J = 28.4, 6.9 Hz, 6H), 1.74 (d, J= 12.2 Hz, 2H), 1.65 – 1.57 (m, 4H), 1.29 – 1.23 (m, 5H), 0.93 (t, J = 7.5 Hz, 3H).

[0346] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0347] Experimental Example 1: Effects of Compounds on JAK Kinase and JAK2 Expression V617F Suppressive activity of mutant cells

[0348] 1. Experimental methods

[0349] (1) Inhibitory activity against JAK kinase

[0350] In a reaction tube, add buffer (8 mM MOPS, pH 7.0, 0.2 mM EDTA, 10 mM MnCl2), the kinase to be tested, the substrate of the kinase to be tested, 10 mM magnesium acetate and γ33P-ATP solution, and different concentrations of compounds in sequence, then add MgATP to the reaction to start the enzyme reaction process and incubate at room temperature for 40 minutes. Finally, the reaction was terminated with 5 μl of 3% phosphate buffer, and 10 μl of the reaction solution was titrated onto the Filtermat A membrane, washed three times with 75 mM phosphate solution for 5 minutes each, and then washed once with methanol, and finally the Filtermat A membrane was dried and scintillation counted. Detailed experimental procedures can be viewed on the website https: / / www.eurofinsdiscoveryservices.com. The number represents the residual activity. The smaller the number, the stronger the kinase activity. The test data is divided into the following types: A: IC 50 <10nM; B: IC 50 11-100 nM; C: IC 50 101-1000 nM; D: IC 50 >1000 nM.

[0351] (2) MTT assay to detect tumor cell proliferation activity

[0352] BaF3JAK2 V617FAfter the cells were collected and counted, they were seeded into 96-well culture plates at a density of 10,000-15,000 cells per well. After 24 hours, the cells were treated with various concentrations of the test compound for 72 hours, and the control wells were added with an equal volume of dimethyl sulfoxide blank solution. After reaching the treatment time point, 20 μL of MTT (5 mg / mL) was added to each well, and the cells were incubated for another 1-4 hours. After the blue precipitate produced by the MTT action was observed under a microscope, the medium containing MTT was discarded. 50 μL of 20% SDS was used to fully dissolve the precipitate in each well and overnight. The absorbance value at a wavelength of 570 nm was measured using an ELISA reader. The inhibition rate of each test compound on cell proliferation activity was calculated according to the formula: inhibition rate = 100%-(control well absorbance value-experimental well absorbance value) / control well absorbance value*100%.

[0353] After calculating the inhibition rate of each concentration of compound on cell proliferation activity, the compound treatment concentration was converted into logarithmic form, and the corresponding inhibition rate was fitted to the dose response curve using Graphpad prism 8.0 software, and the IC 50 value.

[0354] Test data is divided into the following categories: E: IC 50 <200 nM; F: IC 50 201-500 nM; G: IC 50 501-1000 nM; H: IC 50 >1000 nM.

[0355] 2. Experimental results

[0356] The compounds of the present invention have an effect on JAK kinase and JAK2 expression V617F The inhibitory activities of the cells are shown in Table 1.

[0357] Table 1. Effects of the compounds of the present invention on JAK kinases and expression of JAK2 V617F Suppressive activity of mutant cells

[0358]

[0359]

[0360] As shown in Table 1, the compounds of the present invention have an effect on JAK kinase and expression of JAK2 V617F Compared with the positive compound 18e, most of the compounds of the present invention (15b, 15v, 15w, 15x, 15y, 15ab, 15ae, 15ah, 15ai, 15am, 15an, 15aq-15ax) have excellent inhibitory activity on cells expressing JAK2. V617F The mutant has a more excellent cell inhibitory activity.

[0361] Test Example 2: Screening of compound enzyme activity

[0362] 1. Experimental methods

[0363] This test example studies the inhibitory activity of the compounds of the present invention on different kinases, and the experimental method is the same as (1) in Test Example 1.

[0364] 2. Experimental results

[0365] The experimental results are shown in Table 2 and Figure 1 As shown: Compared with the positive compound 18e, the compound of the present invention exhibits excellent JAK2 selectivity.

[0366] Table 2. Preferred compounds IC of the present invention 50 Selective testing

[0367]

[0368] IC 50 (nM): ****<5; ***<50; **<100; *<1000.

[0369] Selectivity: #<10; ##<30; ###<50; ####<100. Selectivity is the IC of other kinases 50 Divide the value by the IC of JAK2 50 The larger the value, the better the selectivity of the compound for JAK2.

[0370] Test Example 3: In vivo pharmacokinetic properties of compounds

[0371] 1. Experimental methods

[0372] The experimental animals were male Sprague-Dawley rats (6-8 weeks old, weighing 270 to 325 g). Oral administration was adopted, and the dose was 5 mg / kg. Oral administration was given to rats in the form of a solution (2% ethanol and 1% Tween 80, pH 5) by gavage. Blood samples (rat superior vena cava) were collected at different time points [0min (before administration), 15min, 30min, 45min, 1h, 2h, 4h, 6h, 8h, 10h, 12h and 24h], and plasma was separated by centrifugation and added to a medium containing EDTA. The concentration of the compound in plasma was determined by LC-MS / MS (Waters Acquity UPLC system; Waters QuattroPremier XE), and the pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin (ver 5.2, Pharsight, CA).

