CN110835336B - Oxygen-containing heterocyclic substituted azole compound and application thereof - Google Patents

Abstract

The invention relates to the field of medicinal chemistry, and discloses oxygen-containing heterocyclic substituted azole compounds and uses thereof. Specifically, it relates to oxygen-containing heterocyclic substituted azole compounds, their preparation methods, pharmaceutical compositions containing these compounds, and their medical uses, especially their use as FMS-like tyrosine kinase 3 inhibitors.

Description

Oxygen-containing heterocyclic substituted azole compounds and uses thereof

technical field

The present invention relates to the field of medicinal chemistry, in particular to oxygen-containing heterocyclic substituted azole compounds, their preparation methods, pharmaceutical compositions containing these compounds and their medical uses.

Background technique

Cell signal transduction plays a key role in regulating cell growth, proliferation, differentiation, apoptosis and other processes. The imbalance of cell proliferation and apoptosis leads to the occurrence of major diseases such as cancer. The essence of cell carcinogenesis is the imbalance of cell signal transduction. When the cell signal transduction pathway that regulates the normal physiological activities of cells is changed under the action of oncogenic factors, the normal biological effects of regulating cell growth, division and differentiation are abnormal, which in turn causes abnormal cell growth, division and cell morphology. changes that lead to the development of cancer. Because it plays a key role in the cell signal transduction pathway and is often accompanied by the overexpression of protein kinases in cancer cells, the development of antitumor drugs targeting protein kinases has broad prospects.

Leukemia is a malignant tumor of the hematopoietic system, and a hematopoietic stem/progenitor cell malignant tumor of the hematopoietic system. Leukemia can be divided into two categories according to the natural history and the degree of cell proliferation in different stages: acute leukemia and chronic leukemia. According to the different types of proliferating leukemia cells, it can be divided into two categories: acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML). Among them, AML accounts for 60%-70% of newly diagnosed adult acute leukemias, and shows an increasing trend year by year (Environmental Health Perspectives, 2007, 115(1): 138-145). At present, the pathogenesis of AML is not completely clear. Cytogenetic and molecular biology studies have found that two types of gene mutations play a major role in the pathogenesis of AML (Future Oncology, 2016, 12(6): 827-838). The first type involves gene mutations of tyrosine kinases in the signal transduction pathway, which cause the continuous activation of tyrosine kinases and lead to uncontrolled cell signal transduction; the second type of mutations involve transcription factors related to hematopoietic regulation, which cause the The loss of differentiation gene function inhibits the differentiation and apoptosis of hematopoietic cells. In view of the key role of protein kinases and their related signaling pathways in the development of AML, selecting appropriate protein kinases as targets to develop inhibitors has become an important strategy for AML treatment.

FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that plays a key role in the proliferation, differentiation and apoptosis of hematopoietic cells and lymphocytes. Studies have shown that more than one-third of AML patients are accompanied by abnormal expression of FLT3. Therefore, the development of inhibitors targeting FLT3 has become a research hotspot in the treatment of malignant hematological diseases (Blood, 2002, 100(5): 1532-1542).

The FLT3 gene sequence was first discovered and characterized in mice. In 1993, Rosnet O et al. (Blood, 1993, 82(4): 1110-1119) cloned its protein structure in human CD34+ hematopoietic progenitor cells. The human FLT3 gene contains 24 codons, is located on chromosome 13 (13ql2), encodes 993 amino acids, and has 85% homology with mouse FLT3. The N-terminal glycosylated FLT3 outside the cell membrane has a molecular weight of 165kDa and is mainly distributed on the cell membrane, while the non-glycosylated FLT3 does not bind to the cell membrane and has a molecular weight of 135-140kDa. FLT3 is predominantly expressed in myeloid cells, cord blood cells and hematopoietic progenitor cells (Blood, 2002, 100(5): 1532-1542).

Like other receptor tyrosine kinases, the structure of the FLT3 receptor includes five immunoglobulin-like extracellular, transmembrane, juxtamembrane, and intracellular tyrosine kinase domains. Griffith et al. (Molecular Cell, 2004, 13(2): 169-178) were the first to resolve the crystal structure of the autoinhibited form of the FLT3 kinase domain, which consists of two parts: C-terminal and N-terminal, wherein the C-terminal The kinase insert domain is divided into two parts: N-lobe and C-lobe. The N-lobe and C-lobe rotate around the insertion domain, forming the catalytic pocket of the kinase, within which the ATP-binding site of the kinase is located. When the N-lobe and C-lobe are in close proximity around the insertion domain, key catalytic residues in the two-part structure interact, placing the kinase in an activated conformation; otherwise, the kinase is in an inactive conformation. The activation loop (A-loop) of the kinase domain is located in the C-lobe, and its structure is part of the starting residues Asp829-Phe830-Gly831 and the terminal residues Trp854-Met855-Ala856. When the key tyrosine residues in the A-loop are not phosphorylated, their structure is folded in the catalytic pocket and the kinase is in an inactive conformation, preventing the substrate and ATP from entering the catalytic pocket; otherwise, the catalytic pocket is opened and the kinase is in an active conformation .

The Juxtamembrane Domain (JM) is a prominent feature in the structure of the FLT3 receptor and is directly involved in the auto-inhibitory regulation of the kinase (Molecular Cell, 2004, 13(2): 169-178). The JM domain can be divided into three parts: the binding part (JM-B), the switching part (JM-S) and the linking part (JM-Z). The JM-B structure is located between residues Tyr572 to Met578, almost buried in the kinase domain, connecting the activating and inactive parts of the intracellular domain; the JM-S structure is located at residues Val579 to Val592 on the surface of the kinase domain C-lobe part, containing two key residues Tyr589 and Tyr591, regulating the activation state of the kinase (The Journal of Biological Chemistry, 2002, 278(34): 31461-31464); JM-Z connects the N-lobe of the kinase domain, located at the residue Between Asp593 and Trp603. The precise regulation mechanism of the FLT3 receptor by the JM domain is not fully understood. A theory suggests that the JM-B and JM-S structures fold, residue Tyr572 in JM-B forms a hydrogen bond with residue Glu661 in the ATP-binding site, and the entire JM-B structure is fixed between the N-lobe and C-lobe. At the same time, the existence of the JM-B structure makes the A-loop in a folded conformation, and finally makes the kinase in an inactive state. When Tyr589 or Tyr591 in JM-S is activated by phosphorylation, the folded conformation of JM-S is disrupted, so that JM-B cannot maintain its original spatial position and lose its inhibitory effect on the kinase domain; on the contrary, when tyrosine residues After dephosphorylation by phosphotransferase, JM-S restores its original conformation, allowing JM-B to return to the inhibitory conformation to achieve auto-inhibitory regulation of the kinase (Molecular Cell, 2004, 13(2): 169-178) .

FLT3 ligand (FLT3ligand, FL) has a variety of isoforms. Human FL isoform has two ligands, soluble and cell-binding, and stem cell growth factor (Stem Cell Factor, SCF), macrophage colony stimulating factor (Macrophage colony-stimulating factor, M-CSF) has homology and is mainly expressed in bone marrow and hematopoietic cells (Nature, 1994, 368(6472): 643-648; Cell, 1993, 75(6): 1157-1167 ). FL alone cannot effectively induce the proliferation and differentiation of lymphoid and bone marrow stem/progenitor cells, but its induction is greatly enhanced under the synergistic effect of other growth factors such as SCF, IL-3, IL-6, etc.

Studies have shown that FLT3 expression is found in leukemia cells of 70% to 100% of AML patients, and more than 30% of them are accompanied by activating mutations of FLT3 (Leukemia, 1996, 10(2): 261-270; Leukemia & Lymphoma, 2014, 55(2):243-255). Mutation of FLT3 usually leads to its abnormal activation. In the absence of ligand binding, autophosphorylation activates downstream signaling pathways, which promotes abnormal proliferation of hematopoietic cells and lymphocytes, and eventually leads to malignant hematological diseases. There are two main types of activating mutations in FLT3: a) internal tandem duplication (ITD) mutations in the juxtamembrane domain; b) point mutations in the activation loop in the tyrosine kinase domain (TKD).

ITD mutation is the first type of FLT3 activating mutation discovered, and about 20% to 25% of AML patients have this mutation (Leukemia, 2000, 14(4): 675-683; Blood, 2001, 98(6): 1752 -1759). ITD mutation refers to the insertion of tandemly repeated base sequences in exons 14 and 15 of the coding FLT3 gene, resulting in changes in the amino acid sequence of the proximal membrane domain of the FLT3 receptor. The insertion position and length of the mutant gene are polymorphic, and the length varies from 3 to 400 bases, but the tandemly replicated sequence is always transcribed in frame (Blood, 2008, 111(10): 4930-4933). The near-membrane domain of FLT3 receptor plays a key role in the regulation of receptor activity. Usually, the near-membrane domain has an auto-inhibitory function on the kinase domain and can inhibit the phosphorylation of the kinase domain. However, ITD mutations disrupt the autoinhibitory activity of the juxtamembrane domain, resulting in the loss of this autoinhibitory effect, allowing FLT3 to dimerize in the absence of ligand and maintain a continuously activated conformation. At the same time, the ITD mutant FLT3 receptor can form a dimer with its wild-type receptor, and phosphorylate its tyrosine residue to activate the downstream signaling pathway (Oncogene, 2002, 21(16): 2555-2563). ITD mutant FLT3 can also strongly activate the STAT5 signaling pathway, promoting cell differentiation and proliferation (Blood, 2006, 108(4): 1339-1345). AML patients with ITD mutation are often accompanied by clinical manifestations such as increased number of leukocytes and increased percentage of blasts and blood cells (Blood, 2002, 100(1): 59-66). Due to the high recurrence rate of AML and many adverse reactions in patients with ITD mutation, patients with ITD mutation have a worse prognosis than ordinary AML patients (Environmental Health Perspectives, 2007, 115(1): 138-145).

The point mutation of FLT3 mainly occurs in the activation loop of TKD. Insertion or deletion of exon 20 of FLT3 gene can mutate the aspartic acid residue 835 at the carbon end of TKD in FLT3. This mutation is present in approximately 7% of AML patients (Blood, 2001, 97(8):2434-2439). The most common mutation is Asp835Tyr, and there are other mutations such as Asp835Val, Asp835Glu and Asp835Asn. A recent study found that an activating mutation also exists at the aspartate residue at position 676 of the FLT3 kinase domain (Blood, 2013, 122(10): 1761-1769). These point mutations stabilize the activation loop in the ATP-bound conformation, resulting in continued activation of FLT3. Introduction of TKD mutant gene into mouse hematopoietic stem cells can lead to oligoclonal lymphoid disorder, indicating that TKD and ITD mutations have different effects on cell signaling pathways (Blood, 2005, 105(12): 4792-4799). In addition, the poor prognosis of patients with TKD-mutant AML is unclear (Blood, 2010, 115(3):453-474).

In addition, FLT3-ITD mutation is also associated with other blood diseases, such as acute promyelocytic leukemia (APL), myelodysplastic syndrome (MDS) and acute lymphoblastic leukaemia , ALL), etc., among which the incidence of FLT3-ITD in APL is about 20%, and that in MDS and ALL is about 8% and 3%, respectively (Hematologic Malignancies, 2002, 9(4): 274).

Given that FLT3 plays a key role in hematological malignancies, especially in the pathogenesis of AML, FLT3-targeted therapy has become the focus of anti-AML drug research. At present, some inhibitors against FLT3, such as Midostaurin (PKC412), Lestaurtinib (CEP-701), Tandutinib (MLN-518), KW2449, Sunitinib (SU11248), Sorafenib (BAY43-9006), etc., have entered clinical research.

