pi3kα allosteric inhibitors

Abstract

The present application relates to allosteric inhibitors of PI3Ka. In particular, to compounds of Formula (I) useful as selective allosteric inhibitors of PI3Ka (H1047R mutation), pharmaceutical compositions comprising said compounds, and the use of said compounds and pharmaceutical compositions for the treatment of PI3Ka mediated diseases, in particular cancer.

Description

[0001] This application claims priority to Chinese Patent Application No. 2022115711994, filed on December 15, 2022. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to compounds that can be used as selective allosteric inhibitors of mutant PI3Kalpha, pharmaceutical compositions comprising such compounds, and the use of the compounds and pharmaceutical compositions for the prevention and / or treatment of diseases mediated by PI3Kalpha, in particular cancer. BACKGROUND

[0003] Phosphatidylinositol-3 kinases (PI3Ks) are intracellular enzymes that phosphorylate the 3-OH group of the inositol ring of phosphatidylinositol membrane lipids, and mainly regulate cell growth, proliferation, differentiation, and migration, etc. (J. Med. Chem. 2019, 62, 4815-4850). PI3Ks can phosphorylate phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) (Nature, 1997, 387, 673-676); and PIP3 can activate downstream messenger proteins, including AKT (protein kinase B, PKB) and mTOR (mammalian target of rapamycin).

[0004] PI3Ks are classified into Class I, Class II, and Class III based on structural features. Class I PI3Ks are the most widely studied, including IA and IB. Class IA includes PI3Kα, PI3Kβ, and PI3Kδ; Class IB is PI3Kγ. PI3Kα and PI3Kβ are widely expressed in all tissues, while PI3Kδ and PI3Kγ are mainly expressed in hematopoietic cells, endothelial cells, and central nervous system. PI3Kα contains a catalytic subunit p110α and a regulatory subunit p85, and mutations in PI3Kα are widely found in various cancers. The Cancer Genome Atlas (TCGA) analysis of more than 3000 cancer mutations showed that the gene PIK3CA encoding PI3Kα is the second most common mutation cancer gene. There are three most common mutations in PI3Kα: E542K, E545K, and H1047R (Proc. Natl. Acad. Sci. 2012, 109, 15259-15264). The E545K mutation can bind to ISR1, increase the response of the insulin receptor, and does not depend on the natural inhibition of p85 (Science, 2007, 317, 239-242); the H1047R mutation in the kinase domain improves the anchoring to the cell membrane, so it can directly activate the PI3K-AKT-mTOR signaling pathway without the activation of RAS (Trends Biochem. Sci. 2015, 40, 88-100). The 2022 ASCO conference reported that in the analysis of 121221 adult cancer patients, the E545K mutation accounted for 20%, the E542K mutation accounted for 11%, and the H1047R mutation accounted for 22%. Therefore, it is particularly necessary to study selective inhibitors targeting mutant PI3Kα.

[0005] The first generation of PI3K inhibitors are pan-PI3K inhibitors, which are developed as ATP-competitive orthosteric inhibitors. Examples include GDC-0941, but due to its inhibition of the entire PI3K family (J. Med. Chem. 2008, 51, 5522-5532), it leads to higher toxic side effects and lower clinical therapeutic window, resulting in limited clinical dosage. Subsequently, with the development of PI3Kδ and PI3Kα selective orthosteric inhibitors, idelalisib, copanlisib, alpelisib were successively approved by FDA for the treatment of cancer patients with specific PI3K mutations. However, clinical reports also show that this class of drugs has greater toxic side effects. Alpelisib has a considerable number of patients with elevated blood glucose in the treatment of breast cancer patients with PI3Kα mutations, and requires the use of metformin and other hypoglycemic drugs (Ann Oncol. 2018, 29(suppl_8): mdy424.010-mdy424.010). At the same time, the increase in blood glucose will greatly activate the insulin receptor pathway (Nature, 2018, 560, 499-503; Cancer Discov. 2019, 9, 482-491), thereby feedback activating PI3Kα, resulting in reduced drug efficacy. Therefore, it is very important to develop inhibitors targeting mutant PI3Kα, which can reduce the inhibition of wild-type PI3Kα, thereby weakening the feedback activation pathway, further improving clinical efficacy and reducing side effects such as hyperglycemia.

