Heterocyclic compound and pharmaceutical use thereof

Abstract

The present invention provides a USP1 small-molecule inhibitor. Specifically, the present invention provides a heterocyclic compound represented by formula (I). The definition of each group is as described in the description. The compound has an excellent USP1 inhibitory effect.

Description

Heterocyclic compound and application thereof in medicine TECHNICAL FIELD

[0001] The present application relates to a heterocyclic compound represented by general formula (I) or stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and application in preparation of drugs for treating diseases related to USP1 activity or expression. BACKGROUND

[0002] The USP family consists of 56 members, which is the largest member and the highest structural diversity among human DUBs (deubiquitinating enzymes). USP1 gene is located in the p31.3-p32.1 band of chromosome 1, which can encode a protein consisting of 785 amino acid residues with a molecular weight of about 88.2 kDa. USP1 contains a highly conserved catalytic domain characteristic of the USP family, which is composed of amino acid residues Cys90 in the N-terminal Cys box, amino acid residues His593 in the C-terminal His box and Asp751, forming a catalytic triad, which is the catalytic core of USP1.

[0003] The main function of USP1 protein is to regulate multiple aspects of DNA damage response (DDR) by modulating the ubiquitination level of specific proteins in the Fanconi anemia (FA) pathway and the translesion DNA synthesis (TLS) pathway. Cells are constantly subjected to DNA damage due to various exogenous and endogenous genotoxins, and cells employ DDR, which contains multiple molecular signals and mechanisms, to repair DNA damage and maintain genome stability. Tumor cells often exhibit genomic instability, and most tumor cells lose one or more DDR pathways or functions, resulting in the survival of tumor cells being highly dependent on the remaining DDR pathways to repair a large amount of DNA damage, and un-repaired damage induces tumor cell apoptosis and necrosis. Knocking out USP1 in cells leads to hypersensitivity to DNA cross-linking agents, which is in line with the phenomenon that USP1 is highly expressed in human tumors, indicating that inhibiting USP1 can be an effective solution to overcome chemoresistance. Scientific research results also support this point of view. Tyagi et al. found that USP1-siRNA enhances the sensitivity of cancer cells to cisplatin; inhibiting USP1 leads to a decrease in MAST1-mediated cisplatin resistance in non-small cell cancer, etc. Another finding of USP1 for tumor treatment is that inhibiting USP1 can effectively solve the problem of resistance to poly ADP-ribose polymerase (PARP) inhibitors. When DNA is damaged, if it cannot be repaired through the homologous recombination (HR) repair pathway, it is homologous recombination defect (HRD). Breast cancer 1 (BRAC1) gene-deficient tumor cells have defects in HR repair and replication fork stability, making BRCA1 gene-deficient cancer cells highly dependent on other DDR pathways, thereby leading to cancer cells being sensitive to DDR inhibitors such as PARP inhibitors. Lim et al. proved that knocking out or inhibiting USP1 leads to replication fork instability and reduces the survival rate of BRCA1 gene-deficient cells, revealing a synthetic lethal relationship. At the same time, the tolerance of BRCA1 gene-deficient tumor cells to PARP inhibitors may come from two main mechanisms: (1) restoration of HR repair; (2) replication fork stabilization. PARP inhibitor-resistant cells that are stabilized by replication forks are still sensitive to USP1 inhibitors, while PARP inhibitor-resistant cells that restore HR through p53-binding protein 1 silencing are resistant to USP1 inhibitors. Therefore, inhibiting USP1 helps to treat BRCA1 gene-deficient tumors that have acquired PARP inhibitor resistance through replication fork stabilization.

[0004] Although there are many studies on inhibitors targeting USP1 at present, no USP1 inhibitor has been approved for marketing, and therefore, there is still a broad prospect for developing effective USP1 small molecule inhibitors. SUMMARY

[0005] The object of the present application is to provide a heterocyclic compound inhibitor having excellent USP1 inhibitory effect.

[0006] In a first aspect of the present application, a heterocyclic compound or stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof represented by Formula I is provided,

[0007] wherein,

[0008] is an aromatic heteroaryl ring;

[0009] represents a single bond or a double bond;

[0010] X1is selected from CR 1 , N or O;

[0011] X2is selected from C or N;

[0012] X3is selected from CR 2 R 3 , CR 2 , NR 4 , N, O, S, S=O, S(=O)2or is absent;

[0013] X4is selected from CR 2 R 3 , CR 3 , NR 4 , N, O, S, S=O or S(=O)2;

[0014] or when X 3 is present, X 3 and X 4 together with the atom to which they are attached form a 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R e ;

[0015] Ring A is selected from C6-C10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R a ;

[0016] Ring B is selected from 3-10 membered cycloalkyl, 4-8 membered heterocyclyl, 7-15 membered spirocyclyl, 7-15 membered bridged cyclyl, 7-15 membered fused cyclyl, wherein the above groups are optionally substituted with one or more R b substituents;

[0017] Ring C is selected from C6-C10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-C10 cycloalkyl, or C3-C10 cycloalkenyl, wherein the above groups are optionally substituted with one or more R c substituents;

[0018] Ring D is selected from C6-C10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R d substituents;

[0019] R 1 , R 2 , R 3 , and R 4 are each independently selected from H atom, -OH, -SH, =0, =S, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -NH2, -NH-(Ci-C6alkyl), -N-(Ci-C6alkyl)2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C6alkyl, -S-(Ci-C6alkyl), -S(O)-(Ci-C6alkyl), -S(O)2-(Ci-C6alkyl), -S(O)2-(amino), -S(O)2NH(Ci-Ci2alkyl), -S(O)2N(Ci-Ci2alkyl)2, phosphoryl, phosphinyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6alkylthio, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-C3-C8cycloalkyl, -(Ci-C6alkylene)-3-8 membered heterocyclyl, and -(Ci-C6alkylene)-C(O)-O-Ci-C6alkyl, wherein the above groups are each independently optionally substituted with one or more R f substituents;

[0020] R a , R b , R c , R d , R e , and R feach independently selected from the group consisting of halogen, CN, -OH, -NH2, NO2, -SH, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -CONH2, -CONH(Ci-C6alkyl), -NHCO-(Ci-C6alkyl), Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-Ciocycloalkyl, -(Ci-C6alkylene)-C3-Ciocycloalkyl, C3-Ciocycloalkyloxy, C2-C6alkenyl, C2-C6alkynyl, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-3-8 membered heterocyclyl, C6-Cioaryl, 5-8 membered heteroaryl, wherein the aforementioned groups are optionally substituted with R g ;

[0021] or R b and R c together with the atom(s) to which they are attached form a 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, wherein the aforementioned groups are optionally substituted with R g ;

[0022] or R c and R d together with the atom(s) to which they are attached form a 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, wherein the aforementioned groups are optionally substituted with R g ;

[0023] each R g is independently selected from the group consisting of D atom, -OH, -COOH, -NH2, NO2, -CN, =0, =S, halogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, C6-Cioaryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, wherein the aforementioned groups are optionally substituted with one or more substituents selected from the group consisting of Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci-C3haloalkoxy, Ci-C3hydroxyalkyl, halogen, cyano, nitro, carboxy, oxo.

[0024] In another preferred embodiment, the compound has the structure according to formula II:

[0025] wherein X1, X2, X3, X4, A, B, C, D are defined herein.

[0026] In another preferred embodiment, X2is C.

[0027] In another preferred embodiment, X1is CR 1 or N, preferably N.

[0028] In another preferred embodiment, R 1 is selected from the group consisting of H atom, -OH, -SH, -COOH, -NH2, -C(O)-NH2, -NO2, -CN, halogen, C1-C6alkyl, -S-(C1-C6alkyl), C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6alkylthio, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -(C1-C6alkylene)-C3-C8cycloalkyl, and -(C1-C6alkylene)-3-8 membered heterocyclyl.

[0029] In another preferred embodiment, R 1 is selected from the group consisting of H atom, halogen, C1-C6alkyl, -S-(C1-C6alkyl), C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6alkylthio, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6hydroxyalkyl.

[0030] In another preferred embodiment, R 1 is selected from the group consisting of H atom and halogen.

[0031] In another preferred embodiment, X3is CR 2 .

[0032] In another preferred embodiment, X4is CR 3 . In another preferred embodiment, the compound has the structure shown in Formula III-1:

[0033] wherein R 2 , R 3 , A, B, C, D are defined herein.

[0034] In another preferred embodiment, R 2 is not H, R 3 is H. In another preferred embodiment, R 3 is not H, R 2 is H.

[0035] In another preferred embodiment, R 1 , R 2 , R 3 , and R 4each independently selected from the group consisting of H, -OH, -SH, -COOH, -COO-(Ci-C4alkyl), -OCO-(Ci-C4alkyl), -NH2, -NH-(Ci-C6alkyl), -N-(Ci-C6alkyl)2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C6alkyl, -S-(Ci-C6alkyl), -S(O)- f substituted.

[0036] In another preferred embodiment, R 1 , R 2 , R 3 and R 4 each independently selected from the group consisting of H, -OH, -COOH, -COO-(Ci-C4alkyl), -OCO-(Ci-C4alkyl), -NH2, -NH-(Ci-C6alkyl), -N-(Ci-C6alkyl)2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C6alkyl, -S-(Ci-C6alkyl), -S(O)- f substituted.

[0037] In another preferred embodiment, R 1 , R 2 , R 3 and R 4each independently is selected from the group consisting of H, -OH, -COOH, -COO-(Ci-C4alkyl), -OCO-(Ci-C4alkyl), -NH2, -NH-(Ci-C6alkyl), -N-(Ci-C6alkyl)2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C4alkyl, -S-(Ci-C4alkyl), C2-C4alkenyl, C2-C4alkynyl, Ci-C4alkoxy, Ci-C4alkoxy-C(O)-NH2, Ci-C4alkoxy-CONH(Ci-C6alkyl), Ci-C4alkoxy-OH, Ci-C4alkoxy-NH2, Ci-C4haloalkyl, Ci-C4haloalkoxy, Ci-C6hydroxyalkyl, C3-C4cycloalkyl, 5-6 membered heterocyclyl, and -(Ci-C3alkylene)-C(O)-O-Ci-C4alkyl.

[0038] In another preferred embodiment, R 1 , R 2 , R 3 , and R 4 each independently is selected from the group consisting of H, -COO-(Ci-C4alkyl), -OCO-(Ci-C4alkyl), -C(O)-NH2, -NO2, -CN, halogen, Ci-C4alkyl, -S-(Ci-C4alkyl), Ci-C4alkoxy, Ci-C4alkoxy-C(O)-NH2, Ci-C4alkoxy-CONH(Ci-C6alkyl), Ci-C4alkoxy-OH, Ci-C4alkoxy-NH2, Ci-C4haloalkyl, Ci-C4haloalkoxy, Ci-C6hydroxyalkyl, C3-C4cycloalkyl, 5-6 membered heterocyclyl, and -(Ci-C3alkylene)-C(O)-O-Ci-C4alkyl.

[0039] In another preferred embodiment, R 1 , R 2 , R 3 , and R 4 each independently is selected from the group consisting of H, halogen, Ci-C4alkyl, Ci-C4alkoxy, Ci-C4haloalkyl, Ci-C4haloalkoxy, C3-C4cycloalkyl, and 5-6 membered heterocyclyl.

[0040] In another preferred embodiment, X 3 and X 4 together with the atom to which they are attached form an E ring, wherein the E ring is optionally substituted with one or more R e .

[0041] In another preferred embodiment, the compound has the structure shown in Formula III-2:

[0042] wherein A, B, C, D are as described herein,

[0043] E ring is 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R e substituents.

[0044] In another preferred embodiment, R e is selected from halogen, CN, -OH, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -NH2, -SH, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C10cycloalkyl, -(Ci-C6alkylene)-C3-C10cycloalkyl.

[0045] In another preferred embodiment, R e is selected from halogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C6cycloalkyl.

[0046] In another preferred embodiment, R e is Ci-C6alkyl, preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl.

[0047] In another preferred embodiment, E ring is 3-8 membered cycloalkyl, 5-8 membered heterocyclyl, 6-10 membered aryl, 5-8 membered heteroaryl.

[0048] In another preferred embodiment, E ring is 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 6 membered aryl, 5-6 membered heteroaryl.

[0049] In another preferred embodiment, E ring is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pentalenyl, hexalene, pyrrolidinyl, piperidinyl, furanyl, thienyl, pyridyl, pyrrolyl, or

[0050] In another preferred embodiment, is

[0051] In another preferred embodiment, ring A is 5-8 membered heteroaryl, C6-C10 aryl, optionally substituted with one or more R a substituents.

[0052] In another preferred embodiment, ring A is 5-6 membered heteroaryl, C6 aryl, optionally substituted with one or more R a substituents.

[0053] In another preferred embodiment, ring A is 5-6 membered heteroaryl, C6 aryl, optionally substituted with one or more Ra substituted 5-8 membered (preferably 5-6 membered) nitrogen containing heteroaryl.

[0054] In another preferred embodiment, ring A is phenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein the above groups are optionally substituted with one or more R a substituted.

[0055] In another preferred embodiment, ring A is substituted with one or more R a substituted, R a is selected from halogen, CN, -OH, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -NH2, -SH, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C10cycloalkyl, -(Ci-C6alkylene)-C3-C10cycloalkyl.

[0056] In another preferred embodiment, R a is selected from halogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C6cycloalkyl.

[0057] In another preferred embodiment, ring A is pyrimidinyl, phenyl or pyrazolyl substituted with multiple R a each independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C6cycloalkyl. a each independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C6cycloalkyl.

[0058] In another preferred embodiment, ring A is pyrimidinyl, phenyl or pyrazolyl substituted with multiple R a each independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C6cycloalkyl. a each independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C6cycloalkyl.

[0059] In another preferred embodiment, ring A is wherein denotes the site of attachment to the parent core.

[0060] In another preferred embodiment, ring B is selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 7-15 membered spiroheterocyclyl, 7-15 membered bridged heterocyclyl, 7-15 membered fused heterocyclyl, wherein the above groups are optionally substituted with one or more R b substituted.

[0061] In another preferred embodiment, ring B is selected from 4-8 membered heterocyclyl, 7-10 membered spiroheterocyclyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused heterocyclyl, wherein the above mentioned groups are optionally substituted by one or more R b substituents.

[0062] In another preferred embodiment, ring B contains a nitrogen atom.

[0063] In another preferred embodiment, ring B contains one nitrogen atom and optionally a further heteroatom selected from the group consisting of: nitrogen, oxygen and sulfur. In another preferred embodiment, ring B is attached to the core via the nitrogen atom.

[0064] In another preferred embodiment, the two heteroatoms in ring B are in a geminal position.

[0065] In another preferred embodiment, ring B is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, wherein the above mentioned groups are optionally substituted by one or more R b substituents.

[0066] In another preferred embodiment, R b is selected from halogen, CN, -OH, -COOH, -COO-(Ci-C6-alkyl), -OCO-(Ci-C6-alkyl), -NH2, -SH, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C10-cycloalkyl, -(Ci-C6-alkylene)-C3-C10-cycloalkyl.

[0067] In another preferred embodiment, R b is selected from halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C6-cycloalkyl.

[0068] In another preferred embodiment, R b is Ci-C6-alkyl, preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl.

[0069] In another preferred embodiment, ring B is selected from the following structures:

[0070] wherein denotes the position of attachment to the C ring, denotes the position of attachment to the core.

[0071] In another preferred embodiment, ring B is selected from the following structures:

[0072] wherein represents the site of attachment to the C ring, represents the site of attachment to the parent core, and "*" represents a racemic mixture.

[0073] In another preferred embodiment, ring C is C6-C10aryl, preferably phenyl.

[0074] In another preferred embodiment, ring C is C6-C10aryl, preferably phenyl, wherein said group is optionally substituted by one or more R c substituents.

[0075] In another preferred embodiment, R c is selected from halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy and C1-C6haloalkoxy.

[0076] In another preferred embodiment, R c is selected from halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy and C1-C4haloalkoxy.

[0077] In another preferred embodiment, R c is halogen, C1-C4alkyl or C1-C4alkoxy, preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, fluorine, chlorine, bromine, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy or t-butoxy.

[0078] In another preferred embodiment, ring D is 5-8 membered heteroaryl, preferably 5-6 membered heteroaryl, optionally substituted by one or more R d substituents.

[0079] In another preferred embodiment, ring D is 5-8 membered nitrogen containing heteroaryl, preferably 5-6 membered nitrogen containing heteroaryl, optionally substituted by one or more R d substituents.

[0080] In another preferred embodiment, ring D is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, wherein the aforementioned groups are optionally substituted by one or more R d substituents.

[0081] In another preferred embodiment, ring D is substituted by one or more R d substituents, R d is selected from halogen, CN, -OH, -NH2, -SH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, -(C1-C6alkylene)-C3-C10cycloalkyl.

[0082] In another preferred embodiment, R d Selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -(C1-C4 alkylene)-C3-C6 cycloalkyl.

[0083] In another preferred embodiment, R d Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, fluorine, chlorine, bromine, trifluoromethyl, dichloromethyl, pentafluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, and cyclobutylethyl.

[0084] In another preferred embodiment, ring D is bounded by multiple R... d Substituted imidazole or pyridinyl groups, the plurality of R groups d Each is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, and -(C1-C4 alkylene)-C3-C6 cycloalkyl.

[0085] In another preferred embodiment, ring D is bounded by multiple R... d Substituted imidazole or pyridinyl groups, the plurality of R groups d Each is independently selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, dichloromethyl, pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, and cyclobutylethyl.

[0086] In another preferred embodiment, ring D is in This indicates the site connected to ring C.

[0087] In another preferred embodiment, the compound has the structure shown in Formula IV:

[0088] in,

[0089] Y1, Y3, Y4, Y5, and Y6 are each independently CR a Or N, Y2 is non-existent, CR a Or N,

[0090] Z1, Z3, Z4, Z5, and Z6 are each independently CR c Or N, Z2 is non-existent, CR c Or N,

[0091] each independently CR d or N, W2 is absent, CR d or N,

[0092] X1, X2, X3, X4, R a , R c , R d , ring B is as described herein.

[0093] In another preferred embodiment, the compound has the structure shown in formula IV-1:

[0094] wherein,

[0095] each Y1, Y3, Y4, Y5, Y6 is independently CR a , CR a R a , N or NR a , Y2 is absent, CR a , CR a R a , N or NR a ,

[0096] each Z1, Z3, Z4, Z5, Z6 is independently CR c , CR c R c , N or NR c , Z2 is absent, CR c , CR c R c , N or NR c ,

[0097] each W1, W3, W4, W5, W6 is independently CR d , CR d R d , N or NR d , W2 is absent, CR d , CR d R d , N or NR d ,

[0098] each P1, P1, P3, P4 is independently CR b R b , O, S or NR b ,

[0099] q is 0, 1, 2 or 3,

[0100] each X1, X2, X3, X4, R a , each R b , each Rc Each R d Ring B and ring B are as described independently in this article.

[0101] In another preferred embodiment, In the context of a ring, this indicates that the ring is an aromatic ring.

[0102] In another preferred embodiment, X1 is CR 1 Or N, X2 is C, X3 is CR 2 X4 is CR 3 , or X 3 and X 4 The atoms bonded to it together form an E ring, wherein the E ring is optionally bounded by one or more R... e replace.

[0103] In another preferred embodiment, Y1 and Y3 are each independently CR. a , N or NR a Y2 is non-existent or CR a Y4, Y5, and Y6 are all CR a .

[0104] In another preferred embodiment, Z1, Z2, Z3, Z4, Z5, and Z6 are each independently CR. c .

[0105] In another preferred embodiment, W1 is C, and W2 is either non-existent or CR. d W3 is CR d CR d R d , N or NR d W4 and W5 are independently CR d W6 is N.

[0106] In another preferred embodiment, P3 and P4 are each independently CR. b R b .

[0107] In another preferred embodiment, R a R b R c R d R e Each is independently selected from halogens, CN, -OH, -COOH, -COO-(C1-C6 alkyl), -OCO-(C1-C6 alkyl), -NH2, -SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, and -(C1-C6 alkylene)-C3-C10 cycloalkyl.

[0108] In another preferred embodiment, R a b c d e each independently is selected from halogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C8cycloalkyl, -(Ci-C6alkylene)-C3-C8cycloalkyl.

[0109] In another preferred embodiment, the compound has the structure of Formula V:

[0110] Y1, Y3are each independently CR a or N,

[0111] n is 0, 1, 2, 3, 4, or 5,

[0112] m is 0, 1, 2, 3, or 4,

[0113] p is 0, 1, or 2,

[0114] X1, X3, X4, R a c d , ring B is as described herein.

[0115] In another preferred embodiment, the compound has the structure of Formula VI-1:

[0116] wherein R 2 3 , ring B is as described herein.

[0117] In another preferred embodiment, the compound has the structure of Formula VI-2:

[0118] wherein ring B is as described herein, and E ring is 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl.

[0119] In another preferred embodiment, the compound has the structure of Formula VII-1:

[0120] wherein R 2 3 , ring B is as described herein.

[0121] In another preferred embodiment, the compound has the structure of Formula VII-2: ​​​​​​​​

[0122] wherein ring B is as described herein, and E ring is a 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl.

[0123] In another preferred embodiment, in Formula VI-1, Formula VI-2, Formula VII-1, or Formula VII-2,

[0124] Ring B is selected from a 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 7-15 membered spiroheterocyclyl, 7-15 membered bridged heterocyclyl, 7-15 membered fused heterocyclyl, wherein the above groups are optionally substituted with one or more R b substituents;

[0125] R 2 and R 3 are each independently selected from H, -OH, -SH, -COOH, -COO-(Ci-C4alkyl), -OCO-(Ci-C4alkyl), -NH2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C6alkyl, -S-(Ci-C6alkyl), -S(O)-(Ci-C6alkyl), -S(O)2-(Ci-C6alkyl), -S(O)2-(amino), C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, C3-C6cycloalkyl, 5-8 membered heterocyclyl, and -(Ci-C3alkylene)-C(O)-O-Ci-C4alkyl, wherein each of the above groups is independently optionally substituted with one or more R f substituents;

[0126] E ring is a 3-8 membered cycloalkyl, 5-8 membered heterocyclyl, 6-10 membered aryl, 5-8 membered heteroaryl.