FLT3-ITD mutations occur in patients with relapsed AML, resulting in tumor cell resistance to inhibitors (Nature, 2012, 485(7397): 260-263). Therefore, it is necessary to develop inhibitors with strong inhibitory activity against FLT3-ITD, which is beneficial to overcome drug resistance. In addition, there is evidence that the side effects of kinase inhibitors are related to their poor selectivity. Selective inhibitors can specifically block a certain signaling pathway, have less impact on other normal signaling pathways, and reduce the possibility of causing side effects, making it easy to introduce personalized treatment plans. Moreover, selective kinase inhibitors can also be used in combination with other targeted drugs to synergistically treat tumors. However, existing FLT3 inhibitors usually also have inhibitory activity against other receptor tyrosine kinases (China Journal of New Drugs, 2016, 17: 1960-1966), so FLT3 selective inhibitors, especially FLT3-ITD selective inhibitors, were found. , is important for the development of drugs to treat AML.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a class of small molecule organic compounds with FLT3-ITD inhibitory activity or pharmaceutically acceptable salts thereof. It includes acid addition salts of compounds of formula I with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, Pyruvic acid, acetic acid, maleic or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid. In addition, it also includes acid salts of inorganic bases, such as salts containing alkaline metal cations, alkaline earth metal cations, and ammonium cations.

Another object of the present invention is to provide a preparation method of the above compound.

Yet another object of the present invention is to provide a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide the above-mentioned compounds or their pharmaceutically acceptable salts and their pharmaceutical compositions for medical use, especially in the prevention, delay or treatment of diseases mediated by FLT3-ITD alone or with participation.

To achieve the above object, the present invention provides a compound having the structure represented by the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein, R ₁ is selected from aryl or Het, wherein each of aryl or Het independently may be optionally substituted by one or more R ₃ ; R ₃ can be hydrogen, alkyl, alkylidene, cyano, halogen, haloalkane group, hydroxyl, mercapto, amino, alkoxy, alkylamino, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, Het, NH ₂ SO ₂ , alkylsulfonamido , arylsulfonamido, Hetsulfonamido, alkylsulfonyl, arylsulfonyl, Hetsulfonyl, HC(O)NH, C(O)H, _NH2C (O), or _NH2C (O )NH, wherein hydroxyl, mercapto, amino, alkyl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, Het, NH ₂ SO ₂ , Alkylsulfonamido, Arylsulfonamido, Hetsulfonamido, Alkylsulfonyl, Arylsulfonyl, Hetsulfonyl, HC(O)NH, C(O)H, _NH2C (O) or _NH2C (O)NH each independently may be optionally substituted with one or more _R4 , _which may be hydrogen, alkyl, halogen, haloalkyl, cyano, hydroxyl, mercapto, amino, alkoxy, alkane amino, alkylthio, _NH2SO2 , alkylsulfonamido, arylsulfonamido, _{Hetsulfonamido} , alkylsulfonyl, arylsulfonyl, Hetsulfonyl, aryl or Het;

R ₂ is selected from aryl or Het, wherein each of aryl or Het independently may be optionally substituted with one or more R _{5 which} may be hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, Amino, alkoxy, alkylamino, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, Het, C ₃ -C ₈ aliphatic carbocycle, NH ₂ SO ₂ , Alkylsulfonamido, Arylsulfonamido, Hetsulfonamido, Alkylsulfonyl, Arylsulfonyl, Hetsulfonyl, HC(O)NH, C(O)H, _NH2C (O) or _NH2C (O)NH, wherein hydroxyl, mercapto, amino, alkoxy, alkylamino, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, Het, _C3- C ₈ aliphatic carbocycle, NH ₂ SO ₂ , alkylsulfonamido, arylsulfonamido, Hetsulfonamido, alkylsulfonyl, arylsulfonyl, Hetsulfonyl, HC(O)NH, C(O)H, _NH2C (O), or _NH2C (O)NH, each independently, may be optionally substituted with one or more _R6 , _which may be hydrogen, alkyl, halogen, haloalkyl, cyano group, hydroxyl, mercapto, amino, alkoxy, alkylamino, alkylthio, NH ₂ SO ₂ , alkylsulfonamido, arylsulfonamido, Hetsulfonamido, alkylsulfonyl, arylsulfonyl , _Hetsulfonyl , C3 _- C8 aliphatic carbocycle, aryl or Het;

A represents imino, methylene, formyl, sulfonyl, carbamoyl or bond;

X, Y or Z each independently represents a N, O, S or CH, NH atomic group, wherein each of the NH or CH atomic groups independently may be optionally substituted by _R7 , _which may be hydrogen, alkyl, cyano, halogen, Haloalkyl, hydroxyl, mercapto, amino, alkoxy, alkylamino, alkylthio, alkoxyalkyl, NH ₂ SO ₂ , alkylsulfonamido, arylsulfonamido, Hetsulfonamido, alkyl Sulfonyl, arylsulfonyl, C3 _- C8 aliphatic carbocycle, _Hetsulfonyl , aralkyl, diarylalkyl, aryl or Het, wherein alkyl, haloalkyl, hydroxyl, alkoxy , alkylthio, alkylamino, alkoxyalkyl, _NH2SO2 , alkylsulfonamido, arylsulfonamido, C3 _{- C8} aliphatic carbocycle, _{Hetsulfonamido} , alkylsulfonyl Acyl, arylsulfonyl, _Hetsulfonyl , aralkyl, diarylalkyl, aryl, or Het each independently may be optionally substituted with one or more _R8 , which may be hydrogen, alkyl, cyano group, halogen, haloalkyl, hydroxyl, amino, alkoxy, alkylthio, alkylamino, alkoxyalkyl, NH ₂ SO ₂ , alkylsulfonamido, arylsulfonamido, Hetsulfonamido, Alkylsulfonyl, arylsulfonyl, C3 _- C8 aliphatic carbocycle, _Hetsulfonyl , aralkyl, diarylalkyl, aryl or Het;

Alkyl is a linear or branched saturated hydrocarbon group with 1-6 carbon atoms; or a cyclic saturated hydrocarbon group with 3-6 carbon atoms; or a linear or branched chain with 1-6 carbon atoms attached A cyclic saturated hydrocarbon group having 3-6 carbon atoms of a saturated hydrocarbon group;

Alkylene is a straight-chain or branched saturated hydrocarbon group having 1-6 carbon atoms; or a cyclic saturated hydrocarbon group having 3-6 carbon atoms; or a straight-chain or branched chain having 1-6 carbon atoms The cyclic saturated hydrocarbon group with 3-6 carbon atoms of the chain saturated hydrocarbon group loses a hydrogen atom;

Alkoxy is a straight-chain or branched-chain saturated hydrocarbon group having 1-6 carbon atoms; or a cyclic saturated hydrocarbon group having 3-6 carbon atoms; or a straight-chain or branched chain having 1-6 carbon atoms A cyclic saturated hydrocarbon group having 3-6 carbon atoms of a chain saturated hydrocarbon group; wherein each carbon atom is optionally substituted by oxygen;

Alkylthio is a straight-chain or branched saturated hydrocarbon group with 1-6 carbon atoms; or a cyclic saturated hydrocarbon group with 3-6 carbon atoms; or a straight-chain or branched chain with 1-6 carbon atoms A cyclic saturated hydrocarbon group having 3-6 carbon atoms of a chain saturated hydrocarbon group; wherein each carbon atom is optionally substituted by sulfur;

Alkylamino is a straight-chain or branched saturated hydrocarbon group with 1-6 carbon atoms; or a cyclic saturated hydrocarbon group with 3-6 carbon atoms; or a straight-chain or branched chain with 1-6 carbon atoms A cyclic saturated hydrocarbon group having 3-6 carbon atoms of a saturated hydrocarbon group; wherein each carbon atom is optionally substituted by an NH atomic group;

Alkoxyalkyl is an alkoxy group as defined above attached to an alkyl group;

Aryl is a carbocyclic ring selected from phenyl, benzyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from hydrogen, alkane group, cyano group, halogen, haloalkyl, hydroxyl, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;

Aralkyl and diarylalkyl are aryl and alkyl as defined above connected;

Het is selected from pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, 1,2,4-oxadiazole base, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl Cyclic heterocycle; or selected from quinolinyl, quinoxalinyl, pyridothienyl, quinazolinyl, pyrimidothienyl, 2,3-dihydrobenzo[1,4]dioxene base, 2,3-dihydrobenzofuran or bicyclic heterocycle of benzo[1,3]dioxolyl; or monocyclic saturated hydrocarbon group selected from 3-8 carbon atoms, 6-12 carbon atoms A bicyclic saturated hydrocarbon group of carbon atoms, a bicyclic hydrocarbon group of a benzene ring of 6-12 carbon atoms and a saturated alicyclic ring, wherein the carbon atoms on the ring are independently optionally substituted by 1 to 4 O, S, N or NH; The ring or bicyclic ring is optionally substituted with 1, 2 or 3 substituents, each of which is independently selected from halogen, haloalkyl, hydroxy, alkyl or alkoxy; halogen is a substituent selected from fluorine, chlorine, bromine or iodine ;

Haloalkyl is a straight or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a straight or branched chain having 1-6 carbon atoms attached A cyclic saturated hydrocarbon group having 3 to 6 carbon atoms of a saturated hydrocarbon group; wherein one or more carbon atoms are substituted with one or more halogen atoms.

The preferred solution of the present invention is:

R ₁ is selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxenyl, benzo[1,3]dioxolyl, Dioxolo[4,5-c]pyridine or dioxolo[4,5-d]pyrimidine, wherein R1 may be optionally substituted with _one or more _R3 ; _R3 may be is hydrogen, alkyl, alkylidene, cyano, halogen, haloalkyl, hydroxyl, amino, mercapto, alkoxy, alkylamino, alkoxyalkyl, aryl, aralkyl, Het, NH ₂ SO ₂ , Alkylsulfonamido, Arylsulfonamido, Hetsulfonamido, Alkylsulfonyl, Arylsulfonyl, Hetsulfonyl, HC(O)NH, C(O)H, NH ₂ C(O) or NH ₂ C(O)NH where hydroxy, mercapto, amino, alkyl, alkoxy, alkylamino, aryl, aralkyl, Het, NH ₂ SO ₂ , alkylsulfonamido, arylsulfonyl each independently amino, Hetsulfonamido, alkylsulfonyl, arylsulfonyl, Hetsulfonyl, HC(O)NH, C(O)H, _NH2C (O), or _NH2C (O)NH Optionally substituted with one or more _R4 , which can be _hydrogen , alkyl, halogen, haloalkyl, cyano, hydroxy, amino, alkoxy, alkylamino, _NH2SO2 , _{alkylsulfonamido} , arylsulfonamido, Hetsulfonamido, alkylsulfonyl, arylsulfonyl, Hetsulfonyl, aryl or Het;

R2 is selected from a phenyl or pyridine ring, wherein _R2 may be optionally substituted with one or more _R5 , _which may be _hydrogen , alkyl, cyano, halogen, haloalkyl, hydroxyl, mercapto, amino, alkoxy base, alkylamino, alkoxyalkyl, aryl, Het, C3 _- C8 aliphatic carbocycle, alkylsulfonamido, arylsulfonamido, _{Hetsulfonamido} , alkylsulfonyl, aryl Alkylsulfonyl, Hetsulfonyl, -SO ₂ -, -C(O)- or -C(O)NH- where hydroxy, amino, alkoxy, alkylamino, alkoxyalkyl, aryl, Het , C ₃ -C ₈ aliphatic carbocycle, alkylsulfonylamino, arylsulfonylamino, Hetsulfonylamino, alkylsulfonyl, arylsulfonyl, Hetsulfonyl, _-SO2- , -C (O) _- or -C(O)NH- each independently may be optionally substituted with one or more _R6 , which may be hydrogen, alkyl, halogen, haloalkyl, cyano, hydroxy, amino, alkoxy group, alkylamino, C ₃ -C ₈ aliphatic carbocyclic ring, NH ₂ SO ₂ , alkylsulfonamido, arylsulfonamido, Hetsulfonamido, alkylsulfonyl, arylsulfonyl, Hetsulfonyl Acyl, Aryl or Het;

A represents imino, methylene, formyl, sulfonyl, carbamoyl or bond;

X, Y or Z each independently represents a N, O, S or CH, NH atomic group, wherein each of the NH or CH atomic groups independently may be optionally substituted by _R7 , _which may be hydrogen, alkyl, halogen, haloalkyl, Hydroxyl, mercapto, amino, alkoxy, alkylamino, alkylthio, alkoxyalkyl, NH ₂ SO ₂ , alkylsulfonamido, arylsulfonamido, Hetsulfonamido, alkylsulfonyl, Arylsulfonyl, C3 _- C8 aliphatic carbocycle, _Hetsulfonyl , aralkyl, aryl or Het where alkyl, hydroxyl, amino, alkoxy, alkylthio, alkylamino, alkoxy Alkyl alkyl, NH ₂ SO ₂ , alkylsulfonamido, arylsulfonamido, C ₃ -C ₈ aliphatic carbocycle, Hetsulfonamido, alkylsulfonyl, arylsulfonyl, Hetsulfonyl , aralkyl, aryl or Het each independently may be optionally substituted with one or more _R8 , _which may be hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, amino, alkoxy, alkane Thio, alkylamino, alkoxyalkyl, _NH2SO2 , alkylsulfonamido, arylsulfonamido, _{Hetsulfonamido} , alkylsulfonyl, arylsulfonyl, C3 _{- C8} Aliphatic carbocyclic, Hetsulfonyl, aralkyl, aryl or Het.

