CN110835336B

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

Info

Publication number: CN110835336B
Application number: CN201810937875.2A
Authority: CN
Inventors: 卢帅; 王志杰; 向黎; 王淑贤; 衡浩; 蔡炅桁; 秦天人; 田洁怡; 陈亚东; 陆涛
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2018-08-16
Filing date: 2018-08-16
Publication date: 2022-10-04
Anticipated expiration: 2038-08-16
Also published as: CN110835336A

Abstract

The invention relates to the field of medicinal chemistry, and discloses an oxygen-containing heterocyclic substituted azole compound and application thereof. In particular to oxygen-containing heterocyclic substituted azole compounds, a preparation method thereof, a medicinal composition containing the compounds and medical application thereof, in particular to application as an FMS-like tyrosine kinase 3 inhibitor.

Description

Oxygen-containing heterocyclic substituted azole compound and application thereof

Technical Field

The invention relates to the field of medicinal chemistry, in particular to oxygen-containing heterocyclic substituted azole compounds, a preparation method thereof, medicinal compositions containing the compounds and medical application thereof.

Background

Cell signal transduction plays a key role in regulating the processes of cell growth, proliferation, differentiation, apoptosis and the like. The imbalance between cell proliferation and apoptosis leads to the development of a major disease such as cancer, the nature of which is a dysregulation of cell signaling. When the cell signal transduction pathway regulating the normal physiological activities of cells in the cells is changed under the action of carcinogenic factors, the normal biological effects of regulating the growth, division and differentiation of the cells are abnormal, so that the abnormal growth and division of the cells and the change of cell morphology are caused, and cancers are caused. Because the protein kinase plays a key role in a cell signal transduction pathway and the cancer cell is often accompanied by the over-expression of the protein kinase, the development of the antitumor drug by taking the protein kinase as a target has a wide prospect.

Leukemia is a malignant neoplastic disease of the hematopoietic system, a hematologic tumor in which hematopoietic stem/progenitor cells undergo malignant lesions. Leukemia can be divided into two categories according to the natural course and different degrees of cell proliferation at different stages: namely acute leukemia and chronic leukemia. Depending on the kind of the proliferating leukemia cells, acute Lymphoblastic Leukemia (ALL) and Acute Myelogenous Leukemia (AML) can be classified into two major categories. AML accounts for 60% -70% of newly diagnosed adult acute leukemia, and shows a trend of increasing year by year (Environmental Health Perspectives,2007, 115 (1): 138-145). The pathogenesis of AML is not completely understood at present, and cytogenetic and molecular biological studies find that two kinds of gene mutations play a major role in the pathogenesis of AML (Future Oncology,2016, 12 (6): 827-838). The first is a genetic mutation involving a tyrosine kinase in the signal transduction pathway, which allows for sustained activation of the tyrosine kinase, resulting in uncontrolled signal transduction of the cell; the second type of mutation relates to a transcription factor related to hematopoietic regulation, and the mutation results in the loss of the function of a gene promoting cell differentiation, so that the differentiation and apoptosis of hematopoietic cells are inhibited. In view of the key role of protein kinase and related signal pathways in the AML development process, the selection of proper protein kinase as a target for developing inhibitors becomes an important strategy for AML treatment

FMS-like tyrosine kinase 3 (FMS-1 ike tyrosine kinase 3, FLT3) is a type III receptor tyrosine kinase and 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 aberrant expression of FLT 3. Therefore, the development of inhibitors targeting FLT3 has been a focus of research for the treatment of hematological malignancies (Blood, 2002, 100 (5): 1532-1542).

The FLT3 gene sequence was first discovered and characterized in mice, and its protein structure was cloned in human CD34+ hematopoietic progenitor cells by Rosnet O et al (Blood, 1993, 82 (4): 1110-1119) 1993. The human FLT3 gene contains 24 codons, is located on chromosome 13 (13 ql 2), encodes 993 amino acids, and has 85% homology with mouse FLT 3. The molecular weight of N-terminal glycosylated FLT3 outside the cell membrane is 165kDa, which is mainly distributed on the cell membrane, while the molecular weight of non-glycosylated FLT3 is 135-140 kDa, which is not combined with the cell membrane. FLT3 is expressed mainly in bone marrow cells, umbilical 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 an extracellular membrane domain consisting of 5 immunoglobulin-like members, a transmembrane domain, a juxtamembrane domain, and an intracellular tyrosine kinase domain. Griffith et al (Molecular Cell,2004, 13 (2): 169-178) originally resolved the crystal structure of FLT3 kinase domain self-inhibited form, which consists of two C-and N-terminal portions, with the C-terminal being divided into two N-and C-lobe portions by an insertion domain. N-lobe and C-lobe rotate around the insertion domain, forming a catalytic pocket for the kinase in which the ATP-binding site of the kinase is located. When the N-lobe and C-lobe are brought into close proximity around the insertion domain, key catalytic residues in the two part structure interact, leaving the kinase in an activated conformation; otherwise, the kinase is in a non-activated conformation. The kinase domain activation loop (A-loop) is located in the C-loop and has the structure of a part with the starting end residues Asp829-Phe830-Gly831 and the terminal end residues Trp854-Met855-Ala 856. When the key tyrosine residue in the A-loop is not phosphorylated, the kinase is in an inactive conformation when the A-loop is structurally folded in the catalytic pocket, and the substrate and ATP are prevented from entering the catalytic pocket; otherwise, the catalytic pocket opening kinase is in an activated conformation.

The membrane-proximal Domain (JM) is a prominent feature in the structure of the FLT3 receptor and is directly involved in the self-inhibitory regulation of kinases (Molecular Cell,2004, 13 (2): 169-178). The JM domain can be divided into three parts: a binding part (JM-B), a conversion part (JM-S) and a linking part (JM-Z). Wherein the JM-B structure is located between residues Tyr572 to Met578, almost buried in the kinase domain, linking the activated and the non-activated part of the intracellular domain; the JM-S structure is located in The part of The C-loop surface residues Val579 to Val592 of The kinase domain and contains two key residues Tyr589 and Tyr591 which regulate The activation state of kinases (The Journal of Biological Chemistry,2002, 278 (34): 31461-31464); JM-Z binds to the N-lobe of the kinase domain, located between residues Asp593 and Trp 603. The precise regulatory mechanisms of the JM domain for the FLT3 receptor are not yet fully understood. It is theorized that JM-B folds with the JM-S structure, that residue Tyr572 in JM-B forms a hydrogen bond with residue Glu661 of the ATP binding site, that the entire JM-B structure is immobilized between N-and C-lobe, preventing the formation of a catalytic pocket between them, and that the presence of the JM-B structure places the A-loop in a folded conformation and ultimately the kinase in a non-activated state. When Tyr589 or Tyr591 in JM-S is activated by phosphorylation, the folding conformation of JM-S is destroyed, so that JM-B can not keep the original spatial position and loses the inhibition effect on a kinase domain; in contrast, when tyrosine residues are dephosphorylated by phosphotransferases, JM-S reverts to the original conformation, allowing JM-B to revert to the inhibitory conformation and thus achieving regulation of kinase self-inhibition (Molecular Cell,2004, 13 (2): 169-178).

