Nitrogen-containing heterocyclic derivative and medical application thereof

Abstract

The invention belongs to the technical field of medicine, and particularly relates to a USP1 inhibitor, a preparation method thereof and application of the USP1 inhibitor in medicine. The invention provides a USP1 inhibitor as shown in a formula (II-1), (II-2), (III) or (IV) and a composition and application thereof. The compound can be used for treating or preventing diseases or symptoms related to abnormal expression of a USP1 signal channel. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and relates to a nitrogen-containing heterocyclic derivative. Specifically, it relates to the free base, isomers, isotope derivatives, solvates and pharmaceutically acceptable salts of such compounds. Further, the present invention also discloses a preparation method and pharmaceutical use of the nitrogen-containing heterocyclic derivative, which can be used as a USP1 inhibitor for treating diseases related to abnormal expression of the USP1 signaling pathway, and has broad application prospects. Background Art

[0002] Ubiquitination is a reversible process that involves the deubiquitinating enzyme (DUB) family and regulates various cellular processes by deubiquitinating substrates. There are approximately 100 DUBs in the human body, which can be divided into 6 families. Among them, ubiquitin-specific proteases (USPs) have more than 50 members and are the largest family of known DUBs. USPs play a role in various physiological functions such as the cell cycle, signal transduction, DNA damage repair, chromosomal translocation, and gene transcription by regulating substrate proteases.

[0003] USP1 is a cysteine isopeptidase of the USP subfamily among DUBs. It has no significant activity by itself, but acquires full enzymatic activity after binding to USP1-associated factor 1 (UAF1) to form a heterodimeric complex (USP1 / UAF1), and plays a role in DNA damage repair. The USP1 / UAF1 complex can deubiquitinate monoubiquitinated proliferating cell nuclear antigen (PCNA), which plays an important role in the translesion synthesis (TLS) pathway. In addition, Fanconi anemia complementation group I (FANCI) and Fanconi anemia complementation group D2 (FAND2) are collectively called the ID complex, which is activated by phosphorylation and monoubiquitination for DNA repair, and the USP1 / UAF1 complex can also deubiquitinate the ID complex in the Fanconi anemia (FA) pathway. These two DNA damage response (DDR) pathways, TLS and FA, are key pathways for repairing DNA damage induced by DNA cross-linking agents such as cisplatin and mitomycin, and PCNA, FANCI, and FAND2 are crucial proteins in these two pathways. Among them, the USP1 / UAF1 complex prevents excessive or improper DNA repair by deubiquitinating PCNA and FAND2 / FANDI, thereby ensuring genomic stability. By querying the expression of USP1 in different tumor tissues and adjacent tissues, it was found that its expression was significantly increased in digestive system tumors such as cholangiocarcinoma, colon cancer, esophageal cancer, liver cancer, and gastric cancer, and was also significantly upregulated in head and neck squamous cell carcinoma, lung cancer, prostate cancer, and ovarian cancer (Antonenko Svitlana, Zavelevich Michael, Telegeev Gennady. The role of USP1 deubiquitinase in the pathogenesis and therapy of cancer[J]. Acta biochimica Polonica, 2023, 70(2): 219-231.). In osteosarcoma cells, USP1 can deubiquitinate the ID complex, promote cell proliferation, and inhibiting USP1 can increase the sensitivity of osteosarcoma cells to chemotherapy (Samuel A. Williams, Heather L. Maecker, Dorothy M. French, et al. USP1 Deubiquitinates ID Proteins to Preserve a Mesenchymal Stem Cell Program in Osteosarcoma[J]. Cell, 2011, 146(6): 918-930.).There are also studies confirming that USP1 is closely related to the development of resistance to various tumor therapeutic drugs. In non-small cell lung cancer (NSCLC) cells with cisplatin resistance, the expression level of USP1 is high, and knocking down USP1 can significantly enhance the sensitivity of cells to cisplatin (Junjun Chen, Thomas S. Dexheimer, Yongxing Ai, et al. Selective and Cell-Active Inhibitors of the USP1 / UAF1 Deubiquitinase Complex Reverse Cisplatin Resistance in Non-small Cell Lung Cancer Cells[J]. Chemistry&Biology, 2011, 18(11): 1390-1400.); in breast cancer cells, USP1 is highly expressed, promoting the proliferation of breast cancer cells and being closely related to poor prognosis of breast cancer (Zhiguo Niu, Xin Li, Suyin Feng, et al. The deubiquitinating enzyme USP1 modulates ERα and modulates breast cancer progression[J]. Journal of Cancer, 2020, 11(23): 6992.).

[0004] In addition, USP1 is also closely associated with some non-tumor diseases. There are literature reports that USP1 can remove the polyubiquitination of NLRP3 and inhibit its ubiquitination-mediated degradation, thereby increasing the cellular NLRP3 level and mediating the activation of the NLRP3 inflammasome and the release of IL-1β. In mice, the specific selective inhibitor ML323 of USP1 can significantly inhibit the secretion of LPS-induced IL-1β and TNF, and improve the inflammatory and edema symptoms in the animal model of acute tubular necrosis, increasing the survival rate of mice (Hui Song, Chunyuan Zhao, Zhongxia Yu, et al. UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression[J]. Nature Communications, 2020, 11(1): 6042-6042.). There are also studies showing that USP1 promotes Th17 cell differentiation through deubiquitination, but weakens Treg cell differentiation, thus promoting the development of inflammatory diseases. ML323 can treat the imbalance between Th17 and Treg cells and relieve the disease progression in the experimental autoimmune encephalomyelitis model mice (Xiaotong Zhu, Peng Wang, Xiaoxia Zhan, et al. USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing TAZ[J]. Cellular & molecular immunology, 2023, 20(3): 252-263.). Therefore, USP1 is expected to become a drug target for treating inflammation-related diseases.

[0005] Patent WO2020132269 discloses a novel triazole heteroaryl derivative, which can be used as a USP1 inhibitor. Its structural characteristics are as follows: the parent nucleus structure is pyrimidine containing an N five-membered heteroaromatic ring, and the N site of the N-containing five-membered heteroaromatic ring is connected to a six-membered aromatic ring (or heteroaromatic ring) through a carbon bond; the representative compound of this patent is KSQ-4279. In 2021, KSQ-4279 carried out a phase I clinical trial in the United States for the treatment of solid tumors (NCT05240898); the indications of breast cancer and ovarian cancer are still in the preclinical stage.

[0006]

[0007] Patent WO2022228399 discloses a novel tricyclic fused derivative, which can be used as a USP1 inhibitor. Its structural characteristics are as follows: the parent nucleus structure is a six-membered aromatic ring (or heteroaromatic ring) fused to a five-membered aromatic ring (or heteroaromatic ring), and the five- and six-membered rings can be further cyclized (fused) through a common carbon atom.

[0008]

[0009] However, there is currently no drug on the market for USP1 inhibitors. Therefore, it is necessary to develop small molecule inhibitors targeting the USP1 protein. The present invention aims to provide a nitrogen heterocyclic derivative USP1 inhibitor with novel structure, excellent activity and good metabolism for the treatment of related tumors. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to provide a small molecule inhibitor targeting USP1 with a completely new structure, having significant USP1 inhibitory activity, for preventing or treating diseases related to abnormal USP1 expression.

[0011] To solve the above technical problems, the technical solutions provided by the present invention are specifically as follows:

[0012] On the one hand, the present invention provides a nitrogen heterocyclic derivative, which is a compound having the following general formula (II-1), (II-2), (III) or (IV), and its prodrug, isomer, solvate or pharmaceutically acceptable salt thereof:

[0013]

[0014] Wherein, X is CR a or N; Y 1 , Y 2 is C, CH or N, Y 3 is CH, S, N or NR c , Y 4 , Y 5 is CH, N or NR c ;

[0015] Z 1 , Z 2 is methylene or oxo; n is 1, 2 or 3; Q is CH 2 or O;

[0016] R 1 is selected from a 4- to 10-membered heterocyclic group, C 6 -C 10 aryl or a 5- to 10-membered heteroaryl group, and the 4- to 10-membered heterocyclic group, C 6 -C 10 aryl or 5- to 10-membered heteroaryl group are each independently optionally substituted with from 0 to 4 Ra , R b , R c , R d or R e is substituted;

[0017] R 5 is selected from C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is each independently optionally substituted with any of 0 to 4 R a , R b , R c , R d or R e is substituted;

[0018] L is -(L 1 ) m -, where L 1 is each independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O) 2 -, -NR f - or -CR d R e -, and m is 0, 1 or 2;

[0019] Cy is selected from C 3 -C 12 cycloalkyl, 4- to 12-membered heterocyclic group, C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the C 3 -C 12 cycloalkyl, 4- to 12-membered heterocyclic group, C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with 0 to 4 R 2 ;

[0020] R a is independently selected from hydrogen, halogen, nitro, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -OR 3 , -SR 3 , -S(O) 2 R 3 , -S(O) 2 NR 3 R 4 , -NR 3 R4 、 -C(O)OR 3 、 -OC(O)R 3 、 -C(O)R 3 、 -C(O)NR 3 R 4 、 -OC(O)NR 3 R 4 、 -N(R 3 )C(O)R 4 、 -N(R 3 )C(O)OR 4 or C 2 -C 6 alkynyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group or 5-6 membered heteroaryl is optionally substituted with 0 to 4 R 2 substituents;

[0021] R b is independently selected from hydrogen, halogen, nitro, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, C 2 -C 6 alkynyl, -OR 3 、 -SR 3 、 -S(O) 2 R 3 、 -S(O) 2 NR 3 R 4 、 -NR 3 R 4 、 -C(O)OR 3 、 -OC(O)R 3 、 -C(O)R 3 、 -C(O)NR 3 R 4 、 -OC(O)NR 3 R 4 、 -N(R 3 )C(O)R 4 or -N(R 3 )C(O)OR 4 , wherein the C 1 -C 6 alkyl, C 1 -C6 Heteroalkyl, C 3 -C 6 Cycloalkyl, 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl or C 2 -C 6 Alkynyl is optionally substituted with 0 to 4 R 2 substituents;

[0022] R c is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl or 4- to 6-membered heterocyclic group, and the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic group may be optionally further substituted with one or more R 2 substituents;

[0023] R d 、R e are each independently selected from hydrogen, deuterium, halogen, cyano, amino, carboxyl, nitro, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 10-membered heterocyclic group, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino or C 1 -C 6 alkylsulfonyl, and the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 10-membered heterocyclic group, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6Alkylamino or C 1 -C 6 alkylsulfonyl may optionally be further substituted by one or more R 2 substituents;

[0024] Alternatively, R d , R e together with the carbon atom to which it is attached form a C 3 -C 8 cycloalkyl or 3- to 10-membered heterocyclic group, and the C 3 -C 8 cycloalkyl or 3- to 10-membered heterocyclic group may optionally be further substituted by one or more R 2 substituents;

[0025] R f is independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic group, and the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic group may optionally be further substituted by one or more R 2 substituents;

[0026] R 3 , R 4 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic group, or R 3 , R 4 together with the attached N atom form a 4- to 6-membered heterocyclic ring, and the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic group or R 3 , R 4 together with the attached N atom form a 4- to 6-membered heterocyclic ring which is substituted by one or more R 2 substituents;

[0027] R 2 is independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, carboxy, nitro, C1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, bis(C 1 -C 6 alkyl)amino, C 3 -C 8 cycloalkyl or 3- to 10-membered heterocyclic group, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, bis(C 1 -C 6 alkyl)amino, C 3 -C 8 cycloalkyl or 3- to 10-membered heterocyclic group may optionally be further substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, carboxyl;

[0028] In some embodiments, the compound has the structure of formula (II-1), formula (II-2) or formula (III):

[0029]

[0030] wherein, Y 1 、Y 2 is C or N, Y 3 is C, S, N or NR c ,Y 4 、Y 5 is C, N or NR c ;

[0031] R c is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C6 Heteroalkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic group, where the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic group is optionally substituted with 0 to 4 R 2 substituents;

[0032] R d and R e are each independently selected from hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or R d and R e together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclic group; where the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or R d and R e together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclic group is optionally substituted with 0 to 4 R 2 substituents;

[0033] R f is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic group, where the C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 4- to 6-membered heterocyclic group is optionally substituted with 0 to 4 R 2 substituents;

[0034] R 2 selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amino, C 3 -C 6 cycloalkyl or a 4- to 6-membered heterocyclic group, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amino, C 3 -C 6 cycloalkyl or a 4- to 6-membered heterocyclic group is optionally substituted with 0 to 4 halogens, cyano, hydroxyl, amino, carboxyl;

[0035] X, R 1 、R 5 、L, Cy, R a and R b are as defined in general formula (II-1), (II-2), (III) or (IV).

[0036] In some embodiments, the is selected from

[0037] In some embodiments, the is selected from

[0038] In some embodiments, the compound has the structure of formula (IV):

[0039]

[0040] wherein R d 、R e are each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2-C 6 alkynyl, C 1 -C 6 alkoxy or R d 、R e forming a C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclic group with the carbon atom to which it is attached; the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or R d 、R e forming a C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclic group optionally substituted with 0 to 4 R 2 substituents;

[0041] R 2 is selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amino, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amino, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclic group optionally substituted with 0 to 4 halogens, cyano, hydroxyl, amino, carboxyl;

[0042] Z 1 、Z 2 、n, Q, R 1 、R 5 and Cy are as defined in general formula (II-1), (II-2), (III) or (IV);

[0043] Preferably, the is selected from

[0044] In some embodiments, the R 5 is selected from

[0045] The R a , R b are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 3 , ethoxy, propoxy, isopropoxy, cyclopropoxy, -NHCH 3 , -N(CH 3 ) 2 , -SO 2 CH 3 ,

[0046] The R c is independently selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -CH 2 F, -CHF 2 or

[0047] The R d , R e are each independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxymethyl, or R d , R e and the cyclopropyl, ethylene oxide, cyclobutyl, cyclopentyl formed by the carbon atom to which they are attached,

[0048] In some embodiments, the R 5 is selected from

[0049] In some embodiments, the R 1 is selected from

[0050] The R a , R bEach independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 3 , ethoxy, propoxy, isopropoxy, cyclopropoxy, -NHCH 3 , -N(CH 3 ) 2 , -SO 2 CH 3 ,

[0051] wherein R c is independently selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -CH 2 F, -CHF 2 ,

[0052] wherein R d , R e are each independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxymethyl, or R d , R e forming cyclopropyl, oxirane, cyclobutyl, cyclopentyl, with the carbon atom to which they are attached

[0053] In some embodiments, R 1 is selected from

[0054] In some embodiments, L is -WCR d R e -, L is selected from -OCR d R e - or -NR f CR d R e -; W is selected from -O- or -NR f -;

[0055] wherein R d and R e are each independently selected from hydrogen, deuterium, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, the C1 -C 6 alkyl, C 3 -C 6 The cycloalkyl group may optionally be further substituted with 0 to 4 substituents selected from deuterium, halogen, hydroxyl, cyano or amino;

[0056] Alternatively, the R d , R e together with the carbon atom to which it is attached form a C 3 -C 6 cycloalkyl group or a 3- to 6-membered heterocyclic group, and the C 3 -C 6 cycloalkyl group or 3- to 6-membered heterocyclic group may optionally be further substituted with 0 to 4 substituents selected from deuterium, halogen, hydroxyl, cyano or amino;

[0057] The R f is selected from hydrogen, deuterium, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group, and the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group may optionally be further substituted with 0 to 4 substituents selected from deuterium, halogen, hydroxyl, cyano or amino.

[0058] In some embodiments, the L is selected from -NHCH 2 -, -N(CH 3 )CH 2 -, -N(CH 3 )CD 2 -, -N(CD 3 )CD 2 -, -OCH(CH 3 )-, -N(CD 3 )CH 2 -, -N(CD 3 )CH(CH 3 )-, -N(CH 3 )CH(CH 3 )-, -N(CH 3 )CH(CF 3 )-, -N(CHF 2 )CH(CH 3 )-, -NHCH(CH 3 )-, -NHCH(CF 3 )-, -N(CH 2 CF 3 )CH(CH 3 )-, -N(CH2 CH 3 )CH(CF 3 )-、-N(CD 3 )CH(CF 3 )-、-N(CH 3 )CH(CHF 2 )-、

[0059] In some embodiments, Cy is selected from

[0060] In some embodiments, the compound has a structure represented by the following formula (IIIa), and its prodrug, isomer, solvate or pharmaceutically acceptable salt thereof:

[0061]

[0062] wherein, Y 4 is selected from C or NR c ; Y 3 is selected from C, S or NR c’ , and the R c’ is selected from hydrogen or C 1 -C 6 alkyl;

[0063] R 5 is selected from a pyrazole, pyridine or pyrimidine ring, and the pyrazole, pyridine or pyrimidine may be optionally substituted by one or more halogens, C 1 -C 6 alkoxy or C 3 -C 8 cycloalkyl;

[0064] W is selected from -NR f - or -O-;

[0065] R c is selected from C 1-6 alkyl;

[0066] R d and R e are each independently selected from hydrogen, deuterium, halogen, cyano, amino, carboxyl, nitro, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3- to 10-membered heterocyclic group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1-C 6 alkylthio, C 1 -C 6 alkylamino, C 1-6 alkylsulfonyl or R d , R e together with the respective connected C atom form C 3 -C 8 cycloalkyl, 3- to 10-membered heterocyclic group; the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3- to 10-membered heterocyclic group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1-6 alkylsulfonyl or R d , R e forms with the connected carbon atom C 3 -C 8 cycloalkyl, 3- to 10-membered heterocyclic group optionally substituted by one or more hydrogen, deuterium, halogen, cyano, amino, carboxyl, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3- to 10-membered heterocyclic group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino or C 1-6 alkylsulfonyl substituted;

[0067] R f is selected from hydrogen or C 1-6 alkyl, the C 1-6 alkyl may be optionally substituted by one or more deuterium.

[0068] In some embodiments, the compound has a structure shown by the following formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) or (Vh), and its prodrug, isomer, solvate or pharmaceutically acceptable salt thereof:

[0069]

[0070] Wherein, X is selected from C or N; W is selected from -NR f -, or -O-;

[0071] R 2 is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;

[0072] R 5 is selected from pyrazole, pyridine, pyrimidine or imidazole, and the pyrazole, pyridine, pyrimidine or imidazole may optionally be further substituted by one or more R b substituents;

[0073] R a is selected from hydrogen, halogen, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkyl or a 4- to 6-membered heterocyclic group, and the C 1 -C 6 alkyl or the 4- to 6-membered heterocyclic group is optionally further substituted by 0 to 4 substituents selected from deuterium or halogen;

[0074] R b is selected from hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 6 alkoxy, and the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 6 alkoxy is optionally further substituted by 0 to 4 substituents selected from deuterium or halogen;

[0075] R d and R e are each independently selected from hydrogen, deuterium, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is optionally further substituted by one or more substituents selected from deuterium or halogen;

[0076] Alternatively, R d , R e together with the carbon atom to which it is attached form a C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclic group, and the C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclic group may optionally be further substituted by one or more substituents selected from deuterium or halogen;

[0077] R c and R f are each independently selected from hydrogen, deuterium, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, and the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl may optionally be further substituted by one or more substituents selected from deuterium or halogen.

[0078] In some embodiments, the compound is a compound having a structure shown in the following formula (VIa), (VIb), (VIc), (VId), (VIe) or (VIf), and its prodrug, isomer, solvate or pharmaceutically acceptable salt thereof:

[0079]

[0080] wherein the definitions of X, W, R c , R d , R e and R 2 are as described in general formulas (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) or (Vh).

[0081] In some embodiments, R 2 is selected from hydrogen.

[0082] In some embodiments, R a is selected from hydrogen, halogen, -CF 3 , -CHF 2 , -SO 2 CH 3 or R b is selected from hydrogen, halogen, hydroxyl, methyl, isopropyl, cyclopropyl, -OCH 3 , -OCF 3 , -OCHF 2 or R c is selected from hydrogen, methyl or isopropyl.

[0083] In some embodiments, W is selected from -NR f -, where R f is independently selected from hydrogen, deuterium, methyl, ethyl, -CD 3 , -CHF 2 or -CH 2 CF 3 .

[0084] In some embodiments, R d , R e are each independently selected from hydrogen, deuterium, methyl, -CF 3 or -CHF 2 ; or, R d , R e together with the carbon atom to which they are attached form cyclopropyl.

[0085] In some embodiments, the compounds of the present invention, their prodrugs, isomers, solvates or pharmaceutically acceptable salts thereof, are selected from the following structures:

[0086]

[0087]

[0088]

[0089]

[0090] On the other hand, the present invention provides a pharmaceutical composition comprising at least one compound of formula (II-1), (II-2), (III), (IV), (IIIa), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (VIa), (VIb), (VIc), (VId), (VIe) or (VIf) as described above, its prodrug, isomer, solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0091] In yet another aspect, the present invention provides the use of a compound of formula (II-1), (II-2), (III), (IV), (IIIa), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (VIa), (VIb), (VIc), (VId), (VIe) or (VIf) as described above, its prodrug, isomer, solvate or pharmaceutically acceptable salt thereof, or its pharmaceutical composition, in the preparation of a drug for preventing and / or treating USP1-mediated diseases or disorders and related diseases or disorders.

[0092] In another aspect, the present invention also provides a compound represented by formula (II-1), (II-2), (III), (IV), (IIIa), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (VIa), (VIb), (VIc), (VId), (VIe) or (VIf) as described above, and its prodrug, isomer, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing and / or treating USP1-mediated diseases or disorders and related diseases or disorders.

[0093] In another aspect, the present invention also provides a method for preventing and / or treating a disease, comprising administering to a patient in need an effective amount of a compound represented by formula (II-1), (II-2), (III), (IV), (IIIa), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (VIa), (VIb), (VIc), (VId), (VIe) or (VIf) as described above, and its prodrug, isomer, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; the disease to be prevented and / or treated is a USP1-mediated disease or disorder and related diseases or disorders.

[0094] In some embodiments, the USP1-mediated diseases or disorders and related diseases or disorders are selected from inflammatory diseases or diseases accompanied by an inflammatory response or cancer diseases;

[0095] The inflammatory diseases or diseases accompanied by an inflammatory response include, but are not limited to, liver fibrosis, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, inflammatory arthritis, gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis, myelodysplastic syndrome, thrombocytopenia, atherosclerosis, type I and type II diabetes and related complications (such as heart failure, retinopathy, diabetic foot), peripheral arterial disease, acute heart failure and hypertension, lupus nephritis, hypertensive nephropathy, acute kidney injury, chronic nephritis, colitis, polymyositis, chronic migraine, neuropathic pain, multiple sclerosis, acne, hidradenitis suppurativa, seborrheic dermatitis, Schnitzler syndrome, systemic lupus erythematosus, psoriasis, dry eye disease, COVID-19 infection and cytokine release syndrome, chronic obstructive pulmonary disease, acute lung injury, bronchitis, asthma, sarcoidosis or cryopyrin-associated periodic syndrome, etc.;

[0096] The cancer diseases include, but are not limited to, cholangiocarcinoma, colorectal cancer, esophageal cancer, liver cancer, kidney cancer, gastric cancer, head and neck squamous cell carcinoma, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), acute B-lymphoblastic leukemia, bladder cancer, pancreatic cancer, osteosarcoma, myeloma, glioma, ovarian cancer, skin cancer, breast cancer, etc.

[0097] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commodity or its active ingredient.

[0098] In the present invention It means that the bond on the ring can be a single bond or a double bond. For example, when When N=N between N and NRc, then Rc may not exist. including, but not limited to, the following situations:

[0099] The "compound" described in the present invention includes, but is not limited to, the following situations of the compound: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, prodrug (ester), etc.

[0100] The "compound" described in the present invention may be asymmetric. For example, it has one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms in the present invention can be isolated in optically active pure form or racemic form. The optically active pure form can be obtained by methods such as resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0101] In the present invention, "isomer" means, unless otherwise specified, including stereoisomers or tautomers. Unless otherwise specified, the term "stereoisomer" refers to a compound having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include, but are not limited to, enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and atropisomers. Any mixture of the resulting stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization. Unless otherwise specified, the term "tautomer" refers to structural isomers that can be interconverted through a low energy barrier with different energies. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons.

[0102] "Pharmaceutically acceptable salts" in the present invention refer to salts of the compounds of the present invention, which are formed by the compounds with specific substituents found in the present invention and one of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxynaphthalene, hydroxyethanesulfonic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid; or when containing relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium salts, ammonium, or organic amines. For example: alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkanesulfonates, arylsulfonates, organic acid salts, amino acid salts, etc.

[0103] "Prodrug" in the present invention means that the prodrug of the compound of the present invention can be easily chemically changed under physiological conditions to convert into the compound of the present invention. In addition, the prodrug can be converted into the compound of the present invention by chemical or biochemical methods in the in vivo environment.

[0104] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, preferably fluorine, chlorine, or bromine.

[0105] The term "oxo group" means that two hydrogen atoms at the same substitution position are replaced by the same oxygen atom to form a double bond, i.e., =O.

[0106] The term "alkyl group" refers to a straight-chain or branched-chain saturated hydrocarbon group composed of carbon atoms and hydrogen atoms, such as C 1-6 alkyl groups, including but not limited to methyl, ethyl, propyl (including n-propyl, isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), hexyl (n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl), etc.

[0107] The term "alkenyl group" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. For example, "C 2-6 alkenyl" means that the group is an alkenyl group and the number of carbon atoms in the carbon chain is between 2 and 6 (i.e., 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include but are not limited to vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, etc.

[0108] The term "alkynyl group" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. For example, "C 2 -C 6 alkynyl" means that the group is an alkynyl group and the number of carbon atoms in the carbon chain is between 2 and 6 (i.e., 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl groups include but are not limited to ethynyl, 1-propynyl, 1-butynyl, 1,3-butadiynyl, 1-pentynyl, 3-methyl-1-butynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 3,3-dimethyl-1-butynyl, 3-ethyl-1-butynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 3-methyl-1,4-pentadiynyl, 1,5-hexadiynyl, etc.

[0109] The term "cycloalkyl group" refers to a monocyclic alkyl group composed of carbon atoms and hydrogen atoms, such as C 3 -C 8 cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0110] The term "alkoxy group" refers to a straight-chain or branched-chain alkyl group connected through an oxygen atom, such as C 1 -C 6Alkoxy groups, including but not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, tert-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy, neopentyloxy), hexyloxy (n-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 2,3-dimethylbutoxy, 2,2-dimethylbutoxy), etc.

[0111] The term "alkylthio" refers to a straight-chain or branched-chain alkyl group linked through a sulfur atom, i.e., -S-alkyl, such as C 1 -C 6 Alkylthio groups, including but not limited to methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, neopentylthio), hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, 2,2-dimethylbutylthio), etc.

[0112] The term "alkylsulfonyl" refers to a straight-chain or branched-chain alkyl group linked through a sulfonyl group, i.e., -SO 2 -alkyl, such as C 1 -C 6 Alkylsulfonyl groups, including but not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl (including n-propylsulfonyl and isopropylsulfonyl), butylsulfonyl (including n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl), pentylsulfonyl (including n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl), hexylsulfonyl (n-hexylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 2,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl), etc.

[0113] The term "alkylamino" refers to an open-chain alkyl group containing a nitrogen atom, including mono-substituted alkylamino and di-substituted alkylamino, such as C 1-6 Alkylamino groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0114] The term "heteroalkyl" refers to a stable straight-chain or branched-chain hydrocarbon group composed of the specified number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si, and S, and wherein the N and S atoms may optionally be oxidized and the N heteroatom may optionally be quaternized. The heteroatoms O, N, and S may be located at any internal position of the heteroalkyl group. The heteroatom Si may be located at any position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule. "Heteroalkyl" may contain up to three units of unsaturation and also includes mono- and poly-halogenated variants, or combinations thereof. Examples include -CH 2 -CH 2 -O-CH 3 ,-CH 2 -CH2 -O-CF 3 ,-CH 2 -CH 2 -NH-CH 3 ,-CH 2 -CH 2 -N(CH 3 )-CH 3 ,-CH 2 -S-CH 2 -CH 3 ,-S(O)-CH 3 ,-CH 2 -CH 2 -S(O) 2 -CH 3 ,-CH=CH-O-CH 3 and -Si(CH 3 ) 3 。Up to two heteroatoms can be consecutive, such as -CH 2 -NH-OCH 3 、-CH 2 -CH=N-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 。

[0115] The term "aryl" refers to a monocyclic or fused polycyclic all-carbon group having a conjugated π-electron system, wherein the ring of the monocyclic group is aromatic and at least one of the fused rings containing a bicyclic or tricyclic group is aromatic, such as tetrahydronaphthyl. Examples of aryl also include phenyl, naphthyl and similar groups. The aryl is optionally substituted with one or more (such as 1 to 3) identical or different substituents (such as halogen, OH, CN, NO 2 , C 1-4 alkyl).

[0116] The term "heterocyclic group" refers to a monocyclic or polycyclic (such as fused-ring, spiro or bridged-ring) group having 2 or more (such as 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms and one or more (such as 1, 2, 3 or 4) heteroatoms selected from O, N or S, and the carbon atoms and heteroatoms on the heterocyclic group are optionally oxo-substituted (such as forming C=O, S(=O) or S(=O) 2 ). Examples of heterocyclic groups include piperazinyl, pyrrolidinyl, dioxanyl, dithianyl, thiomorpholinyl, morpholinyl, tetrahydrofuryl, pyrrolidinyl-fused cyclopropyl, cyclopentyl-fused aziridinyl, pyrrolidinyl-fused cyclobutyl, pyrrolidinyl-fused pyrrolidinyl, pyrrolidinyl-fused piperidinyl, pyrrolidinyl-fused piperazinyl, etc.

[0117] The term "heteroaryl" refers to a monocyclic or polycyclic aromatic group containing one or more (e.g., 1, 2, 3, or 4) identical or different heteroatoms, including monocyclic heteroaryl and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, or 10 ring atoms. The heteroatoms may be oxygen, nitrogen, or sulfur. The carbon atoms and heteroatoms on the heteroaryl are optionally oxo-substituted (e.g., to form C=O, S(=O), or S(=O) 2 ). And the ring containing the monocyclic group is aromatic and at least one of the fused rings containing the bicyclic or tricyclic group is aromatic (but not necessarily a ring containing a heteroatom), such as Examples of heteroaryl also include, but are not limited to, pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl.

[0118] The term "pharmaceutical composition" refers to a mixture composed of one or more compounds of the present application or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present application to an organism.

[0119] In the present invention, "a", "one", "the", "at least one", and "one or more" are used interchangeably. Thus, for example, a mixture composed of "a" pharmaceutically acceptable excipient can be interpreted to mean that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0120] The term "pharmaceutically acceptable excipient" refers to those excipients that have no obvious irritating effect on an organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well-known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0121] The pharmaceutical composition of the present invention can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols, etc.

[0122] The administration routes of the compounds of the present invention, their prodrugs, isomers, solvates, or their pharmaceutically acceptable salts, or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0123] The term "treatment" generally refers to obtaining the desired pharmacological and / or physiological effect. The effect can be therapeutic according to partial or complete stabilization or cure of the disease and / or side effects resulting from the disease. "Treatment" as used herein encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

[0124] The term "effective amount" means the amount of the compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present application constituting a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0125] The present invention also provides a method for preparing a compound of formula (II-1), (II-2), (III), or (IV), which is prepared by the following steps, including but not limited to the following methods:

[0126] Preparation Route 1: Preparation of Compounds of Series II and III

[0127]

[0128] Compound I-a and compound I-b undergo a substitution reaction to obtain compound II-1-a, and compound II-1-a reacts with R 5 B(OH) 2 or R 5 Bpin through Suzuki coupling to obtain compounds of series II-1A, and compounds of series II-1A undergo methylation substitution to obtain compounds of series II-1B. Compound I-a respectively undergoes the above similar steps with compound I-c and compound I-d to obtain compounds of series II-2A, II-2B, IIIA, and IIIB.

[0129] Wherein, R 1 , R 5 , R a , R c , R d , R e , X, Y 1 , Y 2 , Y 3 , Y 4 , Y 5The definitions of and Cy are as described in General Formulas (II-1), (II-2), (III), or (IV). Compounds 2 to 4 and 6 to 15 were synthesized according to this preparation route.

[0130] Preparation Route 2: Preparation of Compounds in Series II to IV

[0131]

[0132] In addition, Compound I-e can also react with I-f through a substitution reaction to obtain Compound II-1-a, and Compound II-1-a reacts with R 5 B(OH) 2 or R 5 Bpin through Suzuki coupling to obtain Compounds in Series II-1A. Compound I-e reacts with Compound I-g, Compound I-h, and Compound I-i respectively through the above similar steps to obtain Compounds in Series II-2A, IIIA, and IVA. Compounds II-1A, II-2A, and IIIA are respectively subjected to methylation substitution to obtain Compounds in Series II-1B, II-2B, and IIIB.

[0133] Among them, R 1 , R 5 , R a , R c , X, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 and the definitions of Cy are as described in General Formulas (II-1), (II-2), (III), or (IV). Compounds 1 and 5 were synthesized according to this preparation route.

[0134] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0135] Based on the target design of USP1 inhibitors, the present invention has developed multiple series of nitrogen-containing heterocyclic derivatives with novel structures. Relevant biological tests have shown that: the relevant compounds have good inhibitory effects on USP1 activity, among which when , the compounds of the present invention significantly inhibit cell proliferation and USP1 / UAF1 enzyme activity, and the compounds have low hERG toxicity and stable metabolism in human liver microsomes; especially when when When, the compounds of the present invention exhibit good pharmacokinetic properties, synergistic effects when combined with olaparib, and show good anti-tumor activity in a mouse breast cancer xenograft model. In addition, the synthetic route of the compounds provided by the present invention is novel, safe, environmentally friendly, and has good production feasibility. Detailed Embodiments

[0136] The following are specific examples of the present invention to further describe the technical solutions of the present invention, but the protection scope of the present invention is not limited to these examples. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0137] In addition, all operations involving raw materials that are prone to oxidation or hydrolysis are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are commercially available raw materials and can be used directly without further purification.

[0138] The starting materials and common intermediates involved in the examples of the present invention can be obtained commercially or prepared by oneself. The preparation processes of the starting materials and common intermediates that need to be prepared by oneself are described in detail below.

