CN116655602A

CN116655602A - PI3K alpha allosteric inhibitors

Info

Publication number: CN116655602A
Application number: CN202310649985.XA
Authority: CN
Inventors: 刘彬; 高峰; 景连栋; 吴勇勇; 郭永起; 姜蕊; 吴卓
Original assignee: Suzhou Puhe Pharmaceutical Technology Co ltd
Current assignee: Suzhou Puhe Pharmaceutical Technology Co ltd
Priority date: 2022-07-12
Filing date: 2023-06-02
Publication date: 2023-08-29

Abstract

The present invention relates to PI3K alpha allosteric inhibitors. In particular, it relates to compounds of formula (I) useful as selective allosteric inhibitors of mutant PI3K alpha, pharmaceutical compositions comprising said compounds, and the use of said compounds and pharmaceutical compositions for the treatment of PI3K alpha mediated diseases, in particular cancer, wherein the variable R ₁ 、R ₂ 、R ₃ 、L ₁ And n is as defined in the specification.

Description

PI3K alpha allosteric inhibitors

The present invention claims priority from chinese patent application 202210816095.9, whose application date is 2022, 7, 12, and chinese patent application 202211692152.3, whose application date is 2022, 12, 29.

Technical Field

The present invention is in the field of medicine, in particular to compounds useful as selective allosteric inhibitors of mutant pi3kα, pharmaceutical compositions comprising such compounds, and the use of said compounds and pharmaceutical compositions for the prevention and/or treatment of diseases mediated by pi3kα, in particular cancer.

Background

Phosphatidylinositol-3 kinase (PI 3K) is a class of intracellular enzymes capable of phosphorylating the 3-OH group of inositol in phosphatidylinositol membrane lipids, mainly regulating cell growth, proliferation, differentiation, migration, etc. (j. Med. Chem.2019,62, 4815-4850). PI3K phosphorylates phosphatidylinositol-4, 5-biphosphate (PIP 2) to phosphatidylinositol-3, 4, 5-triphosphate (PIP 3) (Nature, 1997,387,673-676); PIP3 activates downstream messenger proteins including AKT (protein kinase B, PKB) and mTOR (mammalian target of rapamycin).

PI3 ks are classified into type i, type ii, and type iii according to structural characteristics. Among the most widely studied PI3 ks, type i, include IA and IB. Type ia includes: pi3kα, pi3kβ, pi3kδ; type IB is PI3K gamma. Pi3kα and pi3kβ are widely present in all tissues, while pi3kδ and pi3kγ are mainly present in blood cells, endothelial cells and the central nervous system. Mutations in PI3kα containing the catalytic subunit p110α and the regulatory subunit p85, PI3kα, are widely found in a variety of cancers. Mutation analysis of more than 3000 cancers by cancer genomic profile (TCGA) showed that: the gene PIK3CA encoding pi3kα is the second most common second most mutated oncogene. The most common mutations of pi3kα are 3: E542K, E545K and H1047R (proc.Natl. Acad. Sci.2012,109, 15259-15264). The E545K mutation can bind to ISR1, increasing insulin receptor response, independent of the natural inhibition of p85 (Science, 2007,317,239-242); the H1047R mutation of the kinase domain has an increased anchoring effect on the cell membrane and thus can directly activate the PI3K-AKT-mTOR signaling pathway independent of RAS activation (Trends biochem. Sci.2015,40,88-100). 2022 ASCO conference report: in the analysis of 121221 adult cancer patients, the E545K mutation occupied 20%, the E542K mutation occupied 11%, and the H1047R mutation occupied 22%. Thus, the study of selective inhibitors against mutant pi3kα is particularly necessary.

The first generation of PI3K inhibitors were pan-PI3K inhibitors, which were developed as ATP-competing orthosteric inhibitors. Examples are GDC-0941, but because of its inhibition of the entire PI3K family (j.med. Chem.2008,51, 5522-5532), this results in higher toxic side effects and a lower clinical therapeutic window, thus leading to limited clinical doses. Subsequently, idelalisib, copanlisib, alpelisib was subsequently marketed by the FDA following the development of PI3kδ and PI3kα selective orthosteric inhibitors for the treatment of cancer patients with specific PI3K mutations. However, clinical aspects also report that the medicines have larger toxic and side effects. Alpelisib has a considerable rise in blood glucose in patients with breast cancer with PI3K alpha mutations, requiring the combined use of hypoglycemic agents such as metformin (Ann Oncol.2018,29 (suppl_8): mdy424.010-mdy 424.010). At the same time, an increase in blood glucose also greatly activates the insulin receptor pathway (Nature, 2018,560,499-503;Cancer Discov.2019,9,482-491), thereby feedback activating PI3K alpha, resulting in a decrease in drug efficacy. Therefore, it is very critical to develop inhibitors against mutant pi3kα, which attenuate the feedback activation pathway by reducing inhibition of wild type pi3kα, further enhancing clinical efficacy and reducing side effects such as hyperglycemia.

Despite current advances in the study of selective PI3K alpha positive inhibitors, such as alpelisia from nova, for example, is used in the treatment of er+ and pi3k alpha mutated advanced breast cancer patients, the development of more potent, highly selective inhibitors of mutant pi3k alpha could address unmet clinical needs due to their strong inhibition of wild-type pi3k alpha.

The invention develops a new generation of PI3K alpha allosteric inhibitor, has good selectivity for mutant PI3K alpha (with E545K, E542K and/or H1047R mutation), and is expected to solve the problems.

Disclosure of Invention

In one aspect, the present invention provides a compound of formula (I):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof,

wherein:

R ₁ is C _1-6 Alkyl, saturated or partially unsaturated C _3-14 Carbocyclic groups, phenyl, naphthyl, 5-14 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3-14 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally 1-4 heteroatoms independently selected from R ₄ Is substituted by a substituent of (a);

R ₂ each independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -NO ₂ 、-OR、-SR、-NRR'、-S(O) ₂ R、-S(O) ₂ NRR'、-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) ₂ NR'R”、-N(R)S(O) ₂ R', 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;

L ₁ is a bond or optionally R ₅ Substituted C _2-6 An alkenylene group, an alkylene group,

R ₃ c being phenyl, naphthyl, saturated or partially unsaturated _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 heterocyclyl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally 1-4 heteroatoms independently selected from R ₆ Is substituted by a substituent of (a);

R ₄ and R is ₆ Independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -NO ₂ Oxo, -OR, -SR, -NRR', -S (O) ₂ R、-S(O) ₂ NRR'、-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) ₂ NR'R”、-N(R)S(O) ₂ R', phenyl, C _3-8 Cycloalkyl, a 5-10 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 3-10 membered heterocyclyl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ₅ is halogen, -CN, C _1-6 Alkyl or halo C _1-6 An alkyl group;

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

n is any integer from 0 to 4,

provided that when L ₁ R is a bond ₃ Is a 10-14 membered tricyclic heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 10-14 membered tricyclic heterocyclyl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

wherein the variable R ₁ 、R ₂ 、R ₃ And n is as defined above for the compound of formula (I).

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

Another aspect of the 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.

A further aspect of the 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 the manufacture of a medicament for the prophylaxis and/or treatment of a disease mediated by pi3kα, in particular cancer.

A further aspect of the 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 the prevention and/or treatment of a disease mediated by pi3kα, in particular cancer.

A further aspect of the 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 the prevention and/or treatment of a disease mediated by PI3kα, in particular cancer.

Yet another aspect of the present invention relates to a method for the prevention and/or treatment of a disease 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

Definition of the definition

The following terms, as used in the specification and claims of the present application, have the following meanings unless otherwise indicated. It is understood that where not explicitly defined herein, terms are to be given their meaning as known in the art. Further, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present application in any way. Unless otherwise indicated, when there is an inconsistency in the structural formulas and chemical names of the compounds described herein, the structural formulas are subject.

Unless otherwise indicated, ranges recited herein include the endpoints of the ranges and each integer contained in the range. For example, "n is any integer from 0 to 4" means that n may be 0, 1, 2, 3, or 4. In addition, any subrange composed of these integers is intended to be included within the scope of the present application.

The radical prefix "C" as used herein _x-y "means a range of the number of carbon atoms contained in the group, wherein x and y are integers. For example, C _3-8 Cycloalkyl means cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also to be understood that "C _3-8 "also includes any subrange therein, e.g. C _3-7 、C _3-6 、C _4-7 、C _4-6 、C _5-6 Etc.

The term "alkyl" as used herein refers to a straight or branched saturated monovalent radical having the indicated number of carbon atomsA hydrocarbon group. 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 to 2 carbon atoms (" C _1-2 Alkyl "). 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.

The term "alkenyl" as used herein refers to a straight or branched chain unsaturated monovalent hydrocarbon radical of the specified number of carbon atoms 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 Alkenyl ") or 2 carbon atoms (" vinyl "). Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butadien-1-yl, 1-penten-3-yl, 2-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.

The term "alkenylene" as used herein refers to a divalent group derived from an alkenyl group, wherein alkenyl is as defined above. Alkenylene radicals generally contain 2 to 6 carbon atoms ("C _2-6 Alkenylene "), preferably 2 to 4 carbon atoms (" C) _2-4 Alkenylene ") or 2 carbon atoms (" vinylidene "). Examples of alkenylenes include, but are not limited to, hexenylene, pentenylene, butadienylene, propenylene, and ethenylene.

The term "alkoxy" as used herein refers to an alkyl group (i.e., -O-alkyl ") attached to the parent molecule through an oxygen atom, 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 Alkoxy "). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, pentoxy, hexoxy.

