PI3Kalpha inhibitor compound, pharmaceutical composition and application of PI3Kalpha inhibitor compound and pharmaceutical composition

Abstract

The invention provides a PI3Kalpha inhibitor compound as shown in a formula I, a pharmaceutical composition and application of the PI3Kalpha inhibitor compound and the pharmaceutical composition. The compound has good PI3Kalpha inhibitory activity, can be used for treating diseases related to PI3Kalpha, not only has good biological activity and good safety, but also improves transmembrane activity and drug bioavailability. # imgabs0 #

Description

[0001] The present invention claims the priority of the prior application with patent application number 202311678310.4 and title “PI3Kα inhibitor compounds, pharmaceutical compositions and their applications” filed with the State Intellectual Property Office of China on December 7, 2023; the full text of the prior application is incorporated into the present invention by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical compounds, and in particular relates to PI3Kα inhibitor compounds, pharmaceutical compositions and applications thereof. Background Art

[0003] Phosphatidylinositol 3-kinase (PI3K) is a unique and conserved family of intracellular lipid kinases that possess both phosphatidylinositol kinase activity and serine / threonine (Ser / Thr) kinase activity. The PI3K family includes 15 kinases, which can be divided into three major categories (class I, class II, and class III) based on their structure and substrate specificity.

[0004] The most widely studied of these is class I PI3K, which is a heterodimer consisting of a regulatory subunit p85 and a catalytic subunit p110. There are four types of catalytic subunits: α, β, δ, and γ. Among them, α, β, and δ correspond to p85α, p85β, or p55 regulatory subunits; while the γ type corresponds to p101 and p84 / 87 regulatory subunits. The regulatory subunit has an SH2 domain that can recognize the intracellular kinase domain of RTKs and trigger the activation of the catalytic subunit p110.

[0005] Usually, after class I PI3K is activated by tyrosine kinase or G protein-coupled receptor, it can catalyze PIP2 to generate PIP3 and trigger the activation of serine / threonine kinase AKT. AKT is regulated by PDK and mTOR2, and activation of AKT can promote cell cycle progression; in addition, activation of AKT can trigger the expression of a series of downstream molecules, thereby maintaining cell survival, promoting vascular survival, and promoting cell growth. Homologous phosphatase-tensin (PTEN), as a negative regulator of PI3K signal transduction, can dephosphorylate PIP3 and convert it into PIP2.

[0006] PI3K signaling is one of the most common abnormally activated pathways in cancer and is thought to be associated with a range of human cancers. Early studies have shown that pan-PI3K inhibitors LY294002 and Wortmannin can improve cancer cells' resistance to a variety of therapies, including chemotherapy, radiotherapy, and targeted therapy. In addition to targeting cancer cells, studies have also demonstrated the potential of PI3K inhibitors in cancer immunotherapy.

[0007] In the past two decades, the development of drugs related to the PI3K pathway has been a key research area, and some results have been achieved. Several PI3K inhibitors targeting individual isoforms have now been approved by regulatory authorities. These include inhibitors targeting leukocyte-enriched PI3Kδ, which is mainly found in B-cell malignancies, and alpelisib, a PI3Kα isoform selective inhibitor for the treatment of HR+ / HER2- / PIK3CA-mutated advanced metastatic breast cancer and the treatment of pro-overgrowth syndrome (PROS).

[0008] Unlike PI3Kδ and PI3Kγ, which are mainly expressed in hematopoietic cells, PI3Kα is expressed in most tissues. PI3Kα plays a core role in regulating the body's glucose homeostasis, and PI3Kα inhibition in patients usually causes hyperglycemia or hyperinsulinemia. Studies have also shown that high levels of insulin may have mitogenic and anti-apoptotic effects on cancer cells, thereby offsetting the anti-proliferative effects of PI3Kα inhibitors. Therefore, the development of PI3Kα inhibitors faces challenges in tolerability and safety.

[0009] Alpelisib has an equivalent inhibitory effect on mutant and wild-type PI3Kα. Although the drug is classified as a PI3Kα-specific drug, severe concentration-dependent side effects and drug resistance are often observed. Clinical studies have also shown that the incidence of adverse events (AEs) of Alpelisib ≥ grade 3 (mainly hyperglycemia) is high, which limits patients' tolerance and acceptance of the drug. At the same time, the sensitivity of Alpelisib depends on the PIK3CA mutation. Therefore, there is an urgent need for more accurate, more efficient, and better tolerated inhibitors against mutant PI3Kα to change the current treatment status and meet clinical needs.

[0010] PIK3CA is the gene encoding the PI3Kα catalytic subunit p110α protein and is the most commonly mutated gene in solid tumors. The most common hotspot mutations of the PIK3CA gene occur mainly in the kinase domain of exon 20 (H1047R) and the helical domain of exon 9 (E545K, E542K). These mutations have a greater impact on PI3Kα activity and have been shown to be oncogenic gain-of-function mutations. Among them, approximately 15% of breast cancers will have H1047R mutations, which are relatively uncommon in other tumors. Compared with PIK3CA wild-type patients, patients with PIK3CA-mutated HR+ / HER2- advanced breast cancer have a poorer prognosis, poor response to traditional treatment, and resistance to endocrine therapy and chemotherapy. Some small studies that mainly analyzed ER+ breast and adenocarcinoma tumors have shown that patients with H1047R show a reduced survival rate compared with tumors containing E545K.