[0127] In another preferred embodiment, in Formula VI-1, Formula VI-2, Formula VII-1, or Formula VII-2,

[0128] Ring B is selected from a 4-8 membered heterocyclyl, 7-10 membered spiroheterocyclyl, 7-10 membered bridged heterocyclyl, 7-10 membered fused heterocyclyl, wherein the above groups are optionally substituted with one or more R b substituents, Ring B contains a nitrogen atom, and Ring B is attached to the core through the nitrogen atom;

[0129] R 2 and R 3each independently selected from the group consisting of H, -OH, -COOH, -COO-(Ci-C4alkyl), -OCO-(Ci-C4alkyl), -NH2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C4alkyl, -S-(Ci-C4alkyl), C2-C4alkenyl, C2-C4alkynyl, Ci-C4alkoxy, Ci-C4haloalkyl, Ci-C4haloalkoxy, Ci-C6hydroxyalkyl, C3-C4cycloalkyl, 5-6 membered heterocyclyl, and -(Ci-C3alkylene)-C(O)-O-Ci-C4alkyl;

[0130] E ring is 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 6 membered aryl, 5-6 membered heteroaryl.

[0131] In another preferred embodiment, in Formula VI-1, Formula VI-2, Formula VII-1, or Formula VII-2,

[0132] Ring B is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, wherein the above groups are optionally substituted with one or more Ci-C6alkyl;

[0133] R 2 and R 3 each independently selected from the group consisting of H, -OH, -COOH, -COO-(Ci-C4alkyl), -OCO-(Ci-C4alkyl), -NH2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C4alkyl, -S-(Ci-C4alkyl), C2-C4alkenyl, C2-C4alkynyl, Ci-C4alkoxy, Ci-C4alkoxy-C(O)-NH2, Ci-C4alkoxy-CONH(Ci-C6alkyl), Ci-C4alkoxy-OH, Ci-C4alkoxy-NH2, Ci-C4haloalkyl, Ci-C4haloalkoxy, Ci-C6hydroxyalkyl, C3-C4cycloalkyl, 5-6 membered heterocyclyl;

[0134] E ring is 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 6 membered aryl, 5-6 membered heteroaryl.

[0135] In another preferred embodiment,

[0136] X1is selected from CR 1 or N;

[0137] X2is selected from C;

[0138] X3is selected from CR 2 R 3 , CR 2 and NR 4 ;

[0139] X4is selected from CR2 R 3 , CR 3 , and NR 4 ;

[0140] or X 3 and X 4 together with the atom to which they are attached form a 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R e ;

[0141] Ring A is selected from C6-C10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R a ;

[0142] Ring B is selected from 3-10 membered cycloalkyl, 4-8 membered heterocyclyl, 7-15 membered spirocyclyl, 7-15 membered bridged cyclyl, 7-15 membered fused cyclyl, wherein the above groups are optionally substituted with one or more R b ;

[0143] Ring C is selected from C6-C10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R c ;

[0144] Ring D is selected from C6-C10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R d ;

[0145] R 1 , R 2 , R 3 , and R 4each independently selected from the group consisting of H atom, -OH, -SH, =0, =S, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -NH2, -NH-(Ci-C6alkyl), -N-(Ci-C6alkyl)2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C6alkyl, -S-(Ci-C6alkyl), -S(O)- f -(Ci-C6alkyl), -S(O)2-(Ci-C6alkyl), -S(O)2-(amino), -S(O)2NH(Ci-Ci2alkyl), -S(O)2N(Ci-Ci2alkyl)2, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6alkylthio, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, C6-Cio aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-C3-C8cycloalkyl, -(Ci-C6alkylene)-3-8 membered heterocyclyl, and -(Ci-C6alkylene)-C(O)-O-Ci-C6alkyl, wherein each of the aforementioned groups is independently optionally substituted with one or more R

[0146] R a , R b , R c , R d , R e , and R f each independently selected from the group consisting of halogen, CN, -OH, -NH2, NO2, -SH, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -CONH2, -CONH(Ci-C6alkyl), -NHCO-(Ci-C6alkyl), Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-Cio cycloalkyl, -(Ci-C6alkylene)-C3-Cio cycloalkyl, C3-Cio cycloalkyloxy, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-3-8 membered heterocyclyl, wherein the aforementioned groups are optionally substituted with R g ;

[0147] each R gindependently selected from D atom, -OH, -COOH, -NH2, NO2, -CN, =0, =S, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C6-C10aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, wherein the above groups are optionally substituted with one or more substituents selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, halogen, cyano, nitro, carboxy, oxo.

[0148] In another preferred embodiment,

[0149] X1is selected from CR 1 or N;

[0150] X2is C;

[0151] X3is selected from CR 2 R 3 and CR 2 ;

[0152] X4is selected from CR 2 R 3 and CR 3 ;

[0153] or X 3 and X 4 together with the atom to which they are attached form a 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R e ;

[0154] Ring A is selected from C6-C10aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R a ;

[0155] Ring B is selected from 3-10 membered cycloalkyl, 4-8 membered heterocyclyl, 7-15 membered spirocyclyl, 7-15 membered bridged cyclyl, 7-15 membered fused cyclyl, wherein the above groups are optionally substituted with one or more R b ;

[0156] Ring C is selected from C6-C10aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R c ;

[0157] Ring D is selected from C6-C10aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R d ;

[0158] R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H atom, -OH, -SH, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -NH2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C6alkyl, -S-(Ci-C6alkyl), C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6alkylthio, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, C6-Cio aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-C3-C8cycloalkyl, and -(Ci-C6alkylene)-3-8 membered heterocyclyl, wherein each of the aforementioned groups is independently optionally substituted with one or more R f ;

[0159] R a , R b , R c , R d , R e , and R f are each independently selected from the group consisting of halogen, CN, -OH, -NH2, -SH, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-Cio cycloalkyl, -(Ci-C6alkylene)-C3-Cio cycloalkyl, C3-Cio cycloalkyloxy, C2-C6alkenyl, C2-C6alkynyl, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-3-8 membered heterocyclyl.

[0160] In another preferred embodiment,

[0161] X1is selected from CR 1 or N;

[0162] X2is C;

[0163] X3is CR 2 ;

[0164] X4is CR 3 ;

[0165] or X 3 and X 4 together with the atom to which they are attached form a 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered aryl, or 5-8 membered heteroaryl, wherein the aforementioned groups are optionally substituted with one or more R e ;

[0166] Ring A is selected from C6-C10 aryl, 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R a substituents;

[0167] Ring B is selected from 3-10 membered cycloalkyl, 4-8 membered heterocyclyl, 7-15 membered spirocyclyl, 7-15 membered bridged cyclyl, 7-15 membered fused cyclyl, wherein the above groups are optionally substituted with one or more R b substituents;

[0168] Ring C is selected from C6-C10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R c substituents;

[0169] Ring D is selected from C6-C10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R d substituents;

[0170] R 1 , R 2 , R 3 , and R 4 are each independently selected from H atom, -OH, -SH, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -NH2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C6alkyl, -S-(Ci-C6alkyl), C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6alkoxy-C(O)-NH2, Ci-C6alkoxy-CONH(Ci-C6alkyl), Ci-C6alkoxy-OH, Ci-C6alkoxy-NH2, Ci-C6alkylthio, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-C3-C8cycloalkyl, and -(Ci-C6alkylene)-3-8 membered heterocyclyl, wherein the above groups are each independently optionally substituted with one or more R f substituents;

[0171] R a , R b , R c , R d , R e , and R feach independently selected from halogen, CN, -OH, -NH2, -SH, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, -(C1-C6alkylene)-C3-C10cycloalkyl, C3-C10cycloalkyloxy, 3-8 membered heterocyclyl, -(C1-C6alkylene)-3-8 membered heterocyclyl.

[0172] In another preferred embodiment,

[0173] X1is selected from CR 1 or N;

[0174] X2is C;

[0175] X3is CR 2 ;

[0176] X4is CR 3 ;

[0177] or X 3 and X 4 together with the atom to which they are attached form a 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered aryl, or 5-8 membered heteroaryl, wherein the above groups are optionally substituted with one or more R e ;

[0178] Ring A is selected from C6aryl, 5-8 membered heteroaryl, wherein the above groups are optionally substituted with one or more R a ;

[0179] Ring B is selected from 4-8 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R b ;

[0180] Ring C is selected from C6aryl, wherein the above groups are optionally substituted with one or more R c ;

[0181] Ring D is selected from 5-8 membered heteroaryl, wherein the above groups are optionally substituted with one or more R d ;

[0182] R 1 , R 2 , R 3 , and R 4each independently selected from the group consisting of H atom, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -C(O)-NH2, -NO2, -CN, halogen, Ci-C6alkyl, -S-(Ci-C6alkyl), C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6alkoxy-C(O)-NH2, Ci-C6alkoxy-CONH(Ci-C6alkyl), Ci-C6alkoxy-OH, Ci-C6alkylthio, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, C6-Cio aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-C3-C8cycloalkyl, and -(Ci-C6alkylene)-3-8 membered heterocyclyl, wherein each of the aforementioned groups is independently optionally substituted with one or more R f substituents;

[0183] R a , R b , R c , R d , R e , and R f each independently selected from the group consisting of halogen, -OH, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-Cio cycloalkyl, -(Ci-C6alkylene)-C3-Cio cycloalkyl, C3-Cio cycloalkyloxy, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-3-8 membered heterocyclyl.

[0184] In another preferred embodiment, R a , R b , R c , R d , R e , and R f each independently selected from the group consisting of halogen, CN, -OH, -NH2, -SH, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C6cycloalkyl, C3-C6cycloalkyloxy, 3-8 membered heterocyclyl, C6-Cio aryl, 5-8 membered heteroaryl, wherein each of the aforementioned groups is optionally substituted with R g substituents.

[0185] In another preferred embodiment, R a , R b , R c , R d , R e , and R feach independently selected from halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, -(C1-C6alkylene)-C3-C10cycloalkyl, C3-C10cycloalkyloxy, 3-8 membered heterocyclyl, -(C1-C6alkylene)-3-8 membered heterocyclyl.

[0186] In another preferred embodiment, the "one or more" refers to 1, 2, 3, 4, or 5.

[0187] In another preferred embodiment, X1, X2, X3, X4, A, B, C, D are each independently the corresponding group in compounds 1-70.

[0188] In another preferred embodiment, the compound is selected from the following table:

[0189] In a second aspect of the present application, a method for preparing a heterocyclic compound of Formula I or stereoisomer, tautomer, deuterated analog, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, as described in the first aspect of the present application, is provided, comprising the steps of:

[0190] Xaand Xbare leaving groups selected from halogen, sulfonate, boronic acid, and boronate ester; and R2, R3, ring A, ring B, ring C, ring D are as defined above.

[0191] In a third aspect of the present application, a pharmaceutical composition comprising a heterocyclic compound of Formula I or stereoisomer, tautomer, deuterated analog, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, as described in the first aspect of the present application; and a pharmaceutically acceptable carrier is provided.

[0192] In another preferred embodiment, the pharmaceutical composition further comprises another therapeutic agent for treating a disease associated with USP1 activity or expression.

[0193] In a fourth aspect of the present application, there is provided a use of the heterocyclic compound of Formula I or stereoisomer, tautomer, deuterated analog, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof as described in the first aspect of the present application, or the pharmaceutical composition as described in the second aspect of the present application, as a USP1 inhibitor or for the manufacture of a medicament for treating a disease associated with USP1 activity or expression.

[0194] In another preferred embodiment, the disease associated with USP1 activity or expression is cancer.

[0195] In another preferred embodiment, the cancer is selected from lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer and breast cancer.

[0196] In a fifth aspect of the present application, there is provided a USP1 inhibitor comprising the heterocyclic compound of Formula I or stereoisomer, tautomer, deuterated analog, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof as described in the first aspect of the present application.

[0197] It should be understood that, within the scope of the present application, all combinations between the above technical features of the present application and the technical features specifically described hereinafter (e.g. in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they are not listed one by one here. DETAILED DESCRIPTION

[0198] The present inventors have made extensive and in-depth research and for the first time discovered a novel USP1 small molecule inhibitor with excellent inhibitory effect. On this basis, the present application is completed.

[0199] TERMS

[0200] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0201] As used herein, the terms "comprising", "including", "containing", "have" and "include" are interchangeable and are meant to be non-limiting.

[0202] As used herein, the term "about" when used in the context of a recited numerical value means that the value can vary from the recited value by not more than 1%. For example, as used herein, the expression "about 100" includes all values between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0203] As used herein, the term "C1-C6alkyl" refers to a branched or straight chain alkyl group having from 1 to 6 carbon atoms, including C1-C5alkyl, C1-C4alkyl, C1-C3alkyl, and includes but is not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, and the like.

[0204] As used herein, the term "C2-C6alkenyl" refers to a branched or straight chain alkenyl group having from 2 to 6 carbon atoms, including C2-C5alkenyl, C2-C4alkenyl, C2-C3alkenyl, and includes but is not limited to ethenyl, n-propenyl, i-propenyl, allyl, n-but enyl, i-but enyl, n-pentenyl, i-pentenyl, n-hexenyl, and the like.

[0205] As used herein, the term "C2-C6alkynyl" refers to a branched or straight chain alkynyl group having from 2 to 6 carbon atoms, including C2-C5alkynyl, C2-C4alkynyl, C2-C3alkynyl, and includes but is not limited to ethynyl, n-propynyl, n-butynyl, i-butynyl, n-pentynyl, i-pentynyl, n-hexynyl, and the like.

[0206] As used herein, the term "halogen" includes fluorine, chlorine, bromine, iodine.

[0207] As used herein, the term "C1-C6haloalkyl" refers to a C1-C6alkyl group as described above substituted with halogen, including C1-C4haloalkyl, C1-C3haloalkyl, for example chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl.

[0208] As used herein, the term "C1-C6alkoxy" refers to -O-C1-C6alkyl groups as described above, including C1-C4alkoxy, C1-C3alkoxy, for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentoxy, i-pentoxy, neopentoxy, n-hexoxy, and the like.

[0209] As used herein, the term "C1-C6haloalkoxy" refers to a C1-C6alkoxy group as described above substituted with halogen, including haloC1-C4alkoxy, haloC1-C3alkoxy, for example chloromethoxy, dichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy.

[0210] As used herein, the term "C1-C6hydroxyalkyl" refers to a C1-C6alkyl group as described above substituted with hydroxyl, including C1-C4hydroxyalkyl, C1-C3hydroxyalkyl, for example hydroxymethyl, hydroxyethyl.

[0211] As used herein, the term "C3-C10 cycloalkyl" refers to a non-aromatic cyclic group having 3 to 10 carbon atoms, which may include bridged rings, spiro rings, and fused rings. Specifically, it includes C3-C8 cycloalkyl, C3-C6 cycloalkyl, and C3-C4 cycloalkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0212] As used herein, the term "4-10 membered heterocyclic group" refers to a cyclic hydrocarbon substituent having 4 to 10 ring atoms in a saturated or partially unsaturated monocyclic or polycyclic form. The partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated π-electron system. In the heterocyclic group, one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is an integer 0, 1, or 2), but excluding the -OO-, -OS-, or -SS- ring portions. The remaining ring atoms are carbon. This includes 5-10 membered heterocyclic groups, 5-8 membered heterocyclic groups, and 5-6 membered heterocyclic groups. Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxobutyl, tetrahydrofuranyl, etc.

[0213] Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S(O). r (Where r is an integer 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings has a fully conjugated π-electron system. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiroatoms between rings. "7-15 membered spirocyclic group" refers to a spirocyclic group having 7 to 15 ring atoms, which may include 7-10 membered spirocyclic groups and 7-8 membered spirocyclic groups. Spiroheterocyclic groups include, but are not limited to:

[0214] "Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system. One or more (preferably 1, 2, 3, or 4) rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated π-electron system. The one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S(O). rheteroatoms, the remaining ring atoms being carbon. "7-15 membered fused heterocyclyl" refers to a fused heterocyclyl group having 7 to 15 ring atoms, which can include 7-10 membered fused heterocyclyl, 7-8 membered fused heterocyclyl. Depending on the number of rings making up the ring system, the fused heterocyclyl group can be bicyclic, tricyclic, tetracyclic or polycyclic, and includes but is not limited to:

[0215] "bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which can contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated pi-electron system, wherein one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S(O) r heteroatoms, the remaining ring atoms being carbon. "7-15 membered fused heterocyclyl" refers to a fused heterocyclyl group having 7 to 15 ring atoms, which can include 7-10 membered fused heterocyclyl, 7-8 membered fused heterocyclyl. Depending on the number of rings making up the ring system, the fused heterocyclyl group can be bicyclic, tricyclic, tetracyclic or polycyclic, and includes but is not limited to:

[0216] As used herein, the term "C6-C10 aryl" refers to an aromatic cyclic group having 6 to 10 carbon atoms, which includes C10 aryl, C6 aryl, including but not limited to phenyl, naphthyl.

[0217] As used herein, the term "5-10 membered heteroaryl" refers to an aromatic cyclic group having 5 to 10 ring atoms, and having 1 to 3 heteroatoms selected from N, S, O, which can include fused, bridged, or spirocyclic rings, and includes 5-8 membered heteroaryl, 5-7 membered heteroaryl, 5-6 membered heteroaryl, including but not limited to furan, thiophene, pyridine, pyrrole, pyrazole, imidazole, oxazole, thiazole, triazole, pyrimidine, quinoline, isoquinoline, and the like.

[0218] As used herein, the term "phosphoryl" is -OP

[0219] As used herein, the term "phosphoryl" is -OP

[0220] "stereoisomer" refers to isomers that differ in the way the atoms are arranged in space. Stereoisomers are further subdivided into enantiomers and diastereomers. Stereoisomers that result from the rotation of a single bond are called conformational stereoisomers, sometimes also referred to as rotamers. Stereoisomers that result from a difference in bond lengths, bond angles, the presence of double bonds, or rings are called configuration stereoisomers. Configuration stereoisomers are further subdivided into geometric isomers, which result from the inability of a double bond or ring atom to rotate freely, and optical isomers, which result from the lack of an axis of symmetry in the molecule. In the present invention, "stereoisomer" is understood to include one or more of the above-mentioned enantiomers, configuration stereoisomers, and conformational stereoisomers, unless otherwise specified.

[0221] "tautomer" refers to structural isomers that differ only in the arrangement of atoms in space, and that can interconvert by a low-energy barrier. For example, proton tautomers include interconversions by proton migration, and valence tautomers include interconversions by reorganization of some of the bonding electrons. For example and are tautomers. In the present invention, "tautomer" is understood to include all tautomeric forms of the compounds described herein, unless otherwise specified.

[0222] "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid addition salt, including inorganic and organic acid salts, which can be prepared by methods known in the art.

[0223] Pharmaceutical compositions and administration

[0224] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds described herein and a pharmaceutically acceptable carrier.

[0225] Since the compounds of the present invention have excellent USP1 inhibitory activity, the compounds of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with USP1 inhibition.

[0226] The pharmaceutical composition of the present application comprises a safe and effective amount of the compound of the present application or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present application per dose, more preferably, 10-1000 mg of the compound of the present application per dose. Preferably, the "dose" is one capsule or tablet.

[0227] The "pharmacologically acceptable carrier" means one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "Compatible" means that the components of the composition are capable of being commingled with the compound of the present application and with each other in the composition, without any significant adverse reactions. Examples of suitable pharmacologically acceptable carriers are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., lecithin), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0228] The pharmaceutical composition is in the form of an injection, a capsule, a tablet, a pill, a powder or a granule.

[0229] The mode of administration of the compound or the pharmaceutical composition of the present application is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0230] ​Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such excipients as (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) lubricants, e.g., magnesium stearate, calcium stearate, and colloidal silica; and (h) absorbents, e.g., kaolin and bentonite clay. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents.

[0231] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g., enteric coatings and other coatings well known in the art. They can optionally contain opacifying agents, and can also be of a composition that they release the active compound or compounds in a certain part of the digestive tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0232] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, as well as mixtures thereof.

[0233] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0234] Suspensions, in addition to the active compounds, can contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and sodium carbomate, among others.

[0235] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0236] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.

[0237] A compound of this application can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0238] The therapeutic methods of this application can be administered by themselves or in combination with other therapeutic procedures or therapeutic agents.

[0239] In using the pharmaceutical compositions, therapeutically effective amounts of a compound of this application are administered to a mammal (e.g., human) in need of treatment in dosages suitable to produce the desired effects. For instance, in the case of a 60 kg adult human, typical dosages would range from 1 to 2000 mg, preferably 50 to 1000 mg, per day, administered in dosages suitable to produce the desired effects, i.e., in dosages in which the clinician, in his or her discretion, will ascertain the dosage that provides the desired effect. The specific dose used, however, will depend on the route of administration, the patient's health status, and similar factors. The amount of a compound of this application in the composition will also depend on the specific use or intended use of the composition.

[0240] The principal advantages of the present application include:

[0241] The compounds of the present application have excellent inhibitory effect on USP1.

[0242] The present application is further illustrated by the following examples. It is to be understood that these examples are merely illustrative of the present application and do not in any way limit the scope of the application. Unless otherwise indicated, the methods of the following examples were carried out in accordance with conventional procedures or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0243] In the present application, room temperature refers to ambient temperature, which is 10-35°C. Overnight refers to 8-15 hours. Reflux refers to the temperature of the solvent at reflux under normal pressure.

[0244] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR is determined by a Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). MS is determined by a Finnigan LCQ / Deca (ESI) mass spectrometer. High performance liquid chromatography (HPLC) analysis uses a Gilson-215 high pressure liquid chromatograph.