[0139] The following abbreviations are used in the examples: HNMR: Proton Nuclear Magnetic Resonance; NaH: Sodium Hydride; THF: Tetrahydrofuran; K 2 CO 3 : Potassium Carbonate; Pd(dppf)Cl 2 : Dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II); H 2 O: Water; N 2 : Nitrogen; NH 4 Cl: Ammonium Chloride; EA: Ethyl Acetate; PE: Petroleum Ether; NaCl: Sodium Chloride; Na 2 SO 4 : Sodium Sulfate; DCM: Dichloromethane; MeOH: Methanol; MeI: Methyl Iodide; DMF: N,N-Dimethylformamide; Cs 2 CO 3 : Cesium Carbonate; ACN: Acetonitrile; n-BuLi: n-Butyllithium; Cu(OAc) 2 : Copper(II) Acetate; O 2 : Oxygen; Na 2 CO 3 : Sodium Carbonate; DCE: 1,2-Dichloroethane; Bpy: 2,2'-Bipyridine; LDA: Lithium Diisopropylamide; DIPEA: N,N-Diisopropylethylamine; NaOH: Sodium Hydroxide; H 2 O 2 : Hydrogen Peroxide; Pd(PPh 3 ) 4: Palladium (tetrakis(triphenylphosphine)); KOAc: Potassium acetate; PE: Petroleum ether; NaBH 4 : Sodium borohydride; NaOAc: Sodium acetate; HCl: Hydrogen chloride; NaHCO 3 : Sodium bicarbonate; DIAD: Diisopropyl azodicarboxylate; PPh 3 : Triphenylphosphine; POCl 3 : Phosphorus oxychloride; LiAlD 4 : Lithium aluminum deuteride; CD 3 I: Iodomethane-d; EtI: Iodoethane; I 2 : Iodine; KOH: Potassium hydroxide; MeMgBr: Methylmagnesium bromide; DMP: 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one; Ti(OiPr) 4 : Tetraisopropyl orthotitanate; NaBH 4 : Sodium borohydride; CeCl 3 : Cerium chloride; LiAlH 4 : Lithium aluminum hydride; PBr 3 : Phosphorus tribromide; TEA: Triethylamine; DMSO: Dimethyl sulfoxide; PtO 2 : Platinum(IV) oxide; n-BuOH: n-Butanol; NMP: N-Methylpyrrolidone; CO 2 : Carbon dioxide; tBu: tert-Butyl; HFIP: 1,1,1,3,3,3-Hexafluoro-2-propanol; LiHMDS: Lithium bis(trimethylsilyl)amide; NH 3 ·H 2 O: Ammonia solution; TsOH·H 2 O: p-Toluenesulfonic acid monohydrate; t-BuOK: Potassium tert-butoxide; TMSCF 3 : Trimethyl(trifluoromethyl)silane; OD: Optical density; x mL×y: y times, x mL each time; LC-MS: Liquid chromatography - mass spectrometry.

[0140] Preparation of common intermediate INT1

[0141]

[0142] Step 1: Synthesis of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (INT1-2)

[0143] 3,3-Dibromo-1,1,1-trifluoropropan-2-one (3.10 g, 11.49 mmol), anhydrous NaOAc (0.95 g, 37.06 mmol) and water (6 mL) were successively added to a flask, and the mixture was reacted at 100 °C for 1 hour. Compound INT1-1 (1.70 g, 10.34 mmol), ammonia water (11 mL) and methanol (47 mL) were mixed and added, and the mixture was stirred at room temperature for 0.5 hour, and then heated to 100 °C and reacted for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The reaction mixture was diluted with water (30 mL), extracted with EA (50 mL×3), and the combined organic phases were washed once with saturated NaCl (50 mL), and anhydrous Na 2 SO 4 dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (20% - 50% EA: petroleum ether), and then purified by trituration with a mixed solvent of EA (5 mL) and petroleum ether (30 mL) to obtain compound INT1-2 (1.62 g) with a yield of 58.0%.

[0144] LC-MS (m / z): 271.0 [M+H] + 。

[0145] Step 2: Synthesis of methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (INT1-3)

[0146] Compound INT1-2 (1.09 g, 4.05 mmol), Cs 2 CO 3 (3.96 g, 12.16 mmol) and 2-iodopropane (0.61 mL, 6.08 mmol) were successively added to a flask, ACN (15 mL) was added, and the mixture was reacted at room temperature for 3 days. The mixture was filtered, the filtrate was concentrated, and purified by column chromatography (0 - 10% EA: petroleum ether) to obtain compound INT1-3 (952.0 mg) with a yield of 75.3%.

[0147] LC-MS (m / z): 313.0 [M+H] + 。

[0148] Step 3: Synthesis of (4-(1-isopropyl-4-trifluoromethyl-1H-imidazol-2-yl)phenyl)methanol (INT1-4)

[0149] Compound INT1-3 (952.0 mg, 3.05 mmol) was dissolved in anhydrous THF (20 mL), and under an ice-water bath, LiAlH 4 (580.0 mg, 15.26 mmol) was slowly added, and the mixture was reacted at room temperature for 0.5 hour. The reaction solution was under an ice-water bath, and saturated Na 2 CO3 (2 mL) was quenched, filtered, and the filter cake was rinsed with DCM (20 mL). The filtrate was concentrated and purified by column chromatography (DCM:MeOH = 9:1) to obtain compound INT1-4 (730.0 mg) with a yield of 84.3%.

[0150] LC-MS (m / z): 285.0 [M+H] + 。

[0151] Step 4: Synthesis of 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (INT1)

[0152] Compound INT1-4 (3.73 g, 13.10 mmol) was added to a flask, and ultra-dry THF (40 mL) was added. PBr 3 (8.87 g, 32.77 mmol) was slowly added at 0 °C, and the reaction was carried out at room temperature for 1 hour. It was quenched with an appropriate amount of saturated NaHCO 3 solution at 0 °C, filtered through diatomaceous earth, the filtrate was diluted with water (30 mL), extracted with EA (70 mL × 3), the combined organic phases were washed with saturated NaCl (30 mL), and anhydrous Na 2 SO 4 dried, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EA = 5:1) to obtain compound INT1 (3.79 g) with a yield of 82.3%.

[0153] LC-MS (m / z): 347.0 / 349.0 [M+H] + 。

[0154] Preparation of common intermediate INT2

[0155]

[0156] Step 1: Synthesis of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (INT2-2)

[0157] To the flask, 3,3-dibromo-1,1,1-trifluoropropan-2-one (22.86 g, 84.72 mmol), anhydrous NaOAc (7.02 g, 85.58 mmol) and water (40 mL) were added successively, and the reaction was carried out at 100 °C for 1 hour. After the system was cooled to room temperature, INT2-1 (10.00 g, 72.28 mmol), ammonia water (60 mL) and methanol (300 mL) were mixed and added, stirred at room temperature for 1 hour, and then reacted at 100 °C for 16 hours. After the system was cooled to room temperature, the reaction solution was concentrated by distillation under reduced pressure. The reaction mixture was diluted with water (100 mL), extracted with EA (300 mL × 3), the combined organic phases were washed with saturated NaCl (200 mL), and anhydrous Na 2 SO 4 dried, filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:EA = 5:1) to obtain compound INT2-2 (15.89 g), with a yield of 87.9%.

[0158] LC-MS (m / z): 238.0 [M+H] + 。

[0159] Step 2: Synthesis of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (INT2-3)

[0160] To the flask, compound INT2-2 (15.89 g, 66.99 mmol), Cs 2 CO 3 (65.5 g, 201.03 mmol) and 2-iodopropane (57.00 g, 335.29 mmol) were added successively, DMF (160 mL) was added, and the reaction was carried out at 60 °C for 16 hours. After the system was cooled to room temperature, the reaction mixture was diluted with water (100 mL), extracted with EA (300 mL × 3), the combined organic phases were washed with saturated NaCl (200 mL × 3), and anhydrous Na 2 SO 4 dried, filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:EA = 5:1) to obtain compound INT2-3 (12.38 g), with a yield of 66.2%.

[0161] LC-MS (m / z): 280.0 [M+H] + 。

[0162] Step 3: Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (INT2)

[0163] Compound INT2-3 (12.38 g, 44.33 mmol) was added to a flask, and ultradry THF (130 mL) was added. Lithium aluminum hydride (8.50 g, 224.00 mmol) was slowly added at 0 °C, and the reaction was carried out at room temperature for 0.5 h. It was quenched with saturated Na 2 CO 3 solution at 0 °C, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound INT2 (10.45 g) with a yield of 83.2%.

[0164] LC-MS (m / z): 284.0 [M+H] + 。

[0165] Preparation of common intermediate INT3

[0166]

[0167] Step 1: Synthesis of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (INT3-1)

[0168] Compound INT2-2 (4.24 g, 17.89 mmol) was dissolved in acetonitrile (50 mL), and Cs 2 CO 3 (17.49 g, 53.68 mmol) and MeI (3.81 g, 26.84 mmol) were added successively, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EA = 5:1) to obtain compound INT3-1 (3.36 g) with a yield of 74.7%.

[0169] LC-MS (m / z): 252.0 [M+H] + 。

[0170] Step 2: Synthesis of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (INT3)

[0171] Compound INT3-1 (3.36 g, 13.36 mmol) was added to a flask, and ultradry THF (40 mL) was added. LiAlH 4 (1.53 g, 40.32 mmol) was slowly added at 0 °C, and the reaction was carried out at room temperature for 1 h. It was quenched with an appropriate amount of saturated Na 2 CO 3 solution at 0 °C, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound INT3 (3.02 g) with a yield of 88.4%.

[0172] LC-MS (m / z): 256.0 [M+H] + 。

[0173] Preparation of common intermediate INT4

[0174]

[0175] Step 1: Synthesis of 1-(pyridin-2-yl)piperidine-4-carbonitrile (INT4-2)

[0176] In a sealed tube, dissolve compound INT4-1 (2.00 g, 18.14 mmol) in DMSO (12 mL), add 2-chloropyridine (2.06 g, 18.15 mmol) and TEA (3.68 g, 36.37 mmol) successively, and place it at 150 °C for reaction for 16 hours. After the system cools to room temperature, dilute the reaction mixture with water (20 mL), extract with EA (30 mL×3), combine the organic phases, wash with saturated NaCl (20 mL), and dry over anhydrous Na 2 SO 4 Dry, filter. Concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (petroleum ether:EA = 8:1) to obtain compound INT4-2 (805.0 mg) with a yield of 23.7%.

[0177] LC-MS (m / z): 188.0 [M+H] + 。

[0178] Step 2: Synthesis of (1-(pyridin-2-yl)piperidin-4-yl)methanamine (INT4)

[0179] Add compound INT4-2 (805 mg, 4.30 mmol) to a flask, add ultra-dry THF (10 mL), and slowly add LiAlH 4 (490 mg, 12.91 mmol) under an ice-water bath, and react at room temperature for 1 hour. Quench with saturated Na 2 CO 3 solution under an ice-water bath, filter it through diatomaceous earth, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (DCM:MeOH = 10:1) to obtain compound INT4 (707.0 mg) with a yield of 86.0%.

[0180] LC-MS (m / z): 192.0 [M+H] + 。

[0181] Preparation of common intermediate INT5

[0182]

[0183] Step 1: Synthesis of 2-(4-(Chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (INT5)

[0184] Dissolve compound INT1-4 (730.0 mg, 2.57 mmol) in DCM (10 mL), add SOCl 2 (0.56 mL, 7.71 mmol), and place it at room temperature for reaction for 4 hours. Quench the reaction solution with saturated NaHCO 3 , dilute it with DCM (20 mL), wash it with water (20 mL) and saturated NaCl solution (20 mL), and dry it with anhydrous Na 2 SO 4 . Filter, and concentrate the filtrate under reduced pressure to obtain compound INT5 (657.0 mg) with a yield of 84.4%.

[0185] LC-MS (m / z): 303.0 [M+H] + .

[0186] Preparation of common intermediate INT6

[0187]

[0188] Step 1: Synthesis of methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (INT6-1)

[0189] Dissolve compound INT1-2 (6.32 g, 23.40 mmol) and MeI (7.28 mL, 117.0 mmol) in ACN (230 mL), add Cs 2 CO 3 (15.20 g, 46.8 mmol), and place it at room temperature for reaction for 16 hours. Filter the reaction solution, wash the filter cake with EA, and concentrate the filtrate to dryness. Purify the residue by column chromatography (EA: petroleum ether = 3:7) to obtain INT6-1 (5.90 g) with a yield of 88.8%.

[0190] LC-MS (m / z): 285.0 [M+H] + .

[0191] Step 2: Synthesis of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (INT6-2)

[0192] Dissolve compound INT6-1 (5.90 g, 20.77 mmol) in anhydrous THF (60 mL), and slowly add LiAlH 4(1.25 g, 31.7 mmol) was placed at room temperature for reaction for 4 hours. The reaction solution was placed back in an ice-water bath, and quenched with saturated Na 2 CO 3 aqueous solution (4 mL), filtered, and the filter cake was rinsed with DCM. The filtrate was concentrated to dryness under reduced pressure to obtain the crude product of compound INT6-2 (5.42 g), which was directly used for the next step.

[0193] LC-MS (m / z): 257.0 [M+H] + .

[0194] Step 3: Synthesis of 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (INT6)

[0195] The crude product of compound INT6-2 (5.42 g) was dissolved in DCM (54 mL), and thionyl chloride (12.0 mL, 0.17 mol) was slowly added dropwise under an ice-water bath, and the mixture was placed at room temperature for reaction for 1 hour. The reaction solution was quenched with saturated NaHCO 3 aqueous solution (20 mL), the organic phase was separated and washed with saturated brine (30 mL), and dried with anhydrous Na 2 SO 4 . The filtrate was concentrated under reduced pressure to obtain INT6 (3.54 g), and the two-step yield was 56.0%.

[0196] LC-MS (m / z): 275.0 [M+H] + .

[0197] Example 1: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one (1)

[0198]

[0199] Step 1: Synthesis of (2-chloropyrido[3,2-d]pyrimidin-4-yl)glycine methyl ester (1-2)

[0200] Compound 1-1 (0.30 g, 1.50 mmol) and glycine methyl ester hydrochloride (419.0 mg, 3.00 mmol) were dissolved in THF (8 mL), DIPEA (1.0 mL, 6.00 mmol) was added, and the mixture was placed at room temperature for reaction for 3 hours. The reaction solution was concentrated, and purified by column chromatography (0 - 50% EA: petroleum ether) to obtain compound 1-2 (356.0 mg), with a yield of 93.9%.

[0201] LC-MS (m / z): 253.0 [M+H] + 。

[0202] Step 2: Synthesis of 2-chloro-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one (1-3)

[0203] Dissolve compound 1-2 (356.0 mg, 1.41 mmol) in THF (15 mL), add concentrated hydrochloric acid (0.12 mL) and PtO 2 (32.0 mg, 0.14 mmol), and react at room temperature for 48 hours under a hydrogen atmosphere. Filter the reaction solution, concentrate the filtrate, and purify by column chromatography (DCM:MeOH = 9:1) to obtain compound 1-3 (88.0 mg) with a yield of 27.8%.

[0204] LC-MS (m / z): 225.0 [M+H] + 。

[0205] Step 3: Synthesis of 2-chloro-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one (1-4)

[0206] Dissolve compound 1-3 (88.0 mg, 0.39 mmol) and the common intermediate INT1 (205.0 mg, 0.59 mmol) in DMF (5 mL), add K 2 CO 3 (136.0 mg, 0.98 mmol), and react at room temperature for 16 hours. Dilute the reaction solution with EA (20 mL), wash with water (15 mL × 3) and saturated NaCl (15 mL), dry with anhydrous Na 2 SO 4 Filter, concentrate under reduced pressure, and purify by column chromatography (0 - 75% EA:petroleum ether) to obtain compound 1-4 (102.0 mg) with a yield of 53.3%.

[0207] LC-MS (m / z): 491.0 [M+H] + 。

[0208] Step 4: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one (1)

[0209] Weigh compound 1-4 (102.0 mg, 0.21 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (60.5 mg, 0.31 mmol), Pd(PPh 3 ) 4 (24.0 mg, 0.02 mmol) and K 2 CO 3 (72.0 mg, 0.52 mmol) separately, add dioxane (8 mL) and water (0.8 mL), place it under nitrogen protection, and react at 100 °C in a microwave for 1 hour. Concentrate the reaction solution, purify it by column chromatography (0-100% EA: petroleum ether), and obtain compound 1 (17.2 mg) with a yield of 13.7%.

[0210] LC-MS (m / z): 605.0 [M+H] + 。

[0211] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 8.20 - 8.15 (m, 1H), 7.56 - 7.46 (m, 4H), 4.83 (s, 2H), 4.50 - 4.40 (m, 1H), 4.20 (s, 2H), 3.86 (s, 3H), 3.85 - 3.77 (m, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.02 - 1.93 (m, 2H), 1.84 - 1.74 (m, 1H), 1.40 (d, J = 6.4 Hz, 6H), 1.05 - 0.97 (m, 2H), 0.89 - 0.79 (m, 2H).

[0212] Example 2: Preparation of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyridazin-3(2H)-one (2)

[0213]

[0214] Step 1: Synthesis of 6-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyridazin-3(2H)-one (2-2)

[0215] Compound 2-1 (209.0 mg, 1.00 mmol) and common intermediate INT2 (340.0 mg, 1.20 mmol) were dissolved in anhydrous DMSO (10 mL), DIPEA (0.87 mL, 5.00 mmol) was added, and the mixture was placed in a microwave reactor at 150 °C for 45 minutes under nitrogen protection. After the reaction solution cooled to room temperature, it was diluted with EA (50 mL), washed with water (50 mL × 3) and saturated NaCl (50 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 2-2 (250.0 mg) with a yield of 60.8%.

[0216] LC-MS (m / z): 412.0 [M+H] + 。

[0217] Step 2: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyridazin-3(2H)-one (2)

[0218] Weighed compound 2-2 (99.0 mg, 0.24 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (70.0 mg, 0.36 mmol), Pd(PPh 3 ) 4 (28.0 mg, 0.02 mmol) and K 2 CO 3 (83.0 mg, 0.60 mmol) were added to dioxane (10 mL) and water (1 mL), and the mixture was placed in a microwave reactor at 120 °C for 1 hour under nitrogen protection. The reaction solution was concentrated, purified by column chromatography (0 - 100% EA:petroleum ether), and then purified by reverse preparation to obtain compound 2 (25.3 mg) with a yield of 20.1%.

[0219] LC-MS (m / z): 526.0 [M+H] + 。

[0220] 1 H NMR (400 MHz, DMSO-d 6)δ 12.81 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.68 - 7.50 (m, 3H), 7.47 (d, J = 8.0 Hz, 2H), 6.13 (s, 1H), 4.56 - 4.33 (m, 3H), 3.76 (s, 3H), 1.92 - 1.80 (m, 1H), 1.40 (d, J = 6.4 Hz, 6H), 0.99 - 0.91 (m, 2H), 0.86 - 0.77 (m, 2H).

[0221] Example 3: Synthesis of 6-(4 - cyclopropyl - 6 - methoxypyrimidin - 5 - yl)-4-((4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)benzyl)amino)-2 - methylpyridazin - 3(2H)-one (3)

[0222]

[0223] Step 1: Synthesis of 6 - chloro - 4-((4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)benzyl)amino)-2 - methylpyridazin - 3(2H)-one (3 - 2)

[0224] To the flask were successively added compound 3 - 1 (250.0 mg, 1.12 mmol), common intermediate INT2 (380.4 mg, 1.34 mmol) and DIPEA (1.45 g, 11.22 mmol). Ultra - dry DMSO (10 mL) was added, and the mixture was subjected to microwave reaction at 150 °C for 45 minutes. After the reaction was completed, the reaction mixture was diluted with water (20 mL), extracted with EA (40 mL × 3), the combined organic phases were washed with saturated NaCl (40 mL), and dried over anhydrous Na 2 SO 4 dried, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 3 - 2 (377.0 mg) with a yield of 79.2%.

[0225] LC - MS (m / z): 426.0 [M + H] + .

[0226] Step 2: Synthesis of 6-(4 - cyclopropyl - 6 - methoxypyrimidin - 5 - yl)-4-((4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)benzyl)amino)-2 - methylpyridazin - 3(2H)-one (3)

[0227] To the flask were successively added compound 3 - 2 (377.0 mg, 0.86 mmol), (4 - cyclopropyl - 6 - methoxypyrimidin - 5 - yl)boronic acid (343.6 mg, 1.77 mmol), K 2 CO3 (367.2 mg, 2.66 mmol), Pd(dppf)Cl 2 (64.8 mg, 0.09 mmol), dioxane (10 mL) and water (2 mL) were added, and the mixture was reacted by microwave at 110 °C for 1 hour. After the reaction, the reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (40 mL), and anhydrous Na 2 SO 4 dried, filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA: petroleum ether = 1:1), freeze-dried to obtain compound 3 (405.0 mg), with a yield of 84.9%.

[0228] LC-MS (m / z): 540.0 [M+H] + 。

[0229] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (s, 1H), 8.20 - 8.12 (m, 1H), 7.67 (t, J = 6.4 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.50 - 7.42 (m, 2H), 6.16 (s, 1H), 4.48 (d, J = 6.4 Hz, 2H), 4.46 - 4.41 (m, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 1.90 - 1.81 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 0.99 - 0.92 (m, 2H), 0.86 - 0.78 (m, 2H).

[0230] Example 4: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)(methyl)amino)-2-methylpyridazin-3(2H)-one (4)

[0231]

[0232] Compound 3 (262.0 mg, 0.49 mmol) and ultra-dry DMF (10 mL) were added to a flask. Under a nitrogen atmosphere, NaH (48.7 mg, 1.22 mmol) was added at 0 °C. After stirring for 20 minutes while maintaining the temperature, MeI (139.9 mg, 0.73 mmol) was added, and the mixture was allowed to react for 1 hour. After the reaction, the reaction was quenched with an appropriate amount of saturated ammonium chloride solution under an ice-water bath. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (20 mL × 3), and anhydrous Na 2 SO4 Dry and filter. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA: petroleum ether = 1:1), freeze-dried to obtain Compound 4 (191.2 mg), with a yield of 71.3%.

[0233] LC-MS (m / z): 554.0 [M+H] + 。

[0234] 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.62 (s, 1H), 8.18 (s, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.40 (s, 1H), 5.11 (s, 2H), 4.73 - 4.26 (m, 1H), 3.86 (s, 3H), 3.68 (s, 3H), 2.92 (s, 3H), 2.04 - 1.80 (m, 1H), 1.41 (d, J = 6.6 Hz, 6H), 1.09 - 0.99 (m, 2H), 0.98 - 0.85 (m, 2H).

[0235] Example 5: Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-methoxypyridazin-4-amine (5)

[0236]

[0237] Step 1: Synthesis of 6-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-methoxypyridazin-4-amine (5-2)

[0238] Add Compound 5-1 (50.0 mg, 0.31 mmol) to a flask, add ultra-dry DMF (2 mL), under nitrogen protection, add NaH (31.3 mg, 0.78 mmol) in an ice-water bath. After stirring for 20 minutes at the same temperature, add the common intermediate INT1 (130.6 mg, 0.38 mmol), and raise the temperature to room temperature for reaction for 1 hour. After the reaction is completed, the reaction solution is quenched with saturated ammonium chloride solution in an ice-water bath, diluted with water (10 mL), extracted with EA (30 mL × 3), and the combined organic phases are washed with saturated NaCl (20 mL × 3), anhydrous Na 2 SO 4 Dry and filter. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA: petroleum ether = 1:1) to obtain Compound 5-2 (44.0 mg), with a yield of 33.0%.

[0239] LC-MS (m / z): 426.0 [M+H]+ 。

[0240] Step 2: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-methoxypyridazin-4-amine (5)

[0241] To the flask, add compound 5-2 (44.0 mg, 0.10 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (40.1 mg, 0.21 mmol), K 2 CO 3 (42.9 mg, 0.31 mmol), Pd(dppf)Cl 2 (7.6 mg, 0.01 mmol) successively. Add dioxane (2 mL) and water (0.4 mL). Under nitrogen protection, react at 110 °C in a microwave for 1 hour. After the reaction is completed, dilute the reaction mixture with water (10 mL), extract with EA (30 mL × 3), combine the organic phases, wash with saturated NaCl (40 mL), dry over anhydrous Na 2 SO 4 dry, and filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (DCM:MeOH = 10:1), then by reverse preparative purification, and lyophilize to obtain compound 5 (15.9 mg), with a yield of 28.5%.

[0242] LC-MS (m / z): 540.0 [M+H] + 。

[0243] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (s, 1H), 8.20 - 8.14 (m, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 6.4 Hz, 1H), 6.55 (s, 1H), 4.49 (d, J = 6.4 Hz, 2H), 4.46 - 4.39 (m, 1H), 4.10 (s, 3H), 3.72 (s, 3H), 1.77 - 1.65 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H), 1.02 - 0.89 (m, 2H), 0.83 - 0.69 (m, 2H).

[0244] Example 6: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purin-6-amine (6)

[0245]

[0246] Step 1: Synthesis of 2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purin-6-amine (6-2)

[0247] Dissolve compound 6-1 (300.0 mg, 1.59 mmol), common intermediate INT2 (509.0 mg, 1.80 mmol), and DIPEA (616.0 mg, 4.77 mmol) in n-BuOH (9 mL), and react in an oil bath at 100 °C for 3 hours. Cool the reaction mixture to room temperature, concentrate it under reduced pressure, and purify it by column chromatography (DCM:MeOH = 10:1) to obtain compound 6-2 (650.0 mg) with a yield of 94.1%.

[0248] LC-MS (m / z): 436.0 [M+H] + 。

[0249] Step 2: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9H-purin-6-amine (6)

[0250] Add compound 6-2 (100.0 mg, 0.23 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (90.0 mg, 0.46 mmol), K 2 CO 3 (96.0 mg, 0.69 mmol), and Pd(dppf)Cl 2 (34.0 mg, 0.05 mmol) to a round-bottom flask, add dioxane (4 mL) and water (0.8 mL), and react in a microwave at 120 °C for 0.5 hours under a nitrogen atmosphere. After the reaction is completed, dilute the reaction mixture with water (10 mL), extract it with EA (30 mL×3), combine the organic phases, wash with saturated NaCl (15 mL), and dry with anhydrous Na 2 SO 4 Filter. Concentrate the filtrate under reduced pressure, purify the residue by column chromatography (DCM:MeOH = 10:1), and then purify it by reverse preparation to obtain compound 6 (30.0 mg) with a yield of 23.8%.

[0251] LC-MS (m / z): 550.0 [M+H] + 。

[0252] 1 H NMR (400 MHz, DMSO-d 6)δ 13.05 (s, 1H), 8.61 (s, 1H), 8.48 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.48 (s, 4H), 4.75 (s, 2H), 4.51 - 4.35 (m, 1H), 3.82 (s, 3H), 1.81 - 1.63 (m, 1H), 1.39 (d, J = 6.4 Hz, 6H), 0.95 (s, 2H), 0.74 (s, 2H).

[0253] Example 7: Synthesis of 2-(4 - cyclopropyl - 6 - methoxypyrimidin - 5 - yl)-N-(4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)benzyl)-9 - methyl - 9H - purin - 6 - amine (7)

[0254]

[0255] Step 1: Synthesis of 2,6 - dichloro - 9 - methyl - 9H - purine (7 - 2)

[0256] Dissolve compound 6 - 1 (567.0 mg, 3.00 mmol) in acetonitrile (8 mL), and successively add K 2 CO 3 (622.0 mg, 4.50 mmol) and MeI (0.22 mL, 3.60 mmol), and react at room temperature for 18 hours. Filter the reaction solution, and wash the filter cake with acetonitrile. Concentrate the filtrate and purify it by column chromatography (0 - 60% EA: petroleum ether) to obtain compound 7 - 2 (376.0 mg) with a yield of 61.7%.

[0257] LC - MS (m / z): 203.0 [M + H] + .

[0258] Step 2: Synthesis of 2 - chloro - N-(4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)benzyl)-9 - methyl - 9H - purin - 6 - amine (7 - 3)

[0259] Add compound 7 - 2 (180.0 mg, 0.88 mmol), common intermediate INT2 (302.0 mg, 1.06 mmol) and DIPEA (0.46 mL, 2.66 mmol) to THF (10 mL), and react at 50 °C for 1 hour. Concentrate the reaction solution under reduced pressure and purify it by column chromatography (0 - 100% EA: petroleum ether) to obtain compound 7 - 3 (284.0 mg) with a yield of 71.7%.

[0260] LC - MS (m / z): 450.0 [M + H] + .

[0261] Step 3: Synthesis of 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-9-methyl-9H-purin-6-amine (7)

[0262] Weigh out compound 7-3 (90.0 mg, 0.20 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (58.0 mg, 0.30 mmol), Pd(PPh 3 ) 4 (23.0 mg, 0.02 mmol) and K 2 CO 3 (69.0 mg, 0.50 mmol) respectively, add dioxane (2 mL) and water (0.2 mL), under nitrogen protection, place it in a microwave and react at 90 °C for 1 hour. Concentrate the reaction solution, and purify the concentrate by reverse preparation to obtain compound 7 (63.6 mg), with a yield of 56.5%.

[0263] LC-MS (m / z): 564.0 [M+H] + 。

[0264] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.62 (s, 1H), 8.57 - 8.48 (m, 1H), 8.19 (s, 1H), 8.19 - 8.13 (m, 1H), 7.56 - 7.38 (m, 4H), 4.87 - 4.66 (m, 2H), 4.52 - 4.33 (m, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 1.79 - 1.62 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H), 1.07 - 0.92 (m, 2H), 0.80 - 0.66 (m, 2H).

[0265] Example 8: Synthesis of 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-methyl-7H-purin-6-amine (8)

[0266]

[0267] Step 1: Synthesis of 2,6-dichloro-7-methyl-7H-purine (8-1)

[0268] Dissolve compound 6-1 (567.0 mg, 3.00 mmol) in acetonitrile (8 mL), and successively add K 2 CO 3(622.0 mg, 4.50 mmol) and MeI (0.22 mL, 3.60 mmol) were placed at room temperature for reaction for 18 hours. The reaction solution was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated and purified by column chromatography (DCM:MeOH = 9:1) to obtain compound 8-1 (179.0 mg) with a yield of 29.4%.

[0269] LC-MS (m / z): 203.0 [M+H] + 。

[0270] Step 2: Synthesis of 2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-methyl-7H-purine-6-amine (8-2)

[0271] Compound 8-1 (179.0 mg, 0.88 mmol), common intermediate INT2 (300.0 mg, 1.06 mmol) and DIPEA (0.50 mL, 2.66 mmol) were added to THF (5 mL), and the mixture was reacted at 50 °C for 4 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 94:6) to obtain compound 8-2 (244.0 mg) with a yield of 61.6%.

[0272] LC-MS (m / z): 450.0 [M+H] + 。

[0273] Step 3: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-methyl-7H-purine-6-amine (8)

[0274] Weigh compound 8-2 (90.0 mg, 0.20 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (58.0 mg, 0.30 mmol), Pd(PPh 3 ) 4 (23.0 mg, 0.02 mmol) and K 2 CO 3 (69.0 mg, 0.50 mmol), add dioxane (2 mL) and water (0.2 mL), under nitrogen protection, react at 100 °C in a microwave for 1 hour. The reaction solution was concentrated, and the concentrate was purified by column chromatography (DCM:MeOH = 9:1), and then purified by reverse preparation to obtain compound 8 (20.2 mg) with a yield of 17.9%.

[0275] LC-MS (m / z): 564.0 [M+H] + 。

[0276] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 7.79 (t, J = 6.0 Hz, 1H), 7.56 - 7.43 (m, 4H), 4.78 (d, J = 6.0 Hz, 2H), 4.54 - 4.35 (m, 1H), 4.13 (s, 3H), 3.79 (s, 3H), 1.73 - 1.59 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H), 0.99 - 0.86 (m, 2H), 0.73 - 0.63 (m, 2H).

[0277] Example 9: Preparation of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)imidazo[1,2-b]pyridazin-8-amine (9)

[0278]

[0279] Step 1: Synthesis of 6-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)imidazo[1,2-b]pyridazin-8-amine (9-2)

[0280] Compound 9-1 (200.0 mg, 0.86 mmol) and the common intermediate INT2 (255.9 mg, 0.90 mmol) were dissolved in n-BuOH (1 mL), and DIPEA (333.4 mg, 2.11 mmol) was added. Under nitrogen protection, the mixture was placed in a microwave and reacted at 150 °C for 30 minutes. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure and purified by column chromatography (0 - 40% EA: petroleum ether) to obtain compound 9-2 (360.0 mg) with a yield of 96.3%.

[0281] LC-MS (m / z): 435.0 [M + H] + .

[0282] Step 2: Synthesis of 6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)imidazo[1,2-b]pyridazin-8-amine (9)

[0283] Compound 9-2 (350.0 mg, 0.79 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (194.0 mg, 1.60 mmol), Pd(PPh 3 ) 4 (98.3 mg, 0.08 mmol) and K2 CO 3 (352.4 mg, 2.3 mmol), dioxane (10 mL) and water (1 mL) were added. Under nitrogen protection, the mixture was placed in a microwave and reacted at 100 °C for 0.5 h. The reaction solution was concentrated and purified by column chromatography (0 - 100% EA: petroleum ether), and then further purified by reverse preparation to obtain compound 9 (74.0 mg) with a yield of 16.7%.

[0284] LC-MS (m / z): 549.0 [M+H] + 。

[0285] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (s, 1H), 8.31 (t, J = 6.4 Hz, 1H), 8.19 - 8.15 (m, 1H), 8.10 - 8.05 (m, 1H), 7.61 - 7.56 (m, 1H), 7.55 - 7.50 (m, 4H), 6.13 (s, 1H), 4.78 - 4.61 (m, 2H), 4.51 - 4.33 (m, 1H), 3.78 (s, 3H), 1.80 - 1.68 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H), 1.02 - 0.93 (m, 2H), 0.85 - 0.73 (m, 2H).

[0286] Example 10: Preparation of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)thiazolo[5,4-d]pyrimidin-7-amine (10)

[0287]

[0288] Step 1: Synthesis of 5-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)thiazolo[5,4-d]pyrimidin-7-amine (10-2)

[0289] Compound 10-1 (66.0 mg, 0.32 mmol) and common intermediate INT2 (100.0 mg, 0.35 mmol) were dissolved in n-BuOH (5 mL), then DIPEA (137.0 mg, 0.96 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction solution was diluted with EA (15 mL), concentrated in vacuo, and purified by column chromatography (0 - 100% EA: petroleum ether) to obtain compound 10-2 (144.0 mg) with a yield of 99.2%.

[0290] LC-MS (m / z): 453.0 [M+H] + 。

[0291] Step 2: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)thiazolo[5,4-d]pyrimidin-7-amine (10)

[0292] Compound 10-2 (144.0 mg, 0.32 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (111.0 mg, 0.57 mmol), K 2 CO 3 (105.0 mg, 0.80 mmol) and Pd(PPh 3 ) 4 (37.0 mg, 0.03 mmol) were added to dioxane (5 mL) and water (0.5 mL), stirred and dissolved, and reacted under microwave at 110 °C for 1 hour. After the reaction solution cooled to room temperature, it was diluted with EA (10 mL), concentrated under reduced pressure, and purified by reverse-phase preparation to obtain compound 10 (40.2 mg), with a yield of 22.3%.

[0293] LC-MS (m / z): 567.0 [M+H] + 。

[0294] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.35 (s, 1H), 9.09 (t, J = 6.4 Hz, 1H), 8.63 (s, 1H), 7.62 - 7.36 (m, 5H), 4.78 (d, J = 6.4 Hz, 2H), 4.47 - 4.39 (m, 1H), 3.83 (s, 3H), 1.75 - 1.66 (m, 1H), 1.39 (d, J = 6.4 Hz, 6H), 1.03 - 0.93 (m, 2H), 0.82 - 0.72 (m, 2H).

[0295] Example 11: Preparation of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (11)

[0296]

[0297] Step 1: Synthesis of 1-methyl-4-nitro-1H-pyrazole-3-carboxamide (11-2)

[0298] A mixture of compound 11-1 (2.0 g, 10.80 mmol) and ammonia / methanol solution (15 mL, 7.0 M) was placed in a sealed tube and reacted at 60 °C for 5 hours. After the reaction solution was cooled to room temperature, the reaction solution was concentrated to obtain the crude product of compound 11-2 (1.87 g), and the product was directly used for the next step without further purification.

[0299] LC-MS (m / z): 171.0 [M+H] + 。

[0300] Step 2: Synthesis of 4-amino-1-methyl-1H-pyrazole-3-carboxamide (11-3)

[0301] The crude product of compound 11-2 (1.87 g) was dissolved in MeOH (20 mL), 10% palladium / carbon (containing 55% water, 200.0 mg) was added, and the reaction was carried out at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product of compound 11-3 (1.53 g), and the product was directly used for the next step without further purification.

