PI3Kα allosteric inhibitors

Abstract

The present invention relates to PI3Kα allosteric inhibitors. Specifically, it relates to compounds of formula (I) that can be used as selective allosteric inhibitors of mutant PI3Kα, pharmaceutical compositions containing the compounds, and uses of the compounds and pharmaceutical compositions for treating PI3Kα-mediated diseases, especially cancer, wherein the variables R1, R2, R3, L1, and n are as defined in the specification.

Description

[0001] The present invention claims priority to Chinese patent application No. 202210816095.9, filed on July 12, 2022, and Chinese patent application No. 202211692152.3, filed on December 29, 2022. Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to compounds that can be used as selective allosteric inhibitors of mutant PI3Kα, pharmaceutical compositions containing such compounds, and the use of the compounds and pharmaceutical compositions for preventing and / or treating diseases mediated by PI3Kα, particularly cancer. Background Art

[0003] Phosphatidylinositol 3-kinase (PI3K) is an intracellular enzyme that phosphorylates the 3-OH group of the inositol ring in phosphatidylinositol membrane lipids, primarily regulating cell growth, proliferation, differentiation, and migration (J. Med. Chem. 2019, 62, 4815-4850). PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to produce phosphatidylinositol-3,4,5-triphosphate (PIP3) (Nature, 1997, 387, 673-676); PIP3, in turn, activates downstream messenger proteins, including AKT (protein kinase B, PKB) and mTOR (mammalian target of rapamycin).

[0004] PI3Ks are classified into types I, II, and III based on their structural characteristics. Type I PI3Ks are the most extensively studied and include types IA and IB. Type IA includes PI3Kα, PI3Kβ, and PI3Kδ; type IB is PI3Kγ. PI3Kα and PI3Kβ are ubiquitous in all tissues, while PI3Kδ and PI3Kγ are primarily found in blood cells, endothelial cells, and the central nervous system. PI3Kα contains the catalytic subunit p110α and the regulatory subunit p85. Mutations in PI3Kα are widely found in various cancers. Mutational analysis of over 3,000 cancers by the Cancer Genome Atlas (TCGA) revealed that PIK3CA, the gene encoding PI3Kα, is the second most commonly mutated oncogene. The three most common PI3Kα mutations are E542K, E545K, and H1047R (Proc. Natl. Acad. Sci. 2012, 109, 15259-15264). The E545K mutation can bind to ISR1, increasing insulin receptor responsiveness independent of the natural inhibitory effect of p85 (Science, 2007, 317, 239-242). The H1047R mutation in the kinase domain enhances its anchoring to the cell membrane, thereby directly activating the PI3K-AKT-mTOR signaling pathway independent of RAS activation (Trends Biochem. Sci. 2015, 40, 88-100). A 2022 ASCO meeting report reported that in an analysis of 121,221 adult cancer patients, the E545K mutation accounted for 20%, the E542K mutation accounted for 11%, and the H1047R mutation accounted for 22%. Therefore, the development of selective inhibitors targeting mutant PI3Kα is particularly necessary.

[0005] The first generation of PI3K inhibitors were pan-PI3K inhibitors, developed as ATP-competitive orthosteric inhibitors. An example is GDC-0941. However, its inhibition of the entire PI3K family (J. Med. Chem. 2008, 51, 5522-5532) resulted in significant toxicity and a narrow therapeutic window, limiting clinical dosing. Subsequently, with the development of selective orthosteric inhibitors of PI3Kδ and PI3Kα, idelalisib, copanlisib, and alpelisib were approved by the FDA for the treatment of cancer patients harboring specific PI3K mutations. Despite this, clinical reports indicate significant toxicity and side effects with these drugs. In the treatment of breast cancer patients harboring PI3Kα mutations, alpelisib has been associated with elevated blood sugar in a significant number of patients, requiring concomitant use of glucose-lowering medications such as metformin (Ann Oncol. 2018, 29(suppl_8):mdy424.010–mdy424.010). At the same time, elevated blood sugar levels can significantly activate the insulin receptor pathway (Nature, 2018, 560, 499-503; Cancer Discov. 2019, 9, 482-491), which in turn activates PI3Kα, leading to reduced drug efficacy. Therefore, developing inhibitors targeting mutant PI3Kα is crucial. These inhibitors can reduce the inhibition of wild-type PI3Kα, thereby weakening the feedback activation pathway, further improving clinical efficacy and reducing side effects such as hyperglycemia.

[0006] Although progress has been made in the research of selective PI3Kα orthosteric inhibitors, such as Novartis' alpelisib approved for the treatment of patients with ER+ and PI3Kα mutated advanced breast cancer, due to its strong inhibition of wild-type PI3Kα, the development of more effective and highly selective inhibitors of mutant PI3Kα can address unmet clinical needs.

[0007] The present invention develops a new generation of PI3Kα allosteric inhibitors, which have good selectivity for mutant PI3Kα (having E545K, E542K and / or H1047R mutations) and are expected to solve the above-mentioned problems. Summary of the Invention

[0008] In one aspect, the present invention provides compounds of formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof,

[0011] in:

[0012] R1 is C 1-6 Alkyl, saturated or partially unsaturated C 3-14 a carbocyclic group, a phenyl group, a naphthyl group, a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 3-14 membered heterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-4 substituents independently selected from R4;

[0013] R2 are each independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N( C 3-8 Cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1 is a bond or C optionally substituted by R5 2-6 alkenylene,

[0014] R3 is phenyl, naphthyl, saturated or partially unsaturated C 3-14 a carbocyclic group, a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 3-14 membered heterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-4 substituents independently selected from R6;

[0015] R4 and R6 are independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -NO2, oxo, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N (R)OR', -OC(O)R, -OC(O)NRR', -N(R)C(O)OR', -N(R)C(O)R', -N(R)C(O)NR'R”, -N(R)S(O)2NR'R”, -N(R)S(O)2R', phenyl, C 3-8Cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R5 is halogen, -CN, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0016] R, R' and R" may be the same or different and are each independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and

[0017] n is any integer from 0 to 4,

[0018] Provided that, when L1 is a bond, R3 is a 10-14 membered tricyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 10-14 membered tricyclic heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0019] In some embodiments, the compound of formula (I) has the structure of formula (II):

[0020]

[0021] wherein the variables R1, R2, R3 and n are as defined above for the compounds of formula (I).

[0022] In other embodiments, the compound of formula (I) has the structure of formula (III):

[0023]

[0024]

[0025] wherein the variables R1, R2, R3 and n are as defined above for the compounds of formula (I).

[0026] Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and a pharmaceutically acceptable carrier.

[0027] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for preventing and / or treating diseases mediated by PI3Kα, in particular cancer.

[0028] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and a pharmaceutically acceptable carrier, for use in preventing and / or treating diseases mediated by PI3Kα, in particular cancer.

[0029] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and a pharmaceutically acceptable carrier for preventing and / or treating diseases mediated by PI3Kα, in particular cancer.

[0030] Another aspect of the present invention relates to a method for preventing and / or treating diseases mediated by PI3Kα, in particular cancer, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION

[0031] definition

[0032] Unless otherwise stated, the following terms used in this specification and claims have the following meanings. It should be understood that, where not clearly defined herein, terms shall be given their meanings commonly known in the art. Further, it should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of the present invention in any way. Unless otherwise stated, when there is a discrepancy between the structural formula and the chemical name of the compound described herein, the structural formula shall prevail.

[0033] Unless otherwise indicated, ranges recited herein include the endpoints of the range and each integer contained therein. For example, "n is any integer from 0 to 4" means that n can be 0, 1, 2, 3, or 4. In addition, any subranges consisting of these integers are intended to be included within the scope of the present invention.

[0034] The group prefix "C x-y " represents the range of carbon atoms contained in the group, where x and y are both integers. For example, C 3-8 Cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms, i.e. a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also understood that “C 3-8 " also includes any sub-ranges therein, such as C 3-7 、C 3-6 、C 4-7 、C 4-6 、C 5-6 wait.

[0035] As used herein, the term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon radical having a specified number of carbon atoms. Alkyl groups typically contain 1 to 6 carbon atoms ("C 1-6 alkyl”), preferably 1 to 5 carbon atoms (“C 1-5 alkyl”), more preferably 1 to 4 carbon atoms (“C 1-4 alkyl”), 1-3 carbon atoms (“C 1-3 alkyl") or 1-2 carbon atoms ("C 1-2 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0036] As used herein, the term "alkenyl" refers to a linear or branched unsaturated monovalent hydrocarbon radical having a specified number of carbon atoms and containing at least one double bond. Alkenyl groups typically contain 2 to 6 carbon atoms ("C 2-6 alkenyl”), preferably 2 to 5 carbon atoms (“C 2-5 alkenyl”), more preferably 2 to 4 carbon atoms (“C 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadien-1-yl, 1-penten-3-yl, 2-penten-1-yl, 3-penten-1-yl, 3-penten-2-yl, 1,3-pentadien-1-yl, 1,4-pentadien-3-yl, 1-hexen-3-yl, and 1,4-hexadien-1-yl.

[0037] As used herein, the term "alkenylene" refers to a divalent group derived from an alkenyl group, wherein the alkenyl group is as defined above. An alkenylene group typically contains 2 to 6 carbon atoms ("C 2-6 Alkenylene”), preferably 2-4 carbon atoms (“C 2-4Examples of alkenylene groups include, but are not limited to, hexenylene, pentenylene, butenylene, propenylene, and ethenylene.

[0038] As used herein, the term "alkoxy" refers to an alkyl group attached to the parent molecular group through an oxygen atom (i.e., "-O-alkyl"), wherein alkyl is as defined above. Alkoxy groups typically contain 1 to 6 carbon atoms ("C 1-6 alkoxy”), more preferably 1 to 4 carbon atoms (“C 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0039] The term "halogen" as used herein refers to fluorine, chlorine, bromine, iodine, preferably fluorine and chlorine atoms.

[0040] The term "halo" as used herein means that one or more hydrogen atoms in a substituent are replaced by one or more halogen atoms, which may be the same or different, as defined above. For example, "haloC 1-6 "Alkyl" refers to a "C" group in which one or more hydrogen atoms are replaced by one or more halogen atoms which may be the same or different. 1-6 Alkyl", where "C 1-6 "Alkyl" is as defined above. Halo C 1-6 Examples of alkyl groups include, but are not limited to, chloromethyl, fluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

[0041] As used herein, the term "oxo" refers to a "=0" group.

[0042] As used herein, the term "carbocycle" or "carbocyclic group" refers to a saturated or partially unsaturated non-aromatic cyclic hydrocarbon group having the specified number of carbon atoms and containing no heteroatoms. The carbocycle typically contains 3 to 14 carbon atoms ("C 3-14 Carbocycle"), preferably 3-12 carbon atoms ("C 3-12 Carbocycle"), 3-10 carbon atoms ("C 3-10 Carbocycle"), 3-8 carbon atoms ("C 3-8 carbocycle") or 3-6 carbon atoms ("C 3-6 The carbocycle may be monocyclic or polycyclic, including fused, bridged, and spirocyclic systems. When the carbocycle is a saturated cyclic hydrocarbon group, the term "cycloalkyl" is used. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl, and cyclohexenyl.