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

The term "halo" as used herein means that one or more hydrogen atoms in a substituent is replaced by one or more identical or different halogen atoms as defined hereinbefore. For example, "halo C _1-6 Alkyl "means" C "wherein one or more hydrogen atoms are replaced by one or more identical or different halogen atoms _1-6 Alkyl ", wherein" C _1-6 Alkyl "is as defined above. Halogenated C _1-6 Examples of alkyl groups include, but are not limited to, chloromethyl, fluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The term "oxo" as used herein refers to a "=o" group.

The term "carbocycle" or "carbocyclic group" as used herein refers to a saturated or partially unsaturated, non-aromatic, cyclic hydrocarbon group having the indicated number of carbon atoms and containing no heteroatoms. Carbocycles generally contain 3 to 14 carbon atoms ("C _3-14 Carbocycle "), preferably 3 to 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 to 6 carbon atoms (" C _3-6 Carbocycles "). Carbocycles may be monocyclic or polycyclic, including fused, bridged and spiro ring systems. The term "cycloalkyl" is applied when the carbocycle is a saturated cyclic hydrocarbon group. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl, and cyclohexenyl.

The term "aryl" as used herein refers to a monocyclic or polycyclic aromatic group having 6 to 14, more typically 6 to 10 carbon atoms and no ring heteroatoms. For polycyclic systems, including fused, bridged and spiro ring systems of aromatic and non-aromatic rings that do not contain a ring heteroatom, the term "aryl" (e.g., 5,6,7, 8-tetrahydronaphthalen-2-yl) is applied 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.

The term "heteroatom" as used herein refers to a nitrogen, oxygen or sulfur atom.

The term "heteroaryl" as used herein refers to a monovalent group of aromatic structure containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur and a total of 5 to 14 ring atoms. Heteroaryl groups include 5-6 membered monocyclic systems containing 1-4, preferably 1-2 heteroatoms selected from nitrogen, oxygen and sulfur ("5-6 membered monocyclic heteroaryl") and 8-14 membered polycyclic systems containing 1-4, preferably 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, for example 8-10 membered bicyclic ("8-10 membered bicyclic heteroaryl") and 10-14 membered tricyclic ("10-14 membered tricyclic heteroaryl") groups, wherein at least one ring of the polycyclic systems is aromatic. For polycyclic ring systems, including fused, bridged and spiro ring systems having aromatic and non-aromatic rings, the term "heteroaryl" applies (e.g., 5,6,7, 8-tetrahydroquinolin-3-yl) if at least one ring heteroatom is present and the point of attachment is at an atom (carbon atom or heteroatom) of the aromatic ring. Examples of heteroaryl groups include, but are not limited to, 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, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, benzopyranyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, cinnolinyl, naphthyridinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenoxazinyl, phenazinyl, and phenazozinyl.

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

The term "optional" as used herein means that the immediately following description of the term may or may not occur. For example, "optionally R ₅ Substituted C _2-6 Alkenylene "covered" by R ₅ Substituted C _2-6 Alkenylene radicals and radicals are denoted by R ₅ Substituted C _2-6 Alkenylene "two cases.

The term "pharmaceutically acceptable" as used herein refers to those substances or materials which are, within the scope of sound medical judgment, suitable for contact with the tissues of subjects such as humans or other mammals without undue toxicity, irritation, allergic response, or other problem commensurate with a benefit/risk ratio.

The term "preventing" as used herein refers to reducing or eliminating the likelihood of a disease.

The term "treatment" as used herein refers to the complete or partial elimination of a disease and/or its accompanying symptoms.

The term "subject" as used herein refers to an animal, preferably a mammal, such as a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc., most preferably a human, as the subject of the intended experiment, treatment.

Detailed description of the technical scheme of the invention

The following specific embodiments are provided to enable those skilled in the art to more clearly understand the contents of the present invention. It should be understood that these embodiments are presented by way of example only, and are not intended to limit the scope of the invention.

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

wherein:

R ₅ is halogen, -CN, C _1-6 Alkyl or halo C _1-6 An alkyl group;

n is any integer from 0 to 4,

In some embodiments, R ₁ Is optionally selected from R by 1 to 4 ₄ C substituted by substituent(s) _1-6 An alkyl group. In some embodiments, R ₁ Is optionally 1 to 3, preferably 1 or 2, independently selected from R ₄ Methyl, ethyl, n-propyl, isopropyl, n-butyl substituted by substituents of (a) and (b), Sec-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.

In some embodiments, R ₁ Is optionally selected from R by 1 to 4 ₄ Saturated or partially unsaturated C substituted by substituents of (2) _3-14 A carbocyclic group. In some embodiments, R ₁ Is optionally 1 to 3, preferably 1 or 2, independently selected from R ₄ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl or cyclohexenyl substituted by substituents of (a) preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R ₁ Is optionally selected from R by 1 to 4 ₄ Phenyl or naphthyl substituted by substituents of (a) are preferred.

In some embodiments, R ₁ Is optionally selected from R by 1 to 4 ₄ A 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted with substituents of (a). In some embodiments, R ₁ Is optionally 1 to 3, preferably 1 or 2, independently selected from R ₄ A 5-6 membered monocyclic heteroaryl or an 8-14 membered polycyclic heteroaryl substituted with substituents. In some embodiments, R ₁ Is optionally 1 to 3, preferably 1 or 2, independently selected from R ₄ Substituents of (a) are substituted with pyrrolyl, furyl, 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, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridinyl, benzopyranyl, benzodihydropyranyl, cinnolinyl, naphthyridinyl, pteridinyl, carbazolyl, carboline Group, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl and phenothiazinyl.

In some embodiments, R ₁ Is optionally selected from R by 1 to 4 ₄ A 3-14 membered heterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted with substituents of (a). In some embodiments, R ₁ Is optionally 1 to 3, preferably 1 or 2, independently selected from R ₄ Substituted aziridinyl, oxetanyl, thietanyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuryl, dihydrothienyl, dihydrooxazolyl, isodihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, piperazinyl, dioxanyl, oxathialanyl, azepanyl, morpholinyl, thiomorpholinyl, indolinyl or isoindolinyl.

In some embodiments, R ₂ Each independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -NO ₂ 、-OR、-SR、-NRR'、-S(O) ₂ R、-S(O) ₂ NRR'、-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) ₂ NR'R”、-N(R)S(O) ₂ R', 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, 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 containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur-a 10 membered heterocyclyl group.

In some embodiments, R ₂ Each independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -OR, -NRR', -S (O) ₂ R、-S(O) ₂ NRR ', -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 An alkyl group.

In some embodiments, R ₂ Each independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -OR, -NH ₂ 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 An alkyl group.

In some embodiments, R ₂ Each independently selected from methyl, ethyl, isopropyl, -CF ₃ 、-CHF ₂ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ Phenyl, cyclopropyl, cyclobutyl, pyrazolyl, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl.

In some embodiments, R ₂ Each independently selected from methyl, -CF ₃ 、-CHF ₂ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ 、-OCHF ₂ and-NH ₂ Preferably methyl, -CF ₃ F and Cl.

In some embodiments, L ₁ Is a bond or optionally is R ₅ Substituted C _2-6 Alkenylene derivativesA base.

In some embodiments, L ₁ Is a key.

In some embodiments, L ₁ Is optionally R ₅ Substituted C _2-6 Alkenylene group, wherein R is ₅ Is halogen, -CN, C _1-6 Alkyl or halo C _1-6 An alkyl group.

In some embodiments, L ₁ Is optionally substituted by halogen C _2-6 Alkenylene radicals. In some embodiments, L ₁ Is C optionally substituted by F or Cl _2-4 Alkenylene radicals. In some embodiments, L ₁ Is vinylidene optionally substituted with F.

In some embodiments, L ₁ Is C optionally substituted by-CN _2-6 Alkenylene radicals. In some embodiments, L ₁ Is C optionally substituted by-CN _2-4 Alkenylene radicals. In some embodiments, L ₁ Is vinylidene optionally substituted with-CN.

In some embodiments, L ₁ Is optionally C _1-6 Alkyl substituted C _2-6 Alkenylene radicals. In some embodiments, L ₁ Is optionally C _1-4 Alkyl substituted C _2-4 Alkenylene radicals. In some embodiments, L ₁ Is a vinylidene group optionally substituted with methyl or ethyl.

In some embodiments, L ₁ Is optionally halogenated C _1-6 Alkyl substituted C _2-6 Alkenylene radicals. In some embodiments, L ₁ Is optionally-CF ₃ or-CHF ₂ Substituted C _2-4 Alkenylene radicals. In some embodiments, L ₁ Is optionally-CF ₃ Substituted vinylidene groups.

In some embodiments, R ₃ 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 heterocyclyl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally 1-4 heteroatoms independently selected from R ₆ Is substituted by a substituent of (a).

In some embodiments, R ₃ Is optionally selected from R by 1 to 4 ₆ Phenyl or naphthyl substituted by substituents of (a) are preferred.

In some embodiments, R ₃ Is optionally selected from R by 1 to 4 ₆ Saturated or partially unsaturated C substituted by substituents of (2) _3-14 A carbocyclic group. In some embodiments, R ₃ Is optionally 1 to 3, preferably 1 or 2, independently selected from R ₆ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl or cyclohexenyl substituted by substituents of (a) preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R ₃ Is optionally selected from R by 1 to 4 ₆ A 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted with substituents of (a). In some embodiments, R ₃ Is optionally 1 to 3, preferably 1 or 2, independently selected from R ₆ A 5-6 membered monocyclic heteroaryl, an 8-10 membered bicyclic heteroaryl, or a 10-14 membered tricyclic heteroaryl substituted with substituents. In some embodiments, R ₃ Is optionally 1 to 3, preferably 1 or 2, independently selected from R ₆ Substituted pyrrolyl, furyl, 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, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, thienopyrimidinyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, benzopyranyl, chromanyl, cinnolinyl, naphthyridinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl,

In some embodiments, R ₃ Is optionally selected from R by 1 to 4 ₆ A 3-14 membered heterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, substituted with substituents of (a). In some embodiments, R ₃ Is optionally 1 to 3, preferably 1 or 2, independently selected from R ₆ Substituted aziridinyl, oxetanyl, thietanyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuryl, dihydrothienyl, dihydrooxazolyl, isodihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, piperazinyl, dioxanyl, oxathialanyl, azepanyl, morpholinyl, thiomorpholinyl, indolinyl or isoindolinyl.