Another preferred solution of the present invention is:

R ₁ is selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxenyl, benzo[1,3]dioxolyl, Dioxolo[4,5-c]pyridine or dioxolo[4,5-d]pyrimidine, wherein R1 may be optionally substituted with _one or more _R3 ; _R3 may be is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylidene, cyano, halogen, halogenated C ₁ -C ₆ alkyl, hydroxy, amino, mercapto, C ₁ -C ₆ alkyl oxy, C ₁ -C ₆ alkylamino, phenyl, benzyl, pyridyl, pyrimidinyl, thienyl, oxazolyl, pyrrolyl, NH ₂ SO ₂ , C ₁ -C ₆ alkylsulfonamido, Phenylsulfonylamino, pyridine-2-sulfonylamino, _C1 - _C6 alkylsulfonyl, phenylsulfonyl, pyridine-2-sulfonyl, HC(O)NH, C(O)H or _NH2 C(O), wherein hydroxyl, mercapto, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, phenyl, benzyl, pyridyl, pyrimidinyl, thiophene base, oxazolyl, pyrrolyl, NH ₂ SO ₂ , C ₁ -C ₆ alkylsulfonamido, phenylsulfonamido, pyridine-2-sulfonamido, C ₁ -C ₃ alkylsulfonyl, benzene sulfonyl, pyridine- ₂ -sulfonyl, HC(O)NH, C(O)H or _NH2C (O) each independently may be optionally substituted with one or more _R4 , which may be hydrogen, C ₁ -C ₃ alkyl, halogen, halogenated C ₁ -C ₃ alkyl, cyano, hydroxyl, amino, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylamino, NH ₂ SO ₂ , C ₁ -C ₃ alkylsulfonamido, phenylsulfonamido, pyridine-2-sulfonyl, C ₁ -C ₃ alkylsulfonyl, phenylsulfonyl, pyridine-2-sulfonyl, phenyl, pyridine group, pyrimidinyl, thienyl, oxazolyl or pyrrolyl;

R ₂ is selected from phenyl or pyridyl, wherein R ₂ may be optionally substituted with one or more R ₅ ; R ₅ may be hydrogen, C ₁ -C ₃ alkyl, cyano, halogen, halogenated C ₁ - C ₃ alkyl, hydroxyl, amino, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylamino, piperazinyl, piperidinyl, morpholinyl, tetrahydropyrrolyl, C ₃ -C ₈ aliphatic Carbocyclic ring, C ₁ -C ₃ alkylsulfonylamino, phenylsulfonylamino, pyridine-2-sulfonylamino, C ₁ -C ₃ alkylsulfonyl, phenylsulfonyl, pyridine-2-sulfonyl , -SO ₂ -, -C(O)- or -C(O)NH-, wherein hydroxyl, amino, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylamino, phenyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyrrolyl, C ₃ -C ₈ aliphatic carbocycle, C ₁ -C ₃ alkylsulfonamido, phenylsulfonamido, pyridine-2-sulfonamido, C ₁ -C3 alkylsulfonyl, phenylsulfonyl, pyridine- ₂ -sulfonyl, _-SO2- , -C(O)- or -C(O)NH- each independently may be optionally combined with one or more R ₆ is substituted, R ₆ can be hydrogen, C ₁ -C ₃ alkyl, halogen, cyano, hydroxy, amino, halogenated C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylamino, C ₃ -C ₈ aliphatic carbocycle, NH ₂ SO ₂ , C ₁ -C ₃ alkylsulfonamido, phenylsulfonamido, pyridine-2-sulfonamido, C ₁ - C ₃ alkylsulfonyl, phenylsulfonyl, pyridine-2-sulfonyl, phenyl, piperazinyl, piperidinyl, morpholinyl or tetrahydropyrrolyl;

A represents carbonyl, sulfonyl or bond;

X, Y or Z each independently represent N or CH, NH atomic group, wherein NH or CH atomic group each independently may be optionally substituted by _R7 , _R7 may be hydrogen, _{C1 -} C3 alkyl, halogen, halogenated C ₁ -C ₃ alkyl, hydroxyl, amino, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylamino, C ₁ -C ₃ alkoxy (C ₁ -C ₃ alkyl), NH ₂ SO ₂ , C ₁ -C ₃ alkylsulfonylamino, phenylsulfonylamino, pyridine-2-sulfonylamino, C ₁ -C ₃ alkylsulfonyl, phenylsulfonyl, pyridine-2-sulfonyl, Phenyl (C ₁ -C ₃ alkyl), cyclopropyl, cyclohexyl, cyclopentyl, phenyl, pyridyl, piperidinyl, tetrahydropyrrolyl or morpholinyl, wherein hydroxyl, amino, C ₁ - C ₃ alkoxy, C ₁ -C ₃ alkylamino, C ₁ -C ₃ alkoxy (C ₁ -C ₃ alkyl), NH ₂ SO ₂ , C ₁ -C ₃ alkylsulfonamido, phenyl Sulfonylamino, pyridine-2-sulfonamido, C ₁ -C ₃ alkylsulfonyl, phenylsulfonyl, cyclopropyl, cyclohexyl, cyclopentyl, pyridine-2-sulfonyl, phenyl (C ₁ -C alkyl ₎ , phenyl, pyridyl, piperidinyl, tetrahydropyrrolyl or morpholinyl, each independently may be optionally substituted with one or more _R8 , _which may be hydrogen, cyano, halogen , hydroxyl, amino, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylamino, NH ₂ SO ₂ , C ₁ -C ₃ alkylsulfonamido, phenylsulfonamido, pyridine-2-sulfonyl Amino, C ₁ -C ₃ alkylsulfonyl, phenylsulfonyl, cyclopropyl, cyclohexyl, cyclopentyl, pyridine-2-sulfonyl, phenyl (C ₁ -C3 alkyl), phenyl, pyridine group, piperidinyl, tetrahydropyrrolyl or morpholinyl.

Another preferred solution of the present invention is:

R ₁ is selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxenyl, benzo[1,3]dioxolyl, Dioxolo[4,5-c]pyridine or dioxolo[4,5-d]pyrimidine, wherein R1 may be optionally substituted with _one or more _R3 ; _R3 may be is hydrogen, methyl, ethyl-1,2-idene, cyano, halogen, trifluoromethyl, methoxy, dimethylamino, phenyl, benzyl, pyridyl, NH ₂ SO ₂ , methylsulfonyl amido, mesyl, HC(O)NH, or _NH2C (O), wherein _NH2SO2 , HC(O)NH, or _{NH2C (} O), each independently, may be optionally replaced by one or more R ₄ substituted, R ₄ can be hydrogen, methyl or cyclopropyl, wherein phenyl, pyridyl or benzyl each independently can be optionally substituted by one or more R ₉ , R ₉ can be hydrogen, methyl, methyl oxy, trifluoromethyl, amino, fluoro, chloro or carbamoyl;

R ₂ is selected from phenyl or pyridyl, wherein R ₂ may be optionally substituted by one or more R ₅ ; R ₅ may be hydrogen, methyl, ethyl, halogen, amino, trifluoromethyl, methoxy, Trifluoromethoxy, methylamino, piperazinyl, piperidinyl, morpholinyl, tetrahydropyrrolyl, methylsulfonamido, mesyl, -SO ₂ -, -C(O)- or -C (O)NH-, wherein methyl, amino, piperazinyl, piperidinyl, morpholinyl, tetrahydropyrrolyl, methylsulfonamido, methylsulfonyl, -SO ₂ -, -C(O)- or -C(O)NH- each independently may be optionally substituted with one or more _R6 , _which may be hydrogen, methyl, ethyl, halogen, cyano, hydroxy, amino, trifluoromethyl, trifluoromethyl Fluoromethoxy, methylamino, dimethylamino, isopropylamino, cyclopropyl, cyclopentyl, cyclohexyl, NH ₂ SO ₂ , methylsulfonamido, methanesulfonyl, phenyl, piperazinyl, piper pyridyl, morpholinyl, N-methylpiperazinyl, N-methylpiperidine-4-amino, 3-diethylaminopropylamino, 3-morpholinopropylamino or tetrahydropyrrolyl;

A represents carbonyl, sulfonyl or bond;

X, Y or Z each independently represents an N or CH, NH radical, wherein each of the NH or CH radicals independently may be optionally substituted by _R7 , _which may be hydrogen or methyl.

Another preferred solution of the present invention is:

R ₁ is selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxenyl, benzo[1,3]dioxolyl, Dioxolo[4,5-c]pyridine or dioxolo[4,5-d]pyrimidine, wherein R1 may be optionally substituted with _one or more _R3 ; _R3 may be is hydrogen, methyl, ethyl, ethyl-1,2-idene, isopropyl, halogen or trifluoromethyl;

R ₂ is selected from phenyl or pyridyl, wherein R ₂ may be optionally substituted by one or more R ₅ ; R ₅ may be hydrogen, methyl, halogen, trifluoromethyl, methoxy, trifluoromethoxy , piperazinyl, piperidinyl, N-methylpiperazinyl, N-methylpiperidine-4-amino, morpholinyl, 3-morpholinylpropylamino, tetrahydropyrrolyl, 4-ethyl- Piperazin-1-ylmethyl, 4-hydroxyethyl-piperazin-1-yl, 2-hydroxyethoxy, 2-methoxyethoxy, 3-morpholinopropoxy, 2-diethyl Aminoethylamino, N-methylpiperidin-4-ylmethoxy, 3-diethylaminopropylamino, -SO2- or -C(O)-, where -SO2- or -C(O)- are each independently may be optionally substituted with one or more R6, which may be hydrogen, piperazinyl, piperidinyl, morpholinyl, N _- methylpiperazinyl, N-methylpiperidine- ₄ -amino, 3-diethylaminopropylamino, 3-morpholinopropylamino or tetrahydropyrrolyl;

A represents carbonyl or bond;

X or Z each independently represents an N or NH atomic group, and Y is a CH atomic group.

Another preferred solution of the present invention is:

R ₁ is selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxenyl, benzo[1,3]dioxolyl, Dioxolo[4,5-c]pyridine or dioxolo[4,5-d]pyrimidine, wherein R1 may be optionally substituted with _one or more _R3 ; _R3 may be is hydrogen, methyl, halogen or ethyl-1,2-idene;

R ₂ is selected from phenyl or pyridyl, wherein R ₂ may be optionally substituted by one or more R ₅ ; R ₅ may be hydrogen, methyl, halogen, trifluoromethyl, methoxy, trifluoromethoxy , piperazinyl, piperidinyl, N-methylpiperazinyl, N-methylpiperidine-4-amino, morpholinyl, 3-morpholinylpropylamino, tetrahydropyrrolyl, 4-ethyl- Piperazin-1-ylmethyl, 4-hydroxyethyl-piperazin-1-yl, 2-hydroxyethoxy, 2-methoxyethoxy, 3-morpholinopropoxy, 2-diethyl Aminoethylamino, N-methylpiperidin-4-ylmethoxy, 3-diethylaminopropylamino, -SO2- or -C(O)-, where -SO2- or -C(O)- are each independently may be optionally substituted with one or more R6, which may be hydrogen, piperazinyl, piperidinyl, morpholinyl, N _- methylpiperazinyl, N-methylpiperidine- ₄ -amino, 3-diethylaminopropylamino, 3-morpholinopropylamino or tetrahydropyrrolyl;

A represents carbonyl or bond;

X or Z each independently represents an N or NH atomic group, and Y is a CH atomic group.