[0302] LC-MS (m / z): 141.0 [M+H] + 。

[0303] Step 3: Synthesis of 2-methyl-2,4-dihydro-5H-pyrazolo[4,3-d]pyrimidine-5,7(6H)-dione (11-4)

[0304] The crude product of compound 11-3 (420.0 mg) and urea (1.8 g, 0.03 mol) were dissolved in NMP (5 mL), and the reaction solution was placed at 200 °C for 2 hours. After the reaction solution was cooled to room temperature, it was slurried with methanol (20 mL), filtered, and the filter cake was dried under reduced pressure to obtain the crude product of compound 11-4 (500.0 mg), and the product was directly used for the next step without further purification.

[0305] LC-MS (m / z): 167.0 [M+H] + 。

[0306] Step 4: Synthesis of 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (11-5)

[0307] The crude product of compound 11-4 (500.0 mg) was mixed with phosphorus oxychloride (10 mL), DIPEA (0.5 mL) was added, and the reaction was carried out at 80 °C for 16 hours. The reaction solution was concentrated, the concentrate was diluted with EA (20 mL), and slowly poured into warm water (50 mL). The mixture was adjusted to alkaline with saturated Na 2 CO 3 solution, separated, the aqueous phase was extracted with EA (50 mL), the organic phases were combined, and anhydrous Na2 SO 4 Dry, filter, concentrate under reduced pressure, and purify by column chromatography (0 - 50% EA: petroleum ether) to obtain Compound 11-5 (54.0 mg), with a four-step yield of 7.5%.

[0308] LC-MS (m / z): 203.0 [M+H] + 。

[0309] Step 5: Synthesis of 5-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (11-6)

[0310] Dissolve Compound 11-5 (54.0 mg, 0.27 mmol) and the common intermediate INT2 (90.0 mg, 0.32 mmol) in THF (3 mL), add DIPEA (0.14 mL, 0.80 mmol), and react at 50 °C for 1 hour. Concentrate the reaction solution under reduced pressure and purify by column chromatography (0 - 100% EA: petroleum ether) to obtain Compound 11-6 (75.0 mg), with a yield of 62.7%.

[0311] LC-MS (m / z): 450.0 [M+H] + 。

[0312] Step 6: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (11)

[0313] Weigh 11-6 (75.0 mg, 0.17 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (48.5 mg, 0.25 mmol), Pd(PPh 3 ) 4 (19.0 mg, 0.02 mmol) and K 2 CO 3 (57.0 mg, 0.42 mmol), add dioxane (2 mL) and water (0.2 mL), and under nitrogen protection, react in a microwave at 110 °C for 1 hour. Concentrate the reaction solution and purify by column chromatography (DCM:MeOH = 9:1) to obtain Compound 11 (59.6 mg), with a yield of 63.4%.

[0314] LC-MS (m / z): 564.0 [M+H] + 。

[0315] 11H NMR (400 MHz, DMSO-d 6 ) δ 8.87 (t, J = 6.4 Hz, 1H), 8.59 (s, 1H), 8.37 (s, 1H), 8.18 - 8.13 (m, 1H), 7.52 - 7.43 (m, 4H), 4.75 (d, J = 6.4 Hz, 2H), 4.53 - 4.37 (m, 1H), 4.19 (s, 3H), 3.81 (s, 3H), 1.78 - 1.65 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H), 1.01 - 0.90 (m, 2H), 0.79 - 0.69 (m, 2H).

[0316] Example 12: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N,2-dimethyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (12)

[0317]

[0318] Compound 11 (32.0 mg, 0.06 mmol) was dissolved in ultradry DMF (2 mL). Under a nitrogen atmosphere, NaH (5.7 mg, 0.14 mmol) was added in an ice - water bath. After stirring at the same temperature for 20 minutes, MeI (12.1 mg, 0.09 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride solution in an ice - water bath. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride (20 mL × 3), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 12 (19.3 mg), with a yield of 60.3%.

[0319] LC - MS (m / z): 578.0 [M + H] + .

[0320] 1 1H NMR (400 MHz, DMSO-d 6)δ8.60(s,1H),8.42(s,1H),8.16(s,1H),7.62 - 7.49(m,2H),7.46(d,J=8.0Hz,2H),5.77 - 5.57(m,1H),5.17 - 4.93(m,1H),4.55 - 4.38(m,1H),4.19(s,3H),3.83(s,3H),1.88 - 1.74(m,1H),1.39(d,J=6.4Hz,6H),1.24(s,3H),1.06 - 0.93(m,2H),0.82 - 0.72(m,2H).

[0321] Example 13: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (13)

[0322]

[0323] Step 1: Synthesis of 5-Chloro-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (13-1)

[0324] Dissolve the common intermediate INT3 (60.4 mg, 0.24 mmol) in THF (3 mL), add compound 11-5 (32.0 mg, 0.16 mmol) and DIPEA (101.9 mg, 0.79 mmol), and react at 50 °C for 1 hour. After the system cools to room temperature, the reaction mixture is concentrated under reduced pressure, and the residue is purified by column chromatography (100% EA) to obtain compound 13-1 (36.0 mg) with a yield of 54.1%.

[0325] LC-MS (m / z): 422.0 [M + H] + 。

[0326] Step 2: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (13)

[0327] Add compound 13-1 (36.0 mg, 0.09 mmol), (4-Cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (33.5 mg, 0.17 mmol), K 2 CO 3 (35.4 mg, 0.26 mmol), Pd(dppf)Cl2 (6.3 mg, 0.01 mmol), dioxane (1.5 mL) and water (0.3 mL) were added. Under nitrogen protection, the mixture was placed in a microwave and reacted at 110 °C for 1 hour. After the reaction, the reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated NaCl (40 mL) and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 13 (13.6 mg) with a yield of 29.8%.

[0328] LC-MS (m / z): 536.0 [M+H] + 。

[0329] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.86 (t, J = 6.0 Hz, 1H), 8.58 (s, 1H), 8.37 (s, 1H), 7.91 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 4.74 (d, J = 6.0 Hz, 2H), 4.18 (s, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 1.81 - 1.67 (m, 1H), 1.02 - 0.90 (m, 2H), 0.81 - 0.68 (m, 2H).

[0330] Example 14: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-N-((1-(pyridin-2-yl)piperidin-4-yl)methyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (14)

[0331]

[0332] Step 1: Synthesis of 5-Chloro-2-methyl-N-((1-(pyridin-2-yl)piperidin-4-yl)methyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (14-1)

[0333] The common intermediate INT4 (45.3 mg, 0.24 mmol) was dissolved in THF (3 mL), and compound 11-5 (32.0 mg, 0.16 mmol) and DIPEA (101.9 mg, 0.79 mmol) were added. The mixture was reacted at 50 °C for 1 hour. After the system cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to obtain compound 14-1 (40.0 mg) with a yield of 69.9%.

[0334] LC-MS (m / z): 358.0 [M+H] + 。

[0335] Step 2: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-N-((1-(pyridin-2-yl)piperidin-4-yl)methyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (14)

[0336] To the flask were successively added compound 14-1 (40.0 mg, 0.11 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (43.9 mg, 0.22 mmol), K 2 CO 3 (46.4 mg, 0.34 mmol) and Pd(dppf)Cl 2 (8.2 mg, 0.01 mmol). Dioxane (1.5 mL) and water (0.3 mL) were added, and the mixture was placed in a microwave and reacted at 110 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (40 mL), and dried over anhydrous Na 2 SO 4 . The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 14 (30.6 mg) with a yield of 58.1%.

[0337] LC-MS (m / z): 472.0 [M+H] + 。

[0338] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (s, 1H), 8.31 (s, 1H), 8.29 (t, J = 6.0 Hz, 1H), 8.09 - 8.04 (m, 1H), 7.55 - 7.40 (m, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.62 - 6.46 (m, 1H), 4.25 (d, J = 12.8 Hz, 2H), 4.16 (s, 3H), 3.82 (s, 3H), 3.37 (m, 2H), 2.81 - 2.65 (m, 2H), 2.03 - 1.90 (m, 1H), 1.83 - 1.73 (m, 1H), 1.73 - 1.63 (m, 2H), 1.22 - 1.08 (m, 2H), 1.04 - 0.95 (m, 2H), 0.91 - 0.81 (m, 2H).

[0339] Example 15: Synthesis of 5-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (15)

[0340]

[0341] Step 1: Synthesis of 4-chloro-1-isopropyl-1H-pyrazole (15-2)

[0342] Dissolve compound 15-1 (10.00 g, 97.56 mmol) in ACN (150 mL), and successively add isopropyl iodide (24.90 g, 146.47 mmol) and Cs 2 CO 3 (63.58 g, 195.14 mmol). Under nitrogen protection, react at 80 °C for 2 hours. After the system cools to room temperature, filter the reaction mixture, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA: petroleum ether = 1:5) to obtain compound 15-2 (8.70 g) with a yield of 61.7%.

[0343] LC-MS (m / z): 145.0 [M+H] + .

[0344] Step 2: Synthesis of 4-chloro-1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15-3)

[0345] Dissolve compound 15-2 (8.70 g, 60.18 mmol) in ultradry THF (80 mL). Under nitrogen protection, add n-butyllithium (32.83 mL, 72.23 mmol, 2.2 M in THF) at -78 °C and react for 1 hour. Then add isopropylpinacol borate (13.44 g, 72.23 mmol) at -78 °C and react at room temperature for 2 hours. After the reaction, quench with an appropriate amount of saturated ammonium chloride solution in an ice-water bath, dilute with water (100 mL), extract with EA (100 mL × 3), combine the organic phases, wash with saturated sodium chloride (100 mL), and dry over anhydrous Na 2 SO 4 . Filter, concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA: petroleum ether = 1:5) to obtain compound 15-3 (10.98 g) with a yield of 67.5%.

[0346] LC-MS (m / z): 271.0 [M+H] + .

[0347] Step 3: Synthesis of 5-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (15)

[0348] Add 5-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (88.0 mg, 0.20 mmol), compound 15-3 (132.4 mg, 0.49 mmol), K 2 CO 3 (81.2 mg, 0.59 mmol) and Pd(dppf)Cl 2 (14.4 mg, 0.02 mmol) into a flask in sequence. Add dioxane (1.5 mL) and water (0.3 mL). Under nitrogen protection, carry out microwave reaction at 110 °C for 1 hour. After the reaction is completed, dilute the reaction mixture with water (10 mL), extract with EA (30 mL×3), combine the organic phases, wash with saturated brine (40 mL), dry with anhydrous Na 2 SO 4 , filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (DCM:MeOH = 10:1), freeze-dry to obtain compound 15 (29.9 mg), with a yield of 27.4%.

[0349] LC-MS (m / z): 558.0 [M+H] + .

[0350] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.04 (t, J = 6.0 Hz, 1H), 8.48 (s, 1H), 8.23 - 8.09 (m, 1H), 7.56 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 5.12 - 5.00 (m, 1H), 4.84 (d, J = 6.4 Hz, 2H), 4.50 - 4.38 (m, 1H), 4.21 (s, 3H), 1.38 (d, J = 6.8 Hz, 6H), 1.19 (d, J = 6.4 Hz, 6H).

[0351] Example 16: Synthesis of 5-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (16)

[0352]

[0353] Step 1: Synthesis of 5-chloro-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (16-1)

[0354] Dissolve 11-5 (100.0 mg, 0.49 mmol) in THF (6 mL), and successively add INT3 (150.9 mg, 0.59 mmol) and DIPEA (318.4 mg, 2.46 mmol). React at 50 °C for 1 hour. After the system cools to room temperature, the reaction mixture is concentrated under reduced pressure, and the residue is purified by column chromatography (100% EA) to obtain compound 16-1 (206.0 mg) with a yield of 99.5%.

[0355] LC-MS (m / z): 422.0 [M+H] + .

[0356] Step 2: Synthesis of 5-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (16)

[0357] Successively add compound 16-1 (206.0 mg, 0.49 mmol), compound 15-3 (331.0 mg, 1.22 mmol), K 2 CO 3 (203.0 mg, 1.47 mmol) and Pd(dppf)Cl 2 (35.8 mg, 0.05 mmol) into the flask. Add dioxane (2.5 mL) and water (0.5 mL), and react under microwave at 110 °C for 1 hour under nitrogen protection. After the reaction is completed, the reaction mixture is diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases are washed with saturated brine (40 mL), dried over anhydrous Na 2 SO 4 , filtered, the filtrate is concentrated under reduced pressure, the residue is purified by column chromatography (DCM:MeOH = 10:1), and lyophilized to obtain compound 16 (162.2 mg) with a yield of 62.9%.

[0358] LC-MS (m / z): 530.0 [M+H] + .

[0359] 1 1H NMR (400 MHz, DMSO-d 6)δ9.05 (t, J = 6.0 Hz, 1H), 8.49 (s, 1H), 7.95 - 7.87 (m, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.57 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 5.17 - 5.00 (m, 1H), 4.84 (d, J = 6.0 Hz, 2H), 4.21 (s, 3H), 3.75 (s, 3H), 1.20 (d, J = 6.4 Hz, 6H).

[0360] Example 17: Synthesis of 5-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (17)

[0361]

[0362] To a flask was added compound 16 (83.1 mg, 0.16 mmol), ultra-dry DMF (3 mL) was added, under a nitrogen atmosphere, NaH (15.7 mg, 0.39 mmol) was added at 0 °C, stirred at 0 °C for 20 minutes, MeI (33.4 mg, 0.24 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a proper amount of saturated NH 4 Cl aqueous solution under an ice-water bath. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (20 mL × 3), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA: petroleum ether = 1:1) to obtain compound 17 (58.1 mg), with a yield of 68.1%

[0363] LC-MS (m / z): 544.0 [M + H] + .

[0364] 1 1H NMR (400 MHz, DMSO-d 6 ) δ8.53 (s, 1H), 7.93 (s, 1H), 7.70 (d, J = 6.4 Hz, 2H), 7.66 - 7.55 (m, 1H), 7.50 - 7.32 (m, 2H), 5.67 (s, 1H), 5.41 - 5.27 (m, 0.5H), 5.23 - 5.05 (m, 1.5H), 4.19 (d, J = 21.2 Hz, 3H), 3.83 - 3.68 (m, 4.5H), 3.23 (s, 1.5H), 1.51 - 1.11 (m, 6H).

[0365] Example 18: Synthesis of 5-(1-Isopropyl-4-methyl-1H-pyrazol-5-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (19)

[0366]

[0367] Step 1: Synthesis of 1-Isopropyl-4-methyl-1H-pyrazole (19-2)

[0368] Dissolve compound 19-1 (3.00 g, 36.54 mmol) in ACN (50 mL). Successively add isopropyl iodide (9.32 g, 54.82 mmol) and cesium carbonate (23.82 g, 73.11 mmol). React at 80 °C for 5 hours under nitrogen protection. Filter the reaction mixture, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA: petroleum ether = 1:5) to obtain compound 19-2 (2.37 g) with a yield of 52.2%.

[0369] LC-MS (m / z): 125.0 [M+H] + 。

[0370] Step 2: Synthesis of 1-Isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19-3)

[0371] Dissolve compound 19-2 (2.37 g, 19.08 mmol) in ultradry THF (30 mL). Under nitrogen protection, add a THF solution of n-butyllithium (10.5 mL, 22.90 mmol, 2.2 M) at -78 °C and react for 1 hour. Subsequently, add isopropyl alcohol pinacol borate (4.27 g, 22.95 mmol) at -78 °C and react at room temperature for 4 hours. After the reaction, quench with a saturated NH 4 Cl aqueous solution under an ice-water bath. Add water (40 mL) for dilution, extract with EA (60 mL × 3), combine the organic phases, wash with saturated NaCl (80 mL), dry over anhydrous Na 2 SO 4 4, filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA: petroleum ether = 1:1) to obtain compound 19-3 (2.40 g) with a yield of 50.3%.

[0372] LC-MS (m / z): 251.0 [M+H] + 。

[0373] Step 3: Synthesis of 5-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (19-4)

[0374] To the flask were successively added compound 13-1 (60.0 mg, 0.14 mmol), compound 19-3 (71.2 mg, 0.28 mmol), K 2 CO 3 (59.0 mg, 0.43 mmol) and Pd(dppf)Cl 2 (10.5 mg, 0.01 mmol). Dioxane (2.0 mL) and water (0.4 mL) were added, and the mixture was subjected to microwave reaction at 110 °C for 1 hour under nitrogen protection. After the reaction, the reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (40 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to obtain compound 19-4 (33.0 mg) with a yield of 45.8%.

[0375] LC-MS (m / z): 510.0 [M+H] + 。

[0376] Step 4: Synthesis of 5-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (19)

[0377] To the flask was added compound 19-4 (33.0 mg, 0.06 mmol), and ultra-dry DMF (3 mL) was added. Under a nitrogen atmosphere, NaH (6.5 mg, 0.16 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 20 minutes. MeI (13.8 mg, 0.10 mmol) was added at 0 °C, and the reaction was carried out for 1 hour. After the reaction, the reaction was quenched with an appropriate amount of saturated NH 4 Cl aqueous solution under an ice-water bath. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (20 mL × 3), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA), freeze-dried to obtain compound 19 (19.3 mg) with a yield of 62.2%.

[0378] LC-MS (m / z): 524.0 [M+H]+ .

[0379] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (s, 1H), 7.93 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.49 - 7.36 (m, 2H), 7.35 - 7.22 (m, 1H), 5.72 - 5.61 (m, 1H), 5.38 - 5.27 (m, 1H), 5.22 - 5.10 (m, 1H), 4.18 (d, J = 16.0 Hz, 3H), 3.81 - 3.70 (m, 4.5H), 3.21 (s, 1.5H), 2.26 - 2.04 (m, 3H), 1.47 - 1.11 (m, 6H).

[0380] Example 19: Synthesis of 5-(1-Isopropyl-4-methoxy-1H-pyrazol-5-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (20)

[0381]

[0382] Step 1: Synthesis of 1-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20-2)

[0383] Dissolve compound 20-1 (5.00 g, 25.77 mmol) in dry DMF (50 mL), and successively add isopropyl iodide (6.60 g, 38.82 mmol) and Cs 2 CO 3 (16.80 g, 51.56 mmol). React at 80 °C for 5 hours under nitrogen protection. Filter the reaction mixture, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (DCM:MeOH = 10:1) to obtain compound 20-2 (2.37 g), with a yield of 63.1%.

[0384] LC-MS (m / z): 237.0 [M + H] + .

[0385] Step 2: Synthesis of 1-Isopropyl-1H-pyrazol-4-ol (20-3)

[0386] Dissolve compound 20-2 (3.54 g, 14.97 mmol) in THF (35 mL), and successively add NaOH (12 mL, 30.00 mmol, 2.5 M) and H 2 O 2(3.8 mL, 37.50 mmol, 30%), react at room temperature for 3 hours. After the reaction, adjust the pH to 2 with 2N hydrochloric acid in an ice-water bath, add Na 2 SO 3 to quench, add water (40 mL) to dilute, extract with DCM:MeOH = 10:1 (80 mL × 7), combine the organic phases, wash with saturated NaCl (80 mL), and dry with anhydrous Na 2 SO 4 . Filter, and concentrate the filtrate under reduced pressure. Compound 20-3 (4.33 g) is obtained and used in the next step without purification.

[0387] LC-MS (m / z): 127.0 [M+H] + .

[0388] Step 3: Synthesis of 1-isopropyl-4-methoxy-1H-pyrazole (20-4)

[0389] Dissolve the crude product of compound 20-3 (4.33 g) in DMF (50 mL), and successively add MeI (7.32 g, 51.55 mmol) and Cs 2 CO 3 (22.36 g, 68.62 mmol), react at room temperature for 16 hours. Add water (40 mL) to dilute, extract with EA (60 mL × 3), combine the organic phases, wash with saturated NaCl (50 mL × 3), and dry with anhydrous Na 2 SO 4 . Filter, and concentrate the filtrate under reduced pressure. The residue is purified by column chromatography (DCM:MeOH = 10:1). Compound 20-4 (1.87 g) is obtained with a yield of 38.9%.

[0390] LC-MS (m / z): 141.0 [M+H] + .

[0391] Step 4: Synthesis of 1-isopropyl-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20-5)

[0392] Dissolve compound 20-4 (1.87 g, 13.33 mmol) in ultra-dry THF (20 mL). Under nitrogen protection, add a THF solution of n-butyllithium (13.4 mL, 33.4 mmol, 2.5 M) at -78 °C and react for 1 hour. Then add isopropyl alcohol pinacol borate (3.73 g, 20.05 mmol) at -78 °C and react at room temperature for 4 hours. After the reaction, add an appropriate amount of saturated NH 4Quenched with aqueous Cl solution, diluted with water (40 mL), extracted with EA (60 mL × 3), combined organic phases were washed with saturated NaCl (80 mL), anhydrous Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 20-5 (1.53 g), yield 43.1%.

[0393] LC-MS (m / z): 267.0 [M+H] + 。

[0394] Step 5: Synthesis of 5-(1-isopropyl-4-methoxy-1H-pyrazol-5-yl)-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (20-6)

[0395] To the flask were successively added compound 13-1 (60.0 mg, 0.14 mmol), compound 20-5 (567.8 mg, 2.13 mmol), K 2 CO 3 (59.0 mg, 0.43 mmol) and Pd(dppf)Cl 2 (10.5 mg, 0.01 mmol), dioxane (2.0 mL) and water (0.4 mL) were added, and the mixture was reacted by microwave at 110 °C for 1 hour under nitrogen protection. After the reaction, the reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), combined organic phases were washed with saturated NaCl (40 mL), anhydrous Na 2 SO 4 dried, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give compound 20-6 (30.0 mg), yield 40.5%.

[0396] LC-MS (m / z): 526.0 [M+H] + 。

[0397] Step 6: Synthesis of 5-(1-isopropyl-4-methoxy-1H-pyrazol-5-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (20)

[0398] Compound 20-6 (30.0 mg, 0.06 mmol) was added to a flask, and ultradry DMF (3 mL) was added. Under a nitrogen atmosphere, NaH (5.8 mg, 0.15 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 20 minutes. MeI (12.2 mg, 0.09 mmol) was added at 0 °C, and the reaction was allowed to warm to room temperature and stirred for 1 hour. After the reaction was completed, the reaction was quenched with a saturated NH 4 Cl aqueous solution under an ice-water bath. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), and the combined organic phases were washed with saturated NaCl (20 mL × 3). Anhydrous Na 2 SO 4 dried, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA), freeze-dried to obtain Compound 20 (26.0 mg), with a yield of 86.7%.

[0399] LC-MS (m / z): 540.0 [M+H] + .

[0400] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (s, 1H), 7.93 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.40 - 7.33 (m, 1H), 5.66 (s, 1H), 5.44 - 5.06 (m, 2H), 4.30 - 4.06 (m, 3H), 3.80 - 3.62 (m, 7.5H), 3.21 (s, 1.5H), 1.55 - 0.97 (m, 6H).

[0401] Example 20: Synthesis of 5-(2-Cyclopropylpyridin-3-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (29)

[0402]

[0403] Step 1: Synthesis of 3-Bromo-2-cyclopropylpyridine (29-2)

[0404] Compound 29-1 (1.00 g, 4.22 mmol), cyclopropylboronic acid (725.2 mg, 8.44 mmol), and Pd(PPh 3 ) 4(243.9 mg, 0.21 mmol) was dissolved in dioxane (20 mL). Then, anhydrous potassium carbonate (2.33 g, 16.88 mmol) was weighed and dissolved in water (6 mL) to form a solution, which was added to the reaction system. The system was protected by nitrogen replacement and heated to 90 °C for reaction for 21 hours. The heating was stopped and the mixture was allowed to stand and cool. Water (50 mL) was added to the reaction solution, and the mixture was extracted with EA (50 mL). The organic phase was separated, washed with saturated NaCl (50 mL), and anhydrous Na 2 SO 4 was added for drying. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 95:5) to obtain compound 29-2 (270.0 mg) with a yield of 32.3%.

[0405] LC-MS (m / z): 198.0 / 200.0 [M+H] + 。

[0406] Step 2: Synthesis of 2-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (29-3)

[0407] Compound 29-2 (270.0 mg, 1.36 mmol), bis(pinacolato)diboron (519.3 mg, 2.04 mmol), Pd(dppf)Cl 2 (99.7 mg, 0.136 mmol) and KOAc (401.3 mg, 4.09 mmol) were added to anhydrous dioxane (11 mL). The system was protected by nitrogen replacement and heated to 90 °C for reaction for 16 hours. The heating was stopped and the mixture was allowed to stand and cool. Water (30 mL) and DCM (60 mL) were added to the reaction solution. After sufficient stirring, the mixture was filtered through diatomaceous earth, and the filtrate was collected. The organic phase was separated, and anhydrous Na 2 SO 4 was added for drying. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 90:10) to obtain the crude product of compound 29-3 (370.0 mg), which was directly used in the next step without purification.

[0408] LC-MS (m / z): 164.0 [M+H] + 。

[0409] Step 3: Synthesis of 5-(2-cyclopropylpyridin-3-yl)-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (29-4)

[0410] The crude product of compound 29-3 (44.9 mg), compound 13-1 (60.0 mg, 0.14 mmol) and Pd(PPh3 ) 4 (7.9 mg, 0.01 mmol) was placed in a microwave reaction tube, dioxane (2.5 mL) was added, and then Cs 2 CO 3 (179.3 mg, 0.55 mmol) was dissolved in water (1 mL) to form a solution, and this solution was added to the reaction system. It was protected by nitrogen replacement and sealed. It was heated to 100 °C and reacted by microwave for 1 hour. The heating was stopped and it was allowed to stand and cool. The reaction solution was poured into water (50 mL), DCM (50 mL) was added for extraction, the organic phase was separated, the organic phase was washed twice with saturated NaCl (50 mL), and then anhydrous Na 2 SO 4 was added for drying, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 90:10) to obtain compound 29-4 (53.0 mg) with a yield of 74.3%.

[0411] LC-MS (m / z): 505.0 [M+H] + 。

[0412] Step 4: Synthesis of 5-(2-cyclopropylpyridin-3-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (29)

[0413] Compound 29-4 (53.0 mg, 0.11 mmol) was weighed, dissolved in anhydrous THF (2.5 mL), protected by nitrogen replacement, and under an ice-water bath, NaH (60%, 8.4 mg, 0.21 mmol) was added, and the reaction was kept warm for 15 minutes. Then MeI (44.7 mg, 0.32 mmol) was dissolved in anhydrous THF (1 mL) and added to the reaction system. After continuing the reaction under an ice-water bath for 5 minutes, the temperature was raised to room temperature and the reaction was carried out for 16 hours. Water (30 mL) was added to the reaction solution to quench it, and then DCM (50 mL) was added for extraction. The organic phase was separated, and anhydrous Na 2 SO 4 was added for drying, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 95:5) to obtain compound 29 (10.2 mg) with a yield of 18.7%.

[0414] LC-MS (m / z): 519.0 [M+H] + 。

[0415] 1 H NMR (400 MHz, DMSO-d 6)δ 8.48 (s, 1H), 8.45 - 8.37 (m, 1H), 8.11 - 7.89 (m, 2H), 7.74 - 7.65 (m, 2H), 7.47 - 7.38 (m, 2H), 7.25 - 7.10 (m, 1H), 5.76 - 5.13 (m, 2H), 4.28 - 4.09 (m, 3H), 3.85 - 3.70 (m, 4.5H), 3.26 - 3.20 (m, 1.5H), 3.05 - 2.78 (m, 1H), 1.09 - 0.95 (m, 1H), 0.95 - 0.83 (m, 2H), 0.67 - 0.52 (m, 1H).

[0416] Example 21: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (33)

[0417]

[0418] Step 1: Synthesis of 5-chloro-7-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (33-1)

[0419] Dissolve INT1-4 (100.0 mg, 0.35 mmol) in anhydrous THF (3 mL). Add NaH (21.0 mg, 0.53 mmol) under an ice-water bath. After maintaining the reaction for 0.5 h, add compound 11-5 (85.8 mg, 0.42 mmol), and carry out the reaction at room temperature for 1 h. Quench the reaction solution with saturated NH 4 Cl aqueous solution, extract with EA (20 mL × 2), combine the organic phases, wash with saturated NaCl (20 mL), dry over anhydrous Na 2 SO 4 , filter, concentrate, and purify by column chromatography (EA: petroleum ether = 1:1) to obtain compound 33-1 (154.0 mg) with a yield of 97.0%

[0420] LC-MS (m / z): 451.0 [M + H] + .

[0421] Step 2: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (33)

[0422] Compound 33-1 (154.0 mg, 0.34 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (99.4 mg, 0.51 mmol), K 2 CO 3 (118.0 mg, 0.85 mmol) and Pd(dppf)Cl 2 (39.5 mg, 0.03 mmol) were added to dioxane (3 mL) and water (0.3 mL). Under nitrogen protection, the mixture was placed in a microwave and reacted at 100 °C for 1 hour. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 10:1), and then further purified by reverse preparation to obtain compound 33 (41.2 mg) with a yield of 24.3%.

[0423] LC-MS (m / z): 565.0 [M+H] + 。

[0424] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.70 (s, 1H), 8.67 (s, 1H), 8.22 - 8.18 (m, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 5.69 (s, 2H), 4.56 - 4.43 (m, 1H), 4.25 (s, 3H), 3.85 (s, 3H), 1.82 - 1.69 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.09 - 0.99 (m, 2H), 0.94 - 0.78 (m, 2H).

[0425] Example 22: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methylthiazolo[5,4-d]pyrimidin-7-amine (36)

[0426]

[0427] Compound 10 (19.0 mg, 0.03 mmol) was added to a flask, and ultra-dry DMF (2 mL) was added. Under a nitrogen atmosphere, NaH (3.4 mg, 0.09 mmol) was added at 0 °C. After stirring at 0 °C for 20 minutes, MeI (7.2 mg, 0.05 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a proper amount of saturated NH 4 Cl aqueous solution under an ice-water bath. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), and the combined organic phases were washed with saturated NaCl (20 mL × 3), anhydrous Na 2 SO4 Dry and filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA: petroleum ether = 1:1) to obtain compound 36 (19.3 mg) with a yield of 64.6%.

[0428] LC-MS (m / z): 581.0 [M+H] + 。

[0429] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.30 (s, 1H), 8.64 (s, 1H), 8.20 - 8.14 (m, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.91 - 5.50 (m, 1H), 5.32 - 4.98 (m, 1H), 4.58 - 4.37 (m, 1H), 3.85 (s, 3H), 3.77 - 3.58 (m, 1.5H), 3.24 - 3.06 (m, 1.5H), 1.86 - 1.73 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.08 - 0.97 (m, 2H), 0.93 - 0.75 (m, 2H).

[0430] Example 23: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methyl-7H-purin-6-amine (38)

[0431]

[0432] Step 1: Synthesis of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-N-methylmethanamine (38-2)

[0433] Add compound INT5 (1.50 g, 4.95 mmol), methylamine hydrochloride (1.67 g, 24.7 mmol) and K 2 CO 3 (6.20 g, 44.59 mmol) to DMF (12 mL) and react at room temperature for 16 h. Pour the reaction solution into water (200 mL), extract with EA (120 mL), wash the organic phase with saturated NaCl (100 mL × 3 times), dry over anhydrous Na 2 SO 4 Dry, filter, concentrate under reduced pressure, and purify by column chromatography (DCM:MeOH = 4:1) to obtain compound 38-2 (340.0 mg) with a yield of 21.7%.

[0434] LC-MS (m / z): 298.0 [M+H]+ .

[0435] Step 2: Synthesis of 2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methyl-7H-purin-6-amine (38-3)

[0436] Weigh out compound 38-2 (89.0 mg, 0.30 mmol), 6-1 (73.0 mg, 0.39 mmol) and DIPEA (130.0 mg, 1.01 mmol) respectively in anhydrous THF (4 mL), heat to 50 °C and react for 1.5 hours. Stop heating and let it cool down naturally. The reaction solution is directly concentrated, and the residue is purified by column chromatography (DCM:MeOH = 90:10) to obtain compound 38-3 (126.0 mg) with a yield of 93.5%.

[0437] LC-MS (m / z): 450.0 [M+H] + .

[0438] Step 3: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methyl-7H-purin-6-amine (38)

[0439] Weigh out compound 38-3 (126.0 mg, 0.28 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (150.0 mg, 0.77 mmol) and Pd(dppf)Cl 2 (35.0 mg, 0.05 mmol) and dissolve them in dioxane (3 mL). Then weigh out K 2 CO 3 (200.0 mg, 1.45 mmol) and dissolve it in water (1 mL) to prepare a solution, and add this solution into the reaction system. Protect it by replacing with nitrogen, and heat it to 107 °C by microwave and react for 1 hour. Stop heating and let it cool down naturally. Pour the reaction solution into water (50 mL), add EA (60 mL) for extraction, separate the organic phase, wash the organic phase with water (50 mL × 2), add anhydrous Na 2 SO 4 for drying, filter, concentrate under reduced pressure, and purify by column chromatography (DCM:MeOH = 10:1) to obtain compound 38 (20.3 mg) with a yield of 12.8%.

[0440] LC-MS (m / z): 564.0 [M+H] + .

[0441] 1 1H NMR (400 MHz, DMSO-d 6)δ13.16(s,1H),8.62(s,1H),8.21(s,1H),8.18(s,1H),7.58 - 7.49(m,2H),7.49 - 7.42(m,2H),5.78 - 5.61(m,1H),5.09 - 4.94(m,1H),4.53 - 4.40(m,1H),3.93 - 3.70(m,4.5H),3.23 - 3.08(m,1.5H),1.84 - 1.76(m,1H),1.39(d,J=6.4Hz,6H),1.04 - 0.95(m,2H),0.90 - 0.74(m,2H).

[0442] Example 24: Synthesis of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N,6-dimethyl-1,2,4-triazin-5-amine (49) and 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,6-dimethyl-1,2,4-triazin-5(4H)-imine (68)

[0443]

[0444] Step 1: Synthesis of 3,5-dichloro-6-methyl-1,2,4-triazine (49-2)

[0445] Weigh compound 49-1 (377.0 mg, 2.97 mmol) into a sealed tube, add phosphorus oxychloride (4 mL) and DIPEA (1 mL) at room temperature, and heat to 100 °C for reaction for 1 hour. Stop heating and let it cool down naturally. Drop the reaction solution into warm water (70 mL) to quench, then add EA (50 mL) and stir well. Filter through diatomaceous earth, collect the filtrate, separate the organic phase, wash it with saturated NaCl (50 mL), and dry it with anhydrous Na 2 SO 4 Filter, concentrate under reduced pressure to obtain the crude product of compound 49-2, which is directly used in the next step of the reaction.

[0446] LC-MS(m / z): 164.0[M+H] + .

[0447] Step 2: Synthesis of 3-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-1,2,4-triazin-5-amine (49-3)

[0448] The crude product of compound 49-2 was dissolved in DMF (4 mL), and then anhydrous potassium carbonate (180.0 mg, 1.30 mmol) and compound (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (253.0 mg, 0.89 mmol) were added. The reaction was carried out at room temperature for 16 hours. The reaction solution was poured into water (70 mL), and then extracted with EA (60 mL). The organic phase was separated, washed with saturated NaCl (50 mL × 3), and then anhydrous Na 2 SO 4 was added for drying, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 49-3 (115.0 mg) with a yield of 31.3%.

[0449] LC-MS (m / z): 411.0 [M+H] + 。

[0450] Step 3: Synthesis of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-methyl-1,2,4-triazin-5-amine (49-4)

[0451] Compound 49-3 (115.0 mg, 0.28 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (135.8 mg, 0.70 mmol) and Pd(dppf)Cl 2 (20.5 mg, 0.03 mmol) were dissolved in dioxane (6 mL), and then an aqueous solution of K 2 CO 3 (154.7 mg, 1.12 mmol) in water (3 mL) was added. The reaction was heated to 100 °C under nitrogen protection for 8 hours. After the reaction was cooled to room temperature, water (70 mL) was added and extracted with EA (60 mL). The organic phase was washed with saturated NaCl (50 mL × 3), and anhydrous Na 2 SO 4 was added for drying, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 49-4 (90.0 mg) with a yield of 61.3%.

