Phenyl thiazole derivative, composition and application thereof

Abstract

The invention discloses a phenyl thiazole derivative, a composition and application thereof. The derivative is a compound shown as a structural general formula (I) or pharmaceutically acceptable salt thereof. The composition comprises phenyl thiazole derivatives or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers. The invention also provides application of the phenylthiazole derivative or the pharmaceutically acceptable salt thereof in preparation of drugs for treating proliferative diseases of patients. The invention provides a novel inhibitor aiming at FLT3-ITD mutation, the inhibition activity of the inhibitor on FIT3-ITD is equivalent to that of Quizartinib, the inhibitor has a very good inhibition effect on MV4-11 cells, and a novel lead compound is provided for treatment and prevention of diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemical synthesis, and specifically relates to a class of phenylthiazole derivatives, compositions and applications thereof. Background Art

[0002] Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins. PKs ​​are key regulatory molecules for cellular function and constitute one of the largest and most diverse gene families. By adding phosphatase groups to substrate proteins, the activity, localization, and overall function of many proteins can be directed, and they participate in the orchestration of almost all cellular activities. PKs ​​play a particularly significant role in signal transduction and the coordinated regulation of complex functions such as the cell cycle. In particular, the receptor protein tyrosine kinase (RTK) family of protein kinases, mainly as growth factor receptors, plays an important role in the control of signal transduction pathways in many cellular functions, such as the cell cycle, cell growth, cell differentiation, and apoptosis. Disturbances in the activity of receptor protein tyrosine kinases (RPTKs) have been observed in many disease conditions, including benign and malignant proliferative disorders, inflammatory disorders, and immune system disorders.

[0003] FLT3 (FMS-like tyrosine kinase-3) is a member of the RTK family. Its structure consists of three parts: the extracellular region, the transmembrane region, and the intracellular region. Under normal circumstances, the juxtamembrane region (JM) and the structural domain (TKD) of the receptor tyrosine kinase have self-inhibition functions, which put the kinase in an inactive conformation. When the length of the JM region mutates (ITD) or the active loop of the structural domain is replaced by a mutation, constitutive FLT3 activation is caused, thereby activating multiple downstream signaling pathways, such as PI3K / AKT, RAS / MAPK / ERK, and STAT5. It can activate STAT5 through SRC kinase, phosphorylate the transcription factor FoxO3a, downregulate the balanced nucleoside transporter of cytarabine, and induce the production of reactive oxygen species. These changes lead to DNA damage and repair defects, and promote cell proliferation and resistance to apoptosis.

[0004] FLT3 belongs to type III receptor tyrosine kinase (RTK), which plays an important role in the proliferation, differentiation and survival of hematopoietic stem cells, precursor B cells, etc. In recent years, studies have found that FLT3, as an important receptor tyrosine kinase in cell signal transduction, can lead to abnormal cell proliferation and induce tumorigenesis, especially closely related to the occurrence and development of acute myeloid leukemia (AML), and internal tandem duplication (ITD) is a common type of mutation. Studies have shown that more than 70% of AML patients and acute lymphoblastic leukemia (ALL) patients have high expression of FLT3. Therefore, FLT3 is an important target for the treatment of AML. Since tumorigenesis is related to multiple signal transduction pathways, multi-target receptor tyrosine kinase inhibition is studied to reduce the drug resistance problem of FLT3 receptor tyrosine kinase inhibitors, thereby improving the effect of tumor treatment.

[0005] ITD (internal tandem duplication) mutation is the most common type of mutation in FLT3. It was first discovered by Nakao et al. in 1996. It refers to the insertion of a repetitive sequence in the juxtamembrane domain of the gene. It usually occurs near the arginine residue 595 in the juxtamembrane region and is located on exons 14 / 15 of the gene. The insertion site and sequence are varied, and the length generally varies from 3 to 400 bp. It always appears in multiples of three and retains the transcript reading frame (ORF). The inserted repetitive sequence causes FLT3 to dimerize and continuously self-phosphorylate in the absence of ligand binding, enhancing the activation of tyrosine kinase activity, causing the downstream signaling pathways (RAS / MAPK, PI3K / AKT, etc.) to be continuously activated, leading to dysregulated cell proliferation and promoting the recurrence of AML diseases. About 70% of ITDs occur in the juxtamembrane domain (JMD), and the rest occur in the tyrosine kinase domain (TKD).

[0006] Tandem duplications of the FLT3 gene are inserted within the reading frame, resulting in loss of autoinhibitory function and increased tyrosine kinase activity. Regardless of cytogenetic classification, the appearance of FLT3-ITD indicates a significant increase in the risk of disease recurrence and a poor overall prognosis for patients. Therefore, FLT3-ITD mutation detection has become an important indicator for routine diagnosis of AML. Among newly diagnosed AML patients, approximately 1 / 3 of patients have FLT3 activating mutations, and mutations are associated with poor prognosis. Summary of the invention

[0007] One of the purposes of the present invention is to provide phenylthiazole derivatives and compositions, which can effectively serve as protein kinase inhibitors to treat diseases related to protein kinase-mediated proliferation, have the characteristics of high response rate, small side effects, few adverse reactions, etc., and meet the needs of clinical medication.

[0008] The second object of the present invention is to provide the use of phenylthiazole derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating proliferative diseases in patients.