[0245] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plates. The silica gel plates used in thin layer chromatography (TLC) have a specification of 0.15mm-0.2mm, and the silica gel plates used in thin layer chromatography separation and purification of products have a specification of 0.4mm-0.5mm. Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0246] Known starting materials of the present disclosure can be synthesized or purchased from Shanghai Haohong Biomedicine Technology Co., Ltd., Bide Pharmaceutical and the like according to methods known in the art. Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0247] The reaction progress in the examples is monitored by thin layer chromatography (TLC). The developing agent used in the reaction, the eluent system used in column chromatography for purifying compounds, and the developing agent system used in thin layer chromatography include dichloromethane / methanol system and petroleum ether / ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and a small amount of triethylamine and basic or acidic reagents such as acetic acid can also be added for adjustment.

[0248] Example 1: Synthesis of (±)-4'-cyclopropyl-5-fluoro-4-(2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)pyrrolidin-1-yl)-6'-methoxy-2,5'-bipyrimidine

[0249] Step 1: Synthesis of compound 1-2, 1-isopropyl-4-(trifluoromethyl)-1H-imidazole

[0250] To a single neck flask was added compound 1-1 (5.00 g, 36.7 mmol) and cesium carbonate (35.75 g, 110 mmol) and dissolved in acetonitrile (100 mL) and iodine isopropyl (12.51 g, 73.48 mmol) was added and heated to 80 °C for 12 h. TLC showed no starting material left, the reaction was filtered at room temperature and the filtrate was concentrated under reduced pressure, the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 100:0-90:10, v / v) to give a yellow liquid 4.10 g, yield 62.60%. 1 H NMR (400 MHz, Chloroform-d) δ 7.65 (d, J = 1.7 Hz, 1H), 6.80 (s, 1H), 5.12-4.27 (m, 1H), 1.48 (d, J = 4.9 Hz, 6H). ESI-MS m / z: 179.07 [M+H] + .

[0251] Step 2: Synthesis of compound 1-3, 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H- imidazole

[0252] To a three neck flask was added compound 1-2 (4.10 g, 23.0 mmol) and dissolved in tetrahydrofuran (41 mL). Argon was replaced for three times, cooled to -78 °C, n-BuLi (23.01 mL, 1 mol / L) was injected and kept for 15 min. Carbon tetrabromide (11.50 g, 34.52 mmol) in tetrahydrofuran (41 mL) was injected into the above solution and reacted at -78 °C for 2 h. TLC showed no starting material left, saturated ammonium chloride (25 mL) solution was added dropwise to the reaction under ice bath, extracted with ethyl acetate (2 x 100 mL), the organic phase was washed with water (100 mL), saturated brine (100 mL), dried over anhydrous Na2S04, filtered and the filtrate was concentrated under reduced pressure, the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 40:1-20:1, v / v) to give an orange yellow oily liquid 4.60 g, yield 78.30%. 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 0.9 Hz, 1H), 4.47 (dq, J = 13.2, 6.6 Hz, 1H), 1.41 (d, J = 6.7 Hz, 6H). ESI-MS m / z: 256.5 [M+H] + .

[0253] Step 3: Synthesis of compound 1-5, (±)-4-(2-(4-bromophenyl)pyrrolidin-1-yl)-2- chloro-5-fluoropyrimidine

[0254] To a single neck flask was added compound 1-4 (1.00 g, 4.42 mmol, purchased), 2,4-dichloro-5-fluoropyrimidine (1.10 g, 6.63 mmol) and DIPEA (1.71 g, 13.26 mmol) in tetrahydrofuran (20 mL) and heated to 60 °C for 3 h. TLC showed no starting material left. The reaction was concentrated under reduced pressure and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 15:1-5:1, v / v) to give 1.35 g of white solid, 86.00% yield. 1 HNMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 5.0 Hz, 1H), 7.56-7.38 (m, 2H), 7.03 (d, J = 8.0 Hz, 2H), 5.36 (d, J = 7.7 Hz, 1H), 4.05 (dt, J = 11.6, 5.6 Hz, 1H), 3.82 (q, J = 10.1, 9.2 Hz, 1H), 2.40 (tq, J = 12.8, 7.5, 5.8 Hz, 1H), 2.00 (dt, J = 13.2, 4.0 Hz, 2H), 1.96 (s, 1H). ESI-MS m / z: 357.6 [M+H] + .

[0255] Step 4: Synthesis of compound 1-6, (±)-2-chloro-5-fluoro-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-1-yl)pyrimidine

[0256] To a single neck flask was added compound 1-5 (1.00 g, 2.80 mmol), bis(pinacolato)diboron (1.07 g, 4.20 mmol), potassium acetate (0.55 g, 5.60 mmol) in dioxane (35 mL) and purged with argon three times, then added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (204.90 mg, 0.28 mmol) and heated to 80 °C for 3 h. TLC showed no starting material left. The reaction was concentrated under reduced pressure and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 12:1-5:1, v / v) to give 636.40 mg of yellow solid, 56.30% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 8.1 Hz, 1H), 7.71-7.66 (m, 2H), 7.26-7.20 (m, 2H), 5.03-4.98 (m, 1H), 3.78 (dt, J = 12.5, 4.6 Hz, 1H), 3.71 (dt, J = 12.4, 4.7 Hz, 1H), 2.15 (q, J = 5.2 Hz, 2H), 2.02-1.95 (m, 2H), 1.26 (s, 4H), 1.21 (s, 4H). ESI-MS m / z: 404.0 [M+H] + .

[0257] Step 5: Synthesis of compound 1-7, (±)-2-chloro-5-fluoro-4-(2-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)phenyl)pyrrolidin-1-yl)pyrimidine

[0258] To a single-neck flask was added compound 1-6 (636.40 mg, 1.58 mmol), compound 1-3 (488.40 mg, 1.90 mmol), potassium carbonate (873.50 mg, 6.32 mmol) dissolved with dioxane (13 mL), water (1.50 mL), replaced with argon for three times, added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (115.60 mg, 0.158 mmol), heated to 80 °C for 3 hours. TLC showed no raw material left, the reaction solution was added to saturated ammonium chloride (5 mL) solution, extracted with ethyl acetate (2 x 20 mL), the organic phase was washed with water (20 mL), saturated brine (20 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 12:1-3:1, v / v) to give 277.50 mg of a light yellow solid, with a yield of 38.70%. 1 H NMR (400 MHz, Chloroform-d) δ 7.88-7.71 (m, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.41 (s, 1H), 7.25 (d, J = 16.8 Hz, 2H), 5.46 (d, J = 7.9 Hz, 1H), 4.65-4.41 (m, 1H), 4.20-3.70 (m, 2H), 2.00 (s, 2H), 1.44 (d, J = 13.5 Hz, 6H), 1.25 (d, J = 9.2 Hz, 2H). ESI-MS m / z: 454.0 [M+H] + .

[0259] Step 6: Synthesis of compound 1, (±)-4'-cyclopropyl-5-fluoro-4-(2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)pyrrolidine-1-yl)-6'-methoxy-2,5'-bipyrimidine

[0260] Compounds 1-7 (80.00 mg, 0.176 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (68.29 mg, 0.528 mmol) were added to a single-necked flask at room temperature, dissolved in dioxane (1.60 mL) and water (0.40 mL), and potassium carbonate (72.97 mg, 0.384 mmol) was added. The mixture was purged three times with argon, and X-Phos-Pd G2 (10.07 mg, 0.0128 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no remaining raw material. A saturated ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL). The organic phase was dried with anhydrous Na₂SO₄ and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 8:1-2:1, v / v) to give 63.93 mg of white solid, with a yield of 64.00% and a purity of 98.37%. 1 H NMR(600MHz,Chloroform-d)δ8.54(s,1H),8.11(s,1H),7.46(d,J=7.8Hz,2H), 7.39(s,1H),7.24(d,J=7.7Hz,2H),5.53(d,J=7.9Hz,1H),4.55(hept,J=6.7Hz ,1H),4.10(s,1H),3.85(s,3H),2.37(d,J=14.6Hz,1H),2.03-1.91(m,4H),1.9 1-1.79(m,1H),1.45(d,3H),1.44(d,3H),1.30-1.20(m,2H),0.88-0.74(m,2H). 13C NMR(150MHz,Chloroform-d)δ168.92,166.42,157.63,156.92,150.56(d,J=7.0Hz ),147.96,145.45(d,J=48.3Hz),141.54,141.39,132.19(q,J=38.7Hz),129.30(2 C),128.38,125.83(2C),121.80(q,J=267.0Hz),118.89,116.10(q,J=4.1Hz),62. 02,54.08,49.46,49.43,48.63,29.70,24.03,24.01,13.80,10.72,10.51.ESI-MS m / z calcd for C 29 H 29 F4N7O[M+H] + :568.2442,found:568.2445.

[0261] Example 2: Synthesis of (±)-4'-cyclopropyl-5-fluoro-4-(2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)piperidin-1-yl)-6'-methoxy-2,5'-bipyrimidine

[0262] Compound 2 was prepared by replacing compounds 1-4 in Example 1 with (±)-2-(4-bromophenyl)piperidine, following the same steps as in Example 1. It was a white solid, 43.80 mg, yield 62.10%, purity 97.64%. 1 H NMR(600MHz,Chloroform-d)δ8.56(s,1H),8.23(d,J=6.8Hz,1H),7.51(d,J=8.2Hz,2H),7.40(d ,2H),7.39(s,1H),4.55(hept,J=6.7Hz,1H),4.41(d,J=13.8Hz,1H),3.89(s,3H),3.15-3.05(m ,1H),2.08-2.00(m,1H),1.81(tt,J=8.4,4.7Hz,1H),1.75-1.66(m,4H),1.62-1.55(m,1H),1.4 4(t,J=6.8Hz,6H),1.26-1.16(m,1H),1.16-1.02(m,2H),0.89-0.80(m,1H),0.79-0.63(m,1H). 13C NMR(150MHz,Chloroform-d)δ168.98,166.43,157.61(d,J=6.6Hz),156.99,152.00,14 7.95, 145.06 (d, J = 259.9Hz), 143.07 (d, J = 25.3Hz), 141.40, 132.18 (q, J = 38.8Hz), 129. 55(2C),128.31,127.27(2C),121.81(q,J=267.0Hz),118.88,116.11(q,J=3.8Hz),65.8 6,54.09,48.66,42.66,27.96,25.80,23.99,23.97,19.60,13.96,10.73,10.70.ESI-MS m / z calcd for C 30 H 31 F4N7O[M+H] + :582.2599,found:582.2601.

[0263] Example 3: Synthesis of (±)-4-(4'-cyclopropyl-5-fluoro-6'-methoxy-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0264] Synthesis of general intermediate A1,(±)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0265] Step 1: Synthesis of compound A1-2,2-((tributyltin)methoxy)-N-triphenylmethyltin-1-amine

[0266] At 0°C, a mixture of triphenylchloromethane (7.30 g, 26.25 mmol) and DMF (65 mL) was added dropwise to a solution of 2-aminoethanol (1.50 mL, 15.00 mmol, self-purchased) and triethylamine (3.83 mL, 16.50 mmol) in DMF (100 mL), and the mixture was heated to 40°C and reacted for 24 hours. The reaction solution was cooled to 0°C, and NaH (2.20 g, 55.00 mmol) was slowly added. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 6 hours. The reaction solution was then cooled to 0°C, and tributyltin (14.00 g, 32.50 mmol) was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 24 hours. TLC showed no remaining raw material. The residue was quenched with water (50 mL) in an ice bath, extracted with ethyl acetate (2 × 200 mL), dried and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 100:0-95:5, v / v) to give 11.38 g of a colorless, transparent oil, with a yield of 75.00%. 1 H NMR(400MHz,Chloroform-d)δ7.29(s,15H),3.57(t,J=5.4Hz,1H),3.53(t,J=2.9Hz,2H), 3.00(dt,J=5.9,3.0Hz,2H),2.92(s,2H),1.38-1.24(m,12H),0.95-0.80(m,15H).ESI-MS m / z:608.1[M+H] + .

[0267] Step 2: Synthesis of compound A1-3,2-((tributyltin)methoxy)ethyl-1-amine

[0268] Compound A1-2 (8.00 g, 13.20 mmol) and dichloromethane:2,2,2-trifluoroethanol:AcOH = 7:2:1 (265 mL, v / v) were added to a single-necked flask at room temperature and reacted for 6 hours. TLC showed no starting material remaining. The reaction solution was diluted with dichloromethane (200 mL) at 0 °C, and the pH was slowly adjusted to 8 with saturated NaHCO3. Extraction was performed, and the product was dried and concentrated. The crude product was purified by column chromatography (ethyl acetate / methanol, 100:0-90:10 + 0.1% triethylamine, v / v) to give 4.53 g of a pale yellow oil, with a yield of 80.00%. 1H NMR(400MHz,Chloroform-d)δ3.77-3.69(m,2H),3.34(t,2H),2.83-2.76(m,2H) ,2.03(s,2H),1.52-1.47(m,2H),1.38-1.19(m,12H),0.94-0.84(m,13H).ESI-MS m / z:366.0[M+H] + .

[0269] Step 3: Synthesis of methyl 5,4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate, compound A1-

[0270] At room temperature, methyl 4-formate benzaldehyde (compound A1-4, 17.00 g, 98.38 mmol) and 3,3-dibromo-1,1,1-trifluoro-2-propanone (55.89 g, 0.197 mol) were added to a single-necked flask and dissolved in methanol (500 mL). A mixture of sodium acetate (16.99 g, 0.197 mol) and ammonia (100 mL) was added to the above solution, and the reaction was carried out at room temperature for 18 hours. TLC showed no starting material remaining. The sample was extracted with water (100 mL) and EA (500 mL), and the organic phase was dried and concentrated. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 95:5-85:15, v / v) to give 9.32 g of orange solid, yield 81.50%. 1 H NMR(400MHz,DMSO-d6)δ13.46(s,1H),8.13-8.08(m,2H),8.08-8.03(m,2H),7.99(s,1H),3.87(s,3H).ESI-MS m / z:271.0[M+H] + .

[0271] Step 4: Synthesis of methyl 6,4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate

[0272] Compound A1-5 (11.00 g, 34.60 mmol) and cesium carbonate (33.80 g, 0.104 mol) were added to a single-necked flask at room temperature, dissolved in acetonitrile (200 mL), and iodoisopropane (13.84 g, 69.20 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no residue of starting material. The mixture was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 100:0–90:10, v / v) to give 9.18 g of a yellow solid, in 85.00% yield. 1H NMR (400MHz, Chloroform-d) δ8.16-8.11(m,2H),7.66-7.60(m,2H),7.45(d,J=1.0Hz,1H),4.57(hept,J=6.7Hz,1H),3.94(s,3H),1.46(d,J=6.7Hz,6H).ESI-MS m / z:313.0[M+H] + .

[0273] Step 5: Synthesis of compound A1-7, (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol

[0274] Compound A1-6 (5.00 g, 16.00 mmol) was added to a three-necked flask at room temperature and dissolved in tetrahydrofuran (100 mL). The mixture was then purged with argon and cooled to 0 °C in an ice bath. DIBAL-H (53.37 mL, 1.5 mol / L) was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 3 hours. TLC showed no remaining starting material. The mixture was then diluted with 100 mL of diethyl ether at 0 °C, quenched by slow addition of 4 mL of water, and then slowly added with 4 mL of 15% sodium hydroxide aqueous solution. Water (10 mL) was added, and the mixture was allowed to return to room temperature and stirred for 15 minutes. Anhydrous Na2SO4 was added, and the mixture was stirred for 15 minutes before filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 90:10-80:20, v / v) to give 4.32 g of a white solid, with a yield of 95.00%. 1 H NMR(400MHz,Chloroform-d)δ7.51-7.45(m,2H),7.43(d,J=8.0Hz,3H),4.75(s,2H ),4.60-4.48(m,1H),2.03(d,J=23.1Hz,1H),1.46(dd,J=11.5,6.8Hz,6H).ESI-MS m / z:285.0[M+H] + .

[0275] Step 6: Synthesis of compound A1-8,4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde

[0276] Compound A1-7 (4.32 g, 15.20 mmol) and manganese dioxide (3.96 g, 45.59 mmol) were added to a single-necked flask at room temperature, dissolved in dichloromethane (100 mL), and reacted at room temperature for 12 hours. TLC showed no residue. The mixture was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 100:0–90:10, v / v) to give 3.99 g of a white solid, yield 93.00%. 1H NMR(400MHz,Chloroform-d)δ10.11(d,J=1.8Hz,1H),8.02(dd,J=8.2,1.9Hz,2H),7.78(dd,J=8.2 ,1.9Hz,2H),7.50(s,1H),4.72-4.52(m,1H),1.53(d,J=1.8Hz,3H),1.51(d,J=1.7Hz,3H).ESI-MS m / z:283.0[M+H] + .

[0277] Step 7: Synthesis of compound A1-9, 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-N-(2-((tributyltin)methoxy)ethyl)methylimine

[0278] Compounds A1-8 (3.99 g, 14.13 mmol) and A1-3 (5.66 g, 15.54 mmol) were added to a single-necked flask at room temperature, dissolved in dichloromethane (80 mL), and 4A molecular sieve (1.41 g, 100 mg / mmol) was added. The reaction mixture was reacted at room temperature for 6 hours. The reaction solution was filtered at room temperature, and the filtrate was concentrated under reduced pressure to give 8.44 g of a pale yellow oil, with a yield of 95.00%.

[0279] Step 8: Synthesis of general intermediate A1,(±)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0280] At room temperature, (S,S)-2,2'-isopropylidene bis(4-phenyl-2-oxazoline) (266.19 mg, 0.796 mmol) and Cu(OTf)₂ (287.90 mg, 0.796 mmol) were added to a single-necked flask, dissolved in HFIP (33 mL), and reacted at room temperature for 6 hours to obtain a dark green suspension. A mixture of compound A1-9 (5.00 g, 7.96 mmol) and HFIP (50 mL) was added to the above suspension, and reacted at room temperature for 24 hours. TLC showed no remaining raw material. 10 mL of NH3·H2O:saturated brine (1:1 ratio) was added to the reaction solution, and the mixture was stirred for 30 min. 100 mL of DCM was added, and the mixture was washed with 100 mL of saturated NaCl. The organic phase was dried and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol, 60:1-20:1 + 0.1% triethylamine, v / v) to give 1.67 g of a yellow solid, yield 62.00%. 1H NMR(400MHz,Chloroform-d)δ7.53(d,J=1.1Hz,4H),7.43(s,1H),4.57(hept,J=6.7H z,1H),4.01(dd,J=10.0,3.2Hz,1H),3.94-3.89(m,1H),3.86(dd,J=11.0,3.2Hz,1H) ,3.70(qd,J=12.1,11.5,3.3Hz,1H),3.42(t,J=10.6Hz,1H),3.17(td,J=11.5,3.2Hz ,1H),3.04(d,J=11.7Hz,1H),1.48(s,3H),1.47(s,3H),1.33(p,J=7.7Hz,1H).ESI-MS m / z:340.1[M+H] + .

[0281] Step 9: Synthesis of compound 3-1,(±)-4-(2-chloro-5-fluoropyrimidin-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0282] Compound A1 (80.00 mg, 0.24 mmol) and 2,4-dichloro-5-fluoropyrimidine (58.44 mg, 0.35 mmol) were added to a single-necked flask at room temperature, dissolved in tetrahydrofuran (2 mL), and DIPEA (91.50 mg, 0.71 mmol) was added. The mixture was heated to 60 °C and reacted for 12 hours. TLC showed no starting material remaining. The reaction mixture was concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 10:1–3:1, v / v) to give 60.00 mg of a yellowish-white solid, in 54.10% yield. 1 H NMR (400MHz, Chloroform-d) δ8.07-7.97(m,2H),7.98-7.77(m,2H),7.21(t,J=1.0Hz,1H),7.19(d,J=0.7Hz,1H),4.78(td,J= 5.0,0.9Hz,1H),4.72-4.63(m,1H),4.10-3.99(m,3H),3.93-3.80(m,3H),1.54(d,J=4.9Hz,3H),1.49(d,J=4.9Hz,3H).ESI-MS m / z:470.1[M+H] + .

[0283] Step 10: Synthesis of compound 3,(±)-4-(4'-cyclopropyl-5-fluoro-6'-methoxy-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0284] At room temperature, compound 3-1 (100.00 mg, 0.22 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (82.77 mg, 0.43 mmol) were added to a single-necked flask, dissolved in dioxane (1.20 mL) and water (0.30 mL), and potassium carbonate (53.07 mg, 0.384 mmol) was added. The mixture was purged three times with argon gas, and X-Phos-Pd G2 (17.30 mg, 0.022 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. Add saturated ammonium chloride (5 mL) solution to the reaction solution, extract with ethyl acetate (2 × 10 mL), wash the organic phase with water (10 mL) and saturated brine (10 mL), dry the organic phase with anhydrous Na2SO4 and filter, concentrate the filtrate under reduced pressure, and purify the crude product by column chromatography (petroleum ether / ethyl acetate, 8:1-2:1, v / v) to give 68.20 mg of white solid, yield 58.40%, purity 98.00%. 1 H NMR(500MHz,Chloroform-d)δ8.62(s,1H),8.29(d,J=6.7Hz,1H),7.68(d,J=8.2Hz,2H),7.54(d,J=8.3Hz,2H),7.44(d ,J=1.2Hz,1H),5.90(s,1H),4.58(hept,J=6.7Hz,1H),4.50(d,J=12.2Hz,1H),4.28(d,J=13.9Hz,1H),4.07(dd,J=12. 2,3.6Hz,1H),4.03(dd,J=11.6,3.2Hz,1H),3.94(s,3H),3.82(td,J=11.7,2.8Hz,1H),3.52(ddd,J=15.1,12.1,3.5Hz ,1H),1.78(tt,J=8.3,4.6Hz,1H),1.48(d,J=2.5Hz,3H),1.47(d,J=2.5Hz,3H),1.23-1.17(m,2H),0.91-0.84(m,2H). 13C NMR(125MHz,Chloroform-d)δ168.44,165.90,157.23(d,J=6.5Hz),156.64,150.65(d, J=3.3Hz),147.31,144.67(d,J=259.5Hz),142.98(d,J=25.0Hz),139.71,131.72(q,J=3 8.9Hz),128.92(2C),128.63,127.91(2C),121.29(q,J=267.0Hz),118.17,115.68(q,J =3.3Hz),68.41,66.63,53.64,48.17,41.71,26.41,23.49,23.47,13.48,10.37.ESI-MS m / z calcd for C 29 H 29 F4N7O2[M+H] + :584.2392,found:584.2395.