[0043] The term "aryl" as used herein refers to a monocyclic or polycyclic aromatic group having 6-14, more typically 6-10, carbon atoms and no ring heteroatoms. For polycyclic systems, including fused, bridged, and spirocyclic systems of aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "aryl" (e.g., 5,6,7,8-tetrahydronaphthalene-2-yl) is used when the point of attachment is at an aromatic carbon atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, and indenyl.

[0044] As used herein, the term "heteroatom" refers to a nitrogen, oxygen, or sulfur atom.

[0045] As used herein, the term "heteroaryl" refers to a monovalent group having an aromatic structure containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur and a total of 5 to 14 ring atoms. Heteroaryl includes a 5-6 membered monocyclic ring system containing 1 to 4, preferably 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur ("5-6 membered monocyclic heteroaryl") and an 8-14 membered polycyclic ring system containing 1 to 4, preferably 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, such as an 8-10 membered bicyclic ring ("8-10 membered bicyclic heteroaryl") and a 10-14 membered tricyclic ring ("10-14 membered tricyclic heteroaryl"), wherein at least one ring of the polycyclic ring system is aromatic. For polycyclic ring systems, including fused, bridged, and spiro ring systems having both aromatic and non-aromatic rings, the term "heteroaryl" applies if at least one ring heteroatom is present and the point of attachment is at an atom (carbon or heteroatom) of the aromatic ring (e.g., 5,6,7,8-tetrahydroquinolin-3-yl). Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisoxazolyl, Thiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, benzopyranyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, cinnolinyl, naphthyridinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl and phenothiazinyl.

[0046] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated non-aromatic group containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur and a total of 3-14 ring atoms. Heterocyclyl includes 3-10 membered monocyclic ring systems containing 1-3, preferably 1-2, heteroatoms selected from nitrogen, oxygen and sulfur ("3-10 membered monocyclic heterocyclyl") and 8-14 membered polycyclic ring systems (including fused rings, bridged rings and spiro ring systems) containing 1-4, preferably 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, such as 8-10 membered bicyclic rings ("8-10 membered bicyclic heterocyclyl") and 10-14 membered tricyclic rings ("10-14 membered tricyclic heterocyclyl"). For polycyclic ring systems having aromatic and / or non-aromatic rings, the term "heterocyclyl" applies when there is at least one ring heteroatom and the point of attachment is at an atom (carbon or heteroatom) of the non-aromatic ring (e.g., 5,6,7,8-tetrahydroquinolin-6-yl). Examples of heterocyclic groups include, but are not limited to, aziridinyl, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, isodihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxanyl, oxathianyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl, and isoindolinyl.

[0047] The term "optionally" as used herein means that the situation described immediately after the term may occur, but may not occur. For example, "C optionally substituted with R5 2-6 "Alkenylene" encompasses "C 2-6 Alkenylene" and "C substituted by R5 2-6 There are two cases of "alkenylene".

[0048] As used herein, the term "pharmaceutically acceptable" refers to those substances or materials that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects, such as humans or other mammals, without excessive toxicity, irritation, allergic response, or other problems, and with a commensurate benefit / risk ratio.

[0049] As used herein, the term "prevent" or "prevent" means to reduce or eliminate the likelihood of a disease.

[0050] As used herein, the term "treating" refers to the complete or partial elimination of a disease and / or its attendant symptoms.

[0051] The term "subject" as used herein refers to an animal intended for experimental or therapeutic use, preferably a mammal, such as primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc., most preferably humans.

[0052] Detailed description of the technical solution of the present invention

[0053] The following specific embodiments are provided to enable those skilled in the art to more clearly understand the content of the present invention. It should be understood that these embodiments are only for the purpose of illustration and are not intended to limit the scope of protection of the present invention.

[0054] In a first aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof:

[0055]

[0056] in:

[0057] R1 is C 1-6 Alkyl, saturated or partially unsaturated C 3-14 a carbocyclic group, a phenyl group, a naphthyl group, a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 3-14 membered heterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-4 substituents independently selected from R4;

[0058] R2 are each independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N( C 3-8 Cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1 is a bond or C optionally substituted by R5 2-6 alkenylene,

[0059] R3 is phenyl, naphthyl, saturated or partially unsaturated C 3-14a carbocyclic group, a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 3-14 membered heterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-4 substituents independently selected from R6;

[0060] R4 and R6 are independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -NO2, oxo, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N (R)OR', -OC(O)R, -OC(O)NRR', -N(R)C(O)OR', -N(R)C(O)R', -N(R)C(O)NR'R”, -N(R)S(O)2NR'R”, -N(R)S(O)2R', phenyl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R5 is halogen, -CN, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0061] R, R' and R" may be the same or different and are each independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and

[0062] n is any integer from 0 to 4,

[0063] Provided that, when L1 is a bond, R3 is a 10-14 membered tricyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 10-14 membered tricyclic heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0064] In some embodiments, R1 is C optionally substituted with 1-4 substituents independently selected from R4 1-6 In some embodiments, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, preferably methyl or ethyl, optionally substituted with 1-3, preferably 1 or 2, substituents independently selected from R4.

[0065] In some embodiments, R1 is a saturated or partially unsaturated C optionally substituted with 1-4 substituents independently selected from R4. 3-14 In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl or cyclohexenyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, optionally substituted with 1-3, preferably 1 or 2, substituents independently selected from R4.

[0066] In some embodiments, R1 is phenyl or naphthyl, preferably phenyl, optionally substituted with 1-4 substituents independently selected from R4.

[0067] In some embodiments, R1 is a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted by 1-4 substituents independently selected from R4. In some embodiments, R1 is a 5-6 membered monocyclic heteroaryl group or an 8-14 membered polycyclic heteroaryl group optionally substituted by 1-3, preferably 1 or 2, substituents independently selected from R4. In some embodiments, R1 is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzo Thiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, thienopyrimidinyl, quinolyl, isoquinolyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, chromenyl, chromanyl, cinnolinyl, naphthyridinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, and phenothiazinyl.

[0068] In some embodiments, R is a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted by 1-4 substituents independently selected from R. In some embodiments, R is an aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolid ... dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, isodihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxanyl, oxathianyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl or isoindolinyl.

[0069] In some embodiments, each R2 is independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N( C 3-8 Cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R, R' and R" may be the same or different and are each independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0070] In some embodiments, each R2 is independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -OR, -NRR', -S(O)2R, -S(O)2NRR', -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R, -OC(O)NRR', phenyl, C3-8 Cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0071] In some embodiments, each R2 is independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -OR, -NH2, phenyl, C 3-8 Cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R is selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0072] In some embodiments, each R2 is independently selected from methyl, ethyl, isopropyl, -CF3, -CHF2, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, -OCHF2, -NH2, phenyl, cyclopropyl, cyclobutyl, pyrazolyl, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl.

[0073] In some embodiments, R2 is each independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, -OCHF2 and -NH2, preferably methyl, -CF3, F and Cl.

[0074] In some embodiments, L1 is a bond or C optionally substituted with R5 2-6 Alkenylene.

[0075] In some embodiments, L1 is a bond.

[0076] In some embodiments, L1 is C optionally substituted with R5 2-6 Alkenylene, wherein R5 is halogen, -CN, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0077] In some embodiments, L1 is C optionally substituted with halogen. 2-6 In some embodiments, L1 is C optionally substituted with F or Cl. 2-4In some embodiments, L1 is an optionally substituted vinylene group.

[0078] In some embodiments, L1 is C optionally substituted with -CN 2-6 In some embodiments, L1 is C optionally substituted with -CN. 2-4 In some embodiments, L1 is ethenylene optionally substituted with -CN.

[0079] In some embodiments, L1 is optionally replaced by C 1-6 Alkyl substituted C 2-6 In some embodiments, L1 is optionally replaced by C 1-4 Alkyl substituted C 2-4 In some embodiments, L1 is ethenylene optionally substituted with methyl or ethyl.

[0080] In some embodiments, L1 is optionally halogenated C 1-6 Alkyl substituted C 2-6 In some embodiments, L1 is C optionally substituted with -CF3 or -CHF2. 2-4 In some embodiments, L1 is ethenylene optionally substituted with -CF3.

[0081] In some embodiments, R3 is phenyl, naphthyl, a saturated or partially unsaturated C 3-14 a carbocyclic group, a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 3-14 membered heterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-4 substituents independently selected from R6.

[0082] In some embodiments, R3 is phenyl or naphthyl, preferably phenyl, optionally substituted with 1-4 substituents independently selected from R6.

[0083] In some embodiments, R3 is a saturated or partially unsaturated C optionally substituted with 1-4 substituents independently selected from R6. 3-14 In some embodiments, R3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl or cyclohexenyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, optionally substituted with 1-3, preferably 1 or 2, substituents independently selected from R6.

[0084] In some embodiments, R is a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted by 1-4 substituents independently selected from R. In some embodiments, R is a 5-6 membered monocyclic heteroaryl group, an 8-10 membered bicyclic heteroaryl group, or a 10-14 membered tricyclic heteroaryl group, optionally substituted by 1-3, preferably 1 or 2, substituents independently selected from R. In some embodiments, R3 is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzo thiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, thienopyrimidinyl, quinolyl, isoquinolyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, benzopyranyl, chromanyl, cinnolinyl, naphthyridinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl,

[0085] In some embodiments, R3 is a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted by 1-4 substituents independently selected from R6. In some embodiments, R3 is an aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, isodihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxanyl, oxathianyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl or isoindolinyl.

[0086] In some embodiments, R4 and R6 are independently selected from C 1-6 Alkyl, halogenated C 1-6Alkyl, halogen, -CN, -NO2, oxo, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -S(O)R, -S(O)NRR', -C(O)R, -C(O)OR, -C(O)NRR', -C(O)N (R)OR', -OC(O)R, -OC(O)NRR', -N(R)C(O)OR', -N(R)C(O)R', -N(R)C(O)NR'R”, -N(R)S(O)2NR'R”, -N(R)S(O)2R', phenyl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R, R' and R" may be the same or different and are each independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0087] In some embodiments, R4 and R6 are independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S(O)2R, -S(O)2NRR', -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R, -OC(O)NRR', phenyl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0088] In some embodiments, R4 and R6 are independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S(O)2R, -C(O)R, -C(O)OR, -C(O)NRR', phenyl, C 3-8 Cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0089] In some embodiments, R4 and R6 are independently selected from methyl, ethyl, isopropyl, -CF3, -CHF2, F, Cl, Br, -CN, oxo, -OH, -OCH3, -OC2H5, -OCF3, -OCHF2, -NH2, -S(O)2CH3, -C(O)CH3, -C(O)CF3, -C(O)OH, -C(O)OCH3, -C(O)NH2, phenyl, cyclopropyl, cyclobutyl, pyrazolyl, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl.