In some embodiments, R ₄ And R is ₆ Independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -NO ₂ Oxo, -OR, -SR, -NRR', -S (O) ₂ R、-S(O) ₂ NRR'、-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) ₂ NR'R”、-N(R)S(O) ₂ R', 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.

In some embodiments, R ₄ And R is ₆ Independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S (O) ₂ R、-S(O) ₂ NRR ', -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 An alkyl group.

In some embodiments, R ₄ And R is ₆ Independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S (O) ₂ 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 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 An alkyl group.

In some embodiments, R ₄ And R is ₆ Independently selected from methyl, ethyl, isopropyl, -CF ₃ 、-CHF ₂ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OC ₂ H ₅ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ 、-S(O) ₂ CH ₃ 、-C(O)CH ₃ 、-C(O)CF ₃ 、-C(O)OH、-C(O)OCH ₃ 、-C(O)NH ₂ Phenyl, cyclopropyl, cyclobutyl, pyrazolyl, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, thienyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuraneGroup, piperidinyl, piperazinyl, and morpholinyl.

In some embodiments, R ₄ And R is ₆ Independently selected from methyl, isopropyl, -CF ₃ 、-CHF ₂ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ And C _3-8 Cycloalkyl, preferably methyl, isopropyl, -CF ₃ F, cl, -CN, -OH and cyclopropyl.

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

In some embodiments, n is 1, 2 or 3, R ₂ Each independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -OR, -NH ₂ 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 An alkyl group.

In some embodiments, n is 1 or 2, R ₂ Each independently selected from methyl, -CF ₃ 、-CHF ₂ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ Phenyl, pyrazolyl and cyclopropyl.

In some embodiments, n is 2, R ₂ Each of F and Cl. In some embodiments, n is 2, R ₂ Each is F and methyl. In some embodiments, n is 2, R ₂ Each is Cl and methyl. In some embodiments, n is 2, R ₂ Each is F. In some embodiments, n is 2, R ₂ Each is Cl.

In some embodiments, R ₁ C being saturated or partially unsaturated _3-14 A carbocyclic group, wherein the carbocyclic group is optionally selected from C by 1 to 3 independently _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S (O) ₂ 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 containingSubstituted with 1-3 substituents independently selected from 3-8 membered heterocyclyl groups of nitrogen, oxygen and sulfur heteroatoms wherein R and R' are each independently selected from H, C _1-6 Alkyl and halogenated C _1-6 An alkyl group.

In some embodiments, R ₁ Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl or cyclohexenyl, wherein each of said groups is optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ 、-S(O) ₂ CH ₃ 、-C(O)CH ₃ 、-C(O)CF ₃ 、-C(O)OH、-C(O)OCH ₃ and-C (O) NH ₂ Is substituted by a substituent of (a). In some embodiments, R ₁ Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each of said groups is optionally selected from methyl, -CF, 1, 2 or 3 independently ₃ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OCF ₃ and-NH ₂ Is substituted by a substituent of (a).

In some embodiments, R ₁ Is phenyl, wherein said phenyl is optionally selected from C by 1 to 3 independently _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -OR, -NRR', -S (O) ₂ R, -C (O) OR, -C (O) NRR', phenyl, C _3-8 Cycloalkyl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a substituent containing 1-3-membered heterocyclyl groups 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 An alkyl group.

In some embodiments, R ₁ Is phenyl, wherein said phenyl is optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ 、-S(O) ₂ CH ₃ 、-C(O)CH ₃ 、-C(O)CF ₃ 、-C(O)OH、-C(O)OCH ₃ and-C (O) NH ₂ Is substituted by a substituent of (a). In some embodiments of the present invention, in some embodiments,R ₁ is phenyl, wherein said phenyl is optionally substituted with 1 or 2 groups independently selected from methyl, -CF ₃ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ or-NH ₂ Is substituted by a substituent of (a). In some embodiments, R ₁ Is covered by-CF ₃ And F is substituted phenyl.

In some embodiments, R ₁ Is a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is optionally substituted with 1-3 heteroatoms independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S (O) ₂ R, -C (O) OR, -C (O) NRR', phenyl, C _3-8 Cycloalkyl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a substituent containing 1-3-membered heterocyclyl groups 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 An alkyl group.

In some embodiments, R ₁ 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, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridinyl, benzopyranyl, benzodihydropyranyl, cinnolinyl, naphthyridinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenazinyl, phenoxazinyl, wherein each of said groups is optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ 、-S(O) ₂ CH ₃ 、-C(O)CH ₃ 、-C(O)CF ₃ 、-C(O)OH、-C(O)OCH ₃ and-C (O) NH ₂ Is substituted by a substituent of (a). In some embodiments, R ₁ Is pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, imidazopyridinyl or thienopyridinyl, wherein each of said groups is optionally substituted with 1 or 2 groups independently selected from methyl, -CF ₃ 、-CHF ₂ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OCF ₃ and-NH ₂ Is substituted by a substituent of (a). In some embodiments, R ₁ Is unsubstituted benzothienyl.

In some embodiments, R ₁ Is a 3-14 membered heterocyclic group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclic group is optionally substituted with 1-3 heteroatoms independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S (O) ₂ R, -C (O) OR, -C (O) NRR', phenyl, C _3-8 Cycloalkyl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a substituent containing 1-3-membered heterocyclyl groups 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 An alkyl group.

In some embodiments, R ₁ Is an azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothienyl, dihydrooxazolyl, isodihydrooxazolyl, dihydrothiazolyl, isodihydrothiazole, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxyCyclohexenyl, oxathiahexyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl and isoindolinyl, wherein said groups are optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ 、-S(O) ₂ CH ₃ 、-C(O)CH ₃ 、-C(O)CF ₃ 、-C(O)OH、-C(O)OCH ₃ and-C (O) NH ₂ Is substituted by a substituent of (a). In some embodiments, R ₁ Is an azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxathialanyl, azepanyl, morpholinyl or isoindolinyl group, wherein said groups are optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OCF ₃ and-NH ₂ Is substituted by a substituent of (a). In some embodiments, R ₁ Is covered by-CF ₃ F and-OH substituted isoindolinyl.

In some embodiments, L ₁ Is optionally halogen, -CN, C _1-6 Alkyl or halo C _1-6 Alkyl substituted C _2-6 Alkenylene, R ₃ Is phenyl, wherein said phenyl is optionally selected from C by 1 to 3 independently _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S (O) ₂ R, -C (O) OR, -C (O) NRR', phenyl, C _3-8 Cycloalkyl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a substituent containing 1-3-membered heterocyclyl groups 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 An alkyl group.

In some embodiments, L ₁ Is optionally F, cl, -CN, C _1-6 Alkyl or halo C _1-6 Alkyl substituted C _2-4 Alkenylene, R ₃ Is phenyl, wherein said phenyl is optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ 、-S(O) ₂ CH ₃ 、-C(O)CH ₃ 、-C(O)CF ₃ 、-C(O)OH、-C(O)OCH ₃ and-C (O) NH ₂ Is substituted by a substituent of (a).

In some embodiments, L ₁ Is vinylidene optionally substituted by F, cl or-CN, R ₃ Is phenyl, wherein said phenyl is optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ 、-OCHF ₂ and-NH ₂ Is substituted by a substituent of (a).

In some embodiments, L ₁ Is optionally halogen, -CN, C _1-6 Alkyl or halo C _1-6 Alkyl substituted C _2-6 Alkenylene, R ₃ C being saturated or partially unsaturated _3-14 A carbocyclic group, wherein the carbocyclic group is optionally selected from C by 1 to 3 independently _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S (O) ₂ R, -C (O) OR, -C (O) NRR', phenyl, C _3-8 Cycloalkyl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a substituent containing 1-3-membered heterocyclyl groups 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 An alkyl group.

In some embodiments, L ₁ Is optionally halogen, -CN, C _1-6 Alkyl or halo C _1-6 Alkyl substituted C _2-4 Alkenylene, R ₃ Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl or cyclohexenyl, wherein each of said groups is optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ 、-S(O) ₂ CH ₃ 、-C(O)CH ₃ 、-C(O)CF ₃ 、-C(O)OH、-C(O)OCH ₃ and-C (O) NH ₂ Is substituted by a substituent of (a). In some casesIn embodiments, L ₁ Is vinylidene optionally substituted by F, cl or-CN, R ₃ Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein each of said groups is optionally substituted with 1 or 2 groups independently selected from methyl, -CF ₃ 、-CHF ₂ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ 、-OCHF ₂ and-NH ₂ Is substituted by a substituent of (a).

In some embodiments, L ₁ Is optionally halogen, -CN, C _1-6 Alkyl or halo C _1-6 Alkyl substituted C _2-6 Alkenylene, R ₃ Is a 5-14 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is optionally substituted with 1-3 heteroatoms independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S (O) ₂ R, -C (O) OR, -C (O) NRR', phenyl, C _3-8 Cycloalkyl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a substituent containing 1-3-membered heterocyclyl groups 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 An alkyl group.