Another preferred solution of the present invention is:

R ₁ is selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxenyl, benzo[1,3]dioxolyl, Dioxolo[4,5-c]pyridine or dioxolo[4,5-d]pyrimidine, wherein R1 may be optionally substituted with _one or more _R3 ; _R3 may be is hydrogen, methyl, halogen or ethyl-1,2-idene;

R ₂ is selected from phenyl, wherein R ₂ may be optionally substituted with one or more R ₅ ; R ₅ may be hydrogen, methyl, halogen, trifluoromethyl, methoxy, trifluoromethoxy, piperazine base, piperidinyl, N-methylpiperazinyl, N-methylpiperidine-4-amino, morpholinyl, 3-morpholinylpropylamino, tetrahydropyrrolyl, 4-ethyl-piperazine- 1-ylmethyl, 4-hydroxyethyl-piperazin-1-yl, 2-hydroxyethoxy, 2-methoxyethoxy, 3-morpholinopropoxy, 2-diethylaminoethylamino , N-methylpiperidin-4-ylmethoxy, 3-diethylaminopropylamino, -SO2- or -C(O)-, wherein -SO2- or -C(O)- can be independently any optionally substituted with one or more R6, which can be hydrogen, piperazinyl, piperidinyl, morpholinyl, N _- methylpiperazinyl, N-methylpiperidine- ₄ -amino, 3-di Ethylaminopropylamino, 3-morpholinopropylamino or tetrahydropyrrolyl;

A represents carbonyl or bond;

X or Z each independently represents an N or NH atomic group, and Y is a CH atomic group.

Another preferred solution of the present invention is:

R ₁ is selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxenyl or benzo[1,3]dioxolyl, wherein R ₁ can be optionally substituted by one or more R ₃ ; R ₃ can be hydrogen, methyl, fluorine, chlorine or ethyl-1,2-idene;

R ₂ is selected from phenyl, wherein R ₂ may be optionally substituted with one or more R ₅ ; R ₅ may be hydrogen, methyl, halogen, methoxy, piperazinyl, piperidinyl, N-methylpiperyl Azinyl, N-methylpiperidine-4-amino, morpholinyl, 3-morpholinopropylamino, tetrahydropyrrolyl, 4-ethyl-piperazin-1-ylmethyl, 4-hydroxyethyl -Piperazin-1-yl, 2-hydroxyethoxy, 2-methoxyethoxy, 3-morpholinopropoxy, 2-diethylaminoethylamino, N-methylpiperidin-4-yl Methoxy, 3-diethylaminopropylamino or -C(O) _- , wherein -C(O) _- each independently may be optionally substituted by one or more R6, which may be piperazinyl, piperidine pyridyl, morpholinyl, N-methylpiperazinyl, N-methylpiperidine-4-amino, 3-diethylaminopropylamino, 3-morpholinylpropylamino or tetrahydropyrrolyl;

A represents carbonyl or bond;

X or Z each independently represents an N or NH atomic group, and Y is a CH atomic group.

Another preferred solution of the present invention is:

R ₁ is selected from benzo[1,3]dioxolyl, wherein R ₁ may be optionally substituted by one or more R ₃ ; R ₃ may be hydrogen, methyl, fluorine, chlorine or ethyl-1 , 2- fork group;

R ₂ is selected from phenyl, wherein R ₂ may be optionally substituted with one or more R ₅ ; R ₅ may be hydrogen, methyl, halogen, methoxy, piperazinyl, piperidinyl, N-methylpiperyl Azinyl, N-methylpiperidine-4-amino, morpholinyl, 3-morpholinopropylamino, tetrahydropyrrolyl, 4-ethyl-piperazin-1-ylmethyl, 4-hydroxyethyl -Piperazin-1-yl, 2-hydroxyethoxy, 2-methoxyethoxy, 3-morpholinopropoxy, 2-diethylaminoethylamino, N-methylpiperidin-4-yl Methoxy, 3-diethylaminopropylamino or -C(O) _- , wherein -C(O) _- each independently may be optionally substituted by one or more R6, which may be piperazinyl, piperidine pyridyl, morpholinyl, N-methylpiperazinyl, N-methylpiperidine-4-amino, 3-diethylaminopropylamino, 3-morpholinylpropylamino or tetrahydropyrrolyl;

A represents carbonyl or bond;

X or Z each independently represents an N or NH atomic group, and Y is a CH atomic group.

The compound of the general formula I is preferably a compound of the following structure:

(1) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperin pyridin-4-yl)amino)benzamide

(2) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(4-methylpiperazine -1-yl)benzamide

(3) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(piperidin-1-yl ) benzamide

(4) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-morpholinylbenzamide

(5) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((3-morpholinopropane base)amino)benzamide

(6) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(((3-(diethyl) aminoamino)propyl)amino)benzamide

(7) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-methoxy-4-( (1-Methylpiperidin-4-yl)amino)benzamide

(8) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-3-(4-methylpiperazine -1-yl)benzamide

(9) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-fluoro-4-((1 -Methylpiperidin-4-yl)amino)benzamide

(10) N ¹ -(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N ⁴ -(1-methyl) piperidin-4-yl)benzene-1,4-diamine

(11) 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H - Pyrazol-5-amine

(12) N ¹ -(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N ⁴ -(3-morpholine Propyl)benzene-1,4-diamine

(13) N ⁴ -(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-fluoro-N ¹ -( 1-Methylpiperidin-4-yl)benzene-1,4-diamine

(14) N ¹ -(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-methoxy-N ⁴ -(1-Methylpiperidin-4-yl)benzene-1,4-diamine

(15) N ² -(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N ⁵ -(1-methyl) piperidin-4-yl)pyridine-2,5-diamine

(16) N ¹ -(3-(2,2-dimethyl(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl) -N ⁴ -(1-methylpiperidin-4-yl)benzene-1,4-diamine

(17) (4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)phenyl)(4- Methylpiperazin-1-yl)methanone

(18) 4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-N-(1-methyl) ylpiperidin-4-yl)benzamide

(19) 4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-N-(1-methyl) ylpiperidin-4-yl)benzenesulfonamide

(20) N-(4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)phenyl)- 1-Methylpiperidine-4-carboxamide

(21) 4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-3-methoxy- N-(1-Methylpiperidin-4-yl)benzamide

(22) 4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-2-fluoro-N- (1-Methylpiperidin-4-yl)benzamide

(23) 4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-2-methyl-N -(1-Methylpiperidin-4-yl)benzamide

(24) N-(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-4 -((1-Methylpiperidin-4-yl)amino)benzamide

(25) N-(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-4 -((3-morpholinopropyl)amino)benzamide

(26) N-(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-2 -Methoxy-4-((1-methylpiperidin-4-yl)amino)benzamide

(27) N-(3-(2,3-Dihydro(benzo[b][1,4]dioxene)-6-yl)-1H-pyrazol-5-yl)-3 -(4-Methylpiperazin-1-yl)benzamide

(28) N-(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-2 -Methyl-4-((1-methylpiperidin-4-yl)amino)benzamide

(29) N ¹ -(3-(2,3-dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)- N ⁴ -(1-methylpiperidin-4-yl)benzene-1,4-diamine

(30) N ¹ -(3-(2,3-dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)- 2-Methoxy-N ⁴ -(1-methylpiperidin-4-yl)benzene-1,4-diamine

(31) 4-((3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)amino )-N-(1-methylpiperidin-4-yl)benzamide

(32) 4-((3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)amino )-N-(1-methylpiperidin-4-yl)benzenesulfonamide

(33) N-(4-((3-(2,3-dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5- yl)amino)phenyl)-1-methylpiperidine-4-carboxamide

(34) 4-((3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)amino )-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide

(35) 4-((3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)amino )-3-fluoro-N-(1-methylpiperidin-4-yl)benzamide

(36) N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)-4 -((1-Methylpiperidin-4-yl)amino)benzamide

(37) N-(3-(2,3-Dihydro(benzofuran)-6-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperidin-4-yl) )amino)benzamide

(38) N-(3-(2,3-Dihydro(benzofuran)-5-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperidin-4-yl) )amino)benzamide

(39) N ¹ -(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)- N ⁴ -(1-methylpiperidin-4-yl)benzene-1,4-diamine

(40) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-6-((1-methylpiperin pyridin-4-yl)amino)nicotinamide

(41) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-5-((1-methylpiperin pyridin-4-yl)amino)pyridine-2-carboxamide

(42) N2-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol- ⁵ -yl)-N5-(1-methylpiperin pyridin-4-yl)pyridine-2,5-diamine

(43) 4-((1-Methylpiperidin-4-yl)amino)-N-(3-(spiro[benzo[d][1,3]dioxol-2,1' -Cyclopropane]-5 ^- yl)-1H-pyrazol-5-yl)benzamide

(44) N-(3-(2,2-Dichloro(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)-4 -((1-Methylpiperidin-4-yl)amino)benzamide

(45) N-(3-([1,3]dioxolo[4,5-c]pyridin-6-yl)-1H-pyrazol-5-yl)-4-((1 -Methylpiperidin-4-yl)amino)benzamide

(46) N-(3-([1,3]dioxolo[4,5-d]pyrimidin-5-yl)-1H-pyrazol-5-yl)-4-((1 -Methylpiperidin-4-yl)amino)benzamide

(47) N-(3-([1,3]dioxolo[4,5-c]pyridin-4-yl)-1H-pyrazol-5-yl)-4-((1 -Methylpiperidin-4-yl)amino)benzamide

(48) N-(3-(Benzo[d][1,3]dioxol-4-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperin pyridin-4-yl)amino)benzamide

(49) N-(3-([1,3]dioxolo[4,5-d]pyrimidin-7-yl)-1H-pyrazol-5-yl)-4-((1 -Methylpiperidin-4-yl)amino)benzamide

(50) N-(3-([1,3]dioxolo[4,5-b]pyridin-7-yl)-1H-pyrazol-5-yl)-4-((1 -Methylpiperidin-4-yl)amino)benzamide

(51) N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4 -((1-Methylpiperidin-4-yl)amino)benzamide

(52) N-(3-(2,2-Dichloro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4 -((1-Methylpiperidin-4-yl)amino)benzamide

(53) N-(3-(2,2-Dimethyl(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)- 4-((1-Methylpiperidin-4-yl)amino)benzamide

(54) 4-((1-Methylpiperidin-4-yl)amino)-N-(3-(spiro[benzo[d][1,3]dioxol-2,1' -Cyclopropane]-4-yl)-1H-pyrazol-5-yl)benzamide

(55) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((4-ethylpiperin oxazin-1-yl)methyl)benzamide

(56) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(4-(2-hydroxyl) Ethyl)piperazin-1-yl)benzamide

(57) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(2-hydroxyethoxy ) benzamide

(58) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(2-methoxyethyl) oxy)benzamide

(59) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(3-morpholinopropoxy base) benzamide

(60) N-(3-(Benzo[d][1,3]dioxol-4-yl)-1H-pyrazol-5-yl)-4-((4-ethylpiperin oxazin-1-yl)methyl)benzamide

(61) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(((2-(diethyl) Amino)ethyl)amino)benzamide

(62) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperin pyridin-4-yl)methoxy)benzamide

(63) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl) ) benzamide

(64) N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4 -((1-Methylpiperidin-4-yl)methoxy)benzamide

(65) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(pyrrolidin-1-yl ) benzamide

(66) N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4 -((2-(diethylamino)ethyl)amino)benzamide

(67) N-(3-(Spiro[benzo[d][1,3]dioxol-2,1'-cyclopropane]-4 ^- yl)-1H-pyrazol-5-yl )-4-(3-morpholinopropoxy)benzamide

(68) N-(3-(2,2-Dimethyl(benzo[d][1,3]dioxol-4-yl)-1H-pyrazol-5-yl)- 4-(Piperazin-1-yl)benzamide.

The compound preparation method of the present invention is as follows:

Scheme 1

X=CH or N, Y=CH or N.

Reagents and conditions:

(i) NaH, THF, acetonitrile, 70°C; (ii) _{NH2NH2 ·} HCl, _EtN3 , EtOH, flux; (iii) Al( _CH3 ) ₃ , Toluene, 80°C.