[0009] To achieve the above object, the technical solution adopted by the present invention is: a class of phenylthiazole derivatives is a compound having a structural formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Wherein, Z is -C(O)-, -(CH2) q -、-(CH2) q O-, -(CH2) q C(O)-, -C(O)NH(CH2) q -、-(CH2) q C(O)NH(CH2) q -、-O(CH2) q -, q is an integer from 1 to 4;

[0012] R 1 Selected from C 3-8 - cycloalkyl, wherein n is an integer from 0 to 2; X is N or CH2; Y is -O-, S, -NR 5 -, CH2, wherein R 5 Is H or C 1-10 alkyl;

[0013] R 2 is selected from one of aryl, heterocyclic, heteroaryl, substituted aryl, substituted heterocyclic, substituted heteroaryl, and the substituent is selected from hydrogen, C 1-6 -Alkyl, CH3(CH2) q O-, halogen, C substituted by halogen 1-10 - one of the alkyl groups, q is an integer of 1-4.

[0014] Preferably, R1 is selected from wherein n is 1; X is N; and Y is -O- or CH2.

[0015] Preferably, Z is -(CH2) q O-, q is 2 or 3.

[0016] Preferably, R 2 is one of phenyl, pyridine, isoxazole, substituted phenyl, substituted pyridine, substituted isoxazole, and the substituent is selected from hydrogen, C 1-6 -Alkyl, CH3(CH2) q O-, halogen, C substituted by halogen 1-10- one of the alkyl groups, q is an integer of 1-4.

[0017] Preferably, the substituent in the substituted phenyl is one of hydrogen, methyl, fluorine, chlorine, CH3O-, m-trifluoromethyl, p-chloro, p-methyl, or o-bromine; the substituted pyridine is trifluoromethyl-substituted pyridine, and the substituted isoxazole is tert-butyl-substituted isoxazole.

[0018] Preferably, the phenylthiazole derivative is:

[0019] 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0020] 1-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)-3-phenylurea,

[0021] 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0022] 1-(2-bromo-4-methylphenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0023] 1-(4-methoxyphenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0024] 1-(4-fluorophenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0025] 1-(4-chlorophenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0026] 1-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)-3-(p-tolyl)urea,

[0027] 1-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea,

[0028] 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0029] 1-phenyl-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0030] 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0031] 1-(2-bromo-4-methylphenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0032] 1-(4-methoxyphenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0033] 1-(4-fluorophenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0034] 1-(4-chlorophenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0035] 1-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)-3-(p-tolyl)urea,

[0036] 1-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea,

[0037] 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0038] 1-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)-3-phenylurea,

[0039] 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0040] 1-(2-bromo-4-methylphenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0041] 1-(4-methoxyphenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0042] 1-(4-fluorophenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0043] 1-(4-chlorophenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0044] 1-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)-3-(p-tolyl)urea,

[0045] 1-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea,

[0046] 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(3-(dimethylamino)propoxy)phenyl)thiazol-4-yl)phenyl)urea,

[0047] 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(3-(dimethylamino)propoxy)phenyl)thiazol-4-yl)phenyl)urea.

[0048] On the other hand, the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the phenylthiazole derivative or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0049] The present invention further provides the use of the phenylthiazole derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating proliferative diseases in patients.

[0050] Preferably, the proliferative disease is acute myeloid leukemia, chronic myeloid leukemia, thyroid cancer, gastric cancer, gastrointestinal stromal tumors, colorectal cancer, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, lymphoma, renal cancer, autosomal dominant polycystic kidney disease or myeloma.

[0051] The present invention provides a class of inhibitors targeting FLT3-ITD mutations based on phenylthiazole structural derivatives, which have an inhibitory activity against FIT3-ITD comparable to that of Quizartinib and have a good inhibitory effect on MV4-11 cells, providing a class of novel lead compounds for the treatment and prevention of incurable acute myeloid leukemia. DETAILED DESCRIPTION

[0052] The present invention is further described in detail below in conjunction with embodiments.

[0053] Specific embodiments are further illustrated by the following synthesis schemes and examples, which should not be considered as limiting in any way. The experimental procedures used to generate the data will be discussed in detail below. For all preparations here, multiple doses can be proportioned according to techniques known in the art.

[0054] Compound 1-29 in the specific embodiment of the present invention is a novel phenylthiazole compound. The preparation method of compound 1-29 is to use 4-methoxythiobenzamide and 2-bromo-4'-nitroacetophenone as starting materials, reflux in ethanol to obtain the corresponding intermediate 1, intermediate 1 is demethylated by boron tribromide to obtain intermediate 2, intermediate 2 is subjected to potassium carbonate, potassium iodide and DMF to obtain intermediate 3, intermediate 3 is reduced by Pd / C and H2 to obtain intermediate 4, intermediate 4 is subjected to DMAP, triethylamine and chloroform to obtain the target product phenylthiazole compound (compound 1-29), the specific reaction process is as follows:

[0055]

[0056] Example 1

[0057] Preparation of 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 1), the specific preparation process is as follows:

[0058] (1) Preparation of 2-(4-methoxyphenyl)-4-(4-nitrophenyl)thiazole (Intermediate 1):

[0059]

[0060] 4-Methoxythiobenzamide (1 eq.) and 2-bromo-4'-nitroacetophenone (1 eq.) were used as starting materials and refluxed in ethanol for 8 hours. After the reaction was completed, the mixture was filtered off to obtain a white solid intermediate 1 without purification.

[0061] 1 H NMR (400MHz, DMSO-d6) δ8.5–8.2(m,5H),8.1–7.9(m,2H),7.2–7.0(m,2H),3.8(s,3H).