In some embodiments, L ₁ Is optionally F, cl, -CN, C _1-6 Alkyl or halo C _1-6 Alkyl substituted C _2-4 Alkenylene, R ₃ 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, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridinyl, benzopyranyl, benzopyrimidinyl, quinazolinyl, quinoxalinyl, purinyl, benzofuranyl, pyrimidyl, and benzofuranyl, Chromanyl, cinnolinyl, naphthyridinyl or pteridinyl, wherein the groups are optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ 、-S(O) ₂ CH ₃ 、-C(O)CH ₃ 、-C(O)CF ₃ 、-C(O)OH、-C(O)OCH ₃ 、-C(O)NH ₂ Substituents for cyclopropyl and cyclobutyl. In some embodiments, L ₁ Is vinylidene optionally substituted by F, cl or-CN, R ₃ Is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, indolyl, isoindolyl, benzothienyl, indazolyl, benzimidazolyl, imidazopyridinyl, imidazopyrimidinyl, thienopyridinyl, quinolinyl or isoquinolinyl, wherein each of said groups is optionally substituted with 1 or 2 groups independently selected from methyl, -CF ₃ 、-CHF ₂ 、F、Cl、Br、-CN、-OH、-OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ And substituents for cyclopropyl. In some embodiments, L ₁ Is optionally F-substituted vinylidene, R ₃ Is pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, pyrimidinyl or pyridinyl, wherein each of said groups is optionally substituted with 1 or 2 substituents independently selected from methyl, F, cl, br, -CN, -OH or cyclopropyl.

In some embodiments, L ₁ Is a bond, R ₃ Is a 10-14 membered tricyclic heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said heteroaryl group is optionally substituted with 1-3 heteroatoms independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S (O) ₂ R, -C (O) OR, -C (O) NRR', phenyl, C _3-8 Cycloalkyl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a substituent containing 1-3-membered heterocyclyl groups 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 An alkyl group.

In some embodiments, L ₁ Is a bond, R ₃ Is carbazolyl, carboline group phenanthridinyl, acridinyl, and phenanthroline group, phenazinyl group, phenoxazinyl group, phenothiazinyl group, Wherein each of said groups is optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ 、-S(O) ₂ CH ₃ 、-C(O)CH ₃ 、-C(O)CF ₃ 、-C(O)OH、-C(O)OCH ₃ and-C (O) NH ₂ Is substituted by a substituent of (a).

In some embodiments, L ₁ Is a bond, R ₃ Is that Wherein each of said groups is optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OCF ₃ 、-OCHF ₂ and-NH ₂ Is substituted by a substituent of (a). In some embodiments, L ₁ Is a bond, R ₃ Is->

In some embodiments, L ₁ Is a bond, R ₃ Is a 10-14 membered tricyclic heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said heterocyclyl is optionally substituted with 1-3 heteroatoms independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, oxo, -OR, -NRR', -S (O) ₂ R, -C (O) OR, -C (O) NRR', phenyl, C _3-8 Cycloalkyl, a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a substituent containing 1-3-membered heterocyclyl groups 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 An alkyl group. Preferably, the heterocyclyl is optionally substituted with 1, 2 or 3 groups independently selected from methyl, -CF ₃ 、-CHF ₂ F, cl, br, -CN, oxo, -OH, -OCH ₃ 、-OCF ₃ 、-OCHF ₂ 、-NH ₂ 、-S(O) ₂ CH ₃ 、-C(O)CH ₃ 、-C(O)CF ₃ 、-C(O)OH、-C(O)OCH ₃ and-C (O) NH ₂ Is substituted by a substituent of (a).

In some of these embodiments, compounds of formula (I) are provided wherein:

R ₁ is C _3-12 Cycloalkyl, phenyl, a 5-10 membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 3-10 membered heterocyclyl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally, 1-3 heteroatoms independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -NO ₂ Oxo, -OR, -SR, -NRR', -S (O) ₂ R、-S(O) ₂ Substituents for NRR ', -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',

R ₂ each independently selected from C _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -NO ₂ 、-OR、-SR、-NRR'、-S(O) ₂ R、-S(O) ₂ NRR ', -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 ';

L ₁ for bonding or C optionally substituted by halogen or-CN _2-6 An alkenylene group, an alkylene group,

R ₃ is phenyl, 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 is independently selected from C by 1-3 _1-6 Alkyl, halogenated C _1-6 Alkyl, halogen, -CN, -NO ₂ Oxo, -OR, -SR, -NRR', -S (O) ₂ R、-S(O) ₂ NRR ', -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 _3-8 Substituents of cycloalkyl groups;

r and R' may be the same or different and are each independently selected from H, C _1-6 Alkyl and halogenated C _1-6 Alkyl group, and

n is any integer from 0 to 3,

In some embodiments, compounds of formula (I) are provided wherein:

R ₁ is phenyl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 3-10 membered heterocyclyl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally is substituted with 1-3 heteroatoms independently selected from halogen, -OH, C _1-6 Alkyl and halogenated C _1-6 The substituent of the alkyl group is substituted,

R ₂ each independently selected from halogen or halo C _1-6 An alkyl group;

L ₁ for bonding or for substitution by halogen or-CN _2-4 An alkenylene group, an alkylene group,

R ₃ 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 is independently selected from C by 1-3 _1-6 Alkyl, halogen, -CN, oxo and C _3-8 Substituents of cycloalkyl groups; and

n is any integer from 0 to 2,

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

wherein each variable R ₁ 、R ₂ 、R ₃ And n is as defined above.

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

R ₂ each independently selected from halogen;

R ₃ is a 5-10 membered heteroaryl group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally 1-2 are independently selected from C _1-6 Alkyl, halogen, -CN and C _3-8 Substituted cycloalkyl group, and

n is 1 or 2.

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

R ₁ is phenyl, benzothienyl or indolinyl, and is optionally selected from F, cl, methyl, -CF, 1, 2 or 3 independently ₃ And a substituent group of-OH,

R ₂ each independently selected from F and Cl;

R ₃ 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.

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

wherein each variable R ₁ 、R ₂ 、R ₃ And n is as defined above.

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

R ₂ each independently selected from halogen;

R ₃ is a 10-14 membered tricyclic heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 10-14 membered tricyclic heterocyclyl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally is independently selected from C by 1-3 _1-6 Substituents for alkyl, -CN, oxo, and halo; and

n is 1 or 2.

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

R ₁ is phenyl or indolinyl, and is optionally selected from the group consisting of F, cl, -OH, methyl and-CF, optionally from 1 to 3 ₃ Is substituted by a substituent of (a) and (b),

R ₂ each independently selected from F and Cl;

R ₃ is that

And optionally substituted with 1 to 3 substituents independently selected from methyl, -CN, oxo, F and Cl; and

n is 2.

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

R ₂ each independently selected from F and Cl;

R ₃ is that/>

And

n is 2.

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

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Pharmaceutically acceptable salts of the compounds of the invention refer to salts of the compounds of formula (I) with a pharmaceutically acceptable acid or base. Such salts include the acidic functional groups (e.g., -COOH, -OH, SO) present in the compounds of formula (I) ₃ H, etc.) with suitable 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, with nitrogen-containing organic bases (e.g., ethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, diethylaminoethanol, ethylenediamine, imidazole, morpholine, 2-hydroxyethyl morpholine, dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine)Etc.) and amino acid salts (e.g., lysine salts, arginine salts); and basic functional groups (e.g. -NH) present in the compounds of formula (I) ₂ Etc.) with suitable inorganic or organic anions (acids), including salts with 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, benzenesulfonic acid, toluenesulfonic acid, benzoic acid, malonic acid, ascorbic acid, etc.). Pharmaceutically acceptable salts may 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.

"stereoisomers" of the compounds of the invention are isomers resulting from the different spatial arrangement of the atoms in the molecule. Enantiomers are produced when an asymmetric carbon atom is present in the compound of formula (I); when a carbon-carbon double bond or a cyclic structure is present in the compound of formula (I), a cis-trans isomer is produced. All enantiomers, diastereomers, racemates, cis-trans isomers and mixtures of compounds of formula (I) are included within the scope of the present invention.

The compounds of the present invention may also exist in tautomeric forms. The term "tautomer" refers to alternative forms of compounds having different proton positions, such as enol-ketone, imine-enamine, amide-imide tautomers. All such tautomers are included within the scope of the invention.

"solvate" of a compound of the invention refers to a substance formed by 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, the compound of formula (I) may form an ethanolate with ethanol and a hydrate with water. All such solvates are included within the scope of the invention.

In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant a carrier (or excipient) that does not cause significant irritation to the organism and does not abrogate the biological activity of the active ingredient. The pharmaceutically acceptable carrier may be solid or liquid and may be one or more selected from the group consisting of: fillers, antioxidants, buffers, bacteriostats, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, glidants, release control agents, wetting agents, stabilizers, and suspending agents. One skilled in the art can select an appropriate pharmaceutically acceptable carrier depending on factors such as the intended route of administration, the nature of the active ingredient, and the like.

The pharmaceutical compositions may be formulated into a variety of pharmaceutically acceptable dosage forms, such as dosage forms suitable for oral administration, e.g., tablets, capsules, pills, syrups, elixirs, suspensions, solutions, emulsions, granules, by techniques conventional in the art; 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; formulations suitable for inhalation, such as aerosols, solutions and dry powders; and dosage forms suitable for topical application, such as creams, ointments, lotions, pastes, sprays, foams and gels. These dosage forms may be prepared by conventional methods in the pharmaceutical formulation arts.

In a third aspect of the invention there is provided 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 the manufacture of a medicament for the prophylaxis and/or treatment of a disease mediated by pi3kα, in particular cancer.

In a fourth aspect of the invention, there is provided 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 the prevention and/or treatment of a disease mediated by pi3kα, in particular cancer.

In a fifth aspect of the invention there is provided 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 the prophylaxis and/or treatment of a disease mediated by pi3kα, in particular cancer.

In a sixth aspect of the present invention there is provided a method for the prophylaxis and/or treatment of a disease mediated by pi3kα, in particular cancer, which method 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.