Scheme 2

X=CH or N, Y=CH or N.

Reagents and conditions:

(i) NaH, THF/DMF, 0°C; (ii) NH ₂ NH ₂ ·H ₂ O, EtOH, flux.

The compounds of the present invention can all be prepared by the above-mentioned or similar preparation methods described above. Corresponding raw materials can be selected according to the difference of the substituents and the different positions of the substituents, or the raw materials that are not easy to buy can be prepared according to the general knowledge of organic synthesis.

The biological activity test results show that the compounds of the general formula I and the pharmaceutically acceptable salts thereof provided by the present invention have FLT3-ITD inhibitory effect, and at the same time have a certain inhibitory effect on the growth of leukemia tumor cell lines. The compounds of the present invention can be used to treat various diseases related to FLT3-ITD, including acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome and the like. Therefore, the present invention proposes that the compounds of the present invention and their pharmaceutically acceptable salts can be used for the preparation of antitumor drugs.

The pharmacological tests of the compounds are as follows:

1. Kinase inhibitory activity test

I Experimental Materials

Basic reaction buffer, 20 mM Hepes (pH 7.5), 10 mM _MgCl2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM _Na3VO4 . ₂ mM DTT, 1% DMSO.

II Experimental Procedure

Prepare the substrate in fresh reaction buffer, add all required cofactors to the substrate solution described above, then add the kinase to the prepared substrate solution and mix gently. Compounds were dissolved in 100% DMSO and the solution was added to the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range) and allowed to react at room temperature for 20 min. Then ³³ p-ATP was added to start the reaction (radiation intensity rate 10 mCi/ml), and the reaction was carried out at room temperature for 2 h. The kinase activity was detected by the filter method, and the kinase activity data were expressed as a percentage: the ratio of the kinase activity in the test sample to the blank (DMSO) reaction solution.

III EXPERIMENTAL RESULTS

Table 1 Inhibition rate (%) of compounds on FLT3-ITD

2. In vitro tumor cell inhibitory activity test

Inhibitory activity of the compounds of the present invention on MV4-11 cell line in vitro.

I Experimental Materials

RPMI 1640 medium, 96-well cell culture plate, fetal bovine serum, EnoGeneCell ^TM Counting Kit-8 (CCK-8) cell viability detection kit, ChemBase CBS-CJ-1FD ultra-clean workbench, carbon dioxide incubator, Vi-Cell XR cell counter, Envision 2104 plate reader.

II Experimental Procedure

Cells in exponential growth phase were harvested and viable cell counts were performed with a Vi-Cell XR cytometer. Adjust the cell suspension concentration with the corresponding medium for each cell. Add 90 μL of cell suspension to each well in a 96-well cell culture plate, and the final cell concentration is 7000 cells/well. Each test compound was dissolved in DMSO as a 10 mM stock solution. Then, each was diluted to a 10-fold solution with culture medium, and each well was 2 replicates. 10 μL of the corresponding 10-fold solution was added to each well of each cell line, the final drug concentration was 1 μM, and the final concentration of DMSO was 0.01%. Placed in a 37°C/5% _CO2 incubator for 72h. After 72 hours of drug treatment, according to the Celltiter-GloATP fluorescence activity detection method (CTG method), add 50 μL (1/2 culture volume) of CTG solution pre-thawed and equilibrated to room temperature into each well, and mix with a microplate shaker. After 2 min at room temperature, the fluorescence signal value was measured with an Envision 2104 plate reader. The inhibition rate of each test compound compared with the negative control group was calculated.

Table 2 Inhibitory rate (%) of compounds on MV4-11 cell line

Detailed ways

The melting point was determined by RY-1G digital display micro melting point tester (Tianjin Xintianguang Instrument Co., Ltd.), and the thermometer was uncorrected; ¹ HNMR was determined by BRUKER AVANCE 300 nuclear magnetic resonance apparatus (Broke, Switzerland), and TMS was the internal standard; MS An Agilent 1100 LC/MSD mass spectrometer (Agilent Corporation, USA) and a Q-totmicro MS (Micromass Corporation) were used.

Example 1

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperidine-4 -yl)amino)benzamide (1)

Tetrahydrofuran (12 ml), acetonitrile (5 mL), sodium hydride (0.17 g, 7.1 mmol) and benzo[d][1,3]dioxol-5 were sequentially added to the round-bottomed flask under ice bath condition - methyl formate (0.43 g, 2.4 mmol), stirred for 0.5 h, heated to reflux, and reacted for 5 h. The reaction solution was poured into an ice-water mixture (30 ml), the pH was adjusted to 2, a large amount of yellow solid was precipitated, and the crude product was obtained by suction filtration and drying. The crude product was subjected to column chromatography (PE:EA=2:1) to obtain 0.413 g of a pale yellow solid with a yield of 91%. MS[MH] ⁺ 188.03.

The product obtained in the previous step, hydrazine hydrochloride (0.45g, 4.4mmol), triethylamine (0.44g, 4.4mmol) and ethanol (10ml) were sequentially added to a 25mL round-bottom flask, and the reaction was refluxed for 8h. The reaction solution was diluted with water (50ml), adjusted to pH 9 with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate (20ml×3), the organic phases were combined, washed with saturated brine (20ml×2), anhydrous sodium sulfate dry. After concentration under reduced pressure, column chromatography (EA:PE=6:1) yielded 0.368 g of a pale yellow solid with a yield of 83%. MS[MH] ^- 203.05.

The product obtained in the previous step, methyl 4-((1-methylpiperidin-4-yl)amino)benzoate (0.472 g, 1.9 mmol), and trimethylaluminum (3.55 g) were successively added to a 25 mL double-necked round-bottomed flask. mL, 5.1 mmol) and toluene (6 ml), reacted at 80 °C for 10 h in an argon atmosphere. 95% ethanol (40 mL) was added to the reaction solution to quench the reaction, concentrated under reduced pressure and column chromatography (EA:MeOH=20:1) to obtain 0.34 g of pale yellow solid with a yield of 45%. ¹ H NMR (300 MHz, CDCl ₃ ) δ 12.68 (s, 1H), 10.3 (s, 1H), 7.60-7.53 (m, 2H), 7.25 (d, 1H), 7.19 (d, 1H), 7.01 ( d, 1H), 6.80-6.74 (m, 2H), 6.52 (s, 1H), 6.07 (s, 2H), 4.36 (s, 1H), 3.3-3.2 (m, 1H), 2.75 (d, 2H) , 2.31 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 420.2.

Example 2

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(4-methylpiperazine-1- yl)benzamide (2)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.7 (s, 1H), 10.3 (s, 1H), 7.64-7.57 (m, 2H), 7.35 (d, 1H), 7.22 (d, 1H), 7.06-6.99 (m, 2H), 6.88-6.81 (m, 2H), 6.07 (s, 2H), 3.20 (t, 4H), 2.98 (t, 4H), 2.60 (s, 3H). MS (m/z): [M+H] ⁺ 406.2.

Example 3

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(piperidin-1-yl)benzyl Amide (3)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.7 (s, 1H), 10.3 (s, 1H), 7.59-7.52 (m, 2H), 7.25 (d, 1H), 7.19 (d, 1H), 7.01 (d , 1H), 6.89-6.82(m, 2H), 6.52(s, 1H), 6.07(s, 2H), 3.49-3.43(m, 4H), 1.67-1.57(m, 6H). MS(m/z ): [M+H] ⁺ 391.2.

Example 4

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-morpholinylbenzamide (4)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.7 (s, 1H), 10.3 (s, 1H), 7.59-7.52 (m, 2H), 7.25 (d, 1H), 7.19 (d, 1H), 7.01 (d , 1H), 6.87-6.80(m, 2H), 6.52(s, 1H), 6.07(s, 2H), 3.74(t, 4H), 3.15 (t, 4H). MS(m/z): [M +H] ⁺ 393.2.

Example 5

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((3-morpholinopropyl)amino ) benzamide (5)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.7 (s, 1H), 10.2 (s, 1H), 7.61-7.55 (m, 2H), 7.26-7.16 (m, 2H), 7.01 (d, 1H), 6.80 -6.75(m, 2H), 6.47(s, 1H), 6.07(s, 2H), 4.98(s, 1H), 4.04(t, 4H), 3.38(t, 2H), 3.28(t, 2H), 2.34-2.29 (m, 6H). MS (m/z): [M+H] ⁺ 450.2.

Example 6

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((3-(diethylaminoamino )propyl)amino)benzamide (6)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.7 (s, 1H), 10.3 (s, 1H), 7.60-7.54 (m, 2H), 7.25 (d, 1H), 7.19 (dd, 1H), 7.01 (d , 1H), 6.73-6.67(m, 2H), 6.52(s, 1H), 6.07(s, 2H), 4.78(s, 1H), 3.38(t, 2H), 2.98(t, 2H), 2.69- 2.61 (m, 4H), 2.33-2.3 (m, 21), 1.06-1.03 (m, 6H). MS (m/z): [M+H] ⁺ 436.2.

Example 7

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-methoxy-4-((1- Methylpiperidin-4-yl)amino)benzamide (7)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.69(s, 1H), 10.3(s, 1H), 7.47(d, 1H), 7.25(d, 1H), 7.19(d, 1H), 7.01(d, 1H) ), 6.53-6.44(m, 3H), 6.07(s, 2H), 4.40(s, 1H), 3.91(s, 3H), 3.3- 3.2(m, 1H), 2.75(d, 2H), 2.31( s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 450.2.

Example 8

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-3-(4-methylpiperazine-1- yl)benzamide (8)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.7 (s, 1H), 10.2 (s, 1H), 7.31-7.22 (m, 3H), 7.09 (d, 2H), 7.03 (d, 1H), 6.89 (t , 1H), 6.48(s, 1H), 6.07(s, 2H), 3.20(t, 4H), 2.98(t, 4H), 2.60(s, 3H). MS(m/z): [M+H ] ⁺ 406.2.

Example 9

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-fluoro-4-((1-methyl piperidin-4-yl)amino)benzamide (9)

The preparation method is similar to (1), and a pale yellow solid g is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.7(s, 1H), 10.3(s, 1H), 7.56(d, 1H), 7.25(d, 1H), 7.19(d, 1H), 7.01(d, 1H) ), 6.53(d, 1H), 6.51(s, 1H), 6.29(d, 1H), 6.07(s, 2H), 4.55(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 438.2.

Example 10

N ¹ -(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N ⁴ -(1-methylpiperidine- 4-yl)benzene-1,4-diamine (10)

Into the round bottom flask were added dry tetrahydrofuran (10 ml), sodium hydride (0.24 g, 10 mmol) and 5-acetyl(benzo[d][1,3]dioxole)( 0.657 g, 4 mmol), stirred for 0.5 h, slowly added dropwise 4-(1-methylpiperidin-4-ylamino) benzene isothiocyanate (0.99 g, 4 mmol), and reacted for 2 h. The reaction solution was poured into an ice-water mixture (30 ml), a pale yellow solid was precipitated, and the crude product was obtained by suction filtration and drying. After the crude product was subjected to column chromatography (PE:EA=10:1), 0.58 g of pale yellow solid was obtained with a yield of 35.2%. MS[M+H] ⁺ 412.2.

The product of the previous step, hydrazine hydrochloride (0.43g, 4.1mmol), triethylamine (0.44g, 4.4mmol) and ethanol (15ml) were sequentially added to a 50mL round-bottomed flask, and the reaction was refluxed for 8h. The reaction solution was diluted with water (50ml), adjusted to pH 9 with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate (20ml×3), the organic phases were combined, washed with saturated brine (20ml×2), anhydrous sodium sulfate dry. After concentration under reduced pressure, column chromatography (EA:MeOH=22:1) yielded 0.331 g of a pale yellow solid with a yield of 60%.

¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 8.13 (s, 1H), 7.29-7.21 (m, 2H), 7.10-6.99 (m, 3H), 6.50- 6.44 (m, 2H) , 6.07(s, 2H), 5.95(s, 1H), 3.80(s, 1H), 3.26-3.18(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06(d, 2H) ), 1.95-1.91 (m, 2H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 392.2.