[0062] (2) Preparation of 4-(4-(4-nitrophenyl)thiazol-2-yl)phenol (Intermediate 2):

[0063]

[0064] Dissolve intermediate 1 (5 g, 1 eq.) in dichloromethane (100 ml), slowly add boron tribromide (4 eq.) in an ice bath at 0°C, stir for 30 minutes, remove the ice bath, and react at room temperature overnight. After the reaction is completed, add ice water to quench the reaction solution, extract with dichloromethane three times, retain the organic phase, evaporate the solvent under reduced pressure, and purify the solid residue by silica gel column chromatography to obtain intermediate 2.

[0065] 1 H NMR(400MHz,DMSO-d6)δ8.4(s,1H),8.4–8.2(m,4H),8.0–7.8(m,2H),7.0–6.9(m,2H).MS(m / z)(ESI):calcd for C 15 H 11 N2O3S + [M+H] + :299.0;found:299.0.

[0066] (3) Preparation of 4-(3-(4-(4-(4-nitrophenyl)thiazol-2-yl)phenoxy)propyl)morpholine (Intermediate 3):

[0067]

[0068] Dissolve intermediate 2 (1 eq.) in DMF (20 ml), add potassium carbonate (2 eq.), potassium iodide (0.1 g) and 4-(3-chloropropyl)morpholine hydrochloride (1.2 eq.), stir at 80°C for 8 hours; after the reaction, add 50 ml of water and ethyl acetate respectively, extract and retain the organic phase. Evaporate the solvent under reduced pressure, and purify the solid residue by silica gel column chromatography to obtain intermediate 3.

[0069] 1 HNMR(400MHz, CDCl3)δ8.4–8.3(m,2H),8.2–8.1(m,2H),8.0–7.9(m,2H),7.6(s,1H),7.0–7.0(m, 2H),4.1(t,J=6.2Hz,2H),3.8–3.7(m,4H),2.6–2.5(m,6H),2.1–2.0(m,2H).MS(m / z)(ESI):calcd for C 22 H 24 N3O4S + [M+H] + :426.1; found:426.1.

[0070] (4) Preparation of 4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)aniline (Intermediate 4):

[0071]

[0072] Intermediate 3 (1 eq.) was dissolved in methanol (50 ml), and palladium / carbon catalyst (10% Pd, 0.35 eq.) was added. The mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. The palladium / carbon catalyst was filtered off, the solvent was evaporated under reduced pressure, and the solid residue was purified by silica gel column chromatography to obtain intermediate 4.

[0073] 1 H NMR(400MHz,DMSO-d6)δ8.0–7.9(m,2H),7.7–7.7(m,2H),7.7–7.6(m,1H),7.1–7.0(m,2H),6.6–6.6(m,2H) ,5.3(s,2H),4.1(t,J=6.4Hz,2H),3.6–3.5(m,4H),2.5–2.3(m,6H),2.0–1.8(m,2H).MS(m / z)(ESI):calcd for C 22 H 26 N3O2S + [M+H] + :396.2; found:396.1.

[0074] (5) Preparation of 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 1):

[0075]

[0076] The intermediate 4 (1 eq.) was dissolved in chloroform (10 ml), and DMAP (0.1 eq.), triethylamine (3 drops) and phenyl (5-(tert-butyl) isoxazol-3-yl) carbamate (1.2 eq.) were added in sequence. The mixture was stirred at 55°C for 12-24 h, 100 ml of water was added, and the mixture was extracted with dichloromethane. The organic phase was retained. The solvent was evaporated under reduced pressure, and the solid residue was purified by silica gel column chromatography to obtain a white solid compound 1 (yield: 56.1%).

[0077] 1H NMR(400MHz,DMSO-d6)δ9.6(s,1H),9.0(s,1H),8.1–7.8(m,5H),7.6–7.4(m,2H),7.1–6.9(m,2H),6.6–6.4(m,1 H),4.1(t,J=6.0Hz,2H),3.6–3.5(m,4H),2.5–2.3(m,6H),1.9–1.8(m,2H),1.3(s,9H).HRMS(m / z)(ESI):calcd for C 30 H 36 N5O4S + [M+H] + :562.2; found:561.9.

[0078] Example 2

[0079] Preparation of 1-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)-3-phenylurea (Compound 2):

[0080]

[0081] The phenyl (5-(tert-butyl) isoxazol-3-yl) carbamate in step 5 of Example 1 was replaced by phenyl carbamate, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 2.

[0082] 1 H NMR(400MHz,DMSO-d6)δ8.8(s,1H),8.7(s,1H),8.0–7.9(m,5H),7.6–7.5(m,2H),7.5–7.4(m,2H),7.3–7.2(m,2H),7 .1–7.0(m,2H),7.0–6.9(m,1H),4.1(t,2H),3.6–3.5(m,4H),2.5–2.3(m,6H),2.0–1.9(m,2H).MS(m / z)(ESI):calcd for C 29 H 31 N4O3S + [M+H] + :515.2; found:515.0.

[0083] Example 3

[0084] Preparation of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 3):

[0085]

[0086] The phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced with phenyl(4-chloro-3-(trifluoromethyl)phenyl)carbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 3.

[0087] 1 H NMR(400MHz,DMSO-d6)δ9.3(s,1H),9.1(s,1H),8.2–8.1(m,1H),8.0–7.9(m,5H),7.7–7.5(m,4H),7.1–7 .0(m,2H),4.1(t,J=6.0Hz,2H),3.6–3.5(m,4H),2.5–2.3(m,6H),2.0–1.8(m,2H).MS(m / z)(ESI):calcd for C 30 H 29 ClF3N4O3S + [M+H] + :617.2; found:616.9.