The compounds of the invention are inhibitors of PI3K alpha and are therefore useful in the treatment of PI3K alpha 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. Such 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 myelogenous leukemia, chronic myelogenous leukemia, thyroid cancer, bronchial cancer, intrahepatic bile duct cancer, adrenal cancer, glioma, glioblastoma, renal cancer, bladder cancer, uterine cancer, vaginal cancer, multiple myeloma, esophageal cancer, lymphocytic leukemia, brain cancer, oral cancer, laryngeal cancer, non-hodgkin lymphoma, head and neck cancer, bone cancer, skin cancer, testicular cancer, and the like.

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, PI3kα has an E542K mutation. In some embodiments, PI3K alpha has an E545K mutation. In some embodiments, PI3kα has an H1047R mutation.

The compounds and pharmaceutical compositions of the invention may be administered to a subject in need thereof in a suitable manner, for example by oral, parenteral (intravenous, subcutaneous, intramuscular, intraperitoneal or intrathecal injection), pulmonary, nasal, sublingual, rectal, vaginal, dermal or mucosal administration.

The therapeutically effective amount of the compounds 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 particular compound being administered and the route of administration, etc., and can be selected and adjusted by the attending physician according to routine practice. In general, an effective amount of a compound of the present invention administered in a single dose or in 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 adequate, while in other cases larger doses may be used with acceptable side effects, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.

Examples

The compounds of the present invention may be prepared by a variety of methods, some of which are set forth in the examples below. It should be understood that these specific methods do not limit the present invention in any way. The reagents and starting materials used in the following examples were obtained from commercial suppliers or were prepared by one of ordinary skill in the art.

Commonly used abbreviation notes:

PE = petroleum ether; EA = ethyl acetate; meoh=methanol; DCM = dichloromethane; DCE = dichloroethane; CH (CH) ₃ Cn=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=cyanohydrinCopper; triphosgene = triphosgene; p-tsoh=p-toluenesulfonic acid.

EXAMPLE 1 preparation of key intermediates

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

step 1: under the protection of nitrogen, the raw material a1-1 (18.5 g,100.0 mmol) is dissolved in 120mL of concentrated sulfuric acid, dibromohydantoin a1-2 (14.3 g,50.0 mmol) is slowly added, the temperature is raised to 80 ℃ for reaction for 2 hours, and the reaction solution is cooled to room temperature. The reaction solution was poured into 300mL of ice water, pale yellow solid was washed out, suction filtration was performed, and the cake was washed and dried to obtain intermediate a1-3 (24 g), yield: 91%.

Step 2: 2-chloro-5-fluoro-benzaldehyde a1-4 (2.4 g,15.1 mmol) and (4-methoxyphenyl) methylamine (2.1 g,15.1 mmol) were dissolved in 40mL of methanol, stirred for 5 minutes, then the above intermediate a1-3 (4.0 g,15.1 mmol) and tert-butyl isocyanate (1.2 g,15.1 mmol) were added and reacted at room temperature for 2 hours, and the reaction was stopped by LC-MS monitoring the reaction completion. 100mL of water was added to the system, extraction was performed with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography (PE/EA, 3/1) to give intermediate a1-5 (7.0 g) as a pale yellow solid, yield: 74%. LC-MS: [ M+H ]] ⁺ ＝624.8。

Step 3: the intermediate a1-5 (1.0 g,1.6 mmol) of the above step was dissolved in 10mL of acetonitrile, and 2-tert-butyl-1, 3-tetramethylguanidine (0.4 g,2.3 mmol) as a raw material was added thereto, and the mixture was heated to 50℃for 2 hours. Cooled to room temperature, 50mL of ice water is added to the system, ethyl acetate is used for extraction, the organic phases are combined, anhydrous sodium sulfate is used for drying, the solvent is removed by decompression, crude products a1-6 are obtained, and the next reaction is directly carried out. LC-MS: [ M+H ]] ⁺ ＝521.0。

Step 4: the crude product a1-6 obtained in the above step was dissolved in 5mL of trifluoroacetic acid, triethylsilane (0.9 g,7.5 mmol) was added, and the reaction was stopped after heating to 90℃for 5 hours. Adding saturated sodium bicarbonate water slowly to quench the reaction, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating, and separating by column chromatography (PE/EA, 5/1) to obtain To yellow solid a1 (140 mg), two-step yield: 17%. LC-MS: [ M+H ]] ⁺ ＝505.7。

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

the steps are as follows: intermediate a1 (93 mg,0.18 mmol), reduced iron powder (72 mg,1.3 mmol) and ammonium chloride (69 mg,1.3 mmol) were dissolved in 5mL ethanol, 1mL water was added, the temperature was raised to 80℃for 2 hours, cooled to room temperature, and suction filtration was performed. To the system was added 20mL of ice water, extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated, and the crude product was separated by column chromatography (PE/EA, 3/1) to give intermediate a2 (30 mg), yield: 35%. LC-MS: [ M+H ]] ⁺ ＝475。

Synthesis of intermediates a3, a4

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a3N- (6-bromo-3- (2-chloro-5-fluorophenyl) -2- (4-methoxybenzyl) -1-oxoisoindolin-4-yl) -3-fluoro-5- (trifluoromethyl) benzamide

The steps are as follows: raw material intermediate a2 (50 mg,0.001 mmol) and pyridine (33 mg, 0.04 mmol) were dissolved in 5mL of acetonitrile, and after stirring for 10 minutes, 3-fluoro-5-trifluoromethyl-benzoyl chloride a3-1 (38 mg, 0.002mmol) was added to the system and reacted at room temperature for 16 hours. LC-MS monitored reaction was complete, water 20mL was added to the system, ethyl acetate was used to extract, the organic phases were combined, dried over anhydrous sodium sulfate, flash column chromatography (PE/EA, 3/1) to give yellow solid a3 (30 mg), yield: 45%. LC-MS: [ M+H ] ] ⁺ ＝665。

According to the synthetic route, the following intermediates are synthesized by adopting corresponding raw materials/similar frameworks:

synthesis of intermediates a5, a6, a9

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

Step 1: intermediate a3 (220 mg,0.33 mmol) and vinyl borate a5-1 (53 mg,0.34 mmol) were dissolved in 6mL of a mixed solution of 1, 4-dioxane and water (v/v, 5/1) under nitrogen. Sodium carbonate (52 mg,0.49 mmol) and Pd (dppf) Cl were added ₂ (24 mg,0.033 mmol) was reacted at 110℃for 6 hours. LC-MS detection reaction was complete, 30mL of ice water was added to the system, the organic solvent was distilled off under reduced pressure, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE/EA, 1/1) to give white solid a5-2 (112 mg), yield: 55%. LC-MS: [ M+H ]] ⁺ ＝613。

Step 2: the intermediate a5-2 (100 mg,0.16 mmol) of the above step and potassium osmium sulfate (1 mg) were dissolved in 5mL of acetone, and 5mL of water and NaIO were added ₄ (422 mg,1.63 mmol). Stirring was carried out at room temperature for 6 hours, the reaction was stopped, and filtration was carried out. The solvent was distilled off under reduced pressure, and the residue was separated by column chromatography (PE/EA, 1/1) to give a white solid a5-3 (30 mg), yield: 30%. LC-MS: [ M+H ]] ⁺ ＝615。

Step 3: 0.1mL of hydrazine hydrate was dissolved in 2mL of ethanol; after dissolving the intermediate a5-3 (60 mg,0.1 mmol) in 2mL of ethanol, the hydrazine hydrate solution was added and stirred at room temperature for 4 hours. The mixture was placed in an ice bath, ethylenediamine (0.2 mL), cuCl (20 mg,0.2 mmol) and trifluoromethane (0.3 mL) were added in this order to the system, and the reaction was continued for 6 hours. To the reaction solution was added 30mL of ice water to quench the reaction, followed by filtration, extraction with ethyl acetate, drying over anhydrous sodium sulfate, concentration, and column chromatography (PE/EA, 1/1) to give a pale yellow solid a5 (58 mg), yield: 80%. LC-MS: [ M+H ] ] ⁺ ＝709.8。

synthesis of intermediates a7, a8, a10, a12-a 14:

a7 (E) -N- (6- (2-bromo-2-fluorovinyl) -3- (2-chloro-5-fluorophenyl) -1-oxoisoindolin-4-yl) -3-fluoro-5- (trifluoromethyl) benzamide

The steps are as follows: intermediate a5 (50 mg,0.07 mmol) was dissolved in 5mL methanesulfonic acid under nitrogen, and the temperature was raised to 60℃for 4 hours. LC-MS detected completion of the reaction, quenched by addition of 30mL of saturated aqueous sodium bicarbonate to the system, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM/MeOH, 15/1) to give a yellow solid a7 (28 mg), yield: 66%. LC-MS: [ M+H ]] ⁺ ＝589.7。

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synthesis of intermediate a 11:

step 1: under nitrogen, intermediate a12 (2.6 g,7.3 mmol), pinacol biborate (2.2 g,8.8 mmol) and potassium acetate (2.2 g,21.9 mmol) were dissolved in 52mL 1, 4-dioxane and the catalyst Pd (dppf) Cl was added ₂ (300 mg,0.4 mmol) was reacted at 100℃for 3 hours, and the reaction was monitored by LC-MS and filtered. 100mL of water is added into the filtrate, the mixture is extracted by ethyl acetate, dried by anhydrous sodium sulfate, concentrated and the crude product is passed through a flash column Chromatography (PE/EA, 2/1) gave compound a11-1 (1.3 g), yield: 44%. LC-MS: [ M+H ]] ⁺ ＝403。

Step 2: the intermediate a11-1 (1.0 g,2.5 mmol) and pyridine (1.0 g,12.4 mmol) of the above step were dissolved in 20mL of methylene chloride, and 3-fluoro-5-trifluoromethyl-benzoyl chloride a3-1 (0.8 g,3.7 mmol) was added to react at room temperature for 1 hour to stop the reaction. To the reaction solution was added 100mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (PE/EA, 1/1) to give compound a11 (900 mg), yield: 71%. LC-MS: [ M+H ]] ⁺ =511 [ boric acid ]] ⁺ 。