[0011] Therefore, targeting PI3Kα mutations and developing inhibitors with enhanced selectivity for mutant PI3Kα may provide valuable treatment opportunities for breast cancer patients carrying this mutation, overcoming the problem of compensatory production of insulin or glucose after systemic PI3Kα inhibition. This will create an increased window for drug dosing, selectively inhibiting the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in tissues that control systemic metabolism. It is hoped that the scope of research on PI3Kα inhibitors will be expanded from HR+ / HER2- to HER2+ and TNBC, and from advanced to early stages, so that more patients can benefit. Summary of the invention

[0012] The present invention provides a compound represented by formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt;

[0013]

[0014] Among them, R 1 , R 2 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R 11 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 3-12 Cycloalkyl; each R 11 are the same or different and are independently selected from H, halogen, CN, OH, C 1-12 alkyl;

[0015] Each R 3 are the same or different and are independently selected from H, halogen, CN, OH, unsubstituted or optionally substituted by one, two or more R 31 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, N(R 32 )(R 33 ); each R 31 The same or different, independently selected from halogen, CN, C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12Alkyloxy, C 1-12 Acyl; R 32 , R 33 The same or different, independently selected from H, C 1-12 Alkyl, S(=O) 2 R 311 、S(=O)(=NH)R 312 ; R 311 , R 312 The same or different, independently selected from H, C 1-12 alkyl;

[0016] R 4 Selected from H, halogen, CN, C 1-12 Alkyl, C 1-12 Alkyloxy or C 3-12 Cycloalkyl;

[0017] Y is selected from O, S, N or NH;

[0018] Ring B is selected from C 3-12 Carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring;

[0019] Each R b are the same or different and are independently selected from halogen, CN, OH, oxo (=O), C 1-12 Alkyl, C 1-12 Alkyloxy, C 3-12 Cycloalkyl, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, OH-C 1-12 alkyl;

[0020] L 1 Absent or selected from unsubstituted or optionally substituted by one, two or more R L1 Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-14 Cycloalkylene; each R L1 are the same or different and are independently selected from halogen, CN, OH, C 1-6 alkyl;

[0021] Ring A is selected from C 3-12 Carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring;

[0022] Each R a are the same or different and are independently selected from halogen, CN, OH, C 1-12 Alkyl, C 1-12Alkyloxy, C 3-12 Cycloalkyl, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, OH-C 1-12 alkyl;

[0023] E is absent or selected from unsubstituted or optionally substituted with one, two or more R e Substituted with the following groups: C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, N(R e1 )(R e2 ); each R e are the same or different and are independently selected from halogen, CN, OH, oxo (=O), amino, C 1-12 Alkyl, C 1-12 Alkyloxy, C 3-12 Cycloalkyl, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, halogenated C 3-12 Cycloalkyl; R e1 , R e2 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R e3 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkyl-C 3-12 Cycloalkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl-C 1-12 Alkyl; each R e3 are the same or different and are independently selected from halogen, CN, OH, C 1-12 alkyl;

[0024] m is selected from 0, 1, 2, 3 or 4;

[0025] n is selected from 0, 1, 2, 3 or 4;

[0026] p is selected from 0, 1, 2, 3 or 4;

[0027] q is selected from 0, 1, 2, 3 or 4.

[0028] According to some embodiments, R 1 , R 2 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R 11 Substituted with the following groups: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0029] According to some embodiments, each R 11are the same or different and are independently selected from halogen, C 1-6 alkyl;

[0030] According to some embodiments, each R 11 are the same or different and are independently selected from F, Cl or methyl;

[0031] According to some embodiments, R 1 , R 2 The same or different, independently selected from H, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, tert-butyl, methylcyclopropyl (such as 1-methyl-cyclopropyl-1-yl), fluorocyclopropyl (such as 1-fluoro-cyclopropyl-1-yl).

[0032] According to some embodiments, R 1 Selected from H; R 2 Selected from trifluoromethyl.

[0033] According to some embodiments, each R 3 are the same or different and are independently selected from H, halogen, CN, unsubstituted or optionally substituted by one, two or more R 31 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkyloxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, N(R 32 )(R 33 );

[0034] According to some embodiments, each R 31 The same or different, independently selected from CN, C 1-6 Alkyl, C 1-6 acyl group;

[0035] According to some embodiments, each R 31 The same or different, independently selected from C 1-6 Alkyl; for example, methyl;

[0036] According to some embodiments, R 32 , R 33 The same or different, independently selected from H, C 1-6 Alkyl, -S(=O) 2 -C 1-6 Alkyl, -S(=O)(=NH)-C 1-6 alkyl;

[0037] According to some embodiments, R 32 , R33 The same or different, independently selected from H, methyl, S(=O) 2 CH 3 、S(=O)(=NH)CH 3 .