[0088] Example 4

[0089] Preparation of 1-(2-bromo-4-methylphenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 4):

[0090]

[0091] The phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced with phenyl(2-bromo-4-methylphenyl)carbamate, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 4.

[0092] 1 H NMR(400MHz, DMSO-d6)δ9.5(s,1H),8.1(s,1H),8.0–7.9(m,6H),7.6–7.5(m,2H),7.5–7.4(m,1H),7.2–7. 0(m,3H),4.1(t,2H),3.6–3.5(m,4H),2.5–2.3(m,6H),2.3(s,3H),2.0–1.9(m,2H).MS(m / z)(ESI):calcd for C 30 H 32 BrN4O3S + [M+H] + :607.1; found:607.0.

[0093] Example 5

[0094] Preparation of 1-(4-methoxyphenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 5):

[0095]

[0096] The phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced with phenyl(4-methoxyphenyl)carbamate, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 5.

[0097] 1 H NMR(400MHz,DMSO-d6)δ8.8(s,1H),8.6(s,1H),8.0–7.9(m,5H),7.6–7.5(m,2H),7.4–7.3(m,2H),7.1–7.0(m,2H),7.0 –6.8(m,2H),4.1(t,J=6.4Hz,2H),3.7(s,3H),3.7–3.5(m,4H),2.5–2.3(m,6H),2.0–1.8(m,2H).MS(m / z)(ESI):calcd for C 30 H 33 N4O4S + [M+H] + :545.2; found:545.0.

[0098] Example 6

[0099] Preparation of 1-(4-fluorophenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 6):

[0100]

[0101] The phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced with phenyl(4-fluorophenyl)carbamate, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 6.

[0102] 1H NMR(400MHz,DMSO-d6)δ8.8(s,1H),8.8(s,1H),8.0–7.9(m,5H),7.6–7.4(m,4H),7.2–7.0( m,4H),4.1(t,2H),3.6–3.5(m,4H),2.5–2.3(m,6H),2.0–1.8(m,2H).MS(m / z)(ESI):calcd for C 29 H 30 FN4O3S + [M+H] + :533.2; found:533.0.

[0103] Example 7

[0104] Preparation of 1-(4-chlorophenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 7):

[0105]

[0106] The phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced with phenyl(4-chlorophenyl)carbamate, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 7.

[0107] 1 H NMR (400MHz, DMSO-d6) δ8.9–8.8(m,2H),8.0–7.9(m,5H),7.6–7.4(m,4H),7.4–7.3(m,2H),7.1–7.0( m,2H),4.1(t,J=6.8Hz,2H),3.6–3.5(m,4H),2.5–2.3(m,6H),1.9–1.8(m,2H).MS(m / z)(ESI):calcd for C 29 H 30 ClN4O3S + [M+H] + :549.2; found:548.9.

[0108] Example 8

[0109] Preparation of 1-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)-3-(p-tolyl)urea (Compound 8):

[0110]

[0111] The phenyl (5-(tert-butyl) isoxazol-3-yl) carbamate in step 5 of Example 1 was replaced by phenyl p-tolyl carbamate, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 8.

[0112] 1 H NMR(400MHz,DMSO-d6)δ8.8(s,1H),8.6(s,1H),8.0–7.8(m,5H),7.6–7.5(m,2H),7.4–7.3(m,2H),7.1–7.0(m,4H), 4.0(t,J=6.4,2.0Hz,2H),3.6–3.5(m,4H),2.4–2.3(m,6H),2.3–2.2(m,3H),1.9–1.8(m,2H).MS(m / z)(ESI):calcd for C 30 H 33 N4O3S + [M+H] + :529.2; found:529.3.

[0113] Example 9

[0114] Preparation of 1-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea (Compound 9):

[0115]

[0116] The phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced with phenyl(6-(trifluoromethyl)pyridin-2-yl)carbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 9.

[0117] 1 H NMR(400MHz,DMSO-d6)δ9.9(s,1H),9.7(s,1H),8.1–7.9(m,7H),7.6–7.5(m,2H),7.5–7.5(m,1H),7.1–6 .9(m,2H),4.1(t,J=6.4Hz,2H),3.6–3.5(m,4H),2.5–2.3(m,6H),2.0–1.8(m,2H).MS(m / z)(ESI):calcd for C 29 H 29 F3N5O3S + [M+H] + :584.2; found:584.1.

[0118] Example 10

[0119] Preparation of 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 10):

[0120]

[0121] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(3-chloropropyl)piperidine hydrochloride, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 10.

[0122] 1 H NMR(400MHz,DMSO-d6)δ9.6(s,1H),9.0(s,1H),8.0–7.9(m,5H),7.6–7.5(m,2H),7.1–7.0(m,2H),6.5(s,1H),4.1(t ,J=6.4Hz,2H),2.4–2.3(m,6H),1.9–1.8(m,2H),1.5–1.4(m,4H),1.4–1.3(m,2H),1.3(s,9H).MS(m / z)(ESI):calcd for C 31 H 38 N5O3S + [M+H] + :560.3; found:560.0.

[0123] Embodiment 11

[0124] Preparation of 1-phenyl-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 11):

[0125]

[0126] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 and the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 were replaced with N-(3-chloropropyl)piperidine hydrochloride and phenylcarbamate, respectively. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 11.