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

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step 1: raw material b1-1 (10.0 g,42.1 mmol) was dissolved in 100mL tetrahydrofuran and TMSCF was added ₃ (11.99 g,84.3 mmol) and tetrabutylammonium fluoride TBAF (2.2 g,8.4 mmol) were reacted at room temperature for 12 hours and the completion of the reaction was monitored by LC-MS. The system was quenched by adding saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give crude b1-2.LC-MS: [ M+H ]] ⁺ ＝308.1。

Step 2: the crude product b1-2 (2.0 g) from the previous step was dissolved in 20mL of tetrahydrofuran, borane tetrahydrofuran complex (2.8 g,32.5 mmol) was added and reacted at room temperature for 12 hours, and LC-MS monitored the reaction was complete. The system was quenched by adding 3M hydrochloric acid, adjusting pH to about 8 with 1N aqueous sodium hydroxide solution, extracting with methylene chloride, drying over anhydrous sodium sulfate, concentrating, and separating by column chromatography to give compounds b1-3 (1.3 g). LC-MS: [ M+H ] ] ⁺ ＝294。

Step 3: the intermediates b1-3 (2.0 g,6.5 mmol) of the above step were reacted with Pd (OH) under a hydrogen atmosphere at 4atm (4 atm.) ₂ (38 mg,0.27 mmol) was dissolved in 10mL of methanol, and the reaction was stopped at room temperature for 12 hours. Filtration, evaporation of the solvent under reduced pressure, column chromatography (PE/EA, 7/3) gave b1 (331 mg) as an off-white solid, yield: 60%. LC-MS: [ M+H ]] ⁺ ＝204。

Synthesis of intermediates b2-b 3:

step 1: intermediate a12 (1.5 g,4.2 mmol) and DIEA (1.6 g,12.7 mmol) were dissolved in 15mL of dichloromethane under nitrogen and triphosgene (1.5 g,5.1 mmol) was added and stirred for 2 hours under ice. To the reaction mixture was added intermediate b1 (2.8 g,12.7 mmol), and the reaction was stopped after warming to room temperature for 12 hours. To the reaction solution was added 50mL of ice-water, extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 4/5) to give compounds b2-1 (125 mg) and b2-2 (25 mg). LC-MS: [ M+H ]] ⁺ ＝602。

Step 2: under the protection of nitrogen, the intermediate b2-1 (125 mg,0.2 mmol), pinacol biborate (63 mg,0.3 mmol) and potassium acetate (45 mg,0.5 mmol) of the above step are dissolved in 2mL of 1, 4-dioxane, and the catalyst Pd (dppf) Cl is added ₂ (7.6 mg,0.012 mmol) at 90℃for 2 hours, the LC-MS monitoring reaction was complete, cooled to room temperature and filtered. To the filtrate, 10mL of water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give compound b2, which was directly used for the next reaction. LC-MS: [ M+H ] ] ⁺ ＝650。

According to the above synthetic route, the following intermediates are synthesized by adopting corresponding raw materials/similar frameworks:

synthesis of intermediates c1-c 5:

step 1: raw materials c1-1 (3.0 g,13.6 mmol) and tetrahydropyrrole c1-2 (1.0 g,13.6 mmol) were dissolved in 30mL DMSO, potassium carbonate (2.8 g,20.5 mmol) was added, and the mixture was warmed to 120℃and reacted for 3 hours, and cooled to room temperature. 100mL of water was added to the reaction mixture, extraction was performed with ethyl acetate, and the mixture was taken as a saturated dietBrine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 4/5) to give compound c1-3 (2.0 g), yield: 54%. LC-MS: [ M+H ]] ⁺ ＝271。

Step 2: the intermediate c1-3 (2.0 g,7.4 mmol) and iron powder (2.1 g,36.9 mmol) of the above step were dissolved in a mixed solution of 20mL of ethanol and water (v/v, 9/1), acetic acid (0.7 g,11.1 mmol) was added dropwise, and the mixture was heated to 80℃for 4 hours and cooled to room temperature. To the reaction solution was added 100mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 4/5) to give compound c1-4 (1.0 g), yield: 56%. LC-MS: [ M+H ]] ⁺ ＝241。

Step 3: the intermediate c1-4 (1.0 g,4.1 mmol) of the above step was dissolved in 10mL of ethyl acetate, and H was added dropwise ₂ O ₂ (30%, 2.8g,82.9 mmol), and after completion of the addition, the mixture was heated to 80℃and reacted for 72 hours, and cooled to room temperature. To the reaction solution was added 50mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 4/5) to give compound c1 (500 mg), yield: 51%. LC-MS: [ M+H ] ] ⁺ ＝237。

synthesis of intermediate c 6:

the steps are as follows: under the protection of nitrogen, the raw materials 3-bromophenylhydrazine c6-1 (500 mg,2.6 mmol) and cyclobutylmethyl ketone c6-2 (262 mg,2.6 mmol) are dissolved in 5mL of acetic acid, heated to 100 ℃ for reaction for 1 hour, cooled to room temperature and the solvent is distilled off under reduced pressure. The crude product was separated by flash reverse column chromatography (acetonitrile/water, 3/4) to give c6 (350 mg) as a white solid, yield: 52%. LC-MS: [ M+H ]] ⁺ ＝250。

Synthesis of intermediates c7-c 9:

the steps are as follows: under the protection of nitrogen, the raw materials of 3-bromophenylhydrazine c6-1 (500 mg,2.6 mmol) and cyclopentylmethyl ketone c7-1 (262 mg,2.6 mmol) are dissolved in 5mL of acetic acid, heated to 100 ℃ for reaction for 1 hour, cooled to room temperature and the solvent is distilled off under reduced pressure. The crude product was separated by flash reverse column chromatography (acetonitrile/water, 3/4) to give c7 (70 mg) as a yellow solid, yield: 10%. LC-MS: [ M+H ]] ⁺ ＝264。

synthesis of intermediate c 10:

the steps are as follows: under the protection of nitrogen, the raw materials of 2-amino-6-bromobenzothiazole c10-1 (2.0 g,8.7 mmol) and chloroacetaldehyde c10-2 (6.8 g,87.3 mmol) are dissolved in 40mL of ethanol, heated to 80 ℃ for reaction for 12 hours, cooled to room temperature and the solvent is distilled off under reduced pressure. The crude product was separated by flash reverse column chromatography (acetonitrile/water, 3/4) to give c10 (1.0 g) as a white solid, yield: 41%. LC-MS: [ M+H ] ] ⁺ ＝253。

Intermediate c11, c12 synthesis:

step 1: the starting pyrrolidone c11-2 (400 mg,5.2 mmol) was dissolved in 10mL of DMF under nitrogen, naH (200 mg,6.2 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 2, 4-dichloro-5-nitropyridine c11-1 (1.0 g,5.1 mmol), and the reaction was stopped at room temperature for 3 hours. 100mL of water and ethyl acetate were added to the reaction mixtureEster extraction, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating, and flash reverse column chromatography (acetonitrile/water, 3/5) to obtain compound c11-3 (1.2 g), yield: 96%. LC-MS: [ M+H ]] ⁺ ＝242。

Step 2: the intermediate c11-3 (1.0 g,4.1 mmol), ammonium chloride (886 mg,16.5 mmol) and iron powder (1.1 g,20.5 mmol) were dissolved in 10mL of a mixed solution of ethanol and water (v/v, 4/1), heated to 80℃and reacted for 4 hours, cooled to room temperature and filtered. To the filtrate was added 100mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 7/10) to give compound c11-4 (800 mg), yield: 91%. LC-MS: [ M+H ]] ⁺ ＝212。

Step 3: the intermediate c11-4 (500 mg,2.3 mmol) obtained in the above step was dissolved in 5mL of ethyl acetate, and Compound c11-5 (460 mg,2.8 mmol) was added thereto, and the mixture was heated to 115℃for 4 hours and cooled to room temperature. To the reaction solution was added 50mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 1/1) to give compound c11 (350 mg), yield: 77%. LC-MS: [ M+H ] ] ⁺ ＝194。

intermediate c13 synthesis:

step 1: under nitrogen protection, the starting material, methyl 2-bromo-3-thiophenecarboxylate c13-1 (6.0 g,27.1 mmol) and CuCN (3.2 g,35.3 mmol), were dissolved in 125mL NMP, warmed to 120℃for 14 hours, and cooled to room temperature. 300mL of ice water was added to the system, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 4/5) to give c13-2 (1.6 g) as a brown solid, yield: 35%. LC-MS:[M+H] ⁺ ＝168。

step 2: the intermediate c13-2 (1.6 g,9.6 mmol) of the previous step and titanium tetraisopropoxide Ti (OiPr) are reacted under nitrogen protection at-60 DEG C ₄ (3.0 g,10.5 mmol) was dissolved in 45mL diethyl ether, and Grignard reagent ethyl magnesium bromide (2.8 g,21.1mmol, 2M) was added and stirred at-60℃for 1 hour. Boron trifluoride diethyl etherate (2.7 g,19.1 mmol) was added dropwise to the reaction mixture, and after the addition, the mixture was warmed to room temperature and reacted for 2 hours, and 30mL of 1M diluted hydrochloric acid was added to quench the reaction. Ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 4/5) to give c13-3 (420 mg) as a brown solid, yield: 27%. LC-MS: [ M+H ] ] ⁺ ＝166。