[0090] In some embodiments, R4 and R6 are independently selected from methyl, isopropyl, -CF3, -CHF2, F, Cl, Br, -CN, oxo, -OH, -OCH3, -OCF3, -OCHF2, -NH2 and C 3-8 Cycloalkyl, preferably methyl, isopropyl, -CF3, F, Cl, -CN, -OH and cyclopropyl.

[0091] In some embodiments, n is 0, 1, 2, or 3.

[0092] In some embodiments, n is 1, 2 or 3, and each R2 is independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -OR, -NH2, phenyl, C 3-8 Cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R is selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0093] In some embodiments, n is 1 or 2, and each R2 is independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, -OCHF2, -NH2, phenyl, pyrazolyl, and cyclopropyl.

[0094] In some embodiments, n is 2, R2 is each F and Cl. In some embodiments, n is 2, R2 is each F and methyl. In some embodiments, n is 2, R2 is each Cl and methyl. In some embodiments, n is 2, R2 is each F. In some embodiments, n is 2, R2 is each Cl.

[0095] In some embodiments, R1 is a saturated or partially unsaturated C 3-14Carbocyclic group, wherein the carbocyclic group is optionally substituted by 1-3 independently selected C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S(O)2R, -C(O)R, -C(O)OR, -C(O)NRR', phenyl, C 3-8 substituted by cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0096] In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl, or cyclohexenyl, wherein each of said groups is optionally substituted with 1, 2, or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, oxo, -OH, -OCH3, -OCF3, -OCHF2, -NH2, -S(O)2CH3, -C(O)CH3, -C(O)CF3, -C(O)OH, -C(O)OCH3, and -C(O)NH2. In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each of said groups is optionally substituted with 1, 2, or 3 substituents independently selected from methyl, -CF3, F, Cl, Br, -CN, oxo, -OH, -OCH3, -OCF3, and -NH2.

[0097] In some embodiments, R1 is phenyl, wherein the phenyl is optionally substituted by 1-3 independently selected 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -OR, -NRR', -S(O)2R, -C(O)R, -C(O)OR, -C(O)NRR', phenyl, C 3-8 substituted by cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0098] In some embodiments, R1 is phenyl, wherein the phenyl group is optionally substituted with 1, 2, or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, -OCHF2, -NH2, -S(O)2CH3, -C(O)CH3, -C(O)CF3, -C(O)OH, -C(O)OCH3, and -C(O)NH2. In some embodiments, R1 is phenyl, wherein the phenyl group is optionally substituted with 1 or 2 substituents independently selected from methyl, -CF3, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, or -NH2. In some embodiments, R1 is phenyl substituted with -CF3 and F.

[0099] In some embodiments, R1 is a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is optionally substituted by 1-3 heteroatoms independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S(O)2R, -C(O)R, -C(O)OR, -C(O)NRR', phenyl, C 3-8 substituted by cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0100] In some embodiments, R is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, thienopyrimidinyl, quinolinyl, isoquinolinyl, phenyl, -C(O)CH, -C(O)CF, -C(O)OH, -C(O)OCH, and -C(O)NH. In some embodiments, R is pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, imidazopyridinyl, or thienopyridinyl, each of which is optionally substituted with one or two substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, oxo, -OH, -OCH3, -OCF3, and -NH2. In some embodiments, R is unsubstituted benzothiophenyl.

[0101] In some embodiments, R1 is a 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is optionally substituted by 1-3 heteroatoms independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S(O)2R, -C(O)R, -C(O)OR, -C(O)NRR', phenyl, C 3-8 substituted by cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0102] In some embodiments, R is azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, isodihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxane The invention also includes but is not limited to: alkyl, oxathianyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl and isoindolinyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, oxo, -OH, -OCH3, -OCF3, -OCHF2, -NH2, -S(O)2CH3, -C(O)CH3, -C(O)CF3, -C(O)OH, -C(O)OCH3 and -C(O)NH2. In some embodiments, R is azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxathianyl, azepanyl, morpholinyl, or isoindolinyl, wherein each of the groups is optionally substituted with 1, 2, or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, oxo, -OH, -OCH3, -OCF3, and -NH2. In some embodiments, R is isoindolinyl substituted with -CF3, F, and -OH.

[0103] In some embodiments, L1 is optionally substituted with halogen, -CN, C 1-6 Alkyl or halogenated C 1-6 Alkyl substituted C 2-6 Alkenylene, R3 is phenyl, wherein the phenyl group is optionally substituted by 1-3 independently selected C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S(O)2R, -C(O)R, -C(O)OR, -C(O)NRR', phenyl, C 3-8 substituted by cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0104] In some embodiments, L1 is optionally substituted with F, Cl, -CN, C 1-6 Alkyl or halogenated C 1-6 Alkyl substituted C 2-4Alkenylene, R3 is phenyl, wherein the phenyl group is optionally substituted with 1, 2 or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, -OCHF2, -NH2, -S(O)2CH3, -C(O)CH3, -C(O)CF3, -C(O)OH, -C(O)OCH3 and -C(O)NH2.

[0105] In some embodiments, L1 is vinylene optionally substituted with F, Cl or -CN, and R3 is phenyl, wherein the phenyl is optionally substituted with 1, 2 or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, -OCHF2 and -NH2.

[0106] In some embodiments, L1 is optionally substituted with halogen, -CN, C 1-6 Alkyl or halogenated C 1-6 Alkyl substituted C 2-6 Alkenylene, R3 is a saturated or partially unsaturated C 3-14 Carbocyclic group, wherein the carbocyclic group is optionally substituted by 1-3 independently selected C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S(O)2R, -C(O)R, -C(O)OR, -C(O)NRR', phenyl, C 3-8 substituted by cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0107] In some embodiments, L1 is optionally substituted with halogen, -CN, C 1-6 Alkyl or halogenated C 1-6 Alkyl substituted C 2-4alkenylene, R3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl or cyclohexenyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, -OCHF2, -NH2, -S(O)2CH3, -C(O)CH3, -C(O)CF3, -C(O)OH, -C(O)OCH3 and -C(O)NH2. In some embodiments, L1 is vinylene optionally substituted with F, Cl or -CN, and R3 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each of the groups is optionally substituted with 1 or 2 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, -OCHF2 and -NH2.

[0108] In some embodiments, L1 is optionally substituted with halogen, -CN, C 1-6 Alkyl or halogenated C 1-6 Alkyl substituted C 2-6 Alkenylene, R3 is a 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl is optionally substituted by 1-3 heteroatoms independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S(O)2R, -C(O)R, -C(O)OR, -C(O)NRR', phenyl, C 3-8 substituted by cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0109] In some embodiments, L1 is optionally substituted with F, Cl, -CN, C 1-6 Alkyl or halogenated C 1-6 Alkyl substituted C 2-4alkenylene, R3 is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridyl, thienopyridyl, thiazolyl phenopyrimidinyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, chromenyl, cinnolinyl, naphthyridinyl or pteridinyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, -OCHF2, -NH2, -S(O)2CH3, -C(O)CH3, -C(O)CF3, -C(O)OH, -C(O)OCH3, -C(O)NH2, cyclopropyl and cyclobutyl. In some embodiments, L1 is vinylene optionally substituted with F, Cl, or -CN, and R3 is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, indolyl, isoindolyl, benzothiophenyl, indazolyl, benzimidazolyl, imidazopyridinyl, imidazopyrimidinyl, thienopyridinyl, quinolyl, or isoquinolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, -OH, -OCH3, -OCF3, -OCHF2, -NH2, and cyclopropyl. In some embodiments, L1 is vinylene optionally substituted with F, and R3 is pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, pyrimidinyl, or pyridinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from methyl, F, Cl, Br, -CN, -OH, or cyclopropyl.

[0110] In some embodiments, L1 is a bond, R3 is a 10-14 membered tricyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is optionally substituted by 1-3 heteroatoms independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S(O)2R, -C(O)R, -C(O)OR, -C(O)NRR', phenyl, C 3-8substituted by cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0111] In some embodiments, L1 is a bond, and R3 is carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, wherein each of the groups is optionally substituted by 1, 2 or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, oxo, -OH, -OCH3, -OCF3, -OCHF2, -NH2, -S(O)2CH3, -C(O)CH3, -C(O)CF3, -C(O)OH, -C(O)OCH3 and -C(O)NH2.

[0112] In some embodiments, L1 is a bond, R3 is wherein each of the groups is optionally substituted with 1, 2 or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, oxo, -OH, -OCH3, -OCF3, -OCHF2 and -NH2. In some embodiments, L1 is a bond, R3 is

[0113] In some embodiments, L1 is a bond, R3 is a 10-14 membered tricyclic heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocyclyl is optionally substituted by 1-3 heteroatoms independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S(O)2R, -C(O)R, -C(O)OR, -C(O)NRR', phenyl, C 3-8 substituted by cycloalkyl, 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-8 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein R and R' are each independently selected from H, C 1-6 Alkyl and halogenated C 1-6Preferably, the heterocyclic group is optionally substituted by 1, 2 or 3 substituents independently selected from methyl, -CF3, -CHF2, F, Cl, Br, -CN, oxo, -OH, -OCH3, -OCF3, -OCHF2, -NH2, -S(O)2CH3, -C(O)CH3, -C(O)CF3, -C(O)OH, -C(O)OCH3 and -C(O)NH2.

[0114] In some of the embodiments, a compound of formula (I) is provided, wherein:

[0115] R1 is C 3-12 cycloalkyl, phenyl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3-10 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-3 members independently selected from C 1-6 Alkyl, halogenated C 1-6 substituted with alkyl, halogen, -CN, -NO2, oxo, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R, -OC(O)NRR', -N(R)C(O)OR' and -N(R)C(O)R',

[0116] R2 are each independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -NO2, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R, -OC(O)NRR', -N(R)C(O)OR' and -N(R)C(O)R';

[0117] L1 is a bond or C optionally substituted by halogen or -CN 2-6 alkenylene,

[0118] R3 is phenyl, 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-3 members independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, -CN, -NO2, oxo, -OR, -SR, -NRR', -S(O)2R, -S(O)2NRR', -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R, -OC(O)NRR', -N(R)C(O)OR', -N(R)C(O)R' and C 3-8Substitution of cycloalkyl groups;

[0119] R and R' may be the same or different and are independently selected from H, C 1-6 Alkyl and halogenated C 1-6 alkyl, and n is any integer from 0 to 3,

[0120] Provided that, when L1 is a bond, R3 is a 10-14 membered tricyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 10-14 membered tricyclic heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0121] In some embodiments, a compound of formula (I) is provided, wherein:

[0122] R1 is phenyl, 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-3 heteroatoms independently selected from halogen, -OH, C 1-6 Alkyl and halogenated C 1-6 Alkyl substituents are substituted,

[0123] R2 are each independently selected from halogen or halogenated C 1-6 alkyl;

[0124] L1 is a bond or C substituted by halogen or -CN 2-4 alkenylene,

[0125] R3 is a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 5-14 membered heterocyclyl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-3 heteroatoms independently selected from C 1-6 Alkyl, halogen, -CN, oxo and C 3-8 Substitution of the cycloalkyl group by a substituent; and

[0126] n is any integer from 0 to 2,

[0127] Provided that, when L1 is a bond, R3 is a 10-14 membered tricyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 10-14 membered tricyclic heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0128] In some embodiments, the compound of formula (I) has formula (II):

[0129]

[0130] wherein the variables R1, R2, R3 and n are as defined above.