Example 11

3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazole -5-Amine (11)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.7 (s, 1H), 8.1 (s, 1H), 7.29-7.21 (m, 2H), 7.09-6.99 (m, 3H), 6.74-6.68 (m, 2H) , 6.07(s, 2H), 5.96(s, 1H), 3.20(t, 4H), 2.98(t, 4H), 2.60(s, 3H). MS(m/z): [M+H] ⁺ 378.2 .

Example 12

N ¹ -(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N ⁴ -(3-morpholinopropyl) Benzene-1,4-diamine (12)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.7 (s, 1H), 8.1 (s, 1H), 7.29-7.21 (m, 2H), 7.10-6.99 (m, 3H), 6.49-6.44 (m, 2H) , 6.07(s, 2H), 5.95(s, 1H), 4.04(t, 4H), 3.76(s, 1H), 3.38(t, 2H), 3.28(t, 2H), 2.34-2.29(m, 6H) ).MS(m/z): [M+H] ⁺ 422.2.

Example 13

N ⁴ -(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-fluoro-N ¹ -(1-methyl) ylpiperidin-4-yl)benzene-1,4-diamine (13)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.68 (s, 1H), 8.15 (s, 1H), 7.31 (d, 1H), 7.29-7.21 (m, 2H), 7.02 (d, 1H), 6.79 (dd , 1H), 6.39(d, 1H), 6.07(s, 2H), 5.96(s, 1H), 4.05(s, 1H), 3.26- 3.18(m, 1H), 2.75(d, 2H), 2.31( s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 410.2.

Example 14

N ¹ -(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-methoxy-N ⁴ -(1 -Methylpiperidin-4-yl)benzene-1,4-diamine (14)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68(s, 1H), 8.14(s, 1H), 7.29-7.22(m, 2H), 7.02(d, 1H), 6.76(d, 1H), 6.18-6.10 (m, 2H), 6.07(s, 2H), 5.85(s, 1H), 3.94(s, 3H), 3.82(s, 1H), 3.26-3.18(m, 1H), 2.75(d, 2H), 2.31 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 422.2.

Example 15

N ² -(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N ⁵ -(1-methylpiperidine- 4-yl)pyridine-2,5-diamine (15)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68(s, 1H), 8.26(s, 1H), 8.14(d, 1H), 7.26(s, 1H), 7.28-7.22(m, 1H), 7.02(d , 1H), 6.82(d, 1H), 6.61(d, 1H), 6.33(s, 1H), 6.07(s, 2H), 3.98(s, 1H), 3.26-3.18(m, 1H), 2.75( d, 2H), 2.31 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 393.2.

Example 16

N ¹ -(3-(2,2-dimethyl(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)-N ⁴ -(1-Methylpiperidin-4-yl)benzene-1,4-diamine (16)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 8.13 (s, 1H), 7.29 (d, 1H), 7.21 (d, 1H), 7.10-7.00 (m, 3H), 6.49-6.44 (m, 2H), 5.93 (s, 1H), 3.84 (s, 1H), 3.26-3.18 (m, 1H), 2.75 (d, 2H), 2.31 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.65 (s, 6H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 420.2.

Example 17

(4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)phenyl)(4-methylpiperyl) oxazin-1-yl)methanone (17)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 8.13 (s, 1H), 7.65-7.59 (m, 2H), 7.29-7.21 (m, 2H), 7.05-6.97 (m, 3H) , 6.06 (d, 3H), 3.90 (t, 4H), 3.30 (t, 4H), 2.32 (s, 3H). MS (m/z): [M+H] ⁺ 406.2.

Example 18

4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-N-(1-methylpiperidine -4-yl)benzamide (18)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.69 (s, 1H), 8.13 (s, 1H), 7.74-7.69 (m, 2H), 7.29-7.21 (m, 2H), 7.06-6.99 (m, 3H) , 6.06(d, 3H), 5.97(s, 1H), 3.81-3.77(m, 1H), 2.95(d, 2H), 2.35(s, 3H), 2.10(d, 2H), 1.95-1.91(m , 2H), 1.61-1.58 (m, 2H). MS (m/z): [M+H] ⁺ 420.2.

Example 19

4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-N-(1-methylpiperidine -4-yl)benzenesulfonamide (19)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.69 (s, 1H), 8.13 (s, 1H), 7.76-7.72 (m, 2H), 7.46-7.40 (m, 2H), 7.29-7.21 (m, 2H) , 7.02(d, 1H), 6.07(d, 3H), 4.43(s, 1H), 3.52-3.49(m, 1H), 2.99-2.78(m, 2H), 2.34(s, 3H), 2.10-1.9 (m, 4H), 1.62-1.58 (m, 2H). MS (m/z): [M+H] ⁺ 456.2.

Example 20

N-(4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)phenyl)-1-methan piperidine-4-carboxamide (20)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.69 (s, 1H), 9.50 (s, 1H), 8.14 (s, 1H), 7.52-7.45 (m, 2H), 7.32-7.22 (m, 4H), 7.02 (d, 1H), 6.07 (s, 2H), 6.01 (s, 1H), 3.01 (d, 2H), 2.6-2.57 (m, 1H), 2.33 (s, 3H), 2.09-1.93 (m, 4H) ), 1.6-1.55 (m, 2H). MS (m/z): [M+H] ⁺ 420.2.

Example 21

4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-3-methoxy-N-( 1-Methylpiperidin-4-yl)benzamide (21)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.69(s, 1H), 8.13(s, 1H), 7.63(d, 1H), 7.45(d, 1H), 7.28-7.22(m, 3H), 7.02(d , 1H), 6.07(s, 2H), 5.98(s, 1H), 5.80(s, 1H), 3.94(s, 3H), 3.81- 3.77(m, 1H), 2.95(d, 2H), 2.35( s, 3H), 2.10 (d, 2H), 1.95-1.91 (m, 2H), 1.61-1.58 (m, 2H). MS (m/z): [M+H] ⁺ 450.2.

Example 22

4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-2-fluoro-N-(1- Methylpiperidin-4-yl)benzamide (22)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.69(s, 1H), 8.13(s, 1H), 7.53(d, 1H), 7.29-7.22(m, 2H), 7.02(d, 1H), 6.81-6.73 (m, 2H), 6.06 (d, 3H), 5.96 (s, 1H), 3.81-3.77 (m, 1H), 2.95 (d, 2H), 2.35 (s, 3H), 2.10 (d, 2H), 1.95-1.91 (m, 2H), 1.61-1.58 (m, 2H). MS (m/z): [M+H] ⁺ 438.2.

Example 23

4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-2-methyl-N-(1 -Methylpiperidin-4-yl)benzamide (23)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68(s, 1H), 8.12(s, 1H), 7.49(d, 1H), 7.29-7.22(m, 2H), 7.15(dd, 1H), 7.02(d , 1H), 6.87(d, 1H), 6.07(s, 2H), 6.03(s, 1H), 5.97(s, 1H), 3.81- 3.77(m, 1H), 2.95(d, 2H), 2.43- 2.35 (m, 6H), 2.09 (d, 2H), 1.95-1.91 (m, 2H), 1.61-1.58 (m, 2H). MS (m/z): [M+H] ⁺ 434.2.

Example 24

N-(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-4-(( 1-Methylpiperidin-4-yl)amino)benzamide (24)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.69 (s, 1H), 10.2 (s, 1H), 7.28-7.22 (m, 2H), 7.06-6.99 (m, 2H), 6.86 (dd, 1H), 6.55 (d, 1H), 6.50 (s, 1H), 6.39 (d, 1H), 4.32-4.25 (m, 4H), 3.81-3.77 (m, 2H), 2.95 (d, 2H), 2.32 (s, 3H) ), 2.09 (d, 2H), 1.95-1.91 (m, 2H), 1.61-1.58 (m, 2H). MS (m/z): [M+H] ⁺ 434.2.

Example 25

N-(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-4-(( 3-Morpholinopropyl)amino)benzamide (25)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.69 (s, 1H), 10.2 (s, 1H), 7.62-7.56 (m, 2H), 6.86 (d, 1H), 6.82-6.76 (m, 2H), 6.55 (d, 1H), 6.50(s, 1H), 6.39(d, 1H), 4.32-4.25(m, 4H), 4.04(t, 4H), 3.39(t, 2H), 3.32-3.24(m, 3H) ), 2.33-2.29 (m, 6H). MS (m/z): [M+H] ⁺ 464.2.

Example 26

N-(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-2-methoxy yl-4-((1-methylpiperidin-4-yl)amino)benzamide (26)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.69 (s, 1H), 10.2 (s, 1H), 7.25 (d, 1H), 7.16 (d, 1H), 6.72 (dd, 1H), 6.49 (s, 1H) ), 6.43(d, 1H), 6.36-6.29(m, 2H), 4.32-4.25(m, 4H), 3.91(s, 3H), 3.81-3.77(m, 2H), 2.95(d, 2H), 2.33 (s, 3H), 2.09 (d, 2H), 1.95-1.91 (m, 2H), 1.61-1.58 (m, 2H). MS (m/z): [M+H] ⁺ 464.2.

Example 27

N-(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-3-(4 -Methylpiperazin-1-yl)benzamide (27)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.25 (t, 1H), 7.14 (d, 1H), 7.08 (d, 1H), 6.96 (t, 1H) ), 6.86(dd, 1H), 6.55(d, 1H), 6.49(s, 1H), 6.39(d, 1H), 4.32-4.25(m, 4H), 3.20(t, 4H), 2.98(t, 4H), 2.60 (s, 3H). MS (m/z): [M+H] ⁺ 420.2.

Example 28

N-(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-2-methyl -4-((1-Methylpiperidin-4-yl)amino)benzamide (28)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.69 (s, 1H), 10.2 (s, 1H), 7.42-7.34 (m, 2H), 6.84 (d, 1H), 6.62 (d, 1H), 6.49-6.37 (m, 3H), 4.32-4.25 (m, 4H), 3.81-3.77 (m, 2H), 2.95 (d, 2H), 2.39-2.32 (m, 6H), 2.09 (d, 2H), 1.95-1.91 (m, 2H), 1.61-1.58 (m, 2H). MS (m/z): [M+H] ⁺ 448.2.

Example 29

N ¹ -(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-N ⁴ - (1-Methylpiperidin-4-yl)benzene-1,4-diamine (29)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68(s, 1H), 8.12(s, 1H), 6.90(d, 1H), 6.87-6.76(m, 4H), 6.57(d, 1H), 6.39(d , 1H), 5.76(s, 1H), 4.32-4.25(m, 4H), 3.64(s, 1H), 3.26-3.18(m, 1H), 2.75(d, 2H), 2.32(s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 406.2.

Example 30

N ¹ -(3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)-2-methan Oxy-N ⁴ -(1-methylpiperidin-4-yl)benzene-1,4-diamine (30)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.68 (s, 1H), 8.11 (s, 1H), 6.89 (d, 1H), 6.73 (dd, 1H), 6.57 (d, 1H), 6.44 (d, 1H) ), 6.32(d, 1H), 6.08(d, 1H), 5.72(s, 1H), 4.32-4.25(m, 4H), 3.94(s, 3H), 3.26-3.18(m, 2H), 2.75( d, 2H), 2.32 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 436.2.

Example 31

4-((3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)amino)-N -(1-Methylpiperidin-4-yl)benzamide (31)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.69 (s, 1H), 8.12 (s, 1H), 7.77-7.72 (m, 2H), 7.06-7.01 (m, 2H), 6.91 (dd, 1H), 6.56 (d, 1H), 6.40 (d, 1H), 5.98 (s, 1H), 5.82 (s, 1H), 4.32-4.25 (m, 4H), 3.81-3.77 (m, 1H), 2.75 (d, 2H) ), 2.32 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 434.2.

Example 32

4-((3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)amino)-N -(1-Methylpiperidin-4-yl)benzenesulfonamide (32)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.69 (s, 1H), 8.13 (s, 1H), 7.56-7.50 (m, 2H), 7.46-7.40 (m, 2H), 6.97 (dd, 1H), 6.64 (d, 1H), 6.50 (d, 1H), 5.83 (s, 1H), 4.32-4.25 (m, 4H), 4.41 (s, 1H), 3.51-3.49 (m, 1H), 3.0-2.81 (m , 2H), 2.34 (s, 3H), 2.10-1.9 (m, 4H), 1.62-1.58 (m, 2H). MS (m/z): [M+H] ⁺ 470.2.