[0373] 2. Experimental results

[0374] Table 3. In vivo pharmacokinetic properties of compounds

[0375]

[0376] Maximum blood concentration C max (ng / mL): *<100; **<1000; ***<5000

[0377] Half-life T 1 / 2 (h): #<1; ##<5; ###<10

[0378] Clearance Clz / F (L / h / kg): &<5; &&<20; &&&<50; &&&&<100

[0379] Area under the plasma concentration-time curve AUC 0-t (ng·h / mL): *<100; **<1000; ***<5000; ****<20000

[0380] The above experimental results (Table 3) suggest that compared with the positive compound 18e, some of the macrocyclic compounds of the present invention exhibit excellent in vivo pharmacokinetic properties and good drugability, among which compound 15au has the best drugability.

[0381] Experimental Example 4: Kinase selectivity results of compound 15au

[0382] 1. Experimental methods

[0383] The experimental method is the same as (1) in Experiment 1.

[0384] 2. Experimental results

[0385] The kinase selectivity results of compound 15au are shown in Tables 4 and Figure 2 shown.

[0386] Table 4. IC of compound 15au against related kinases 50 Test Results

[0387]

[0388] IC 50 (nM): *****<5; ****<50; ***<100; **<1000; *<10000

[0389] The above results: 206 kinase activity screening results and IC 50 Tests showed that compound 15au had good selectivity for JAK2.

[0390] Experimental Example 5: Study on the in vivo treatment of myelofibrosis with compound 15au

[0391] 1. Experimental methods

[0392] Ba / F3-JAK2 V617F Driving malignant tumor mouse models

[0393] Routine culture of Ba / F3-JAK2 V617F Cells were transplanted into immunodeficient BALB / c-nude mice by tail vein injection (200 μL), Ba / F3-JAK2 V617F The inoculum size of the mouse model driving malignant tumors was 3.0×10 6 / mouse, batch induction modeling. Drug administration began on the fourth day after successful modeling, and treatment continued for 13 days. The mice were divided into 4 groups, with 6 mice in each group. 6 untreated mice served as the baseline control group. At the end of the experiment, all mice were euthanized, and the spleen and liver were collected and weighed. The 5-6 week old Balb / C mice used in the experiment were purchased from Beijing Warfark Biotechnology Co., Ltd. All animal experiments followed the Guide for the Care and Use of Laboratory Animals, and all mouse experimental protocols have been approved by the Animal Care and Use Committee of Sichuan University (Chengdu, Sichuan, China).

[0394] 2. Experimental results

[0395] Table 5. IC of compound 15au against related kinases 50 Test Results

[0396]

[0397] a QD, once a day, the calculation method of spleen weight recovery ratio is (spleen weight of drug administration group - spleen weight of model group) / spleen weight of model group

[0398] In Table 5, Fed is the market positive drug Fedratinib. Figure 3 and Table 5) show that compound 15au can effectively treat myelofibrosis and is far superior to the marketed drug Fedratinib.

[0399] In summary, the present invention provides a compound with a highly selective inhibitory effect on JAK2, and the compound also has good in vivo pharmacokinetic properties and good drugability. Therefore, the compound of the present invention can be used to prepare JAK2 inhibitors for preventing and / or treating diseases related to JAK2, and has good application prospects.

Claims

1. A compound or a salt thereof, characterized in that: The compound is shown in Formula I: in, linker is selected from n is an integer selected from 1 to 6; m is an integer selected from 0 to 3; Each R3 and R4 are independently selected from hydrogen, C1-C6 alkyl; or R3 and R4 on the same carbon atom are connected to form a C3 cycloalkyl; R2 is selected from hydrogen, C1-C6 alkyl; X is selected from CH or N; When X is selected from CH, R1 is selected from -NR5R6; R5 is selected from hydrogen, C1-C6 alkyl; R6 is selected from hydrogen, C2-C6 alkenyl, -C(O)R7, -C(O)NR7R8, substituted or unsubstituted C1-C6 alkyl; the substituent of the alkyl is selected from hydroxyl, C3-C6 cycloalkyl, halogen, -C(O)R 10 ; In the -C(O)R7, R7 is selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, pyrrolidinyl, piperidinyl; In the -C(O)NR7R8, R7 and R8 are independently selected from hydrogen and C1-C6 alkyl; R 10 Selected from hydrogen, C1-C6 alkyl; When X is selected from N, R1 is selected from hydrogen, C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkyl; the substituent of the alkyl is selected from hydroxyl, C3-C6 cycloalkyl.