[0131] In some embodiments, in the compound of formula (II):

[0132] R1 is phenyl, 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-3 heteroatoms independently selected from halogen, -OH, C 1-6 Alkyl and halogenated C 1-6 Alkyl substituents are substituted,

[0133] R2 are each independently selected from halogen;

[0134] R3 is a 5-10 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-2 heteroatoms independently selected from C 1-6 Alkyl, halogen, -CN and C 3-8 The cycloalkyl group is substituted with a substituent, and

[0135] n is 1 or 2.

[0136] In some embodiments, in the compound of formula (II):

[0137] R1 is phenyl, benzothienyl or indolinyl, and is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, methyl, -CF3 and -OH,

[0138] R2 are each independently selected from F and Cl;

[0139] R3 is pyrazolyl, imidazolyl, oxazolyl, triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl or indazolyl, and is optionally substituted with 1 or 2 substituents independently selected from methyl, isopropyl, F, Cl, -CN and cyclopropyl, and n is 2.

[0140] In some embodiments, the compound of formula (I) has formula (III):

[0141]

[0142] wherein the variables R1, R2, R3 and n are as defined above.

[0143] In some embodiments, in the compound of formula (III):

[0144] R1 is phenyl, 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by 1-3 heteroatoms independently selected from halogen, -OH, C 1-6 Alkyl and halogenated C 1-6 Alkyl substituents are substituted,

[0145] R2 are each independently selected from halogen;

[0146] R3 is a 10-14 membered tricyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 10-14 membered tricyclic heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and is optionally substituted by 1-3 members independently selected from C 1-6 substituted with alkyl, -CN, oxo, and halogen substituents; and

[0147] n is 1 or 2.

[0148] In some embodiments, in the compound of formula (III):

[0149] R1 is phenyl or indolinyl, and is optionally substituted by 1-3 substituents independently selected from F, Cl, -OH, methyl and -CF3,

[0150] R2 are each independently selected from F and Cl;

[0151] R3 is

[0152] and is optionally substituted with 1-3 substituents independently selected from methyl, -CN, oxo, F and Cl; and n is 2.

[0153] In some embodiments, in the compound of formula (III):

[0154] R1 is phenyl or indolinyl, and is optionally substituted by 1-3 substituents independently selected from F, Cl, -OH, methyl and -CF3,

[0155] R2 are each independently selected from F and Cl;

[0156] R3 is and n is 2.

[0157] In some embodiments of this aspect, the following compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, or solvates thereof, are provided:

[0158]

[0159]

[0160]

[0161] The pharmaceutically acceptable salts of the compounds of the present invention refer to salts formed by compounds of formula (I) and pharmaceutically acceptable acids or bases. Such salts include salts formed by acidic functional groups (e.g., -COOH, -OH, SO3H, etc.) present in the compounds of formula (I) and appropriate inorganic or organic cations (bases), such as alkali metal salts (e.g., lithium, sodium, potassium, rubidium, cesium salts), alkaline earth metal salts (e.g., magnesium, calcium, strontium, barium salts), aluminum salts, ammonium salts, and nitrogen-containing organic bases (e.g., ethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, diethylaminoethanol, ethylenediamine, imidazole, morpholine, 2-hydroxyethylmorpholine, dibenzylethylenediamine, trimethylamine, piperidine, The pharmaceutically acceptable salts include salts formed by basic functional groups (e.g., -NH2, etc.) present in the compound of formula (I) and appropriate inorganic or organic anions (acids), including salts formed by inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, etc.) or organic acids (fumaric acid, maleic acid, glycolic acid, lactic acid, oxalic acid, salicylic acid, succinic acid, tartaric acid, malic acid, acetic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, benzylsulfonic acid, toluenesulfonic acid, benzoic acid, malonic acid, ascorbic acid, etc.). Pharmaceutically acceptable salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting the compound of formula (I) with an organic or inorganic acid or base in a solvent or dispersant or by anion exchange or cation exchange with other salts.

[0162] "Stereoisomers" of the compounds of the present invention refer to isomers resulting from differences in the spatial arrangement of atoms in the molecule. When asymmetric carbon atoms are present in the compounds of formula (I), enantiomers are produced; when carbon-carbon double bonds or cyclic structures are present in the compounds of formula (I), cis-trans isomers are produced. All enantiomers, diastereomers, racemates, cis-trans isomers, and mixtures thereof of the compounds of formula (I) are encompassed within the scope of the present invention.

[0163] The compounds of the present invention may also exist as tautomers. The term "tautomer" refers to alternative forms of compounds with different proton positions, such as enol-ketone, imine-enamine, and amide-imidic acid tautomers. All of these tautomers are included within the scope of the present invention.

[0164] A "solvate" of a compound of the present invention refers to a substance formed by the association of a compound of formula (I) with a solvent. The solvent may be an organic solvent (e.g., methanol, ethanol, propanol, dimethyl sulfoxide, etc.), water, or the like. For example, a compound of formula (I) may form an ethanolate with ethanol and a hydrate with water. All such solvates are encompassed within the scope of the present invention.

[0165] In a second aspect of the present invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, and a pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a carrier (or excipient) that does not cause significant stimulation to an organism and does not eliminate the biological activity of the active ingredient. A pharmaceutically acceptable carrier can be solid or liquid and can be one or more selected from the following: fillers, antioxidants, buffers, antibacterial agents, dispersants, adsorbents, surfactants, adhesives, preservatives, disintegrants, sweeteners, flavorings, glidants, release control agents, wetting agents, stabilizers and suspending agents. Those skilled in the art can select a suitable pharmaceutically acceptable carrier based on factors such as the intended route of administration and the properties of the active ingredient.

[0166] The pharmaceutical composition can be formulated into various pharmaceutically acceptable dosage forms using conventional techniques in the art, such as dosage forms suitable for oral administration, such as tablets, capsules, pills, syrups, elixirs, suspensions, solutions, emulsions, and granules; dosage forms suitable for parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution; dosage forms suitable for transdermal administration, such as transdermal patches; dosage forms suitable for rectal administration, such as suppositories; dosage forms suitable for inhalation, such as aerosols, solutions, and dry powders; and dosage forms suitable for topical administration, such as creams, ointments, lotions, pastes, sprays, foams, and gels. These dosage forms can be prepared using conventional methods in the field of pharmaceutical preparations.

[0167] In the third aspect of the present invention, provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and a pharmaceutically acceptable carrier in the preparation of a medicament for preventing and / or treating diseases mediated by PI3Kα, in particular cancer.

[0168] In a fourth aspect of the present invention, provided is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and a pharmaceutically acceptable carrier, for use in preventing and / or treating diseases mediated by PI3Kα, in particular cancer.

[0169] In a fifth aspect of the present invention, provided is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and a pharmaceutically acceptable carrier for use in preventing and / or treating diseases mediated by PI3Kα, in particular cancer.

[0170] In the sixth aspect of the present invention, a method for preventing and / or treating diseases mediated by PI3Kα, in particular cancer, is provided, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and a pharmaceutically acceptable carrier.

[0171] The compounds of the present invention are inhibitors of PI3Kα and are therefore useful in treating PI3Kα-mediated diseases. The term "PI3Kα-mediated disease" refers to a disease associated with the activity of PI3Kα or in which PI3Kα plays a role. Such diseases include, but are not limited to, cancer. The cancers include, for example, breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric cancer, liver cancer, small cell lung cancer, non-small cell lung cancer, melanoma, ovarian cancer, cervical cancer, pancreatic cancer, prostate cancer, acute myeloid leukemia, chronic myeloid leukemia, thyroid cancer, bronchial cancer, intrahepatic bile duct cancer, adrenal cancer, glioma, glioblastoma, kidney cancer, bladder cancer, uterine cancer, vaginal cancer, multiple myeloma, esophageal cancer, lymphocytic leukemia, brain cancer, oral cancer, laryngeal cancer, non-Hodgkin's lymphoma, head and neck cancer, bone cancer, skin cancer, testicular cancer, and the like.

[0172] In some embodiments, the PI3Kα is a mutant PI3Kα. In some embodiments, the PI3Kα has at least one mutation selected from the group consisting of: E542K, E545K, and H1047R. In some embodiments, the PI3Kα has an E542K mutation. In some embodiments, the PI3Kα has an E545K mutation. In some embodiments, the PI3Kα has an H1047R mutation.

[0173] The compounds and pharmaceutical compositions of the present invention can be administered to a subject in need thereof in an appropriate manner, for example, orally, parenterally (intravenously, subcutaneously, intramuscularly, intraperitoneally or intrathecally), pulmonary, nasal, sublingual, rectal, vaginal, skin or mucosal administration.

[0174] The therapeutically effective amount of the compound of the present invention will depend on a variety of factors, including, for example, the general health of the subject, the disease to be treated and its severity, the specific compound and route of administration, etc., and can be selected and adjusted by the attending physician according to conventional practice. In general, the effective amount of the compound of the present invention administered in a single dose or multiple doses is generally in the range of about 0.001 to about 500 mg / kg body weight / day, preferably about 0.1 to about 50 mg / kg body weight / day, more preferably about 1 to about 25 mg / kg body weight / day. In some cases, dosage levels below the lower limit of the above range may be more than sufficient, while in other cases, larger doses can be used under acceptable side effects, so the above dosage ranges are not intended to limit the scope of the present invention in any way.

[0175] Example

[0176] The compounds of the present invention can be prepared by a variety of methods, some of which are described in the following examples. It should be understood that these specific methods do not constitute any limitation of the present invention. The reagents and starting materials used in the following examples are obtained from commercial suppliers or are easily prepared by those of ordinary skill in the art.