FLT3ligand (FLT 3ligand, FL) has many subtypes, human FL subtype has both soluble and Cell-bound ligands, has homology with Stem Cell growth Factor (Stem Cell Factor, SCF), macrophage colony-stimulating Factor (M-CSF), and is expressed mainly in bone marrow and hematopoietic cells (Nature, 1994, 368 (6472): 643-648 Cell,1993, 75 (6): 1157-1167). FL alone is not effective in inducing the proliferative differentiation of lymphoid and myeloid stem/progenitor cells, but its induction is greatly enhanced by 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, with more than 30% being accompanied by activating mutations of FLT3 (Leukemia, 1996, 10 (2): 261-270 Leukemia &Lymphoma,2014, 55 (2): 243-255). FLT3 mutation usually leads to its abnormal activation, and in the absence of ligand binding, autophosphorylation occurs to activate downstream signaling pathways, which promotes abnormal proliferation of hematopoietic cells and lymphocytes, ultimately leading to hematological malignancies. There are two main types of activating mutations in FLT 3: a) Internal Tandem Duplication (ITD) mutations of the juxtamembrane domain; b) Point mutations of the activation loop in The Kinase Domain (TKD).

ITD mutations are the earliest group of FLT3 activating mutations that were observed, with approximately 20% to 25% of AML patients being associated with this mutation (Leukemia, 2000, 14 (4): 675-683 blood,2001, 98 (6): 1752-1759. ITD mutation is the insertion of the 14 and 15 exons of FLT3 gene into the base sequence of tandem repeats, resulting in the alteration of the amino acid sequence of the membrane-proximal domain of the FLT3 receptor. Although the position and length of the insertion of the mutant gene are polymorphic and vary from 3 to 400 nucleotides in length, the tandem-replicated sequence is always transcribed in frame (Blood, 2008, 111 (10): 4930 to 4933). The membrane-proximal domain of the FLT3 receptor plays a key role in the regulation of receptor activity, and in general, the membrane-proximal domain has a self-inhibitory function on the kinase domain, and is capable of inhibiting the phosphorylation of the kinase domain. However, ITD mutations disrupt the self-inhibitory activity of the juxtamembrane domain, resulting in a loss of this self-inhibitory effect, allowing FLT3 to dimerize in the absence of ligand and remain in a continuously active conformation. Meanwhile, ITD mutant FLT3 receptor can form a dimer with its wild type receptor, phosphorylate its tyrosine residue, and activate downstream signal pathways (Oncogene, 2002, 21 (16): 2555-2563). ITD mutant FLT3 also strongly activates STAT5 signaling pathway, promoting differentiation and proliferation of cells (Blood, 2006, 108 (4): 1339-1345). AML patients with ITD mutations often have clinical manifestations of increased white Blood cell count, increased percentage of primitive bone marrow cells and Blood cells (Blood, 2002, 100 (1): 59-66). Because of the high AML recurrence rate and the high number of adverse effects in patients after ITD mutation, the adverse prognosis is worse in ITD mutant patients compared to normal AML patients (Environmental Health Perspectives,2007, 115 (1): 138-145).

The point mutation of FLT3 mainly occurs on the activation loop of TKD. Insertion or deletion of exon 20 of FLT3 gene can mutate aspartic acid residue 835 of TKD carbon end in FLT 3. This mutation is present in about 7% of AML patients (Blood, 2001, 97 (8): 2434-2439). The most common mutation is Asp835Tyr, while there are other mutations such as Asp835Val, asp835Glu and Asp835Asn, etc. Recent studies have found that there is also an activating mutation at the aspartic acid residue 676 of the kinase domain of FLT3 (Blood, 2013, 122 (10): 1761-1769). These point mutations stabilize the activation loop in a conformation upon binding ATP, thereby allowing sustained activation of FLT 3. Introduction of the TKD mutant gene into murine hematopoietic stem cells leads to oligoclonal lymphoid disorders (oligomeric lymphoid disorders), suggesting that TKD and ITD mutations have different effects on cellular signaling pathways (Blood, 2005, 105 (12): 4792-4799). In addition, poor prognosis in TKD-mutated AML patients is not clear (Blood, 2010, 115 (3): 453-474).

Furthermore, FLT3-ITD type mutations have been associated with other hematological disorders, such as Acute Promyelocytic Leukemia (APL), myelodysplastic syndrome (MDS), and Acute Lymphoid Leukemia (ALL), where the incidence of FLT3-ITD in APL is about 20% and MDS and ALL are about 8% and 3%, respectively (hematogenous magnetics, 2002,9 (4): 274).

Given that FLT3 plays a key role in hematological malignancies, especially in the pathogenesis of AML, FLT 3-targeted therapy has become the focus of anti-AML drug research. Currently, some inhibitors against FLT3, such as Midostatin (PKC 412), lestaurtinib (CEP-701), tandatiniib (MLN-518), KW2449, sunitinib (SU 11248), sorafenib (BAY 43-9006), etc., have entered clinical studies.

Recurrent AML patients develop FLT3-ITD mutations that lead to resistance of the tumor cells to the inhibitor (Nature, 2012, 485 (7397): 260-263). Therefore, there is a need to develop inhibitors having strong inhibitory activity against FLT3-ITD, thereby facilitating the overcoming of drug resistance. Furthermore, there is evidence that side effects of kinase inhibitors are associated with poor selectivity. The selective inhibitor can specifically block a certain signal channel, has small influence on other normal signal channels, reduces the possibility of causing side effects, and is easy to introduce a personalized treatment scheme. Moreover, the selective kinase inhibitor can be combined with other targeted drugs to synergistically treat tumors. However, existing FLT3 inhibitors generally have inhibitory activity against other receptor tyrosine kinases as well (china new journal of medicine 2016, 17, 1960-1966), and therefore the discovery of FLT3 selective inhibitors, especially FLT3-ITD selective inhibitors, is very important for the development of drugs for the treatment of AML.

Disclosure of Invention

The invention aims to provide a small-molecule organic compound with FLT3-ITD inhibitory activity or a pharmaceutically acceptable salt thereof. Which comprises the acid addition salt of a compound of formula I with: 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, apricot kernel acid. Also included are acid salts of inorganic bases such as: contains alkali metal cation, alkaline earth metal cation, and ammonium cation salt.