[0127] 1H NMR(400MHz,DMSO-d6)δ9.4(s,1H),9.3(s,1H),8.0–7.9(m,5H),7.6–7.4(m,4H),7.3–7.2(m,2H),7.2–7.0(m,2H),7.0–6 .9(m,1H),4.1(t,J=5.4Hz,2H),3.3–2.8(m,6H),2.3–2.1(m,2H),1.8–1.7(m,4H),1.6–1.4(m,2H).MS(m / z)(ESI):calcd forC 30 H 33 N4O2S + [M+H] + :513.2; found:513.0.

[0128] Example 12

[0129] Preparation of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 12):

[0130]

[0131] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(3-chloropropyl)piperidine hydrochloride; the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced by phenyl(4-chloro-3-(trifluoromethyl)phenyl)carbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1, to obtain white solid compound 12.

[0132] 1 H NMR(400MHz,DMSO-d6)δ9.5(s,1H),9.2(s,1H),8.3–8.0(m,1H),8.0–7.9(m,5H),7.7–7.4(m,4H),7.2–7.0(m,2H ),4.1(t,J=6.2Hz,2H),2.5–2.4(m,4H),2.0–1.9(m,2H),1.6–1.4(m,6H),1.3–1.2(m,2H).MS(m / z)(ESI):calcd for C 31 H 31 ClF3N4O2S + [M+H] + :615.2; found:615.0.

[0133] Example 13

[0134] Preparation of 1-(2-bromo-4-methylphenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 13):

[0135]

[0136] Replace 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 with N-(3-chloropropyl)piperidine hydrochloride; replace phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 with phenyl(2-bromo-4-methylphenyl)carbamate, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 1 to obtain white solid compound 13.

[0137] 1 H NMR(400MHz,DMSO-d6)δ9.6(s,1H),8.1(s,1H),8.0–7.8(m,6H),7.7–7.5(m,2H),7.5–7.4(m,1H),7.2–7.0 (m,3H),4.1(t,J=12.8,7.2Hz,2H),2.4–2.1(m,9H),1.9–1.8(m,2H),1.6–1.3(m,6H).MS(m / z)(ESI):calcd for C 31 H 34 BrN4O2S + [M+H] + :605.2; found:605.1.

[0138] Embodiment 14

[0139] Preparation of 1-(4-methoxyphenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 14):

[0140]

[0141] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(3-chloropropyl)piperidine hydrochloride; the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced by phenyl(4-methoxyphenyl)carbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1, to obtain a white solid compound 14.

[0142] 1H NMR(400MHz, DMSO-d6)δ8.8(s,1H),8.5(s,1H),8.0–7.8(m,5H),7.6–7.5(m,2H),7.4–7.3(m,2H),7.1–7.0(m,2H),6.9–6. 8(m,2H),4.1(t,2H),3.7(s,3H),2.4–2.2(m,6H),2.0–1.8(m,2H),1.5–1.4(m,4H),1.4–1.3(m,2H).MS(m / z)(ESI):calcd forC 31 H 35 N4O3S + [M+H] + :543.2; found:543.1.

[0143] Embodiment 15

[0144] Preparation of 1-(4-fluorophenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 15):

[0145]

[0146] Replace 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 with N-(3-chloropropyl)piperidine hydrochloride; replace phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 with phenyl(4-fluorophenyl)carbamate, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 1 to obtain white solid compound 15.

[0147] 1 H NMR(400MHz,DMSO-d6)δ8.9(s,1H),8.8(s,1H),8.0–7.9(m,5H),7.6–7.4(m,4H),7.2–7.0(m,4H ),4.1(t,J=6.4Hz,2H),2.5–2.2(m,6H),2.0–1.8(m,2H),1.6–1.3(m,6H).MS(m / z)(ESI):calcd for C 30 H 32 FN4O2S + [M+H] + :531.2; found:531.0.

[0148] Example 16

[0149] Preparation of 1-(4-chlorophenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 16):

[0150]

[0151] Replace 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 with N-(3-chloropropyl)piperidine hydrochloride; replace phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 with phenyl(4-chlorophenyl)carbamate, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 1 to obtain white solid compound 16.

[0152] 1 H NMR(400MHz,DMSO-d6)δ9.0–8.7(m,2H),8.0–7.8(m,5H),7.6–7.4(m,4H),7.4–7.2(m,2H),7.1– 6.9(m,2H),4.0(t,2H),2.4–2.2(m,6H),1.9–1.7(m,2H),1.6–1.3(m,6H).MS(m / z)(ESI):calcd for C 30 H 32 ClN4O2S + [M+H] + :547.2; found:546.9.

[0153] Embodiment 17

[0154] Preparation of 1-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)-3-(p-tolyl)urea (Compound 17):

[0155]

[0156] Replace 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 with N-(3-chloropropyl)piperidine hydrochloride; replace phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 with phenyl p-tolylcarbamate, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 1 to obtain white solid compound 17.

[0157] 1H NMR(400MHz,DMSO-d6)δ8.9(s,1H),8.7(s,1H),8.0–7.8(m,5H),7.6–7.5(m,2H),7.4–7.3(m,2H),7.2–7.0(m,4H),4.1 (t,J=6.2Hz,2H),2.5–2.3(m,6H),2.3(s,3H),2.0–1.8(m,2H),1.6–1.5(m,4H),1.4–1.3(m,2H).MS(m / z)(ESI):calcd for C 31 H 35 N4O2S + [M+H] + :527.2; found:527.1.