[0285] The synthesis steps of compounds 4-31 were all carried out in accordance with the steps of Example 3. Some intermediates used in the synthesis of different compounds are different from those in Example 3. The replacement compounds will be specifically described in the examples of compounds 4-31.

[0286] Example 4: Synthesis of (±)-4'-cyclopropyl-5-fluoro-4-(2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-4-methylpiperazin-1-yl)-6'-methoxy-2,5'-bipyrimidine

[0287] Synthesis of compound 4-1,(±)-4'-cyclopropyl-5-fluoro-4-(2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)piperazin-1-yl)-6'-methoxy-2,5'-bipyrimidine

[0288] Compound A1-1 in step 1 of Example 3 was replaced with tert-butyl (2-aminoethyl)carbamate, and compound 4-1 was prepared by following the same steps as in Example 3. The result was 95.80 mg of white solid, with a yield of 36.40%.

[0289] Step 1: Synthesis of compound 4,(±)-4'-cyclopropyl-5-fluoro-4-(2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-4-methylpiperazin-1-yl)-6'-methoxy-2,5'-bipyrimidine

[0290] Compound 4-1 (50.00 mg, 0.086 mmol) and cesium carbonate (83.68 g, 0.257 mol) were added to a single-necked flask at room temperature, dissolved in acetonitrile (2 mL), and iodomethane (36.48 mg, 0.26 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no residue of starting material. The mixture was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 10:1–3:1, v / v) to give 33.30 mg of a white solid, yield 65.00%, purity 97.23%. 1 H NMR(600MHz,Chloroform-d)δ8.61(s,1H),8.27(d,J=6.8Hz,1H),7.65(d,J=8.1Hz,2H),7.51(d,J=8.3Hz ,2H),7.43(d,J=1.4Hz,1H),5.45-5.29(m,1H),4.59(p,J=6.7Hz,1H),4.41(d,J=13.8Hz,1H),3.94(s,3H) ,3.46-3.37(m,2H),2.93-2.87(m,1H),2.58(dd,J=12.2,4.2Hz,1H),2.36(s,3H),2.30(td,J=11.7,3.1Hz ,1H),1.81(dq,J=8.3,4.7,4.2Hz,1H),1.47(dd,J=6.7,3.8Hz,6H),1.23-1.14(m,2H),0.93-0.82(m,2H). 13 C NMR(150MHz,Chloroform-d)δ168.56,166.00,157.19(d,J=6.5Hz),156.67,150.86,1 47.57,144.67(d,J=258.9Hz) 142.87(d,J=25.2Hz),140.90,131.57(q,J=38.6Hz),128 .89(2C),128.19,127.73(2C),121.38(q,J=266.9Hz),118.33,115.72(q,J=4.1Hz),5 6.81,54.84,53.74(2C),48.19,45.91,29.29,23.59(2C),13.58,10.45,10.43.ESI-MS m / z calcd for C 30 H 32 F4N8O[M+H] + :597.2708,found:597.2710.

[0291] Example 5: Synthesis of (±)-4-(4'-cyclopropyl-5-fluoro-6'-methoxy-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-1,4-oxazacycloheptane

[0292] Compound A1-3 in step 8 of Example 3 was replaced with 3-((tributyltinyl)methoxy)propyl-1-amine (purchased by the manufacturer), and compound 5 was prepared by following the same steps as in Example 3. It was a white solid, 25.20 mg, with a yield of 42.50% and a purity of 96.68%. 1 H NMR(600MHz,Chloroform-d)δ8.60(s,1H),8.21(d,J=6.8Hz,1H),7.53(d,J=7.9Hz,2H),7.43(d,J=1.4Hz,1H),7.41(d, J=8.1Hz,2H),4.57(hept,J=6.7Hz,1H),4.32(dd,J=13.6,5.7Hz,1H),4.08(ddd,J=12.7,5.9,2.9Hz,1H),3.90(s,3H), 3.86(d,J=15.0Hz,1H),3.64(dt,J=47.7,13.4Hz,2H),2.23(ddt,J=13.7,4.8,2.5Hz,1H),1.89(d,J=14.7Hz,2H),1.77 (s,1H),1.48(d,J=1.5Hz,3H),1.47(d,J=1.5Hz,3H),1.28(d,J=13.3Hz,1H),1.13(d,J=20.3Hz,2H),0.92-0.69(m,2H). 13 C NMR(150MHz,Chloroform-d)δ168.52,165.99,156.94(d,J=6.3Hz),156.58(2C),151.2 8,147.36,144.45(d,J=259.4Hz), 142.56(d,J=25.5Hz), 140.01,131.78(q,J=38.7Hz), 129.18(2C),128.62,126.36,121.37(q,J=267.0Hz),118.42,115.79(q,J=3.9Hz),74.5 8,72.37,53.65,48.26,43.59,30.84,29.28,23.58,23.56,13.48,10.38,10.27.ESI-MS m / zcalcd for C 30 H 31F4N7O2[M+H] + :598.2548,found:598.2550.

[0293] Example 6: Synthesis of (±)-4-(4'-cyclopropyl-6'-methoxy-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0294] Replacing 2,4-dichloro5-fluoropyrimidine in step 9 of Example 3 with 2,4-dichloropyrimidine, the product was synthesized according to the route to obtain 30.80 mg of a white solid, with a yield of 51.30% and a purity of 95.23%. 1 H NMR(500MHz,Chloroform-d)δ8.60(s,1H),8.38(d,J=6.2Hz,1H),7.62-7.54(m,2H),7.52-7.46(m,2H),7.41(q,J=1.2H z,1H),6.45(d,J=6.2Hz,1H),4.55(hept,J=6.6Hz,1H),4.44(dd,J=12.1,1.4Hz,1H),4.06(dd,J=11.5,3.7Hz,1H),4.0 1(dd,J=12.1,3.7Hz,1H),3.98-3.93(m,1H),3.92(s,3H),3.74(td,J=11.7,3.2Hz,1H),3.49-3.46(m,1H),3.45-3.39( m,1H),1.77(tt,J=8.0,4.6Hz,1H),1.45(d,J=1.4Hz,3H),1.44(d,J=1.4Hz,3H),1.18-1.12(m,2H),0.89-0.78(m,2H). 13 C NMR(125MHz,Chloroform-d)δ168.84,166.38,162.50,161.64,157.04,156.56,147.81,140.39,132.22(q,J=38.7Hz),129.42(2C),129.05,128.25(2 C),121.80(q,J=266.5Hz),119.47,116.18(q,J=3.7Hz),101.18,69.43,66 .65,54.12,48.66,40.30,24.00,23.97,15.28,13.97,10.88,10.82.ESI-MS m / z calcd for C 29 H 30F3N7O2[M+H] + :566.2468,found:566.2487.

[0295] Example 7: Synthesis of methyl (±)-4'-cyclopropyl-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholinyl)-6'-methoxy-[2,5'-bipyrimidine]-5-carboxylic acid

[0296] In step 9 of Example 3, 2,4-dichloro-5-fluoropyrimidine was replaced with methyl 2,4-dichloropyrimidine-5-carboxylate, and 26.80 mg of a white solid was synthesized according to the route, with a yield of 42.80% and a purity of 100%. 1 H NMR(500MHz,Chloroform-d)δ8.91(s,1H),8.63(s,1H),7.65(d,J=7.9Hz,2H),7.57 -7.49(m,2H),7.43(d,J=1.6Hz,1H),4.65-4.47(m,2H),4.04(dd,J=12.3,3.5Hz,1H) ,3.96-3.93(m,5H),3.91(s,3H),3.77(td,J=11.7,2.6Hz,1H),3.72-3.53(m,2H),1 .79(tt,J=8.3,4.7Hz,1H),1.48-1.46(m,6H),1.29-1.16(m,2H),0.92-0.82(m,2H). 13 C NMR(125MHz,Chloroform-d)δ168.99,166.43,166.37,163.58,160.75,160. 42,157.39,147.88,139.91,132.21(q,J=38.7Hz),129.47(2C),128.95,128 .06(2C),121.82(q,J=266.8Hz),118.62,116.19(q,J=4.1Hz),107.48,68.9 5(2C),66.87,54.20(2C),52.59,48.66,24.02,24.00,14.09,10.96.ESI-MS m / z calcd for C 31 H 32 F3N7O4[M+H] + :624.2541,found:624.2546.

[0297] Example 8: Synthesis of (±)-4'-cyclopropyl-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholinyl)-6'-methoxy-[2,5'-bipyrimidine]-5-carboxylic acid ethyl ester

[0298] In step 9 of Example 3, 2,4-dichloro-5-fluoropyrimidine was replaced with ethyl 2,4-dichloropyrimidine-5-carboxylate, and 20.60 mg of a white solid was synthesized according to the route, with a yield of 39.80% and a purity of 100%. 1 H NMR(500MHz,Chloroform-d)δ8.89(s,1H),8.61(s,1H),7.64(d,J=8.1Hz,2H),7.55-7.51(m,2H),7.42(d ,J=1.2Hz,1H),4.60-4.53(m,2H),4.37(qd,J=7.1,5.5Hz,2H),4.05-4.01(m,1H),3.95-3.90(m,5H),3.7 6(td,J=11.6,2.7Hz,1H),3.60(ddd,J=15.3,12.0,3.6Hz,1H),3.27(s,1H),1.79(tt,J=8.3,4.7Hz,1H), 1.46(d,J=1.9Hz,3H),1.45(d,J=1.9Hz,3H),1.38(t,J=7.1Hz,3H),1.27-1.14(m,2H),0.92-0.76(m,2H). 13 C NMR(125MHz,Chloroform-d)δ168.98,166.36,166.11,163.46,160.69,160.27, 157.36,147.87,139.96,132.20(q,J=38.6Hz),129.44(2C),128.91,128.02(2C) ,121.81(q,J=266.9Hz),118.63,116.16(q,J=4.0Hz),107.92,68.91,66.87,61 .71,54.17,48.63,45.78,29.70,24.00,23.98,14.26,14.07,10.94(2C).ESI-MS m / z calcd for C 32 H 34 F3N7O4[M+H] + :638.2697,found:638.2704.

[0299] Example 9: Synthesis of (±)-4'-cyclopropyl-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholinyl)-6'-methoxy-[2,5'-bipyrimidine]-5-carboxamide

[0300] In Example 3, step 9, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloropyrimidine-5-carboxamide, and 50.70 mg of a white solid was synthesized according to the route, with a yield of 65.80% and a purity of 98.91%. 1 H NMR(500MHz,Chloroform-d)δ8.69(s,1H),8.63(s,1H),7.63(d,J=8.1Hz,2H),7.51(d,J=8.3Hz,2H),7.43(d,J= 1.4Hz,1H),6.50(s,1H),5.99(s,1H),5.95-5.93(m,1H),4.56(hept,J=6.7Hz,1H),4.42(dd,J=12.2,2.3Hz,1H) ,4.07(dd,J=12.2,3.6Hz,1H),3.97(dt,J=11.6,3.0Hz,1H),3.93(s,3H),3.83(dt,J=11.6,6.9Hz,1H),3.56(dd ,J=7.5,3.0Hz,2H),1.73(tt,J=8.3,4.7Hz,1H),1.47(s,3H),1.46(s,3H),1.22-1.13(m,2H),0.91-0.87(m,2H). 13 CNMR(125MHz,Chloroform-d)δ169.02,168.54,166.41,163.47,160.56,157.5 1,157.43,147.83,140.24,132.19(q,J=39.2,38.8Hz),129.48(2C),129.04,12 8.32(2C),121.92(q,J=267.1Hz),118.68,116.28(q,J=3.9Hz),112.78,69.32 ,66.79,54.97,54.22,48.74,45.35,24.04,24.03,14.10,11.05,10.95.ESI-MS m / z calcd for C 30 H 31 F3N8O3[M+H] + :609.2544,found:609.2549.

[0301] Example 10: Synthesis of (±)-4'-cyclopropyl-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholinyl)-6'-methoxy-[2,5'-bipyrimidine]-5-carboxynitrile

[0302] Replacing 2,4-dichloro-5-fluoropyrimidine in step 9 of Example 3 with 2,4-dichloro-5-cyanopyrimidine, 25.10 mg of a white solid was synthesized according to the route, with a yield of 36.80% and a purity of 94.89%. 1 H NMR(500MHz,Chloroform-d)δ8.67(d,J=4.4Hz,2H),7.77-7.56(m,2H),7.55-7.52(m,2H),7.44 (s,1H),4.74-4.64(m,1H),4.62-4.56(m,1H),4.53(d,J=12.4Hz,1H),4.09(dd,J=11.7,3.7Hz,1 H),4.03(d,J=10.6Hz,2H),4.01(s,3H),3.73(q,J=20.9,16.5Hz,1H),3.43-3.29(m,1H),1.75-1 .72(m,1H),1.48(d,J=6.8Hz,3H),1.47(d,3H),1.31-1.25(m,2H),0.99(dd,J=30.2,7.2Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ168.91,166.28,164.07,161.54,157.54,147 .57,141.06,139.41,132.30(q,J=38.7Hz),129.63(2C),129.57,128.21(2C ),121.92(q,J=265.8Hz),120.23,118.33,116.28(q,J=5.0Hz),105.61,69 .20,66.45,54.17,48.72,40.68,26.92,23.99,14.10,11.07,11.02.ESI-MS m / zcalcd for C 30 H 29 F3N8O2[M+H] + :591.2438,found:591.2439.

[0303] Example 11: Synthesis of (±)-4-(5-chloro-4'-cyclopropyl-6'-methoxy-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0304] Replacing 2,4-dichloro-5-fluoropyrimidine in step 9 of Example 3 with 2,4,5-trichloropyrimidine, the product was synthesized according to the route to obtain 33.20 mg of a white solid, with a yield of 48.60% and a purity of 99.31%. 1 H NMR(500MHz,Chloroform-d)δ8.61(s,1H),8.49(s,1H),7.61(d,J=8.3Hz,2H),7.52(d,J=8.4Hz,2H),7. 42(d,J=1.3Hz,1H),4.57(hept,J=6.7Hz,1H),4.38(dd,J=12.1,2.8Hz,1H),4.17-4.09(m,1H),4.04(dd ,J=12.1,3.5Hz,1H),3.96(dt,J=11.4,3.1Hz,1H),3.91(s,3H),3.85(td,J=11.3,10.9,2.7Hz,1H),3.5 6-3.44(m,2H),1.69(tt,J=8.0,4.7Hz,1H),1.46(t,J=6.9Hz,6H),1.24-1.12(m,2H),0.92-0.81(m,2H). 13 C NMR(126MHz,Chloroform-d)δ168.97,166.40,160.14,160.00,157.74,157.32,147.82,140.13,132.25(q,J=38.7Hz),129.37(2C),128.98,128.24( 2C),121.81(q,J=267.0Hz),118.28,116.19(q,J=3.8Hz),116.04,69.18,6 7.09,65.87,56.16,54.19,48.66,24.02(2C),13.99,10.99,10.83.ESI-MS m / z calcd for C 29 H 29 ClF3N7O2[M+H] + :600.2096,found:600.2092.

[0305] Example 12: Synthesis of (±)-4-(4'-cyclopropyl-6'-methoxy-5-(trifluoromethyl)-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0306] In Example 3, step 9, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5-trifluoromethylpyrimidine, and 35.40 mg of a white solid was synthesized according to the route, with a yield of 32.10% and a purity of 98.41%. 1 H NMR(500MHz,Chloroform-d)δ8.65(s,1H),8.64(s,1H),7.68(dd,J=8.1,6.3Hz,2H),7.49(d,J=7.9H z,2H),7.41(s,1H),5.98(dd,J=9.9,3.4Hz,1H),4.67-4.54(m,2H),4.48(dd,J=15.4,11.8Hz,1H),4 .12-3.98(m,2H),3.92(d,J=7.8Hz,3H),3.78-3.68(m,1H),3.40-3.26(m,1H),1.72-1.57(m,1H),1. 46(d,3H),1.45(d,3H),1.24-1.10(m,1H),0.95(dd,J=8.1,3.7Hz,1H),0.88(td,J=7.0,3.9Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ168.60,165.98,165.91,162.05(q,J=3.1Hz),161.72,158.02, 157.99,156.95(q,J=4.1Hz),147.93(q,J=9.8Hz),140.68,132.21(q,J=38.5Hz),129.31,129 .03,128.62,128.52,121.99(qd,J=267.0Hz,2C),116.27,116.18(q,J=3.6Hz),113.55(q,J=3 2.4Hz),69.22,67.08,54.05,48.64,39.80,29.71,24.00,23.98,14.29,11.04,10.54.ESI-MS m / zcalcd for C 30 H 29 F6N7O2[M+H] + :634.2360,found:634.2365.

[0307] Example 13: Synthesis of (±)-4-(4'-cyclopropyl-6'-methoxy-5-(2,2,2-trifluoroethyl)-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0308] Replacing 2,4-dichloro-5-fluoropyrimidine in step 9 of Example 3 with 2,4-dichloro-5-trifluoroethylpyrimidine, 20.80 mg of a white solid was synthesized according to the route, with a yield of 26.80% and a purity of 95.12%. 1 H NMR(500MHz,Chloroform-d)δ8.68(s,1H),8.63(s,1H),7.43(s,4H),7.41(d,J=1.3Hz, 1H),5.02(dd,J=7.8,3.6Hz,1H),4.51(hept,J=6.7Hz,1H),4.05-3.92(m,3H),3.92-3. 86(m,1H),3.87(s,3H),3.76-3.53(m,2H),3.37-3.24(m,2H),1.49(d,J=6.7Hz,3H),1. 42(d,J=6.7Hz,3H),1.28(dd,J=6.8,2.0Hz,1H),1.26-1.17(m,2H),0.83-0.75(m,2H). 13 C NMR(125MHz,Chloroform-d)δ168.87,167.58,166.51,162.56,159.99,157.40,14 7.66,140.11,132.25(q,J=38.6Hz),129.22(2C),129.15,128.13(2C),124.35,121 .76(q,J=267.0Hz),118.42,116.20(q,J=3.9Hz),114.74,71.41,66.85,59.77,54 .15,50.57,48.64,32.78(q,J=30.8Hz),24.04,23.98,13.84,11.16,10.68.ESI-MS m / z calcd for C 31 H 31 F6N7O2[M+H] + :648.2516,found:648.2514.

[0309] Example 14: Synthesis of (±)-4-(4'-cyclopropyl-6'-methoxy-5-nitro-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0310] Replacing 2,4-dichloro-5-fluoropyrimidine with 2,4-dichloro-5-nitropyrimidine in step 9 of Example 3, the product was synthesized according to the route to obtain 26.20 mg of a white solid, with a yield of 28.20%. Purity: 100%. 1 H NMR(500MHz,Chloroform-d)δ9.06(d,J=0.9Hz,1H),8.65(d,J=1.4Hz,1H),7.67(d,J=8.1Hz,2H),7.60-7.48(m, 2H),7.44(d,J=1.3Hz,1H),4.71-4.48(m,2H),4.06(dd,J=12.4,3.5Hz,1H),4.00(dd,J=11.9,3.5Hz,1H),3.96(d ,J=1.1Hz,3H),3.80(td,J=11.7,2.7Hz,1H),3.67(ddd,J=13.4,11.9,3.7Hz,1H),1.82(tt,J=8.3,4.6Hz,1H),1. 49(d,J=4.0Hz,3H),1.48(d,J=4.0Hz,4H),1.24(dd,J=4.4,2.8Hz,2H),0.93(d,J=2.6Hz,2H),0.91-0.83(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.18,166.32,164.18,157.77,155.80,154.56,147.68,139.08,132.28(q,J=37.9Hz),129.66(2C),129.45,128.08( 2C),121.86(q,J=267.0Hz),120.73,117.80,116.29(q,J=4.2Hz),68.91,6 6.42,54.30,48.72,45.49,29.72,24.03,24.01,14.23,11.18(2C).ESI-MS m / z calcd for C 29 H 29 F3N8O4[M+H] + :611.2337,found:611.2341.

[0311] Example 15: Synthesis of (±)-4-(4'-cyclopropyl-6'-methoxy-5-methyl-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0312] In Example 3, step 9, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5-methylpyrimidine, and 31.50 mg of a white solid was synthesized according to the route, with a yield of 53.60% and a purity of 100%. 1 H NMR(500MHz,Chloroform-d)δ8.59(s,1H),8.39(d,J=0.9Hz,1H),7.50(d,J=8.3Hz,2H),7.45(d,J=8.3Hz,2H),7.41(d,J= 1.3Hz,1H),5.27(t,J=4.4Hz,1H),4.55(hept,J=6.7Hz,1H),4.11(dd,J=11.8,5.1Hz,1H),4.03(dd,J=11.9,3.6Hz,1H),3 .92(tdd,J=13.3,6.5,3.3Hz,2H),3.86(s,3H),3.56(ddd,J=13.2,5.4,3.1Hz,1H),3.41(ddd,J=13.2,7.5,3.3Hz,1H),2. 35(s,3H),1.52(tt,J=8.4,4.6Hz,1H),1.48(d,J=6.7Hz,3H),1.43(d,J=6.7Hz,3H),1.18-1.05(m,2H),0.80-0.71(m,2H). 13 C NMR(125MHz,Chloroform-d)δ168.86,166.51,165.28,160.13,159.06,157. 05,147.82,140.87,132.21(q,J=38.8Hz),129.20(2C),128.76,128.07(2C), 121.79(q,J=267.0Hz),118.99,118.00,116.15(q,J=4.0Hz),70.40,67.13,5 7.29,54.09,48.62,46.27,24.03,24.01,16.51,13.79,10.94,10.57.ESI-MS m / z calcd for C 30 H 32 F3N7O2[M+H] + :580.2642,found:580.2648.