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

Intermediate c14, c15 synthesis:

the steps are as follows: under nitrogen protection at-60 ℃, the raw materials, namely, methyl 2-cyano-5-bromo-benzoate c14-1 (500 mg,2.0 mmol) and titanium tetraisopropoxide Ti (OiPr) ₄ (829 mg,2.9 mmol) was dissolved in 12mL diethyl ether, and Grignard reagent ethyl magnesium bromide (2.6 mL,5.2mmol, 2M) was added and stirred at-60℃for 1 hour. Boron trifluoride diethyl etherate (0.5 mL,4.1 mmol) was added dropwise to the reaction mixture, and after the addition, the mixture was warmed to room temperature and reacted for 2 hours, and 30mL of 1M diluted hydrochloric acid was added to quench the reaction. Ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 7/10) to give green solid c14 (200 mg), yield: 40%. LC-MS: [ M+H ]] ⁺ ＝238。

Intermediate c16 synthesis:

step 1: the starting material 2-amino-3-hydroxy-4-bromo-nitrobyc 16-1 (3.0 g,12.8 mmol) and 1, 2-dibromoethane (9.6 g,51.4 mmol) were dissolved in 30mL DMSO under nitrogen, cesium carbonate (16.7 g,51.4 mmol) was added, and the mixture was allowed to react at 85℃for 3 hours and cooled to room temperature. 100mL ice water was added to the system, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 3/4) to give a red solid, c16-2 (2.1 g), yield: 63%. LC-MS: [ M+H ]] ⁺ ＝259。

Step 2: the intermediate c16-2 (2.0 g,7.7 mmol), ammonium chloride (1.6 g,30.8 mmol) and iron powder (1.2 g,23.1 mmol) were dissolved in a 20mL mixed solution of ethanol and water (v/v, 3/1), heated to 80℃for 2 hours, cooled to room temperature, and filtered. To the filtrate was added 100mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 7/10) to give compound c16-3 (1.5 g), yield: 85%. LC-MS: [ M+H ]] ⁺ ＝229。

Step 3: under the protection of nitrogen, the intermediate c16-3 (500 mg,2.1 mmol) in the previous step was dissolved in 5mL trimethyl orthoformate, p-TsOH (100 mg,0.4 mmol) was added, and the reaction was stopped after heating to 100℃for 2 hours. 100mL ice water was added to the system, extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, concentrated, and the crude product separated by flash reverse column chromatography (acetonitrile/water, 3/5) to give a red solid, c16 (1.0 g), yield: 92%. LC-MS: [ M+H ] ] ⁺ ＝239。

Intermediate c17 synthesis:

step 1: the starting material, 2-hydroxy-4-bromo-benzaldehyde c17-1 (500 mg,2.5 mmol) and aqueous ammonia (0.8 mL) were dissolved in 5mL of methanol under nitrogen, glyoxal (720 mg,12.4 mmol) was added, and the mixture was warmed to 40℃and allowed to react for 36 hours, and cooled to room temperature. 100mL of ice water was added to the system, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash reverse column chromatography (acetonitrile/water, 3/4) to give c17-2 (400 mg) as a yellow solid, yield: 67%. LC-MS: [ M+H ]] ⁺ ＝239。

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

Intermediate c18-c27 synthesis:

the steps are as follows: 1N-isopropyl-4-iodoimidazole c18-1 (50 mg,0.2 mmol) and iPrMgCl (0.3 mL, 2M) were dissolved in 4mL anhydrous tetrahydrofuran under nitrogen protection in an ice bath, and stirred for 1 hour under ice bath. Adding tributyltin chloride n-Bu into the reaction solution ₃ SnCl (138 mg,0.4 mmol) was reacted further for 1 hour, and the reaction was stopped. To the reaction solution was added 20mL of a saturated aqueous potassium fluoride solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give c18 (80 mg) as a yellow oil, which was directly subjected to the next reaction. LC-MS: [ M+H ]] ⁺ ＝401。

According to the above synthetic route, the following intermediates (c 19-c 27) were synthesized using the corresponding starting materials:

example 2: synthesis of target molecules P1-P2, P6-P7, P18-P19

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

Step 1: under nitrogen, intermediate a7 (100 mg,0.17 mmol), 1-H-4-pyrazolylboronic acid pinacol ester P1-1 (40 mg,0.2 mmol) and sodium carbonate (60 mg,0.56 mmol) were dissolved in 5mL of a mixed solution of 1, 4-dioxane and water (v/v, 9/1), and Pd (dppf) Cl was added ₂ (14 mg,0.017 mmol) was reacted at 110℃for 4 hours. Cooled to room temperature, filtered with suction, the system was added with water, extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM/MeOH, 12/1) to give P1 (8.0 mg) as a pale yellow solid, yield: 8%. LC-MS: [ M+H ]] ⁺ =577. HPLC purity: 96.06%.

¹ H NMR(400MHz,DMSO-d ₆ )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)。

The other compounds (P2, P6-P7) of example 2 were synthesized following the above synthetic route using the corresponding starting materials/intermediates:

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example 3: synthesis of target molecule P3

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) indoline-1-carboxamide

Step 1: under nitrogen, intermediate a10 (50 mg,0.125 mmol), 1-N-methyl-4-pyrazolylboronic acid pinacol ester P2-1 (26 mg,0.135 mmol) and sodium carbonate (27 mg,0.25 mmol) were dissolved in 5mL of a mixed solution of 1, 4-dioxane and water (v/v, 9/1), and Pd (dppf) Cl was added ₂ (9 mg,0.013 mmol) was reacted at 110℃for 4 hours. Cooled to room temperature, filtered with suction, the system was added with water, extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM/MeOH, 12/1) to give yellow solid P3-1 (30 mg), yield: 60%. LC-MS: [ M+H ]] ⁺ ＝401。

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

¹ H NMR(400MHz,DMSO-d ₆ )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)。

Step 3: the solid P3 was chromatographed by HPLC to give the diastereomers P3a (peak 1) and P3b (peak 2)

The other compounds (P4-P5) of example 3 were synthesized following the above synthetic route, using the corresponding starting materials or intermediates:

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example 4: synthesis of target molecule H1

H1N- (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) indoline-1-carboxamide

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 16mL of a mixed solution of 1, 4-dioxane and water (v/v, 3/1), and the catalyst DCM-Pd (dppf) Cl was added ₂ (34 mg,0.042 mmol), warmed to 100℃and reacted for 4 hours, cooled to room temperature and suction filtered. Water was added to the system, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, and concentration was performed. The crude product was separated by flash column chromatography (DCM/MeOH, 10/1) to give compound H1-2 (310 mg), yield: 85%. LC-MS: [ M+H ]] ⁺ ＝433。

Step 2: triphosgene (26 mg,0.088 mmol) and pyridine (28 mg,0.35 mmol) were dissolved in 3mL of dichloromethane in an ice bath. To the reaction solution was added 3mL of a dichloromethane solution of step intermediate H1-2 (95 mg,0.22 mmol), and the mixture was stirred for 30 minutes after the completion of the addition. Intermediate b1 (50 mg,0.22 mmol) was added to the system and the reaction was stopped at room temperature for 1 hour. The solvent was evaporated under reduced pressure, 40mL of saturated aqueous sodium bicarbonate was added to the system, extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, and separated by TLC thin layer chromatography (DCM/MeOH, 8/1) to give H1 (52 mg) as a pale yellow solid, yield: 34%. LC-MS: [ M+H ] ] ⁺ ＝681。

¹ HNMR(400MHz,DMSO-d ₆ )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＝12.0Hz,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)。

Example 5: synthesis of target molecule H2

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The steps are as follows: 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 2mL of a mixed solution of 1, 4-dioxane and water (v/v, 3/1), and catalyst Pd (PPh) ₃ ) ₂ Cl ₂ (16 mg,0.02 mmol), warmed to 90℃and reacted for 1 hour, cooled to room temperature and suction filtered. To the filtrate was added 10mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC (column GreenSep Naphthyl 4.6.6X 100mm,3 μm; mobile phase A: hex (1% 2M NH) ₃ -MeOH); mobile phase B: meOH) to give compound H2a (9.2 mg), yield: 9%. LC-MS: [ M+H ]] ⁺ ＝680。

¹ H NMR(400MHz,DMSO-d ₆ )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).

The other compounds (H2 b) of example 5 were synthesized following the above synthetic route, using the corresponding starting materials or intermediates:

example 6: synthesis of target molecule H3-H19

The steps are as follows: 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 2mL of a mixed solution of 1, 4-dioxane and water (v/v, 3/1), and catalyst Pd was added(PPh ₃ ) ₂ Cl ₂ (16 mg,0.02 mmol), warmed to 100℃for 3 hours, cooled to room temperature and suction filtered. To the filtrate was added 10mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated by HPLC (Column: xselect CSH C18 OBD Column 30X 150mm 5 μm; mobile phase A:10mmol/L NH) ₄ HCO ₃ The method comprises the steps of carrying out a first treatment on the surface of the Mobile phase B: CH ₃ CN) to give compound H3 (17 mg), yield: 17%. LC-MS: [ M+H ]] ⁺ ＝641。

¹ H NMR(400MHz,DMSO-d ₆ )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).

The other compounds (H4-H19) of example 6 were synthesized following the above synthetic route using the corresponding starting materials or intermediates:

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example 7: synthesis of target molecule P8-P17

The steps are as follows: intermediate a7 (59 mg,0.1 mmol) and intermediate c18 (20 mg,0.1 mmol) were dissolved in 1mL of DMF under nitrogen, and catalyst Pd (dppf) Cl was added ₂ (14 mg,0.017 mmol) was reacted at 130℃for 3 hours. Cooling to room temperature, suction filtering, adding water 5mL into the filtrate, extracting with ethyl acetate, mixing organic phases, drying with anhydrous sodium sulfate,concentration and flash reverse column chromatography (acetonitrile/water, 1/1) gave P8 (6.5 mg) as a pale yellow solid, yield: 11%. LC-MS: [ M+H ]] ⁺ ＝619。

¹ H NMR(300MHz,DMSO-d ₆ )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).