[0452] LC-MS (m / z): 525.0 [M+H] + 。

[0453] Step 4: Synthesis of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N,6-dimethyl-1,2,4-triazin-5-amine (49) and 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,6-dimethyl-1,2,4-triazin-5(4H)-imine (68)

[0454] Dissolve compound 49-4 (90.0 mg, 0.17 mmol) in THF (5 mL). Under ice-water bath and nitrogen protection, add NaH (60%, 13.7 mg, 0.34 mmol). After stirring for 15 minutes, add a solution of MeI (121.8 mg, 0.86 mmol) in anhydrous THF (1 mL). After addition, react for 10 minutes and then raise the temperature to room temperature and continue the reaction for 2 hours. Quench the reaction by adding ice water (30 mL), extract with EA (50 mL), wash the organic phase with saturated NaCl (50 mL), and dry with anhydrous Na 2 SO 4 dry, filter, concentrate under reduced pressure, and purify by column chromatography (DCM:MeOH = 10:1) to obtain compound 49 (11.0 mg) with a yield of 11.9%.

[0455] LC-MS (m / z): 539.0 [M+H] + 。

[0456] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.65 (s, 1H), 8.20 - 8.15 (m, 1H), 7.59 - 7.50 (m, 2H), 7.46 - 7.39 (m, 2H), 4.93 (s, 2H), 4.55 - 4.34 (m, 1H), 3.83 (s, 3H), 3.30 (s, 3H), 2.79 (s, 3H), 1.80 - 1.65 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.05 - 0.95 (m, 2H), 0.91 - 0.77 (m, 2H).

[0457] Meanwhile, compound 68 (44.0 mg) can be obtained with a yield of 47.6%.

[0458] LC-MS (m / z): 539.0 [M+H] + 。

[0459] 1 H NMR (400 MHz, DMSO-d 6)δ 8.81 (s, 1H), 8.22 - 8.16 (m, 1H), 7.52 (s, 4H), 4.93 - 4.80 (m, 1H), 4.77 - 4.67 (m, 1H), 4.52 - 4.38 (m, 1H), 3.98 (s, 3H), 3.70 (s, 3H), 2.46 (s, 3H), 2.06 - 1.96 (m, 1H), 1.41 (d, J = 6.4 Hz, 6H), 1.17 - 0.98 (m, 3H), 0.89 - 0.79 (m, 1H).

[0460] Example 25: Synthesis of 6-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-3-methoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridazin-4-amine (61)

[0461]

[0462] Step 1: Synthesis of 6-chloro-3-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridazin-4-amine (61-1)

[0463] Dissolve compound 5-1 (100.0 mg, 0.63 mmol) in anhydrous DMF (5 mL). Add NaH (50.0 mg, 1.25 mmol) under an ice-water bath. After maintaining the reaction for 20 minutes, add INT6 (172.0 mg, 0.63 mmol) and let the reaction proceed at room temperature for 1 hour. Quench the reaction mixture with saturated aqueous NH 4 Cl solution, extract with EA (20 mL × 2), combine the organic phases, wash with water (20 mL × 3) and saturated NaCl (20 mL), dry with anhydrous Na 2 SO 4 , filter, concentrate the filtrate, and purify by column chromatography (EA: petroleum ether = 80:20) to obtain compound 61-1 (120.0 mg) with a yield of 48.2%

[0464] LC-MS (m / z): 398.0 [M + H] + .

[0465] Step 2: Synthesis of 6-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-3-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridazin-4-amine (61-2)

[0466] Mix compound 61-1 (120.0 mg, 0.30 mmol), compound 15-3 (122.0 mg, 0.45 mmol), K 2 CO3 (104.2 mg, 0.75 mmol) and Pd(dppf)Cl 2 (22.1 mg, 0.03 mmol) were added to dioxane (3 mL) and water (0.3 mL). Under nitrogen protection, the mixture was placed in a microwave and reacted at 110 °C for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA: petroleum ether = 75:25) to obtain compound 61-2 (35.0 mg) with a yield of 23.0%.

[0467] LC-MS (m / z): 506.0 [M+H] + 。

[0468] Step 3: Synthesis of 6-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-3-methoxy-N-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridazin-4-amine (61)

[0469] Compound 61-2 (35.0 mg, 0.07 mmol) was dissolved in anhydrous DMF (2 mL). Under nitrogen protection, NaH (4.1 mg, 0.10 mmol) was added in an ice-water bath. After stirring at the same temperature for 20 minutes, MeI (19.6 mg, 0.14 mmol) was added, and the mixture was allowed to react at room temperature for 0.5 hour. In the ice-water bath, the reaction solution was quenched with saturated NH 4 Cl aqueous solution, diluted with water (10 mL), and extracted with EA (20 mL × 2). The combined organic phases were washed with water (20 mL) and saturated NaCl (20 mL), dried over anhydrous Na 2 SO 4 4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA: petroleum ether = 1:1) to obtain compound 61 (11.1 mg) with a yield of 31.0%.

[0470] LC-MS (m / z): 520.0 [M+H] + 。

[0471] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.96 - 7.89 (m, 1H), 7.75 - 7.66 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H), 6.89 (s, 1H), 4.93 - 4.72 (m, 3H), 4.08 (s, 3H), 3.78 (s, 3H), 3.05 (s, 3H), 1.35 (d, J = 6.4 Hz, 6H).

[0472] Example 26: Synthesis of 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one (62)

[0473]

[0474] Step 1: Synthesis of 2-chloro-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one (62-2)

[0475] Dissolve compound 62-1 (100.0 mg, 0.45 mmol) and INT6 (146.7 mg, 0.53 mmol) in DMF (4 mL), add Cs 2 CO 3 (290.0 mg, 0.89 mmol), and place it at 80 °C for reaction for 2 hours. After the reaction solution cools to room temperature, dilute it with EA (20 mL), wash it with water (15 mL × 3) and saturated NaCl (15 mL), and dry it with anhydrous Na 2 SO 4 Dry, filter, concentrate under reduced pressure, and purify by column chromatography (100% EA) to obtain compound 62-2 (66.0 mg) with a yield of 32.1%.

[0476] LC-MS (m / z): 463.0 [M+H] + .

[0477] Step 2: Synthesis of 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,5,9,10-tetrahydro-6H,8H-pyrido[3,2,1-de]pteridin-6-one (62)

[0478] Add compound 62-2 (66.0 mg, 0.14 mmol), compound 15-3 (57.9 mg, 0.21 mmol), K 2 CO 3 (49.3 mg, 0.36 mmol) and Pd(dppf)Cl 2 (10.4 mg, 0.01 mmol) to dioxane (2 mL) and water (0.2 mL). Under nitrogen protection, place it in a microwave at 110 °C for reaction for 1 hour. Filter the reaction solution, concentrate the filtrate under reduced pressure, and purify the residue by reverse preparation to obtain compound 62 (31.0 mg) with a yield of 38.8%.

[0479] LC-MS (m / z): 571.0 [M+H] + 。

[0480] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.93 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 5.20 - 5.04 (m, 1H), 4.91 (s, 2H), 4.23 (s, 2H), 3.91 - 3.79 (m, 2H), 3.77 (s, 3H), 2.80 (t, J = 6.0 Hz, 2H), 2.13 - 1.92 (m, 2H), 1.26 (d, J = 6.4 Hz, 6H).

[0481] Example 27: Synthesis of 5-(1-Isopropyl-4-methyl-1H-imidazol-5-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (63)

[0482]

[0483] Step 1: Synthesis of 5-Bromo-1-isopropyl-4-methyl-1-imidazole (63-2)

[0484] Compound 63-1 (3.22 g, 20.0 mmol) and isopropyl iodide (10.0 mL, 100.0 mmol) were added to ACN (100 mL), and Cs 2 CO 3 (13.03 g, 40.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (DCM:MeOH = 96:4) to obtain compound 63-2 (1.40 g) with a yield of 34.5%.

[0485] LC-MS (m / z): 203.0 / 205.0 [M+H] + 。

[0486] Step 2: Synthesis of (1-Isopropyl-4-methyl-1H-imidazol-5-yl)boronic acid (63-3)

[0487] Compound 63-2 (609.0 mg, 3.00 mmol) was dissolved in anhydrous THF (20 mL). Under nitrogen protection, a solution of n-butyllithium in n-hexane (2.2 M, 2.72 mL, 6.0 mmol) was added dropwise at a temperature below -70 °C. After keeping the reaction mixture at the same temperature for 0.5 h, isopropyl alcohol pinacol borate (1.67 g, 9.00 mmol) was added, and the reaction was continued at -20 °C for 3 h. The reaction mixture was quenched with saturated NH 4 Cl, diluted with EA (30 mL), filtered, and the filtrate was concentrated to obtain the crude product of compound 63-3, which was directly used in the next step.

[0488] Step 3: Synthesis of 5-(1-isopropyl-4-methyl-1H-imidazol-5-yl)-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (63-4)

[0489] Compound 13-1 (60.0 mg, 0.14 mmol), the crude product of 63-3, K 2 CO 3 (49.1 mg, 0.36 mmol) and Pd(dppf)Cl 2 (10.4 mg, 0.01 mmol) were added to dioxane (5 mL) and water (0.5 mL). Under nitrogen protection, the reaction was carried out at 100 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 63-4 (57.0 mg) with a yield of 78.8%.

[0490] LC-MS (m / z): 510.0 [M+H] + .

[0491] Step 4: Synthesis of 5-(1-isopropyl-4-methyl-1H-imidazol-5-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (63)

[0492] Compound 63-4 (57.0 mg, 0.11 mmol) was dissolved in anhydrous DMF (2 mL). Under nitrogen protection, NaH (8.9 mg, 0.22 mmol) was added in an ice-water bath. After stirring at the same temperature for 30 min, MeI (47.6 mg, 0.33 mmol) was added, and the reaction was continued at room temperature for 1 h. In an ice-water bath, the reaction mixture was quenched with an aqueous solution of saturated NH 4 Cl, diluted with water (10 mL), extracted with EA (20 mL × 2). The combined organic phases were washed with water (20 mL) and saturated NaCl (20 mL), and dried over anhydrous Na 2 SO4 It was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse preparative chromatography to obtain Compound 63 (14.2 mg), with a yield of 24.7%.

[0493] LC-MS (m / z): 524.0 [M+H] + 。

[0494] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.39 (s, 1H), 7.93 (s, 1H), 7.81 - 7.74 (m, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.46 - 7.36 (m, 2H), 5.75 - 5.61 (m, 1H), 5.60 - 5.45 (m, 0.5H), 5.37 - 5.25 (m, 0.5H), 5.21 - 5.07 (m, 1H), 4.25 - 4.09 (m, 3H), 3.80 - 3.71 (m, 4.5H), 3.28 - 3.12 (m, 1.5H), 2.47 - 2.20 (m, 3H), 1.52 - 1.13 (m, 6H).

[0495] Example 28: Synthesis of 5-(4-chloro-1-cyclopropyl-1H-pyrazol-5-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (64)

[0496]

[0497] Step 1: Synthesis of 4-chloro-1-cyclopropyl-1H-pyrazole (64-2)

[0498] Compound 64-1 (3.00 g, 29.40 mmol), cyclopropylboronic acid (10.20 g, 118.74 mmol), 2,2'-bipyridine (5.10 g, 32.65 mmol), and Na 2 CO 3 (6.90 g, 65.10 mmol) and cupric acetate anhydrous (5.90 g, 32.48 mmol) were successively added to a flask. DCE (100 mL) was added, and the reaction was carried out at 90 °C for 16 hours under an oxygen atmosphere. After the reaction was completed, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain Compound 64-2 (1.41 g), with a yield of 33.2%.

[0499] LC-MS (m / z): 143.0 [M+H] + 。

[0500] Step 2: Synthesis of 4-chloro-1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64-3)

[0501] Dissolve compound 64-2 (1.41 g, 9.92 mmol) in ultradry THF (15 mL). Under nitrogen protection, add a THF solution of LDA (10 mL, 19.9 mmol, 2.0 M) at -78 °C and react for 1 hour. Subsequently, add isopropyl alcohol pinacol borate (2.80 g, 15.05 mmol) at -78 °C and react at room temperature for 4 hours. After the reaction is completed, quench with a saturated aqueous solution of NH 4 Cl under an ice-water bath, add water (40 mL) for dilution, extract with EA (60 mL × 3), combine the organic phases, wash with saturated NaCl (80 mL), and dry over anhydrous Na 2 SO 4 Filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (DCM:MeOH = 10:1) to obtain compound 64-3 (987.0 mg) with a yield of 37.1%.

[0502] LC-MS (m / z): 269.0 [M+H] + .

[0503] Step 3: Synthesis of 5-(4-chloro-1-cyclopropyl-1H-pyrazol-5-yl)-2-methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (64-4)

[0504] Add compound 13-1 (60.0 mg, 0.14 mmol), compound 64-3 (95.5 mg, 0.36 mmol), K 2 CO 3 (59.0 mg, 0.43 mmol), and Pd(dppf)Cl 2 (10.5 mg, 0.01 mmol) to the flask in sequence. Add dioxane (2.0 mL) and water (0.4 mL), and react under microwave irradiation at 110 °C for 1 hour under nitrogen protection. After the reaction is completed, dilute the reaction mixture with water (10 mL), extract with EA (30 mL × 3), combine the organic phases, wash with saturated NaCl (40 mL), and dry over anhydrous Na 2 SO 4 Filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (100% EA) to obtain compound 64-4 (33.0 mg) with a yield of 44.0%.

[0505] LC-MS (m / z): 528.0 [M+H] + .

[0506] Step 4: Synthesis of 5-(4-chloro-1-cyclopropyl-1H-pyrazol-5-yl)-N,2-dimethyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (64)

[0507] Add compound 64-4 (33.0 mg, 0.06 mmol) to a flask, add ultra-dry DMF (3 mL), under a nitrogen atmosphere, add NaH (6.3 mg, 0.16 mmol) at 0 °C, stir at 0 °C for 20 minutes, add MeI (13.4 mg, 0.09 mmol) at 0 °C, and raise the temperature to room temperature and react for 1 hour. After the reaction is completed, quench the reaction with an appropriate amount of saturated NH 4 Cl aqueous solution under an ice-water bath. Dilute the reaction mixture with water (10 mL), extract with EA (30 mL × 3), combine the organic phases, wash with saturated NaCl (20 mL × 3), and dry with anhydrous Na 2 SO 4 Dry, filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA), lyophilize to obtain compound 64 (23.1 mg), with a yield of 70.0%.

[0508] LC-MS (m / z): 542.0 [M+H] + .

[0509] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 7.92 (s, 1H), 7.76 - 7.63 (m, 2H), 7.59 - 7.49 (m, 1H), 7.47 - 7.37 (m, 2H), 5.68 (s, 1H), 5.17 (s, 1H), 4.43 - 4.32 (m, 0.5H), 4.19 (d, J = 19.6 Hz, 3H), 4.11 - 4.05 (m, 0.5H), 3.84 - 3.79 (m, 1.5H), 3.76 (s, 3H), 3.24 (s, 1.5H), 1.06 - 0.97 (m, 1H), 0.96 - 0.83 (m, 2H), 0.69 - 0.58 (m, 1H).

[0510] Example 29: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-methoxy-N-methylpyridazin-4-amine (65)

[0511]

[0512] Compound 5 (12.4 mg, 0.02 mmol) was dissolved in ultradry DMF (3 mL). NaH (2.3 mg, 0.06 mmol) was added at 0 °C under a nitrogen atmosphere. After stirring for 20 minutes, MeI (4.9 mg, 0.03 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a proper amount of saturated NH 4 Cl aqueous solution under an ice-water bath. The reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated NaCl (20 mL × 3), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA) and lyophilized to obtain compound 65 (7.7 mg) with a yield of 60.6%.

[0513] LC-MS (m / z): 554.0 [M+H] + .

[0514] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (s, 1H), 8.18 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.84 (s, 1H), 4.77 (s, 2H), 4.55 - 4.41 (m, 1H), 4.06 (s, 3H), 3.82 (s, 3H), 2.95 (s, 3H), 1.81 - 1.71 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.06 - 0.96 (m, 2H), 0.91 - 0.84 (m, 2H).

[0515] Example 30: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)(methyl)amino)pyridazine-3-carbonitrile (66)

[0516]

[0517] Step 1: Synthesis of 6-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyridazine-3-carbonitrile (66-1)

[0518] INT2 (358.2 mg, 1.26 mmol) was dissolved in DMF (6 mL). 4,6-Dichloropyridazine-3-carbonitrile (200.0 mg, 1.15 mmol) and K 2 CO 3(476.6 mg, 3.45 mmol), reacted at room temperature for 16 h. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL×3), the combined organic phases were washed with saturated NaCl (30 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 66-1 (350.0 mg), with a yield of 72.3%.

[0519] LC-MS (m / z): 421.0 [M+H] + 。

[0520] Step 2: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyridazine-3-carbonitrile (66-2)

[0521] To a flask were successively added compound 66-1 (515.0 mg, 1.22 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (474.9 mg, 2.45 mmol), K 2 CO 3 (507.5 mg, 3.67 mmol) and Pd(dppf)Cl 2 (89.6 mg, 0.12 mmol), dioxane (9.0 mL) and water (1.8 mL) were added, and the reaction was carried out at 110 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with EA (30 mL×3), the combined organic phases were washed with saturated NaCl (40 mL), and dried over anhydrous Na 2 SO 4 dried, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA) to give compound 66-2 (70.0 mg), with a yield of 10.7%.

[0522] LC-MS (m / z): 535.0 [M+H] + 。

[0523] Step 3: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)(methyl)amino)pyridazine-3-carbonitrile (66)

[0524] Compound 66-2 (70.0 mg, 0.13 mmol) was dissolved in ultradry DMF (3 mL). Under a nitrogen atmosphere, NaH (13.1 mg, 0.33 mmol) was added in an ice-water bath and stirred for 20 minutes. Then MeI (27.9 mg, 0.20 mmol) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with an appropriate amount of saturated NH 4 Cl aqueous solution. The reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated NaCl (20 mL × 3), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 50:1), freeze-dried to obtain compound 66 (5.6 mg), with a yield of 7.9%.

[0525] LC-MS (m / z): 549.0 [M+H] + .

[0526] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (s, 1H), 8.26 - 8.23 (m, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 5.03 (s, 2H), 4.58 - 4.45 (m, 1H), 3.83 (s, 3H), 3.49 (s, 3H), 1.81 - 1.72 (m, 1H), 1.47 (d, J = 6.4 Hz, 6H), 1.11 - 1.05 (m, 2H), 0.96 - 0.88 (m, 2H).

[0527] Example 31: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N,3-dimethylpyridazin-4-amine (67)

[0528]

[0529] Step 1: Synthesis of 6-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-methylpyridazin-4-amine (67-1) Weigh INT2 (312.8 mg, 1.10 mmol), 4,6-dichloro-3-methylpyridazine (200.0 mg, 1.10 mmol) and anhydrous K 2 CO 3(610.4 mg, 4.42 mmol), DMF (3 mL) was added, and the mixture was heated to 55 °C and reacted for 16 hours. Heating was stopped and the mixture was allowed to stand and cool. Water (70 mL) was added to the reaction solution, and then EA (50 mL) was added for extraction. The organic phase was separated, washed with saturated NaCl (50 mL × 3), and then anhydrous Na 2 SO 4 was added for drying. After filtration, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:CH 3 OH = 90:10) to obtain compound 67-1 (249.0 mg) with a yield of 55.0%.

[0530] LC-MS (m / z): 410.0 [M+H] + .

[0531] Step 2: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-methylpyridazin-4-amine (67-2)

[0532] Compound 67-1 (249.0 mg, 0.61 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (176.8 mg, 0.91 mmol) and Pd(dppf)Cl 2 (44.5 mg, 0.06 mmol) were weighed respectively and added to dioxane (4 mL). Then K 2 CO 3 (251.9 mg, 1.82 mmol) was dissolved in water (2 mL) to prepare a solution, and this solution was added to the reaction system. Then the system was protected by nitrogen replacement and heated to 100 °C for 16 hours. Heating was stopped and the mixture was allowed to stand and cool. Water (70 mL) was added to the reaction solution, and then EA (50 mL) was added for extraction. The organic phase was separated and washed with saturated NaCl (50 mL × 2). Anhydrous Na 2 SO 4 was added for drying. After filtration, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 90:10) to obtain compound 67-2 (51.0 mg) with a yield of 16.0%.

[0533] LC-MS (m / z): 524.0 [M+H] + .

[0534] Step 3: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N,3-dimethylpyridazin-4-amine (67)

[0535] Compound 67-2 (51.0 mg, 0.10 mmol) was dissolved in anhydrous THF (3 mL), protected by purging with nitrogen. Under an ice-water bath, NaH (60%, 11.7 mg, 0.29 mmol) was added. After maintaining the reaction temperature for 15 minutes, MeI (96.7 mg, 0.682 mmol) was dissolved in anhydrous THF (1 mL) and added to the reaction system. The reaction was maintained at the same temperature for 10 minutes and then continued at room temperature for 1.5 hours. Water (30 mL) was added dropwise to the reaction solution to quench the reaction, and then extracted with EA (70 mL). The organic layer was separated, and anhydrous Na 2 SO 4 was added for drying, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 90:10) to obtain compound 67 (8.7 mg) with a yield of 16.6%.

[0536] LC-MS (m / z): 538.0 [M+H] + 。

[0537] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 8.20 - 8.18 (m, 1H), 7.59 - 7.54 (m, 2H), 7.49 - 7.42 (m, 2H), 7.07 (s, 1H), 4.56 (s, 2H), 4.53 - 4.43 (m, 1H), 3.81 (s, 3H), 2.91 (s, 3H), 2.73 (s, 3H), 1.72 - 1.63 (m, 1H), 1.42 (d, J = 6.4 Hz, 6H), 1.05 - 0.99 (m, 2H), 0.91 - 0.82 (m, 2H).

[0538] Example 32: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methyl-d 2 )-N,2-dimethyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (69)

[0539]

[0540] Step 1: Synthesis of (4-(1-Isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methyl-d 2 -amine (69-2)

[0541] Compound INT2-3 (139.7 mg, 0.50 mmol) was dissolved in anhydrous THF (5 mL). Under an ice-water bath, LiAlD 4(63.0 mg, 1.50 mmol) was placed at room temperature for 10 minutes. The reaction solution was quenched with saturated Na 2 CO 3 solution, filtered, and the filter cake was rinsed with DCM. The filtrate was concentrated to obtain compound 69-2 (117.0 mg) with a yield of 82.0%.

[0542] LC-MS (m / z): 286.0 [M+H] + 。

[0543] Step 2: Synthesis of 5-chloro-N-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methyl-d 2 )-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (69-3)

[0544] Compound 69-2 (117.0 mg, 0.41 mmol), compound 11-5 (75.7 mmol, 0.37 mmol), and DIPEA (0.13 mL, 0.74 mmol) were dissolved in THF (2 mL) and reacted at 50 °C for 0.5 h. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 93:7) to obtain compound 69-3 (153.0 mg) with a yield of 82.6%.

[0545] LC-MS (m / z): 452.0 [M+H] + 。

[0546] Step 3: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methyl-d 2 )-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (69-4)

[0547] Compound 69-3 (153.0 mg, 0.34 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (131.4 mg, 0.68 mmol), K 2 CO 3 (117.0 mg, 0.85 mmol), and Pd(dppf)Cl 2 (24.8 mg, 0.03 mmol) were added to dioxane (5 mL) and water (0.5 mL). Under nitrogen protection, the mixture was reacted at 105 °C for 16 h. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 69-4 (94.0 mg) with a yield of 49.2%.

[0548] LC-MS (m / z): 566.0 [M+H] + 。

[0549] Step 4: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methyl-d 2 )-N,2-dimethyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (69)

[0550] Dissolve compound 69-4 (94.0 mg, 0.17 mmol) in anhydrous DMF (3 mL). Under nitrogen protection, add NaH (19.9 mg, 0.50 mmol) in an ice-water bath. After stirring for 10 minutes while maintaining the temperature, add MeI (70.7 mg, 0.50 mmol), and raise the temperature to room temperature for reaction for 0.5 hour. In an ice-water bath, quench the reaction solution with saturated NH 4 Cl aqueous solution, dilute with water (10 mL), extract with EA (20 mL × 2), combine the organic phases, wash with water (20 mL) and saturated NaCl (20 mL), and dry with anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate under reduced pressure, purify the residue by column chromatography, and then by reverse preparative purification to obtain compound 69 (58.1 mg), with a yield of 60.4%.

[0551] LC-MS (m / z): 580.0 [M+H] + 。

[0552] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.60 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 7.56 - 7.50 (m, 2H), 7.49 - 7.44 (m, 2H), 4.52 - 4.37 (m, 1H), 4.19 (s, 3H), 3.83 (s, 3H), 3.77 - 3.69 (m, 1.5H), 3.19 - 3.07 (m, 1.5H), 1.92 - 1.75 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H), 1.07 - 0.93 (m, 2H), 0.91 - 0.70 (m, 2H).

[0553] Example 33: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methyl-d 2 )-2-methyl-N-(methyl-d 3 )-2H-pyrazolo[4,3-d]pyrimidin-7-amine (70)

[0554]

[0555] Dissolve compound 69-4 (146.0 mg, 0.26 mmol) in anhydrous THF (3 mL). Under ice-water bath and nitrogen protection, add NaH (31.0 mg, 0.77 mmol). After stirring for 10 minutes, add CD 3 I (112.2 mg, 0.77 mmol), and raise the temperature to room temperature for reaction for 0.5 h. Quench the reaction solution with saturated NH 4 Cl solution under ice-water bath, dilute with water (10 mL), extract with EA (20 mL×2). Combine the organic phases, wash with saturated NaCl (20 mL), dry over anhydrous Na 2 SO 4 , filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (DCM:MeOH = 10:1) to obtain compound 70 (18.9 mg) with a yield of 12.6%.

[0556] LC-MS (m / z): 583.0 [M+H] + .

[0557] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.61 - 7.50 (m, 2H), 7.50 - 7.44 (m, 2H), 4.55 - 4.38 (m, 1H), 4.19 (s, 3H), 3.83 (s, 3H), 1.87 - 1.74 (m, 1H), 1.40 (d, J = 6.4 Hz, 6H), 1.11 - 0.92 (m, 2H), 0.90 - 0.72 (m, 2H).

[0558] Example 34: Synthesis route of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3,5-difluoro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methylpyridin-4-amine (71)

[0559]

[0560] Step 1: Synthesis of 3,5-difluoro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridin-4-amine (71-1)

[0561] Weigh 3,5-difluoropyridin-4-amine (400.0 mg, 3.07 mmol) and dissolve it in anhydrous DMF (3 mL). Protect it by purging with nitrogen, then control the temperature with an ice-water bath. Add NaH (60%, 155.5 mg, 6.48 mmol), and then continue the reaction for 30 minutes under the ice-water bath. Weigh compound INT5 (327.0 mg, 1.08 mmol) and dissolve it in anhydrous DMF (1.3 mL), and add it dropwise into the reaction system. After continuing the reaction for 10 minutes under the ice-water bath, raise the temperature to room temperature and continue the reaction for 1 hour. Combine the reaction solutions, add water (50 mL) to the reaction solution, then add EA (60 mL) for extraction. Separate the organic phase, wash the organic phase with saturated NaCl (70 mL × 3), and then add anhydrous Na 2 SO 4 Dry, filter, concentrate under reduced pressure, and purify by column chromatography (PE:EA = 1:1) to obtain the crude product of compound 71-1 (339.0 mg), which is directly used for the next reaction.

[0562] LC-MS (m / z): 397.0 [M+H] + 。

[0563] Step 2: Synthesis of 3,5-difluoro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methylpyridin-4-amine (71-2)

[0564] Weigh the crude product of compound 71-1 (339.0 mg) and dissolve it in anhydrous THF (4 mL). Protect it by purging with nitrogen, control the temperature with an ice-water bath, then add NaH (60%, 102.6 mg, 2.57 mmol), keep the temperature for 15 minutes. Then weigh MeI (849.7 mg, 5.98 mmol) and dissolve it in anhydrous THF (1.5 mL), and add it to the reaction system. After continuing the reaction for 10 minutes under the ice-water bath, raise the temperature to room temperature and react for 16 hours. Add water (50 mL) to the reaction solution, then add EA (60 mL) for extraction. Separate the organic phase, add anhydrous Na 2 SO 4 Dry, filter, concentrate under reduced pressure, and purify by column chromatography (PE:EA = 1:1) to obtain compound 71-2 (118.0 mg), with a two-step yield of 7.7%.

[0565] LC-MS (m / z): 411.0 [M+H] + 。

[0566] Step 3: Synthesis of 3,5-difluoro-2-iodo-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methylpyridin-4-amine (71-3)

[0567] Weigh compound 71-2 (76.0 mg, 0.19 mmol) and dissolve it in anhydrous THF (1.5 mL). Protect it by displacing the air with nitrogen. At -78 °C, slowly add n-butyllithium (2.5 M solution in n-hexane, 0.11 mL, 0.28 mmol) dropwise. Continue to keep the temperature for reaction for 25 minutes. Then, dissolve iodine (42.0 mg, 0.17 mmol) in anhydrous THF (0.6 mL) and add it dropwise. Keep the temperature for reaction for 20 minutes and then gradually raise the temperature to room temperature and react for 2 hours. Quench the reaction solution with water (20 mL), extract it with EA (20 mL×2), combine the organic phases, wash with saturated NaCl (20 mL), and dry with anhydrous Na 2 SO 4 dry, filter, concentrate under reduced pressure, and purify by column chromatography (PE:EA = 1:1) to obtain compound 71-3 (18.0 mg) with a yield of 18.2%.

[0568] LC-MS (m / z): 537.0 [M+H] + 。

[0569] Step 4: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3,5-difluoro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methylpyridin-4-amine (71)

[0570] Weigh (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (16.3 mg, 0.08 mmol) and compound 71-3 (18.0 mg, 0.03 mmol), and Pd(dppf)Cl 2 (3.7 mg, 0.01 mmol) and dissolve them in dioxane (2 mL). Then weigh anhydrous K 2 CO 3 (18.6 mg, 0.13 mmol) and dissolve it in water (0.6 mL) to prepare a solution. Add this solution to the reaction system, protect it by displacing the air with nitrogen, and heat to 90 °C for reaction for 12 hours. Pour the reaction solution into water (50 mL), add EA (50 mL) for extraction, separate the organic phase, wash the organic phase with saturated NaCl (50 mL×2), and dry with anhydrous Na 2 SO 4 dry, filter, concentrate under reduced pressure, and purify by column chromatography (PE:EA = 1:1) to obtain compound 71 (10.2 mg) with a yield of 54.4%.

[0571] LC-MS (m / z): 559.0 [M+H] + 。

[0572] 1 H NMR (400 MHz, DMSO-d 6)δ8.68(s,1H),8.42 - 8.38(m,1H),8.22 - 8.16(m,1H),7.61 - 7.54(m,2H),7.50 - 7.43(m,2H),4.59(s,2H),4.54 - 4.41(m,1H),3.86(s,3H),3.08 - 3.01(m,3H),1.72 - 1.59(m,1H),1.41(d,J=6.4Hz,6H),1.12 - 0.97(m,2H),0.98 - 0.84(m,2H).

[0573] Example 35: Synthesis of 3 - cyclopropyl - 6-(4 - cyclopropyl - 6 - methoxypyrimidin - 5 - yl)-N-(4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)benzyl)-N - methylpyridazin - 4 - amine (72)

[0574]

[0575] Step 1: Synthesis of 3,6 - dichloro - N-(4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)benzyl)pyridazin - 4 - amine (72 - 1)

[0576] Dissolve INT2 (3.30 g, 11.65 mmol) in ACN (30 mL), and successively add 3,4,6 - trichloropyridazine (2.57 g, 14.01 mmol) and DIPEA (4.52 g, 34.97 mmol). React at room temperature for 16 hours. The reaction mixture is evaporated to dryness under reduced pressure, and the residue is purified by column chromatography (EA: petroleum ether = 1:1) to obtain compound 72 - 1 (2.54 g) with a yield of 50.9%.

[0577] LC - MS (m / z): 430.0[M + H] + 。

[0578] Step 2: Synthesis of 6 - chloro - 3 - cyclopropyl - N-(4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)benzyl)pyridazin - 4 - amine (72 - 2)

[0579] Add compound 72 - 1 (300.0 mg, 0.70 mmol), cyclopropylboronic acid (89.9 mg, 1.05 mmol), Na 2 CO 3 (184.8 mg, 1.74 mmol) and Pd(PPh 3 ) 2 Cl 2(14.7 mg, 0.02 mmol), toluene (2.0 mL) and water (0.5 mL) were added, and the mixture was reacted under microwave irradiation at 110 °C for 1 h under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with EA (20 mL × 3), the combined organic phases were washed with saturated NaCl (30 mL), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA: petroleum ether = 1:1) to give compound 72-2 (81.0 mg) with a yield of 26.7%.

[0580] LC-MS (m / z): 436.0 [M+H] + 。

[0581] Step 3: Synthesis of 3-cyclopropyl-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridazin-4-amine (72-3)

[0582] To a flask were successively added compound 72-2 (71.0 mg, 0.16 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (63.2 mg, 0.33 mmol), K 2 CO 3 (67.6 mg, 0.49 mmol) and Pd(dppf)Cl 2 (12.0 mg, 0.02 mmol). Dioxane (2.5 mL) and water (0.5 mL) were added, and the mixture was reacted under microwave irradiation at 110 °C for 1 h under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with EA (20 mL × 3), the combined organic phases were washed with saturated NaCl (30 mL), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to give compound 72-3 (59.0 mg) with a yield of 66.3%.

[0583] LC-MS (m / z): 550.0 [M+H] + 。

[0584] Step 4: Synthesis of 3-cyclopropyl-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methylpyridazin-4-amine (72)

[0585] Compound 72-3 (59.0 mg, 0.11 mmol) was dissolved in ultradry DMF (5 mL). Under a nitrogen atmosphere, NaH (10.8 mg, 0.27 mmol) was added in an ice-water bath. After stirring for 20 minutes, MeI (22.9 mg, 0.16 mmol) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with an appropriate amount of saturated NH 4 Cl aqueous solution. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (20 mL × 3), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA), freeze-dried to obtain compound 72 (9.0 mg), with a yield of 15.0%.

[0586] LC-MS (m / z): 564.0 [M+H] + 。

[0587] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.65 (s, 1H), 8.23 - 8.14 (m, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H), 4.64 (s, 2H), 4.54 - 4.38 (m, 1H), 3.80 (s, 3H), 2.90 (s, 3H), 2.42 - 2.26 (m, 1H), 1.73 - 1.56 (m, 1H), 1.41 (d, J = 7.6 Hz, 6H), 1.35 - 1.28 (m, 2H), 1.14 - 1.07 (m, 2H), 1.03 - 0.97 (m, 2H), 0.89 - 0.82 (m, 2H).

[0588] Example 36: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methyl-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (73)

[0589]

[0590] Step 1: Synthesis of 6-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (73-1)

[0591] Dissolve compound 72-1 (200.0 mg, 0.46 mmol) in ultradry ACN (10 mL), add sodium trifluoroethanolate (576.6 mg, 4.65 mmol), and react at 50 °C for 16 h. After the reaction solution is cooled to room temperature, concentrate it under reduced pressure. The residue is purified by column chromatography (EA: petroleum ether = 1:1) to obtain compound 73-1 (154.0 mg) with a yield of 67.7%.