[0313] Example 16: Synthesis of (±)-4-(4'-cyclopropyl-5-ethyl-6'-methoxy-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0314] In Example 3, step 9, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5-ethylpyrimidine, and 42.10 mg of a white solid was synthesized according to the route, with a yield of 55.60% and a purity of 100%. 1 H NMR(500MHz,Chloroform-d)δ8.60(d,J=2.0Hz,1H),8.48(d,J=2.2Hz,1H),7.47(d,2H),7.43(d,J=7.0Hz,2 H),7.40(s,1H),5.15(t,J=4.5Hz,1H),4.54(hept,J=7.0Hz,1H),4.05-3.97(m,2H),3.92(td,J=4.9,2.6Hz, 2H),3.85(d,J=2.2Hz,3H),3.39(dt,J=6.1,3.2Hz,2H),2.89-2.66(m,2H),1.48(dd,J=6.8,2.0Hz,3H),1.4 2(d,J=6.0Hz,3H),1.37(td,J=7.5,2.0Hz,3H),1.26(d,J=5.6Hz,1H),1.20-1.02(m,2H),0.80-0.70(m,2H). 13 C NMR(125MHz,Chloroform-d)δ168.89,166.57,165.55,159.92,157.78,157.09 ,147.83,140.91,132.24(q,J=38.6Hz),129.14(2C),128.77,128.16(2C),124 .66,121.79(q,J=267.2Hz),118.95,116.15(q,J=4.2Hz),70.88,67.11,58.29 ,54.11,48.63,48.08,24.06,24.02,22.12,13.79,13.62,11.03,10.58.ESI-MS m / z calcd for C 31 H 34 F3N7O2[M+H] + :594.2799,found:594.2801.

[0315] Example 17: Synthesis of (±)-4-(4'-cyclopropyl-5,6'-dimethoxy-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0316] Replacing 2,4-dichloro-5-fluoropyrimidine in step 9 of Example 3 with 2,4-dichloro-5-methoxypyrimidine, the product was synthesized according to the route to obtain 38.60 mg of a white solid, with a yield of 48.30% and a purity of 100%. 1 H NMR(500MHz,Chloroform-d)δ8.59(s,1H),8.10(s,1H),7.63(d,J=8.1Hz,2H),7.52-7.48(m,2H),7. 42(d,J=1.3Hz,1H),4.57(hept,J=6.7Hz,1H),4.48-4.33(m,2H),4.04(dd,J=12.1,3.5Hz,1H),3.95 (dd,J=4.5,2.3Hz,1H),3.93(s,3H),3.92(s,3H),3.81(td,J=11.4,2.6Hz,1H),3.54-3.34(m,1H),1 .78(tt,J=8.4,4.7Hz,1H),1.46(s,3H),1.45(s,3H),1.16(dq,J=6.1,3.1Hz,2H),0.88-0.83(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.13,166.63,156.97,154.36,153.90,148. 08,141.28,141.13,137.80,132.23(q,J=38.6Hz),129.32(2C),128.76,128 .45(2C),121.91(q,J=267.1Hz),119.19,116.22(q,J=4.0Hz),68.95,67.43 ,56.20,55.14,54.20,48.72,42.76,24.07(2C),14.02,10.87,10.80.ESI-MS m / z calcd for C 30 H 32 F3N7O3[M+H] + :596.2591,found:596.2594.

[0317] Example 18: Synthesis of (±)-4-(4',5-dicyclopropyl-6'-methoxy-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0318] In step 9 of Example 3, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5-cyclopropylpyrimidine, and 22.60 mg of a yellow solid was synthesized according to the route, with a yield of 36.20% and a purity of 98.90%. 1 H NMR(500MHz,Chloroform-d)δ8.59(s,1H),8.27(s,1H),7.55(d,J=8.4Hz,2H),7.47(d,J=8.2Hz,2H),7.41(d,J=1.4Hz,1H),5.68(d ,J=3.7Hz,1H),4.56(hept,J=6.7Hz,1H),4.25(dd,J=11.9,3.9Hz,1H),4.06(dd,J=11.9,3.5Hz,1H),4.03-3.92(m,2H),3.88(s,3H ),3.59(ddd,J=12.3,9.1,3.0Hz,1H),1.93(td,J=8.4,4.2Hz,1H),1.61(tt,J=8.3,4.7Hz,1H),1.47(d,J=6.7Hz,3H),1.44(d,J=6. 7Hz,3H),1.28-1.18(m,2H),1.11(tdd,J=14.0,6.3,4.5Hz,2H),1.00(tq,J=8.8,4.2Hz,1H),0.93-0.82(m,2H),0.82-0.75(m,2H). 13 C NMR(125MHz,Chloroform-d)δ168.91,166.49,164.88,159.48,157.02,156.18 ,147.86,141.01,132.21(q,J=38.7Hz),129.22(2C),128.71,128.14(2C),121. 79(q,J=267.0Hz),121.34,119.03,116.13(q,J=3.9Hz),69.91,67.31,56.53,5 4.10,48.62,45.47,24.01(2C),13.86,11.50,10.92,10.66,9.00,7.37.ESI-MS m / z calcd for C 32 H 34 F3N7O2[M+H]+ :606.2799,found:606.2807.

[0319] Example 19: Synthesis of (±)-4'-cyclopropyl-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholinyl)-6'-methoxy-[2,5'-bipyrimidin]-5-yl)methanol

[0320] Replacing 2,4-dichloro-5-fluoropyrimidine in step 9 of Example 3 with (2,4-dichloropyrimidin-5-yl)methanol, 18.50 mg of a white solid was synthesized according to the route, with a yield of 24.30% and a purity of 94.81%. 1 H NMR (500MHz, Chloroform-d) δ8.64(d,J=4.1Hz,1H),8.51(d,J=8.8Hz,1H),7.67(d,J=8.0Hz,1H),7.61(d,J=8.0Hz,1H),7. 48(s,1H),7.46(s,1H),7.40(d,J=1.4Hz,1H),5.93(d,J=3.2Hz,1H),4.56(dtd,J=11.0,8.6,5.6Hz,2H),4.46(dd,J=11.9, 9.3Hz,1H),4.37-4.30(m,2H),4.01(dq,J=13.5,4.4Hz,2H),3.93(d,J=13.9Hz,3H),3.88-3.67(m,2H),3.32(dddd,J=30.0 ,13.9,12.2,3.7Hz,1H),1.77-1.59(m,1H),1.46(s,3H),1.44(s,3H),1.14(qd,J=8.0,7.5,4.1Hz,2H),0.91-0.81(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.52,165.82,161.17,159.35,159.21,157.74, 148.06,141.37,132.21(q,J=37.2Hz),129.22,129.19,128.61,128.37,122.06 121.91(q,J=266.9Hz),121.89,116.57,116.19(q,J=4.0Hz),69.50,67.18,6 0.04,54.24,52.73,48.63,39.87,24.02,24.00,14.14,10.97,10.89.ESI-MS m / z calcd for C 30H 32 F3N7O3[M+H] + :596.2591,found:596.2596.

[0321] Example 20: Synthesis of (±)-4-(4'-cyclopropyl-6'-methoxy-5-(methylthio)-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0322] In step 9 of Example 3, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5-methylthiopyrimidine, and 40.50 mg of a white solid was synthesized according to the route, with a yield of 53.30% and a purity of 100%. 1 H NMR(500MHz,Chloroform-d)δ8.58(s,1H),8.42(s,1H),7.51(d,J=8.3Hz,2H),7.43(d,J=8.4Hz,2H),7.39(d,J=1.3H z,1H),5.44(t,J=4.4Hz,1H),4.54(p,J=6.7Hz,1H),4.09-3.97(m,2H),3.98-3.86(m,2H),3.85(s,3H),3.67(ddd,J= 13.0,5.7,3.2Hz,1H),3.55(ddd,J=13.1,6.8,3.5Hz,1H),2.52(s,3H),1.47(d,J=6.7Hz,3H),1.41(d,J=6.7Hz,3H), 1.15(ddt,J=9.0,4.2,1.8Hz,1H),1.05(ddd,J=9.6,4.7,2.8Hz,1H),0.90-0.80(m,1H),0.75(dq,J=8.0,2.1Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ169.03,166.56,163.25,158.66,157.19,154. 85,147.84,140.58,132.25(q,J=38.6Hz),129.16(2C),128.83,128.15(2C), 121.80(q,J=267.0Hz),121.67,118.44,116.13(q,J=4.0Hz),70.62,67.22,5 7.75,54.16,48.63,46.33,24.06,24.03,15.53,13.82,11.09,10.68.ESI-MS m / z calcd for C30 H 32 F3N7O2S[M+H] + :612.2363,found:612.2368.

[0323] Example 21: Synthesis of (±)-4-(4'-cyclopropyl-6,6'-dimethoxy-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0324] Replacing 2,4-dichloro-5-fluoropyrimidine in step 9 of Example 3 with 2,4-dichloro-6-methoxypyrimidine, the product was synthesized according to the route to obtain 38.40 mg of a white solid, with a yield of 51.20% and a purity of 94.85%. 1 H NMR(500MHz,Chloroform-d)δ8.60(s,1H),7.65(d,J=8.0Hz,2H),7.51(d,J=8.1Hz,2H),7.43(s,1H),6.1 9(s,1H),5.94(d,J=3.6Hz,1H),4.59(td,J=13.5,4.9Hz,2H),4.48(d,J=12.0Hz,1H),4.03(ddd,J=15.9,1 1.6,3.7Hz,2H),3.95(s,3H),3.94(s,3H),3.73(td,J=11.7,3.1Hz,1H),3.34(ddd,J=14.1,12.2,3.8Hz,1 H),1.96(tt,J=8.6,4.8Hz,1H),1.48(d,J=2.5Hz,3H),1.47(d,3H),1.21-1.11(m,2H),0.93-0.83(m,2H). 13 C NMR(125MHz,Chloroform-d)δ170.57,169.23,166.19,162.16,161.39,157. 21,148.13,141.66,132.11(q,J=35.4Hz),129.22(2C),128.56,128.35(2C), 122.52(q,J=264.5Hz),118.39,116.08(d,J=4.0Hz),98.86,69.40,67.27,5 4.10,53.34,52.87,48.63,39.91,24.04,24.01,14.02,11.01,10.94.ESI-MS m / z calcd for C 30 H 32 F3N7O3[M+H]+ :592.2591,found:592.2596.

[0325] Example 22: Synthesis of (±)-4-(4'-cyclopropyl-6'-methoxy-6-methyl-[2,5'-bipyrimidin]-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0326] Replacing 2,4-dichloro-5-fluoropyrimidine in step 9 of Example 3 with 2,4-dichloro-6-methylpyrimidine, the product was synthesized according to the route to obtain 45.20 mg of a white solid, with a yield of 55.40% and a purity of 95.23%. 1 H NMR(500MHz,Chloroform-d)δ8.61(s,1H),7.60(d,J=8.0Hz,2H),7.51(d,J=8.2Hz,2H),7.43(d,J=1 .6Hz,1H),6.32(s,1H),4.57(hept,J=6.8Hz,1H),4.46(d,J=12.1Hz,1H),4.09-4.01(m,2H),3.98-3. 94(m,1H),3.94(s,3H),3.76(td,J=11.8,3.2Hz,1H),3.51-3.40(m,2H),2.45(s,3H),1.76(tt,J=8. 4,4.7Hz,1H),1.47(d,J=2.5Hz,3H),1.46(d,J=2.5Hz,3H),1.18(t,J=5.3Hz,2H),0.91-0.80(m,2H). 13 C NMR(125MHz,Chloroform-d)δ168.79,166.43,166.39,162.34,162.01,156. 95,147.88,140.60,132.22(q,J=38.7Hz),129.38(2C),128.95,128.31(2C), 121.81(q,J=266.9Hz),119.65,116.16(q,J=3.8Hz),99.85,69.48,66.70,5 4.06,52.64,48.66,40.29,24.53,24.01,23.98,13.99,10.82,10.79.ESI-MS m / z calcd for C 30 H 32 F3N7O2[M+H] + :580.2642,found:580.2645.

[0327] Example 23: Synthesis of (±)-4'-cyclopropyl-6-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholinyl)-6'-methoxy-[2,5'-bipyrimidine]-4-carboxynitrile

[0328] In Example 3, step 9, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-6-cyanopyrimidine, and 19.20 mg of a white solid was synthesized according to the route, with a yield of 33.70% and a purity of 100%. 1 H NMR(500MHz,Chloroform-d)δ8.62(s,1H),7.60(d,J=8.0Hz,2H),7.53(d,J=8.1Hz,2H),7.44-7. 42(m,1H),6.83(s,1H),4.61-4.50(m,1H),4.47(d,J=12.2Hz,1H),4.12(dd,J=11.5,3.7Hz,1H), 4.05-3.99(m,1H),3.93(s,3H),3.76(td,J=11.8,3.0Hz,1H),3.53-3.45(m,1H),1.74-1.71(m,1 H),1.47(s,3H),1.46(s,3H),1.29-1.24(m,2H),1.21(dd,J=4.6,3.0Hz,2H),0.89-0.85(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.68,165.98,161.85,160.78,160.65,158.5 4,147.85,145.79,140.10,132.30(q,J=38.7Hz),129.46(2C),129.26,128.5 9(2C),121.80(q,J=267.0Hz),120.25,116.17(q,J=5.0Hz),115.47,67.05,6 6.97,54.33,48.69,29.73,24.02,24.00,15.30,14.13,11.50,11.13.ESI-MS m / z calcd for C 30 H 30 F3N8O2[M+H] + :591.2438,found:591.2443.

[0329] Example 24: Synthesis of (±)-4-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0330] In Example 3, step 9, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and 53.60 mg of a white solid was synthesized according to the route, with a yield of 65.30% and a purity of 100%. 1 H NMR(500MHz,Chloroform-d)δ8.61(s,1H),7.61(d,J=7.9Hz,2H),7.51(d,J=8.1Hz,2H),7.43(s,1H),4.58(hept,J =6.7Hz,1H),4.50(d,J=12.1Hz,1H),4.23(s,1H),4.01(ddd,J=42.5,11.8,3.5Hz,2H),3.94(s,3H),3.75(td,J=11 .6,2.8Hz,1H),3.46(td,J=12.8,12.0,3.5Hz,1H),3.11-3.00(m,2H),2.97(td,J=7.9,3.8Hz,2H),2.10(p,J=7.6H z,2H),1.81(tt,J=8.3,4.7Hz,1H),1.48-1.46(m,6H),1.29-1.25(m,1H),1.18(d,J=4.3Hz,2H),0.91-0.82(m,2H). 13 C NMR(125MHz,Chloroform-d)δ174.75,168.88,166.47,160.26,159.93,156.84, 147.92,140.98,132.18(q,J=38.7Hz),129.39(2C),128.79,128.15(2C),121.8 0(q,J=267.0Hz),119.59,116.12(q,J=4.0Hz),113.59,69.11,67.29,54.07(2C ),48.64,41.89,34.17,31.84,23.99,23.97,21.95,13.98,10.81,10.76.ESI-MS m / z calcd for C 32 H 34 F3N7O2[M+H] + :606.2799,found:606.2802.

[0331] Example 25: (±)-4-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5,6,7,8-tetrahydroquinazolin-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0332] In step 9 of Example 3, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5,6,7,8-tetrahydroquinazoline, and 42.40 mg of a white solid was synthesized according to the route, with a yield of 51.60% and a purity of 100%. 1 H NMR(500MHz,Chloroform-d)δ8.57(s,1H),7.45(d,J=8.4Hz,2H),7.42(d,J=8.2Hz,2H),7.40(d,J=1.3Hz,1H),5.05(dd,J=7.1,3.6H z,1H),4.55(hept,J=6.7Hz,1H),4.01(dd,J=11.7,3.7Hz,1H),3.91(ddq,J=11.1,6.6,3.3Hz,3H),3.82(s,3H),3.35(tdd,J=14.4,6 .1,3.6Hz,2H),2.87(dq,J=18.2,7.6,6.4Hz,2H),2.63(ddd,J=15.6,9.4,4.8Hz,1H),2.00(q,J=6.4Hz,2H),1.79(ddd,J=59.8,11.0 ,6.3Hz,2H),1.50(d,J=6.7Hz,3H),1.41(d,J=6.8Hz,4H),1.07(ddt,J=46.2,7.9,3.4Hz,2H),0.91-0.82(m,2H),0.76-0.67(m,2H). 13C NMR(125MHz,Chloroform-d)δ168.77,166.72,166.54,166.23,158.97,156.94,14 7.90,141.14,132.22(q,J=38.7Hz),129.09(2C),128.62,128.10(2C),121.79(q, J=267.0Hz),119.89,119.22,116.13(q,J=3.8Hz),71.29,67.19,58.62,53.99,48 .62,47.94,32.13,26.94,24.09,24.02,22.53,22.36,13.74,11.02,10.48.ESI-MS m / z calcd for C 33 H 36 F3N7O2[M+H] + :620.2955,found:620.2959.

[0333] Example 26: Synthesis of (±)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholinyl)-5,7-dihydrofurano[3,4-d]pyrimidine

[0334] In step 9 of Example 3, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5,7-dihydrofuranopyrimidine, and 43.10 mg of a white solid was synthesized according to the route, with a yield of 53.50% and a purity of 100%. 1H NMR(500MHz,Chloroform-d)δ8.62(s,1H),7.61(d,J=7.9Hz,2H),7.53(d,J=7.9Hz,2H),7.43(s,1H),5.29(dt,J=11 .2,2.6Hz,1H),5.21(d,J=11.6Hz,1H),5.01(dt,J=5.2,2.5Hz,2H),4.57(hept,J=6.7Hz,1H),4.51(d,J=12.2Hz,1H) ,4.02(ddd,J=11.7,6.9,3.6Hz,2H),3.95(s,3H),3.74(td,J=11.7,2.9Hz,1H),3.55-3.45(m,1H),1.80(tt,J=8.3,4 .7Hz,1H),1.47(d,J=2.9Hz,3H),1.46(d,J=2.9Hz,3H),1.36-1.24(m,2H),1.20(d,J=4.9Hz,2H),0.92-0.83(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.67,168.93,166.42,161.99,158.01,157.1 2,147.75,140.29,132.22(q,J=38.8Hz),129.50(2C),129.13,128.16(2C),12 2.45(q,J=266.9Hz),119.08,116.21(d,J=3.8Hz),108.75,72.98,72.63,69.0 9,67.05,54.13(2C),48.68,29.69,23.99,23.97,14.03,10.91,10.86.ESI-MS m / z calcd for C 31 H 32 F3N7O3[M+H] + :608.2591,found:608.2595.

[0335] Example 27: Synthesis of (±)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholinyl)furano[3,2-d]pyrimidine

[0336] By replacing 2,4-dichloro-5-fluoropyrimidine in step 9 of Example 3 with 2,4-dichlorofurano[3,2-d]pyrimidine, 33.50 mg of a white solid was synthesized according to the route, with a yield of 44.80% and a purity of 98.46%.1 H NMR(500MHz,Chloroform-d)δ8.60(s,1H),7.78(d,J=2.2Hz,1H),7.70(d,J=8.2Hz,2H),7.49(d,J=8.3H z,2H),7.40(d,J=1.3Hz,1H),6.92(d,J=2.2Hz,1H),4.76-4.67(m,1H),4.55-4.52(m,1H),4.07(dt,J=11 .6,3.8Hz,2H),3.92(s,3H),3.83(td,J=11.8,2.8Hz,1H),3.62-3.55(m,1H),1.79(tt,J=8.0,4.7Hz,1H ),1.44(d,J=3.2Hz,3H),1.43(d,J=3.2Hz,3H),1.32-1.22(m,2H),1.19-1.14(m,2H),0.87-0.79(m,2H). 13 C NMR(125MHz,Chloroform-d)δ168.92,166.47,157.18,156.90,152.67,148.24 ,148.13,147.89,140.49,132.80,132.18(q,J=38.6Hz),129.36(2C),129.01,1 28.55(2C),121.80(q,J=267.0Hz),119.69,116.16(q,J=3.8Hz),108.29,68.99 ,67.29,65.86,54.10,48.65,23.99,23.95,15.28,14.02,10.82,10.80.ESI-MS m / z calcd for C 31 H 30 F3N7O3[M+H] + :606.2435,found:606.2439.

[0337] Example 28: Synthesis of (±)-4-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)thieno[3,2-d]pyrimidin-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0338] In step 9 of Example 3, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichlorothieno[3,2-d]pyrimidine, and 42.50 mg of a white solid was synthesized according to the route, with a yield of 51.30% and a purity of 100%. 1H NMR(500MHz,Chloroform-d)δ8.64(s,1H),7.81(d,J=5.5Hz,1H),7.67(d,J=8.1Hz,2H),7.56-7.51(m,2H ),7.51(d,J=1.8Hz,1H),7.42(d,J=1.4Hz,1H),4.58(d,J=2.2Hz,1H),4.58-4.52(m,2H),4.10(dd,J=12. 3,3.4Hz,2H),3.94(s,3H),3.85(td,J=11.7,2.9Hz,1H),3.72-3.60(m,1H),3.49(q,J=7.0Hz,1H),1.83( tt,J=8.3,4.7Hz,1H),1.47(d,J=2.5Hz,3H),1.45(d,J=2.5Hz,3H),1.23-1.20(m,2H),0.91-0.80(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.00,166.52,162.64,158.32,158.25,157.00 ,147.83,140.36,132.20(q,J=38.5Hz),132.13,129.44(2C),129.05,128.32( 2C),125.60,121.79(q,J=267Hz),119.44,116.17(q,J=3.8Hz),112.67,69.12 ,67.11,65.86,54.09,48.65,23.99,23.96,15.28,14.06,10.86,10.82.ESI-MS m / z calcd for C 31 H 30 F3N7O2S[M+H] + :622.2207,found:622.2208.