[0158] Embodiment 18

[0159] Preparation of 1-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea (Compound 18):

[0160]

[0161] Replace 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 with N-(3-chloropropyl)piperidine hydrochloride; replace phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 with phenyl(6-(trifluoromethyl)pyridin-2-yl)carbamate, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 1 to obtain white solid Compound 18.

[0162] 1 H NMR(400MHz, DMSO-d6)δ9.9(s,1H),9.7(s,1H),8.1–7.8(m,7H),7.7–7.4(m,3H),7.2–7.0(m,2H),4.1(t,J= 7.4,5.4Hz,2H),2.4–2.2(m,6H),1.9–1.8(m,2H),1.6–1.4(m,4H),1.4–1.3(m,2H).HRMS(m / z)(ESI):calcd for C 30 H 31 F3N5O2S + [M+H] + :582.2; found:581.9.

[0163] Embodiment 19

[0164] Preparation of 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 19):

[0165]

[0166] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(2-chloroethyl)morpholine hydrochloride, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 19.

[0167] 1 H NMR(400MHz,DMSO-d6)δ9.6(s,1H),9.0(s,1H),8.0–7.9(m,5H),7.6–7.5(m,2H),7.1–7.1(m,2H),6.6–6.5(m ,1H),4.2–4.1(m,2H),3.6–3.5(m,4H),2.8–2.7(m,2H),2.5–2.4(m,4H),1.3(s,9H).HRMS(m / z)(ESI):calcd for C 29 H 34 N5O4S + [M+H] + :548.2; found:547.9.

[0168] Embodiment 20

[0169] Preparation of 1-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)-3-phenylurea (Compound 20):

[0170]

[0171] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(2-chloroethyl)morpholine hydrochloride; the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced by phenylcarbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 20.

[0172] 1H NMR(400MHz,DMSO-d6)δ8.8(s,1H),8.7(s,1H),8.0–7.9(m,5H),7.6–7.5(m,2H),7.5–7.4(m,2H),7.3–7.2(m,2H),7.1–7 .1(m,2H),7.0–7.0(m,1H),4.2(t,J=5.8Hz,2H),3.6–3.6(m,4H),2.7–2.7(m,2H),2.5–2.5(m,4H).MS(m / z)(ESI):calcd forC 28 H 29 N4O3S + [M+H] + :501.2; found:501.0.

[0173] Embodiment 21

[0174] Preparation of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 21):

[0175]

[0176] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(2-chloroethyl)morpholine hydrochloride; the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced by phenyl(4-chloro-3-(trifluoromethyl)phenyl)carbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1, to obtain white solid compound 21.

[0177] 1 H NMR(400MHz, DMSO-d6)δ9.3(s,1H),9.1(s,1H),8.2–8.1(m,1H),8.0–7.9(m,5H),7.7–7.5(m,4H),7.1–7. 1(m,2H),4.2(t,J=5.8Hz,2H),3.6–3.5(m,4H),2.8–2.7(m,2H),2.5–2.5(m,4H).HRMS(m / z)(ESI):calcd for C 29 H 27 ClF3N4O3S + [M+H] + :603.1; found:602.9.

[0178] Embodiment 22

[0179] Preparation of 1-(2-bromo-4-methylphenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 22):

[0180]

[0181] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(2-chloroethyl)morpholine hydrochloride; the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced by phenyl(2-bromo-4-methylphenyl)carbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 22.

[0182] 1 H NMR(400MHz,DMSO-d6)δ9.5(s,1H),8.1(s,1H),8.0–7.9(m,6H),7.6–7.5(m,2H),7.5–7.4(m,1H),7.2–7.0(m, 3H),4.2(t,J=5.4Hz,2H),3.6–3.6(m,4H),2.8–2.7(m,2H),2.5–2.5(m,4H),2.3(s,3H).MS(m / z)(ESI):calcd for C 29 H 30 BrN4O3S + [M+H] + :593.1; found:593.0.

[0183] Embodiment 23

[0184] Preparation of 1-(4-methoxyphenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 23):

[0185]

[0186] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(2-chloroethyl)morpholine hydrochloride; the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced by phenyl(4-methoxyphenyl)carbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 23.

[0187] 1H NMR(400MHz, DMSO-d6)δ8.8(s,1H),8.5(s,1H),8.0–7.8(m,5H),7.6(d,J=8.4Hz,2H),7.4–7.3(m,2H),7.2–7.0(m,2H),6 .9–6.8(m,2H),4.2(t,J=5.8Hz,2H),3.7(s,3H),3.6–3.5(m,4H),2.8–2.7(m,2H),2.5–2.5(m,4H).MS(m / z)(ESI):calcd forC 29 H 31 N4O4S + [M+H] + :531.2; found:531.0.

[0188] Embodiment 24

[0189] Preparation of 1-(4-fluorophenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 24):

[0190]

[0191] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(2-chloroethyl)morpholine hydrochloride; the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced by phenyl(4-fluorophenyl)carbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 24.

[0192] 1 H NMR(400MHz,DMSO-d6)δ8.8(s,1H),8.8(s,1H),8.0–7.9(m,5H),7.6–7.4(m,4H),7.2–7.0(m,4H), 4.2(t,J=5.8,2.4Hz,2H),3.7–3.5(m,4H),2.8–2.6(m,2H),2.5–2.4(m,4H).MS(m / z)(ESI):calcd for C 28 H 28 FN4O3S + [M+H] + :519.2; found:518.9.