[0038] According to some embodiments, each R 3 are the same or different and are independently selected from H, F, Cl, CN, methyl, methoxy, difluoromethoxy, trifluoromethoxy, methylamino, -NH-S(=O) 2 CH 3 、-NH-S(=O)(=NH)CH 3 , morpholinyl (such as ), tetrahydropyrrolyl (such as ), phenyl, methylpyrazolyl (such as ), cyclopropyl;

[0039] According to some embodiments, each R 3 are the same or different and are independently selected from H, F or Cl.

[0040] According to some embodiments, m is selected from 1 or 2.

[0041] According to some embodiments, R 4 Selected from H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0042] According to some embodiments, R 4 Selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl.

[0043] According to some embodiments, Ring B is selected from a 5-6 membered heterocyclic ring, a 5-6 membered heteroaromatic ring;

[0044] According to some embodiments, Ring B is selected from a 5-membered heteroaromatic ring;

[0045] According to some embodiments, ring B is selected from an imidazole ring (eg ), dihydroimidazole ring (such as ), triazole ring (such as ).

[0046] According to some embodiments, each R b The same or different, independently selected from halogen, CN, C 1-6 alkyl.

[0047] According to some embodiments, each R b are the same or different and are independently selected from F, Cl, CN or methyl.

[0048] According to some embodiments, Rb Selected from methyl.

[0049] According to some embodiments, q is selected from 0 or 1.

[0050] According to some embodiments, L 1 Absent or selected from methylene.

[0051] According to some embodiments, Ring A is selected from C 3-8 Carbocyclic ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring;

[0052] According to some embodiments, ring A is selected from a pyrimidine ring, a benzene ring, a pyridine ring, a pyrazine ring, a pyridazine ring, a thiophene ring, a furan ring, a pyrazole ring, a pyrrole ring, a thiazole ring, an oxazole ring, an imidazole ring, a triazole ring, a quinoline ring, a quinazoline ring, a pyrrolopyridine ring (such as ), tetrahydroquinoline ring (such as ), cyclopentadienylpyridine ring (such as ), pyrazolopyrimidine ring (such as ), naphthyridine ring (such as ), pyrazolopyridine ring (such as ), imidazopyridine ring (such as ), quinoline ring (such as ), indazole ring (such as ), benzimidazole ring (such as ).

[0053] According to some embodiments, Ring A is selected from a pyrimidine ring.

[0054] According to some embodiments, each R a are the same or different and are independently selected from halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkyloxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkyloxy, OH-C 1-6 alkyl;

[0055] According to some embodiments, n is selected from 0.

[0056] According to some embodiments, E is absent and p is selected from 0;

[0057] According to some embodiments, E is selected from unsubstituted or optionally substituted with one, two or more R e Substituted groups: 3-10 membered heterocyclic group, N(R e1 )(R e2 );

[0058] According to some embodiments, E is selected from unsubstituted or optionally substituted with one, two or more R e Substituted groups: 3-8 membered heterocyclic group, N(R e1 )(R e2 );

[0059] According to some embodiments, R e1 , R e2 The same or different, independently selected from H, C 1-6 Alkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, C 3-8 Cycloalkyl.

[0060] According to some embodiments, E is selected from unsubstituted or optionally substituted with one, two or more R e Substituted with the following groups: NH 2 , azetidinyl (such as: ), piperidinyl, tetrahydropyrrolyl, morpholinyl, piperazinyl,

[0061] According to some embodiments, each R e are the same or different and are independently selected from halogen, OH, CN, oxo, NH 2 , C 1-6 Alkyl, C 1-6 Alkyloxy, C 3-6 Cycloalkyl;

[0062] According to some embodiments, each R e The same or different, independently selected from F, OH, NH 2 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, cyclopropyl.

[0063] According to some embodiments, the compound represented by Formula I may have the structure shown below:

[0064]

[0065] Among them, R 1 , R 2 , R 3 , R 4 , Y, L 1 , Ring A, Ring B, E, R a , R b , R e , R e1 , R e2 , m, n, p, q have the definitions described in this document.

[0066] According to some embodiments, the compound represented by Formula I may have the structure shown below:

[0067]

[0068] Among them, R 1 , R 2 , R 3 , R 4 , Y, ring A, E, R a , R b , R e , m, n, p, q have the definitions described in this document.

[0069] According to some embodiments, the compound represented by Formula I may have the structure shown below:

[0070]

[0071] Among them, E, R e , R 3 , R 4 , R b , p, q have the definitions described herein.

[0072] According to some embodiments, the compound represented by Formula I may have the structure shown below:

[0073]

[0074]

[0075]

[0076] The present invention also provides a method for preparing the compound represented by formula I, comprising the following steps:

[0077]

[0078] Among them, R 2 , R 3 , R 4 , Y, L 1 , Ring A, Ring B, E, R a , R b , R e , m, n, p, q have the definitions given herein; R 1 is H; Z is selected from a leaving group, such as a halogen; X is selected from a nucleophilic group, such as B(OH) 2 ; When there is NH on ring B, NH is protected by a protecting group (such as SEM); when E-(R e ) p For NH 2 When NH 2It is protected by a protecting group (such as Boc) and deprotected to obtain a compound.