Example 33

N-(4-((3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)amino )phenyl)-1-methylpiperidine-4-carboxamide (33)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.69 (s, 1H), 9.50 (s, 1H), 8.14 (s, 1H), 7.54-7.48 (m, 2H), 7.39-7.33 (m, 2H), 6.95 (dd, 1H), 6.84-6.78 (m, 2H), 5.86 (s, 1H), 4.32-4.25 (m, 4H), 3.01 (d, 2H), 22.6-2.57 (m, 1H), 2.33 (s) , 3H), 2.09-1.93 (m, 4H), 1.6-1.55 (m, 2H). MS (m/z): [M+H] ⁺ 434.2.

Example 34

4-((3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)amino)-3 -Methoxy-N-(1-methylpiperidin-4-yl)benzamide (34)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.69 (s, 1H), 8.13 (s, 1H), 7.64 (d, 1H), 7.46 (d, 1H), 7.23 (d, 1H), 6.91 (dd, 1H) ), 6.56(d, 1H), 6.39(d, 1H), 5.98(s, 1H), 5.61(s, 1H), 4.32-4.25(m, 4H), 3.94(s, 3H), 3.81-3.77( m, 1H), 2.95 (d, 2H), 2.35 (s, 3H), 2.10 (d, 2H), 1.95-1.91 (m, 2H), 1.61- 1.58 (m, 2H). MS (m/z) : [M+H] ⁺ 464.2.

Example 35

4-((3-(2,3-Dihydro(benzo[b][1,4]dioxen)-6-yl)-1H-pyrazol-5-yl)amino)-3 -Fluoro-N-(1-methylpiperidin-4-yl)benzamide (35)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.69 (s, 1H), 8.13 (s, 1H), 7.58 (dd, 1H), 7.47 (d, 1H), 7.15 (d, 1H), 6.91 (dd, 1H) ), 6.56(d, 1H), 6.39(d, 1H), 5.99(s, 1H), 5.63(s, 1H), 4.32-4.25(m, 4H), 3.81-3.77(m, 1H), 2.96( d, 2H), 2.34 (s, 3H), 2.10-1.96 (m, 4H), 1.61-1.58 (m, 2H). MS (m/z): [M+H] ⁺ 452.2.

Example 36

N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)-4-(( 1-Methylpiperidin-4-yl)amino)benzamide (36)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.3 (s, 1H), 7.60-7.53 (m, 2H), 7.29 (d, 1H), 7.20 (dd, 1H), 7.05 (d , 1H), 6.80-6.74(m, 2H), 6.51(s, 1H), 4.36(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 456.2.

Example 37

N-(3-(2,3-Dihydro(benzofuran)-6-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperidin-4-yl)amino) Benzamide (37)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.3 (s, 1H), 7.59-7.54 (m, 2H), 7.34 (d, 1H), 7.22-7.15 (m, 2H), 6.79 -6.74(m, 2H), 6.53(s, 1H), 4.51(s, 1H), 4.27(t, 2H), 3.3-3.2(m, 1H), 2.98(t, 2H), 2.75(d, 2H) ), 2.32 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 418.2.

Example 38

N-(3-(2,3-Dihydro(benzofuran)-5-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperidin-4-yl)amino) Benzamide (38)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.3 (s, 1H), 7.60-7.52 (m, 3H), 7.39 (d, 1H), 6.94 (d, 1H), 6.81-6.74 (m, 2H), 6.50(s, 1H), 4.36(s, 1H), 4.27(t, 2H), 3.3-3.2(m, 1H), 2.98(t, 2H), 2.75(d, 2H), 2.32 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 418.2.

Example 39

N ¹ -(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)-N ⁴ - (1-Methylpiperidin-4-yl)benzene-1,4-diamine (39)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.68 (s, 1H), 8.13 (s, 1H), 7.33-7.23 (m, 2H), 7.06 (t, 3H), 6.50-6.43 (m, 2H), 5.94 (s, 1H), 3.81 (s, 1H), 3.26-3.18 (m, 1H), 2.75 (d, 2H), 2.32 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H) ), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 428.2.

Example 40

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-6-((1-methylpiperidine-4 -yl)amino)nicotinamide (40)

The preparation method is similar to (1), and a yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.68 (s, 1H), 10.3 (s, 1H), 8.73 (d, 1H), 7.53 (dd, 1H), 7.25 (d, 1H), 7.20 (dd, 1H) ), 7.02(d, 1H), 6.84(d, 1H), 6.52(s, 1H), 6.07(s, 2H), 4.2(s, 1H), 3.26- 3.18(m, 1H), 2.75(d, 2H), 2.32 (s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 421.2.

Example 41

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-5-((1-methylpiperidine-4 -yl)amino)pyridine-2-carboxamide (41)

The preparation method is similar to (1), and a yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.68 (s, 1H), 10.3 (s, 1H), 8.81 (d, 1H), 7.93 (d, 1H), 7.40 (dd, 1H), 7.29-7.22 (m , 2H), 7.03(d, 1H), 6.51(s, 1H), 6.07(s, 2H), 3.88(s, 1H), 3.26-3.18 (m, 1H), 2.75(d, 2H), 2.32( s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 421.2.

Example 42

N ² -(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N ⁵ -(1-methylpiperidine- 4-yl)pyridine-2,5-diamine (42)

The preparation method is similar to (10), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.68 (s, 1H), 8.32 (s, 1H), 8.15 (d, 1H), 7.29-7.20 (m, 2H), 7.02 (d, 1H), 6.85 (dd , 1H), 6.61(d, 1H), 6.39(s, 1H), 6.07(s, 2H), 3.86(s, 1H), 3.26- 3.18(m, 1H), 2.75(d, 2H), 2.31( s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.47-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 393.2.

Example 43

4-((1-Methylpiperidin-4-yl)amino)-N-(3-(spiro[benzo[d][1,3]dioxol-2,1'-cyclopropane ]-5 ^- yl)-1H-pyrazol-5-yl)benzamide (43) was prepared analogously to (1) to give a pale yellow solid. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.3 (s, 1H), 7.59-7.54 (m, 2H), 7.27 (d, 1H), 7.20 (dd, 1H), 7.03 (d , 1H), 6.74-6.68(m, 2H), 6.52(s, 1H), 4.37(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H), 0.89-0.75 (m, 4H). MS (m/z): [M+H] ⁺ 446.2.

Example 44

N-(3-(2,2-Dichloro(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)-4-(( 1-Methylpiperidin-4-yl)amino)benzamide (44)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.3 (s, 1H), 7.59-7.53 (m, 2H), 7.37 (d, 1H), 7.25 (dd, 1H), 7.14 (d , 1H), 6.80-6.74(m, 2H), 6.50(s, 1H), 4.35(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.32(s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 488.1.

Example 45

N-(3-([1,3]dioxolo[4,5-c]pyridin-6-yl)-1H-pyrazol-5-yl)-4-((1-methyl piperidin-4-yl)amino)benzamide (45)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.7 (s, 1H), 10.3 (s, 1H), 8.50 (s, 1H), 7.55-7.48 (m, 2H), 7.44 (s, 1H), 6.80-6.73 (m, 2H), 6.38(s, 1H), 5.95(s, 2H), 4.44(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 420.2.

Example 46

N-(3-([1,3]dioxolo[4,5-d]pyrimidin-5-yl)-1H-pyrazol-5-yl)-4-((1-methyl piperidin-4-yl)amino)benzamide (46)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.7 (s, 1H), 10.2 (s, 1H), 8.59 (s, 1H), 7.60-7.54 (m, 2H), 6.83 (s, 1H), 6.81-6.74 (m, 2H), 5.95(s, 2H), 4.36(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06(d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 422.2.

Example 47

N-(3-([1,3]dioxolo[4,5-c]pyridin-4-yl)-1H-pyrazol-5-yl)-4-((1-methyl piperidin-4-yl)amino)benzamide (47)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68(s, 1H), 10.2(s, 1H), 8.36(d, 1H), 7.60-7.54(m, 2H), 7.22(d, 1H), 6.86(s) , 1H), 6.80-6.74(m, 2H), 5.95(s, 2H), 4.42(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 421.2.

Example 48

N-(3-(Benzo[d][1,3]dioxol-4-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperidine-4 -yl)amino)benzamide (48)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.59-7.53 (m, 2H), 7.21 (dd, 1H), 7.04-6.94 (m, 2H), 6.80 -6.74(m, 2H), 6.48(s, 1H), 5.95(s, 2H), 4.44(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H) ), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 420.2.

Example 49

N-(3-([1,3]dioxolo[4,5-d]pyrimidin-7-yl)-1H-pyrazol-5-yl)-4-((1-methyl piperidin-4-yl)amino)benzamide (49)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 8.69 (s, 1H), 7.59-7.53 (m, 2H), 6.79-6.73 (m, 2H), 6.33 (s, 1H), 5.96(s, 2H), 5.15(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06(d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 422.2.

Example 50

N-(3-([1,3]dioxolo[4,5-b]pyridin-7-yl)-1H-pyrazol-5-yl)-4-((1-methyl piperidin-4-yl)amino)benzamide (50)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.76 (d, 1H), 7.55-7.48 (m, 2H), 7.09 (d, 1H), 6.80-6.74 (m, 2H), 6.38(s, 1H), 5.95(s, 2H), 4.44(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06 (d, 2H), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 421.2.

Example 51

N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4-(( 1-Methylpiperidin-4-yl)amino)benzamide (51)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.69 (s, 1H), 10.2 (s, 1H), 7.60-7.53 (m, 2H), 7.22 (dd, 1H), 7.06-6.98 (m, 2H), 6.81 -6.74(m, 2H), 6.47(s, 1H), 4.37(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06(d, 2H) ), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 456.2.

Example 52

N-(3-(2,2-Dichloro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4-(( 1-Methylpiperidin-4-yl)amino)benzamide (52)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.59-7.53 (m, 2H), 7.27 (dd, 1H), 7.16-7.06 (m, 2H), 6.80 -6.74(m, 2H), 6.60(s, 1H), 4.35(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06(d, 2H) ), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ^- 488.1.

Example 53

N-(3-(2,2-Dimethyl(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4-( (1-Methylpiperidin-4-yl)amino)benzamide (53)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.59-7.53 (m, 2H), 7.20 (dd, 1H), 7.04-6.95 (m, 2H), 6.80 -6.74(m, 2H), 6.49(s, 1H), 4.51(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06(d, 2H) ), 1.95-1.91 (m, 2H), 1.66 (s, 6H), 1.48-1.42 (m, 2H). MS (m/z): [M+H] ⁺ 448.2.

Example 54

4-((1-Methylpiperidin-4-yl)amino)-N-(3-(spiro[benzo[d][1,3]dioxol-2,1'-cyclopropane ]-4 ^- yl)-1H-pyrazol-5-yl)benzamide (54)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.3 (s, 1H), 7.59-7.53 (m, 2H), 7.21 (dd, 1H), 7.05-6.96 (m, 2H), 6.74 -6.68(m, 2H), 6.43(s, 1H), 4.37(s, 1H), 3.3-3.2(m, 1H), 2.75(d, 2H), 2.31(s, 3H), 2.06(d, 2H) ), 1.95-1.91 (m, 2H), 1.48-1.42 (m, 2H), 0.88-0.76 (m, 4H). MS (m/z): [M+H] ⁺ 446.2.

Example 55

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((4-ethylpiperazine-1 -yl)methyl)benzamide (55)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.72-7.67 (m, 2H), 7.42-7.36 (m, 2H), 7.25 (d, 1H), 7.20 (dd, 1H), 7.01 (d, 1H), 6.51 (s, 1H), 6.07 (s, 2H), 4.26 (s, 2H), 2.50 (t, 4H), 2.42 (q, 2H), 2.11 ( t, 4H), 1.05 (t, 3H). MS (m/z): [M+H] ⁺ 434.2.

Example 56

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(4-(2-hydroxyethyl) Piperazin-1-yl)benzamide (56)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.58-7.52 (m, 2H), 7.25 (d, 1H), 7.19 (dd, 1H), 7.01 (d , 1H), 6.87-6.81(m, 2H), 6.52(s, 1H), 6.07(s, 2H), 3.58(q, 2H), 3.19(t, 4H), 2.78(t, 4H), 2.58( t, 2H), 2.15 (t, 1H). MS (m/z): [M+H] ⁺ 436.2.