Another object of the present invention is to provide a process for the preparation of the above compounds.

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

It is a further object of the present invention to provide a medical use of the above compounds or pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof, especially in the prevention, delay of progression or treatment of diseases mediated by FLT3-ITD alone or in involvement.

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

wherein R is ₁ Is selected from aryl or Het, wherein aryl or Het independently of each other may optionally be substituted by one or more R ₃ Substitution; r ₃ Can be hydrogen, alkyl, alkylidene, cyano, halogen, haloalkyl, hydroxy, mercapto, amino, alkoxy, alkylamino, alkylthio, alkoxyalkyl, arylalkyl, diarylalkyl, aryl, het, NH ₂ SO ₂ Alkyl sulphonamido, aryl sulphonamido, het sulphonamido, alkyl sulphonyl, aryl sulphonyl, het sulphonyl, HC (O) NH, C (O) H, NH ₂ C (O) or NH ₂ C (O) NH, wherein hydroxy, mercapto, amino, alkyl, alkoxy, alkylamino, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, het, NH ₂ SO ₂ Alkylsulfonylamino, arylsulfonylamino, het sulfonylamino, alkylsulfonyl, arylsulfonyl, het sulfonyl, HC (O) NH, C (O) H, NH ₂ C (O) or NH ₂ C (O) NH independently of one another may optionally be substituted by one or more R ₄ Substituted, R ₄ Can be hydrogen, alkyl, halogen, haloalkyl, cyano, hydroxy, mercapto, amino, alkoxy, alkylamino, alkylthio, NH ₂ SO ₂ An alkylsulfonylamino, an arylsulfonylamino, a Het sulfonylamino, an alkylsulfonyl, an arylsulfonyl, a Het sulfonyl, an aryl, or a Het;

R ₂ is selected from aryl or Het, wherein aryl or Het independently of each other may optionally be substituted by one or more R ₅ Substituted, R ₅ Can 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 Alkylsulfonylamino, arylsulfonylamino, het sulfonylamino, alkylsulfonyl, arylsulfonyl, het sulfonyl, HC (O) NH, C (O) H, NH ₂ C (O) or NH ₂ C (O) NH, wherein hydroxy, mercapto, amino, alkoxy, alkylAmino, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, het, C ₃ -C ₈ Aliphatic carbocycle, NH ₂ SO ₂ Alkyl sulfonamido, aryl sulfonamido, het sulfonamido, alkyl sulfonyl, aryl sulfonyl, het sulfonyl, HC (O) NH, C (O) H, NH ₂ C (O) or NH ₂ C (O) NH independently of one another may optionally be substituted by one or more R ₆ Substituted, R ₆ Can be hydrogen, alkyl, halogen, haloalkyl, cyano, hydroxy, mercapto, amino, alkoxy, alkylamino, alkylthio, NH ₂ SO ₂ Alkylsulfonamido, arylsulfonamido, het sulfonamido, alkylsulfonyl, arylsulfonyl, het sulfonyl, C ₃ -C ₈ Aliphatic carbocycle, aryl or Het of (a);

a represents an imino group, a methylene group, a formyl group, a sulfonyl group, a carbamoyl group or a bond;

x, Y or Z each independently represents N, O, S or CH, NH radicals, wherein NH or CH radicals each independently may optionally be substituted by R ₇ Substituted, R ₇ Can be hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxyl, mercapto, amino, alkoxy, alkylamino, alkylthio, alkoxyalkyl, NH ₂ SO ₂ Alkylsulfonamido, arylsulfonamido, het sulfonamido, alkylsulfonyl, arylsulfonyl, C ₃ -C ₈ Or (c) aliphatic carbocycle, het sulfonyl, aralkyl, diarylalkyl, aryl, or Het wherein alkyl, haloalkyl, hydroxy, alkoxy, alkylthio, alkylamino, alkoxyalkyl, NH ₂ SO ₂ Alkyl-sulfonylamino, aryl-sulfonylamino, C ₃ -C ₈ The aliphatic carbocyclic ring, het sulfonylamino, alkylsulfonyl, arylsulfonyl, het sulfonyl, aralkyl, diarylalkyl, aryl, or Het independently of each other may optionally be substituted with one or more R ₈ Substituted, R ₈ Can be hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, amino, alkoxy, alkylthio, alkylamino, alkoxyalkyl, NH ₂ SO ₂ Alkylsulfonylamino, arylsulfonylamino, het sulfonylamino, alkylsulfonylArylsulfonyl radical, C ₃ -C ₈ (ii) aliphatic carbocycle, het sulfonyl, aralkyl, diarylalkyl, aryl, or Het;

alkyl is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is bonded;

alkylene is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a group formed by losing one hydrogen atom for a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms is bonded;

alkoxy is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms linked to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom is optionally substituted by oxygen;

alkylthio is a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms linked to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom is optionally substituted with sulfur;

alkylamino is a straight or branched chain saturated hydrocarbon radical having 1-6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms linked to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; wherein each carbon atom is optionally substituted with an NH radical;

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, alkyl, cyano, halo, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;

aralkyl, diarylalkyl is an aryl as defined above attached to an alkyl group;

het is a monocyclic heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, pyridothienyl, quinazolinyl, pyrimidothiophenyl, 2,3-dihydrobenzo [1,4] dioxinyl, 2,3-dihydrobenzofuran, or benzo [1,3] dioxolyl; or selected from monocyclic saturated hydrocarbyl of 3-8 carbon atoms, bicyclic saturated hydrocarbyl of 6-12 carbon atoms, bicyclic hydrocarbyl of 6-12 carbon atoms which is benzo-fused saturated aliphatic ring, wherein the carbon atoms on the ring are independently optionally substituted with 1-4O, S, N or NH; each monocyclic or bicyclic ring is optionally substituted with 1,2 or 3 substituents, each substituent independently selected from halo, haloalkyl, hydroxy, alkyl or alkoxy; halogen is a substituent selected from fluorine, chlorine, bromine or iodine;

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

The preferred scheme of the invention is as follows:

R ₁ selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo [1,4]Dioxinyl, benzo [1,3]Dioxolyl, dioxolo [4,5-c]Pyridine or dioxane penteno [4,5-d]Pyrimidines, wherein R ₁ May optionally be substituted by one or more R ₃ Substitution; r ₃ Can be hydrogen, alkyl, alkylidene, cyano, halogen, haloalkyl, hydroxy, amino, mercapto, alkoxy, alkylamino, alkoxyalkyl, aryl, aralkyl, het, NH ₂ SO ₂ Alkyl sulfonyl amino, aryl sulfonyl aminoAlkyl sulfonyl, aryl sulfonyl, het sulfonyl, HC (O) NH, C (O) H, NH ₂ C (O) or NH ₂ C (O) NH, wherein hydroxy, mercapto, amino, alkyl, alkoxy, alkylamino, aryl, arylalkyl, het, NH ₂ SO ₂ Alkylsulfonylamino, arylsulfonylamino, het sulfonylamino, alkylsulfonyl, arylsulfonyl, het sulfonyl, HC (O) NH, C (O) H, NH ₂ C (O) or NH ₂ C (O) NH independently of each other may optionally be substituted by one or more R ₄ Substituted, R ₄ Can be hydrogen, alkyl, halogen, haloalkyl, cyano, hydroxy, amino, alkoxy, alkylamino, NH ₂ SO ₂ An alkylsulfonylamino, an arylsulfonylamino, a Het sulfonylamino, an alkylsulfonyl, an arylsulfonyl, a Het sulfonyl, an aryl, or a Het;

R ₂ selected from phenyl or pyridine rings, wherein R ₂ May optionally be substituted by one or more R ₅ Substituted, R ₅ Can be hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, mercapto, amino, alkoxy, alkylamino, alkoxyalkyl, aryl, het, C ₃ -C ₈ Aliphatic carbocycle, alkylsulfonamido, arylsulfonamido, het sulfonamido, alkylsulfonyl, arylsulfonyl, het sulfonyl, -SO ₂ -, -C (O) -or-C (O) NH-, where hydroxy, amino, alkoxy, alkylamino, alkoxyalkyl, aryl, het, C ₃ -C ₈ Aliphatic carbocycle, alkylsulfonylamino, arylsulfonylamino, het sulfonylamino, alkylsulfonyl, arylsulfonyl, het sulfonyl, -SO ₂ -, -C (O) -or-C (O) NH-may each independently be optionally substituted by one or more R ₆ Substituted, R ₆ Can be hydrogen, alkyl, halogen, haloalkyl, cyano, hydroxy, amino, alkoxy, alkylamino, C ₃ -C ₈ Aliphatic carbocycle, NH ₂ SO ₂ An alkylsulfonylamino, an arylsulfonylamino, a Het sulfonylamino, an alkylsulfonyl, an arylsulfonyl, a Het sulfonyl, an aryl or a Het;

x, Y or Z each independently represents N, O, S or CH, NH radicals, wherein NH or CH radicals each independently may optionally be substituted by R ₇ Substituted, R ₇ Can be hydrogen, alkyl, halogen, haloalkyl, hydroxyl, mercapto, amino, alkoxy, alkylamino, alkylthio, alkoxyalkyl, NH ₂ SO ₂ Alkylsulfonamido, arylsulfonamido, het sulfonamido, alkylsulfonyl, arylsulfonyl, C ₃ -C ₈ Or (c) aliphatic carbocycle, het sulfonyl, aralkyl, aryl or Het wherein alkyl, hydroxy, amino, alkoxy, alkylthio, alkylamino, alkoxyalkyl, NH ₂ SO ₂ Alkyl-sulfonylamino, aryl-sulfonylamino, C ₃ -C ₈ Each independently of the aliphatic carbocycle, het sulfonylamino, alkylsulfonyl, arylsulfonyl, het sulfonyl, aralkyl, aryl or Het of (a) may optionally be substituted with one or more R ₈ Substituted, R ₈ Can be hydrogen, alkyl, cyano, halogen, haloalkyl, hydroxy, amino, alkoxy, alkylthio, alkylamino, alkoxyalkyl, NH ₂ SO ₂ Alkylsulfonamido, arylsulfonamido, het sulfonamido, alkylsulfonyl, arylsulfonyl, C ₃ -C ₈ Or (iv) aliphatic carbocycle, het sulfonyl, aralkyl, aryl or Het.

Another preferred embodiment of the present invention is:

R ₁ selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo [1,4]Dioxinyl, benzo [1,3]Dioxolyl, dioxolo [4,5-c]Pyridine or dioxacyclopenteno [4,5-d]Pyrimidines, wherein R ₁ May optionally be substituted by one or more R ₃ Substitution; r ₃ Can be hydrogen or C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkylidene, cyano, halogen, halogenated C ₁ -C ₆ Alkyl, hydroxy, amino, mercapto, C ₁ -C ₆ Alkyloxy, C ₁ -C ₆ Alkylamino, phenyl, benzyl, pyridyl, pyrimidinyl, thienyl, oxazolyl, pyrrolyl, NH ₂ SO ₂ 、C ₁ -C ₆ Alkylsulfonylamino, phenylsulfonamido, pyridine-2-sulfonylamino, C ₁ -C ₆ Alkylsulfonyl, phenylsulfonyl, pyridine-2-sulfonyl, HC (O) NH, C (O) H or NH ₂ C (O), wherein hydroxy, mercapto, amino, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Alkylamino, phenyl, benzyl, pyridyl, pyrimidinyl, thienyl, oxazolyl, pyrrolyl, NH ₂ SO ₂ 、C ₁ -C ₆ Alkylsulfonylamino, phenylsulfonylamino, pyridine-2-sulfonylamino, C ₁ -C ₃ Alkylsulfonyl, phenylsulfonyl, pyridine-2-sulfonyl, HC (O) NH, C (O) H or NH ₂ C (O) independently of one another may optionally be substituted by one or more R ₄ Substituted, R ₄ Can be hydrogen or C ₁ -C ₃ Alkyl, halogen, halogenated C ₁ -C ₃ Alkyl, cyano, hydroxy, amino, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino, NH ₂ SO ₂ 、C ₁ -C ₃ Alkylsulfonylamino, phenylsulfonylamino, pyridine-2-sulfonyl, C ₁ -C ₃ Alkylsulfonyl, phenylsulfonyl, pyridine-2-sulfonyl, phenyl, pyridyl, pyrimidinyl, thienyl, oxazolyl, or pyrrolyl;