[0079] The present invention further provides a pharmaceutical composition comprising the compound of formula I described in the present invention and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the pharmaceutical composition described in the present invention further comprises a therapeutically effective amount of the compound of formula I described in the present invention and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0081] The carrier in the pharmaceutical composition is "acceptable" in that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject being treated. One or more pharmaceutical excipients may be used for delivery of the active compound.

[0082] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of PI3Kα inhibitors.

[0083] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a drug for preventing and / or treating cancer, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer and / or benign overgrowth syndrome.

[0084] The present invention further provides the use of the compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of a drug for preventing and / or treating PIK3CA-associated overgrowth (PROS).

[0085] The present invention also provides a method for preventing and / or treating a PI3Kα-mediated disease or condition, which comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound or pharmaceutical composition of the present invention alone, or, optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0086] According to some embodiments, the PI3Kα-mediated disease or symptom is selected from cancer, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer and / or benign overgrowth syndrome;

[0087] According to some embodiments, the PI3Kα-mediated disease or condition is PIK3CA-associated overgrowth (PROS).

[0088] Beneficial Effects

[0089] The compounds provided by the present invention have good PI3Kα inhibitory activity and can be used for the treatment of diseases related to PI3Kα. The compounds of the present invention not only have good biological activity and good safety, but also improve transmembrane activity and drug bioavailability.

[0090] Definition and explanation of terms

[0091] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and / or claims of this application.

[0092] The term "optional" (or "optionally", "optionally") in the general formula definitions of the present application means the situation of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be selectively substituted by one, two or more R.

[0093] "More" means three or more.

[0094] Unless otherwise specified, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-12" is equivalent to recording each integer value in the numerical range "1-12", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

[0095] The term "C 1-12 The term "alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms. 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0096] The term "alkyloxy" has the same meaning as "alkoxy", which should be understood as "-O-alkyl", wherein alkyl is as defined above. Exemplary alkyloxy groups include methoxy, ethoxy, and the like. The term "C 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 12 carbon atoms, preferably "C 3-10 Cycloalkyl", more preferably "C 3-8 The term "Cycloalkyl" 3-12 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 3-12 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diazaspiro[3,4]octanyl, or a tricyclic hydrocarbon group such as adamantyl.

[0097] The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-10 The term "C 6-14 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 Aryl), especially a ring having 6 carbon atoms ("C6 aryl), such as phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0098] The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, furthermore, may be benzo-fused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4- , 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbozolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-pyridinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9- 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]oxazolyl, 2-, 4- or 54H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3 1-, 2-, 3-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14 membered heteroaryl group is connected to other groups to form the compound of the present invention, it can be a carbon atom on the 5-14 membered heteroaryl ring connected to other groups, or it can be a heteroatom on the 5-14 membered heteroaryl ring connected to other groups. When the 5-14 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, the hydrogen bonded to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen bonded to the heteroatom on the heteroaryl ring may be substituted.

[0099] Unless otherwise defined, the term "3-14 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (e.g., fused, bridged, spiro) or a 10-, 11-, 12-, 13- or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)-. 2 -state. For example, the "3-14 membered heterocyclyl" can be a 3-14 membered N-containing heterocyclyl (containing at least one N). Preferably, the heterocyclyl can be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclyl can be connected to the rest of the molecule through any one of the carbon atoms or a nitrogen atom (if present). The heterocyclyl can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group may include, but is not limited to, a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-14 membered heterocyclic group is connected with other groups to form the compound of the present invention, it may be a carbon atom on the 3-14 membered heterocyclic group connected with other groups, or it may be a heterocyclic atom on the 3-14 membered heterocyclic group ring connected with other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, it may be a nitrogen atom on the piperazinyl group connected with other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinyl, it may be a nitrogen atom on the piperidinyl ring and a carbon atom on the para position thereof connected with other groups.

[0100] L 1 When it is absent, ring A and ring B are directly connected via a chemical bond.

[0101] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

[0102] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0103] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

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

[0105] "Halo" means substituted with one or more halogens.

[0106] In the present invention, the compounds involved also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually occurring in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F and Cl, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 32 P. 35 S. 18 F and 36 Cl. Compounds of the invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or said prodrugs containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, those incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon 14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 H or D) substitution may provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances. The presence of hydrogen in the substituents of the present invention without the separate listing of the term deuterium or tritium does not exclude deuterium or tritium, but may also include deuterium or tritium.

[0107] Those skilled in the art will appreciate that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form an inner salt.

[0108] The compounds of the present invention may exist in the form of solvates (e.g. hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio.