[0592] LC-MS (m / z): 494.0 [M+H] + 。

[0593] Step 2: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (73-2)

[0594] Add compound 73-1 (154.0 mg, 0.31 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (121.1 mg, 0.62 mmol), K 2 CO 3 (129.4 mg, 0.94 mmol) and Pd(dppf)Cl 2 (22.9 mg, 0.03 mmol) to a flask in sequence. Add dioxane (2.5 mL) and water (0.5 mL), and react under microwave irradiation at 110 °C for 1 h under nitrogen protection. After the reaction is completed, dilute the reaction mixture with water (10 mL), extract with EA (30 mL × 3), combine the organic phases, wash with saturated NaCl (30 mL), dry over anhydrous Na 2 SO 4 and filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA: petroleum ether = 1:1), and lyophilize to obtain compound 73-2 (147.0 mg) with a yield of 77.8%.

[0595] LC-MS (m / z): 608.0 [M+H] + 。

[0596] Step 3: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methyl-3-(2,2,2-trifluoroethoxy)pyridazin-4-amine (73)

[0597] Compound 73-2 (147.0 mg, 0.24 mmol) was dissolved in ultradry DMF (5 mL). Under a nitrogen atmosphere, NaH (24.2 mg, 0.61 mmol) was added in an ice-water bath and stirred for 20 minutes. Then MeI (51.6 mg, 0.36 mmol) was added and the reaction was carried out at a constant temperature for 1 hour. After the reaction was completed, the reaction was quenched with an appropriate amount of saturated NH 4 Cl solution in an ice-water bath. The reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated NaCl (20 mL × 3) and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA), then by reverse preparative purification, and freeze-dried to obtain compound 73 (29.5 mg) with a yield of 19.7%.

[0598] LC-MS (m / z): 622.0 [M+H] + 。

[0599] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 8.29 - 8.11 (m, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.97 (s, 1H), 5.17 (q, J = 9.2 Hz, 2H), 4.80 (s, 2H), 4.56 - 4.36 (m, 1H), 3.82 (s, 3H), 3.02 (s, 3H), 1.84 - 1.68 (m, 1H), 1.41 (d, J = 6.4 Hz, 6H), 1.09 - 0.98 (m, 2H), 0.93 - 0.83 (m, 2H).

[0600] Example 37: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-(difluoromethoxy)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-N-methylpyridazin-4-amine (74)

[0601]

[0602] Step 1: Synthesis of 4-bromo-6-chloro-3-(difluoromethoxy)pyridine (74-1)

[0603] Compound 2-1 (1.00 g, 4.77 mmol) was dissolved in ACN (22 mL). An aqueous solution (20 mL) of KOH (5.20 g, 92.79 mmol) and diethyl bromodifluoromethylphosphonate (3.77 g, 14.32 mmol) were added under an ice-water bath, and the reaction was kept warm for 1 hour. The reaction solution was diluted with water (50 mL), extracted with EA (50 mL × 2), the organic phases were combined, washed with saturated NaCl (50 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (EA: petroleum ether = 5:95) to obtain compound 74-1 (209.0 mg) with a yield of 16.9%.

[0604] LC-MS (m / z): 259.0 / 261.0 [M+H] + 。

[0605] Step 2: Synthesis of 6-chloro-3-(difluoromethoxy)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridazin-4-amine (74-2)

[0606] Compound 74-1 (84.0 mg, 0.32 mmol), intermediate INT2 (91.7 mmol, 0.32 mmol) and DIPEA (0.17 mL, 0.97 mmol) were dissolved in DMF (2 mL), and the reaction was carried out at 80 °C for 6 hours. After the reaction solution was cooled to room temperature, it was diluted with water (10 mL), extracted with EA (20 mL × 2), the organic phases were combined, washed with water (10 mL × 2) and saturated NaCl (10 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (EA: petroleum ether = 40:60) to obtain compound 74-2 (124.0 mg) with a yield of 83.9%.

[0607] LC-MS (m / z): 462.0 [M+H] + 。

[0608] Step 3: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-(difluoromethoxy)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyridazin-4-amine (74-3)

[0609] Compound 74-2 (124.0 mg, 0.27 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (104.1 mg, 0.54 mmol), K 2 CO 3(92.8 mg, 0.67 mmol) and Pd(dppf)Cl 2 (19.6 mg, 0.03 mmol) were added to dioxane (3 mL) and water (0.3 mL). Under nitrogen protection, the mixture was placed in a microwave and reacted at 110 °C for 1 hour. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 74-3 (134.0 mg) with a yield of 86.6%.

[0610] LC-MS (m / z): 576.0 [M+H] + 。

[0611] Step 4: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methyl-d 2 )-2-methyl-N-(methyl-d 3 )-2H-pyrazolo[4,3-d]pyrimidin-7-amine (74)

[0612] Compound 74-3 (134.0 mg, 0.23 mmol) was dissolved in anhydrous DMF (2 mL). Under nitrogen protection, NaH (18.6 mg, 0.47 mmol) was added in an ice-water bath. After stirring at the same temperature for 20 minutes, MeI (66.0 mg, 0.47 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was quenched with saturated NH 4 Cl aqueous solution, diluted with water (10 mL), extracted with EA (20 mL × 2). The combined organic phases were washed with water (20 mL) and saturated NaCl (20 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography and then by reverse preparative purification to obtain compound 74 (44.4 mg) with a yield of 32.3%.

[0613] LC-MS (m / z): 590.0 [M+H] + 。

[0614] 1 H NMR (400 MHz, DMSO-d 6)δ8.66(s,1H),8.21 - 8.16(m,1H),7.87(t,J=71.6Hz,1H),7.57(d,J=8.0Hz,2H),7.44(d,J=8.0Hz,2H),7.10(s,1H),4.78(s,2H),4.52 - 4.42(m,1H),3.81(s,3H),3.07(s,3H),1.82 - 1.70(m,1H),1.41(d,J=6.8Hz,6H),1.08 - 0.99(m,2H),0.94 - 0.84(m,2H).

[0615] Example 38: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (75)

[0616]

[0617] Step 1: Synthesis of 1-(4-(1-Isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethanamine (75-1)

[0618] Dissolve compound INT2-3 (500.0 mg, 1.79 mmol) in anhydrous THF (5 mL). Under nitrogen protection, add a toluene / THF solution of methylmagnesium bromide (1.4 M, 2.56 mL, 3.58 mmol) in an ice-water bath, and place the reaction mixture at 60 °C for 4 hours. Re-cool the reaction mixture in an ice-water bath, add LiAlH 4 (136.1 mg, 3.58 mmol), and continue to react at 60 °C for 1 hour. After the reaction mixture is cooled to room temperature, quench it with saturated Na 2 CO 3 aqueous solution, filter, and wash the filter cake with MeOH. Concentrate the filtrate to obtain the crude product of compound 75-1 (880.0 mg), which is directly used in the next step.

[0619] LC-MS (m / z): 298.0 [M+H] + .

[0620] Step 2: Synthesis of 5-Chloro-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (75-2)

[0621] The crude compound 75-1 (880.0 mg), compound 11-5 (302.8 mmol, 1.49 mmol), and DIPEA (0.52 mL, 2.98 mmol) were dissolved in THF (10 mL) and reacted at 50 °C for 1 hour. After the reaction solution cooled to room temperature, it was filtered, and the filter cake was rinsed with EA. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (100% EA) to obtain compound 75-2 (653.0 mg) with a yield of 94.5%.

[0622] LC-MS (m / z): 464.0 [M+H] + 。

[0623] Step 3: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (75)

[0624] Compound 75-2 (653.0 mg, 1.41 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (546.1 mg, 2.82 mmol), K 2 CO 3 (486.3 mg, 3.52 mmol), and Pd(dppf)Cl 2 (103 mg, 0.14 mmol) were added to dioxane (15 mL) and water (1.5 mL). Under nitrogen protection, the mixture was reacted at 100 °C for 16 hours. The reaction solution was diluted with water (30 mL) and extracted with EA (30 mL × 2). The combined organic phases were washed with saturated NaCl (20 mL) and dried over anhydrous Na 2 SO 4 and filtered. After concentration under reduced pressure, the residue was purified by column chromatography (DCM:MeOH = 85:15) to obtain compound 75 (667.0 mg) with a yield of 81.9%.

[0625] LC-MS (m / z): 578.0 [M+H] + 。

[0626] 1 H NMR (400 MHz, DMSO-d 6)δ8.79(d, J = 8.0 Hz, 1H), 8.59(s, 1H), 8.36(s, 1H), 8.20 - 8.15(m, 1H), 7.56(d, J = 8.0 Hz, 2H), 7.48(d, J = 8.0 Hz, 2H), 5.64 - 5.53(m, 1H), 4.51 - 4.36(m, 1H), 4.20(s, 3H), 3.77(s, 3H), 1.72 - 1.62(m, 1H), 1.59(d, J = 7.2 Hz, 3H), 1.43 - 1.35(m, 6H), 0.97 - 0.87(m, 2H), 0.79 - 0.70(m, 1H), 0.69 - 0.57(m, 1H).

[0627] Example 39: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-N-(methyl-d 3 )-2H-pyrazolo[4,3-d]pyrimidin-7-amine (76)

[0628]

[0629] Compound 75 (100.0 mg, 0.17 mmol) was dissolved in anhydrous DMF (2 mL). Under nitrogen protection, NaH (13.9 mg, 0.35 mmol) was added in an ice-water bath. After stirring at the same temperature for 25 minutes, CD 3 I (50.2 mg, 0.35 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. In an ice-water bath, the reaction mixture was quenched with saturated NH 4 Cl aqueous solution, diluted with water (10 mL), extracted with EA (20 mL × 2). The combined organic phases were washed with saturated NaCl (20 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse preparative HPLC to obtain compound 76 (48.7 mg), with a yield of 47.3%.

[0630] LC-MS (m / z): 595.0 [M + H] + .

[0631] 1 1H NMR (400 MHz, DMSO-d 6)δ8.61(s,1H),8.49 - 8.38(m,1H),8.19(s,1H),7.66 - 7.50(m,4H),7.38 - 7.21(m,0.5H),6.69 - 6.55(m,0.5H),4.54 - 4.37(m,1H),4.19(s,3H),3.84(s,3H),1.94 - 1.80(m,1H),1.76 - 1.59(m,3H),1.49 - 1.33(m,6H),1.11 - 0.96(m,2H),0.92 - 0.71(m,2H).

[0632] Example 40: Synthesis of 5-(4 - cyclopropyl - 6 - methoxypyrimidin - 5 - yl)-7-(1-(4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)phenyl)ethoxy)-2 - methyl - 2H - pyrazolo[4,3 - d]pyrimidine (77)

[0633]

[0634] Step 1: Synthesis of 4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)benzaldehyde (77 - 2)

[0635] Dissolve compound INT1 - 4 (1.00 g, 3.52 mmol) in DCM (20 mL), add DMP (3.46 g, 8.15 mmol) at room temperature, and react for 2 hours. Filter the reaction mixture and wash the filter cake with DCM. Wash the filtrate successively with saturated aqueous sodium thiosulfate (20 mL), water (20 mL), and saturated NaCl (20 mL), and dry over anhydrous Na 2 SO 4 dry, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA: petroleum ether = 20:80) to obtain the crude product of compound 77 - 2 (1.13 g), which is directly used in the next step of the reaction.

[0636] LC - MS (m / z): 283.0 [M + H] + .

[0637] Step 2: Synthesis of 1-(4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)phenyl)ethyl - 1 - ol (77 - 3)

[0638] Dissolve the crude product of compound 77 - 2 (1.13 g) in anhydrous THF (20 mL). Under nitrogen protection, add a toluene / THF solution of MeMgBr (1.4 M, 3.77 mL, 5.28 mmol) in an ice - water bath, and place the reaction mixture at room temperature for 0.5 hour. Quench the reaction mixture with saturated NH 4Quenched with aqueous Cl solution, extracted with EA (30 mL×2), the organic phases were combined, washed with saturated NaCl (20 mL), and dried with anhydrous Na 2 SO 4 dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA: petroleum ether = 40:60) to obtain compound 77-3 (741.0 mg), with a two-step yield of 70.6%.

[0639] LC-MS (m / z): 299.0 [M+H] + 。

[0640] Step 3: Synthesis of 5-chloro-7-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethoxy)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (77-4)

[0641] Compound 77-3 (149.0 mg, 0.50 mmol) was dissolved in anhydrous THF (5 mL), NaH (40.0 mg, 1.00 mmol) was added under an ice-water bath, after reacting with heat preservation for 0.5 h, 11-5 (121.8 mg, 0.60 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction solution was quenched with saturated NH 4 Cl aqueous solution, extracted with EA (20 mL×2), the organic phases were combined, washed with saturated NaCl (20 mL), and dried with anhydrous Na 2 SO 4 dried, filtered, concentrated, and purified by column chromatography (EA: petroleum ether = 75:25) to obtain compound 77-4 (245.0 mg), with a yield of 99.9%

[0642] LC-MS (m / z): 465.0 [M+H] + 。

[0643] Step 4: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-N-(methyl-d 3 )-2H-pyrazolo[4,3-d]pyrimidin-7-amine (77)

[0644] Compound 77-4 (245.0 mg, 0.50 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (194.0 mg, 1.00 mmol), K 2 CO 3 (172.7 mg, 1.25 mmol) and Pd(dppf)Cl 2(36.6 mg, 0.05 mmol) was added to dioxane (3 mL) and water (0.3 mL). Under nitrogen protection, the reaction was carried out at 100 °C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 95:5), and then further purified by reverse preparation to obtain compound 77 (36.8 mg) with a yield of 12.7%.

[0645] LC-MS (m / z): 579.0 [M+H] + 。

[0646] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.68 (s, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 6.55 (q, J = 6.4 Hz, 1H), 4.53 - 4.38 (m, 1H), 4.26 (s, 3H), 3.79 (s, 3H), 1.74 (d, J = 6.4 Hz, 3H), 1.68 - 1.59 (m, 1H), 1.46 - 1.35 (m, 6H), 1.03 - 0.96 (m, 2H), 0.85 - 0.78 (m, 1H), 0.76 - 0.68 (m, 1H).

[0647] Example 41: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-N-(methyl-d 3 )-2H-pyrazolo[4,3-d]pyrimidin-7-amine (78)

[0648]

[0649] Step 1: Synthesis of 5-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (78-1)

[0650] INT2 (200.0 mg, 0.71 mmol) was dissolved in THF (10 mL). 11-5 (157.7 mg, 0.78 mmol) and DIPEA (456.2 mg, 3.53 mmol) were added successively, and the reaction was carried out at 50 °C for 1 hour. After the system cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to obtain the crude product of compound 78-1 (330.0 mg), which was directly used for the next step of the reaction.

[0651] LC-MS (m / z): 450.0 [M+H] + 。

[0652] Step 2: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (78-2)

[0653] To the flask were successively added the crude product of compound 78-1 (330.0 mg), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (284.6 mg, 1.47 mmol), K 2 CO 3 (304.2 mg, 2.20 mmol) and Pd(dppf)Cl 2 (53.7 mg, 0.07 mmol). Dioxane (9.0 mL) and water (1.8 mL) were added, and the mixture was reacted under microwave at 110 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (40 mL), dried over anhydrous Na 2 SO 4 , filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to obtain compound 78-2 (329.0 mg) with a yield of 79.7%.

[0654] LC-MS (m / z): 564.0 [M+H] + 。

[0655] Step 3: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-N-(methyl-d 3 )-2H-pyrazolo[4,3-d]pyrimidin-7-amine (78)

[0656] Compound 78-2 (329.0 mg, 0.58 mmol) was dissolved in ultra-dry DMF (10 mL). Under a nitrogen atmosphere and in an ice-water bath, NaH (58.4 mg, 1.46 mmol) was added, and the mixture was stirred for 20 minutes. CD 3 I (92.3 mg, 0.64 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction was quenched with an appropriate amount of saturated NH 4 Cl aqueous solution in an ice-water bath. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (20 mL × 3), dried over anhydrous Na 2 SO 4Dry and filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (DCM:MeOH = 10:1), freeze-dry to obtain compound 78 (246.0 mg) with a yield of 72.8%.

[0657] LC-MS (m / z): 581.0 [M+H] + 。

[0658] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 8.45 (s, 1H), 8.18 (s, 1H), 7.67 - 7.33 (m, 4H), 5.67 (s, 1H), 5.05 (s, 1H), 4.47 (s, 1H), 4.20 (s, 3H), 3.84 (s, 3H), 1.91 - 1.73 (m, 1H), 1.40 (d, J = 6.4 Hz, 6H), 1.10 - 0.67 (m, 4H).

[0659] Example 42: Synthesis of (R)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-N-(methyl-d 3 )-2H-pyrazolo[4,3-d]pyrimidin-7-amine (79)

[0660]

[0661] Step 1: Synthesis of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-one (79-1)

[0662] Dissolve INT2-3 (6.00 g, 21.48 mmol) in ultradry THF (60 mL), add a toluene / THF solution of MeMgBr (1.4 M, 30.8 mL, 43.00 mmol) in an ice-water bath, and react at 60 °C for 2 hours. After the reaction, quench the reaction with a saturated aqueous NH 4 Cl solution in an ice-water bath. Dilute the reaction mixture with water (40 mL), extract with EA (50 mL × 3), combine the organic phases, wash with saturated NaCl (60 mL), and dry over anhydrous Na 2 SO 4 Dry and filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA:petroleum ether = 1:1) to obtain compound 79-1 (4.69 g) with a yield of 73.2%.

[0663] LC-MS (m / z): 297.0 [M+H] + 。

[0664] Step 2: Synthesis of (R)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (79-2)

[0665] Dissolve compound 79-1 (600.0 mg, 2.02 mmol) in ultradry THF (10 mL), and successively add (R)-tert-butanesulfinamide (490.9 mg, 4.05 mmol) and Ti(OiPr) 4 (2.31 g, 8.13 mmol). React at 80 °C for 16 h under a nitrogen atmosphere. After the reaction is completed, quench the reaction with ice-water bath, filter, dilute the filtrate with water (20 mL), extract with EA (30 mL×3), combine the organic phases, wash with saturated NaCl (40 mL), and dry with anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA: petroleum ether = 1:1) to obtain compound 79-2 (610.0 mg) with a yield of 75.5%.

[0666] LC-MS (m / z): 400.0 [M+H] + 。

[0667] Step 3: Synthesis of (R)-N-((R)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (79-3)

[0668] Dissolve compound 79-2 (610.0 mg, 1.53 mmol) in MeOH (10 mL), add cerium chloride (188.6 mg, 0.76 mmol), and add NaBH 4 (87.1 mg, 2.29 mmol) under a nitrogen atmosphere and in an ice-water bath. React for 1 h. After the reaction is completed, quench the reaction with saturated NH 4 Cl aqueous solution in an ice-water bath, filter, dilute the filtrate with water (10 mL), extract with EA (20 mL×3), combine the organic phases, wash with saturated NaCl (30 mL), and dry with anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure. Obtain compound 79-3 (572.0 mg) with a yield of 92.8%.

[0669] LC-MS (m / z): 402.0 [M+H] + 。

[0670] Step 4: Synthesis of (R)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-amine hydrochloride (79-4)

[0671] Dissolve compound 79-3 (572.0 mg, 1.42 mmol) in dioxane (10 mL), add a dioxane solution of hydrogen chloride (10 mL, 4 M), and react at room temperature for 2 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure. Compound 79-4 (423.6 mg) is obtained with a yield of 89.4%.

[0672] LC-MS (m / z): 298.0 [M+H] + 。

[0673] Step 5: Synthesis of (R)-5-chloro-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (79-5)

[0674] Dissolve compound 79-4 (423.6 mg, 1.27 mmol) in THF (10 mL), sequentially add 11-5 (347.1 mg, 1.71 mmol) and DIPEA (920.8 mg, 7.12 mmol), and react at 50 °C for 2 hours. After the system cools to room temperature, concentrate the reaction mixture under reduced pressure, and purify the residue by column chromatography (100% EA) to obtain compound 79-5 (575.0 mg) with a yield of 97.7%.

[0675] LC-MS (m / z): 464.0 [M+H] + 。

[0676] Step 6: Synthesis of (R)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (79-6)

[0677] Sequentially add compound 79-5 (575.0 mg, 1.24 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (481.0 mg, 2.48 mmol), K 2 CO 3 (514.0 mg, 3.72 mmol) and Pd(dppf)Cl 2(90.7 mg, 0.12 mmol), dioxane (9.0 mL) and water (1.8 mL) were added, and the mixture was reacted under microwave irradiation at 110 °C for 1 h under nitrogen protection. After completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (40 mL), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to give compound 79-6 (297.0 mg), with a yield of 41.5%.

[0678] LC-MS (m / z): 578.0 [M + H] + 。

[0679] Step 7: Synthesis of (R)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-N-(methyl-d 3 )-2H-pyrazolo[4,3-d]pyrimidin-7-amine (79)

[0680] Compound 79-6 (297.0 mg, 0.51 mmol) was dissolved in ultradry DMF (10 mL). Under a nitrogen atmosphere, NaH (51.5 mg, 1.29 mmol) was added in an ice-water bath, and the mixture was stirred for 20 min. CD 3 I (111.9 mg, 0.77 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 h. After completion of the reaction, the reaction was quenched with a saturated aqueous solution of NH 4 Cl in an ice-water bath. The reaction mixture was diluted with water (20 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (30 mL × 3), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1), freeze-dried to give compound 79 (192.7 mg), with a yield of 63.2%.

[0681] LC-MS (m / z): 595.0 [M + H] + 。

[0682] 1 H NMR (400 MHz, DMSO-d 6)δ8.61(s,1H),8.53 - 8.37(m,1H),8.19(s,1H),7.67 - 7.44(m,4H),7.36 - 7.21(m,0.5H),6.69 - 6.52(m,0.5H),4.55 - 4.40(m,1H),4.20(s,3H),3.85(s,3H),1.93 - 1.81(m,1H),1.81 - 1.56(m,3H),1.41(dd,J=6.4,3.6Hz,6H),1.11 - 0.93(m,2H),0.95 - 0.69(m,2H).

[0683] Example 43: Synthesis of (S)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-N-(methyl-d 3 )-2H-pyrazolo[4,3-d]pyrimidin-7-amine (80)

[0684]

[0685] Step 1: Synthesis of (S)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethylidene)-2-methylpropane-2-thioamide (80-1)

[0686] Dissolve compound 79-1 (600.0 mg, 2.02 mmol) in dry THF (10 mL), and successively add (S)-tert-butanesulfinamide (490.9 mg, 4.05 mmol) and Ti(OiPr) 4 (2.31 g, 8.13 mmol). React at 80 °C for 16 h under a nitrogen atmosphere. After the reaction is completed, quench the reaction with ice-water bath, filter, dilute the filtrate with water (20 mL), extract with EA (30 mL×3), combine the organic phases, wash with saturated NaCl (40 mL), and dry over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA: petroleum ether = 1:1) to obtain compound 80-1 (690.0 mg) with a yield of 85.4%.

[0687] LC-MS (m / z): 400.0 [M+H] + .

[0688] Step 2: Synthesis of (S)-N-((S)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methylpropane-2-thioamide (80-2)

[0689] Dissolve compound 80-1 (690.0 mg, 1.73 mmol) in MeOH (10 mL), add cerium chloride (213.4 mg, 0.86 mmol), and under a nitrogen atmosphere, add NaBH 4 (98.5 mg, 2.59 mmol) under an ice-water bath and react for 1 hour. After the reaction is completed, quench the reaction with a saturated aqueous solution of NH 4 Cl under an ice-water bath, filter, dilute the filtrate with water (10 mL), extract with EA (20 mL×3), combine the organic phases, wash with saturated NaCl (30 mL), and dry with anhydrous Na 2 SO 4 Filter, concentrate the filtrate under reduced pressure to obtain compound 80-2 (634.0 mg) with a yield of 91.4%.

[0690] LC-MS (m / z): 402.0 [M+H] + .

[0691] Step 3: Synthesis of (S)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-amine (80-3)

[0692] Dissolve compound 80-2 (634.0 mg, 1.58 mmol) in dioxane (10 mL), add hydrogen chloride / dioxane solution (10 mL, 4 M), and react at room temperature for 2 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure, and purify the residue by column chromatography (DCM:MeOH = 10:1) to obtain the crude product of compound 80-3 (654.0 mg).

[0693] LC-MS (m / z): 298.0 [M+H] + .

[0694] Step 4: Synthesis of (S)-5-chloro-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (80-4)

[0695] Dissolve the crude product of compound 80-3 (654.0 mg) in THF (15 mL), successively add 11-5 (535.9 mg, 3.13 mmol) and DIPEA (1.43 g, 11.06 mmol), and react at 50 °C for 2 hours. Wait for the system to cool to room temperature, concentrate the reaction mixture under reduced pressure, and purify the residue by column chromatography (100% EA) to obtain compound 80-4 (591.0 mg) with a two-step yield of 80.6%.

[0696] LC-MS (m / z): 464.0 [M+H] +。

[0697] Step 5: Synthesis of (S)-5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (80-5)

[0698] To the flask were successively added compound 80-4 (591.0 mg, 1.27 mmol), (4-Cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (493.4 mg, 2.54 mmol), K 2 CO 3 (528.3 mg, 3.82 mmol) and Pd(dppf)Cl 2 (93.3 mg, 0.13 mmol). Dioxane (9.0 mL) and water (1.8 mL) were added. The mixture was reacted under microwave at 110 °C for 1 hour under nitrogen protection. After the reaction, the reaction mixture was diluted with water (20 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (40 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to obtain compound 80-5 (600.0 mg) with a yield of 81.6%.

[0699] LC-MS (m / z): 578.0 [M+H] + 。

[0700] Step 6: Synthesis of (S)-5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-N-(methyl-d 3 )-2H-pyrazolo[4,3-d]pyrimidin-7-amine (80)

[0701] Compound 80-5 (600.0 mg, 1.04 mmol) was dissolved in ultra-dry DMF (10 mL). Under nitrogen atmosphere, NaH (103.9 mg, 2.60 mmol) was added in an ice-water bath and stirred for 20 minutes. CD 3 I (225.9 mg, 1.56 mmol) was added and the mixture was reacted at room temperature for 1 hour. After the reaction, the reaction was quenched with a proper amount of saturated NH 4 Cl aqueous solution in an ice-water bath. The reaction mixture was diluted with water (20 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (30 mL × 3), dried over anhydrous Na 2 SO 4Dry and filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (DCM:MeOH = 10:1), lyophilize to obtain Compound 80 (310.2 mg), with a yield of 50.3%.

[0702] LC-MS (m / z): 595.0 [M+H] + 。

[0703] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 8.51 - 8.37 (m, 1H), 8.19 (s, 1H), 7.68 - 7.45 (m, 4H), 7.35 - 7.22 (m, 0.5H), 6.64 - 6.48 (m, 0.5H), 4.59 - 4.38 (m, 1H), 4.19 (s, 3H), 3.84 (s, 3H), 1.94 - 1.79 (m, 1H), 1.78 - 1.59 (m, 3H), 1.41 (dd, J = 6.0, 3.2 Hz, 6H), 1.07 - 0.94 (m, 2H), 0.93 - 0.65 (m, 2H).

[0704] Example 44: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-N,2-dimethyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (81)

[0705]

[0706] Dissolve Compound 75 (100.0 mg, 0.17 mmol) in ultra-dry DMF (5 mL). Under a nitrogen atmosphere, add NaH (17.4 mg, 0.44 mmol) in an ice-water bath, stir for 20 minutes, then add MeI (37.7 mg, 0.26 mmol), and react at room temperature for 1 hour. After the reaction is completed, quench the reaction with an appropriate amount of saturated NH 4 Cl aqueous solution in an ice-water bath. Dilute the reaction mixture with water (10 mL), extract with EA (30 mL × 3), combine the organic phases, wash with saturated NaCl (20 mL × 3), and dry over anhydrous Na 2 SO 4 Dry and filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (DCM:MeOH = 10:1), lyophilize to obtain Compound 81 (67.4 mg), with a yield of 66.1%.

[0707] LC-MS (m / z): 592.0 [M+H] + 。

[0708] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 8.49 - 8.40 (m, 1H), 8.21 - 8.16 (m, 1H), 7.64 - 7.46 (m, 4H), 7.34 - 7.19 (m, 0.5H), 6.69 - 6.52 (m, 0.5H), 4.56 - 4.38 (m, 1H), 4.19 (s, 3H), 3.84 (s, 3H), 3.49 (s, 1.5H), 2.90 (s, 1.5H), 1.91 - 1.80 (m, 1H), 1.79 - 1.58 (m, 3H), 1.45 - 1.35 (m, 6H), 1.08 - 0.95 (m, 2H), 0.93 - 0.71 (m, 2H).

[0709] Example 45: Synthesis of 4-(5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yl)-8-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3,4,5-tetrahydrobenz[f][1,4]oxazepine (82)

[0710]

[0711] Step 1: Synthesis of 5-bromo-2-(((2-hydroxyethyl)amino)methyl)phenol (82-2)

[0712] Dissolve compound 82-1 (9.00 g, 44.78 mmol) in THF (90 mL) and MeOH (15 mL), add 2-aminoethanol (3.29 g, 53.86 mmol), and add NaBH 4 (3.39 g, 89.61 mmol) portionwise under an ice-water bath. After addition, react at 40 °C for 4 hours. Distill the reaction mixture to dryness under reduced pressure to obtain the crude product of compound 82-2 (11.02 g), which is directly used in the next step.

[0713] LC-MS (m / z): 246.0 / 248.0 [M + H] + .

[0714] Step 2: Synthesis of tert-butyl (4-bromo-2-hydroxybenzyl)(2-hydroxyethyl)carbamate (82-3)

[0715] Dissolve the crude product of compound 82-2 (11.02 g) in EA (50 mL) and saturated NaHCO 3 solution (30 mL), add Boc 2O (10.26 g, 47.02 mmol), react at room temperature for 16 h. After the reaction is completed, the reaction mixture is diluted with water (100 mL), extracted with EA (200 mL × 3), the combined organic phases are washed with saturated NaCl (200 mL), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (DCM:MeOH = 10:1) to obtain a solid mixture (12.92 g). The solid is dissolved in MeOH (50 mL), and K 2 CO 3 (7.25 g, 52.46 mmol) is added, and the reaction is carried out at room temperature for 16 h. The reaction mixture is filtered, the filtrate is distilled to dryness under reduced pressure, the reaction mixture is diluted with water (80 mL), adjusted to pH 7 - 8 with 2N hydrochloric acid, extracted with EA (200 mL × 3), the combined organic phases are washed with saturated NaCl (200 mL), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (DCM:EA = 3:1) to obtain compound 82 - 3 (8.31 g), and the two - step yield is 53.6%.

[0716] LC - MS (m / z): 290.0 / 292.0 [M + H - tBu] + 。

[0717] Step 3: Synthesis of tert - butyl 8 - bromo - 2,3 - dihydrobenzo[f][1,4]oxazepine - 4(5H) - carboxylate (82 - 4)

[0718] Dissolve compound 82 - 3 (8.11 g, 23.43 mmol) in DCM (400 mL), add PPh 3 (9.22 g, 35.15 mmol). Under an ice - water bath, DIAD (7.11 g, 35.15 mmol) diluted with DCM (100 mL) is added dropwise, and the reaction is carried out at room temperature for 16 h. The reaction mixture is concentrated under reduced pressure, and the residue is purified by column chromatography (EA:petroleum ether = 1:15) to obtain compound 82 - 4 (5.78 g), with a yield of 75.1%.

[0719] Step 4: Synthesis of tert - butyl 8 - formyl - 2,3 - dihydrobenzo[f][1,4]oxazepine - 4(5H) - carboxylate (82 - 5)

[0720] Compound 82-4 (1.00 g, 3.05 mmol) was dissolved in ultradry THF (10 mL). Under nitrogen protection, a THF solution of n-butyllithium (2.8 mL, 6.09 mmol, 2.2 M) was added at -78 °C, and the reaction was carried out for 1 hour. Subsequently, ultradry DMF (1.12 g, 15.32 mmol) was added at -78 °C, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction was quenched with a saturated aqueous solution of NH 4 Cl at an ice-water bath, diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (20 mL), and anhydrous Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA: petroleum ether = 1:5) to obtain compound 82-5 (109.0 mg) with a yield of 13.0%.

[0721] LC-MS (m / z): 222.0 [M + H - tBu] + .

[0722] Step 5: Synthesis of tert-butyl 8-(4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (82-6)

[0723] To the flask were successively added 3,3-dibromo-1,1,1-trifluoropropan-2-one (117.8 mg, 0.44 mmol), anhydrous NaOAc (36.2 mg, 0.44 mmol), water (0.4 mL) was added, and the reaction was carried out at 100 °C for 1 hour. After the system was cooled to room temperature, compound 82-5 (109.0 mg, 0.39 mmol), ammonia water (0.7 mL) and MeOH (3 mL) were mixed and added, stirred at room temperature for 1 hour, and then reacted at 100 °C for 16 hours. After the system was cooled to room temperature, the reaction solution was concentrated by distillation under reduced pressure. The reaction mixture was diluted with water (10 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl (20 mL), and anhydrous Na 2 SO 4 dried, filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: EA = 1:1) to obtain compound 82-6 (134.0 mg) with a yield of 89.3%.

[0724] LC-MS (m / z): 384.0 [M + H] + .

[0725] Step 6: Synthesis of tert-butyl 8-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (82-7)

[0726] Dissolve compound 82-6 (134.0 g, 0.35 mmol) in ACN (5 mL), and successively add Cs 2 CO 3 (341.7 mg, 1.05 mmol) and 2-iodopropane (297.1 mg, 1.75 mmol), and react at 80 °C for 16 hours. Concentrate the reaction solution under reduced pressure, and purify the residue by column chromatography (petroleum ether:EA = 5:1) to obtain compound 82-7 (110.0 mg) with a yield of 74.3%.

[0727] LC-MS (m / z): 426.0 [M+H] + 。

[0728] Step 7: Synthesis of 8-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (82-8)

[0729] Dissolve compound 82-7 (110.0 g, 0.26 mmol) in EA (2 mL), add hydrogen chloride / ethyl acetate solution (2 mL, 4 M), and react at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure to obtain compound 82-8 (84.0 mg) with a yield of 99.4%.

[0730] LC-MS (m / z): 326.0 [M+H] + 。

[0731] Step 8: Synthesis of 4-(5-chloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yl)-8-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (82-9)

[0732] Dissolve compound 11-5 (58.1 mg, 0.29 mmol) in THF (6 mL), successively add compound 82-8 (84.0 mg, 0.26 mmol) and DIPEA (168.1 mg, 1.30 mmol), and react at 50 °C for 1 hour. Wait for the system to cool to room temperature, concentrate the reaction mixture under reduced pressure, and purify the residue by column chromatography (EA:petroleum ether = 1:1) to obtain compound 82-9 (100.0 mg) with a yield of 78.7%.

[0733] LC-MS (m / z): 492.0 [M+H] + 。

[0734] Step 9: Synthesis of 4-(5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yl)-8-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3,4,5-tetrahydrobenz[f][1,4]oxazepine (82)

[0735] To the flask were successively added compound 82-9 (100.0 mg, 0.20 mmol), (4-Cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (77.6 mg, 0.40 mmol), K 2 CO 3 (82.9 mg, 0.60 mmol) and Pd(dppf)Cl 2 (14.7 mg, 0.02 mmol). Dioxane (2.0 mL) and water (0.4 mL) were added, and the mixture was subjected to microwave reaction at 110 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water (10 mL), extracted with EA (30 mL×3), the combined organic phases were washed with saturated NaCl (30 mL), dried over anhydrous Na 2 SO 4 , filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1), freeze-dried to obtain compound 82 (56.7 mg), with a yield of 46.1%.