[0006] Although progress has been made in the development of selective PI3Kα orthosteric inhibitors, such as alpelisib approved by Novartis for the treatment of ER+ and PI3Kα mutant advanced breast cancer patients, due to its strong inhibition of wild-type PI3Kα, the development of more effective and highly selective mutant PI3Kα inhibitors can solve the unmet clinical needs. Among ER+ breast cancer patients, H1047R accounts for the highest proportion of PI3Kα mutations (~20%), so it is more important to find a highly selective mutant PI3Kα inhibitor.

[0007] The present application develops a new generation of PI3Kα allosteric inhibitors, which have good selectivity for mutant PI3Kα (H1047R mutation) and are expected to solve the above problems. SUMMARY

[0008] In one aspect, the present application provides a compound of formula (I):

[0009]

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

[0011] wherein:

[0012] Ring A and Ring B are fused to form an 8-14 membered heteroaryl;

[0013] Ring C is phenyl, 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10 membered bicyclic heteroaryl, 6-10 membered bicyclic heterocyclyl, 10-14 membered tricyclic heteroaryl, or 10-14 membered tricyclic heterocyclyl;

[0014] X1, X2, and X3are each independently selected from CR x and N; R x is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or CN;

[0015] each R1is independently selected from C 1-6 alkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, or C 3-6 cycloalkyl;

[0016] each R2is independently selected from H, C 1-6 alkyl, haloC 1-6 alkyl, CN, or C 3-6 cycloalkyl;

[0017] each R3is independently selected from H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, CN, or C 3-6 cycloalkyl;

[0018] each R4is independently selected from H, halogen, C 1-6 alkyl, haloC 1-6 alkyl, CN, C 3-6 cycloalkyl, acetyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, 5-6 membered heterocyclyl, or 5-6 membered heteroaryl;

[0019] R5is independently selected from C 1-6 alkyl, haloC 1-6alkyl, halo, -CN, -OR, -SR, -NRR', -S(0)2R, -S(0)2NRR', -S(0)R, -S(0)NRR', -C(0)R, -C(0)OR, -C(0)NRR', -C(0)N(R)OR', -OC(0)R, -OC(0)NRR', -N(R)C(0)OR', -N(R)C(0)R', -N(R)C(0)NR'R", -N(R)S(0)2NR'R", -N(R)S(0)2R', -(CH2) n NRR', phenyl, C 3-8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl; wherein the phenyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl can be further substituted with R*;

[0020] R* is selected from H, halo, C 1-6 alkyl, haloC 1-6 alkyl, CN, C 3-6 cycloalkyl, or -NRR';

[0021] R, R', and R" can be the same or different, each being independently selected from H, C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl;

[0022] m is selected from 0, 1, 2, 3, 4;

[0023] n is selected from 0, 1, 2, 3, 4.

[0024] In some embodiments, the compound of Formula (I) has the structure of Formula (II):

[0025]

[0026] wherein the variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for the compound of Formula (I). In other embodiments, the compound of Formula (I) has the structure of Formula (III):

[0027]

[0028] wherein the variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for the compound of Formula (I). In other embodiments, the compound of Formula (I) has the structure of Formula (IV):

[0029]

[0030] The variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of formula (I). In some other embodiments, the compounds of formula (I) have the structure of formula (V):

[0031]

[0032] The variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of formula (I). In some other embodiments, the compounds of formula (I) have the structure of formula (VI):

[0033]

[0034] The variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of formula (I). In some other embodiments, the compounds of formula (I) have the structure of formula (VII-1):

[0035]

[0036] The variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of formula (I). In some other embodiments, the compounds of formula (I) have the structure of formula (VII-2):

[0037]

[0038] The variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of formula (I). In other embodiments, the compounds of formula (I) have the structure of formula (VIII):

[0039]

[0040] The variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of formula (I). In some other embodiments, the compounds of formula (I) have the structure of formula (IX):

[0041]

[0042] The variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of formula (I). In some other embodiments, the compounds of formula (I) have the structure of formula (X):

[0043]

[0044] wherein the variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of Formula (I). In other embodiments, the compounds of Formula (I) have the structure of Formula (XI):

[0045]

[0046] wherein the variables R1, R2, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of Formula (I). In other embodiments, the compounds of Formula (I) have the structure of Formula (XI):

[0047]

[0048] wherein the variables R1, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of Formula (I). In other embodiments, the compounds of Formula (I) have the structure of Formula (XIII):

[0049]

[0050] wherein the variables R1, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of Formula (I). In other embodiments, the compounds of Formula (I) have the structure of Formula (XIV):

[0051]

[0052] wherein the variables R1, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of Formula (I). In other embodiments, the compounds of Formula (I) have the structure of Formula (XV):

[0053]

[0054] wherein the variables R1, R3, R4, R5, X1, X2, X3, m, n, and ring C are as defined above for compounds of Formula (I).