[0193] Embodiment 25

[0194] Preparation of 1-(4-chlorophenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 25):

[0195]

[0196] Replace 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 with N-(2-chloroethyl)morpholine hydrochloride; replace phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 with phenyl(4-chlorophenyl)carbamate, and the remaining required raw materials, reagents and preparation methods are the same as those in Example 1 to obtain white solid compound 25.

[0197] 1 H NMR(400MHz,DMSO-d6)δ9.0–8.8(m,2H),8.0–7.9(m,5H),7.6–7.4(m,4H),7.4–7.3(m,2H),7.1– 7.0(m,2H),4.1(t,2H),3.6–3.5(m,4H),2.8–2.6(m,2H),2.5–2.4(m,4H).MS(m / z)(ESI):calcd for C 28 H 28 ClN4O3S + [M+H] + :535.2; found:534.9.

[0198] Embodiment 26

[0199] Preparation of 1-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)-3-(p-tolyl)urea (Compound 26):

[0200]

[0201] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(2-chloroethyl)morpholine hydrochloride; the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced by phenyl p-tolylcarbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1, to obtain a white solid compound 26.

[0202] 1H NMR(400MHz,DMSO-d6)δ8.8(s,1H),8.6(s,1H),8.0–7.9(m,5H),7.6–7.5(m,2H),7.4–7.3(m,2H),7.1–7.0(m,4H ),4.2(t,J=5.8Hz,2H),3.6–3.5(m,4H),2.7(t,J=5.8Hz,2H),2.5–2.4(m,4H),2.3(s,3H).MS(m / z)(ESI):calcd for C 29 H 31 N4O3S + [M+H] + :515.2; found:515.0.

[0203] Embodiment 27

[0204] Preparation of 1-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea (Compound 27):

[0205]

[0206] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N-(2-chloroethyl)morpholine hydrochloride; the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 of Example 1 was replaced by phenyl(6-(trifluoromethyl)pyridin-2-yl)carbamate, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 1, to obtain white solid compound 27.

[0207] 1 H NMR(400MHz,DMSO-d6)δ9.9(s,1H),9.7(s,1H),8.1–7.9(m,7H),7.7–7.4(m,3H),7.2–7.0(m,2H), 4.2(t,J=5.4Hz,2H),3.7–3.5(m,4H),2.7(t,J=5.6Hz,2H),2.5–2.4(m,4H).MS(m / z)(ESI):calcd for C 28 H 27 F3N5O3S + [M+H] + :570.2; found:569.8.

[0208] Embodiment 28

[0209] Preparation of 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(3-(dimethylamino)propoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 28):

[0210]

[0211] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N,N-dimethylaminochloropropane hydrochloride, and the remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound 28.

[0212] 1 H NMR(400MHz,DMSO-d6)δ9.6(s,1H),9.1(s,1H),8.1–7.8(m,5H),7.6–7.5(m,2H),7.1–7.0(m,2H),6.6–6.5 (m,1H),4.1(t,2H),2.4–2.3(m,2H),2.2–2.1(m,6H),1.9–1.8(m,2H),1.3(s,9H).HRMS(m / z)(ESI):calcd for C 28 H 34 N5O3S + [M+H] + :520.2; found:520.0.

[0213] Embodiment 29

[0214] Preparation of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(3-(dimethylamino)propoxy)phenyl)thiazol-4-yl)phenyl)urea (Compound 29):

[0215]

[0216] The 4-(3-chloropropyl)morpholine hydrochloride in step 3 of Example 1 was replaced by N,N-dimethylaminochloropropane hydrochloride and the phenyl(5-(tert-butyl)isoxazol-3-yl)carbamate in step 5 was replaced by phenyl(4-chloro-3-(trifluoromethyl)phenyl)carbamate, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain a white solid compound 29.

[0217] 1H NMR(400MHz,DMSO-d6)δ9.2(s,1H),9.0(s,1H),8.1(s,1H),8.0–7.9(m,5H),7.7–7.5(m,4H),7.1–7.0 (m,2H),4.1(t,J=6.4Hz,2H),2.4(t,J=7.2Hz,2H),2.1(s,6H),1.9–1.8(m,2H).MS(m / z)(ESI):calcd for C 28 H 27 ClF3N4O2S + [M+H] + :575.1; found:574.9.

[0218] Embodiment 30

[0219] FLT3-ITD kinase inhibition assay

[0220] All enzymatic reactions were performed at 30°C with a reaction time of 40 minutes. The 50 μl reaction mixture contained 40 mM Tris, pH 7.4, 10 mM MgCl2, 0.1 mg / ml BSA, 1 mM DTT, 10 μM ATP, kinase and enzyme substrate. The compounds were diluted with 10% DMSO and 5 μl of the dilution was added to the 50 μl reaction to give a final DMSO concentration of 1% for all reactions. The Kinase-Glo Plus Fluorescent Kinase Assay Kit was used for detection. It measures kinase activity by quantifying the amount of ATP remaining in the solution after the kinase reaction. The fluorescent signal is correlated with the amount of ATP present and negatively correlated with the amount of kinase activity. IC was calculated using nonlinear regression with a normalized dose-response fit using Prism GraphPad software. 50 The results in Table 1 show that compounds 1, 2, 18, 19, 21 and 28 exhibited comparable inhibitory activity against FLT3-ITD as Quizartinib. “++++” indicates IC 50 The value is less than 10 nM or the inhibition rate is 80-100%, and "+++" indicates IC 50 The value is 10-100nM or the inhibition rate is 60-80%, "++" means IC 50 Value 100-1000nM or inhibition rate 40-60%, "+" indicates IC 50 The value was greater than 1000 nM or the inhibition rate was less than 40%.