[0109] According to its molecular structure, the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution agent. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms. Chromatographic enantiomer resolution can also be advantageously carried out with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0110] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0111] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0112] The term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. DETAILED DESCRIPTION

[0113] The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

[0114] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0115] Example 1

[0116]

[0117] The first step 5,7-difluoro-3-methylbenzofuran-2-carboxaldehyde 001-b

[0118] Under nitrogen protection, potassium tert-butoxide (57.37 g) was added to a solution of 001-a (11 g) in tetrahydrofuran (300 mL) at 25°C, and then the reaction solution was cooled to 0°C, 1,1-dichloroethylene (18.59 g) was added, and stirring was continued at 25°C for 12 hours. TLC showed that new spots were generated. The reaction mixture was quenched by adding water (400 mL) at 0°C, and then extracted with ethyl acetate (3×300 mL). The organic phases were combined, backwashed with saturated brine (1×300 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (150 mL) and sulfuric acid (5M, 100 mL) was added. The reaction mixture was reacted at room temperature for 16 hours. TLC showed that new spots were generated. The reaction mixture was poured into ice water (300 mL) to quench, and then extracted with dichloromethane (3×200 mL). The organic phases were combined, backwashed with saturated brine (1×300 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (5:1) to obtain compound 001-b (8.1 g).

[0119] 1 H NMR (400 MHz, CDCl 3 )δ10.06(s,1H),7.18–7.13(m,1H),7.09–7.02(m,1H),2.60(s,3H).

[0120] Step 2 1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-ol 001-c

[0121] To a solution of 001-b (1.6 g) in N,N-dimethylformamide (30 mL) at 0°C, (trifluoromethyl)trimethylsilane (2.32 g) and potassium carbonate (0.56 g) were added, and the reaction solution was stirred at room temperature for 10 minutes before potassium carbonate (1.76 g) was added. The reaction mixture was reacted at room temperature for 1 hour. Then water (20 mL) was slowly added, and the reaction mixture was stirred for 30 minutes. TLC showed that new spots were generated. Water (80 mL) was added to the reaction solution for dilution and extracted with ethyl acetate (3×60 mL). The organic phases were combined, backwashed with saturated brine (1×80 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column dry chromatography, petroleum ether / ethyl acetate (5:1) to obtain compound 001-c (2 g).

[0122] 1 H NMR (400 MHz, DMSO-d 6)δ7.46–7.30(m,2H),7.20(d,1H),5.65–5.49(m,1H),2.28(s,3H).

[0123] Step 3 1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethane-1-one 001-d

[0124] 2-Iodoacylbenzoic acid (3.15 g) was added to a solution of 001-c (2 g) in acetonitrile (20 mL) at room temperature. Stir at 80°C for 16 hours. TLC showed new spots were generated. The reaction solution was filtered, diluted with water (100 mL), and then extracted with ethyl acetate (3×80 mL). The organic phases were combined, backwashed with saturated brine (1×80 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, petroleum ether / ethyl acetate (5:1) to obtain compound 001-d (1.6 g).

[0125] 1 H NMR (400 MHz, DMSO-d 6 )δ7.81–7.73(m,2H),2.64(s,3H).

[0126] Step 4: 2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole 001-f

[0127] Under nitrogen protection, sodium hydride (1.67 g, 60% dispersed in mineral oil) was added to a solution of 001-e (11 g) in tetrahydrofuran (150 mL) at 0°C, and the reaction was stirred at 0°C for 30 minutes. Then, 2-(trimethylsilyl)ethoxymethyl chloride (19.46 g) was added and the reaction was stirred at 20°C for 1 hour. TLC showed that new spots were generated. The reaction mixture was quenched by adding saturated aqueous ammonium chloride (500 mL) at 0°C, and then extracted with ethyl acetate (3×300 mL). The organic phases were combined, backwashed with saturated brine (1×300 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-20%) to obtain compound 001-f (21 g).

[0128] 1 H NMR (400 MHz, CDCl 3 )δ7.28(d,1H),7.19(d,1H),5.77(s,2H),3.70–3.58(m,2H),1.01–0.92(m,2H),0.00(s,9H).

[0129] Step 5: 4-bromo-2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole 001-g

[0130] Under nitrogen protection, N-bromosuccinimide (2.41 g) was added to a solution of 001-f (3 g) in N,N-dimethylformamide (30 mL) at room temperature, and the reaction was stirred at 30°C for 12 hours. TLC showed the formation of new spots. The reaction mixture was quenched by adding water (80 mL) at 0°C, and then extracted with ethyl acetate (3×40 mL). The organic phases were combined, backwashed with saturated brine (1×60 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-15%) to obtain compound 001-g (1 g).

[0131] 1 H NMR (400 MHz, CDCl 3 )δ7.27(s,1H),5.74(s,2H),3.73–3.57(m,2H),0.99–0.94(m,2H),0.00(s,9H).

[0132] Step 6: 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-amine 001-h

[0133] Under nitrogen protection, ammonium chloride (149.24 mg) and iron powder (467.46 mg) were added to a solution of 001-g (900 mg) in ethanol (24 mL) and water (8 mL) at room temperature, and the mixture was stirred at 70 ° C for 1 hour. LCMS showed that the product was generated. The mixture was filtered, diluted with water (80 mL) and extracted with dichloromethane / methanol = 10:1 (60 mL×2), backwashed with saturated brine (1×80 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by dry method by silica gel column chromatography, dichloromethane / ethyl acetate (3:1) to obtain compound 001-h (670 mg).