[0177] Notes on commonly used abbreviations:

[0178] PE = petroleum ether; EA = ethyl acetate; MeOH = methanol; DCM = dichloromethane; DCE = dichloroethane; CH3CN = acetonitrile; 1,4-dioxane = 1,4-dioxane; DMSO = dimethyl sulfoxide; HFIP = hexafluoroisopropanol; DMF = N,N-dimethylformamide; Hex = n-hexane; IPA = isopropanol; NMP = N-methylpyrrolidone; TEA = triethylamine; DIEA = diisopropylethylamine; CuI = cuprous iodide; CuCN = cuprous cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid.

[0179] Example 1 Preparation of key intermediates

[0180] Synthesis of intermediate a1 (6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitroisoindolin-1-one):

[0181]

[0182] Step 1: Under nitrogen, dissolve raw material a1-1 (18.5 g, 100.0 mmol) in 120 mL of concentrated sulfuric acid. Slowly add dibromohydantoin a1-2 (14.3 g, 50.0 mmol). Heat to 80°C and react for 2 hours. Cool to room temperature. Pour the reaction solution into 300 mL of ice water, wash out the pale yellow solid, filter, wash the filter cake, and dry to obtain intermediate a1-3 (24 g) in a 91% yield.

[0183] Step 2: Dissolve 2-chloro-5-fluoro-benzaldehyde a1-4 (2.4 g, 15.1 mmol) and (4-methoxyphenyl)methanamine (2.1 g, 15.1 mmol) in 40 mL of methanol. Stir for 5 minutes, then add intermediate a1-3 (4.0 g, 15.1 mmol) and tert-butyl isocyanate (1.2 g, 15.1 mmol). React at room temperature for 2 hours. LC-MS monitoring indicates completion of the reaction, and the reaction is stopped. Add 100 mL of water to the system, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and separate by column chromatography (PE / EA, 3 / 1) to obtain intermediate a1-5 (7.0 g) as a pale yellow solid in a yield of 74%. LC-MS: [M+H] + =624.8.

[0184] Step 3: Dissolve the intermediate a1-5 (1.0 g, 1.6 mmol) in 10 mL of acetonitrile, add 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.4 g, 2.3 mmol), and heat to 50°C for 2 hours. Cool to room temperature, add 50 mL of ice water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain crude a1-6, which is directly used in the next step. LC-MS: [M+H] + =521.0.

[0185] Step 4: Dissolve the crude product a1-6 from the previous step in 5 mL of trifluoroacetic acid, add triethylsilane (0.9 g, 7.5 mmol), and heat to 90°C for 5 hours to terminate the reaction. Saturated aqueous sodium bicarbonate solution is slowly added to the system to quench the reaction. Extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography (PE / EA, 5 / 1) to obtain a1 (140 mg) as a yellow solid. Yield: 17% for both steps. LC-MS: [M+H] + =505.7.

[0186] Synthesis of intermediate a2 (4-amino-6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)isoindolin-1-one):

[0187]

[0188] Procedure: Dissolve intermediate a1 (93 mg, 0.18 mmol), reduced iron powder (72 mg, 1.3 mmol), and ammonium chloride (69 mg, 1.3 mmol) in 5 mL of ethanol, add 1 mL of water, heat to 80°C, react for 2 hours, cool to room temperature, and filter. Add 20 mL of ice water to the system, extract with ethyl acetate, wash the organic phase with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 3 / 1) to obtain intermediate a2 (30 mg) in a 35% yield. LC-MS: [M+H] + =475.

[0189] Synthesis of intermediates a3 and a4

[0190]

[0191] a3: N-(6-bromo-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0192] Procedure: Dissolve the raw intermediate a2 (50 mg, 0.001 mmol) and pyridine (33 mg, 0.004 mmol) in 5 mL of acetonitrile and stir for 10 minutes. Then, add 3-fluoro-5-trifluoromethyl-benzoyl chloride a3-1 (38 mg, 0.002 mmol) and allow to react at room temperature for 16 hours. After completion of the reaction, LC-MS monitoring was performed. Add 20 mL of water and extract with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by flash column chromatography (PE / EA, 3 / 1) to afford a3 (30 mg) as a yellow solid in a 45% yield. LC-MS: [M+H] + =665.

[0193] According to the above synthetic route, the corresponding raw materials / similar skeletons were used to synthesize the following intermediates:

[0194]

[0195]

[0196] Synthesis of intermediates a5, a6, and a9

[0197]

[0198] a5: (E)-N-(6-(2-bromo-2-fluorovinyl)-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0199] Step 1: Under nitrogen, intermediate a3 (220 mg, 0.33 mmol) and vinylboronic acid ester a5-1 (53 mg, 0.34 mmol) were dissolved in 6 mL of a mixture of 1,4-dioxane and water (v / v, 5 / 1). Sodium carbonate (52 mg, 0.49 mmol) and Pd(dppf)Cl2 (24 mg, 0.033 mmol) were added, and the mixture was heated to 110°C and reacted for 6 hours. LC-MS analysis confirmed the reaction was complete. 30 mL of ice water was added to the system, and the organic solvent was evaporated under reduced pressure. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE / EA, 1 / 1) to afford a5-2 (112 mg) as a white solid in a 55% yield. LC-MS: [M+H] + =613.

[0200] Step 2: Dissolve the intermediate a5-2 (100 mg, 0.16 mmol) and potassium osmate (1 mg) in 5 mL of acetone. Add 5 mL of water and NaIO4 (422 mg, 1.63 mmol). Stir at room temperature for 6 hours, stop the reaction, and filter. Evaporate the solvent under reduced pressure, and separate by column chromatography (PE / EA, 1 / 1) to obtain a5-3 (30 mg) as a white solid in a 30% yield. LC-MS: [M+H] + =615.

[0201] Step 3: Dissolve 0.1 mL of hydrazine hydrate in 2 mL of ethanol; dissolve the intermediate a5-3 (60 mg, 0.1 mmol) from the previous step in 2 mL of ethanol and add the aforementioned hydrazine hydrate solution. Stir at room temperature for 4 hours. Place the mixture in an ice bath, and add ethylenediamine (0.2 mL), CuCl (20 mg, 0.2 mmol), and tribromofluoromethane (0.3 mL) to the system in sequence. Continue the reaction for 6 hours. Add 30 mL of ice water to the reaction solution to quench the reaction, filter, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography (PE / EA, 1 / 1) to obtain a5 (58 mg) as a pale yellow solid in an 80% yield. LC-MS: [M+H] + =709.8.

[0202] According to the above synthetic route, the corresponding raw materials / similar skeletons were used to synthesize the following intermediates:

[0203]

[0204] Synthesis of intermediates a7, a8, a10, a12-a14:

[0205] a7: (E)-N-(6-(2-bromo-2-fluorovinyl)-3-(2-chloro-5-fluorophenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide: Under nitrogen, intermediate a5 (50 mg, 0.07 mmol) was dissolved in 5 mL of methanesulfonic acid and the mixture was heated to 60°C for 4 hours. LC-MS analysis indicated that the reaction was complete. The reaction was quenched by adding 30 mL of saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM / MeOH, 15 / 1) to afford a7 (28 mg) as a yellow solid in a 66% yield. LC-MS: [M+H] + =589.7.

[0206] According to the above synthetic route, the corresponding raw materials / similar skeletons were used to synthesize the following intermediates:

[0207]

[0208] Synthesis of intermediate a11:

[0209]

[0210] Step 1: Under nitrogen, intermediate a12 (2.6 g, 7.3 mmol), pinacol diboronate (2.2 g, 8.8 mmol), and potassium acetate (2.2 g, 21.9 mmol) were dissolved in 52 mL of 1,4-dioxane. Catalyst Pd(dppf)Cl2 (300 mg, 0.4 mmol) was added and the mixture was reacted at 100°C for 3 hours. The reaction was complete after LC-MS monitoring and filtered. The filtrate was added with 100 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 2 / 1) to afford compound a11-1 (1.3 g) in a 44% yield. LC-MS: [M+H] + =403.

[0211] Step 2: Dissolve the intermediate a11-1 (1.0 g, 2.5 mmol) and pyridine (1.0 g, 12.4 mmol) in 20 mL of dichloromethane. Add 3-fluoro-5-trifluoromethyl-benzoyl chloride a3-1 (0.8 g, 3.7 mmol) and allow to react at room temperature for 1 hour. Stop the reaction. Add 100 mL of water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash column chromatography (PE / EA, 1 / 1) to obtain compound a11 (900 mg) in a yield of 71%. LC-MS: [M+H] + =511[boric acid]+.

[0212] Synthesis of intermediate b1 (3-(trifluoromethyl)indolin-3-ol):

[0213]

[0214] Step 1: Dissolve raw material b1-1 (10.0 g, 42.1 mmol) in 100 mL of tetrahydrofuran, add TMSCF3 (11.99 g, 84.3 mmol) and tetrabutylammonium fluoride (TBAF) (2.2 g, 8.4 mmol), and react at room temperature for 12 hours. LC-MS monitoring of the reaction is complete. Add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain crude product b1-2. LC-MS: [M+H] + =308.1.

[0215] Step 2: Dissolve the crude product b1-2 (2.0 g) from the previous step in 20 mL of tetrahydrofuran, add borane tetrahydrofuran complex (2.8 g, 32.5 mmol), and react at room temperature for 12 hours. LC-MS monitors the reaction for completion. 3 M hydrochloric acid is added to the system to quench the reaction, and the pH is adjusted to approximately 8 with 1 N aqueous sodium hydroxide solution. Extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography to obtain compound b1-3 (1.3 g). LC-MS: [M+H] + =294.

[0216] Step 3: Under a hydrogen atmosphere at 4 atm (4 standard atmospheres), the intermediate b1-3 from the previous step (2.0 g, 6.5 mmol) and Pd(OH)2 (38 mg, 0.27 mmol) were dissolved in 10 mL of methanol and allowed to react at room temperature for 12 hours. The reaction was then stopped. The mixture was filtered, the solvent was evaporated under reduced pressure, and the product was separated by column chromatography (PE / EA, 7 / 3) to afford an off-white solid b1 (331 mg) in a 60% yield. LC-MS: [M+H] + =204.

[0217] Synthesis of intermediate b2-b3:

[0218]

[0219]

[0220] Step 1: Dissolve intermediate a12 (1.5 g, 4.2 mmol) and DIEA (1.6 g, 12.7 mmol) in 15 mL of dichloromethane in an ice bath under nitrogen protection. Add triphosgene (1.5 g, 5.1 mmol) and stir in an ice bath for 2 hours. Add intermediate b1 (2.8 g, 12.7 mmol) to the reaction solution, warm to room temperature, and react for 12 hours before stopping the reaction. Add 50 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography (acetonitrile / water, 4 / 5) to obtain compounds b2-1 (125 mg) and b2-2 (25 mg). LC-MS: [M+H] + =602.