[0339] Example 29: Synthesis of (±)-4-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-methylthiopheno[3,2-d]pyrimidin-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0340] In step 9 of Example 3, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-6-methylthiopheno[3,2-d]pyrimidine, and 43.50 mg of a white solid was synthesized according to the route, with a yield of 53.60% and a purity of 100%. 1H NMR(500MHz,Chloroform-d)δ8.62(s,1H),7.64(d,J=8.1Hz,2H),7.51(d,J=8.2Hz,2H),7.41(d,J=1 .4Hz,1H),7.19(s,1H),6.15(s,1H),4.60-4.53(m,2H),4.52-4.44(m,1H),4.11-4.04(m,2H),3.93( s,3H),3.82(td,J=11.7,2.9Hz,1H),3.66-3.58(m,1H),2.62(d,J=1.1Hz,3H),1.81(tt,J=8.4,4.7H z,1H),1.46(d,J=3.0Hz,3H),1.45(d,J=3.1Hz,3H),1.18(dd,J=4.7,2.7Hz,2H),0.90-0.84(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.03,166.54,163.15,158.08,157.59,157.00,1 47.88,147.65,140.45,132.24(q,J=38.5Hz),129.47(2C),129.02,128.29(2C), 123.37,121.92(q,J=266.9Hz),119.49,116.19(q,J=4.0Hz),112.13,69.17,67. 16,54.11,48.67,42.38,26.95,24.03,24.00,16.17,14.06,10.86,10.82.ESI-MS m / z calcd for C 32 H 32 F3N7O2S[M+H] + :636.2363,found:636.2361.

[0341] Example 30: Synthesis of (±)-4-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0342] In step 9 of Example 3, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichlorothiopheno[2,3-d]pyrimidine, and 35.20 mg of a white solid was synthesized according to the route, with a yield of 47.60% and a purity of 100%. 1H NMR(500MHz,Chloroform-d)δ8.63(s,1H),7.66(d,J=8.0Hz,2H),7.55(d,J=8.3Hz,2H),7.43(d,J=1.3Hz,1H), 7.30(d,J=6.1Hz,1H),7.23(d,J=6.2Hz,1H),6.01(s,1H),4.62-4.56(m,1H),4.56-4.50(m,2H),4.08(dd,J=12. 2,3.7Hz,1H),4.04(dd,J=11.1,2.9Hz,1H),3.94(s,3H),3.82(td,J=11.5,2.9Hz,1H),3.70-3.61(m,1H),1.86( tt,J=8.4,4.6Hz,1H),1.47(s,3H),1.46(s,3H),1.21(dq,J=6.2,3.2Hz,2H),0.88(ddt,J=7.1,4.1,1.5Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ170.51,169.12,166.57,158.60,157.06,156.82 ,147.80,140.28,132.23(q,J=38.7Hz),129.68(2C),129.15,128.00(2C),122 .81,121.98(q,J=267.0Hz),120.11,119.30,116.21(q,J=3.8Hz),114.55,69. 12,66.95(2C),54.11,48.69,24.00(2C),14.07,10.91(2C),10.87(2C).ESI-MS m / z calcd for C 32 H 32 F3N7O2S[M+H] + :622.2207,found:622.2204.

[0343] Example 31: Synthesis of (±)-4-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)-3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholine

[0344] In step 9 of Example 3, 2,4-dichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine, and 21.50 mg of a white solid was synthesized according to the route, with a yield of 31.50% and a purity of 98.21%.1 H NMR(500MHz,Chloroform-d)δ12.57(s,1H),8.70(s,1H),7.65(d,J=7.9Hz,2H),7.51(d,J=7.9 Hz,2H),7.42(s,1H),6.73(t,J=2.9Hz,1H),6.39(s,1H),4.60-4.56(m,2H),4.10(ddd,J=19.2 ,12.0,3.6Hz,2H),3.94(s,3H),3.84(td,J=11.7,3.1Hz,1H),3.66(s,1H),1.97(q,J=7.4,6.5 Hz,1H),1.46(dd,J=6.7,4.5Hz,6H),1.44-1.22(m,2H),1.23-1.17(m,2H),0.84-0.76(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.48,166.66,157.07,157.00,153.81,152.89 ,147.95,140.92,132.20(q,J=38.6Hz),129.44(2C),128.81,128.14(2C),121 .83(q,J=267.0Hz),121.16,119.46,116.14(q,J=3.8Hz),101.23,100.95,69. 33,67.07,54.15(2C),48.64,24.02,23.99,14.15,14.10,11.11,11.03.ESI-MS m / z calcd for C 31 H 31 F3N8O2[M+H] + :605.2595,found:605.2597.

[0345] Example 32: Synthesis of 5-(4-cyclopropyl-6-methoxy-5-methyl-[2,5-bipyrimidin]-4-yl)-6-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0346] Synthesis of general intermediate A2,(±)-6-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0347] Step 1: Synthesis of compound A2-2,2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazolium

[0348] At room temperature, 4-bromobenzaldehyde (A2-1, 4.00 g, 21.62 mmol) and 3,3-dibromo-1,1,1-trifluoro-2-propanone (6.48 g, 24.00 mol) were added to a single-necked flask and dissolved in methanol (48 mL). A mixture of sodium acetate (5.88 g, 43.24 mol) and ammonia (14 mL) was added to the above solution, and the reaction was carried out at room temperature for 18 hours. TLC showed no starting material remaining. The reaction solution was quenched with water (50 mL) at room temperature, extracted with ethyl acetate (2 × 60 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 95:5-85:15, v / v) to give 4.10 g of yellow solid, yield 65.20%. 1 H NMR(400MHz,Chloroform-d)δ7.97(d,J=4.4Hz,1H),7.95-7.92(m,2H),7.76-7.71(m,2H).ESI-MS m / z:290.9[M+H] + .

[0349] Step 2: Synthesis of compound A2-3,2-(4-bromophenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazolium

[0350] Compound A2-2 (4.00 g, 13.74 mmol) and cesium carbonate (8.96 g, 27.48 mmol) were added to a single-necked flask at room temperature, dissolved in acetonitrile (80 mL), and iodopropane (4.70 g, 27.48 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no starting material remaining. The reaction solution was filtered at room temperature, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 100:0–90:10, v / v) to give 3.73 g of a yellow solid, yield 81.50%. 1 H NMR(400MHz,Chloroform-d)δ7.64-7.59(m,2H),7.47-7.41(m,3H),4.53(hept,J=6.7Hz,1H),1.47(d,3H),1.45(d,3H).ESI-MS m / z:333.0[M+H] + .

[0351] Step 3: Synthesis of methyl pent-4-enoate of compound A2-4,(E)-2-((tert-butoxycarbonyl)amino)-5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)pent-4-enoate

[0352] At room temperature, compound A2-3 (3.70 g, 11.10 mmol) and N-Boc-L-allylglycine methyl ester (3.30 g, 14.43 mmol) were added to a single-necked flask, dissolved in DMF (60 mL), and DIPEA (2.87 g, 22.20 mmol) was added. The mixture was purged three times with argon gas, and then [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (716.70 mg, 1.11 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no remaining raw material. A saturated ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 200 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL). The organic phase was dried with anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 15:1-5:1, v / v) to give 3.84 g of white solid, with a yield of 71.90%. 1 H NMR(400MHz,Chloroform-d)δ7.49(d,J=8.2Hz,2H),7.45(s,1H),7.43(d,2H),6.59-6.47(m,1H),6.18(dt,J=15.3,7.4Hz,1H),5.15(d ,J=8.3Hz,1H),4.66-4.46(m,1H),4.13(q,J=7.2Hz,1H),3.77(s,3H),2.89-2.72(m,1H),2.70-2.53(m,1H),1.49-1.41(m,15H).ESI-MS m / z:482.2[M+H] + .

[0353] Step 4: Synthesis of compound A2-5,(±)-1-(tert-butyl)2-methyl4-iodo-5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)pyrrolidine-1,2-dicarboxylate

[0354] Compound A2-4 (3.84 g, 7.97 mmol), iodine (10.11 g, 39.85 mmol), and potassium carbonate (5.43 g, 39.85 mmol) were added to a single-necked flask at room temperature and dissolved in acetonitrile (100 mL). The reaction was carried out at room temperature for 16 hours. TLC showed no starting material remaining. Saturated sodium thiosulfate solution was added until the reaction solution decolorized. The mixture was extracted with ethyl acetate (2 × 200 mL), and the organic phase was washed with water (200 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 15:1–5:1, v / v) to give 3.92 g of white solid, yield 81.00%.1 H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.95(d,J=8.9Hz,2H),7.43-7.33(m,2 H),5.34-5.24(m,1H),4.74-4.64(m,1H),4.62(dt,J=5.5,4.6Hz,1H),4.55(t,J= 5.9Hz,1H),3.68(s,3H),2.60(ddd,J=12.5,5.9,4.7Hz,1H),2.43(ddd,J=12.5,6 .0,4.7Hz,1H),1.54(d,J=4.9Hz,3H),1.49(d,J=4.9Hz,3H),1.45(s,10H).ESI-MS m / z: 608.0 [M+H] + .

[0355] Step 5: Synthesis of tert-butyl pyrrolidine-1-carboxylate of compound A2-6,(±)-5-(hydroxymethyl)-3-iodo-2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)pyrrolidine-1-carboxylate

[0356] Compound A2-5 (3.92 g, 6.45 mmol) was added to a three-necked flask at room temperature and dissolved in tetrahydrofuran (80 mL). The solution was purged with argon and cooled to 0 °C in an ice bath. DIBAL-H (21.50 mL, 1.50 mol / L) was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 hour. TLC showed no starting material remaining. At 0 °C, 50 mL of diethyl ether was added for dilution, and water (2 mL) was slowly added to quench the reaction. 2 mL of 15% sodium hydroxide aqueous solution was slowly added, followed by water (8 mL). The mixture was allowed to return to room temperature and stirred for 15 minutes. Anhydrous Na2SO4 was added for drying, and the mixture was stirred for 15 minutes before filtration. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 9:1-2:1, v / v) to give 3.36 g of a white solid, with a yield of 90.00%. 1H NMR(400MHz,Chloroform-d)δ7.58-7.55(m,2H),7.45(d,J=1.3Hz,1H),7.33(d,J=7.9Hz,2H),5.1 3(d,J=4.9Hz,1H),4.97(d,J=10.2Hz,1H),4.56(hept,J=6.9Hz,1H),4.35(qd,J=7.1,2.3Hz,1H),4 .20(ddd,J=12.1,7.2,2.2Hz,1H),4.06(q,J=6.2Hz,1H),3.87(q,J=11.1Hz,1H),2.82(dt,J=14.1 ,7.1Hz,1H),2.23(ddt,J=13.7,10.9,4.6Hz,1H),1.48(dd,J=6.7,4.6Hz,6H),1.17(s,9H).ESI-MS m / z:580.16[M+H] + .

[0357] Step 6: Synthesis of compound A2-7,(±)-6-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester

[0358] Compound A2-6 (3.36 g, 5.80 mmol) was added to a single-necked flask at room temperature and dissolved in tetrahydrofuran (200 mL). 1,8-diazacyclo[5,4,0]undecene-7 (1.77 g, 11.60 mmol) was then added, purged with argon, and the mixture was heated to 60 °C for 12 hours. TLC showed no remaining starting material. A saturated ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 200 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 10:1–3:1, v / v) to give 1.64 g of a white solid, yield 62.60%. 1H NMR(600MHz,Chloroform-d)δ7.53(d,J=8.0Hz,2H),7.44(d,J=1.4Hz,1H),7.31( d,J=8.1Hz,2H),5.49(dt,J=5.4,1.9Hz,1H),5.07-5.02(m,1H),4.64(dd,J=9.8,1 .9Hz,1H),4.54(p,J=6.7Hz,1H),3.94(ddd,J=11.9,9.8,1.9Hz,1H),3.75(ddd,J =11.9,6.5,1.7Hz,1H),1.48-1.42(m,7H),1.31-1.26(m,1H),1.19(s,9H).ESI-MS m / z: 452.1 [M+H] + .

[0359] Step 7: Synthesis of compound A2,(±)-6-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0360] Compound A2-7 (1.64 g, 3.63 mmol) was added to a single-necked flask at room temperature, dissolved in dichloromethane (20 mL), and then HCl / dioxane (4 M, 20 mL) was added. The reaction was carried out at room temperature for 2 hours. TLC showed no starting material remaining. After drying, 1.20 g of a white solid was obtained, with a yield of 94.10%.

[0361] Step 8: Synthesis of compound 32-1,5-(2-chloro-5-methylpyrimidin-4-yl)-6-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0362] Compound A2 (200.00 mg, 0.57 mmol) and 2,4-dichloro-5-methylpyrimidine (215.50 mg, 1.14 mmol) were added to a single-necked flask at room temperature, dissolved in DMF (2 mL), and DIPEA (219.07 mg, 1.71 mmol) was added. The mixture was heated to 60 °C and reacted for 12 hours. TLC showed no starting material remaining. A saturated ammonium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phase was washed with water (20 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 10:1–3:1, v / v) to give 120 mg of white solid, yield 41.8%. 1H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.97(s,1H),7.96-7.93(m,2H),7.45-7 .27(m,2H),5.02-4.90(m,1H),4.72-4.60(m,1H),4.50(tt,J=5.0,2.5Hz,1H),4.2 3(dt,J=4.9,2.0Hz,1H),4.18-4.05(m,2H),2.39-2.34(m,1H),2.34(s,3H),2.12( ddd,J=12.2,5.1,2.0Hz,1H),1.54(d,J=4.9Hz,3H),1.49(d,J=4.9Hz,3H).ESI-MS m / z: 478.2 [M+H] + .

[0363] Step 9: Synthesis of compound 32,5-(4-cyclopropyl-6-methoxy-5-methyl-[2,5-bipyrimidin]-4-yl)-6-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0364] At room temperature, compound 32-1 (100.00 mg, 0.24 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (75.40 mg, 0.26 mmol) were added to a single-necked flask, dissolved in dioxane (2.40 mL) and water (0.60 mL), followed by the addition of potassium carbonate (97.25 mg, 0.71 mmol). The mixture was purged three times with argon gas, and X-Phos-Pd G2 (18.73 mg, 0.0238 mmol) was added. The mixture was then heated to 80 °C and reacted for 12 hours. TLC showed no remaining raw material. Saturated ammonium chloride (2 mL) solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL). The organic phase was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 8:1-2:1, v / v) to give 38.60 mg of white solid, yield 27.50%, purity 100%. 1H NMR(500MHz,Chloroform-d)δ8.62(s,1H),8.08-8.02(m,1H),7.41(s,1H),7.40-7.39(m,2H),7 .21-7.17(m,2H),6.11(dt,J=4.8,2.0Hz,1H),5.94-5.86(m,2H),5.73(s,1H),4.49(p,J=6.7Hz, 1H),3.92(s,3H),3.79(dd,J=11.3,4.1Hz,1H),3.48(q,J=7.0Hz,1H),2.83(s,1H),2.18-2.16( m,3H),1.74(tt,J=8.4,4.6Hz,1H),1.49-1.40(m,6H),1.19(t,J=2.4Hz,2H),0.95-0.83(m,2H). 13 CNMR(125MHz,Chloroform-d)δ169.08,166.36,161.70,159.73,158.24,157.0 8,147.64,143.69,132.18(q,J=38.5Hz),129.76(2C),129.11,126.30,126.07, 121.72(q,J=267.0Hz),119.00,116.19(q,J=3.9Hz),115.14,70.76,68.94,65. 87,64.89,54.07,48.65,23.97(2C),17.56,15.28,13.90,10.88,10.85.ESI-MS m / z calcd for C 31 H 32 F3N7O2[M+H] + :592.2642,found:592.2642.

[0365] Example 33: Synthesis of 5-(4-cyclopropyl-5,6-dimethoxy-[2,5-bipyrimidin]-4-yl)-6-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane

[0366] By replacing 2,4-dichloro-5-methylpyrimidine in step 8 of Example 32 with 2,4-dichloro-5-methylpyrimidine, 30.80 mg of a white solid was synthesized according to the route, with a yield of 21.30% and a purity of 100%. 1H NMR(500MHz,Chloroform-d)δ8.60(s,1H),7.80(s,1H),7.43(d,J=8.3Hz,2H),7.40(d,J=1.3Hz,1H),7.19(d ,J=7.8Hz,2H),6.24(dt,J=4.7,2.0Hz,1H),5.88(ddt,J=24.0,6.3,2.0Hz,2H),5.66-5.61(m,1H),4.50(hept ,J=6.7Hz,1H),4.01(d,J=10.8Hz,1H),3.92(s,3H),3.80(dt,J=11.7,4.2Hz,1H),3.61(s,3H),3.48(q,J=7. 0Hz,1H),1.70(s,1H),1.45(d,J=6.7Hz,3H),1.42(d,J=6.7Hz,3H),1.19(d,J=3.3Hz,2H),0.92-0.80(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.29,166.43,157.02,154.05,152.88,147.88 ,144.04,140.51,136.49,132.22(q,J=38.7Hz),129.49(2C),128.72,126.19, 125.50,121.78(q,J=267Hz),118.83,116.20(q,J=4.0Hz),71.49,69.61,65.6 4,55.30,54.07,48.65,29.73,23.99(2C),15.31,13.92,10.98,10.91.ESI-MS m / z calcd for C 31 H 32 F3N7O3[M+H] + :608.2591,found:608.2594.

[0367] Example 34: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(6-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)furano[3,2-d]pyrimidine

[0368] In Example 32, step 8, 2,4-dichloro-5-methylpyrimidine was replaced with 2,4-dichlorofurano[3,2-d]pyrimidine, and 62.50 mg of a white solid was synthesized according to the route, with a yield of 40.50% and a purity of 100%.1 H NMR(500MHz,Chloroform-d)δ8.62(s,1H),7.62(s,1H),7.46-7.42(m,2H),7.39(d,J=1.3Hz,1H),7.37-7.35(m ,2H),6.78-6.71(m,1H),6.39-6.32(m,1H),6.00(dt,J=6.3,2.1Hz,1H),5.89(d,J=6.3Hz,1H),5.56(dq,J=4.9, 2.4Hz,1H),4.51(hept,J=6.7Hz,1H),4.05(t,J=10.4Hz,1H),3.92(s,3H),3.89-3.81(m,1H),3.48(q,J=7.0Hz ,1H),1.79-1.71(m,1H),1.45(d,J=6.7Hz,3H),1.41(d,J=6.7Hz,3H),1.21(t,J=7.0Hz,2H),1.01-0.86(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.24,166.33,157.09,157.07,151.91,148.96,14 7.75,147.15,143.58,133.03,132.36,132.13(q,J=38.6Hz),129.62,129.04,126. 32,125.87,121.72(q,J=267.0Hz),119.07,116.18(q,J=3.7Hz),107.98,70.69,65 .85,54.05,53.44,48.63,29.69,23.97,23.94,15.27,13.99,11.14,11.01.ESI-MS m / z calcd for C 32 H 30 F3N7O3[M+H] + :618.2435,found:618.2437.

[0369] Example 35: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-(4-(3-fluoro-6-methoxypyridin-2-yl)phenyl)morpholinyl)furan[3,2-d]pyrimidine

[0370] Step 1: Synthesis of compound 35-2,2-(triphenylmethylamino)isoprop-2-ol

[0371] Isopropanolamine (2.00 g, 26.63 mmol) and triethylamine (2.96 g, 29.29 mmol) were added to a single-necked flask at room temperature and dissolved in DMF (50 mL). Triphenylchloromethane (11.13 g, 39.94 mmol) was added to the above solution, and the reaction was carried out at room temperature for 18 hours. TLC showed no starting material remaining. The reaction solution was quenched with saturated ammonium chloride solution (100 mL) at room temperature, extracted with dichloromethane (2 × 100 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 20:1–10:1, v / v) to give 2.26 g of white solid, yield 26.74%. 1 H NMR(400MHz,Chloroform-d)δ7.54-7.46(m,6H),7.30(dd,J=8.5,6.9Hz,6H),7.24-7.16(m,3H ),3.88-3.77(m,1H),2.79(s,1H),2.27-2.15(m,2H),1.99-1.71(m,1H),1.14(d,J=6.2Hz,3H).

[0372] Step 2: Synthesis of compound 35-3,2-((tributyltin)methoxy)-N-triphenylisopropyl-1-amine

[0373] Compound 35-2 (2.26 g, 7.12 mmol) was added to a single-necked flask at room temperature and dissolved in DMF (50 mL). The mixture was placed in an ice-water bath, and sodium hydride (258.26 mg, 10.68 mmol) was added to the solution. After reacting at 0°C for 10 minutes, tributyltin-iodomethane (3.38 g, 7.83 mmol) was slowly added dropwise to the reaction mixture. The mixture was then allowed to react at room temperature for 18 hours. TLC showed no remaining starting material. The reaction mixture was placed in an ice bath, and 100 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 200 mL), washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 15:1–5:1, v / v) to give 2.56 g of a colorless oil, with a yield of 57.95%. 1H NMR(400MHz,Chloroform-d)δ7.54-7.48(m,6H),7.28(dd,J=8.5,6.9Hz,6H),7.21-7.15(m,3 H),1.51(tt,J=8.1,6.0Hz,6H),1.34-1.24(m,6H),1.13(d,J=6.2Hz,3H),0.96-0.87(m,15H).