[0134] LCMS: (ESI, m / z): 292.1 [M+H] +

[0135] Step 7: 4-bromo-N-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-amine 001-i

[0136] Under nitrogen protection, 001d (635.15 mg) and tetraisopropyl titanate (1562.07 mg) were added to a solution of 001h (670 mg,) in tetrahydrofuran (15 mL) at room temperature, and the reaction solution was stirred at 75 ° C for 16 hours, and then sodium borohydride (259.89 mg, 6.87 mmol, 3 eq) was added and stirred at room temperature for 30 minutes. LCMS showed that the product was generated. Water (60 mL) was added to the reaction solution to quench, and the filtrate was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (3×60 mL). The organic phases were combined, backwashed with saturated brine (1×60 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography dry method, petroleum ether / ethyl acetate (3:1) to obtain compound 001-i (1 g).

[0137] LCMS: (ESI, m / z): 540.1 [M+H] +

[0138] Step 8: Tert-butyl (5-(2-((1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyrimidin-2-yl)carbamate 001-k

[0139] Under nitrogen protection, 001-j (0.53 g), sodium carbonate (0.39 g) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (0.14 g) were added to a solution of 001-i (1 g) in N,N-dimethylformamide (16 mL) and water (4 mL) at room temperature. The reaction was continued to stir at 90°C for 2 hours. LCMS showed that the product was generated. The reaction mixture was quenched by adding water (100 mL) at room temperature, and then extracted with ethyl acetate (3×60 mL). The organic phases were combined, backwashed with saturated brine (1×60 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, ethyl acetate / petroleum ether (0-40%) to obtain compound 001-k (0.85 g).

[0140] LCMS (ESI, m / z) = 655.3 [M+H] +

[0141] Step 9 5-(2-((1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)amino)-1H-imidazol-4-yl)pyrimidin-2-amine 001

[0142] 001-k (400 mg) was dissolved in trifluoroacetic acid (10 mL) at room temperature and stirred for 2.5 hours at room temperature. LCMS showed that the product was generated. The reaction mixture was adjusted to pH = 8 by adding ammonia water, and then the reaction solution was spin-dried and dissolved with methanol (5 mL). The residue was purified by prep-HPLC (chromatographic column specifications: Xbridge C18 9 mm × 250 mm, 10 μm; mobile phase A: water (10 mmol NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 42% B to 47% B) was purified to obtain compound 001 (27 mg).

[0143] LCMS (ESI, m / z) = 425.1 [M+H] +

[0144] 1 H NMR (400 MHz, DMSO-d 6 )δ10.33(s,1H),8.52(s,2H),7.42-7.32(m,3H),7.00(d,1H),6.47(s,2H),6.16–6.02(m,1H),2.38(s,3H).

[0145] Biological evaluation

[0146] Test Example 1: The purpose of this test is to determine the inhibitory effect of the test compound on PI3Kα and PI3Kα(H1047R) using the ADP-Glo ​​luciferase luminescence detection method.

[0147] Test materials and instruments

[0148] A. Reagent Information

[0149]

[0150] B. Consumables Information

[0151]

[0152] C. Instrument Information

[0153]

[0154] Experimental procedures

[0155] a. Preparation of reaction buffer

[0156] Take 10 ml as an example, prepare and use it on the day of the experiment:

[0157]

[0158] b. Compound Preparation

[0159] The test compound was prepared into a 100x concentration stock solution with DMSO, and the compound was graded diluted using a multichannel electronic pipette. 50 nL of the test compound was transferred to a 384-well microvolume assay plate using the automated micropipette system Echo550, where only 50 nL of 100% DMSO solution was added to the wells in the negative control and positive control areas.

[0160] c. Experimental steps

[0161] The PI3Kα and PI3Kα(H1047R) enzyme solutions and substrate mixed solutions were prepared using reaction buffer. The final concentrations of enzyme and substrate in the reaction solution were as follows:

[0162]

[0163] After the compound transfer is completed, 2.5 μL of PI3Ks enzyme solution (compound wells and ZPE wells) or 2.5 μL of reaction buffer (HPE wells) is added to each well of the 384-well test plate as shown in the figure, centrifuged at 1000 rpm for 1 minute, and then the 384-well plate is placed in a constant temperature incubator and pre-incubated at 25°C for 10 minutes. After the incubation is completed, 2.5 μL of substrate mixed solution is added to each well to start the reaction (the total reaction volume is 5 μL), and the 384-well plate is placed in a constant temperature incubator and reacted at 25°C for 60 minutes. After the reaction, 5 μL of ADP-Glo ​​reagent (Promega, #V9102, thawed in advance and equilibrated to room temperature) was added to stop the reaction, and then incubated in a constant temperature incubator at 25°C for 60 minutes, and then 10 μL of Kinase Detection Substrate (Promega, #V9102, thawed in advance and equilibrated to room temperature) was added to each well, centrifuged and mixed, and then incubated in a constant temperature incubator at 25°C for 30 minutes. The fluorescence value was read on the Envision 2104 multi-function plate reader, and the reaction signal value read in each well was the raw data, and the raw data was used to analyze the half-inhibitory concentration of the compound on PI3K kinase.