[0221] Step 2: Under nitrogen protection, the intermediate b2-1 (125 mg, 0.2 mmol), pinacol diboronate (63 mg, 0.3 mmol), and potassium acetate (45 mg, 0.5 mmol) were dissolved in 2 mL of 1,4-dioxane. The catalyst Pd(dppf)Cl2 (7.6 mg, 0.012 mmol) was added and reacted at 90°C for 2 hours. The reaction was complete after LC-MS monitoring. The mixture was cooled to room temperature and filtered. 10 mL of water was added to the filtrate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound b2, which was used directly in the next reaction. LC-MS: [M+H] + =650.

[0222] According to the above synthetic route, the corresponding raw materials / similar skeletons were used to synthesize the following intermediates:

[0223]

[0224] Synthesis of intermediates c1-c5:

[0225]

[0226] Step 1: Dissolve raw materials c1-1 (3.0 g, 13.6 mmol) and tetrahydropyrrole c1-2 (1.0 g, 13.6 mmol) in 30 mL of DMSO, add potassium carbonate (2.8 g, 20.5 mmol), heat to 120°C, react for 3 hours, and cool to room temperature. Add 100 mL of water to the reaction solution, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography (acetonitrile / water, 4 / 5) to obtain compound c1-3 (2.0 g) in a yield of 54%. LC-MS: [M+H] + =271.

[0227] Step 2: Dissolve intermediate c1-3 (2.0 g, 7.4 mmol) and iron powder (2.1 g, 36.9 mmol) in 20 mL of a mixture of ethanol and water (v / v, 9 / 1). Add acetic acid (0.7 g, 11.1 mmol) dropwise. After addition, heat to 80°C and react for 4 hours. Cool to room temperature. Add 100 mL of water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (acetonitrile / water, 4 / 5) to obtain compound c1-4 (1.0 g) in a 56% yield. LC-MS: [M+H] + =241.

[0228] Step 3: Dissolve intermediate c1-4 (1.0 g, 4.1 mmol) in 10 mL of ethyl acetate and add H2O2 (30%, 2.8 g, 82.9 mmol) dropwise. Heat to 80°C and react for 72 hours before cooling to room temperature. Add 50 mL of water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (acetonitrile / water, 4 / 5) to afford compound c1 (500 mg) in a 51% yield. LC-MS: [M+H] + =237.

[0229] According to the above synthetic route, the corresponding raw materials / similar skeletons were used to synthesize the following intermediates:

[0230]

[0231] Synthesis of intermediate C6:

[0232]

[0233] Procedure: Under nitrogen, dissolve the raw materials 3-bromophenylhydrazine c6-1 (500 mg, 2.6 mmol) and cyclobutyl methyl ketone c6-2 (262 mg, 2.6 mmol) in 5 mL of acetic acid. Heat to 100°C for 1 hour, cool to room temperature, and evaporate the solvent under reduced pressure. The crude product is separated by flash reverse-phase column chromatography (acetonitrile / water, 3 / 4) to obtain c6 (350 mg) as a white solid in a 52% yield. LC-MS: [M+H] + =250.

[0234] Synthesis of intermediates C7-C9:

[0235]

[0236] Procedure: Under nitrogen, 3-bromophenylhydrazine c6-1 (500 mg, 2.6 mmol) and cyclopentylmethyl ketone c7-1 (262 mg, 2.6 mmol) were dissolved in 5 mL of acetic acid. The mixture was heated to 100°C for 1 hour, cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was separated by flash reverse-phase column chromatography (acetonitrile / water, 3 / 4) to afford c7 (70 mg) as a yellow solid in a 10% yield. LC-MS: [M+H] + =264.

[0237] According to the above synthetic route, the corresponding raw materials / similar skeletons were used to synthesize the following intermediates:

[0238]

[0239] Synthesis of intermediate c10:

[0240]

[0241] Procedure: Under nitrogen, dissolve the raw materials 2-amino-6-bromobenzothiazole c10-1 (2.0 g, 8.7 mmol) and chloroacetaldehyde c10-2 (6.8 g, 87.3 mmol) in 40 mL of ethanol. Heat to 80°C and react for 12 hours. Cool to room temperature and evaporate the solvent under reduced pressure. The crude product is separated by flash reverse-phase column chromatography (acetonitrile / water, 3 / 4) to afford c10 (1.0 g) as a white solid in a 41% yield. LC-MS: [M+H] + =253.

[0242] Synthesis of intermediates c11, c12:

[0243]

[0244] Step 1: Under nitrogen, dissolve the raw material pyrrolidone c11-2 (400 mg, 5.2 mmol) in 10 mL of DMF, add NaH (200 mg, 6.2 mmol), and stir at room temperature for 30 minutes. Add 2,4-dichloro-5-nitropyridine c11-1 (1.0 g, 5.1 mmol) to the reaction solution, react at room temperature for 3 hours, and then stop the reaction. Add 100 mL of water to the reaction solution, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography (acetonitrile / water, 3 / 5) to obtain compound c11-3 (1.2 g) in a yield of 96%. LC-MS: [M+H] + =242.

[0245] Step 2: Dissolve the intermediate c11-3 (1.0 g, 4.1 mmol) from the previous step, ammonium chloride (886 mg, 16.5 mmol), and iron powder (1.1 g, 20.5 mmol) in 10 mL of a mixture of ethanol and water (v / v, 4 / 1). Heat to 80°C and react for 4 hours. Cool to room temperature and filter. Add 100 mL of water to the filtrate, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (acetonitrile / water, 7 / 10) to obtain compound c11-4 (800 mg) in a 91% yield. LC-MS: [M+H] + =212.

[0246] Step 3: Dissolve the intermediate c11-4 (500 mg, 2.3 mmol) from the previous step in 5 mL of ethyl acetate, add compound c11-5 (460 mg, 2.8 mmol), heat to 115°C, react for 4 hours, and cool to room temperature. Add 50 mL of water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (acetonitrile / water, 1 / 1) to obtain compound c11 (350 mg) in a yield of 77%. LC-MS: [M+H] + =194.

[0247] According to the above synthetic route, the corresponding raw materials / similar skeletons were used to synthesize the following intermediates:

[0248]

[0249] Synthesis of intermediate c13:

[0250]

[0251] Step 1: Under nitrogen, dissolve the raw materials, methyl 2-bromo-3-thiophenecarboxylate c13-1 (6.0 g, 27.1 mmol) and CuCN (3.2 g, 35.3 mmol) in 125 mL of NMP. Heat to 120°C and react for 14 hours, then cool to room temperature. Add 300 mL of ice water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (acetonitrile / water, 4 / 5) to obtain c13-2 (1.6 g), a brown solid, in a 35% yield. LC-MS: [M+H] + =168.

[0252] Step 2: Under nitrogen at -60°C, the intermediate c13-2 (1.6 g, 9.6 mmol) and titanium tetraisopropoxide Ti(OiPr)4 (3.0 g, 10.5 mmol) were dissolved in 45 mL of diethyl ether. Grignard reagent ethylmagnesium bromide (2.8 g, 21.1 mmol, 2 M) was added and stirred at -60°C for 1 hour. Boron trifluoride in diethyl ether (2.7 g, 19.1 mmol) was added dropwise to the reaction mixture. After addition, the mixture was warmed to room temperature and allowed to react for 2 hours. The reaction was quenched by adding 30 mL of 1 M dilute hydrochloric acid. Extraction was performed with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse phase column chromatography (acetonitrile / water, 4 / 5) to afford c13-3 (420 mg) as a brown solid in a 27% yield. LC-MS: [M+H] + =166.

[0253] Step 3: Under nitrogen, the intermediate c13-3 (420 mg, 2.5 mmol) from the previous step was dissolved in 12 mL of acetonitrile and N-bromosuccinimide (NBS) (226 mg, 1.3 mmol) was added. The reaction was allowed to react at room temperature for 6 hours, and then stopped. 100 mL of ice water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (acetonitrile / water, 4 / 5) to obtain c13 (120 mg) as a yellow solid in a yield of 19%. LC-MS: [M+H] + =244.

[0254] Synthesis of intermediates c14 and c15:

[0255]

[0256] Procedure: At -60°C, under nitrogen, the raw materials 2-cyano-5-bromobenzoic acid methyl ester c14-1 (500 mg, 2.0 mmol) and tetraisopropoxytitanium Ti(OiPr)4 (829 mg, 2.9 mmol) were dissolved in 12 mL of ether. Grignard reagent ethylmagnesium bromide (2.6 mL, 5.2 mmol, 2 M) was added and stirred at -60°C for 1 hour. Boron trifluoride in ether (0.5 mL, 4.1 mmol) was added dropwise to the reaction solution. After addition, the temperature was raised to room temperature and the reaction was allowed to react for 2 hours. The reaction was quenched by adding 30 mL of 1 M dilute hydrochloric acid. The organic phases were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse phase column chromatography (acetonitrile / water, 7 / 10) to obtain c14 (200 mg) as a green solid in a 40% yield. LC-MS: [M+H] + =238.

[0257] According to the above synthetic route, the corresponding raw materials / similar skeletons were used to synthesize the following intermediates:

[0258]

[0259] Synthesis of intermediate c16:

[0260]

[0261] Step 1: Under nitrogen, dissolve the raw materials 2-amino-3-hydroxy-4-bromo-nitrobenzene c16-1 (3.0 g, 12.8 mmol) and 1,2-dibromoethane (9.6 g, 51.4 mmol) in 30 mL of DMSO. Add cesium carbonate (16.7 g, 51.4 mmol), heat to 85°C, and react for 3 hours. Cool to room temperature. Add 100 mL of ice water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (acetonitrile / water, 3 / 4) to obtain c16-2 (2.1 g) as a red solid in a 63% yield. LC-MS: [M+H] + =259.

[0262] Step 2: Dissolve the intermediate c16-2 (2.0 g, 7.7 mmol) from the previous step, ammonium chloride (1.6 g, 30.8 mmol), and iron powder (1.2 g, 23.1 mmol) in 20 mL of a mixture of ethanol and water (v / v, 3 / 1). Heat to 80°C and react for 2 hours. Cool to room temperature and filter. Add 100 mL of water to the filtrate, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (acetonitrile / water, 7 / 10) to obtain compound c16-3 (1.5 g) in an 85% yield. LC-MS: [M+H] + =229.

[0263] Step 3: Under nitrogen, the intermediate c16-3 (500 mg, 2.1 mmol) from the previous step was dissolved in 5 mL of trimethyl orthoformate. p-TsOH (100 mg, 0.4 mmol) was added and the mixture was heated to 100°C for 2 hours to terminate the reaction. 100 mL of ice water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (acetonitrile / water, 3 / 5) to obtain c16 (1.0 g) as a red solid in a 92% yield. LC-MS: [M+H] + =239.

[0264] Synthesis of intermediate c17:

[0265]

[0266] Step 1: Under nitrogen, dissolve the raw material 2-hydroxy-4-bromo-benzaldehyde c17-1 (500 mg, 2.5 mmol) and ammonia (0.8 mL) in 5 mL of methanol. Add glyoxal (722 mg, 12.4 mmol), heat to 40°C, and react for 36 hours. Cool to room temperature. Add 100 mL of ice water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography (acetonitrile / water, 3 / 4) to obtain c17-2 (400 mg) as a yellow solid in a 67% yield. LC-MS: [M+H] + =239.