[0736] LC-MS (m / z): 606.0 [M+H] + .

[0737] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.75 - 8.55 (m, 1H), 8.47 - 8.38 (m, 1H), 8.16 (s, 1H), 7.84 - 7.67 (m, 1H), 7.27 - 7.19 (m, 1H), 7.15 (s, 1H), 5.69 (s, 1H), 5.07 (s, 1H), 4.93 (s, 1H), 4.56 - 4.42 (m, 1.5H), 4.39 - 4.25 (m, 4H), 4.24 - 4.10 (m, 1.5H), 3.81 (s, 2H), 3.32 - 3.22 (m, 1H), 1.80 - 1.64 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H), 1.08 - 0.97 (m, 2H), 0.90 - 0.76 (m, 2H).

[0738] Example 46: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (83)

[0739]

[0740] Step 1: Synthesis of 4-(1-Isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (77-2)

[0741] Dissolve compound INT1-4 (3.50 g, 12.30 mmol) in DCM (50 mL). Add Dess-Martin periodinane (7.80 g, 18.50 mmol) portionwise at 0 °C and keep the reaction mixture at this temperature for 1 hour. Dilute the reaction mixture with water (50 mL), extract with DCM (50 mL × 3), combine the organic phases, wash with saturated NaCl aqueous solution (30 mL), and dry over anhydrous Na 2 SO 4 dry, filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (petroleum ether: EA = 40%) to obtain compound 77-2 (3.30 g) with a yield of 95.0%.

[0742] LC-MS (m / z): 283.0 [M+H] + .

[0743] Step 2: Synthesis of N-(4-(1-Isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzylidene)-2-methylpropane-2-sulfonamide (83-1)

[0744] Add compound 77-2 (1.80 g, 6.38 mmol) and tert-butylsulfinamide (1.16 g, 9.57 mmol) to a sealed tube in sequence. Add tetrahydrofuran (30 mL), then add titanium(IV) isopropoxide (2.27 g, 7.98 mmol), and react at 80 °C for 16 hours under nitrogen protection. After the reaction is completed, cool to room temperature, quench the reaction by adding water (10 mL), dilute with EA (30 mL), filter, extract the filtrate with EA (30 mL × 3), combine the organic phases, wash with saturated NaCl aqueous solution (40 mL), and dry over anhydrous Na 2 SO 4 dry, filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (petroleum ether: EA = 55%) to obtain compound 83-1 (1.50 g) with a yield of 61.0%.

[0745] LC-MS (m / z): 386.0 [M+H] + .

[0746] Step 3: Synthesis of 2-methyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)propan-2-thioamide (83-2)

[0747] Dissolve tetrabutylammonium difluorotriphenylsilicate (421.0 mg, 0.78 mmol) in ultradry THF (5 mL). Under a nitrogen atmosphere, at -78 °C, add a THF solution (5 mL) of compound 83-1 (1.50 g, 3.90 mmol), stir for 20 minutes, and then add TMSCF 3 (1.38 g, 9.75 mmol). Allow the temperature to rise to 0 °C naturally and react for 2 hours. After the reaction is completed, quench the reaction with saturated NaHCO 3 aqueous solution (5 mL) under an ice-water bath. Dilute the reaction mixture with water (10 mL), extract with EA (30 mL × 3), combine the organic phases, wash with saturated NaCl aqueous solution (20 mL), and dry over anhydrous Na 2 SO 4 Dry, filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (petroleum ether:EA = 60%), and obtain compound 83-2 (1.18 g) with a yield of 66.4%.

[0748] LC-MS (m / z): 456.0 [M+H] + .

[0749] Step 4: Synthesis of N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)propan-2-thioamide (83-3)

[0750] Dissolve NaH (53.0 mg, 1.32 mmol) in ultradry DMF (3 mL). Under a nitrogen atmosphere, in an ice bath, add a DMF solution (5 mL) of compound 83-2 (400.0 mg, 0.88 mmol), stir for 1 hour, then add methyl iodide (142.0 mg, 1.32 mmol) in an ice bath, and react at room temperature for 2 hours. After the reaction is completed, quench the reaction with saturated ammonium chloride aqueous solution under an ice-water bath. Dilute the reaction mixture with water (50 mL), extract with EA (30 mL × 3), combine the organic phases, wash with saturated NaCl aqueous solution (20 mL × 3), and dry over anhydrous Na 2 SO 4 Dry, filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (petroleum ether:EA = 50%), and obtain compound 83-3 (135.0 mg) with a yield of 32.7%.

[0751] LC-MS (m / z): 470.0 [M+H] + 。

[0752] Step 5: Synthesis of 2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-N-methylethane-1-amine (83-4)

[0753] Dissolve compound 83-3 (135.0 mg, 0.29 mmol) in HCl / MeOH (5 mL, 3 M), and stir at room temperature for 1 hour. After the reaction is completed, concentrate under reduced pressure. Adjust the pH value to 8 - 9 with saturated NaHCO 3 aqueous solution, add water (20 mL) for dilution, extract with EA (30 mL × 3), combine the organic phases and wash with saturated NaCl aqueous solution (20 mL × 3), and dry with anhydrous Na 2 SO 4 dry, filter. Concentrate the filtrate under reduced pressure to obtain the crude product of compound 83-4 (89.0 mg).

[0754] LC-MS (m / z): 366.0 [M+H] + 。

[0755] Step 6: Synthesis of 5-chloro-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (83-5)

[0756] Add the crude product of compound 83-4 (89.0 mg), 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (74.0 mg, 0.36 mmol) and DIPEA (93.0 mg, 0.72 mmol) to THF (2 mL), place in a sealed tube, and react at 100 °C for 48 hours under nitrogen protection. After the reaction is completed, cool to room temperature, dilute the reaction mixture with water (20 mL), extract with EA (20 mL × 3), combine the organic phases and wash with saturated NaCl aqueous solution (40 mL), and dry with anhydrous Na 2 SO 4 dry, filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (petroleum ether: EA = 50%), and obtain compound 83-5 (30.0 mg) with a two-step yield of 19.5%.

[0757] LC-MS (m / z): 532.0 [M+H] + 。

[0758] Step 7: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (83)

[0759] To a microwave tube were successively added compound 83-5 (30.0 mg, 0.06 mmol), (4-Cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (17.0 mg, 0.09 mmol), Pd(dppf)Cl 2 (93.0 mg, 5.60 μmol) and K 2 CO 3 (23.0 mg, 0.17 mmol). 1,4-Dioxane (2 mL) and water (0.2 mL) were added, and the mixture was subjected to microwave reaction at 100 °C for 1 hour under nitrogen protection. After the reaction was completed, it was cooled to room temperature. The reaction mixture was diluted with water (20 mL), extracted with EA (20 mL × 3), and the combined organic phases were washed with saturated NaCl aqueous solution (40 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to obtain compound 83 (4.7 mg), with a yield of 13.0%.

[0760] LC-MS (m / z): 646.0 [M+H] + .

[0761] 1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.66 - 8.54 (m, 2H), 8.22 (s, 1H), 8.20 - 8.11 (m, 0.5H), 7.77 - 7.66 (m, 3H), 7.65 - 7.58 (m, 1H), 7.57 - 7.49 (m, 0.5H), 4.51 (s, 1H), 4.29 - 4.19 (m, 3H), 3.89 - 3.82 (m, 3H), 3.61 (s, 1H), 3.05 (s, 1H), 1.94 - 1.77 (m, 1H), 1.45 - 1.39 (m, 6H), 1.06 - 1.01 (m, 2H), 0.90 - 0.84 (m, 2H).

[0762] Example 47: Synthesis of (R)-5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine ((R)-83)

[0763]

[0764] Step 1: Synthesis of (S)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzylidene)-2-methylpropane-2-sulfonamide ((R)-83-1)

[0765] To a sealed tube were successively added compound 77-1 (750.0 mg, 1.95 mmol), (S)-tert-butanesulfinamide (353.7 mg, 2.92 mmol), and tetrahydrofuran (8 mL). Isopropyl titanate (665.1 mg, 2.34 mmol) was added, and the reaction was carried out at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature. The reaction mixture was quenched with water (10 mL), diluted with EA (30 mL), filtered, and the filtrate was extracted with EA (30 mL × 3). The combined organic phases were washed with saturated NaCl aqueous solution (20 mL), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EA = 55%) to obtain compound (R)-83-1 (802.0 mg) with a yield of 78.3%.

[0766] LC-MS (m / z): 386.0 [M+H] + .

[0767] Step 2: Synthesis of (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)propane-2-thioamide ((R)-83-2)

[0768] Tetrabutylammonium difluorotriphenylsilicate (224.9 mg, 0.42 mmol) was dissolved in ultradry THF (10 mL). Under a nitrogen atmosphere and at -78 °C, a THF solution (5 mL) of compound (R)-83-1 (802.0 mg, 2.08 mmol) was added, and the mixture was stirred for 20 minutes. Then TMSCF 3 (739.4 mg, 5.20 mmol) was added, and the reaction was allowed to warm to 0 °C and proceed for 2 hours. After the reaction was completed, the reaction was quenched with saturated NaHCO 3 aqueous solution (5 mL) under an ice-water bath. The reaction mixture was diluted with water (20 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated NaCl aqueous solution (20 mL), and dried over anhydrous Na 2 SO 4Dry and filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (petroleum ether: EA = 60%), obtaining compound (R)-83-2 (500.0 mg) with a yield of 52.8%.

[0769] LC-MS (m / z): 456.0 [M+H] + 。

[0770] Step 3: Synthesis of (S)-N,2-dimethyl-N-((R)-2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)propan-2-thioamide ((R)-83-3)

[0771] Add compound (R)-83-2 (500.0 mg, 1.10 mmol) to THF (5 mL) under a nitrogen atmosphere and in an ice bath. Dropwise add LiHMDS (2.2 mL, 2.20 mmol). After stirring for 0.5 h, add methyl iodide (937.0 mg, 6.60 mmol) in the ice bath and react at room temperature for 2 h. After the reaction is completed, quench the reaction with saturated ammonium chloride aqueous solution in an ice-water bath, dilute with water (50 mL), extract with EA (30 mL × 3), combine the organic phases, wash with saturated NaCl aqueous solution (20 mL × 3), and anhydrous Na 2 SO 4 Dry and filter. Concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (petroleum ether: EA = 50%), obtaining compound (R)-83-3 (450.0 mg) with a yield of 87.3%.

[0772] LC-MS (m / z): 470.0 [M+H] + 。

[0773] Step 4: Synthesis of (R)-2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-N-methylethan-1-amine ((R)-83-4)

[0774] Dissolve compound (R)-83-3 (450.0 mg, 0.96 mmol) in MeOH (1.5 mL), add a methanol solution of hydrogen chloride (3.5 mL, 4 M), and stir at room temperature for 1 h. After the reaction is completed, concentrate under reduced pressure, add water (20 mL) to dilute, adjust the pH value to 8 - 9 with saturated NaHCO 3 aqueous solution in an ice-water bath, extract with EA (30 mL × 3), combine the organic phases, wash with saturated NaCl aqueous solution (20 mL × 3), and anhydrous Na 2 SO 4Dry and filter. The filtrate was concentrated under reduced pressure to obtain compound (R)-83-4 (285.0 mg), and the crude product was directly used in the next reaction.

[0775] LC-MS (m / z): 366.0 [M+H] + 。

[0776] Step 5: Synthesis of (R)-5-chloro-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine ((R)-83-5)

[0777] Add the crude product of compound (R)-83-4 (285.0 mg), 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (235.6 mg, 1.17 mmol) and DIPEA (301.9 mg, 2.34 mmol) to n-butanol (5 mL), place in a sealed tube, and react at 110 °C for 48 hours under nitrogen protection. After the reaction, cool to room temperature, concentrate the reaction solution, add water (20 mL) for dilution, extract with EA (20 mL × 3), combine the organic phases and wash with saturated NaCl aqueous solution (40 mL), anhydrous Na 2 SO 4 Dry and filter. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EA = 50%), to obtain compound (R)-83-5 (102.0 mg), and the two-step yield was 18.4%.

[0778] LC-MS (m / z): 532.0 [M+H] + 。

[0779] Step 6: Synthesis of (R)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine ((R)-83)

[0780] Add compound (R)-83-5 (102.0 mg, 0.19 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (55.8 mg, 0.29 mmol), Pd(dppf)Cl 2 (14.0 mg, 19.18 μmol) and K 2 CO 3(79.4 mg, 0.58 mmol), 1,4-dioxane (4 mL) and water (0.4 mL) were added, and the mixture was reacted under microwave irradiation at 100 °C for 1 h under nitrogen protection. After the reaction was completed, it was cooled to room temperature. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL × 3). The combined organic phases were washed with saturated aqueous NaCl solution (40 mL) and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to give compound (R)-83 (65.3 mg), with a yield of 52.7%.

[0781] LC-MS (m / z): 646.0 [M+H] + 。

[0782] 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.63 - 8.58 (m, 2H), 8.22 (s, 1H), 8.16 (s, 0.5H), 7.71 (s, 3H), 7.61 (s, 1H), 7.53 (s, 0.5H), 4.51 (s, 1H), 4.25 (s, 3H), 3.85 (s, 3H), 3.61 (s, 1.5H), 3.05 (s, 1.5H), 1.88 - 1.81 (m, 1H), 1.43 - 1.41 (m, 6H), 1.04 - 1.03 (m, 2H), 0.91 - 0.83 (m, 2H).

[0783] Example 48: Synthesis of (S)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine ((S)-83)

[0784]

[0785] Step 1: Synthesis of (R)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzylidene)-2-methylpropane-2-sulfonamide ((S)-83-1)

[0786] To the sealed tube, compound 77-2 (750.0 mg, 2.66 mmol), (R)-tert-butanesulfinamide (483.0 mg, 3.99 mmol) and THF (10 mL) were added successively. Isopropyl titanate (943.9 mg, 3.32 mmol) was added, and the reaction was carried out at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature. The reaction mixture was quenched by adding water (10 mL), diluted with EA (30 mL), filtered, and the filtrate was extracted with EA (30 mL×3). The combined organic phases were washed with saturated NaCl aqueous solution (20 mL), and anhydrous Na 2 SO 4 was dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EA = 35%), and compound (S)-83-1 (870.0 mg) was obtained with a yield of 85.3%.

[0787] LC-MS (m / z): 386.0 [M+H] + 。

[0788] Step 2: Synthesis of (R)-2-methyl-N-((S)-2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)propan-2-thioamide ((S)-83-2)

[0789] Tetrabutylammonium difluorotriphenylsilicate (243.8 mg, 0.45 mmol) was dissolved in ultradry THF (10 mL). Under a nitrogen atmosphere, at -78 °C, a THF solution (5 mL) of compound (S)-83-1 (870.0 mg, 2.26 mmol) was added, and the mixture was stirred for 20 minutes. Then TMSCF 3 (801.4 mg, 5.64 mmol) was added, and the temperature was allowed to rise to 0 °C naturally and the reaction was carried out for 2 hours. After the reaction was completed, the reaction was quenched with saturated NaHCO 3 aqueous solution (5 mL) under an ice-water bath. The reaction mixture was diluted with water (20 mL), extracted with EA (30 mL×3), the combined organic phases were washed with saturated NaCl aqueous solution (20 mL), and anhydrous Na 2 SO 4 was dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EA = 60%), and compound (S)-83-2 (421.0 mg) was obtained with a yield of 40.9%.

[0790] LC-MS (m / z): 456.0 [M+H] + 。

[0791] Step 3: Synthesis of (R)-N,2-dimethyl-N-((S)-2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)propane-2-thioamide ((S)-83-3)

[0792] Compound (S)-83-2 (421.0 mg, 0.92 mmol) was added to THF (10 mL) under a nitrogen atmosphere and ice bath. LiHMDS (1.9 mL, 1.85 mmol) was added dropwise. After stirring for 0.5 h, methyl iodide (656.0 mg, 4.62 mmol) was added under ice bath, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution under an ice-water bath, diluted with water (50 mL), extracted with EA (30 mL×3), the combined organic phases were washed with saturated aqueous NaCl solution (20 mL×3), and anhydrous Na 2 SO 4 was dried, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EA = 38%), and compound (S)-83-3 (271.0 mg) was obtained with a yield of 62.6%.

[0793] LC-MS (m / z): 470.0 [M+H] + 。

[0794] Step 4: Synthesis of (S)-2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-N-methylethane-1-amine ((S)-83-4)

[0795] Compound (S)-83-3 (271.0 mg, 0.58 mmol) was dissolved in MeOH (5 mL), and a methanol solution of hydrogen chloride (5 mL, 4 M) was added. The mixture was stirred at room temperature for 1 h. After the reaction was completed, it was concentrated under reduced pressure, diluted with water (20 mL), and the pH value was adjusted to 8 - 9 with saturated aqueous NaHCO 3 solution under an ice-water bath, extracted with EA (30 mL×3), the combined organic phases were washed with saturated aqueous NaCl solution (20 mL×3), and anhydrous Na 2 SO 4 was dried, filtered. The filtrate was concentrated under reduced pressure to obtain the crude product of compound (S)-83-4 (217.0 mg), which was directly used for the next reaction.

[0796] LC-MS (m / z): 366.0 [M+H] + 。

[0797] Step 5: Synthesis of (S)-5-chloro-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine ((S)-83-5)

[0798] The crude product of (S)-83-4 (217.0 mg), 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (180.9 mg, 0.89 mmol) and DIPEA (381.3 mg, 2.95 mmol) were added to THF (4 mL), placed in a sealed tube, and reacted at 120 °C for 48 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EA = 70%), and compound (S)-83-5 (233.0 mg) was obtained, with a two-step yield of 75.9%.

[0799] LC-MS (m / z): 532.0 [M+H] + 。

[0800] Step 6: Synthesis of (S)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine ((S)-83)

[0801] Compound (S)-83-5 (233.0 mg, 0.44 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (170.0 mg, 0.88 mmol), Pd(dppf)Cl 2 (32.1 mg, 0.04 mmol) and K 2 CO 3 (181.7 mg, 1.31 mmol) were successively added to a microwave tube, 1,4-dioxane (4 mL) and water (0.8 mL) were added, and the mixture was subjected to microwave reaction at 100 °C for 1 hour under nitrogen protection. After the reaction was completed, it was cooled to room temperature, the reaction mixture was diluted with water (20 mL), extracted with EA (20 mL × 3), the combined organic phases were washed with saturated NaCl aqueous solution (40 mL), and dried over anhydrous Na 2 SO 4 The residue was concentrated under reduced pressure. The residue was purified by column chromatography (EA), and compound (S)-83 (45.4 mg) was obtained, with a yield of 16.1%.

[0802] LC-MS (m / z): 646.0 [M+H] + 。

[0803] 1H NMR (600 MHz, DMSO-d6) δ 8.67 - 8.54 (m, 2H), 8.26 - 8.20 (m, 1H), 8.19 - 8.11 (m, 0.5H), 7.79 - 7.67 (m, 3H), 7.66 - 7.58 (m, 1H), 7.57 - 7.47 (m, 0.5H), 4.51 (s, 1H), 4.25 (s, 3H), 3.86 (s, 3H), 3.61 (s, 1.5H), 3.05 (s, 1.5H), 1.96 - 1.71 (m, 1H), 1.49 - 1.36 (m, 6H), 1.09 - 0.99 (m, 2H), 0.94 - 0.81 (m, 2H).

[0804] Example 49: Synthesis of 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-3-fluoro-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-5-methoxypyridin-4-amine (84)

[0805]

[0806] Step 1: Synthesis of 2-Chloro-3-fluoro-5-methoxypyridine (84-2)

[0807] Dissolve compound 84-1 (2.00 g, 13.56 mmol) in acetone (20 mL). Add K 2 CO 3 (3.75 g, 27.12 mmol) and MeI (2.31 g, 16.27 mmol) sequentially at room temperature and react for 16 hours. Filter the reaction mixture, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 6%) to obtain compound 84-2 (1.41 g) with a yield of 64.6%.

[0808] LC-MS (m / z): 162.0 [M + H] + .

[0809] Step 2: Synthesis of 2-Chloro-3-fluoro-4-iodo-5-methoxypyridine (84-3)

[0810] Dissolve compound 84-2 (322.0 mg, 2.00 mmol) in anhydrous THF (7 mL). At -78 °C, add n-butyllithium (1.1 mL, 2.2 M solution in THF) dropwise. After maintaining the reaction for 30 minutes, add I 2 (659.9 mg, 2.60 mmol), and continue to react for 2 hours while maintaining the temperature. Treat the reaction mixture with saturated NH 4Quenched with Cl solution, warmed to room temperature, diluted with water (20 mL), extracted with EA (20 mL × 2), combined organic phases, washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 6%) to give compound 84-3 (513.0 mg), with a yield of 89.2%.

[0811] LC-MS (m / z): 288.0 [M+H] + 。

[0812] Step 3: Synthesis of 2-chloro-3-fluoro-N-(1-(4-(1-isopropyl-4-(trifluoromethyl))-1H-imidazol-2-yl)phenyl)ethyl)-5-methoxypyridin-4-amine (84-4)

[0813] Compound 84-3 (143.8 mg, 0.50 mmol), compound 75-1 (178.4 mg, 0.60 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol) and Xantphos (57.9 mg, 0.10 mmol) were added to anhydrous dioxane (5 mL), and Cs 2 CO 3 (325.6 mg, 1.00 mmol) was added. The reaction mixture was placed under nitrogen protection and reacted at 80 °C for 20 hours. After the reaction mixture was cooled to room temperature, it was diluted with water (20 mL), extracted with EA (20 mL × 2), combined organic phases, washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, concentrated, and the residue was purified by column chromatography (MeOH:DCM = 5%) to give compound 84-4 (201.0 mg), with a yield of 88.0%.

[0814] LC-MS (m / z): 457.0 [M+H] + 。

[0815] Step 4: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-3-fluoro-N-(1-(4-1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-5-methoxypyridin-4-amine (84)

[0816] Compound 84-4 (201.0 mg, 0.44 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (170.7 mg, 0.88 mmol), Pd(dppf)Cl 2 (32.2 mg, 44.0 μmol) and anhydrous K2 CO 3 (152.0 mg, 1.10 mmol) was added to a mixed solvent of dioxane (5 mL) and water (0.5 mL). The reaction solution was placed at 100 °C for 16 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was diluted with water (15 mL) and extracted with EA (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, concentrated, and the residue was purified by reverse preparation (100% ACN) to obtain compound 84 (40.5 mg) with a yield of 16.1%.

[0817] LC-MS (m / z): 571.0 [M+H] + 。

[0818] 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.60 (s, 1H), 8.20 - 8.10 (m, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.48 - 7.45 (m, 2H), 7.44 - 7.38 (m, 1H), 5.92 - 5.80 (m, 1H), 5.16 - 5.01 (m, 1H), 4.52 - 4.36 (m, 1H), 3.97 (d, J = 10.2 Hz, 3H), 3.83 (s, 1.5H), 3.65 (s, 1.5H), 1.76 - 1.63 (m, 0.5H), 1.55 (d, J = 6.6 Hz, 3H), 1.43 - 1.35 (m, 6H), 1.29 - 1.21 (m, 0.5H), 1.10 - 1.01 (m, 0.5H), 0.99 - 0.84 (m, 2H), 0.82 - 0.76 (m, 0.5H), 0.76 - 0.69 (m, 0.5H), 0.62 - 0.54 (m, 0.5H).

[0819] Example 50: Synthesis of 5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (85)

[0820]

[0821] Step 1: Synthesis of 1-(4-(1-Isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropylamine (85-1)

[0822] Dissolve INT2-3 (300.0 mg, 1.07 mmol) in anhydrous THF (8 mL), add Ti(OiPr) 4 (336.0 mg, 1.18 mmol) at -78 °C, then slowly add dropwise EtMgBr (1 M, 2.36 mmol), and then raise the temperature to room temperature and react for 1 hour. Slowly add dropwise BF 3 ·Et 2 O (305.0 mg, 2.15 mmol) to the reaction solution, and continue to react at room temperature for 1.5 hours. Quench the reaction solution with hydrochloric acid (1 N), dilute with water (20 mL), adjust to a pH value greater than 8 with aqueous NaOH solution (1 N), then extract with EA (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous Na 2 SO 4 2SO4, filter, concentrate, and purify the residue by column chromatography (MeOH:DCM = 5%) to obtain compound 85-1 (70.0 mg) with a yield of 21.1%.

[0823] LC-MS (m / z): 310.0 [M+H] + 。

[0824] Step 2: Synthesis of 5-chloro-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (85-2)

[0825] Dissolve compound 85-1 (70.0 mg, 0.23 mmol) and 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (55.0 mg, 0.27 mmol) in THF (5 mL), add DIPEA (88.0 mg, 0.68 mmol), and react at 50 °C for 3 hours. After the reaction solution is cooled to room temperature, concentrate the reaction, and purify the residue by column chromatography (100% EA) to obtain compound 85-2 (60.0 mg) with a yield of 55.8%.

[0826] LC-MS (m / z): 476.0 [M+H] + 。

[0827] Step 3: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (85)

[0828] Compound 85-2 (60.0 mg, 0.13 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (49.1 mg, 0.25 mmol), Pd(dppf)Cl 2 (10.0 mg, 13.7 μmol) and anhydrous K 2 CO 3 (44.0 mg, 0.32 mmol) were added to a mixed solvent of dioxane (5 mL) and water (0.5 mL), and the reaction was carried out at 100 °C under nitrogen protection for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with water (15 mL), extracted with EA (20 mL × 2), the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 and filtered, concentrated, and the residue was purified by reverse preparation (100% ACN) to obtain compound 85 (34.2 mg) with a yield of 46.0%.

[0829] LC-MS (m / z): 590.0 [M+H] + 。

[0830] 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.05 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 4.42 (hept, J = 6.6 Hz, 1H), 4.21 (s, 3H), 3.76 (s, 3H), 1.73 (tt, J = 8.2, 4.8 Hz, 1H), 1.53 - 1.41 (m, 2H), 1.40 - 1.29 (m, 8H), 0.90 - 0.80 (m, 2H), 0.67 - 0.55 (m, 2H).

[0831] Example 51: Synthesis of (E)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (86)

[0832]

[0833] Step 1: Synthesis of 2-(4-iodophenyl)-4-(trifluoromethyl)-1H-imidazole (86-2)

[0834] To the flask, 3,3-dibromo-1,1,1-trifluoropropan-2-one (17.44 g, 64.66 mmol), anhydrous KOAc (7.07 g, 86.21 mmol) and water (10 mL) were added successively, and the reaction was carried out at 100 °C for 1 hour. After the system was cooled to room temperature, 86-1 (10.00 g, 43.10 mmol), ammonia water (18 mL) and methanol (80 mL) were mixed and added, and the mixture was stirred at room temperature for 1 hour, and then the reaction was carried out at 100 °C for 16 hours. After the system was cooled to room temperature, the reaction solution was concentrated by distillation under reduced pressure. The reaction mixture was diluted with water (100 mL), extracted with EA (30 mL × 3), the combined organic phases were washed with saturated brine (200 mL), and anhydrous Na 2 SO 4 dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 15% - 40%) to obtain compound 86-2 (9.68 g) with a yield of 66.4%.

[0835] LC-MS (m / z): 339.0 [M+H] + 。

[0836] Step 2: Synthesis of 2-(4-iodophenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (86-3)

[0837] 86-2 (9.68 g, 28.63 mmol), Cs 2 CO 3 (13.98 g, 42.95 mmol), 2-iodopropane (24.34 g, 143.15 mmol), and DMF (100 mL) were placed in a sealed tube and reacted at 80 °C for 48 hours. After the system was cooled to room temperature, the reaction mixture was diluted with EA (100 mL), filtered, and the filtrate was washed with water (400 mL × 4) and saturated brine (200 mL), and anhydrous Na 2 SO 4 dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:PE = 45%) to obtain compound 86-3 (3.83 g) with a yield of 35.2%.

[0838] LC-MS (m / z): 381.0 [M+H] + 。

[0839] Step 3: Synthesis of 1-isopropyl-2-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenyl)-4-(trifluoromethyl)-1H-imidazole (86-4)

[0840] 86-3 (1.20 g, 3.16 mmol), vinylboronic acid pinacol ester (1.46 g, 9.47 mmol), Pd[P(tBu) 3 2 (161.3 mg, 0.32 mmol) and TEA (1.31 mL, 9.47 mmol) were dissolved in anhydrous THF (20 mL), and the reaction was carried out at 65 °C under nitrogen protection for 6 hours. After the reaction solution was cooled to room temperature, it was concentrated to dryness, and the residue was purified by column chromatography (EA:PE = 15% - 40%) to obtain compound 86-4 (0.99 g) with a yield of 77.2%.

[0841] LC-MS (m / z): 407.0 [M+H] + 。

[0842] Step 4: Synthesis of (E)-5-chloro-7-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (86-5)

[0843] 86-4 (0.99 g, 2.44 mmol), 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (543.8 mg, 2.44 mmol), Pd(PPh 3 ) 4 (281.8 mg, 0.24 mmol) and K 3 PO 4 (1.08 g, 4.88 mmol) were added to a mixed solvent of dioxane (25 mL) and water (2.5 mL), and the reaction was carried out at 90 °C under nitrogen protection for 1.5 hours. After the reaction solution was cooled to room temperature, it was diluted with water (40 mL), extracted with EA (40 mL×2), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na 2 SO 4 , filtered, concentrated, and the residue was purified by column chromatography (EA:PE = 80%) to obtain compound 86-5 (621.0 mg) with a yield of 56.9%.

[0844] LC-MS (m / z): 447.0 [M+H] + 。

[0845] Step 5: Synthesis of (E)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (86)

[0846] ​86-5 (620.0 mg, 1.39 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (538.0 mg, 2.77 mmol), Pd(dppf)Cl 2 (101.5 mg, 0.14 mmol) and anhydrous K 2 CO 3 (479.3 mg, 3.47 mmol) were added to a mixed solvent of dioxane (14 mL) and water (1.4 mL). The reaction mixture was placed under nitrogen protection and reacted at 100 °C for 16 hours. After the reaction mixture was cooled to room temperature, it was diluted with water (20 mL), extracted with EA (20 mL × 2), the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 . After filtration and concentration, the residue was purified by column chromatography (100% EA) to obtain compound 86 (643.0 mg) with a yield of 82.5%.

[0847] LC-MS (m / z): 561.0 [M+H] + .

[0848] 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.86 (s, 1H), 8.70 (s, 1H), 8.60 (d, J = 16.2 Hz, 1H), 8.23 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 16.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 4.58 (hept, J = 6.6 Hz, 1H), 4.40 (s, 3H), 3.85 (s, 3H), 1.66 (tt, J = 8.4, 4.8 Hz, 1H), 1.45 (d, J = 6.6 Hz, 6H), 1.12 - 0.99 (m, 2H), 0.94 - 0.85 (m, 2H).

[0849] Example 52: Synthesis of 6-cyclopropyl-5-(7-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)(methyl)amino)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-5-yl)pyrimidin-4-ol (87)

[0850]

[0851] Compound 12 (100.0 mg, 0.17 mmol) was added to 2N dilute hydrochloric acid (5 mL), and the mixture was reacted at 50 °C for 2 hours and then at 70 °C for 2 hours. After the reaction mixture was cooled to room temperature, it was extracted with EA (10 mL) and dried over anhydrous Na 2 SO4 Dry, filter, concentrate, and purify the residue by column chromatography (MeOH:DCM = 10%), to obtain Compound 87 (65.8 mg) with a yield of 67.4%.

[0852] LC-MS (m / z): 564.0 [M+H] + 。

[0853] 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.39 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.60 - 7.40 (m, 4H), 5.73 - 5.56 (m, 1H), 5.13 - 5.00 (m, 1H), 4.48 - 4.38 (m, 1H), 4.18 (s, 3H), 3.83 - 3.63 (m, 1.5H), 3.21 - 3.04 (m, 1.5H), 1.77 - 1.59 (m, 1H), 1.39 (d, J = 6.6 Hz, 6H), 1.02 - 0.85 (m, 2H), 0.83 - 0.76 (m, 1H), 0.73 - 0.55 (m, 1H).

[0854] Example 53: Synthesis of (R)-2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-((1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (88)

[0855]

[0856] Step 1: Synthesis of (R)-2-Chloro-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-amine (88-2)

[0857] Add 88-1 (100.0 mg, 0.48 mmol), 79-4 (194.0 mg, 0.58 mmol) and DIPEA (0.25 mL, 1.46 mmol) to THF (3 mL), and react at 50 °C for 24 hours. Concentrate the reaction solution, and purify the residue by column chromatography (EA:PE = 45%) to obtain Compound 88-2 (122.0 mg) with a yield of 54.0%.

[0858] LC-MS (m / z): 468.0 [M+H] + 。

[0859] Step 2: Synthesis of (R)-2-chloro-4-((1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (88-3)

[0860] Dissolve 88-2 (120.0 mg, 0.26 mmol) in TFA (2 mL), add H 2 O 2 (0.2 mL, 35%) at room temperature, and place the reaction mixture at 45 °C for 0.5 h. Concentrate the reaction solution to dryness, and purify the residue by column chromatography (EA:PE = 45%) to obtain compound 88-3 (112.0 mg) with a yield of 87.4%.

[0861] LC-MS (m / z): 500.0 [M+H] + .

[0862] Step 3: Synthesis of (R)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (88)

[0863] Add 88-3 (112.0 mg, 0.22 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (86.9 mg, 0.45 mmol), Pd(dppf)Cl 2 (16.4 mg, 22.0 μmol) and anhydrous K 2 CO 3 (77.4 mg, 0.56 mmol) to a mixed solvent of dioxane (3 mL) and water (0.3 mL). Under nitrogen protection, place the reaction mixture at 100 °C for 16 h. After the reaction mixture is cooled to room temperature, dilute it with water (20 mL), extract it with EA (20 mL×2), combine the organic phases, wash them with saturated brine (20 mL), dry over anhydrous Na 2 SO 4 , filter, concentrate, purify the residue by column chromatography (100% EA), and then by reverse preparative purification (ACN as the mobile phase) to obtain compound 88 (72.1 mg) with a yield of 52.4%.

[0864] LC-MS (m / z): 614.0 [M+H] + .

[0865] 1 H NMR (600 MHz, DMSO-d 6)δ8.64(s,1H),8.29(d,J=8.4Hz,1H),8.17(s,1H),7.58-7.48(m,4H),5.67-5.59(m,1H),4.44(hept,J=6.6Hz,1H),3.80(s,3H),3.67(t,J=6.6Hz,2H),3.33-3.28(m,2H),1.69-1.62(m,1H),1.60(d,J=7.2Hz,3H),1.45-1.32(m,6H),1.02-0.94(m,2H),0.87-0.81(m,1H),0.75-0.64(m,1H).

[0866] Example 54: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (89)

[0867]

[0868] Step 1: Synthesis of 2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-amine (89-2)

[0869] Dissolve 83-2 (350.0 mg, 0.77 mmol) in HCl / MeOH (5 mL, 4 M), and stir at room temperature for 1 hour. After the reaction is completed, concentrate under reduced pressure. Dilute the residue with water (20 mL), and adjust the pH value to 8-9 with saturated NaHCO 3 aqueous solution. Extract with EA (50 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 3), and dry over anhydrous Na 2 SO 4 . Filter, concentrate the filtrate under reduced pressure to obtain the crude product of compound 89-2 (250.0 mg), which is directly used in the next step of the reaction.

[0870] LC-MS (m / z): 352.0 [M+H] + .