Example 57

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(2-hydroxyethoxy)benzyl Amide (57)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.76-7.69 (m, 2H), 7.25 (d, 1H), 7.19 (dd, 1H), 7.04-6.95 (m, 3H), 6.52 (s, 1H), 6.07 (s, 2H), 4.45 (t, 2H), 3.74-3.68 (m, 2H), 2.21 (t, 1H). MS (m/z): [M+H] ⁺ 358.1.

Example 58

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(2-methoxyethoxy) Benzamide (58)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.79-7.72 (m, 2H), 7.33-7.26 (m, 2H), 7.06-7.01 (m, 2H) , 7.02-6.95(m, 2H), 6.07(s, 2H), 4.17(t, 2H), 3.78(t, 2H), 3.47(s, 3H). MS(m/z): [M+H] ⁺ 382.2.

Example 59

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(3-morpholinopropoxy)benzene Formamide (59)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.76-7.70 (m, 2H), 7.25 (d, 1H), 7.19 (dd, 1H), 7.08-6.98 (m, 3H), 6.52(s, 1H), 6.07(s, 2H), 4.07-3.98(m, 6H), 2.85(t, 2H), 2.34(t, 4H), 1.84(p, 2H). MS (m/z): [M+H] ⁺ 451.2.

Example 60

N-(3-(Benzo[d][1,3]dioxol-4-yl)-1H-pyrazol-5-yl)-4-((4-ethylpiperazine-1 -yl)methyl)benzamide (60)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.72-7.67 (m, 2H), 7.42-7.36 (m, 2H), 7.20 (d, 1H), 7.04 -6.94(m, 2H), 6.48(s, 1H), 5.95(s, 2H), 4.26(s, 2H), 2.50(t, 4H), 2.42(q, 2H), 2.11(t, 4H), 1.07 (t, 3H). MS (m/z): [M+H] ⁺ 434.2.

Example 61

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((2-(diethylamino)ethyl yl)amino)benzamide (61)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.59-7.53 (m, 2H), 7.25 (d, 1H), 7.19 (dd, 1H), 7.01 (d , 1H), 6.74-6.68(m, 2H), 6.51(s, 1H), 6.07(s, 2H), 4.67(s, 1H), 3.47(t, 2H), 2.75(t, 2H), 2.51( q, 4H), 1.00 (t, 6H). MS (m/z): [M+H] ⁺ 422.2.

Example 62

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperidine-4 -yl)methoxy)benzamide (62)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.75-7.70 (m, 2H), 7.25 (d, 1H), 7.19 (dd, 1H), 7.07-6.98 (m, 3H), 6.52 (s, 1H), 6.07 (s, 2H), 3.96 (d, 2H), 3.2-3.15 (m, 2H), 2.29-2.26 (m, 5H), 1.85-1.64 (m , 3H), 1.47-1.43 (m, 2H). MS (m/z): [M+H] ⁺ 435.2.

Example 63

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl)benzyl Amide (63)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.58-7.52 (m, 2H), 7.25 (d, 1H), 7.19 (dd, 1H), 7.01 (d , 1H), 6.87-6.81(m, 2H), 6.52(s, 1H), 6.07(s, 2H), 3.60(t, 4H), 2.89(t, 4H), 1.20(s, 1H). MS( m/z): [M+H] ⁺ 392.2.

Example 64

N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4-(( 1-Methylpiperidin-4-yl)methoxy)benzamide (64)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300 MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.76-7.69 (m, 2H), 7.21 (dd, 1H), 7.07-6.98 (m, 4H), 6.47 (s,1H), 3.96(d,2H), 3.2-3.15(m,2H), 2.29-2.26(m,5H), 1.85-1.64(m,3H), 1.47-1.43(m,2H).MS (m/z): [M+H] ⁺ 471.2.

Example 65

N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(pyrrolidin-1-yl)benzyl Amide (65)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.61-7.54 (m, 2H), 7.32 (d, 1H), 7.18 (dd, 1H), 7.03 (d , 1H), 6.71-6.64(m, 2H), 6.47(s, 1H), 6.07(s, 2H), 3.37-3.29(m, 4H), 2.42-2.32(m, 4H). MS(m/z ): [M+H] ⁺ 377.2.

Example 66

N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4-(( 2-(Diethylamino)ethyl)amino)benzamide (66)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.65-7.59 (m, 2H), 7.16 (dd, 1H), 7.05-7.00 (m, 2H), 6.74 -6.68(m, 2H), 6.39(s, 1H), 4.74(s, 1H), 3.47(t, 2H), 2.75(t, 2H), 2.51(q, 4H), 1.00(t, 6H). MS (m/z): [M+H] ⁺ 458.2.

Example 67

N-(3-(Spiro[benzo[d][1,3]dioxol-2,1'-cyclopropane]-4 ^- yl)-1H-pyrazol-5-yl)-4 -(3-Morpholinepropoxy)benzamide (67)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.75-7.69 (m, 2H), 7.21 (d, 1H), 7.05-6.94 (m, 4H), 6.44 (s, 1H), 4.07-3.98 (m, 6H), 2.85 (t, 2H), 2.34 (t, 4H), 1.84 (p, 2H), 0.88-0.76 (m, 4H). MS (m/z ): [M+H] ⁺ 477.2.

Example 68

N-(3-(2,2-Dimethyl(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4-( Piperazin-1-yl)benzamide (68)

The preparation method is similar to (1), and a pale yellow solid is obtained. ¹ H NMR (300MHz, CDCl3) δ 12.68 (s, 1H), 10.2 (s, 1H), 7.62-7.56 (m, 2H), 7.28 (dd, 1H), 7.06-6.95 (m, 2H), 6.83 -6.76(m, 2H), 6.45(s, 1H), 3.60(t, 4H), 2.89(t, 4H), 1.66(s, 6H), 1.17(s, 1H). MS(m/z): [M+H] ⁺ 420.2.

Claims (5)

1. Compounds (1) to (54) and pharmaceutically acceptable salts thereof: (1) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperin pyridin-4-yl)amino)benzamide (2) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(4-methylpiperazine -1-yl)benzamide (3) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(piperidin-1-yl ) benzamide (4) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-morpholinylbenzamide (5) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((3-morpholinopropane base)amino)benzamide (6) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(((3-(diethyl) aminoamino)propyl)amino)benzamide (7) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-methoxy-4-( (1-Methylpiperidin-4-yl)amino)benzamide (8) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-3-(4-methylpiperazine -1-yl)benzamide (9) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-fluoro-4-((1 -Methylpiperidin-4-yl)amino)benzamide (10) N1-(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N4-(1-methylpiperidine- 4-yl)benzene-1,4-diamine (11) 3-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H - Pyrazol-5-amine (12) N1-(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N4-(3-morpholinopropyl) Benzene-1,4-diamine (13) N4-(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-fluoro-N1-(1-methyl) ylpiperidin-4-yl)benzene-1,4-diamine (14) N1-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-2-methoxy-N4-( 1-Methylpiperidin-4-yl)benzene-1,4-diamine (15) N2-(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N5-(1-methylpiperidine-4 -yl)pyridine-2,5-diamine (16) N1-(3-(2,2-dimethyl(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)- N4-(1-Methylpiperidin-4-yl)benzene-1,4-diamine (17) (4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)phenyl)(4- Methylpiperazin-1-yl)methanone (18) 4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-N-(1-methyl) ylpiperidin-4-yl)benzamide (19) 4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-N-(1-methyl) ylpiperidin-4-yl)benzenesulfonamide (20) N-(4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)phenyl)- 1-Methylpiperidine-4-carboxamide (21) 4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-3-methoxy- N-(1-Methylpiperidin-4-yl)benzamide (22) 4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-2-fluoro-N- (1-Methylpiperidin-4-yl)benzamide (23) 4-((3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)amino)-2-methyl-N -(1-Methylpiperidin-4-yl)benzamide (24) N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)-4 -((1-Methylpiperidin-4-yl)amino)benzamide (25) N1-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)-N4_ (1-Methylpiperidin-4-yl)benzene-1,4-diamine (26) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-6-((1-methylpiperin pyridin-4-yl)amino)nicotinamide (27) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-5-((1-methylpiperin pyridin-4-yl)amino)pyridine-2-carboxamide (28) N2-(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-N5-(1-methylpiperidine-4 -yl)pyridine-2,5-diamine (29) 4-((1-Methylpiperidin-4-yl)amino)-N-(3-(spiro[benzo[d][1,3]dioxol-2,1' -Cyclopropane]-5-yl)-1H-pyrazol-5-yl)benzamide (30) N-(3-(2,2-Dichloro(benzo[d][1,3]dioxol)-5-yl)-1H-pyrazol-5-yl)-4- ((1-Methylpiperidin-4-yl)amino)benzamide (31) N-(3-([1,3]dioxolo[4,5-c]pyridin-6-yl)-1H-pyrazol-5-yl)-4-((1 -Methylpiperidin-4-yl)amino)benzamide (32) N-(3-([1,3]dioxolo[4,5-d]pyrimidin-5-yl)-1H-pyrazol-5-yl)-4-((1- Methylpiperidin-4-yl)amino)benzamide (33) N-(3-([1,3]dioxolo[4,5-c]pyridin-4-yl)-1H-pyrazol-5-yl)-4-((1 -Methylpiperidin-4-yl)amino)benzamide (34) N-(3-(Benzo[d][1,3]dioxol-4-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperin pyridin-4-yl)amino)benzamide (35) N-(3-([1,3]dioxolo[4,5-d]pyrimidin-7-yl)-1H-pyrazol-5-yl)-4-((1 -Methylpiperidin-4-yl)amino)benzamide (36) N-(3-([1,3]dioxolo[4,5-b]pyridin-7-yl)-1H-pyrazol-5-yl)-4-((1- Methylpiperidin-4-yl)amino)benzamide (37) N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4-( (1-Methylpiperidin-4-yl)amino)benzamide (38) N-(3-(2,2-Dichloro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4- ((1-Methylpiperidin-4-yl)amino)benzamide (39) N-(3-(2,2-Dimethyl(benzo[d][1,3]dioxol-4-yl)-1H-pyrazol-5-yl)- 4-((1-Methylpiperidin-4-yl)amino)benzamide (40) 4-((1-Methylpiperidin-4-yl)amino)-N-(3-(spiro[benzo[d][1,3]dioxol-2,1' -Cyclopropane]-4-yl)-1H-pyrazol-5-yl)benzamide (41) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((4-ethylpiperin oxazin-1-yl)methyl)benzamide (42) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(4-(2-hydroxyl) Ethyl)piperazin-1-yl)benzamide (43) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(2-hydroxyethoxy ) benzamide (44) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(2-methoxyethoxy base) benzamide (45) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(3-morpholinopropoxy base) benzamide (46) N-(3-(Benzo[d][1,3]dioxol-4-yl)-1H-pyrazol-5-yl)-4-((4-ethylpiperin oxazin-1-yl)methyl)benzamide (47) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(((2-(diethyl) Amino)ethyl)amino)benzamide (48) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-((1-methylpiperidine -4-yl)methoxy)benzamide (49) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl) ) benzamide (50) N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4- ((1-Methylpiperidin-4-yl)methoxy)benzamide (51) N-(3-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)-4-(pyrrolidin-1-yl) ) benzamide (52) N-(3-(2,2-Difluoro(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4 -((2-(diethylamino)ethyl)amino)benzamide (53) N-(3-(Spiro[benzo[d][1,3]dioxol-2,1′-cyclopropane]-4-yl)-1H-pyrazol-5-yl) -4-(3-Morpholinepropoxy)benzamide (54) N-(3-(2,2-Dimethyl(benzo[d][1,3]dioxol)-4-yl)-1H-pyrazol-5-yl)-4 -(Piperazin-1-yl)benzamide. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt comprises an acid addition salt of the compound with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p- Toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or benzenesulfonic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid. 3. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 4. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating a disease associated with FLT3. 5. The use of claim 4, wherein the disease associated with FLT3 is acute myeloid leukemia.