[0267] Step 2: Under nitrogen, the intermediate c17-2 (400 mg, 1.6 mmol) and 1,2-dibromoethane (1.26 g, 6.6 mmol) from the previous step were dissolved in 4 mL of DMF. Cesium carbonate (2.1 g, 6.69 mmol) was added, and the mixture was heated to 85°C for 12 hours before cooling to room temperature. 100 mL of ice water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (acetonitrile / water, 3 / 5) to obtain c17 (270 mg) as a yellow solid in a 61% yield. LC-MS: [M+H] + =265.

[0268] Synthesis of intermediates C18-C27:

[0269]

[0270] Procedure: Dissolve 1N-isopropyl-4-iodoimidazole c18-1 (50 mg, 0.2 mmol) and iPrMgCl (0.3 mL, 2 M) in 4 mL of anhydrous tetrahydrofuran in an ice bath under nitrogen protection and stir for 1 hour in an ice bath. Add tributyltin chloride n-Bu3SnCl (138 mg, 0.4 mmol) to the reaction solution and continue the reaction for 1 hour before stopping the reaction. Add 20 mL of saturated potassium fluoride aqueous solution to the reaction solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain c18 (80 mg) as a yellow oil, which is directly used in the next step. LC-MS: [M+H] + =401.

[0271] According to the above synthetic route, the corresponding raw materials were used to synthesize the following intermediates (c19-c27):

[0272]

[0273] Example 2: Synthesis of target molecules P1-P2, P6-P7, P18-P19

[0274]

[0275] P1: (Z)-N-(3-(2-chloro-5-fluorophenyl)-6-(2-fluoro-2-(1H-pyrazol-4-yl)vinyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0276] Step 1: Under nitrogen, intermediate a7 (100 mg, 0.17 mmol), 1-H-4-pyrazoleboronic acid pinacol ester P1-1 (40 mg, 0.2 mmol), and sodium carbonate (60 mg, 0.56 mmol) were dissolved in 5 mL of a mixture of 1,4-dioxane and water (v / v, 9 / 1). Pd(dppf)Cl2 (14 mg, 0.017 mmol) was added and the mixture was heated to 110°C for 4 hours. The mixture was cooled to room temperature, filtered, and water was added. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM / MeOH, 12 / 1) to afford P1 (8.0 mg) as a pale yellow solid in 8% yield. LC-MS: [M+H] + =577. HPLC purity: 96.06%.

[0277] 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),10.56(s,1H),9.20(s,1H),8.17(s,1H),7.96(d,J=8.4Hz,2H),7.75(d,J= 8.8Hz,1H),7.67(d,J=3.9Hz,2H),7.33(dd,J=8.6,5.2Hz,2H),7.10(s,1H),6.59(d,J=41.8Hz,1H),5.99(s,1H).

[0278] According to the above synthetic route, the corresponding raw materials / intermediates were used to synthesize other compounds (P2, P6-P7) of Example 2:

[0279]

[0280] Example 3: Synthesis of target molecule P3

[0281]

[0282] P3: (Z)-N-(3-(2-chloro-5-fluorophenyl)-6-(2-fluoro-2-(1-methyl-1H-pyrazol-4-yl)vinyl)-1-oxoisoindolin-4-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indolin-1-carboxamide

[0283] Step 1: Under nitrogen, intermediate a10 (50 mg, 0.125 mmol), 1-N-methyl-4-pyrazoleboronic acid pinacol ester P2-1 (26 mg, 0.135 mmol), and sodium carbonate (27 mg, 0.25 mmol) were dissolved in 5 mL of a mixture of 1,4-dioxane and water (v / v, 9 / 1). Pd(dppf)Cl2 (9 mg, 0.013 mmol) was added and the mixture was heated to 110°C for 4 hours. The mixture was cooled to room temperature, filtered, and water was added. The mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM / MeOH, 12 / 1) to afford P3-1 (30 mg) as a yellow solid in a 60% yield. LC-MS: [M+H] + =401.

[0284] Step 2: In an ice bath, under nitrogen protection, the yellow solid P3-1 (30 mg, 0.075 mmol) and pyridine (16 mg, 0.2 mmol) from the previous step were dissolved in 2 mL of dichloromethane. A dichloromethane solution of triphosgene (7 mg, 2.0 mL) was slowly added dropwise and stirred under ice bath for 1 hour. Intermediate b1 (25 mg, 0.11 mmol) was added to the reaction solution and stirring was continued for 30 minutes. 40 mL of ice water was added to the system to quench the reaction, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and separated by TLC thin-layer chromatography (DCM / MeOH, 12 / 1) to obtain a light yellow solid P3 (12 mg). Yield: 25%, LC-MS: [M+H] + =648.

[0285] 1 H NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.81(d,J=41.0Hz,1H),8.12(s,1H),7.89(d,J=23.8Hz,2H),7.74(s,1H),7.62(d,J=32.4Hz,2H),7.47 –7.31(m,2H),7.31–7.19(m,2H),7.12(s,1H),6.51(d,J=41.3Hz,1H),6.04(s,1H),4.11(dd,J=82.3,11.6Hz,3H),3.51(s,1H),3.16(s,1H).

[0286] Step 3: Solid P3 was separated by HPLC preparative chromatography to obtain diastereoisomers P3a (peak 1) and P3b (peak 2)

[0287] According to the above synthetic route, other compounds (P4-P5) of Example 3 were synthesized using corresponding raw materials or intermediates:

[0288]

[0289]

[0290] Example 4: Synthesis of target molecule H1

[0291]

[0292] H1: N-(3-(2-chloro-5-fluorophenyl)-6-(2,3-dihydro-1H-benzopyrrolo[1,2-a]imidazol-7-yl)-1-oxoisoindolin-4-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indolin-1-carboxamide

[0293] Step 1: Under nitrogen, intermediate a12 (298 mg, 0.84 mmol), starting material H1-1 (239 mg, 0.84 mmol), and sodium carbonate (220 mg, 2.1 mmol) were dissolved in 16 mL of a mixture of 1,4-dioxane and water (v / v, 3 / 1). Catalyst DCM-Pd(dppf)Cl2 (34 mg, 0.042 mmol) was added and the mixture was heated to 100°C for 4 hours. The mixture was cooled to room temperature and filtered. Water was added to the system, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (DCM / MeOH, 10 / 1) to obtain compound H1-2 (310 mg) in an 85% yield. LC-MS: [M+H] + =433.

[0294] Step 2: In an ice bath, dissolve triphosgene (26 mg, 0.088 mmol) and pyridine (28 mg, 0.35 mmol) in 3 mL of dichloromethane. Add 3 mL of a dichloromethane solution of intermediate H1-2 (95 mg, 0.22 mmol) dropwise to the reaction solution. Stir for 30 minutes. Continue to add intermediate b1 (50 mg, 0.22 mmol) to the system, react at room temperature for 1 hour, and then stop the reaction. Evaporate the solvent under reduced pressure, add 40 mL of saturated sodium bicarbonate aqueous solution to the system, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and separate by TLC (DCM / MeOH, 8 / 1) to obtain a light yellow solid H1 (52 mg) in a yield of 34%. LC-MS: [M+H] + =681.

[0295] 1HNMR(400MHz,DMSO-d6)δ9.25(s,1H),9.14(s,1H),8.92(s,1H),8.84(s,1H),7.90-7.15(m,1H),6.65(br,1H),6.01(s,1H),4.28(d,J=12.0H z,1H),4.19(t,J=6.8Hz,2H),4.03(d,J=11.6Hz,1H),56(d,J=11.6Hz,1H),3.43(d,J=12.0Hz,1H),3.00(t,J=6.8Hz,2H),2.71-2.60(m,2H).

[0296] Example 5: Synthesis of target molecule H2

[0297]

[0298] Under nitrogen, intermediate b2 (100 mg, 0.1 mmol), intermediate c1 (40 mg, 0.2 mmol), and sodium carbonate (49 mg, 0.4 mmol) were dissolved in 2 mL of a mixture of 1,4-dioxane and water (v / v, 3 / 1). Catalyst Pd(PPh3)2Cl2 (16 mg, 0.02 mmol) was added, and the mixture was heated to 90°C for 1 hour. The mixture was cooled to room temperature and filtered. 10 mL of water was added to the filtrate, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: GreenSep Naphthyl 4.6*100 mm, 3 μm; mobile phase A: Hexane (1% 2M NH3-MeOH); mobile phase B: MeOH) to afford compound H2a (9.2 mg) in a 9% yield. LC-MS: [M+H] + =680.

[0299] 1 H NMR(400MHz, DMSO-d6)δ9.15(s,1H),8.88(d,J=33.4Hz,1H),8.02–7.78(m,3H),7.66(d,J=55.2Hz,3H),7.41–7.11(m,4H) ,6.66(s,1H),6.11(d,J=17.4Hz,1H),4.31–4.03(m,3H),3.64–3.42(m,2H),2.99(d,J=7.8Hz,2H),2.67(t,J=7.3Hz,2H).

[0300] According to the above synthetic route, other compounds (H2b) of Example 5 were synthesized using corresponding raw materials or intermediates:

[0301]

[0302]

[0303] Example 6: Synthesis of target molecule H3-H19

[0304]

[0305] Under nitrogen, intermediate a11 (96 mg, 0.2 mmol), intermediate c2 (40 mg, 0.2 mmol), and cesium carbonate (153 mg, 0.5 mmol) were dissolved in 2 mL of a mixture of 1,4-dioxane and water (v / v, 3 / 1). Catalyst Pd(PPh3)2Cl2 (16 mg, 0.02 mmol) was added and the mixture was heated to 100°C for 3 hours. The mixture was cooled to room temperature and filtered. The filtrate was added with 10 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSHC18 OBD Column 30*150mm 5μm; mobile phase A: 10 mmol / L NH4HCO3; mobile phase B: CH3CN) to afford compound H3 (17 mg) in a 17% yield. LC-MS: [M+H] + =641.

[0306] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),9.27(d,J=29.5Hz,1H),7.96(d,J=8.2Hz,1H),7.84(s,1H),7.74(dd,J=25.2,8.2Hz,3H),7.51–7 .27(m,3H),7.12(td,J=8.3,3.1Hz,1H),6.74(s,1H),6.06(s,1H),4.19(t,J=7.0Hz,2H),3.01(t,J=7.5Hz,2H),2.69(p,J=7.5Hz,2H).