R ₂ selected from phenyl or pyridyl, wherein R ₂ May optionally be substituted by one or more R ₅ Substitution; r ₅ Can be hydrogen or C ₁ -C ₃ Alkyl, cyano, halogen, halogenated C ₁ -C ₃ Alkyl, hydroxy, amino, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino, piperazinyl, piperidinyl, morpholinyl, tetrahydropyrrolyl, C ₃ -C ₈ Aliphatic carbocycle of (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-, where hydroxy, amino, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino, phenyl, piperazinyl,Piperidinyl, morpholinyl, tetrahydropyrrolyl, C ₃ -C ₈ Aliphatic carbocycle of (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-may each independently be optionally substituted by one or more R ₆ Substituted, R ₆ Can be hydrogen or C ₁ -C ₃ Alkyl, halogen, cyano, hydroxy, amino, halogenated C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino radical, C ₃ -C ₈ Aliphatic carbocycle, NH ₂ SO ₂ 、C ₁ -C ₃ Alkylsulfonylamino, phenylsulfonylamino, pyridine-2-sulfonylamino, C ₁ -C ₃ Alkylsulfonyl, phenylsulfonyl, pyridine-2-sulfonyl, phenyl, piperazinyl, piperidinyl, morpholinyl, or tetrahydropyrrolyl;

a represents a carbonyl group, a sulfonyl group or a bond;

x, Y or Z each independently represent N or CH, NH radicals, where NH or CH radicals each independently may optionally be substituted by R ₇ Substituted, R ₇ Can be hydrogen or C ₁ -C ₃ Alkyl, halogen, halogenated C ₁ -C ₃ Alkyl, hydroxy, amino, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino radical, 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 hydroxy, amino, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino radical, C ₁ -C ₃ Alkoxy (C) ₁ -C ₃ Alkyl), NH ₂ SO ₂ 、 C ₁ -C ₃ Alkylsulfonamido, phenylsulfonylAmido, pyridine-2-sulfonylamino, C ₁ -C ₃ Alkylsulfonyl, phenylsulfonyl, cyclopropyl, cyclohexyl, cyclopentyl, pyridine-2-sulfonyl, phenyl (C) ₁ -C ₃ Alkyl), phenyl, pyridyl, piperidinyl, tetrahydropyrrolyl or morpholinyl each independently may optionally be substituted by one or more R ₈ Substituted, R ₈ Can be hydrogen, cyano, halogen, hydroxy, amino, C ₁ -C ₃ Alkoxy radical, C ₁ -C ₃ Alkylamino, NH ₂ SO ₂ 、 C ₁ -C ₃ Alkylsulfonylamino, phenylsulfonylamino, pyridine-2-sulfonylamino, C ₁ -C ₃ Alkylsulfonyl, phenylsulfonyl, cyclopropyl, cyclohexyl, cyclopentyl, pyridine-2-sulfonyl, phenyl (C) ₁ -C3 alkyl), phenyl, pyridyl, piperidyl, tetrahydropyrrolyl or morpholinyl.

Another preferred embodiment of the present invention is:

R ₁ selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo [1,4]Dioxinyl, benzo [1,3]Dioxolyl, dioxolo [4,5-c]Pyridine or dioxacyclopenteno [4,5-d]Pyrimidines, wherein R ₁ May optionally be substituted by one or more R ₃ Substitution; r ₃ Can be hydrogen, methyl, ethyl-1,2-ylidene, cyano, halogen, trifluoromethyl, methoxy, dimethylamino, phenyl, benzyl, pyridyl, NH ₂ SO ₂ Methylsulfonylamino, methylsulfonyl, HC (O) NH or NH ₂ C (O), wherein NH ₂ SO ₂ HC (O) NH or NH ₂ C (O) independently of one another may optionally be substituted by one or more R ₄ Substituted, R ₄ Can be hydrogen, methyl or cyclopropyl, wherein phenyl, pyridyl or benzyl independently of each other can optionally be substituted by one or more R ₉ Substituted, R ₉ Can be hydrogen, methyl, methoxy, trifluoromethyl, amino, fluoro, chloro or carbamoyl;

R ₂ selected from phenyl or pyridyl, wherein R ₂ May optionally be substituted by one or more R ₅ Substitution; r ₅ Can be hydrogen, methyl, ethyl, halogen, amino, trifluoromethyl, methylOxy, trifluoromethoxy, methylamino, piperazinyl, piperidinyl, morpholinyl, tetrahydropyrrolyl, methylsulfonylamino, methanesulfonyl, -SO ₂ -, -C (O) -or-C (O) NH-, wherein methyl, amino, piperazinyl, piperidinyl, morpholinyl, tetrahydropyrrolyl, methylsulfonylamino, methylsulfonyl, -SO ₂ -, -C (O) -or-C (O) NH-may each independently be optionally substituted by one or more R ₆ Substituted, R ₆ Can be hydrogen, methyl, ethyl, halogen, cyano, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, methylamino, dimethylamino, isopropylamino, cyclopropyl, cyclopentyl, cyclohexyl, NH ₂ SO ₂ Methylsulfonylamino, methylsulfonyl, phenyl, piperazinyl, piperidinyl, morpholinyl, N-methylpiperazinyl, N-methylpiperidin-4-amino, 3-diethylaminopropylamino, 3-morpholinopropylamino or tetrahydropyrrolyl;

a represents a carbonyl group, a sulfonyl group or a bond;

x, Y or Z each independently represent N or CH, NH radicals, where NH or CH radicals each independently may optionally be substituted by R ₇ Substituted, R ₇ May be hydrogen or methyl.

Another preferred embodiment of the present invention is:

R ₁ selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo [1,4]Dioxinyl, benzo [1,3]Dioxolyl, dioxolo [4,5-c]Pyridine or dioxane penteno [4,5-d]Pyrimidines, wherein R ₁ May optionally be substituted by one or more R ₃ Substitution; r ₃ Can be hydrogen, methyl, ethyl-1,2-ylidene, isopropyl, halogen or trifluoromethyl;

R ₂ selected from phenyl or pyridyl, wherein R ₂ May optionally be substituted by one or more R ₅ Substitution; r is ₅ Can be hydrogen, methyl, halogen, trifluoromethyl, methoxy, trifluoromethoxy, piperazinyl, piperidinyl, N-methylpiperazinyl, N-methylpiperidin-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-ylmethoxy, 3-diethylaminopropylamino, -SO 2-or-C (O) -, wherein-SO 2-or-C (O) -each independently may optionally be substituted by one or more R ₆ Substituted, R ₆ Can be hydrogen, piperazinyl, piperidinyl, morpholinyl, N-methylpiperazinyl-4-amino, 3-diethylaminopropylamino, 3-morpholinopropylamino or tetrahydropyrrolyl;

a represents a carbonyl group or a bond;

x or Z each independently represents N or NH, and Y is CH.

Another preferred embodiment of the present invention is:

R ₁ selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo [1,4]Dioxinyl, benzo [1,3]Dioxolyl, dioxolo [4,5-c]Pyridine or dioxacyclopenteno [4,5-d]Pyrimidines, wherein R ₁ May optionally be substituted by one or more R ₃ Substitution; r ₃ Can be hydrogen, methyl, halogen or ethyl-1,2-ylidene;

R ₂ selected from phenyl or pyridyl, wherein R ₂ May optionally be substituted by one or more R ₅ Substitution; r is ₅ Can be hydrogen, methyl, halogen, trifluoromethyl, methoxy, trifluoromethoxy, piperazinyl, piperidinyl, N-methylpiperazinyl, N-methylpiperidin-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-ylmethoxy, 3-diethylaminopropylamino, -SO 2-or-C (O) -, wherein each-SO 2-or-C (O) -independently may optionally be substituted by one or more R ₆ Substituted, R ₆ Can be hydrogen, piperazinyl, piperidinyl, morpholinyl, N-methylpiperazinyl-4-amino, 3-diethylaminopropylamino, 3-morpholinopropylamino or tetrahydropyrrolyl;

a represents a carbonyl group or a bond;

x or Z each independently represents N or NH, and Y is a CH group.