[0871] Step 3: Synthesis of 5-chloro-2-methyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (89-3)

[0872] 89-2 (250.0 mg), 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (216.7 mg, 1.07 mmol), and DIPEA (276.6 mg, 2.14 mmol) were added to THF (5 mL), and the reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction solution was cooled to room temperature, the reaction mixture was diluted with water (30 mL), extracted with EA (30 mL × 3), the organic phases were combined, washed with saturated brine (40 mL × 2), and dried over anhydrous Na 2 SO 4 dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 70%) to obtain compound 89-3 (125.0 mg) with a two-step yield of 31.4%.

[0873] LC-MS (m / z): 518.0 [M+H] + 。

[0874] Step 5: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (89)

[0875] 89-3 (125.0 mg, 0.24 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (70.1 mg, 0.36 mmol) were added to dioxane (4 mL), and then Pd(dppf)Cl 2 (17.5 mg, 24.1 μmmol), K 2 CO 3 (100.0 mg, 0.72 mmol) and water (0.4 mL) were added, and the reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction solution was cooled to room temperature, the reaction mixture was diluted with water (20 mL), extracted with EA (20 mL × 3), the combined organic phases were washed with saturated brine (40 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (100% EA) to obtain compound 89 (111.0 mg) with a yield of 72.8%.

[0876] LC-MS (m / z): 632.0 [M+H] + 。

[0877] 1 H NMR (600 MHz, DMSO-d 6)δ9.63(d, J = 9.6Hz, 1H), 8.63(s, 1H), 8.52(s, 0.2H), 8.48(s, 0.8H), 8.19(s, 1H), 7.90(d, J = 7.8Hz, 2H), 7.67(s, 0.4H), 7.62(d, J = 7.8Hz, 1.6H), 7.28(s, 0.2H), 6.61 - 6.53(m, 0.8H), 4.52 - 4.41(m, 1H), 4.29(s, 0.6H), 4.24(s, 2.4H), 3.80(s, 3H), 1.75 - 1.62(m, 1H), 1.45 - 1.37(m, 6H), 1.05 - 0.96(m, 2H), 0.90 - 0.70(m, 2H).

[0878] Example 55: Synthesis of (R)-5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine ((R)-89)

[0879]

[0880] Step 1: Synthesis of (R)-2,2,2-Trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-amine ((R)-89-1)

[0881] Dissolve compound (R)-83-2 (120.0 mg, 0.26 mmol) in HCl / MeOH (4M, 2 mL), and stir at room temperature for 2 hours. After the reaction is completed, concentrate under reduced pressure. Adjust the pH value to 8 - 9 with saturated NaHCO 3 aqueous solution, add water (20 mL) for dilution, extract with DCM (30 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), and dry with anhydrous Na 2 SO 4 Filter, and concentrate the filtrate under reduced pressure to obtain the crude product of (R)-89-1 (90.0 mg), which is directly used in the next step of the reaction.

[0882] LC-MS (m / z): 352.0 [M + H] + .

[0883] Step 2: Synthesis of (R)-5-Chloro-2-methyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine ((R)-89-2)

[0884] The crude product of (R)-89-1 (90.0 mg), 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (78.0 mg, 0.40 mmol), DIPEA (99.0 mg, 0.77 mmol) and n-butanol (2 mL) were added into a sealed tube and reacted at 100 °C for 16 h under nitrogen protection. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 60%), and compound (R)-89-2 (123.0 mg) was obtained with a two-step yield of 90.4%.

[0885] LC-MS (m / z): 518.0 [M+H] + 。

[0886] Step 3: Synthesis of (R)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine ((R)-89)

[0887] (R)-89-1 (123.0 mg, 0.24 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (69.0 mg, 0.36 mmol), Pd(dppf)Cl 2 (18.0 mg, 24.6 μmol) and K 2 CO 3 (98.0 mg, 0.71 mmol) were added into dioxane (3 mL) and water (0.3 mL), and reacted by microwave at 100 °C for 1 h under nitrogen protection. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (100% EA), and compound (R)-89 (73.2 mg) was obtained with a yield of 48.8%.

[0888] LC-MS (m / z): 632.0 [M+H] + 。

[0889] 1 H NMR (600 MHz, DMSO-d 6)δ9.65(d,J=9.6Hz,1H),8.63(s,1H),8.54 - 8.45(m,1H),8.20(s,1H),7.94 - 7.85(m,2H),7.70 - 7.59(m,2H),7.28(s,0.2H),6.61 - 6.52(m,0.8H),4.51 - 4.41(m,1H),4.32 - 4.19(m,3H),3.80(s,3H),1.74 - 1.61(m,1H),1.44 - 1.36(m,6H),1.05 - 0.96(m,2H),0.90 - 0.72(m,2H).

[0890] Example 56: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methyl-N-(2,2,2-trifluoroethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (90)

[0891]

[0892] Dissolve compound 75 (578.0 mg, 1.00 mmol) in anhydrous DMF (5 mL). Under an ice-water bath, add NaH (120.0 mg, 2.00 mmol). After maintaining the reaction temperature for 15 minutes, add 2,2,2-trifluoroethyl trifluoromethanesulfonate (696.3 mg, 3.00 mmol), and allow the reaction to proceed at room temperature for 1 hour. Quench the reaction mixture with saturated NH 4 Cl aqueous solution, dilute with water (20 mL), extract with EA (20 mL×2), combine the organic phases, wash with water (20 mL×3) and saturated brine (20 mL), dry over anhydrous Na 2 SO 4 , filter, concentrate, and purify the residue by column chromatography (MeOH:DCM = 5%), to obtain compound 90 (118.2 mg) with a yield of 17.9%.

[0893] LC-MS (m / z): 660.0 [M+H] + .

[0894] 1 1H NMR (600 MHz, DMSO-d 6)δ8.61(s,1H),8.60 - 8.53(m,1H),8.17(s,1H),7.63 - 7.45(m,4H),7.38 - 7.21(m,0.5H),6.47 - 6.11(m,0.5H),5.48 - 5.25(m,1H),4.78 - 4.58(m,1H),4.50 - 4.37(m,1H),4.23(s,3H),3.80(s,3H),1.77(d,J=6.6Hz,3H),1.76 - 1.70(m,1H),1.42 - 1.34(m,6H),1.07 - 0.92(m,2H),0.88 - 0.74(m,2H).

[0895] Example 57: Synthesis of (R)-5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-ethyl-2-methyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (91)

[0896]

[0897] Dissolve compound (R)-89 (150.0 mg, 0.28 mmol) in anhydrous DMF (5 mL). Under nitrogen protection at -20 °C, add NaH (14.3 mg, 0.36 mmol) and react for 1 hour. Then add EtI (56.6 mg, 0.36 mmol) and react for 2 hours. Add saturated NH 4 Cl aqueous solution (20 mL) to quench the reaction. Extract with EA (30 mL × 3). Combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous Na 2 SO 4 Filter, concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (100% EA), and then by reverse preparative purification (100% ACN) to obtain compound 91 (36.6 mg), with a yield of 23.4%.

[0898] LC-MS (m / z): 660.0 [M + H] + .

[0899] 1 1H NMR (600 MHz, DMSO-d 6)δ 8.74 - 8.73 (d, J = 10.4 Hz, 1H), 8.26 - 8.26 (m, 1H), 8.18 - 8.17 (m, 1H), 7.65 - 7.64 (d, J = 7.9 Hz, 1H), 7.58 - 7.57 (d, J = 7.9 Hz, 1H), 7.53 - 7.51 (m, 2H), 6.06 - 6.02 (m, 0.5H), 5.93 - 5.90 (m, 0.5H), 4.48 - 4.44 (m, 1H), 4.06 (s, 3H), 3.95 (s, 2H), 3.79 (s, 1H), 3.73 - 3.58 (m, 2H), 1.83 - 1.80 (m, 0.5H), 1.41 - 1.39 (m, 6H), 1.23 - 1.21 (m, 1H), 1.14 - 1.10 (m, 3H), 1.05 - 0.96 (m, 2H), 0.88 - 0.88 (m, 0.5H), 0.78 - 0.77 (m, 0.5H), 0.47 - 0.45 (m, 0.5H).

[0900] Example 58: Synthesis of (R)-2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-N-(2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-9H-purin-6-amine (92)

[0901]

[0902] Step 1: Synthesis of 2-Chloro-N-methyl-9-(tetrahydro-2H-pyran-2-yl)-N-((R)-2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-9H-purin-6-amine (92-1)

[0903] Add (R)-93-5 (500.0 mg, 1.48 mmol), 4,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 4.89 mmol), DIPEA (573.8 mg, 4.44 mmol) and n-butanol (10 mL) into a sealed tube, and react at 100 °C under nitrogen protection for 48 hours. After the reaction solution is cooled to room temperature, the reaction mixture is diluted with water (30 mL), extracted with EA (30 mL × 3), the organic phases are combined, washed with saturated brine (40 mL × 2), dried over anhydrous Na 2 SO 4 dried, filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography (EA:PE = 70%), to obtain compound 92-1 (15.0 mg), with a yield of 1.8%.

[0904] LC-MS (m / z): 574.0 [M+H] + 。

[0905] Step 2: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-9-(tetrahydro-2H-pyran-2-yl)-N-((R)-2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-9H-purin-6-amine (92-2)

[0906] 92-1 (15.0 mg, 26.1 μmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (7.6 mg, 39.1 μmol), Pd(dppf)Cl 2 (1.9 mg, 2.6 μmol) and K 2 CO 3 (10.8 mg, 78.5 μmol) were added to dioxane (3 mL) and water (0.3 mL), and the mixture was subjected to microwave reaction at 100 °C under nitrogen protection for 1 hour. After the reaction solution was cooled to room temperature, the reaction mixture was diluted with water (20 mL), extracted with EA (20 mL × 3), the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (100% EA) to obtain compound 92-2 (4.0 mg) with a yield of 22.3%.

[0907] LC-MS (m / z): 688.0 [M+H] + 。

[0908] Step 3: Synthesis of (R)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-N-(2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-9H-purin-6-amine (92)

[0909] 92-2 (4.0 mg, 5.2 μmol) was dissolved in HCl / MeOH (4 M, 3 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (100% EA) to obtain compound 92 (3.4 mg) with a yield of 96.8%.

[0910] LC-MS (m / z): 604.0 [M+H] + 。

[0911] 1 H NMR (600 MHz, DMSO-d 6)δ 13.47 (s, 1H), 8.65 (s, 1H), 8.41 - 8.34 (m, 1H), 7.97 (s, 1H), 7.87–7.86 (d, J = 8.0 Hz, 2H), 7.69 - 7.59 (m, 2H), 7.20 (s, 0.5H), 6.66 (s, 0.5H), 3.86 (s, 3H), 3.81 (s, 3H), 3.31 (s, 3H), 1.88 - 1.81 (m, 1H), 1.06 - 1.02 (m, 2H), 0.89 - 0.88 (m, 2H).

[0912] Example 59: Synthesis of (R)-6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-N-(2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ((R)-93)

[0913]

[0914] Step 1: Synthesis of 4-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde ((R)-93-1)

[0915] Dissolve compound INT6-2 (3.10 g, 12.10 mmol) in DCM (50 mL), add DMP (7.70 g, 18.15 mmol) portionwise at 0 °C, and keep the reaction at this temperature for 1 hour. Dilute the reaction mixture with water (150 mL), extract with DCM (100 mL × 3), dry over anhydrous Na 2 SO 4 , filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 30%) to obtain compound (R)-93-1 (2.60 g) with a yield of 84.5%.

[0916] LC-MS (m / z): 255.0 [M + H] + .

[0917] Step 2: Synthesis of (S)-2-Methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzylidene)propane-2-sulfinamide ((R)-93-2)

[0918] Add (R)-93-1 (3.20 g, 12.50 mmol), tert-butylsulfinamide (2.27 g, 18.75 mmol), and THF (30 mL) to a sealed tube in sequence, and then add Ti(OiPr) 4(4.50 g, 15.60 mmol), reacted at 80 °C for 16 h under nitrogen protection. After the reaction was completed, it was cooled to room temperature. The reaction mixture was quenched by adding water (50 mL), diluted with EA (30 mL), filtered, and the filtrate was extracted with EA (50 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 2), and dried over anhydrous Na 2 SO 4 dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 60%), to obtain compound (R)-93-2 (2.10 g), with a yield of 46.7%.

[0919] LC-MS (m / z): 358.0 [M+H] + 。

[0920] Step 3: Synthesis of (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)propane-2-sulfonamide ((R)-93-3)

[0921] Dissolve TBAT (750.0 mg, 1.39 mmol) in ultradry THF (10 mL), add a THF solution (10 mL) of (R)-93-2 (2.50 g, 6.99 mmol) at -78 °C under nitrogen protection, stir at the same temperature for 20 min, add TMSCF 3 (2.96 g, 20.82 mmol), and allow it to warm up to 0 °C naturally and then continue the reaction for 3 h while maintaining the temperature. After the reaction was completed, the reaction was quenched with a saturated NaHCO 3 aqueous solution (15 mL) under an ice-water bath. The reaction mixture was diluted with water (25 mL), extracted with EA (50 mL × 3), the combined organic phases were washed with saturated brine (30 mL × 2), and dried over anhydrous Na 2 SO 4 dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 60%), to obtain compound (R)-93-3 (1.70 g), with a yield of 56.9%.

[0922] LC-MS (m / z): 428.0 [M+H] + 。

[0923] Step 4: Synthesis of (S)-N,2-dimethyl-N-((R)-2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)propane-2-sulfinamide ((R)-93-4)

[0924] (R)-93-3 (1.70 g, 3.98 mmol) was added to THF (15 mL). LiHMDS (1 M, 8 mL) was added dropwise under an ice bath and nitrogen protection. After stirring for 0.5 h, MeI (1.69 g, 11.94 mmol) was added under the ice bath, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction was quenched with a saturated NH 4 Cl aqueous solution (25 mL). The reaction mixture was diluted with water (50 mL), extracted with EA (50 mL×3), the organic phases were combined, washed with saturated brine (40 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 50%), and compound (R)-93-4 (1.40 g) was obtained with a yield of 79.7%.

[0925] LC-MS (m / z): 442.0 [M+H] + .

[0926] Step 5: Synthesis of (R)-2,2,2-trifluoro-N-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-amine ((R)-93-5)

[0927] (R)-93-4 (1.40 g, 3.17 mmol) was dissolved in HCl / MeOH (4 M, 15 mL), and stirred at room temperature for 1 h. After the reaction was completed, it was concentrated under reduced pressure, diluted with water (20 mL), and the pH value was adjusted to 8-9 with a saturated NaHCO 3 aqueous solution. It was extracted with EA (50 mL×3), the organic phases were combined, washed with saturated brine (30 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound (R)-93-5 (1.00 g), which was directly used for the next reaction.

[0928] LC-MS (m / z): 338.0 [M+H] + .

[0929] Step 6: Synthesis of 6-chloro-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-((R)-2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ((R)-93-6)

[0930] (R)-93-5 (450.0 mg, 1.33 mmol), 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 4.89 mmol), DIPEA (515.7 mg, 3.99 mmol) and n-butanol (10 mL) were added into a sealed tube, and the reaction was carried out at 100 °C under nitrogen protection for 48 hours. After the reaction was completed, it was cooled to room temperature. The reaction mixture was diluted with water (30 mL), extracted with EA (30 mL×3), the organic phases were combined, washed with saturated brine (40 mL×2), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 70%) to obtain compound (R)-93-6 (101.0 mg) with a two-step yield of 12.3%.

[0931] LC-MS (m / z): 574.0 [M+H] + 。

[0932] Step 7: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-((R)-2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ((R)-93-7)

[0933] (R)-93-6 (101.0 mg, 0.18 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (51.2 mg, 0.26 mmol), Pd(dppf)Cl 2 (12.8 mg, 17.6 μmol) and K 2 CO 3 (73.0 mg, 0.53 mmol) were added to dioxane (4 mL) and water (0.4 mL), and the reaction was carried out under microwave irradiation at 100 °C for 1 hour under nitrogen protection. After the reaction was completed, it was cooled to room temperature. The reaction mixture was diluted with water (20 mL), extracted with EA (20 mL×3), the organic phases were combined, washed with saturated brine (40 mL), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (100% EA) to obtain compound (R)-93-7 (40.0 mg) with a yield of 33.1%.

[0934] LC-MS (m / z): 688.0 [M+H] + 。

[0935] Step 8: Synthesis of (R)-6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-N-(2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ((R)-93)

[0936] Dissolve (R)-93-7 (40.0 mg, 58.2 μmol) in HCl / MeOH (4 M, 5 mL), and stir at room temperature for 1 hour. After the reaction is completed, concentrate under reduced pressure and separate by thin-layer chromatography (100% EA) to obtain compound (R)-93 (18.3 mg) with a yield of 52.1%.

[0937] LC-MS (m / z): 604.0 [M+H] + 。

[0938] 1 H NMR (600 MHz, DMSO-d 6 ) δ 13.90 (s, 1H), 8.67 (s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 7.85 - 7.84 (d, J = 8.1 Hz, 2H), 7.59 - 7.58 (d, J = 8.1 Hz, 2H), 7.48 (s, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.32 (s, 3H), 1.92 - 1.91 (m, 1H), 1.07 - 1.05 (m, 2H), 0.89 - 0.87 (m, 2H).

[0939] Example 60: Synthesis of (S)-6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-N-(2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ((S)-93)

[0940]

[0941] Step 1: Synthesis of (R)-2-Methyl-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzylidene)propane-2-sulfinamide ((S)-93-1)

[0942] Sequentially add (R)-93-1 (5.08 g, 19.98 mmol), R-tert-butanesulfinamide (3.63 g, 29.95 mmol), THF (100 mL) and Ti(OiPr) 4(7.10 g, 24.98 mmol), reacted at 80 °C for 16 h under nitrogen protection. After the reaction was completed, it was cooled to room temperature. The reaction mixture was quenched with water (50 mL), filtered, and the filter cake was washed with EA (40 mL). The filtrate was extracted with EA (30 mL × 3). The combined organic phases were washed with saturated brine (40 mL) and dried over anhydrous Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 50%) to obtain compound (S)-93-1 (5.84 g) with a yield of 81.8%.

[0943] LC-MS (m / z): 358.0 [M+H] + 。

[0944] Step 3: Synthesis of (R)-2-methyl-N-((S)-2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)propane-2-sulfonamide ((S)-93-2)

[0945] Dissolve (S)-93-1 (5.84 g, 16.34 mmol) in ultradry THF (100 mL). Under nitrogen protection at -78 °C, add a THF solution (10 mL) of TBAT (1.77 g, 3.27 mmol), stir for 20 min, and then add TMSCF 3 (5.79 g, 40.72 mmol). Allow it to warm up to 0 °C naturally and react for 3.5 h. After the reaction is completed, quench the reaction with a saturated NH 4 Cl aqueous solution (5 mL) under an ice-water bath. Dilute the reaction mixture with water (10 mL), extract with EA (30 mL × 3), wash the combined organic phases with saturated brine (20 mL), and dry over anhydrous Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 60%) to obtain compound (S)-93-2 (4.06 g) with a yield of 58.1%.

[0946] LC-MS (m / z): 428.0 [M+H] + 。

[0947] Step 4: Synthesis of (R)-N,2-dimethyl-N-((S)-2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)propane-2-sulfonamide ((S)-93-3)

[0948] (S)-93-2 (2.00 g, 4.68 mmol) was added to THF (15 mL). LiHMDS (1 M, 9.37 mL) was added dropwise under an ice bath and nitrogen protection. After stirring for 0.5 h, MeI (2.66 g, 18.7 mmol) was added under the ice bath, and the reaction was carried out at room temperature for 2 h. The reaction was quenched with saturated NH 4 Cl aqueous solution under an ice-water bath. The reaction mixture was diluted with water (30 mL), extracted with EA (30 mL × 3), the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 60%), and compound (S)-93-3 (1.80 g) was obtained with a yield of 87.2%.

[0949] LC-MS (m / z): 442.0 [M+H] + .

[0950] Step 5: Synthesis of (S)-2,2,2-trifluoro-N-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-amine ((S)-93-4)

[0951] (S)-93-3 (1.80 g, 4.08 mmol) was dissolved in HCl / MeOH (4 M, 10 mL), and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure. The pH value was adjusted to 8 - 9 with saturated NaHCO 3 3 aqueous solution under an ice-water bath. The solution was diluted with water (20 mL), extracted with DCM (30 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 3), and dried over anhydrous Na 2 SO 4 4. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound (S)-93-4 (1.26 g), which was directly used in the next step of the reaction.

[0952] LC-MS (m / z): 338.0 [M+H] + .

[0953] Step 6: Synthesis of 6-chloro-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-((S)-2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ((S)-93-5)

[0954] The crude product of (S)-93-4 (617.0 mg), 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 3.66 mmol), DIPEA (944.0 mg, 7.32 mmol) and n-butanol (3 mL) were added into a sealed tube, and the reaction was carried out at 100 °C for 24 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 80%), and compound (S)-93-5 (177.0 mg) was obtained with a two-step yield of 7.6%.

[0955] LC-MS (m / z): 574.0 [M+H] + 。

[0956] Step 7: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-((S)-2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ((S)-93-6)

[0957] (S)-93-5 (177.0 mg, 0.31 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (90.0 mg, 0.46 mmol), Pd(dppf)Cl 2 (23.0 mg, 0.03 mmol) and K 2 CO 3 (127.0 mg, 0.92 mmol) were added to dioxane (5 mL) and water (0.5 mL), and the reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction solution was cooled to room temperature, the reaction mixture was diluted with water (20 mL), extracted with EA (20 mL×3), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (100% EA) to obtain compound (S)-93-6 (128.0 mg) with a yield of 60.4%.

[0958] LC-MS (m / z): 688.0 [M+H] + 。

[0959] Step 8: Synthesis of (S)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-N-(2,2,2-trifluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine ((S)-93)

[0960] (S)-93-6 (128.0 mg, 0.19 mmol) was dissolved in methanol (3 mL), and TsOH·H 2 O (176.8 mg, 0.93 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was diluted with EA (30 mL) and washed with saturated NaHCO 3 solution (10 mL × 3), and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (100% EA) and then by reverse preparative purification (100% ACN) to obtain compound (S)-93 (50.1 mg) with a yield of 44.6%.

[0961] LC-MS (m / z): 604.0 [M+H] + .

[0962] 1 1H NMR (600 MHz, DMSO-d 6 ) δ 13.88 (s, 1H), 8.66 (s, 1H), 8.39 (s, 1H), 7.97 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.48 (s, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.35 (s, 3H), 1.95 - 1.88 (m, 1H), 1.08 - 1.04 (m, 2H), 0.92 - 0.84 (m, 2H).

[0963] Example 61: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(3,3-difluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutyl)-N,2-dimethyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (94)

[0964]

[0965] Step 1: Synthesis of 2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole (94-2)

[0966] Dissolve 1,1-dibromo-3,3,3-trifluoroacetone (32.08 g, 118.90 mmol) in water (50 mL), add sodium acetate (9.75 g, 118.90 mmol), and react at 100 °C for 1 hour. After the reaction solution is cooled to room temperature, add a methanol (70 mL) solution containing 94-1 (20.00 g, 108.10 mmol) and ammonia water (50 mL) to the reaction solution, stir at room temperature for 0.5 hour, and then heat to 100 °C and react for 16 hours. After the reaction solution is cooled, concentrate the reaction solution, extract with EA (200 mL × 3), combine the organic phases, and use anhydrous Na 2 SO 4 dry, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 20%), to obtain compound 94-2 (16.00 g) with a yield of 50.9%.

[0967] LC-MS (m / z): 291.0 / 293.0 [M+H] + 。

[0968] Step 2: Synthesis of 2-(4-bromophenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (94-3)

[0969] Dissolve 94-2 (16.00 g, 54.97 mmol) and K 2 CO 3 (25.66 g, 185.70 mmol) in ACN (350 mL), add MeI (43.90 g, 309.37 mmol), and stir at room temperature for 16 hours. Add water (1 L) to the reaction mixture, extract with EA (500 mL × 3), combine the organic phases, wash with saturated brine (500 mL × 2), and use anhydrous Na 2 SO 4 dry, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 50%), to obtain compound 94-3 (12.00 g) with a yield of 71.6%.

[0970] LC-MS (m / z): 305.0 / 307.0 [M+H] + 。

[0971] Step 3: Synthesis of 2-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)acetonitrile (94-4)

[0972] Dissolve 94-3 (6.00 g, 19.67 mmol), 4-isoxazoleboronic acid pinacol ester (2.00 g, 29.39 mmol) and Pd(dpp)Cl 2(1.43 g, 1.95 mmol) was dissolved in DMF (150 mL), and an aqueous solution of KF (3.42 g, 58.83 mmol) (59 mL) was added. The mixture was stirred at 120 °C under nitrogen protection for 16 hours. The reaction mixture was quenched by adding water (500 mL), and extracted with EA (350 mL × 3). The organic phases were combined, washed with saturated brine (350 mL × 2), and dried over anhydrous Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 50%), and compound 94-4 (2.10 g) was obtained with a yield of 40.2%.

[0973] LC-MS (m / z): 266.0 [M+H] + 。

[0974] Step 4: Synthesis of 3,3-dimethoxy-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutane-1-carbonitrile (94-5)

[0975] 94-4 (2.10 g, 7.92 mmol) and 1,3-dibromo-2,2-dimethoxypropane (2.30 g, 8.80 mmol) were dissolved in DMF (25 mL), and NaH (633.6 mg, 15.84 mmol) was added. The mixture was stirred at 60 °C under nitrogen protection for 16 hours. The reaction mixture was quenched by adding water (100 mL), and extracted with EA (150 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), and dried over anhydrous Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 50%), and compound 94-5 (1.40 g) was obtained with a yield of 48.4%.

[0976] LC-MS (m / z): 366.0 [M+H] + 。

[0977] Step 5: Synthesis of 3,3-dimethoxy-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutane-1-carboxylic acid (94-6)

[0978] 94-5 (1.40 g, 3.83 mmol) was added to dioxane (15 mL), and then an aqueous solution of NaOH (306.4 mg, 7.66 mmol) (2 M, 3.8 mL) was added. The reaction was carried out at 90 °C for 16 hours. After the reaction solution was cooled to room temperature, the pH value was adjusted to 1-2 with 1N HCl, and extracted with EA (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 2), and dried over anhydrous Na 2SO 4 Dry, filter, and concentrate the filtrate under reduced pressure to obtain the crude product of 94-6 (1.24 g), which is directly used for the next reaction.

[0979] LC-MS (m / z): 383.0 [M-H] - 。

[0980] Step 6: Synthesis of methyl 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-3-oxocyclobutane-1-carboxylate (94-7)

[0981] Dissolve 94-6 (1.24 g) in methanol (10 mL), add concentrated hydrochloric acid (4 mL), and react at room temperature for 16 hours. Concentrate the reaction solution under reduced pressure, dilute the residue with water (40 mL), extract with EA (40 mL × 3), combine the organic phases, and dry over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA:PE = 60%) to obtain compound 94-7 (250.0 mg) with a two-step yield of 18.5%.

[0982] LC-MS (m / z): 353.0 [M+H] + 。

[0983] Step 7: Synthesis of methyl 3,3-difluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutane-1-carboxylate (94-8)

[0984] Dissolve 94-7 (250.0 mg, 0.71 mmol) in ultra-dry DCM (5 mL), add DAST (580.3 mg, 3.60 mmol), and stir at room temperature for 16 hours. Concentrate the reaction solution under reduced pressure. Purify the residue by column chromatography (EA:PE = 60%) to obtain compound 94-8 (80.0 mg) with a yield of 30.1%.

[0985] LC-MS (m / z): 375.0 [M+H] + 。

[0986] Step 8: Synthesis of 3,3-difluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutane-1-carboxylic acid (94-9)

[0987] 94-8 (80.0 mg, 0.21 mmol) was added to THF (5 mL), followed by the addition of water (2 mL) and lithium hydroxide monohydrate (42.0 mg, 1.00 mmol). The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The pH value was adjusted to 1 - 2 with 1N HCl, and then extracted with EA (30 mL × 3). The organic phases were combined and dried over anhydrous Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of 94-9 (50.0 mg), which was directly used in the next step of the reaction.

[0988] LC-MS (m / z): 359.0 [M-H] - 。

[0989] Step 9: Synthesis of 3,3-difluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutane-1-carbonyl azide (94-10)

[0990] The crude product of 94-9 (50.0 mg) was added to toluene (5 mL), followed by the addition of diphenylphosphoryl azide (57.8 mg, 0.21 mmol) and triethylamine (42.5 mg, 0.42 mmol). The reaction was carried out at 80 °C under nitrogen protection for 4 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain the crude product of 94-10 (102.0 mg), which was directly used in the next step of the reaction.

[0991] LC-MS (m / z): 386.0 [M+H] + 。

[0992] Step 10: Synthesis of tert-butyl 3,3-difluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutyl)carbamate (94-11)

[0993] The crude product of 94-10 (102.0 mg) was dissolved in tert-butanol (5 mL), and stirred at 80 °C under nitrogen protection for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 60%), to obtain compound 94-11 (30.0 mg), with a three-step yield of 32.5%

[0994] LC-MS (m / z): 432.0 [M+H] + 。

[0995] Step 11: Synthesis of 3,3-difluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutan-1-amine (94-12)

[0996] 94-11 (30.0 mg, 69.6 μmol) was added to HCl / MeOH (4 M, 5 mL), and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The pH value was adjusted to 8 - 9 with saturated NaHCO 3 aqueous solution, and extracted with EA (20 mL × 3). Anhydrous Na 2 SO 4 was used for drying, and then filtered. The filtrate was concentrated under reduced pressure to obtain compound 94-12 (22.0 mg) with a yield of 95.4%.

[0997] LC-MS (m / z): 332.0 [M + H] + 。

[0998] Step 12: Synthesis of 5-chloro-N-(3,3-difluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (94-13)

[0999] 94-12 (20.2 mg, 99.5 μmol) and DIPEA (25.8 mg, 0.20 mmol) were added to n-butanol (2 mL), and the reaction was carried out at 120 °C under nitrogen protection for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 70%) to obtain compound 94-13 (13.0 mg) with a yield of 39.4%.

[1000] LC-MS (m / z): 498.0 [M + H] + 。

[1001] Step 13: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(3,3-difluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (94-14)

[1002] 94-13 (34.0 mg, 68.3 μmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (19.9 mg, 0.10 mmol), Pd(dppf)Cl 2 (5.0 mg, 6.8 μmol) and K 2 CO 3(28.3 mg, 0.20 mmol) was added to dioxane (4 mL), followed by the addition of water (0.4 mL). The reaction was carried out at 100 °C under microwave irradiation and nitrogen protection for 1 hour. After the reaction solution was cooled to room temperature, it was diluted with water (20 mL) and extracted with EA (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to obtain compound 94-14 (15.0 mg) with a yield of 35.9%.

[1003] LC-MS (m / z): 612.0 [M+H] + 。

[1004] Step 14: Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(3,3-difluoro-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclobutyl)-N,2-dimethyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (94)

[1005] 94-14 (15.0 mg, 24.5 μmol) was dissolved in DMF (3 mL). NaH (1.5 mg, 36.8 μmol) was added at -15 °C, and the reaction was carried out under nitrogen protection for 0.5 hour. Then MeI (10.4 mg, 73.5 μmol) was added, and the reaction was kept at a certain temperature for 2 hours. The reaction solution was quenched with water (20 mL) and extracted with EA (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparation (100% ACN) to obtain compound 94 (0.8 mg) with a yield of 5.2%.

[1006] LC-MS (m / z): 626.0 [M+H] + 。

[1007] Example 62: Synthesis of (R)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-N-(methyl-d 3 )-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (95)

[1008]

[1009] (R)-89 (120.0 mg, 0.19 mmol) was added to DMF (3 mL). Under ice-salt bath and nitrogen protection, NaH (11.4 mg, 0.29 mmol) was added, and the mixture was kept warm for reaction for 0.5 h. Then CD 3 I (80.9 mg, 0.57 mmol) was added, and the mixture was kept warm for reaction for 2 h. After the reaction was completed, the reaction mixture was quenched by adding water (20 mL), and extracted with EA (25 mL × 3). The organic phases were combined, washed with saturated NaCl aqueous solution (30 mL × 2), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure and purified by preparative column to obtain compound 95 (22.9 mg) with a yield of 18.6%.

[1010] LC-MS (m / z): 649.0 [M+H] + .

[1011] 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.64 - 8.56 (m, 2H), 8.22 (s, 1H), 8.18 - 8.13 (m, 0.5H), 7.76 - 7.66 (m, 3H), 7.63 - 7.58 (m, 1H), 7.54 - 7.50 (m, 0.5H), 4.55 - 4.51 (m, 1H), 4.25 (s, 3H), 3.85 (s, 3H), 1.91 - 1.77 (m, 1H), 1.43 - 1.41 (m, 6H), 1.04 - 1.03 (m, 2H), 0.92 - 0.83 (m, 2H).

[1012] Example 63: Synthesis of (R)-6-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (96)

[1013]

[1014] Step 1: Synthesis of 6-Chloro-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-N-((R)-2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (96-1)

[1015] (R)-83-4 (851.0 mg, 2.33 mmol), 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (636.0 mg, 2.33 mmol), DIPEA (2.03 mL, 11.65 mmol) and n-butanol (23 mL) were added into a sealed tube, and the reaction was carried out at 120 °C for 4 hours under nitrogen protection. After the reaction solution was cooled to room temperature, the reaction mixture was diluted with EA (50 mL), washed with water (30 mL) and saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (EA:DCM = 8%), to obtain compound 96-1 (130.0 mg) with a yield of 9.3%.

[1016] LC-MS (m / z): 602.0 [M+H] + 。

[1017] Step 2: Synthesis of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-H-((R)-2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (96-2)

[1018] 96-1 (130.0 mg, 0.22 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (84.0 mg, 0.43 mmol), Pd(dppf)Cl 2 (16.0 mg, 0.02 mmol) and K 2 CO 3 (90.0 mg, 0.65 mmol) were added to dioxane (3 mL) and water (0.6 mL), and the reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction solution was cooled to room temperature, the reaction solution was concentrated to dryness and purified by column chromatography (EA:PE = 50%) to obtain compound 96-2 (101.0 mg) with a yield of 65.3%.

[1019] LC-MS (m / z): 716.0 [M+H] + 。

[1020] Step 3: Synthesis of (R)-6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-methyl-N-(2,2,2-trifluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (96)

[1021] 96 - 2 (101.0 mg, 0.14 mmol) was dissolved in MeOH (3 mL), and TsOH·H 2 O (134.0 mg, 0.71 mmol) was added. The reaction was carried out at room temperature for 3 hours. The reaction solution was diluted with EA (20 mL) and washed successively with aqueous NaHCO 3 solution (20 mL), water (20 mL), and saturated brine (20 mL), dried over anhydrous NaSO 4 , filtered, and the filtrate was concentrated. The residue was purified by column chromatography (MeOH:DCM = 3%) to obtain compound 96 (57.1 mg) with a yield of 64.1%.

[1022] LC-MS (m / z): 632.0 [M + H] + .

[1023] 1 H NMR (600 MHz, DMSO-d 6 ) δ 13.90 (brs, 1H), 8.66 (s, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.49 (s, 1H), 4.49 (hept, J = 6.6 Hz, 1H), 3.88 (s, 3H), 3.35 (s, 3H), 1.91 (tt, J = 8.4, 4.8 Hz, 1H), 1.45 - 1.39 (m, 6H), 1.09 - 1.00 (m, 2H), 0.92 - 0.82 (m, 2H).

[1024] Example 64: Synthesis of (R)-5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (97)

[1025]

[1026] Step 1: Synthesis of methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (97 - 2)

[1027] 97-1 (2.00 g, 12.05 mmol) and 1,1,1-trifluoropentane-2,4-dione (1.86 g, 12.05 mmol) were dissolved in HFIP (10 mL). HFIP (10 mL) containing triethylamine (2.43 g, 24.10 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (EA:PE = 12%), to obtain compound 97-2 (2.51 g) with a yield of 73.4%.