[0055] Another aspect of the application 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.

[0056] Still another aspect of the present application 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, especially cancer.

[0057] Still another aspect of the present application 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, especially cancer.

[0058] Still another aspect of the present application relates to a method for the prevention and / or treatment of a disease mediated by PI3Kα, especially 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

[0059] DEFINITIONS

[0060] Unless otherwise indicated, the following terms used in the present application specification and claims are intended to have the following meanings. It is to be understood that, unless otherwise indicated, terms used in this document are to be given their broadest meaning consistent with their use in the context in which they appear. Further, it is to be understood that the use of a term in several places in this document does not mean that such term is intended to have the same meaning in all places. Further, it is to be understood that the use of a term in the singular in this document also includes the plural and, vice versa, unless otherwise indicated. Further, it is to be understood that the use of "or" in this document means "and / or" unless otherwise indicated. Further, it is to be understood that the use of "comprise", "comprises" or "comprising" in this document means "including, but not limited to" or "containing, but not limited to" unless otherwise indicated. Further, it is to be understood that the use of "first", "second", "third", etc. in this document is intended for descriptive purposes and does not require that the described items be in any way mutually exclusive.

[0061] Unless otherwise indicated, all ranges recited herein include the endpoints and every integer within the range. For example, "a range of 0-4" means that m or n can be 0, 1, 2, 3, or 4. Further, any sub-range of these integers is intended to be included in the scope of the present application.

[0062] The group prefix "C x-y " as used herein means a range of the number of carbon atoms contained in the group, wherein x and y are each an integer. For example, C 3-8 Cycloalkyl means a cycloalkyl group having 3-8 carbon atoms, i.e. a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also to be understood that "C 3-8" also includes any subranges therein, e.g., C 3-7 , C 3-6 , C 4-7 , C 4-6 , C 5-6 , etc.

[0063] The term "alkyl," as used herein, refers to a straight or branched chain saturated monovalent hydrocarbon group having the indicated number of carbon atoms. Alkyl groups typically contain from 1 to 6 carbon atoms ("C 1-6 alkyl"), preferably from 1 to 5 carbon atoms ("C 1-5 alkyl"), more preferably from 1 to 4 carbon atoms ("C 1-4 alkyl"), from 1 to 3 carbon atoms ("C 1-3 alkyl"), or from 1 to 2 carbon atoms ("C 1-2 alkyl"). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, and n-hexyl.

[0064] The term "alkenyl," as used herein, refers to a straight or branched chain unsaturated monovalent hydrocarbon group having the indicated number of carbon atoms containing at least one double bond. Alkenyl groups typically contain from 2 to 6 carbon atoms ("C 2-6 alkenyl"), preferably from 2 to 5 carbon atoms ("C 2-5 alkenyl"), more preferably from 2 to 4 carbon atoms ("C 2-4 alkenyl"), or 2 carbon atoms ("ethenyl"). Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3- butadien-1-yl, 1-penten-3-yl, 2-penten-1-yl, 3-penten-1-yl, 3-penten-2-yl, 1,3- pentadien-1-yl, 1,4-pentadien-3-yl, 1-hexen-3-yl, and 1,4-hexadien-1-yl.

[0065] The term "alkenylene," as used herein, refers to a divalent group derived from an alkenyl group, wherein alkenyl is as previously defined. Alkenylene groups typically contain from 2 to 6 carbon atoms ("C 2-6 alkenylene"), preferably from 2 to 4 carbon atoms ("C 2-4 alkenylene"), or 2 carbon atoms ("ethenylene"). Examples of alkenylene groups include, but are not limited to, hexenylene, pentenylene, butenylene, propenylene, and ethenylene.

[0066] The term "alkoxy," as used herein, refers to an alkyl group (i.e., "-O-alkyl") attached to the parent molecular moiety through an oxygen atom, wherein alkyl is as previously defined. Alkoxy groups typically contain from 1 to 6 carbon atoms ("C 1-6 alkoxy"), more preferably from 1 to 4 carbon atoms ("C 1-4Alkoxy groups (including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy).