Another preferred embodiment of the present invention is:

R ₂ is selected from phenyl, wherein R ₂ May optionally be substituted by one or more R ₅ Substitution; r is ₅ Can be hydrogen, methyl, halogen, trifluoromethyl, methoxy, trifluoromethoxy, piperazinyl, piperidinyl, N-methylpiperazinyl, N-methylpiperidin-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-ylmethoxy, 3-diethylaminopropylamino, -SO 2-or-C (O) -, wherein-SO 2-or-C (O) -each independently may optionally be substituted by one or more R ₆ Substituted, R ₆ Can be hydrogen, piperazinyl, piperidinyl, morpholinyl, N-methylpiperazinyl, N-methylpiperidin-4-amino, 3-diethylaminopropylamino, 3-morpholinopropylamino or tetrahydropyrrolyl;

a represents a carbonyl group or a bond;

x or Z each independently represents N or NH, and Y is a CH group.

Another preferred embodiment of the present invention is:

R ₁ selected from 2,3-dihydrobenzofuran, 2,3-dihydrobenzo [1,4]Dioxinyl or benzo [1,3]Dioxolyl wherein R ₁ May optionally be substituted by one or more R ₃ Substitution; r ₃ Can be hydrogen, methyl, fluorine, chlorine or ethyl-1,2-ylidene;

R ₂ is selected from phenyl, wherein R ₂ May optionally be substituted by one or more R ₅ Substitution; r is ₅ Can be hydrogen, methyl, halogen, methoxy, piperazinyl, piperidinyl, N-methylpiperazinyl, N-methylpiperidin-4-amino, morpholinyl, 3-morpholinylpropanylamino, tetrakisHydropyrrolyl, 4-ethyl-piperazin-1-ylmethyl, 4-hydroxyethyl-piperazin-1-yl, 2-hydroxyethoxy, 2-methoxyethoxy, 3-morpholinopropoxy, 2-diethylaminoethylamino, N-methylpiperidin-4-ylmethoxy, 3-diethylaminopropylamino or-C (O) -, where-C (O) -may each independently optionally be substituted by one or more R ₆ Substituted, R ₆ Can be piperazinyl, piperidinyl, morpholinyl, N-methylpiperazinyl, N-methylpiperidin-4-amino, 3-diethylaminopropylamino, 3-morpholinopropylamino or tetrahydropyrrolyl;

a represents a carbonyl group or a bond;

x or Z each independently represents N or NH, and Y is a CH group.

Another preferred embodiment of the present invention is:

R ₁ selected from benzo [1,3]Dioxolyl wherein R ₁ May optionally be substituted by one or more R ₃ Substitution; r ₃ Can be hydrogen, methyl, fluorine, chlorine or ethyl-1,2-ylidene;

R ₂ is selected from phenyl, wherein R ₂ May optionally be substituted by one or more R ₅ Substitution; r ₅ Can be hydrogen, methyl, halogen, methoxy, piperazinyl, piperidinyl, N-methylpiperazinyl, N-methylpiperidin-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-ylmethoxy, 3-diethylaminopropylamino or-C (O) -, where-C (O) -each independently can optionally be substituted by one or more R ₆ Substituted, R ₆ Can be piperazinyl, piperidinyl, morpholinyl, N-methylpiperazinyl, N-methylpiperidin-4-amino, 3-diethylaminopropylamino, 3-morpholinopropylamino or tetrahydropyrrolyl;

a represents a carbonyl group or a bond;

x or Z each independently represents N or NH, and Y is a CH group.

The compounds of formula I are preferably compounds of the following structure:

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

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

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

(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-morpholinopropyl) amino) benzamide

(6) N- (3- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrazol-5-yl) -4- ((3- (diethylamino) 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-methylpiperazin-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-methylpiperidin-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-morpholinopropyl) benzene-1,4-diamine

(13)N ⁴ - (3- (benzo [ d ]][1，3]Dioxolen-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]Dioxolen-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-methylpiperidin-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-methylpiperidin-4-yl) benzamide

(19) 4- ((3- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrazol-5-yl) amino) -N- (1-methylpiperidin-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] dioxine) -6-yl) -1H-pyrazol-5-yl) -4- ((1-methylpiperidin-4-yl) amino) benzamide

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

(26) N- (3- (2,3-dihydro (benzo [ b ] [1,4] dioxine) -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] dioxine) -6-yl) -1H-pyrazol-5-yl) -3- (4-methylpiperazin-1-yl) benzamide

(28) N- (3- (2,3-dihydro (benzo [ b ] [1,4] dioxine) -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]Dioxin) -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]Dioxin) -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] dioxine) -6-yl) -1H-pyrazol-5-yl) amino) -N- (1-methylpiperidin-4-yl) benzamide

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

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

(34) 4- ((3- (2,3-dihydro (benzo [ b ] [1,4] dioxine) -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] dioxine) -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-methylpiperidin-4-yl) amino) nicotinamide

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

(42) N2- (3- (benzo [ d ])][1，3]Dioxol-5-yl) -1H-pyrazol-5-yl) -N ⁵ - (1-methylpiperidin-4-yl) pyridine-2,5-diamine

(43) 4- ((1-methylpiperidin-4-yl) amino) -N- (3- (spiro [ benzo [ d ] s)][1，3]Dioxole-2,1' -cyclopropane] ^- 5-yl) -1H-pyrazol-5-yl) benzamides

(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-methylpiperidin-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-ethylpiperazin-1-yl) methyl) benzamide

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

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

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

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

(62) N- (3- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrazol-5-yl) -4- ((1-methylpiperidin-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]Dioxole-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 compounds of the invention are prepared as follows:

Scheme 1

x = CH or N, Y = CH or N.

Reagents and conditions：

(i)NaH，THF，acetonitrile，70℃；(ii)NH ₂ NH ₂ ·HCl，EtN ₃ ，EtOH，reflux；(iii)Al(CH ₃ ) ₃ ，Toluene，80℃.

Scheme 2

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

Reagents and conditions：

(i)NaH，THF/DMF，0℃；(ii)NH ₂ NH ₂ ·H ₂ O，EtOH，reflux.

The compounds of the present invention can be prepared by the above-mentioned or similar preparation methods, and the corresponding raw materials can be selected according to the difference of the substituent and the position of the substituent, or raw materials which are not easy to purchase can be prepared according to general organic synthesis knowledge.