[0374] Step 3: Synthesis of compound 35-4,2-((tributyltin)methoxy)isopropyl-1-amine

[0375] Compound 35-3 (2.56 g, 4.22 mmol) was added to a single-necked flask at room temperature and dissolved in acetic acid: 2,2,2-trifluoroethanol: dichloromethane (7:2:1, v / v, 86 mL). The reaction was allowed to proceed for 18 hours at room temperature. TLC showed no starting material remaining. Saturated sodium bicarbonate solution (100 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 × 200 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / ammonia / methanol, 50:1–30:1, v / v) to give 1.17 g of a colorless oil, yield 76.12%. 1 H NMR(400MHz,Chloroform-d)δ3.81(d,J=9.9Hz,1H),3.53(d,J=9.8Hz,1H),3.20-3.08(m,1H),2.69(dd,J=13.1,3.6Hz,1H),2.5 6(dd,J=13.1,7.1Hz,1H),1.58-1.45(m,6H),1.29(dq,J=14.6,7.3Hz,6H),1.06(d,J=6.2Hz,3H),0.88(td,J=7.7,3.2Hz,15H).

[0376] Step 4: Synthesis of compound 35-5,5-(4-(1-isopropyl-4-methyl-1H-imidazol-2-yl)phenyl)-2-methylmorpholine

[0377] At room temperature, copper(II) trifluoromethanesulfonate (101.72 mg, 0.28 mmol) and (S,S)-2,2'-isopropylidene bis(4-phenyl-2-oxazoline) (94.05 mg, 0.28 mmol) were added to a single-necked flask, dissolved in hexafluoroisopropanol (10 mL), and reacted at room temperature for 6 hours. In another single-necked flask, compound 35-4 (1.17 g, 2.81 mmol) and 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (793.86 mg, 6.64 mmol) were added, dissolved in DCM (30 mL), and 4A molecular sieve was added. After reacting at room temperature for 6 hours, the reaction solution was dried over anhydrous sodium sulfate, concentrated, and an imine intermediate was obtained. This intermediate was dissolved in hexafluoroisopropanol (10 mL) and added dropwise to the above solution, and reacted at room temperature for 24 hours. TLC showed no remaining raw material. Ammonia (30 mL) was added, and the mixture was stirred for 15 minutes. The mixture was then extracted with DCM. The organic phase was washed with water (100 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 5:1-1:1, v / v) to give 252.31 g of a yellow oil, with a yield of 29.93%. 1 H NMR(400MHz,Chloroform-d)δ7.56-7.46(m,4H),7.40(d,J=1.4Hz,1H),4.53(h,J=6.7Hz,1H),3.96(dd,J=10.4,3.2Hz,1H),3.92-3.86(m,1H),3. 82-3.71(m,1H),3.52(t,J=10.8Hz,1H),3.08(dd,J=11.7,2.4Hz,1H),2.75(t,J=11.0Hz,1H),1.44(dd,J=6.7,1.2Hz,6H),1.20(d,J=6.2Hz,3H).

[0378] Step 5: Synthesis of compound 35-6, 2-chloro-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-methylmorpholine)furan[3,2-d]pyrimidine

[0379] At room temperature, compound 35-5 (135.40 mg, 0.40 mmol), 2,4-dichlorofurano[3,2-d]pyrimidine (108.62 mg, 0.57 mmol), and DIEA (99.04 mg, 0.80 mmol) were added to a sealed tube, dissolved in dioxane (10 mL), and the mixture was heated to 120 °C for 18 hours. TLC showed no starting material remaining. 1 M HCl (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 4:1-1:1, v / v) to give 142.00 mg of a yellow solid, with a yield of 73.25%. 1 H NMR(400MHz,Chloroform-d)δ7.74(d,J=2.2Hz,1H),7.61(d,J=8.1Hz,2H),7.52(d,J= 8.1Hz,2H),7.42(d,J=1.3Hz,1H),7.32(d,J=7.0Hz,1H),6.80(d,J=2.2Hz,1H),5.89(t ,J=4.0Hz,1H),4.56(p,J=6.7Hz,1H),4.33(ddd,J=13.3,8.9,3.7Hz,2H),4.25-4.03(m ,2H),3.84(dd,J=13.7,4.0Hz,1H),1.45(dd,J=6.7,1.3Hz,6H),1.37(d,J=6.5Hz,3H).

[0380] Step 6: Synthesis of compound 35,2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-2-methylmorpholine)furan[3,2-d]pyrimidine

[0381] Compound 3-6 (142.00 mg, 0.28 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (108.90 mg, 0.56 mmol) were added to a single-necked flask at room temperature and dissolved in dioxane (3.6 mL) and water (0.9 mL). Potassium carbonate (116.37 mg, 0.84 mmol) was then added. The mixture was purged three times with argon gas, and X-Phos-Pd G2 (22.08 mg, 0.02 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no remaining raw material. Saturated ammonium chloride (2 mL) solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL). The organic phase was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 8:1-1:1, v / v) to give 50.00 mg of white solid, yield 28.75%, purity 100%. 1 H NMR(400MHz,Chloroform-d)δ8.59(s,1H),7.76(d,J=2.2Hz,1H),7.64(d,J=8.0Hz,2H),7.48(d,J=7.9Hz,2H),7.40(s, 1H), 6.90 (d, J = 2.2Hz, 1H), 6.01 (d, J = 3.8Hz, 1H), 4.53 (p, J = 6.7Hz, 1H), 4.45 (dd, J = 13.7, 2.6Hz, 1H), 4.33 (dd, J = 12.4, 4.3Hz,1H),4.22(dq,J=6.0,3.2,2.4Hz,1H),4.17(dd,J=12.4,3.2Hz,1H),3.89(s,3H),3.78(dd,J=13.7,4.1Hz,1H),2 .07-1.91(m,2H),1.76(dt,J=8.1,3.8Hz,1H),1.43(d,J=6.6Hz,6H),1.38(d,J=6.5Hz,3H),1.15(dd,J=4.7,2.8Hz,2H).

[0382] Example 36: Synthesis of 4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholinyl)-2-(2-isopropylpyridin-3-yl)furano[3,2-d]pyrimidine (compound 61)

[0383] Following the synthesis method of Example 27, a white solid was prepared with a yield of 76%. 1H NMR(500MHz,Chloroform-d)δ8.61(dd,J=4.8,1.8Hz,1H),7.91(dd,J=7.8,1.8Hz,1H),7.80(d ,J=2.2Hz,1H),7.62-7.59(m,2H),7.54-7.50(m,2H),7.40(q,J=1.2Hz,1H),7.18(dd,J=7.7,4. 7Hz,1H),6.93(d,J=2.2Hz,1H),6.16(s,1H),4.78-4.72(m,1H),4.62-4.51(m,2H),4.12-4.03 (m,2H),3.83(td,J=11.8,2.8Hz,1H),3.68-3.54(m,2H),1.45-1.40(m,6H),1.24-1.19(m,6H).

[0384] Example 37: Synthesis of 2-(4-chloro-1-isopropyl-1H-pyrazol-5-yl)-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)morpholinyl)furano[3,2-d]pyrimidine (compound 64)

[0385] Following the synthesis method of Example 27, a yellow solid was prepared with a yield of 67%. 1 H NMR(500MHz,Chloroform-d)δ7.81(d,J=2.2Hz,1H),7.64(d,J=8.2Hz,2H),7.52( dd,J=6.0,2.3Hz,3H),7.41(d,J=1.3Hz,1H),6.95(d,J=2.2Hz,1H),6.20(s,1H), 5.31(hept,J=6.4Hz,1H),4.77(d,J=13.8Hz,1H),4.63-4.53(m,2H),4.13-4.04( m,2H),3.84(td,J=11.8,2.8Hz,1H),3.58(t,J=13.0Hz,1H),1.47-1.42(m,12H).

[0386] Example 38: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-(4-(3-fluoro-6-methoxypyridin-2-yl)phenyl)morpholinyl)furan[3,2-d]pyrimidine (compound 68)

[0387] Step 1: Synthesis of compound A3-2,2-(triphenylmethylamino)ethanol-1-ol

[0388] Ethanolamine (3.00 g, 49.11 mmol) and triethylamine (7.45 g, 73.67 mmol) were added to a single-necked flask at room temperature and dissolved in DMF (50 mL). Triphenylchloromethane (15.06 g, 54.02 mmol) was added to the above solution, and the reaction was carried out at room temperature for 18 hours. TLC showed no starting material remaining. The reaction solution was quenched with saturated ammonium chloride solution (100 mL) at room temperature, extracted with dichloromethane (2 × 100 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 20:1 - 10:1, v / v) to give 5.69 g of white solid, yield 38.19%. 1 H NMR (400MHz, Chloroform-d) δ7.56-7.42(m,6H),7.31-7.23(m,6H),7.20-7.14(m,3H),3.64(dd,J=5.8,4.7Hz,2H),2.33(t,J=5.3Hz,2H),1.42(s,1H).

[0389] Step 2: Synthesis of compound A3-3,2-((tributyltinyl)methoxy)-N-triphenylethane-1-amine

[0390] Compound A3-2 (5.69 g, 18.75 mmol) was added to a single-necked flask at room temperature and dissolved in DMF (10 mL). The mixture was cooled to 0 °C in an ice bath. Sodium hydride (675 mg, 28.13 mmol) was added to the solution, and the reaction was carried out at 0 °C for 10 minutes. Tributyltin-iodomethane (8.89 g, 20.63 mmol) was then slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was allowed to react at room temperature for 18 hours. TLC showed no starting material remaining. The reaction mixture was then quenched in an ice bath with saturated ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (2 × 100 mL), and the organic phase was washed with water (100 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 15:1–5:1, v / v) to give 5.20 g of a colorless oil, with a yield of 45.72%. 1H NMR(400MHz,Chloroform-d)δ7.51-7.44(m,6H),7.25(dd,J=8.3,6.8Hz,6H),7.18-7.12(m,3H),3.64(s,2H),3.4 8-3.42(m,2H),2.31(t,J=5.0Hz,2H),2.14(s,1H),1.59-1.42(m,6H),1.27(h,J=7.3Hz,6H),0.92-0.81(m,15H).

[0391] Step 3: Synthesis of compound A3-4,2-((tributyltin)methoxy)ethyl-1-amine

[0392] Compound A3-3 (5.20 g, 8.57 mmol) was added to a single-necked flask at room temperature and dissolved in acetic acid: 2,2,2-trifluoroethanol: dichloromethane (7:2:1, v / v, 170 mL). The reaction was allowed to proceed for 18 hours at room temperature. TLC showed no starting material remaining. Saturated sodium bicarbonate solution (200 mL) was added to the reaction mixture, and the mixture was extracted with DCM (2 × 200 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / ammonia / methanol, 50:1–30:1, v / v) to give 2.60 g of a colorless oil, yield 83.21%. 1 H NMR (400MHz, Chloroform-d) δ3.71(s,2H),3.35-3.29(m,2H),2.81-2.75(m,2H),1.59-1.38(m,6H),1.35-1.22(m,6H),0.88(td,J=7.7,5.2Hz,15H).

[0393] Step 4: Synthesis of compound A3-5,3-(4-bromophenyl)morpholine

[0394] At room temperature, copper(II) trifluoromethanesulfonate (480.33 mg, 1.33 mmol) and (S,S)-2,2'-isopropylidene bis(4-phenyl-2-oxazoline) (440.14 mg, 1.33 mmol) were added to a single-necked flask, dissolved in hexafluoroisopropanol (10 mL), and reacted at room temperature for 6 h. Compound A3-4 (2.66 g, 7.30 mmol) and 4-bromobenzaldehyde (1.23 g, 6.64 mmol) were added to another single-necked flask, dissolved in DCM (80 mL), and then... After reacting with molecular sieves at room temperature for 6 hours, the reaction solution was dried over anhydrous sodium sulfate and concentrated to obtain an imine intermediate. This intermediate was dissolved in hexafluoroisopropanol (10 mL) and added dropwise to the above solution. The reaction was continued at room temperature for 24 hours. TLC showed no remaining starting material. Ammonia was added, and the mixture was stirred for 15 minutes. Extraction was performed with DCM (50 mL). The organic phase was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 5:1-1:1, v / v) to give 1.28 g of a yellow solid, with a yield of 79.61%. 1 H NMR(400MHz,Chloroform-d)δ7.48-7.43(m,2H),7.30-7.25(m,2H),3.93-3.84(m,2H),3.78(dd,J=11.0,3.2Hz,1H),3.63(td ,J=11.3,2.7Hz,1H),3.33(dd,J=11.0,10.0Hz,1H),3.12(td,J=11.6,3.3Hz,1H),2.99(dt,J=11.7,2.1Hz,1H),1.81(s,1H).

[0395] Step 5: Synthesis of compound A3-6, tert-butyl 3-(4-bromophenyl)morpholine-4-carboxylate

[0396] Compound A3-5 (1.28 g, 5.29 mmol) was added to a single-necked flask at room temperature and dissolved in tetrahydrofuran (100 mL). Di-tert-butyl dicarbonate (3.46 g, 15.86 g) and DMAP (64.59 mg, 0.53 mmol) were then added, and the mixture was reacted at room temperature for 6 hours. TLC showed no remaining starting material. A saturated ammonium chloride solution (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 100 mL). The organic phase was washed with water (100 mL) and saturated brine (100 mL). After drying the organic phase with anhydrous Na₂SO₄, the mixture was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 10:1–5:1, v / v) to give 1.11 g of a white solid, yield 61.52%. 1H NMR (400MHz, Chloroform-d) δ7.50-7.43(m,2H),7.38-7.33(m,2H),5.03(d,J=3.6Hz,1H),4.28(d,J=12.0Hz,1H),3.87(ddd,J=15.7, 11.6, 3.7Hz, 2H), 3.78 (dd, J=13.8, 2.9Hz, 1H), 3.58 (ddd, J=12.1, 11.3, 3.0Hz, 1H), 3.07 (ddd, J=13.6, 12.1, 3.7Hz, 1H), 1.47 (s, 9H).

[0397] Step 6: Synthesis of tert-butyl morpholine-4-carboxylate, compound A3,3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)morpholine-4-carboxylate

[0398] At room temperature, compound A3-6 (1.11 g, 3.25 mmol), pinacol diborate (1.24 g, 4.88 mmol), and potassium acetate (638.35 mg, 6.50 mmol) were added to a single-necked flask, dissolved in dioxane (200 mL), purged three times with argon, and then [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (237.96 mg, 0.33 mmol) were added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no remaining raw material. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 200 mL). The organic phase was washed with water (200 mL) and saturated brine (200 mL). The organic phase was dried with anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 30:1-20:1, v / v) to give 650.00 mg of yellow oil, with a yield of 51.05%. 1 H NMR(400MHz,Chloroform-d)δ7.81-7.75(m,2H),7.47-7.42(m,2H),5.08(d,J=3.4Hz,1H),4.35(d,J=11.9Hz,1H),3.86 (tq,J=8.0,3.9Hz,3H),3.82-3.76(m,1H),3.59(td,J=11.7,3.0Hz,1H),3.17-3.05(m,1H),1.46(s,9H),1.34(s,12H).

[0399] Step 7: Synthesis of compound 68-1,3-(4-(6-fluoro-3-methoxypyridin-2-yl)phenyl)morpholine-4-carboxylic acid tert-butyl ester

[0400] At room temperature, compound A3 (300.00 mg, 0.77 mmol), 2-bromo-6-fluoro-3-methoxypyridine (236.79 mg, 1.15 mmol), and cesium carbonate (624.16 mg, 1.92 mmol) were added to a single-necked flask and dissolved in dioxane:water (4:1, 20 ml). The mixture was purged three times with argon gas, and then [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (51.09 mg, 0.08 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no remaining raw material. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 50 mL). The organic phase was washed with water (50 mL) and saturated brine (50 mL). The organic phase was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 10:1-4:1, v / v) to give 270 mg of yellow oil, with a yield of 90.71%.

[0401] Step 8: Synthesis of compound 68-2,3-(4-(6-fluoro-3-methoxypyridin-2-yl)phenyl)morpholine

[0402] Compound 68-1 (270 mg, 3.63 mmol) was added to a single-necked flask at room temperature, dissolved in dichloromethane (2 mL), and then reacted with HCl / dioxane (4 M, 2 mL) at room temperature for 2 hours. TLC showed no starting material remaining. After drying, 190 mg of a white solid was obtained, with a yield of 94.81%. LC-MS m / z: 288.9 [M+H] +

[0403] Step 9: Synthesis of compound 68-3,2-chloro-4-(3-(4-(6-fluoro-3-methoxypyridin-2-yl)phenyl)morpholinyl)furan[3,2-d]pyrimidine

[0404] At room temperature, compound 68-2 (190.00 mg, 0.66 mmol), 2,4-dichlorofurano[3,2-d]pyrimidine (186.82 mg, 0.99 mmol), and DIEA (170.34 mg, 1.32 mmol) were added to a sealed tube, dissolved in dioxane (10 mL), and the mixture was heated to 120 °C for 18 hours. TLC showed no reactant remaining. 1 M HCl (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 4:1–1:1, v / v) to give 265.00 mg of a yellow solid, yield 91.22%. LC-MS m / z: 441.0 [M+H] +

[0405] Step 9: Synthesis of compound 68, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-(4-(3-fluoro-6-methoxypyridin-2-yl)phenyl)morpholine)furan[3,2-d]pyrimidine

[0406] Compound 68-3 (265.00 mg, 0.60 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (139.93 mg, 0.72 mmol) were added to a single-necked flask at room temperature and dissolved in dioxane (3.6 mL) and water (0.9 mL). Potassium carbonate (207.69 mg, 1.50 mmol) was then added. The mixture was purged three times with argon gas, and X-Phos-Pd G2 (94.39 mg, 0.01 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no remaining raw material. Saturated ammonium chloride (2 mL) solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL). The organic phase was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 8:1-1:1, v / v) to give 125.26 mg of white solid, yield 37.50%, purity 100%. 1 H NMR(400MHz,Chloroform-d)δ8.62(s,1H),7.92-7.81(m,2H),7.79(d,J=2.2Hz,1H),7.65(d,J=8.2Hz, 2H),7.50(s,1H),7.32(d,J=8.4Hz,1H),6.93(d,J=2.2Hz,1H),6.16(s,1H),4.71(d,J=13.9Hz,1H),4.5 7(d,J=12.0Hz,1H),4.08(dt,J=11.6,3.0Hz,2H),3.93(s,3H),3.83(td,J=11.8,2.8Hz,1H),3.65(d,J= 13.4Hz,1H),2.64(s,6H),1.81(dq,J=8.1,4.3,3.8Hz,1H),1.20-1.15(m,2H),0.87-0.84(m,2H).LC-MS m / z:555.1[M+H] + .

[0407] Example 39: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-(4-(6-methoxy-3-trifluoromethylpyridin-2-yl)phenyl)morpholinyl)furan[3,2-d]pyrimidine (compound 69)

[0408] Step 1: Synthesis of compound 69-1,3-(4-(6-methoxy-3-trifluoromethylpyridin-2-yl)phenyl)morpholine-4-carboxylic acid tert-butyl ester

[0409] At room temperature, compound A3 (300.00 mg, 0.77 mmol), 2-chloro-3-methoxy-6-trifluoromethylpyridine (243.18 mg, 1.15 mmol), and cesium carbonate (624.16 mg, 1.92 mmol) were added to a single-necked flask and dissolved in dioxane:water (4:1, 20 ml). The mixture was purged three times with argon gas, and then [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (51.09 mg, 0.08 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no remaining raw material. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 50 mL). The organic phase was washed with water (50 mL) and saturated brine (50 mL). The organic phase was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 10:1-4:1, v / v) to give 300 mg of yellow oil, with a yield of 89.29%.

[0410] Step 2: Synthesis of Compound 69-2,3-(4-(6-methoxy-3-trifluoromethylpyridin-2-yl)phenyl)morpholine. At room temperature, compound 69-1 (300 mg, 0.68 mmol) was added to a single-necked flask, dissolved in dichloromethane (2 mL), and then HCl / dioxane (4 M, 2 mL) was added. The reaction was carried out at room temperature for 2 hours. TLC showed no starting material remaining. After drying, 220 mg of a white solid was obtained, yielding 95.03%. LC-MS m / z: 339.0 [M+H] + .

[0411] Step 3: Synthesis of compound 69-3,2-chloro-4-(3-(4-(6-methoxy-3-trifluoromethylpyridin-2-yl)phenyl)morpholinyl)furan[3,2-d]pyrimidine

[0412] At room temperature, compound 69-2 (220.00 mg, 0.76 mmol), 2,4-dichlorofurano[3,2-d]pyrimidine (216.31 mg, 1.14 mmol), and DIEA (197.24 mg, 1.53 mmol) were added to a sealed tube, dissolved in dioxane (10 mL), and the mixture was heated to 120 °C for 18 hours. TLC showed no reactant remaining. 1 M HCl (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 4:1–1:1, v / v) to give 300.30 mg of a yellow solid, yield 89.18%. LC-MS m / z: 491.0 [M+H] + .

[0413] Step 4: Synthesis of compound 69, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-(4-(6-methoxy-3-trifluoromethylpyridin-2-yl)phenyl)morpholinyl)furan[3,2-d]pyrimidine

[0414] Compound 69-3 (300.30 mg, 0.68 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (158.57 mg, 0.82 mmol) were added to a single-necked flask at room temperature and dissolved in dioxane (3.6 mL) and water (0.9 mL). Potassium carbonate (235.35 mg, 1.70 mmol) was then added. The mixture was purged three times with argon gas, and XPhos-Pd G2 (94.39 mg, 0.01 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no remaining raw material. Saturated ammonium chloride (2 mL) solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL). The organic phase was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 8:1-1:1, v / v) to give 127.00 mg of white solid, yield 33.62%, purity 100%. 1H NMR(400MHz,Chloroform-d)δ8.62(d,J=3.0Hz,1H),7.96-7.87(m,2H),7.82-7.78(m,1H),7.67(dd,J=8.4,3.0Hz ,2H),7.61(dd,J=8.6,3.0Hz,1H),7.35(dd,J=8.6,3.2Hz,1H),6.95-6.91(m,1H),6.16(s,1H),5.31(s,1H),5.30 (d,J=0.8Hz,1H),4.72(d,J=13.6Hz,1H),4.56(dd,J=12.1,3.2Hz,1H),3.99-3.90(m,6H),3.84(tt,J=11.6,2.9H z,1H),3.76-3.59(m,1H),1.80(tt,J=8.1,4.0Hz,1H),1.18(td,J=5.5,4.4,3.1Hz,2H),0.90-0.82(m,2H).LC-MS m / z:606.0[M+H] + .