[0221] Table 1 Compounds inhibit FLT3-ITD kinase

[0222]

[0223]

[0224] Embodiment 31

[0225] IC of compounds against MV4-11 cell line 50 value

[0226] MV4-11 is a well characterized FLT3-dependent human cell line that contains an internal tandem duplication (ITD) found in patients with acute myeloid leukemia and expresses a constitutively active FLT3 receptor. This cell line was used to determine the ability of the compounds provided herein to inhibit FLT3 in intact cells.

[0227] MV4-11 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum. For proliferation assay, cells were cultured overnight in low serum medium (0.5% fetal bovine serum), then 40,000 or 10,000 cells were seeded in 96-well plates per well, different concentrations of compounds were added, and incubated at 37°C for 72 h, 10 μL of CCK8 solution was added to each well and incubated for 1-4 h, absorbance was measured at 450 nm using a multifunctional microplate reader (Synergy H1, Agilent BioTek, USA), and inhibition rate was calculated. The results are shown in Table 2. Inhibition rate calculation: (All raw data should be subtracted from the background value). "++++" indicates IC 50 Values ​​less than 10 nM, “+++” indicates IC 50 Value 10-100nM, "++" indicates IC 50 Value 100-1000nM, "+" indicates IC 50 The value is greater than 1000nM.

[0228] Table 2 IC values ​​of compounds against MV4-11 cell line 50 value

[0229]

[0230]

[0231] The results in Table 2 show that compounds 8, 12, 15, 21, 25, 28 and 29 all have good inhibitory activity against MV4-11 cells, and compound 28 has higher inhibitory activity against MV4-11 cells than other compounds, and is comparable to the activity of Quizartinib.

Claims

1. A phenylthiazole derivative, characterized in that: A compound having the general structural formula (I) or a pharmaceutically acceptable salt thereof: Wherein, Z is -C(O)-, -(CH2) q -、-(CH2) q O-, -(CH2) q C(O)-, -C(O)NH(CH2) q -、-(CH2) q C(O)NH(CH2) q -、-O(CH2) q -, q is an integer from 1 to 4; R 1 Selected from C 3-8 - cycloalkyl, wherein n is an integer from 0 to 2; X is N or CH2; Y is -O-, S, -NR 5 -, CH2, wherein R 5 Is H or C 1-10 alkyl; R 2 is selected from one of aryl, heterocyclic, heteroaryl, substituted aryl, substituted heterocyclic, substituted heteroaryl, and the substituent is selected from hydrogen, C 1-6 -Alkyl, CH3(CH2) q O-, halogen, C substituted by halogen 1-10 - one of the alkyl groups, q is an integer of 1-4.

2. The phenylthiazole derivative according to claim 1, characterized in that: R1 is selected from wherein n is 1; X is N; and Y is -O- or CH2.

3. A phenylthiazole derivative according to claim 1 or 2, characterized in that: Z is -(CH2) q O-, q is 2 or 3.

4. A phenylthiazole derivative according to claim 1 or 2, characterized in that: R 2 is one of phenyl, pyridine, isoxazole, substituted phenyl, substituted pyridine, substituted isoxazole, and the substituent is selected from hydrogen, C 1-6 -Alkyl, CH3(CH2) q O-, halogen, C substituted by halogen 1-10 - one of the alkyl groups, q is an integer of 1-4.

5. The phenylthiazole derivative according to claim 4, characterized in that: The substituent in the substituted phenyl group is one of hydrogen, methyl, fluorine, chlorine, CH3O-, m-trifluoromethyl, p-chloro, p-methyl, and o-bromine; the substituted pyridine is trifluoromethyl-substituted pyridine, and the substituted isoxazole is tert-butyl-substituted isoxazole.

6. The phenylthiazole derivative according to claim 1, characterized in that: The derivatives are: 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)-3-phenylurea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(2-bromo-4-methylphenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-methoxyphenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-fluorophenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-chlorophenyl)-3-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)-3-(p-tolyl)urea, 1-(4-(2-(4-(3-morpholinopropoxy)phenyl)thiazol-4-yl)phenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea, 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-phenyl-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(2-bromo-4-methylphenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-methoxyphenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-fluorophenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-chlorophenyl)-3-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)-3-(p-tolyl)urea, 1-(4-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)thiazol-4-yl)phenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea, 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)-3-phenylurea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(2-bromo-4-methylphenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-methoxyphenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-fluorophenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-chlorophenyl)-3-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)-3-(p-tolyl)urea, 1-(4-(2-(4-(2-morpholinethoxy)phenyl)thiazol-4-yl)phenyl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea, 1-(5-(tert-butyl)isothiazol-3-yl)-3-(4-(2-(4-(3-(dimethylamino)propoxy)phenyl)thiazol-4-yl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(4-(3-(dimethylamino)propoxy)phenyl)thiazol-4-yl)phenyl)urea.

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a therapeutically effective amount of the phenylthiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, and one or more pharmaceutically acceptable carriers.

8. Use of the phenylthiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the preparation of a medicament for treating a proliferative disease in a patient.

9. The use according to claim 8, wherein the proliferative disease is acute myeloid leukemia, chronic myeloid leukemia, thyroid cancer, gastric cancer, gastrointestinal stromal tumors, colorectal cancer, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, lymphoma, renal cancer, autosomal dominant polycystic kidney disease or myeloma.

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