[0307] According to the above synthetic route, other compounds (H4-H19) of Example 6 were synthesized using corresponding raw materials or intermediates:

[0308]

[0309]

[0310]

[0311] Example 7: Synthesis of target molecules P8-P17

[0312]

[0313] Procedure: Under nitrogen, intermediate a7 (59 mg, 0.1 mmol) and intermediate c18 (20 mg, 0.1 mmol) were dissolved in 1 mL of DMF. Catalyst Pd(dppf)Cl2 (14 mg, 0.017 mmol) was added and the mixture was heated to 130°C for 3 hours. The mixture was cooled to room temperature and filtered. 5 mL of water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (acetonitrile / water, 1 / 1) to afford P8 (6.5 mg) as a pale yellow solid in an 11% yield. LC-MS: [M+H] + =619.

[0314] 1 H NMR (300MHz, DMSO-d6) δ10.54(s,1H),9.17(s,1H),7.97(s,1H),7.76(s,2H),7.74–7.63(m,4H),7.32(dd,J=8.8,5.2Hz,1H), 7.10(td,J=8.4,3.0Hz,1H),6.67–6.95(m,1H),6.65–6.51(s,1H),5.97(s,1H),4.48(p,J=6.8Hz,1H),1.45(d,J=6.7Hz,6H).

[0315] According to the above synthetic route, the corresponding raw materials / intermediates were used to synthesize other compounds (P9-P17) of Example 7:

[0316]

[0317]

[0318]

[0319] Example 8: Chiral resolution of target molecule P1

[0320]

[0321] Split conditions:

[0322] Chromatographic column: WelFlash C18-I, 20-40 μm, 120 g; Mobile phase A: Water (10 mmol / L NH4HCO3); Mobile phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 50% B to 65% B in 15 min;

[0323] P1a:1 H NMR (400MHz, DMSO-d6) δ13.27(s,1H),10.53(s,1H),9.18(s,1H),8.18(s,1H),7.95(d,J=8.8Hz,2H),7.85(s,1H),7.75(d,J =9.1Hz,1H),7.67(d,J=4.0Hz,2H),7.33(dd,J=8.9,5.1Hz,1H),7.10(td,J=8.3,3.0Hz,1H),6.64-6.53(s,1H),5.99(s,1H).

[0324] P1b: 1 H NMR (400MHz, DMSO-d6) δ13.27(s,1H),10.53(s,1H),9.18(s,1H),8.18(s,1H),7.95(d,J=8.8Hz,2H),7.85(s,1H),7.75(d,J =9.1Hz,1H),7.67(d,J=4.0Hz,2H),7.33(d,J=8.9,5.1Hz,1H),7.10(td,J=8.3,3.0Hz,1H),6.64-6.53(s,1H),5.99(s,1H).

[0325] Example 9: Analysis of the inhibitory activity of compounds against kinase PI3Kα (545K mutation) and wild-type PI3Kα

[0326] Using ECHO (PE, model 550), 40 nL of solvent DMSO as a control, the positive compound alpelisib, or the test compound (3-fold dilution from 3 μM in 10 concentration gradients) was added to a 384-well plate (ProxiPlate-384plus, PerkinElmer, catalog number 6008280). 2 μL of 2× PI3Kα (Invitrogen, catalog number PV4788) or PI3Kα E545K mutant (Promega, catalog number V1731) working solution was added to each well, the mixture was shaken for 30 seconds, and the mixture was incubated at 25°C for 15 minutes. Add 2 μL of 2× substrate working solution (Promega, catalog number V1701) to each well, seal the plate, and incubate at 25°C for 1 hour. Add 4 μL of ADP-Glo ​​reagent buffer (Promega, catalog number V9102) containing 10 mM MgCl2 to each well, seal the plate, and incubate at 25°C for 40 minutes. Subsequently, add 8 μL of kinase assay solution (Promega, catalog number V9102) to each well, seal the plate, and incubate at 25°C for 40 minutes. Scan the plate using Envision 2105 and record the luminescence signal.

[0327] Data Analysis:

[0328] Inhibition rate (%) = [1-(average RLU of the test compound-average RFU of the positive control) / (average RFU of the vehicle control-average RFU of the positive compound)] × 100%

[0329] RLU: relative luminescence signal value.

[0330] RFU: relative fluorescence unit signal value.

[0331] IC 50 Value calculation:

[0332] Y = lower platform signal + (upper platform signal - lower platform signal) / (1 + 10^((logIC 50 -X) × Hill slope)

[0333] X: log value of compound concentration;

[0334] Y: inhibition rate (%).

[0335] Table 1: Half maximal inhibitory concentration (IC) of compounds against kinases PI3Kα wild type and PI3Kα (E545K) 50 )

[0336]

[0337] ND = Not tested.

[0338] The above experimental results show that the compounds of the present invention have a good inhibition on mutant PI3Kα and a weak inhibition on wild-type PI3Kα, which reflects the selective inhibition of the compounds of the present invention on mutant PI3Kα.

[0339] Example 10: The compound inhibits the phosphorylation of AKT downstream of intracellular PI3Kα (E545K) (pAKT) activity.

[0340] Intracellular inhibition experiment of the compound of the present invention on mutant PI3Kα (E545K) HCC2185 cells:

[0341] HCC2185 cells cultured in RPMI 1640 (Gibco, Cat. No. A10491-01) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin were seeded into 384-well microplates and incubated at 37°C, 5% CO2 for 12 hours. Using an Echo 550 (Labcyte, Echo 550), 200 μL of various compound concentrations (final dimethyl sulfoxide concentration 0.5%) were added to each well and incubated at 37°C for 2 hours. The cells were then fixed in 8% fixative (Solarbio, Cat. No. P1112) and washed once with phosphate-buffered saline (PBS). After washing, blocking solution (LI-COR, Cat. No. 927-40000) was added to each well and blocked for 1 hour at room temperature. After removing the blocking solution, anti-phospho-Akt (S473) Rabbit mAb (CST, Cat. No. 4060S) and GAPDH (D4C6R) Mouse mAb (CST, Cat. No. 97166S) antibody working solutions were added to each well and incubated at 4°C for 12 hours. The microplate was washed three times with PBS containing 0.1% Tween-80 (PBST), and IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR, Cat. No. 926-32211) and IRDye 680RD Goat anti-Mouse IgG (H+L) (LI-COR, Cat. No. 926-68070) antibody working solutions were added, and the microplate was incubated at room temperature in the dark. After washing the microplate three times with PBST, the microplate was centrifuged at 1000 rpm for 1 minute and the plate was scanned and read using an Odyssey CLx (LI-COR) instrument. The signal values ​​were recorded and the IC was calculated. 50 value.

[0342] The pAKT inhibition results of the compounds on E545K mutated breast cancer cells HCC2185 are shown in Table 2 below:

[0343] Table 2: Inhibition results of compounds on HCC2185 pAKT in E545K mutant cells

[0344] Compound <![CDATA[pAKT(S473)-HCC2185 IC 50 / μM]]> P1 0.32 P2 0.58 P12 0.34

[0345] ND=Not Tested The above results indicate that the molecules of the present invention have a good inhibitory effect on cells harboring the PI3KαE545K mutation.

[0346] Example 11: The compound inhibits the phosphorylation of AKT (pAKT) downstream of intracellular PI3Kα (H1047R).

[0347] Intracellular inhibition of mutant PI3Kα (H1047R) by compounds of the present invention in HCC1954 (or MDA-MB-453) cells: HCC1954 cells (or MDA-MB-453) cultured in RPMI1640 (Gibco, Cat. No. A10491-01) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin were seeded in 384-well microplates and incubated at 37°C, 5% CO2 for 12 hours. Using an Echo 550 (Labcyte, Echo 550), 200 μL of compound at varying concentrations (final dimethyl sulfoxide concentration 0.5%) was added to each well and incubated at 37°C for 2 hours. The cells were then fixed in 8% fixative (Solarbio, Cat. No. P1112) and washed once with phosphate-buffered saline (PBS). After washing, blocking solution (LI-COR, Cat. No. 927-40000) was added to each well and blocked for 1 hour at room temperature. After removing the blocking solution, anti-phospho-Akt (S473) Rabbit mAb (CST, Cat. No. 4060S) and GAPDH (D4C6R) Mouse mAb (CST, Cat. No. 97166S) working solutions were added to each well and incubated at 4°C for 12 hours. The microplate was washed three times with PBS containing 0.1% Tween-80 (PBST), and IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR, Cat. No. 926-32211) and IRDye 680RD Goat anti-Mouse IgG (H+L) (LI-COR, Cat. No. 926-68070) working solutions were added. The microplate was incubated at room temperature in the dark. After washing the microplate three times with PBST, the microplate was centrifuged at 1000 rpm for 1 minute and the plate was scanned and read using an Odyssey CLx (LI-COR) instrument. The signal values ​​were recorded and the IC was calculated. 50 value.

[0348] The pAKT inhibition results of the compounds on H1047R mutated breast cancer cells HCC1954 are shown in Table 3 below:

[0349] Table 3: Inhibition results of compounds on pAKT in HCC1954 cells

[0350] Compound <![CDATA[pAKT(S473)-HCC1954 IC 50 / μM]]> P1 1.39 P1a 0.62 P1b 6.90 P2 1.98 P12 2.52 P16a 1.70 P12 2.52 P16a 1.70 H5 1.75 H13 1.56 H14 0.92 H15 0.99 Control molecule 1 1.53

[0351] ND = Not Tested

[0352] The above results of the control molecule 1 structure show that the molecule of the present invention has a good inhibitory effect on cells with PI3KαH1047R mutation.

[0353] The pAKT inhibition results of the compounds on PI3KαH1047R mutated breast cancer cells MDA-MB-453 are shown in Table 4 below:

[0354] Table 4: Inhibition results of compounds on pAKT in MDA-MB-453 cells

[0355] Compound <![CDATA[pAKT(S473)-MDA-MB-453IC 50 / μM]]> P18 0.22

[0356] Example 12: Liver microsome stability test of the compound.

[0357] The details are as follows:

[0358] The compounds of the present invention were subjected to a liver microsome stability test. The test compounds were co-incubated with liver microsomes of different species with or without the addition of NADPH. The final concentration of the test compound in the test system was 1 μM, the final concentration of NADPH was 1 mM, and the final concentration of liver microsomes was 0.5 mg / mL. The concentration of the compound in the incubation supernatant at different time points within 60 minutes was measured and the pharmacokinetic parameters (such as clearance Cl) were calculated. int ).

[0359] Table 5, Metabolic Stability of Compounds in Human Liver Microsomes:

[0360]

[0361] This result indicates that the molecule of the present invention has good metabolic stability in the human body and is expected to be administered at a lower dose clinically.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. A pharmaceutical composition comprising the compound according to any one of claims 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. Use of the compound according to any one of claims 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating a PI3Kα-mediated disease.

4. The use according to claim 3, wherein the disease is cancer. The use according to claim 3 , wherein the PI3Kα has at least one mutation selected from the group consisting of E542K, E545K and H1047R.

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