[0067] The term "halogen" as used in this article refers to fluorine, chlorine, bromine, and iodine, with fluorine and chlorine atoms being preferred.

[0068] As used herein, the term "halogenated" refers to the substitution of one or more hydrogen atoms in a substituent by one or more identical or different halogen atoms as defined above. For example, "halogenated C 1-6 "Alkyl" refers to a compound in which one or more hydrogen atoms are replaced by one or more identical or different halogen atoms. 1-6 Alkyl group, where "C" is an alkyl group. 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.

[0069] The term "oxo" as used in this article refers to the "=O" group.

[0070] As used herein, the term "carbocyclic ring" or "carbocyclic group" refers to a saturated or partially unsaturated non-aromatic cyclic hydrocarbon group having a specified number of carbon atoms and containing no heteroatoms. Carbocyclic rings typically contain 3–14 carbon atoms ("C..."). 3-14 Carbon ring), preferably 3-12 carbon atoms ("C") 3-12 Carbon ring ("C"), 3-10 carbon atoms ("C") 3-10 Carbon ring ("C"), 3-8 carbon atoms ("C") 3-8 Carbon ring ("C") or 3-6 carbon atoms ("C") 3-6 The carbon ring can be monocyclic or polycyclic, including fused rings, bridged rings, and spirocyclic systems. When the carbon ring is a saturated cyclic hydrocarbon group, the term "cycloalkyl" is used. Examples of carbon ring groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, cyclopentenyl, and cyclohexenyl.

[0071] As used herein, the term "aryl" refers to an aromatic group having 6-14, more typically 6-10, carbon atoms and no cyclic heteroatoms. For polycyclic systems, including fused-ring, bridged-ring, and spirocyclic systems of aromatic and non-aromatic rings without cyclic heteroatoms, the term "aryl" (e.g., 5,6,7,8-tetrahydronaphth-2-yl) is used when the linking point is located at an aromatic carbon atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, and indenyl.

[0072] The term "heteroatom" as used in this article refers to nitrogen, oxygen, or sulfur atoms.

[0073] The term "heteroaryl" as used herein refers to a monovalent radical of an aromatic character containing 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur and a total of 5-14 ring atoms. Heteroaryl includes 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, e.g., 8-10 membered bicyclic ("8-10 membered bicyclic heteroaryl") and 10-14 membered tricyclic ("10-14 membered tricyclic heteroaryl"), containing 1-4, preferably 1-3, heteroatoms selected from nitrogen, oxygen, and sulfur, wherein at least one ring of the polycyclic system is aromatic. For polycyclic systems, including fused, bridged, and spirocyclic systems having aromatic and non-aromatic rings, the term "heteroaryl" applies if there is at least one ring heteroatom and the point of attachment is at an atom (carbon atom or heteroatom) of an aromatic ring (e.g., 5,6,7,8-tetrahydroquinolin-3-yl). Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, benzopyranyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, cinnolinyl, naphthyridinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, and phenothiazinyl.

[0074] The term "heterocyclyl," as used herein, refers to saturated or partially unsaturated nonaromatic groups containing 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur and a total of 3-14 ring atoms. Heterocyclyl groups include 3-10 membered monocyclic ring systems containing 1-3, preferably 1-2, heteroatoms selected from nitrogen, oxygen, and sulfur ("3-10 membered monocyclic heterocyclyl groups") and 8-14 membered polycyclic ring systems (including fused, bridged, and spiro ring systems) containing 1-4, preferably 1-3, heteroatoms selected from nitrogen, oxygen, and sulfur, such as 8-10 membered bicyclic ("8-10 membered bicyclic heterocyclyl groups") and 10-14 membered tricyclic ("10-14 membered tricyclic heterocyclyl groups"). For polycyclic ring systems having both aromatic and / or nonaromatic rings, the term "heterocyclyl" is applied when there is at least one ring heteroatom and the point of attachment is at an atom (carbon atom or heteroatom) of the nonaromatic ring (e.g., 5,6,7,8-tetrahydroquinolin-6-yl). Examples of heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, isodihydrooxazolyl, dihydrothiazolyl, isodihydrothiazole, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxanyl, oxathianyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl, and isoindolinyl.

[0075] The term "optionally," as used herein, means that the depiction immediately following such term can or can not occur. For example, "phenyl optionally substituted with R5" encompasses both "phenyl unsubstituted with R5" and "phenyl substituted with R5."