The biological activity test result shows that the compound shown in the general formula I and the pharmaceutically acceptable salt thereof have FLT3-ITD inhibition effect and a certain inhibition effect on the growth of leukemia tumor cell strains. The compounds of the invention are useful in the treatment of a variety of disorders associated with FLT3-ITD, including acute myelogenous leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, and the like. Therefore, the compound and the pharmaceutically acceptable salt thereof can be used for preparing antitumor drugs.

The pharmacological test of the compounds is as follows:

1. kinase inhibitory Activity assay

I test materials

Basic reaction buffer, 20mM Hepes (pH 7.5), 10mM MgCl ₂ ，1mM EGTA，0.02％Brij35，0.02mg/ml BSA，0.1 mM Na ₃ VO ₄ .2mM DTT，1％DMSO。

II Experimental procedure

The substrate is prepared in fresh reaction buffer, all the required cofactors are added to the above substrate solution, and the kinase is added to the prepared substrate solution and gently mixed. The compound was dissolved in 100% DMSO and the solution was added to the kinase reaction mixture by Acoustic technique (Echo 550; nanoliter scale) and allowed to react for 20min at room temperature. Then is added to ³³ The reaction was started with p-ATP (radioactivity 10 mCi/ml) and allowed to proceed at room temperature for 2h. Kinase activity was measured by the filter method, and the kinase activity data are expressed as a percentage: the ratio of kinase activity to blank (DMSO) reaction was tested in the samples.

III results of the experiment

Inhibition ratio (%) of FLT3-ITD by Compound in Table 1

2. In vitro tumor cell inhibitory Activity assay

The compounds of the invention have inhibitory activity against MV4-11 cell lines in vitro.

I test materials

RPMI 1640 medium, 96-well cell culture plates, fetal bovine serum, enoGeneCell ^TM A Counting Kit-8 (CCK-8) Cell viability detection Kit, a ChemBase CBS-CJ-1FD super clean bench, a carbon dioxide incubator, a Vi-Cell XR Cell counter and an Envision 2104 plate reader.

II Experimental procedure

Cells in exponential growth phase were collected and counted for viable cells using a Vi-Cell XR Cell counter. The cell suspension concentration was adjusted with the corresponding medium for each cell. Add 90. Mu.L of cell suspension to each well in 96 well cell culture plates to a final cell concentration of 7000 cells/well. Each test compound was dissolved in DMSO as a 10mM stock solution. Then diluted to 10-fold solution with medium, 2 wells each. 10 μ L of the corresponding 10-fold solution was added to each well of each cell, with a final drug concentration of 1 μ M and a final DMSO concentration of 0.01%, respectively. Placing at 37 ℃/5% CO ₂ Culturing in an incubator for 72h. After 72 hours of drug treatment, according to the instructions of Celltiter-GloATP fluorescence activity detection method (CTG method), 50. Mu.L (1/2 culture volume) of CTG solution which is pre-melted and equilibrated to room temperature is added into each well, the mixture is mixed evenly for 2min by a microplate shaker, and after the mixture is placed for 10min at room temperature, the fluorescence signal value is measured by an Envision 2104 plate reader. The inhibition rate of each test compound was calculated in comparison with the negative control group.

TABLE 2 inhibition ratio (%) of MV4-11 cell line by Compound

Detailed Description

The melting point is measured by a RY-1G digital display micro melting point tester (New Tianguan instruments, tianjin) without correcting a thermometer; ¹ HNMR was measured using a BRUKER AVANCE 300 nuclear magnetic resonance spectrometer (Bruker, switzerland), TMS as an internal standard; MS adopts Agilent 1100 LC/MSD mass spectrometer (American agile)Lun corporation) and Q-totmicro MS (micro corporation).

Example 1

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

Tetrahydrofuran (12 mL), acetonitrile (5 mL), sodium hydride (0.17g, 7.1mmol) and benzo [ d ] were added to a round bottom flask in this order under ice bath conditions][1，3]Dioxole-5-carboxylic acid methyl ester (0.43g, 2.4 mmol), stirred for 0.5h, heated to reflux, and reacted for 5h. The reaction solution was poured into an ice water mixture (30 ml), the pH was adjusted to 2, a large amount of yellow solid precipitated, filtered off with suction and dried to give a crude product. After column chromatography of the crude product (PE: EA = 2: 1), 0.413g of a pale yellow solid was obtained in 91% yield. MS [ M-H ]] ⁺ 188.03。

A25 mL round-bottomed flask was charged with the product obtained in the previous step, hydrazine hydrochloride (0.45g, 4.4 mmol), triethylamine (0.44g, 4.4 mmol) and ethanol (10 mL) in this order, and the mixture was reacted under reflux for 8 hours. The reaction mixture was diluted with water (50 ml), adjusted to pH 9 with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate (20 ml. Times.3), the organic phases were combined, washed with saturated brine (20 ml. Times.2), and dried over anhydrous sodium sulfate. After concentration under reduced pressure and column chromatography (EA: PE = 6: 1), pale yellow solid 0.368g was obtained, yield 83%. MS [ M-H ]] ^- 203.05。

A25 mL two-necked round-bottomed flask was charged with the product obtained in the above step, methyl 4- ((1-methylpiperidin-4-yl) amino) benzoate (0.472g, 1.9 mmol), trimethylaluminum (3.55mL, 5.1 mmol) and toluene (6 mL) in this order, and reacted at 80 ℃ for 10 hours under an argon atmosphere. The reaction mixture was quenched by adding 95% ethanol (40 mL), concentrated under reduced pressure, and subjected to column chromatography (EA: meOH = 20: 1) to obtain 0.34g of a pale yellow solid with a yield of 45%. ¹ H NMR (300MHz，CDCl ₃ )δ12.68(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-methylpiperazin-1-yl) benzamide (2)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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) benzamide (3)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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- (diethylamino) propyl) amino) benzamide (6)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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-methylpiperazin-1-yl) benzamide (8)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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-methylpiperidin-4-yl) amino) benzamide (9)

The preparation is analogous to (1) to give g as a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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-methylpiperidin-4-yl) benzene-1,4-diamine (10)

To a round-bottomed flask, dry tetrahydrofuran (10 ml), sodium hydride (0.24g, 10mmol) and 5-acetyl group (benzo [ d ] was added in this order under ice-bath conditions][1，3]Dioxol) (0.657g, 4mmol), stirred for 0.5h, 4- (1-methylpiperidin-4-ylamino) benzeneisothiocyanate (0.99g, 4mmol) was slowly added dropwise, and reacted for 2h. The reaction solution was poured into an ice-water mixture (30 ml) to precipitate a pale yellow solid, which was then filtered off and dried to obtain a crude product. After column chromatography of the crude product (PE: EA = 10: 1), 0.58g of pale yellow solid is obtained, yield 35.2%. MS [ M + H ]] ⁺ 412.2。

The product obtained in the previous step, hydrazine hydrochloride (0.43g, 4.1mmol), triethylamine (0.44g, 4.4mmol) and ethanol (15 mL) were added in this order to a 50mL round-bottomed flask and reacted under reflux for 8 hours. The reaction mixture was diluted with water (50 ml), adjusted to pH 9 with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate (20 ml. Times.3), the organic phases were combined, washed with saturated brine (20 ml. Times.2), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by column chromatography (EA: meOH = 22: 1) gave 0.331g of a pale yellow solid in 60% yield.