[0164] Experimental Results

[0165] This experiment uses XLfit, a software developed by IDBS and integrated into the Microsoft Excel environment, to process and analyze test data. First, calculate the average reaction signals of the positive control wells and negative control wells respectively, and then use the formula "single-well inhibition rate = (negative control signal average value - single-well signal value) / (negative control signal average value - positive control signal average value) * 100%" to calculate the reaction inhibition rate percentage of each compound well. Then import the concentration and corresponding inhibition rate data into the XLfit software, use the Dose Response One Site 205 model in the software, and use the four-parameter method to fit the inhibition rate-concentration curve, and calculate the half-inhibitory concentration (IC 50 value).

[0166]

[0167] Experimental conclusion

[0168] The above data show that the representative compounds of the present invention have good PI3Kα inhibitory activity.

[0169] The above is an exemplary description of the implementation of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-mentioned implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims

1. A compound of formula I and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt; in, R1 and R2 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R 11 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 3-12 Cycloalkyl; each R 11 are the same or different and are independently selected from H, halogen, CN, OH, C 1-12 alkyl; Each R3 is the same or different and is independently selected from H, halogen, CN, OH, unsubstituted or optionally substituted with one, two or more R 31 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, N(R 32 )(R 33 ); each R 31 The same or different, independently selected from halogen, CN, C 1-12 Alkyl, C 1-12 Alkyloxy, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, C 1-12 Acyl; R 32 , R 33 The same or different, independently selected from H, C 1-12 Alkyl, S(=O)2R 311 、S(=O)(=NH)R 312 ; R 311 , R 312 The same or different, independently selected from H, C 1-12 alkyl; R4 is selected from H, halogen, CN, C 1-12 Alkyl, C 1-12 Alkyloxy or C 3-12 Cycloalkyl; Y is selected from O, S, N or NH; Ring B is selected from C 3-12 Carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring; Each R b are the same or different and are independently selected from halogen, CN, OH, oxo (=O), C 1-12 Alkyl, C 1-12 Alkyloxy, C 3-12 Cycloalkyl, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, OH-C 1-12 alkyl; L1 is absent or selected from unsubstituted or optionally substituted with one, two or more R L1 Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-14 Cycloalkylene; each R L1 are the same or different and are independently selected from halogen, CN, OH, C 1-6 alkyl; Ring A is selected from C 3-12 Carbocyclic ring, 3-14 membered heterocyclic ring, C 6-14 Aromatic ring, 5-14 membered heteroaromatic ring; Each R a are the same or different and are independently selected from halogen, CN, OH, C 1-12 Alkyl, C 1-12 Alkyloxy, C 3-12 Cycloalkyl, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, OH-C 1-12 alkyl; E is absent or selected from unsubstituted or optionally substituted with one, two or more R e Substituted with the following groups: C 3-12 Cycloalkyl, 3-14 membered heterocyclic group, N(R e1 )(R e2 ); each R e are the same or different and are independently selected from halogen, CN, OH, oxo (=O), amino, C 1-12 Alkyl, C 1-12 Alkyloxy, C 3-12 Cycloalkyl, halogenated C 1-12 Alkyl, halogenated C 1-12 Alkyloxy, halogenated C 3-12 Cycloalkyl; R e1 , R e2 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R e3 Substituted with the following groups: C 1-12 Alkyl, C 1-12 Alkyl-C 3-12 Cycloalkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl-C 1-12 Alkyl; each R e3 are the same or different and are independently selected from halogen, CN, OH, C 1-12 alkyl; m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1, 2, 3 or 4; q is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1 and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: R1 and R2 are the same or different and are independently selected from H, unsubstituted or optionally substituted with one, two or more R 11 Substituted with the following groups: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl; Preferably, each R 11 are the same or different and are independently selected from halogen, C 1-6 alkyl; Preferably, each R 11 are the same or different and are independently selected from F, Cl or methyl; Preferably, R1 and R2 are the same or different and are independently selected from H, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, tert-butyl, methylcyclopropyl (such as 1-methyl-cyclopropyl-1-yl), fluorocyclopropyl (such as 1-fluoro-cyclopropyl-1-yl); Preferably, R1 is selected from H; R2 is selected from trifluoromethyl; Preferably, each R3 is the same or different and is independently selected from H, halogen, CN, unsubstituted or optionally substituted by one, two or more R 31 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkyloxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, N(R 32 )(R 33 ); Preferably, each R 31 The same or different, independently selected from CN, C 1-6 Alkyl, C 1-6 acyl group; Preferably, each R 31 The same or different, independently selected from C 1-6 Alkyl; for example, methyl; Preferably, R 32 , R 33 The same or different, independently selected from H, C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)-C 1-6 alkyl; Preferably, R 32 , R 33 are the same or different and are independently selected from H, methyl, S(=O)2CH3, S(=O)(=NH)CH3; Preferably, each R3 is the same or different and is independently selected from H, F, Cl, CN, methyl, methoxy, difluoromethoxy, trifluoromethoxy, methylamino, -NH-S(=O)2CH3, -NH-S(=O)(=NH)CH3, morpholinyl (such as ), tetrahydropyrrolyl (such as ), phenyl, methylpyrazolyl (such as ), cyclopropyl; Preferably, each R3 is the same or different and is independently selected from H, F or Cl; Preferably, m is selected from 1 or 2; Preferably, R4 is selected from H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; Preferably, R4 is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl; Preferably, L1 is absent or selected from methylene; Preferably, ring A is selected from C 3-8 Carbocyclic ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring; Preferably, ring A is selected from pyrimidine ring, benzene ring, pyridine ring, pyrazine ring, pyridazine ring, thiophene ring, furan ring, pyrazole ring, pyrrole ring, thiazole ring, oxazole ring, imidazole ring, triazole ring, quinoline ring, quinazoline ring, pyrrolopyridine ring (such as ), tetrahydroquinoline ring (such as ), cyclopentadienylpyridine ring (such as ), pyrazolopyrimidine ring (such as ), naphthyridine ring (such as ), pyrazolopyridine ring (such as ), imidazopyridine ring (such as ), quinoline ring (such as ), indazole ring (such as ), benzimidazole ring (such as ); Preferably, ring A is selected from a pyrimidine ring; Preferably, each R a are the same or different and are independently selected from halogen, CN, OH, C 1-6 Alkyl, C 1-6 Alkyloxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkyloxy, OH-C 1-6 alkyl; Preferably, n is selected from 0.