[0415] Example 40: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-(4-(3-fluoro-6-methoxypyridin-2-yl)phenyl)morpholinyl)furan[3,2-d]pyrimidine (compound 70)

[0416] Step 1: Synthesis of compound 70-2,2-(((tributyltin)methyl)mercapto)ethyl-1-amine

[0417] Compound 70-1 (200.00 mg, 2.59 mmol) was added to a single-necked flask at room temperature and dissolved in ethanol (20 mL). Tributyltin-iodomethane (1.23 g, 2.85 mmol) and potassium carbonate (1.0 g, 7.78 mmol) were added, and the mixture was refluxed at 70 °C for 12 hours. TLC showed no starting material remaining. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 100 mL). The organic phase was washed with water (100 mL) and saturated brine (100 mL). The organic phase was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 15:1–5:1, v / v) to give 770.00 mg of a yellow oil, with a yield of 78.11%. 1H NMR(400MHz,Chloroform-d)δ2.88(dd,J=6.7,5.8Hz,2H),2.56(dd,J=6.7,5.7 Hz,2H),1.87(s,2H),1.50-1.44(m,7H),1.35-1.25(m,7H),0.96-0.85(m,16H).

[0418] Step 2: Synthesis of compound 70-3,3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)thiomorpholine

[0419] At room temperature, copper(II) trifluoromethanesulfonate (146.49 mg, 0.41 mmol) and (S,S)-2,2'-isopropylidene bis(4-phenyl-2-oxazoline) (135.45 mg, 0.41 mmol) were added to a single-necked flask, dissolved in hexafluoroisopropanol (10 mL), and reacted at room temperature for 6 hours. Compound 70-2 (770.00 g, 2.03 mmol) and 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (571.63 mg, 2.03 mmol) were added to another single-necked flask, dissolved in DCM (30 mL), and then... After reacting with molecular sieves at room temperature for 6 hours, the reaction solution was dried over anhydrous sodium sulfate and concentrated to obtain an imine intermediate. This intermediate was dissolved in hexafluoroisopropanol (10 mL) and added dropwise to the above solution. The reaction was continued at room temperature for 24 hours. TLC showed no remaining starting material. Ammonia (30 mL) was added, and the mixture was stirred for 15 minutes. Extraction was performed using DCM. The organic phase was washed with water (100 mL) and saturated brine (200 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 5:1-1:1, v / v) to obtain 320.00 g of a yellow oil, with a yield of 44.46%. 1 H NMR(400MHz,Chloroform-d)δ7.54-7.45(m,4H),7.41(q,J=1.2Hz,1H),4.56(p,J=6.7Hz,1H),4.00(dd,J=10.5,2.3Hz,1H),3.48(dt,J=12.1,3.1Hz,1H),3 .20(td,J=11.9,2.3Hz,1H),2.93(ddd,J=13.2,11.8,3.0Hz,1H),2.84(dd,J= 13.1,10.6Hz,1H),2.48(ddt,J=19.9,13.1,2.4Hz,2H),1.46(d,J=6.7Hz,6H).

[0420] Step 3: Synthesis of compound 70-4,2-chloro-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)thiomorpholine)furan[3,2-d]pyrimidine

[0421] At room temperature, compound 70-3 (160.00 mg, 0.45 mmol), 2,4-dichlorofurano[3,2-d]pyrimidine (127.62 mg, 0.67 mmol), and DIEA (116.37 mg, 0.90 mmol) were added to a sealed tube, dissolved in dioxane (10 mL), and the mixture was heated to 120 °C for 18 hours. TLC showed no starting material remaining. 1 M HCl (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate, 4:1-1:1, v / v) to give 140.00 mg of a yellow solid, yield 61.22%. 1 H NMR(400MHz,Chloroform-d)δ7.75(d,J=2.2Hz,1H),7.63-7.56(m,2H),7.55-7.49 (m,2H),7.43(q,J=1.2Hz,1H),6.83(d,J=2.2Hz,1H),6.53(s,1H),5.02(d,J=14.4H z,1H),4.59(q,J=6.7Hz,1H),3.57-3.34(m,2H),3.26(ddd,J=14.5,3.8,1.7Hz,1H) ,3.07(td,J=12.7,3.3Hz,1H),2.61(d,J=12.6Hz,1H),1.47(dd,J=6.6,2.4Hz,6H).

[0422] Step 4: Synthesis of compound 70, 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(3-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)thiomorpholine)furan[3,2-d]pyrimidine

[0423] At room temperature, compound 70-4 (70.00 mg, 0.14 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (53.47 mg, 0.28 mmol) were added to a single-necked flask, dissolved in dioxane (3.6 mL) and water (0.9 mL), and potassium carbonate (57.14 mg, 0.41 mmol) was added. The mixture was purged three times with argon gas, and X-Phos-Pd G2 (21.66 mg, 0.03 mmol) was added. The mixture was heated to 80 °C and reacted for 12 hours. TLC showed no remaining raw material. Saturated ammonium chloride (2 mL) solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phase was washed with water (10 mL) and saturated brine (10 mL). The organic phase was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate, 8:1-1:1, v / v) to give 30.00 mg of white solid, yield 35.02%, purity 100%. 1 H NMR(400MHz,Chloroform-d)δ8.61(s,1H),7.80(d,J=2.2Hz,1H),7.56(s,4H),7.42(d,J=1.3Hz,1H ),6.96(d,J=2.2Hz,1H),6.65(s,1H),5.06(d,J=14.3Hz,1H),4.58(q,J=6.7Hz,1H),3.92(s,3H),3 .52(t,J=13.2Hz,1H),3.45-3.38(m,1H),3.27-3.20(m,1H),3.14-3.07(m,1H),2.59(d,J=13.0Hz, 1H),1.84(tt,J=8.4,4.7Hz,1H),1.46(t,J=6.6Hz,6H),1.20-1.12(m,2H),0.91-0.86(m,2H).LC-MS m / z:622.1[M+H] + .

[0424] Biological evaluation

[0425] Test Example 1: USP1 / UAF1 Enzyme Inhibitory Activity

[0426] Ub-7-amido-4-methylcoumarin (AMC) was used as a substrate to monitor the activity of USP1 / UAF1; free AMC resulted in increased fluorescence. To determine the IC50 value for inhibiting USP1 / UAF1... 50Seven different concentrations of inhibitors were added to the reaction mixture containing 0.4 nM USP1 / UAF1. The buffer solutions included 50 mM Tris-HCl, 0.5 mM EDTA, 5 mM DTT, 0.01% Triton X-100, and 0.05% BSA (pH 7.6). The reaction was carried out at 37°C for 1 hour. The reaction was stopped by adding 10 μL of citric acid to a final concentration of 10 mM. Synergy was used as the reagent. TM The H1 (BioTek) 345nm excitation / 445nm emission optical module was used to measure fluorescence intensity.

[0427] Table 1 provides the inhibitory activities of representative compounds of this application. Where A: ≤100 nM; B: >100 nM to ≤500 nM; C: >500 nM

[0428] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A heterocyclic compound as shown in Formula I or stereoisomer, tautomer, deuterated analog, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein, is an aromatic heteroaryl ring; represents a single or double bond; X1is selected from CR 1 , N or O; X2is selected from C or N; X3is selected from CR 2 R 3 , CR 2 , NR 4 , N, O, S, S=0, S(=0)2, or null; X4is selected from CR 2 R 3 , CR 3 , NR 4 , N, O, S, S=0, or S(=0)2; Or when X 3 When it exists, X 3 and X 4 The atoms attached thereto form 3-10 membered cycloalkyl, 4-10 membered heterocyclic, 5-10 membered aryl, or 5-10 membered heteroaryl groups, wherein the above groups are optionally surrounded by one or more R groups. e replace; Ring A is selected from C6-C10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R a substituents; Ring B is selected from 3-10 membered cycloalkyl, 4-8 membered heterocyclyl, 7-15 membered spirocyclyl, 7-15 membered bridged cyclyl, 7-15 membered fused cyclyl, wherein the above groups are optionally substituted with one or more R b substituents; Ring C is selected from C6-C10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-C10 cycloalkyl, or C3-C10 cycloalkenyl, wherein the above groups are optionally substituted with one or more R c substituents; Ring D is selected from C6-C10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R d substituents; R 1 R 2 R 3 and R 4 Each is independently selected from H atom, -OH, -SH, =O, =S, -COOH, -COO-(C1-C6 alkyl), -OCO-(C1-C6 alkyl), -NH2, -NH-(C1-C6 alkyl), -N-(C1-C6 alkyl)2, -C(O)-NH2, -NO2, -CN, halogen, C1-C6 alkyl, -S-(C1-C6 alkyl), -S(O)-(C1-C6 alkyl), -S(O)2-(C1-C6 alkyl), -S(O)2-(amino), -S(O)2NH(C1-C12 alkyl), -S(O)2N (C1-C12 alkyl)2, phosphoryl, phosphorite, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 heteroaryl, C3-C8 cycloalkyl, 3-8 heterocyclic, -(C1-C6 alkylene)-C3-C8 cycloalkyl, -(C1-C6 alkylene)-3-8 heterocyclic and -(C1-C6 alkylene)-C(O)-O-C1-C6 alkyl, wherein each of the above groups is independently optionally divided by one or more R f replace; R a , R b , R c , R d , R e , and R f are each independently selected from halogen, CN, -OH, -NO2, -NH2, -SH, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -CONH2, -CONH(Ci-C6alkyl), -NHCO-(Ci-C6alkyl), Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C10cycloalkyl, -(Ci-C6alkylene)-C3-C10cycloalkyl, C3-C10cycloalkyloxy, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-3-8 membered heterocyclyl, C6-C10aryl, 5-8 membered heteroaryl, wherein the aforementioned groups are optionally substituted with R g ; or R b and the atom to which they are attached together form a 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, wherein the above groups are optionally substituted with R c and the atom to which they are attached together form a 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, wherein the above groups are optionally substituted with R g substituents; Or R c and R d The atoms attached to it together form 5-10 membered cycloalkyl groups and 5-10 membered heterocyclic groups, wherein the above groups are optionally R g replace; Each R g The group is independently selected from D atom, -OH, -COOH, -NH2, -NO2, -CN, =O, =S, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 heteroaryl, C3-C8 cycloalkyl, 3-8 heterocyclic, wherein the above groups are optionally substituted by one or more substituents selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, halogen, cyano, nitro, carboxyl, oxo.

2. The compound of claim 1, wherein, X1is selected from CR 1 or N; X2is selected from C; X3is selected from CR 2 R 3 , CR 2 and NR 4 ; X4is selected from CR 2 R 3 , CR 3 and NR 4 ; or X 3 and X 4 with the atom to which it is attached to form a 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R e substituents; Ring A is selected from C6-C10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R a substituents; Ring B is selected from 3-10 membered cycloalkyl, 4-8 membered heterocyclyl, 7-15 membered spirocyclyl, 7-15 membered bridged cyclyl, 7-15 membered fused cyclyl, wherein the above groups are optionally substituted with one or more R b substituents; Ring C is selected from C6-C10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R c substituents; Ring D is selected from C6-C10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R d substituents; R 1 R 2 R 3 and R 4 Each is independently selected from H atom, -OH, -SH, =O, =S, -COOH, -COO-(C1-C6 alkyl), -OCO-(C1-C6 alkyl), -NH2, -NH-(C1-C6 alkyl), -N-(C1-C6 alkyl)2, -C(O)-NH2, -NO2, -CN, halogen, C1-C6 alkyl, -S-(C1-C6 alkyl), -S(O)-(C1-C6 alkyl), -S(O)2-(C1-C6 alkyl), -S(O)2-(amino), -S(O)2NH(C1-C12 alkyl), -S (O)2N(C1-C12 alkyl)2, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 alkathioyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 heteroaryl, C3-C8 cycloalkyl, 3-8 heterocyclic, -(C1-C6 alkylene)-C3-C8 cycloalkyl, -(C1-C6 alkylene)-3-8 heterocyclic and -(C1-C6 alkylene)-C(O)-O-C1-C6 alkyl, wherein each of the above groups is independently optionally divided by one or more R f replace; R a , R b , R c , R d , R e , and R f are each independently selected from halogen, CN, -OH, -NH2, NO2, -SH, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -CONH2, -CONH(Ci-C6alkyl), -NHCO-(Ci-C6alkyl), Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C10cycloalkyl, -(Ci-C6alkylene)-C3-C10cycloalkyl, C3-C10cycloalkyloxy, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-3-8 membered heterocyclyl, wherein the above groups are optionally substituted with R g ; Each R g Independently selected from D atom, -OH, -COOH, -NH2, NO2, -CN, =O, =S, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C6-C10 aryl, 5-10 heteroaryl, C3-C8 cycloalkyl, 3-8 heterocyclic, wherein the above groups are optionally substituted by one or more substituents selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, halogen, cyano, nitro, carboxyl, oxo.

3. The compound of claim 1, wherein, X1is selected from CR 1 or N; X2is C; X3is selected from CR 2 R 3 and CR 2 ; X4is selected from CR 2 R 3 and CR 3 ; or X 3 and X 4 with the atom to which it is attached to form a 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R e substituents; Ring A is selected from C6-C10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R a substituents; Ring B is selected from 3-10 membered cycloalkyl, 4-8 membered heterocyclyl, 7-15 membered spirocyclyl, 7-15 membered bridged cyclyl, 7-15 membered fused cyclyl, wherein the above groups are optionally substituted with one or more R b substituents; Ring C is selected from C6-C10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R c substituents; Ring D is selected from C6-C10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R d substituents; R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H atom, -OH, -SH, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -NH2, -C(O)-NH2, -NO2, -CN, halogen, Ci-C6alkyl, -S-(Ci-C6alkyl), C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6alkylthio, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, C6-Cio aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-C3-C8cycloalkyl, and -(Ci-C6alkylene)-3-8 membered heterocyclyl, wherein each of the aforementioned groups is independently optionally substituted with one or more R f ; R a , R b , R c , R d , R e and R f are each independently selected from halogen, CN, -OH, -NH2, -SH, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, -(C1-C6alkylene)-C3-C10cycloalkyl, C3-C10cycloalkyloxy, C2-C6alkenyl, C2-C6alkynyl, 3-8 membered heterocyclyl, -(C1-C6alkylene)-3-8 membered heterocyclyl.

4. The compound of claim 1, wherein, X1is selected from CR 1 or N; X2is C; X3is CR 2 ; X4 is CR 3 ; or X 3 and X 4 with the atom to which it is attached to form a 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 5-10 membered aryl, or 5-8 membered heteroaryl, wherein the above groups are optionally substituted with one or more R e substituents; Ring A is selected from C6aryl, 5-8 membered heteroaryl, wherein the above groups are optionally substituted with one or more R a substituents; Ring B is selected from 4-8 membered heterocyclyl, wherein the above groups are optionally substituted with one or more R b substituents; Ring C is selected from C6aryl, wherein the above group is optionally substituted with one or more R c substituents; Ring D is selected from a 5-8 membered heteroaryl, wherein the above groups are optionally substituted with one or more R d substituents; R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H atom, -COOH, -COO-(Ci-C6alkyl), -OCO-(Ci-C6alkyl), -C(O)-NH2, -NO2, -CN, halogen, Ci-C6alkyl, -S-(Ci-C6alkyl), C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6alkoxy-C(O)-NH2, Ci-C6alkoxy-CONH(Ci-C6alkyl), Ci-C6alkoxy-OH, Ci-C6alkylthio, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, C6-Cio aryl, 5-10 membered heteroaryl, C3-C8cycloalkyl, 3-8 membered heterocyclyl, -(Ci-C6alkylene)-C3-C8cycloalkyl and -(Ci-C6alkylene)-3-8 membered heterocyclyl, wherein each of the aforementioned groups is independently optionally substituted with one or more R f ; R a , R b , R c , R d , R e and R f are each independently selected from halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, -(C1-C6alkylene)-C3-C10cycloalkyl, C3-C10cycloalkyloxy, 3-8 membered heterocyclyl, -(C1-C6alkylene)-3-8 membered heterocyclyl.

5. The compound of claim 1, wherein, X1is selected from CR 1 or N; X2is C; X3is CR 2 ; X4 is CR 3 ; or X 3 and X 4 with the atom to which it is attached collectively form an E ring, wherein the E ring is optionally substituted with one or more R e substituents; E ring is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, monooxapentacyclyl, dioxahexacyclyl, pyrrolidinyl, piperidinyl, furanyl, thienyl, pyridyl, pyrrolyl, or Ring A is phenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein the above groups are optionally substituted with one or more R a substituents; Ring B is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, wherein the above groups are optionally substituted with one or more R b substituents; Ring C is phenyl, wherein said group is optionally substituted with one or more R c substituents; Ring D is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the foregoing groups are optionally substituted with one or more R d substituents; R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, -COO-(Ci-C4alkyl), -OCO-(Ci-C4alkyl), -C(O)-NH2, -NO2, -CN, halogen, Ci-C4alkyl, -S-(Ci-C4alkyl), Ci-C4alkoxy, Ci-C4alkoxy-C(O)-NH2, Ci-C4alkoxy-CONH(Ci-C6alkyl), Ci-C4alkoxy-OH, Ci-C4alkoxy-NH2, Ci-C4haloalkyl, Ci-C4haloalkoxy, Ci-C6hydroxyalkyl, C3-C4cycloalkyl, 5-6 membered heterocyclyl, and -(Ci-C3alkylene)-C(O)-O-Ci-C4alkyl; R a , R b , R c , R d , R e , and R f are each independently selected from halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, -(C1-C6alkylene)-C3-C10cycloalkyl, C3-C10cycloalkyloxy, 3-8 membered heterocyclyl, -(C1-C6alkylene)-3-8 membered heterocyclyl.

6. The compound of any one of claims 1-5, wherein, Ring B is selected from 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, 7-15 membered spiroheterocyclyl, 7-15 membered bridged heterocyclyl, 7-15 membered fused heterocyclyl, wherein the above groups are optionally substituted with one or more R b substituents, and ring B contains a nitrogen atom; Preferably, ring B is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl, wherein the above groups are optionally substituted with one or more R b substituted; More preferably, ring B is selected from the following structures: wherein represents the site of attachment to the C ring, represents the site of attachment to the parent nucleus.

7. The compound of any one of claims 1-6, wherein The compound has a structure as shown in formula IV: wherein, Y1, Y3, Y4, Y5, Y6are each independently CR a or N, Y2is absent, CR a or N, Z1, Z3, Z4, Z5, Z6are each independently CR c or N, Z2is absent, CR c or N W1, W3, W4, W5, W6are each independently CR d or N, W2is absent, CR d or N, X1, X2, X3, X4, R a , R c , R d , ring B is as described in any one of claims 1-6.

8. The compound of any one of claims 1-6, wherein The compound has a structure as shown in formula IV-1 below: wherein, Y1, Y3, Y4, Y5, Y6 are each independently CR a , CR a R a , N or NR a , Y2 is absent, CR a , CR a R a , N or NR a , Z1, Z3, Z4, Z5, Z6are each independently CR c , CR c R c , N or NR c , Z2is absent, CR c , CR c R c , N or NR c , W1, W3, W4, W5, W6are each independently CR d , CR d R d , N or NR d , W2is absent, CR d , CR d R d , N or NR d , P1, P1, P3, P4 are each independently CR b R b , O, S or NR b , q is 0, 1, 2, or 3, X1, X2, X3, X4, each R a , each R b , each R c , each R d , each ring B is independently as described in any one of claims 1-6.

9. The compound of claim 8, wherein X1is CR 1 or N, X2is C, X3is CR 2 , X4is CR 3 , or X 3 and X 4 together with the atom to which they are attached form an E ring, wherein the E ring is optionally substituted with one or more R e ; Y1, Y3are each independently CR a , N or NR a , Y2is absent or CR a , Y4, Y5, Y6are each CR a ; Z1, Z2, Z3, Z4, Z5, Z6are each independently CR c ; W1is C, W2is absent or CR d , W3is CR d , W4is CR d R d , N or NR d , W4, W5are independently CR d , W6is N; P3, P4are each independently CR b R b .

10. The compound of any one of claims 1-9, wherein, The compound has a structure as shown in formula V: Y1, Y3are each independently CR a or N, n is 0, 1, 2, 3, 4, or 5, m is 0, 1, 2, 3, or 4, p is 0, 1, or 2, X1, X3, X4, R a , R c , R d , ring B is as described in any one of claims 1-9.

11. The compound of any one of claims 1-10, wherein, The compound has a structure as shown in formula VI-1 below: wherein R 2 , R 3 , ring B is as defined in any one of claims 1 to 10; or, The compound has a structure as shown in formula VI-2 below: wherein, the definition of ring B is as described in any one of claims 1-10, and E ring is a 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl; Preferably, the compound has the structure shown in formula VII-1 below: wherein R 2 , R 3 , ring B is as defined in any one of claims 1 to 10; or, The compound has the structure shown in formula VII-2 below: wherein, the definition of ring B is as described in any one of claims 1-10, and E ring is a 3-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl.

12. The compound of any one of claims 1-11, wherein, The compound is selected from the following table:

13. A pharmaceutical composition comprising the heterocyclic compound of Formula I or stereoisomer, tautomer, deuterated analog, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal of claim 1; and a pharmaceutically acceptable carrier.

14. Use of the heterocyclic compound of Formula I or stereoisomer, tautomer, deuterated analog, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal of claim 1, or the pharmaceutical composition of claim 13, as a USP1 inhibitor or for the manufacture of a medicament for treating a disease associated with USP1 activity or expression.

15. The use according to claim 14, characterized in that, The disease associated with USP1 activity or expression is cancer.

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