¹ H NMR(300MHz，CDCl3)δ12.68(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-pyrazol-5-amine (11)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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]Dioxolen-5-yl) -1H-pyrazol-5-yl) -N ⁴ - (3-Morpholinopropyl) benzene-1,4-diamine (12)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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]Dioxolen-5-yl) -1H-pyrazol-5-yl) -2-fluoro-N ¹ - (1-methylpiperidin-4-yl) benzene-1,4-diamine (13)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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]Dioxolen-5-yl) -1H-pyrazol-5-yl) -2-methoxy-N ⁴ - (1-methylpiperidin-4-yl) benzene-1,4-diamine (14)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperidin-4-yl) pyridine-2,5-diamine (15)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperazin-1-yl) methanone (17)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperidin-4-yl) benzamide (18)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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-methylpiperidin-4-yl) benzenesulfonamide (19)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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-methylpiperidine-4-carboxamide (20)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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 process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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 process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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 process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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] dioxin) -6-yl) -1H-pyrazol-5-yl) -4- ((1-methylpiperidin-4-yl) amino) benzamide (24)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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] dioxine) -6-yl) -1H-pyrazol-5-yl) -4- ((3-morpholinopropyl) amino) benzamide (25)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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] dioxine) -6-yl) -1H-pyrazol-5-yl) -2-methoxy-4- ((1-methylpiperidin-4-yl) amino) benzamide (26)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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] dioxin) -6-yl) -1H-pyrazol-5-yl) -3- (4-methylpiperazin-1-yl) benzamide (27)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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] dioxine) -6-yl) -1H-pyrazol-5-yl) -2-methyl-4- ((1-methylpiperidin-4-yl) amino) benzamide (28)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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]Dioxin) -6-yl) -1H-pyrazol-5-yl) -N ⁴ - (1-methylpiperidin-4-yl) benzene-1,4-diamine (29)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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]Dioxin) -6-yl) -1H-pyrazol-5-yl) -2-methoxy-N ⁴ - (1-methylpiperidin-4-yl) benzene-1,4-diamine (30)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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] dioxin) -6-yl) -1H-pyrazol-5-yl) amino) -N- (1-methylpiperidin-4-yl) benzamide (31)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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] dioxine) -6-yl) -1H-pyrazol-5-yl) amino) -N- (1-methylpiperidin-4-yl) benzenesulfonamide (32)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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] dioxine) -6-yl) -1H-pyrazol-5-yl) amino) phenyl) -1-methylpiperidine-4-carboxamide (33)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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] dioxin) -6-yl) -1H-pyrazol-5-yl) amino) -3-methoxy-N- (1-methylpiperidin-4-yl) benzamide (34)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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] dioxine) -6-yl) -1H-pyrazol-5-yl) amino) -3-fluoro-N- (1-methylpiperidin-4-yl) benzamide (35)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperidin-4-yl) amino) nicotinamide (40)

The preparation is analogous to (1) to give a yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperidin-4-yl) amino) pyridine-2-carboxamide (41)

The preparation process is analogous to (1), giving a yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperidin-4-yl) pyridine-2,5-diamine (42)

The preparation process is analogous to (10), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 ] s)][1，3]Dioxole-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)δ12.68(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperidin-4-yl) amino) benzamide (45)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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-methylpiperidin-4-yl) amino) benzamide (46)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.7(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-methylpiperidin-4-yl) amino) benzamide (47)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperidin-4-yl) amino) benzamide (48)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperidin-4-yl) amino) benzamide (49)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperidin-4-yl) amino) benzamide (50)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.69(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 ] s)][1，3]Dioxole-2,1' -cyclopropane] ^- 4-Yl) -1H-pyrazol-5-yl) benzamide (54)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-ethylpiperazin-1-yl) methyl) benzamide (55)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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) benzamide (57)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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) benzamide (59)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-ethylpiperazin-1-yl) methyl) benzamide (60)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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) amino) benzamide (61)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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-methylpiperidin-4-yl) methoxy) benzamide (62)

The preparation method is similar to (1) and lightYellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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) benzamide (63)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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) benzamide (65)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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]Dioxole-2,1' -cyclopropane] ^- 4-Yl) -1H-pyrazol-5-yl) -4- (3-Morpholinopropoxy) benzamide (67)

The preparation process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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 process is analogous to (1), giving a pale yellow solid. ¹ H NMR(300MHz，CDCl3)δ12.68(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

1. Compounds (1) to (54) and pharmaceutically acceptable salts thereof:

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

(10) N1- (3- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrazol-5-yl) -N4_ (1-methylpiperidin-4-yl) benzene-1,4-diamine

(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-methylpiperidin-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-methylpiperidin-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

(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-methylpiperidin-4-yl) amino) nicotinamide

(27) N- (3- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrazol-5-yl) -5- ((1-methylpiperidin-4-yl) amino) pyridine-2-carboxamide

(28) N2 (3- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrazol-5-yl) -N5 (1-methylpiperidin-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-methylpiperidin-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-ethylpiperazin-1-yl) methyl) benzamide

(42) N- (3- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrazol-5-yl) -4- (4- (2-hydroxyethyl) 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) benzamide

(45) N- (3- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrazol-5-yl) -4- (3-morpholinopropoxy) benzamide

(46) N- (3- (benzo [ d ] [1,3] dioxol-4-yl) -1H-pyrazol-5-yl) -4- ((4-ethylpiperazin-1-yl) methyl) benzamide

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

(48) N- (3- (benzo [ d ] [1,3] dioxol-5-yl) -1H-pyrazol-5-yl) _4- ((1-methylpiperidin-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] dioxole-2,1' -cyclopropane ] _ 4-yl) -1H-pyrazol-5-yl) -4- (3-morpholinopropoxy) 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: hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, p-toluenesulphonic, naphthalenesulphonic, citric, tartaric, lactic, pyruvic, acetic, maleic or benzenesulphonic, succinic, fumaric, salicylic, phenylacetic or mandelic acid.

3. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a disease associated with FLT 3.

5. The use according to claim 4, wherein the disease associated with FLT3 is acute myeloid leukemia.