3. The compound according to claim 1 or 2, and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: Ring B is selected from a 5-6 membered heterocyclic ring, a 5-6 membered heteroaromatic ring; Preferably, ring B is selected from a 5-membered heteroaromatic ring; Preferably, ring B is selected from imidazole rings (such as ), dihydroimidazole ring (such as ), triazole ring (such as ); Preferably, each R b The same or different, independently selected from halogen, CN, C 1-6 alkyl; Preferably, each R b are the same or different and are independently selected from F, Cl, CN or methyl; Preferably, R b Selected from methyl; Preferably, q is selected from 0 or 1.

4. The compound according to any one of claims 1 to 3 and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: E does not exist, p is selected from 0; Preferably, E is selected from unsubstituted or optionally substituted with one, two or more R e Substituted groups: 3-10 membered heterocyclic group, N(R e1 )(R e2 ); Preferably, E is selected from unsubstituted or optionally substituted with one, two or more R e Substituted groups: 3-8 membered heterocyclic group, N(R e1 )(R e2 ); Preferably, R e1 , R e2 The same or different, independently selected from H, C 1-6 Alkyl, C 1-6 Alkyl-C 3-8 Cycloalkyl, C 3-8 Cycloalkyl; Preferably, E is selected from unsubstituted or optionally substituted with one, two or more R e Substituted with the following groups: NH2, azetidinyl (eg: ), piperidinyl, tetrahydropyrrolyl, morpholinyl, piperazinyl, Preferably, each R e are the same or different and are independently selected from halogen, OH, CN, oxo, NH2, C 1-6 Alkyl, C 1-6 Alkyloxy, C 3-6 Cycloalkyl; Preferably, each R e The same or different, independently selected from F, OH, NH2, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, cyclopropyl.

5. The compound according to any one of claims 1 to 4 and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown below: Among them, R1, R2, R3, R4, Y, L1, Ring A, Ring B, E, R a , R b , R e , R e1 , R e2 , m, n, p, q have the definitions as described in any one of claims 1-4; Preferably, the compound has the structure shown below: Among them, R1, R2, R3, R4, Y, Ring A, E, R a , R b , R e , m, n, p, q have the definitions as described in any one of claims 1-4; Preferably, the compound has the structure shown below: Among them, E, R e , R3, R4, R b , p, q have the definitions as described in any one of claims 1-4.

6. The compound according to any one of claims 1 to 5 and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown below:

7. A method for preparing the compound according to any one of claims 1 to 6, comprising the following steps: Among them, R2, R3, R4, Y, L1, Ring A, Ring B, E, R a , R b , R e , m, n, p, q have the definitions described herein; R1 is H; Z is selected from leaving groups, such as halogen; X is selected from nucleophilic groups, such as B(OH)2; when NH is present on ring B, NH is protected by a protecting group (such as SEM); when E-(R e ) p When it is NH2, NH2 is protected by a protecting group (such as Boc), and the compound is obtained by deprotection.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof.

9. Use of the compound according to any one of claims 1 to 6 and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 8 in the preparation of a PI3Kα inhibitor; and / or, use in the preparation of a medicament for preventing and / or treating cancer, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer and / or benign overgrowth syndrome; And / or, use in the preparation of a medicament for preventing and / or treating PIK3CA-associated overgrowth (PROS).

10. A method for preventing and / or treating a disease or condition mediated by PI3Kα, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound according to any one of claims 1 to 6 and its racemate, stereoisomer, tautomer, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8; Preferably, the PI3Kα-mediated disease or symptom is selected from cancer, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, skin cancer and / or benign overgrowth syndrome; Preferably, the PI3Kα-mediated disease or symptom is PIK3CA-associated overgrowth (PROS).

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