2. The compound or salt thereof according to claim 1, characterized in that: The compound is shown in Formula II: in, linker is selected from X is selected from CH or N; When X is selected from CH, R1 is selected from -NR5R6; R5 is selected from hydrogen, C1-C6 alkyl; R6 is selected from hydrogen, C2-C6 alkenyl, -C(O)R7, -C(O)NR7R8, substituted or unsubstituted C1-C6 alkyl; the substituent of the alkyl is selected from hydroxyl, C3-C6 cycloalkyl, halogen, -C(O)R 10 ; In the -C(O)R7, R7 is selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, pyrrolidinyl, piperidinyl; In the -C(O)NR7R8, R7 and R8 are independently selected from hydrogen and C1-C6 alkyl; R 10 Selected from hydrogen, C1-C6 alkyl; When X is selected from N, R1 is selected from hydrogen, C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkyl; the substituent of the alkyl is selected from hydroxyl, C3-C6 cycloalkyl.

3. The compound or salt thereof according to claim 2, characterized in that: The compound is shown in formula III-A: in, linker is selected from R5 is selected from hydrogen, C1-C6 alkyl; R6 is selected from hydrogen, C2-C6 alkenyl, -C(O)R7, -C(O)NR7R8, substituted or unsubstituted C1-C6 alkyl; the substituent of the alkyl is selected from hydroxyl, C3-C6 cycloalkyl, halogen, -C(O)R 10 ; In the -C(O)R7, R7 is selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, pyrrolidinyl, piperidinyl; In the -C(O)NR7R8, R7 and R8 are independently selected from hydrogen and C1-C6 alkyl; R 10 Selected from hydrogen, C1-C6 alkyl.

4. The compound or salt thereof according to claim 2, characterized in that: The compound is shown in formula III-B: in, linker is selected from R1 is selected from hydrogen, C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkyl; the substituent of the alkyl is selected from hydroxyl, C3-C6 cycloalkyl.

5. The compound or salt thereof according to claim 3, characterized in that: The compound is shown in Formula IV: in, linker is selected from R6 is selected from hydrogen, C2-C6 alkenyl, -C(O)R7, -C(O)NR7R8, substituted or unsubstituted C1-C6 alkyl; the substituent of the alkyl is selected from hydroxyl, C3-C6 cycloalkyl, halogen, -C(O)R 10 ; In the -C(O)R7, R7 is selected from C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, pyrrolidinyl, piperidinyl; In the -C(O)NR7R8, R7 and R8 are independently selected from hydrogen and C1-C6 alkyl; R 10 Selected from hydrogen, C1-C6 alkyl.

6. The compound or salt thereof according to any one of claims 1 to 5, characterized in that: The compound is selected from one of the following compounds:

7. Use of a compound or a salt thereof in the preparation of a JAK2 inhibitor or a drug for preventing and / or treating a disease associated with JAK2, characterized in that: The compound is as described in any one of claims 1 to 6.

8. The use according to claim 7, characterized in that: The diseases related to JAK2 are immune diseases, inflammatory diseases, solid tumors, and hematological tumors; The solid tumor is selected from lymphoma, ovarian cancer, breast cancer, prostate cancer, bladder cancer, kidney cancer, esophageal cancer, cervical cancer, pancreatic cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, thyroid cancer, brain cancer, or a combination thereof; The blood tumor is selected from acute myeloid leukemia, chronic myeloid leukemia, myeloma, acute lymphocytic leukemia, acute granulocytic leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic neutrophilic leukemia, acute undifferentiated cell leukemia, or a combination thereof; The inflammatory-related disease is selected from acute pancreatitis, chronic pancreatitis, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, hepatitis, systemic inflammatory response syndrome, postoperative or post-traumatic inflammation, nephritis, meningitis, cystitis, pharyngitis, spondylitis, arthritis, dermatitis, bronchitis; The immune disease is selected from celiac disease, psoriasis, Sjögren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylarthritis, polymyositis, dermatomyositis, periarteritis nodosa, mixed connective tissue disease, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, myasthenia gravis, graft-versus-host disease, and Addison's disease.

9. The use according to claim 8, characterized in that: The lymphoma is selected from B-cell lymphoma, chronic lymphocytic lymphoma, lymphoplasmacytic lymphoma; the myeloma is selected from multiple myeloma; the inflammatory lung disease is selected from pneumonia; the arthritis is selected from rheumatoid arthritis; the dermatitis is selected from radiation dermatitis and atopic dermatitis; the hepatitis is selected from chronic active hepatitis; the systemic lupus erythematosus is selected from deep lupus erythematosus.

10. The use according to claim 9, characterized in that: The B-cell lymphoma is selected from diffuse large B-cell lymphoma.

11. The use according to claim 9, characterized in that: The pneumonia is selected from chronic pneumonia.

12. The use according to claim 7, characterized in that: The diseases associated with JAK2 are epidermal hyperplasia, psoriasis, myelofibrosis, spinal cord sarcoma, myelodysplasia, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, gastric mucosal damage, pulmonary infarction, silicosis, pulmonary sarcoidosis, type II diabetes, and thrombocytopenia.

13. A drug, characterized in that: The invention relates to a preparation prepared by taking the compound or salt thereof as the active ingredient and adding pharmaceutically acceptable auxiliary materials or supplementary ingredients.

Images