[1028] LC-MS (m / z): 285.0 [M+H] + 。

[1029] Step 2: Synthesis of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (97-3)

[1030] 97-2 (2.51 g, 8.84 mmol) was dissolved in ultradry THF (20 mL). At 0 °C, LiAlH 4 (503.8 mg, 13.26 mmol) was added portionwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with MeOH (20 mL) in an ice-water bath. The reaction mixture was concentrated under reduced pressure, diluted with water (50 mL) and saturated aqueous potassium sodium tartrate solution (150 mL), and extracted with EA (150 mL × 3). The combined organic phases were washed with saturated brine (150 mL × 2), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of 97-2 (2.05 g), which was directly used in the next step of the reaction.

[1031] LC-MS (m / z): 257.0 [M+H] + 。

[1032] Step 3: Synthesis of 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzaldehyde (97-4)

[1033] The crude product of 97-3 (2.05 g) was dissolved in DCM (50 mL). At 0 °C, DMP (5.98 g, 12.02 mmol) was added portionwise, and the reaction was carried out with heat preservation for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL × 3), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 38%) to obtain compound 97-4 (1.31 g) with a two-step yield of 58.4%.

[1034] LC-MS (m / z): 255.0 [M+H] + 。

[1035] Step 4: Synthesis of (S,E)-2-methyl-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylidene)propane-2-sulfinamide (97-5)

[1036] Add 97-4 (1.31 g, 5.16 mmol), (S)-tert-butylsulfinamide (936.5 mg, 7.74 mmol) and THF (10 mL) into a sealed tube in sequence, add Ti(OiPr) 4 (1.91 g, 6.71 mmol), and react at 80 °C for 16 hours under nitrogen protection. After the reaction is completed, cool to room temperature, quench the reaction by adding water (50 mL) to the reaction mixture, dilute with EA (30 mL), filter, extract the filtrate with EA (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), and use anhydrous Na 2 SO 4 dry, filter. Concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 60%), to obtain compound 97-5 (1.35 g), with a yield of 73.3%.

[1037] LC-MS (m / z): 358.0 [M+H] + .

[1038] Step 5: Synthesis of (S)-2-methyl-N-((R)-2,2,2-trifluoro-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)propane-2-sulfinamide (97-6)

[1039] Dissolve TBAT (410.3 mg, 0.76 mmol) in ultra-dry THF (10 mL), add the THF solution (10 mL) of 97-5 (1.35 g, 3.78 mmol) at -78 °C under nitrogen protection, stir for 20 minutes while maintaining the temperature, add TMSCF 3 (1.61 g, 11.34 mmol), and continue to react for 3 hours while maintaining the temperature after naturally warming up to 0 °C. After the reaction is completed, quench the reaction with saturated NaHCO 3 aqueous solution (20 mL) under an ice-water bath, dilute the reaction mixture with water (50 mL), extract with EA (50 mL × 3), combine the organic phases and wash with saturated brine (30 mL × 2), and use anhydrous Na 2 SO 4 dry, filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (EA:PE = 50%), to obtain compound 97-6 (1.25 g), with a yield of 77.2%.

[1040] LC-MS (m / z): 428.0 [M+H]+ .

[1041] Step 6: Synthesis of (S)-N,2-dimethyl-N-((R)-2,2,2-trifluoro-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)propan-2-sulfinamide (97-7)

[1042] Add 97-6 (1.25 g, 2.92 mmol) to THF (10 mL), dropwise add LiHMDS (1 M, 5.9 mL) under ice bath and nitrogen protection. After stirring for 0.5 h, add MeI (1.25 g, 8.76 mmol) under ice bath and react at 0 °C for 2 h. After the reaction is completed, quench the reaction with saturated NH 4 Cl aqueous solution (20 mL) under ice-water bath. Dilute the reaction mixture with water (30 mL), extract with EA (50 mL×3), combine the organic phases, wash with saturated brine (30 mL×2), and dry with anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 35%) to obtain compound 97-7 (912.0 mg) with a yield of 70.9%.

[1043] LC-MS (m / z): 442.0 [M+H] + .

[1044] Step 7: Synthesis of (R)-2,2,2-trifluoro-N-methyl-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-1-ethanamine hydrochloride (97-8)

[1045] Add 97-7 (912 mg, 2.07 mmol) to HCl / EA (4 M, 15 mL), then add MeOH (10 mL), and stir at room temperature for 1 h. After the reaction is completed, concentrate under reduced pressure, dilute with water (20 mL), and adjust the pH value to 8-9 with saturated NaHCO 3 aqueous solution under ice-water bath. Extract with EA (30 mL×3), combine the organic phases, wash with saturated brine (30 mL), and dry with anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate under reduced pressure to obtain the crude product of 97-8 (612.0 mg), which is directly used for the next step of the reaction.

[1046] LC-MS (m / z): 338.0 [M+H] + .

[1047] Step 8: Synthesis of (R)-5-chloro-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (97-9)

[1048] Add 97-8 (400.0 mg, 1.07 mmol), 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (362.4 mg, 1.79 mmol), DIPEA (460.5 mg, 3.57 mmol) and n-BuOH (4 mL) into a sealed tube, and react at 120 °C for 16 hours under nitrogen protection. After the reaction solution is cooled to room temperature, concentrate it under reduced pressure. The residue is purified by column chromatography (EA:PE = 0% - 62%) to obtain compound 97-9 (175.0 mg), and the two-step yield is 25.9%.

[1049] LC-MS (m / z): 504.0 [M+H] + 。

[1050] Step 9: Synthesis of (R)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N,2-dimethyl-N-(2,2,2-trifluoro-1-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine (97)

[1051] Add 97-9 (175.0 mg, 0.35 mmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (102.8 mg, 0.53 mmol), Pd(dppf)Cl 2 (25.6 mg, 35.0 μmol) and K 2 CO 3 (144.9 mg, 1.05 mmol) into a mixed solvent of dioxane (5 mL) and water (1 mL), and react at 90 °C for 16 hours under nitrogen protection. After the reaction solution is cooled to room temperature, concentrate it under reduced pressure. Add water (20 mL) to dilute the residue, extract it with EA (20 mL × 3), combine the organic phases, wash with saturated brine (30 mL), dry with anhydrous Na 2 SO 4 , filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (EA:PE = 0% - 100%) to obtain compound 97 (30.4 mg), with a yield of 14.1%.

[1052] LC-MS (m / z): 618.0 [M+H] + 。

[1053] 11H NMR (600 MHz, DMSO-d 6 ) δ 8.65 - 8.57 (m, 2H), 8.19 - 8.14 (m, 0.5H), 7.78 - 7.69 (m, 3H), 7.67 - 7.61 (m, 1H), 7.58 - 7.50 (m, 0.5H), 6.80 (s, 1H), 4.25 (s, 3H), 3.85 (s, 3H), 3.61 (s, 1.5H), 3.05 (s, 1.5H), 2.38 (s, 3H), 1.88 - 1.80 (m, 1H), 1.04 - 1.03 (m, 2H), 0.91 - 0.86 (m, 2H).

[1054] Example 65: Synthesis of (R)-5-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-N-(2,2-difluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-N,2-dimethyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (98)

[1055]

[1056] Step 1: Synthesis of (S)-N-((R)-2,2-Difluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (98-1)

[1057] Dissolve (R)-83-1 (834.0 mg, 2.17 mmol) in THF (10 mL). Under nitrogen protection at -78 °C, add TMSCF 3 (667.0 mg, 5.42 mmol), and then slowly add dropwise THF (5 mL) containing t-BuOK (5.4 mL, 1 M). Keep the temperature at -78 °C for 15 minutes, and then transfer to room temperature and stir for 15 minutes. Quench the reaction mixture by adding water (30 mL), extract with EA (30 mL × 3), combine the organic phases, wash with saturated brine (30 mL × 2), dry over anhydrous Na 2 SO 4 , filter, concentrate, and purify the residue by column chromatography (EA:PE = 10 - 30%). Compound 98-1 (105.0 mg) is obtained with a yield of 11.1%.

[1058] LC-MS (m / z): 438.0 [M + H]+.

[1059] Step 2: Synthesis of (S)-N-((R)-2,2-Difluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-N,2-dimethylpropane-2-sulfinamide (98-2)

[1060] 98 - 1 (105.0 mg, 0.24 mmol) was added to THF (5 mL). Under ice - bath and nitrogen protection, LiHMDS (1 M, 0.48 mL) was added dropwise. After stirring for 0.5 h, MeI (102.0 mg, 0.72 mmol) was added under ice - bath, and the mixture was stirred with heat preservation for 2 h. The reaction solution was quenched with aqueous NH 4 Cl solution (5 mL), diluted with water (20 mL), extracted with EA (30 mL×3), the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 10 - 40%), to obtain compound 98 - 2 (85.0 mg) with a yield of 79.2%.

[1061] LC - MS (m / z): 452.0 [M + H] + 。

[1062] Step 3: Synthesis of (R)-2,2 - difluoro - 1-(4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)phenyl)-N - methyl - 1 - ethanamine (98 - 3)

[1063] 98 - 2 (85.0 mg, 0.19 mmol) was dissolved in HCl / MeOH (4 M, 5 mL), and the mixture was reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, diluted with water (10 mL), adjusted to pH 8 - 9 with aqueous NaHCO 3 solution, extracted with EA (20 mL×3), and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated to obtain the crude product of 98 - 3 (59.0 mg), which was directly used for the next reaction.

[1064] LC - MS (m / z): 348.0 [M + H] + 。

[1065] Step 4: Synthesis of (R)-5 - chloro - N-(2,2 - difluoro - 1-(4-(1 - isopropyl - 4-(trifluoromethyl)-1H - imidazol - 2 - yl)phenyl)ethyl)-N,2 - dimethyl - 2H - pyrazolo[4,3 - d]pyrimidin - 7 - amine (98 - 4)

[1066] 98-3 crude product (59.0 mg), 5,7-dichloro-2-methyl-2H-pyrazolo[4,3-d]pyrimidine (52.8 mg, 0.26 mmol), DIPEA (65.8 mg, 0.51 mmol) and n-BuOH (2 mL) were added into a sealed tube, and the reaction was carried out at 110 °C for 24 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was diluted with water (20 mL), extracted with EA (20 mL×3), washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (EA:PE = 70%), to obtain compound 98-4 (25.0 mg), with a two-step yield of 25.6%.

[1067] LC-MS (m / z): 514.0 [M+H] + 。

[1068] Step 5: Synthesis of (R)-5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(2,2-difluoro-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethyl)-N,2-dimethyl-2H-pyrazolo[4,3-d]pyrimidin-7-amine (98)

[1069] 98-4 (25.0 mg, 48.6 μmol), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (14.1 mg, 72.9 μmol), Pd(dppf)Cl 2 (3.6 mg, 4.9 μmol) and K 2 CO 3 (20.7 mg, 0.15 mmol) were added to a mixed solvent of dioxane (3 mL) and water (0.6 mL), and the reaction was carried out at 90 °C for 16 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was diluted with water (20 mL), extracted with EA (20 mL×3), the organic phases were combined and washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 dried, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (MeOH:DCM = 10%), to obtain compound 98 (18.9 mg), with a yield of 61.7%.

[1070] LC-MS (m / z): 628.0 [M+H] + 。

[1071] 1 H NMR (600 MHz, DMSO-d 6)δ8.62(s,1H),8.56 - 8.51(d,J=34.0Hz,1H),8.21(s,1H),7.70 - 7.58(m,4.5H),7.27 - 6.98(m,1H),6.81 - 6.77(m,0.5H),4.53 - 4.45(m,1H),4.25 - 4.22(d,J=21.7Hz,3H),3.85 - 3.83(m,3H),3.67(s,1.5H),3.06(s,1.5H),1.87 - 1.77(m,1H),1.41 - 1.40(m,6H),1.03 - 1.01(m,2H),0.91 - 0.82(m,2H).

[1072] Example 66: Inhibitory Experiment on the Proliferation of MDA - MB - 436 Cells

[1073] In this experiment, MDA - MB - 436 cells were used. After treatment with the test compound, the ability of cell proliferation was detected. At the beginning of the experiment, MDA - MB - 436 cells were added to a 96 - well plate, 500 cells per well, and allowed to adhere overnight. The next day, the compound diluted in gradient was added and the plate was placed in an incubator at 37°C with 5% CO 2 and continued to be cultured. On the 5th day of drug administration, the old culture medium was discarded, and the test compound diluted in gradient was added again. On the 10th day of drug administration, the 96 - well plate was taken out, CCK8 detection reagent was added, and after incubation at 37°C for 2 hours, the OD value was detected at 450 nM using a TEcan microplate reader. Using GraphPad Prism software, the IC 50 value was calculated. The results are shown in Table 1.

[1074] Table 1 Inhibitory Activity of the Compound on the Proliferation of MDA - MB - 436 Cells

[1075]

[1076]

Note

[1077] Example 67: Test on the Inhibitory Activity of USP1 / UAF1 Enzyme Activity

[1078] In this experiment, Ub-RhO110 was used as a substrate to detect the activity of deubiquitinating enzyme USP1 / UAF1 after drug treatment. At the beginning of the experiment, 0.5 nM of USP1 / UAF1 protein was added into a 384-well plate, and then the test compounds with gradient dilution were added. After incubation at room temperature for 15 min, 500 nM Ub-RhO110 was added. After incubation at room temperature for 20 min, detection was performed using a Tecan microplate reader at an excitation wavelength of 485 nM and an emission wavelength of 535 nM. Using GraphPad Prism software, the IC 50 value was calculated. The results are shown in Table 2.

[1079] Table 2 Inhibitory activity of compounds against USP1 / UAF1 enzyme

[1080]

[1081] Example 68: Inhibitory effect of compounds on hERG ion channel

[1082] The inhibitory effect of compounds on the human hERG ion channel stably expressed in HEK293 cells was tested by traditional patch clamp. The compounds were formulated into a concentration of 10 μM. Each cell was used as its own control. The compounds were perfused using a perfusion system utilizing their own gravity. After the current was stabilized in each cell, the hERG current magnitudes before and after adding the compounds were compared, and the blocking effect of the compounds on the hERG current was calculated. The results are shown in Table 3.

[1083] Table 3 Blocking effect of compounds on hERG current

[1084]

[1085] Example 69: Detection of metabolic stability of test compounds

[1086] 1. Preparation of experimental materials

[1087] 1.1 Incubation buffer

[1088] Weigh a certain amount of anhydrous sodium dihydrogen phosphate into a centrifuge tube, add an appropriate amount of ultrapure water, vortex and mix well to prepare a sodium dihydrogen phosphate solution with a concentration of 0.1 mol / L for standby; weigh a certain amount of anhydrous disodium hydrogen phosphate into a centrifuge tube, add an appropriate amount of ultrapure water, vortex and mix well to prepare a disodium hydrogen phosphate solution with a concentration of 0.1 mol / L for standby; the sodium dihydrogen phosphate solution (0.1 mol / L) and the disodium hydrogen phosphate solution (0.1 mol / L) were mixed in a reagent bottle at a ratio of 19:81 (v:v), mixed well to obtain a PB buffer solution with a concentration of 100 mmol / L (the concentration is based on the phosphate ion concentration), and stored at 2 - 8 °C for standby.

[1089] 1.2 Liver microsomes

[1090] Human liver microsomes (HLM).

[1091] 1.3 Initiation factor (NADPH and UDPGA mixed solution)

[1092] Accurately weigh an appropriate amount of NADPH into a 1.5 mL centrifuge tube, add an appropriate amount of PB solution, vortex and mix well to prepare a NADPH solution with a concentration of 40 mmol / L, place it on ice for later use; accurately weigh an appropriate amount of UDPGA into a 1.5 mL centrifuge tube, add an appropriate amount of PB solution, vortex and mix well to prepare a UDPGA solution with a concentration of 40 mmol / L, place it on ice for later use; respectively transfer the same volume of NADPH and UDPGA solutions into the same centrifuge tube, vortex and mix well to prepare a NADPH and UDPGA mixed solution, place it on ice for later use.

[1093] 1.4 Positive substrate working solution (testosterone and 7-hydroxycoumarin mixture)

[1094] Accurately weigh an appropriate amount of testosterone reference substance, dissolve it in dimethyl sulfoxide (DMSO), vortex and mix well to dissolve it, prepare a 20 mmol / L testosterone stock solution, and store it in a -20°C refrigerator; accurately weigh an appropriate amount of 7-hydroxycoumarin reference substance, dissolve it in dimethyl sulfoxide (DMSO), vortex and mix well to dissolve it, prepare a 20 mmol / L 7-hydroxycoumarin stock solution, and store it in a -20°C refrigerator; respectively transfer the same volume of testosterone stock solution and 7-hydroxycoumarin stock solution into the same 1.5 mL centrifuge tube, and dilute it with 50% methanol-water to a 20 μmol / L mixed substrate working solution, and place it on ice for later use.

[1095] 1.5 Test substrate working solution

[1096] Accurately weigh an appropriate amount of the test substance reference substance, dissolve it in dimethyl sulfoxide (DMSO), vortex and mix well to dissolve it, prepare a 10 mmol / L test substance stock solution, and store it in a -20°C refrigerator for later use; transfer an appropriate amount of the test substance stock solution into a 1.5 mL centrifuge tube, and dilute it with a 50% methanol-water diluent to a 20 μmol / L substrate working solution, and place it on ice for later use.

[1097] 2 Experimental method

[1098] The experimental design was divided into three groups, namely the positive control group (PC), the negative control group (NC), and the experimental group. The test substance was incubated with liver microsomes for a certain period of time under the conditions of NADPH and UDPGA (using the absence of NADPH and UDPGA as the negative control and setting a positive control). A termination solution was added to terminate the reaction, and the remaining amount of the test substance in the sample was detected using an LC-MS / MS instrument. The concentration of the test substance at different reaction times was compared with that at T0 to obtain the stability of the test substance in liver microsomes. Generally, the final protein concentration of liver microsomes in the reaction system was 1.0 mg / mL. All incubations were carried out in a 37°C water bath.

[1099] 2.1 Experimental grouping

[1100] Experimental group: The test substance was incubated with liver microsomes for 60 min under the conditions of NADPH and UDPGA.

[1101] Negative control group (NC): The test substance was incubated with liver microsomes for 60 min without any coenzymes.

[1102] Positive control group (PC): The probe substrates of CYP3A4 and UGT, testosterone and 7-hydroxycoumarin, were incubated with liver microsomes for 60 min under the conditions of NADPH and UDPGA.

[1103] 2.2 Experimental procedures

[1104] (1) Take the liver microsomes and thaw them on ice, gently shake and mix well.

[1105] (2) Experimental group and negative control group (NC): Take an appropriate amount of PB buffer, add an appropriate amount of the working solution of the test substance substrate, and then transfer an appropriate amount of liver microsomes into a 1.5 mL centrifuge tube. Pipette 20 - 30 times to mix well, ensuring that the final concentration of liver microsomes is 1 mg / mL.

[1106] (3) Positive control group (PC): Take an appropriate amount of PB buffer, add an appropriate amount of the working solution of the positive substrate, and then transfer an appropriate amount of liver microsomes into a 1.5 mL centrifuge tube. Pipette 20 - 30 times to mix well, ensuring that the final concentration of liver microsomes is 1 mg / mL.

[1107] (4) Experimental group: Aliquot 90 μL of the solution in (2) respectively, pre-incubate in a 37°C water bath for 5 min, then add 10 μL of the 20 mmol / L mixed initiating factor to start the reaction. After reaching the set incubation times, add an appropriate amount of pre-cooled methanol solution containing an internal standard to terminate the reaction.

[1108] (5) Negative control group (NC): Pipette 90 μL of the solution in (2) for aliquoting. After pre-incubating in a 37 °C water bath for 5 min, add 10 μL of PB buffer. After reaching each set incubation time, add an appropriate amount of pre-cooled methanol solution containing internal standard to terminate the reaction.

[1109] (6) Positive control group (PC): Pipette 90 μL of the solution in (3) for aliquoting. After pre-incubating in a 37 °C water bath for 5 min, add 10 μL of the starting factor at 20 mmol / L to initiate the reaction. After reaching each set incubation time, add an appropriate amount of pre-cooled methanol solution containing internal standard to terminate the reaction.

[1110] (7) Vortex the samples prepared above at 2500 rpm for 1 min, centrifuge at 17000 g and 4 °C for 10 min, and take the supernatant for LC-MS / MS detection.

[1111] 3.3 Data processing and analysis

[1112] Quantify the stability samples using a standard curve to obtain the concentration of the test substance at each time point, and calculate the percentage of the remaining amount of the parent compound relative to the amount of the parent compound before incubation (0 min); alternatively, calculate the percentage of the remaining amount of the parent compound relative to the amount of the parent compound before incubation (0 min) by the ratio of the peak area of the test substance to the peak area of the internal standard. The data is calculated according to the following formula: Parent remaining percentage (%of 0 min) = T 60 Amount of parent compound at T 0 Amount of parent compound × 100%; T 60 : Incubation time point of 60 min; T 0 : Incubation time point of 0 min. The results are shown in Table 4.

[1113] Table 4 In vitro metabolic stability of the compound in human liver microsomes

[1114]

[1115] Example 70: In vivo pharmacokinetic evaluation of the test compound in mice

[1116] Balb / c mice, female, fasted overnight (with free access to water), blood was collected from the orbital venous plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, and 48 h after oral gavage (PO). Approximately 0.1 mL of blood was collected for each sample, anticoagulated with dipotassium ethylenediaminetetraacetate (EDTA-2K), placed on ice after collection, and centrifuged at 4 °C within 1 hour to separate plasma (2000 g / min, 10 min), and stored at -20 °C for further analysis. The plasma concentration of the parent drug was determined by LC-MS / MS, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.1. The results are shown in Table 5.

[1117] Table 5 Pharmacokinetic test results of the test compound in mice

[1118]

[1119] The results showed that the compound of the present invention had high plasma exposure and low clearance rate after single oral gavage in mice.

[1120] Example 71: Evaluation of in vitro combined efficacy indicators of the test compound and olaparib

[1121] In this experiment, MDA-MB-436 cells were used. After treatment with the test compound, the ability of each test compound to combine with olaparib to produce combined efficacy was detected. At the beginning of the experiment, MDA-MB-436 cells were added to a 96-well plate, 500 cells per well, and allowed to adhere overnight. The next day, the cells were treated with a 7×7 drug matrix. Both the test compound and the PARP inhibitor olaparib started from 500 nM and were serially diluted 3-fold, with a total of 7 concentration points. After drug administration, the 96-well plate was placed in an incubator at 37 °C with 5% CO 2 and continued to be cultured. On the 5th day, the old culture medium was d...

Claims

1. A nitrogen-containing heterocyclic derivative, which is a compound having the following general structural formula (II-1), (II-2), (III) or (IV) and its prodrug, isomer, solvate or pharmaceutically acceptable salt: in, X is CR a or N; Y 1 , Y 2 C, CH or N, Y 3 is CH, S, N or NR c , Y 4 , Y 5 is CH, N or NR c ; Z 1 , Z 2 is methylene or oxo; n is 1, 2 or 3; Q is CH2 or O; R 1 is selected from 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the 4-10 membered heterocyclic group, C6-C 10 The aryl or 5-10 membered heteroaryl groups are each independently selected from 0 to 4 R a , R b , R c , R d or R e replace; R 5 Selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 The aryl or 5-10 membered heteroaryl groups are each independently selected from 0 to 4 R a , R b , R c , R d or R e replace; L is -(L1) m -, wherein L1 is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, -NR f -or-CR d R e -, m is 0, 1 or 2; Cy is selected from C3-C 12 Cycloalkyl, 4-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C3-C 12 Cycloalkyl, 4-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted with 0 to 4 R 2 replace; R a independently selected from hydrogen, halogen, nitro, cyano, oxo, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, -OR 3 、-SR 3 、-S(O)2R 3 、-S(O)2NR 3 R 4 、-NR 3 R 4 、-C(O)OR 3 、-OC(O)R 3 、-C(O)R 3 、-C(O)NR 3 R 4 、-OC(O)NR 3 R 4 、-N(R 3 )C(O)R 4 、-N(R 3 )C(O)OR 4 or C2-C6 alkynyl, the C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted by 0 to 4 R 2 replace; R b independently selected from hydrogen, halogen, nitro, cyano, oxo, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, C2-C6 alkynyl, -OR 3 、-SR 3 、-S(O)2R 3 、-S(O)2NR 3 R 4 、-NR 3 R 4 、-C(O)OR 3 、-OC(O)R 3 、-C(O)R 3 、-C(O)NR 3 R 4 、-OC(O)NR 3 R 4 、-N(R 3 )C(O)R 4 or -N(R 3 )C(O)OR 4 The C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl or C2-C6 alkynyl is optionally substituted by 0 to 4 R 2 replace; R c independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl may be further optionally substituted by one or more R 2 replace; R d , R e Each is independently selected from hydrogen, deuterium, halogen, cyano, amino, carboxyl, nitro, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino or C1-C6 alkylsulfone, and the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino or C1-C6 alkylsulfone may be further substituted by one or more R 2 replace; Or, R d , R e Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl or a 3-10 membered heterocyclic group, wherein the C3-C8 cycloalkyl or the 3-10 membered heterocyclic group may be further optionally substituted by one or more R 2 replace; R f independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl may be further optionally substituted by one or more R 2 replace; R 3 , R 4 Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, or R 3 , R 4 The C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 heterocyclic group or R 3 , R 4 Together with the N atom to which it is attached, a 4-6 membered heterocyclic ring is formed by one or more R 2 replace; R 2 independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, carboxyl, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C1-C6 alkylsulfone, di(C1-C6 alkyl)amino, C3-C8 cycloalkyl or 3-10 membered heterocyclyl, and the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C1-C6 alkylsulfone, di(C1-C6 alkyl)amino, C3-C8 cycloalkyl or 3-10 membered heterocyclyl may be optionally further substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, carboxyl.

2. The compound according to claim 1, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: Having the structure of formula (II-1), formula (II-2) or formula (III): Among them, Y 1 , Y 2 C or N, Y 3 C, S, N or NR c , Y 4 , Y 5 C, N or NR c ; R c is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by 0 to 4 R 2 replace; R d , R e Each is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or R d , R e The C3-C6 cycloalkyl or 3-6 membered heterocyclic group formed with the connected carbon atom; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or R d , R e The C3-C6 cycloalkyl group and the 3-6 membered heterocyclic group formed with the carbon atom to which they are attached are optionally substituted with 0 to 4 R 2 replace; R f is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted by 0 to 4 R 2 replace; R 2 is selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl or 4-6 membered heterocyclyl is optionally substituted with 0 to 4 halogen, cyano, hydroxy, amino or carboxyl groups; X, R 1 , R 5 ,L,Cy,R a and R b The definition is as stated in claim 1.

3. The compound according to claim 1-2, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: Said Selected from 4. The compound according to claim 1-2, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: Said Selected from 5. The compound according to claim 1-2, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: Having the structure of formula (IV): Among them, R d , R e Each is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or R d , R e The C3-C6 cycloalkyl or 3-6 membered heterocyclic group formed with the connected carbon atom; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or R d , R e The C3-C6 cycloalkyl group and the 3-6 membered heterocyclic group formed with the carbon atom to which they are attached are optionally substituted with 0 to 4 R 2 replace; R 2 Selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, 4-6 membered heterocyclyl is optionally substituted by 0 to 4 halogen, cyano, hydroxyl, amino, carboxyl; Z 1 , Z 2 ,n,Q,R 1 , R 5 and Cy is as defined in claim 1; Preferably, the Selected from 6. The compound according to claim 1-5, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: The R 5 Selected from The R a , R b Each is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCF3, -OCH3, ethoxy, propoxy, isopropoxy, cyclopropyloxy, -NHCH3, -N(CH3)2, <h2 style=";text-align:left;direction:ltr">-SO2CH3、<h2 style=";text-align:left;direction:ltr"> The R c are independently selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -CH2F, -CHF2 or The R d , R e are each independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxymethyl, or R d , R e The cyclopropyl, ethylene oxide, cyclobutyl, cyclopentyl, 7. The compound according to claim 6, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: The R 5 Selected from 8. The compound according to claims 1 to 7, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: The R 1 Selected from The R a , R b Each is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, ethynyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCF3, -OCH3, ethoxy, propoxy, isopropoxy, cyclopropyloxy, -NHCH3, -N(CH3)2, <h2 style=";text-align:left;direction:ltr">-SO2CH3、<h2 style=";text-align:left;direction:ltr"> The R c independently selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -CH2F, -CHF2, The R d , R e are each independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxymethyl, or R d , R e The cyclopropyl, ethylene oxide, cyclobutyl, cyclopentyl, 9. The compound according to claim 8, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: The R 1 Selected from 10. The compound according to claim 1-9, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: The L is -WCR d R e -, L is selected from -OCR d R e -or-NR f CR d R e -; The W is selected from -O- or -NR f -; The R d and R e Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, and the C1-C6 alkyl, C3-C6 cycloalkyl may be optionally further substituted with 0 to 4 substituents selected from deuterium, halogen, hydroxyl, cyano or amino; Alternatively, the R d , R e Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 3-6 membered heterocyclic group may be optionally further substituted by 0 to 4 substituents selected from deuterium, halogen, hydroxyl, cyano or amino; The R f is selected from hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl may be further substituted with 0 to 4 substituents selected from deuterium, halogen, hydroxyl, cyano or amino.

11. The compound according to claim 10, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: L-NHCH2-、-N(CH3)CH2-、-N(CH3)CD2-、-N(CD3)CD2-、-OCH(CH3)-、-N(CD3)CH2-、-N(CD3)CH(CH3)-、-N(CH3)CH(CH3)-、-N(CH3)CH(CF3)-、-N(CHF2)CH(CH3)-、-NHCH(CH3)-、-NHCH(CF3)-、-N(CH2CF3)CH(CH3)-、-N(CH2CH3)CH(CF3)-、-N(CH2CH3)CH(CF3)-、-N(CD3)CH(CF3)-、 12. The compound according to claims 1 to 11, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: The Cy is selected from 13. The compound according to claims 1 to 12, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: The compound has a structure shown in the following formula (IIIa): Among them, Y 4 Select from C or NR c ; Y 3 Selected from C, S or NR c’ ; said R c’ Selected from hydrogen or C1-C6 alkyl; R 5 is selected from pyrazole, pyridine or pyrimidine rings, wherein the pyrazole, pyridine or pyrimidine ring may be optionally substituted with one or more halogen, C1-C6 alkoxy or C3-C8 cycloalkyl; W is selected from -NR f -or-O-; R c Selected from C 1-6 alkyl; R d , R e Each is independently selected from hydrogen, deuterium, halogen, cyano, amino, carboxyl, nitro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylthio, C1-C6 alkylamino, C 1-6 Alkylsulfone or R d , R e Together with the C atoms to which they are connected, they form a C3-C8 cycloalkyl group or a 3-10-membered heterocyclic group; the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C8 cycloalkyl group, a 3-10-membered heterocyclic group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkylthio group, a C1-C6 alkylamino group, a C 1-6 Alkylsulfone or R d , R e The C3-C8 cycloalkyl and 3-10 membered heterocyclic groups formed with the attached carbon atoms may be optionally substituted with one or more hydrogen, deuterium, halogen, cyano, amino, carboxyl, nitro, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-10 membered heterocyclic groups, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylthio, C1-C6 alkylamino or C 1-6 Alkylsulfone substitution; R f Selected from hydrogen or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more deuterium.

14. The compound according to claims 1 to 12, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: The compound has a structure shown in the following formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) or (Vh): wherein X is selected from CH or N; W is selected from -NR f -or-O-; R 2 is selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl or C1-C6 alkoxy; R 5 is selected from pyrazole, pyridine, pyrimidine or imidazole, wherein the pyrazole, pyridine, pyrimidine or imidazole may be further substituted with one or more R b replace; R a is selected from hydrogen, halogen, C1-C6 alkylsulfone, C1-C6 alkyl or 4-6 membered heterocyclyl, wherein the C1-C6 alkyl or 4-6 membered heterocyclyl may be further substituted with 0 to 4 substituents selected from deuterium or halogen; R b is selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy may be further substituted with 0 to 4 substituents selected from deuterium or halogen; R d , R e Each is independently selected from hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl may be further substituted with one or more substituents selected from deuterium or halogen; Or, R d , R e Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 3-6 membered heterocyclic group may be optionally further substituted by one or more substituents selected from deuterium or halogen; R c , R f Each is independently selected from hydrogen, deuterium, C1-C6 alkyl or C3-C6 cycloalkyl, and the C1-C6 alkyl or C3-C6 cycloalkyl may be optionally further substituted by one or more substituents selected from deuterium or halogen.

15. The compound according to claims 1 to 14, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: The compound has a structure as shown in the following formula (VIa), (VIb), (VIc), (VId), (VIe) or (VIf): Among them, X, W, R c , R d , R e and R 2 The definition as set forth in claim 14.

16. The compound according to claims 1 to 15, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: R 2 Selected from hydrogen.

17. The compound according to claims 1 to 16, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: R a Selected from hydrogen, halogen, -CF3, -CHF2, -SO2CH3 or R b is selected from hydrogen, halogen, hydroxy, methyl, isopropyl, cyclopropyl, -OCH3, -OCF3, -OCHF2 or R c is selected from hydrogen, methyl or isopropyl.

18. The compound according to claims 1 to 17, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: W is selected from -NR f -, the R f Selected from hydrogen, deuterium, methyl, ethyl, -CD3, -CHF2 or -CH2CF3.

19. The compound according to claims 1 to 18, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: R d , R e are each independently selected from hydrogen, deuterium, methyl, -CF3 or -CHF2; or, R d , R e Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

20. The compound according to claims 1 to 19, and its prodrug, isomer, solvate or pharmaceutically acceptable salt, characterized in that: Select from the following structures:

21. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises at least one compound according to any one of claims 1 to 20, and a prodrug, isomer, solvate or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

22. Use of a compound as claimed in any one of claims 1 to 20 and its prodrug, isomer, solvate or pharmaceutically acceptable salt or the pharmaceutical composition as claimed in claim 21 in the preparation of a medicament for preventing and / or treating USP1-mediated diseases or conditions and related diseases or conditions; The USP1-mediated disease or condition and related diseases or conditions are selected from inflammatory diseases or diseases accompanied by inflammatory response or cancer diseases; The inflammatory diseases or diseases accompanied by inflammatory responses include, but are not limited to, liver fibrosis, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, inflammatory arthritis, gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis, myelodysplastic syndrome, thrombocytopenia, atherosclerosis, type I and type II diabetes and related complications (e.g., heart failure, retinopathy, diabetic foot), peripheral arterial disease, acute heart failure and hypertension, lupus nephritis, hypertensive nephropathy, acute kidney injury, chronic nephritis, colorectal inflammation, polymyositis, chronic migraine, neuropathic pain, multiple sclerosis, acne, suppurative hidradenitis, seborrheic dermatitis, Schnitzler syndrome, systemic lupus erythematosus, psoriasis, dry eye disease, novel coronavirus infection and cytokine release syndrome, chronic obstructive pulmonary disease, acute lung injury, bronchitis, asthma, sarcoidosis or pyromycin-associated periodic syndrome, etc.; The cancer diseases include, but are not limited to, bile duct cancer, colorectal cancer, esophageal cancer, liver cancer, kidney cancer, gastric cancer, head and neck squamous cell carcinoma, prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), acute B-lymphocytic leukemia, bladder cancer, pancreatic cancer, osteosarcoma, myeloma, glioma, ovarian cancer, skin cancer or breast cancer, etc.

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