The other compounds of example 7 (P9-P17) were synthesized following the above synthetic route, using the corresponding starting materials/intermediates:

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example 8: chiral resolution of target molecule P1

Resolution conditions:

chromatographic column: welflash C18-I,20-40um,120g; mobile phase A water (10 mmol/L NH) ₄ HCO ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the Mobile phase B, acetonitrile; the method comprises the steps of carrying out a first treatment on the surface of the Flow rate: 60mL/min; gradient 50%B to 65%B in 15min;

P1a： ¹ H NMR(400MHz,DMSO-d ₆ )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).

P1b： ¹ H NMR(400MHz,DMSO-d ₆ )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).

example 9: analysis of inhibitory Activity of Compounds on kinase PI3K alpha (545K mutation) and wild type PI3K alpha

Using ECHO (PE, model 550), 40nL of solvent DMSO as control, positive compound alpeliib or test compound (10 concentration gradients diluted 3 times from 3. Mu.M) was added to 384 well plates (ProxiPlate-384 plus, perkinelmer, cat. No. 6008280), 2. Mu.L of 2 XPi3K.alpha. (Invitrogen, cat. No. PV 4788) or PI 3K.alpha.E545K mutant (Promega, cat. No. V1731) working solution was added to each well, mixed by shaking for 30 seconds, and incubated at 25℃for 15 minutes. To each well was added 2. Mu.L of 2 Xsubstrate working solution (Promega, catalog number V1701) and incubated at 25℃for 1 hour in a plate; mu.L of a solution containing 10mM MgCl was added to each well ₂ ADP-Glo reagent buffer (Promega, catalog number V9102), plates incubated at 25℃for 40 min; subsequently, 8. Mu.L of a kinase assay solution (Promega, catalog number V9102) was added to each well, and incubated at 25℃for 40 minutes in the plate; the plate was swept using Envision 2105 and the luminescence signal values were recorded.

Data analysis:

inhibition ratio (%) = [1- (RLU mean of test compound-RFU mean of positive control)/(RFU mean of vehicle control-RFU mean of positive compound) ] ×100%

RLU: relative luminescence signal values.

RFU: relative fluorescence unit signal value.

IC ₅₀ Calculating a value:

y=lower plateau signal + (upper plateau signal-lower plateau signal)/(1+10 ((log ic) ₅₀ -X) X Hill slope)

X is the log value of the compound concentration;

inhibition (%).

Table 1: half Inhibition Concentration (IC) of compounds against kinase PI3K alpha wild type and PI3K alpha (E545K) ₅₀ )

N.d. =untested.

The experimental result shows that the compound has better inhibition on the mutant PI3K alpha and weaker inhibition on the wild PI3K alpha, and the selective inhibition on the mutant PI3K alpha by the compound is reflected.

Example 10: phosphorylation inhibition (pAKT) activity of compounds against AKT downstream of intracellular PI3kα (E545K).

Intracellular inhibition assay of the compounds of the invention on mutant PI3kα (E545K) HCC2185 cells:

HCC2185 cells cultured in RPMI1640 (Gibco, cat.no. a 10491-01) containing 10% fetal bovine serum and 1% penicillin were seeded on 384-well microplates and incubated for 12 hours at 37 ℃ under 5% carbon dioxide. 200 μl of the compound at different concentrations (final concentration of dimethyl sulfoxide 0.5%) was added to each well using Echo550 (labyte, echo 550) and incubated at 37deg.C for 2 hours. Cells were then fixed in 8% fixative (Solarbio, cat. No. p 1112) and washed once with Phosphate Buffer (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 removal of blocking solution, anti-phospho-Akt (S473) Rabbit mAb (CST, cat.No.4060S) and GAPDH (D4℃ 6R) Mouse mAb (CST, cat.No.97166S) antibody working solution were added to each well and incubated at 4 ℃ for 12 hours. The microwell plates were washed three times with PBS solution (PBST) containing 0.1% Tween-80, IRDye 800CW gold 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 microwell plates were incubated at room temperature in the absence of light. After washing the microplate three times using PBST, the microplate was centrifuged at 1000rpm for 1 minute, the read plate was scanned using an Odyssey CLx (LI-COR) instrument, signal values were recorded and IC was calculated ₅₀ Values.

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

table 2: results of inhibition of HCC2185 pAKT by Compounds on E545K mutant cells

Compounds of formula (I)	pAKT(S473)-HCC2185 IC ₅₀ /μM
		P1	0.32
P2	0.58
		P12	0.34

N.d. =untested

The above results indicate that: the molecule provided by the invention has a good inhibition effect on PI3K alpha E545K mutant cells.

Example 11: the compounds have inhibitory (pAKT) activity against phosphorylation of AKT downstream of intracellular PI3kα (H1047R).

Intracellular inhibition assay of the compounds of the invention for mutant pi3kα (H1047R) HCC1954 (or MDA-MB-453):

HCC1954 cells (or MDA-MB-453) cultured in RPMI1640 (Gibco, cat. No. A10491-01) containing 10% fetal bovine serum and 1% penicillin were seeded on 384-well microplates and incubated at 37℃for 12 hours under 5% carbon dioxide. 200 μl of the compound at different concentrations (final concentration of dimethyl sulfoxide 0.5%) was added to each well using Echo550 (labyte, echo 550) and incubated at 37deg.C for 2 hours. Cells were then fixed in 8% fixative (Solarbio, cat. No. p 1112) and washed once with Phosphate Buffer (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 removal of blocking solution, anti-phospho-Akt (S473) Rabbit mAb (CST, cat.No.4060S) and GAPDH (D4℃ 6R) Mouse mAb (CST, cat.No.97166S) antibody working solution were added to each well and incubated at 4 ℃ for 12 hours. Microplates were washed three times with PBS solution (PBST) containing 0.1% Tween-80, IRDye 800CW gold anti-Rabbit IgG (H+L) (LI-COR, cat. No. 926-32211) and IRDye 680RD Goat anti Mouse IgG (H+L) (LI-COR, ca) t.No. 926-68070) antibody working solution, and microwell plates were incubated at room temperature in the dark. After washing the microplate three times using PBST, the microplate was centrifuged at 1000rpm for 1 minute, the read plate was scanned using an Odyssey CLx (LI-COR) instrument, signal values were recorded and IC was calculated ₅₀ Values.

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

table 3: inhibition of pAKT by compounds on HCC1954 cells

Compounds of formula (I)	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

N.d. =untested

Control molecule 1 Structure

The above results indicate that: the molecule provided by the invention has a good inhibition effect on PI3K alpha H1047R mutant cells.

The pAKT inhibition results of the compounds against PI3kαh1047r mutated breast cancer cells MDA-MB-453 are shown in table 4 below:

table 4: inhibition of pAKT of MDA-MB-453 cells by Compounds

Compounds of formula (I)	pAKT(S473)-MDA-MB-453IC ₅₀ /μM
		P18	0.22

Example 12: liver microsomal stability assay of the compounds.

The method comprises the following steps:

the compound of the invention is subjected to liver microsome stability test research, the compound to be tested is incubated with liver microsomes of different species with or without NADPH, the final concentration of the compound to be tested in a test system is 1 mu M, the final concentration of NADPH is 1mM, and the final concentration of the liver microsome is 0.5mg/mL. The concentration of compound in the incubation supernatants at various time points over 60 minutes was measured and pharmacokinetic parameters (e.g., clearance Cl _int )。

Table 5 metabolic stability of compounds in human liver microsomes:

the results show that the molecules of the invention have better metabolic stability in human bodies and are expected to be clinically administered at lower doses.

Claims

1. A compound of formula (I):

wherein:

L ₁ is a bond or optionally R ₅ Substituted C _2-6 Alkenylene;

R ₅ is halogen, -CN, C _1-6 Alkyl or halo C _1-6 An alkyl group;

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 containing 1-4A 3-10 membered heterocyclic group independently selected from heteroatoms of nitrogen, oxygen and sulfur, and

n is any integer from 0 to 4,

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof, wherein:

n is any integer from 0 to 3.

3. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof, wherein:

R ₁ Is phenyl, benzothienyl or indolinyl, and is optionally substituted with 1 to 3 groups independently selected from halogen, -OH, C _1-6 Alkyl and halogenated C _1-6 Substituent substitution of alkyl;

R ₂ each independently selected from halogen or halo C _1-6 An alkyl group;

L ₁ for bonding or for substitution by halogen or-CN _2-4 Alkenylene;

n is any integer from 0 to 2.

Provided that when L ₁ R is a bond ₃ Is a 10-14 membered tricyclic heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur or a 10-14 membered tricyclic heterocyclyl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally is independently selected from C by 1-3 _1-6 Alkyl, halogen, -CN, oxo and C _3-8 The substituents of cycloalkyl groups are substituted.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof, having formula (II):

wherein:

R ₂ each independently selected from halogen;

n is 1 or 2.

5. The compound of claim 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof, wherein:

R ₁ is phenyl or indolinyl, and is optionally substituted with 1-3 groups independently selected from halogen, -OH, C _1-6 Alkyl and halogenated C _1-6 The substituent of the alkyl group is substituted,

R ₂ each independently selected from halogen;

n is 1 or 2.

6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof, having formula (III):

wherein:

R ₂ each independently selected from halogen;

n is 1 or 2.

7. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof, wherein:

R ₂ each independently selected from halogen;

n is 1 or 2.

8. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof, wherein the compound is selected from the group consisting of:

9. A pharmaceutical composition comprising a compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for the manufacture of a medicament for the prevention and/or treatment of PI3K alpha mediated diseases.

11. The use of claim 10, wherein the disease is cancer.

12. The use of claim 10, wherein the PI3kα has at least one mutation selected from the group consisting of: E542K, E545K and H1047R.