[0076] The term "pharmaceutically acceptable," as used herein, refers to those substances or materials that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject, such as a human or other mammal, without excessive toxicity, irritation, allergic response, or other problem commensurate with a reasonable benefit / risk ratio.

[0077] The term "prevent," as used herein, means to reduce or eliminate the likelihood of a disease.

[0078] The term "treat," as used herein, means to completely or partially eliminate a disease and / or its attendant symptoms.

[0079] The term "subject," as used herein, means an animal, preferably a mammal, such as a primate (e.g., human), bovine, ovine, caprine, equine, canine, feline, lagomorph, rodent, mouse, etc., most preferably a human, that is the intended recipient of an experiment, treatment, etc.

[0080] Detailed description of the technical solutions of the present application

[0081] The following specific embodiments are provided to enable those skilled in the art to more clearly understand the present application. It is understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present application.

[0082] In some embodiments of this aspect, there are provided the following compounds, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof:

[0083]

[0084]

[0085]

[0086]

[0087] A pharmaceutically acceptable salt of a compound of the present application refers to a salt of a compound of Formula (I) with a pharmaceutically acceptable acid or base. Such salts include salts of acidic functional groups (e.g., -COOH, -OH, SO3H, etc.) present in a compound of Formula (I) with appropriate inorganic or organic cations (bases), such as alkali metal salts (e.g., lithium, sodium, potassium, rubidium, cesium salts), alkaline earth metal salts (e.g., magnesium, calcium, strontium, barium salts), aluminum salts, ammonium salts, salts with nitrogen-containing organic bases (e.g., ethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, diethylaminoethanol, ethylenediamine, imidazole, morpholine, 2-hydroxyethylmorpholine, dibenzylethylene-diamine, trimethylamine, piperidine, pyrrolidine, benzylamine, and the like), and amino acid salts (e.g., lysine salts, arginine salts); and salts of basic functional groups (e.g., -NH2, etc.) present in a compound of Formula (I) with appropriate inorganic or organic anions (acids), including inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and the like) 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, and the like). Pharmaceutically acceptable salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting a 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.

[0088] "stereoisomers" of the compounds of the present application refer to isomers that differ only in the arrangement of atoms in space. Enantiomeric forms arise when there are asymmetric carbon atoms in the compounds of Formula (I); diastereomeric forms arise when there are carbon-carbon double bonds or ring structures in the compounds of Formula (I). All enantiomeric, diastereomeric, racemic, cis / trans isomeric, and mixtures of the compounds of Formula (I) are included within the scope of the present application.

[0089] The compounds of the present application can also exist in tautomeric forms. The term "tautomers" refers to alternative forms of a compound in which a proton position is different, such as enol-keto, imine-enamine, amide-imidic acid tautomers. All such tautomers are included within the scope of the present application.

[0090] The "solvates" of the compounds of the present application refer to the compounds of Formula (I) associated with a solvent to form a physical complex that can be disassociated into the original compound and solvent on physical or chemical disruption. The solvent can be organic solvent (e.g., methanol, ethanol, propanol, dimethylsulfoxide, etc.), water, etc. For example, the compounds of Formula (I) can form ethanolate with ethanol, hydrate with water. All such solvates are included within the scope of the present application.

[0091] In a second aspect of the present application, 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. The term "pharmaceutically acceptable carrier" refers to a carrier (or excipient) that does not cause significant irritation to an organism, and does not abrogate the biological activity of the active ingredient. The pharmaceutically acceptable carrier can be either solid or liquid, and can be one or more of a variety of agents that are selected from the group consisting of fillers, antioxidants, buffering agents, bacteriostatic agents, dispersing agents, adsorbents, surfactants, binders, preservatives, disintegrants, sweetening agents, flavoring agents, glidants, release controlling agents, wetting agents, stabilizers, and suspending agents. The appropriate pharmaceutically acceptable carrier can be selected by one skilled in the art depending on, for example, the intended route of administration, the nature of the active ingredient, and the like.

[0092] The pharmaceutical composition can be formulated into various pharmaceutically acceptable dosage forms by conventional methods in the pharmaceutical art, for example, dosage forms suitable for oral administration, such as tablets, capsules, pills, syrups, elixirs, suspensions, solutions, emulsions, granules; dosage forms suitable for parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution; dosage forms suitable for transdermal administration, such as transdermal patches; dosage forms suitable for rectal administration, such as suppositories; dosage forms suitable for inhalation, such as aerosols, solutions, and dry powders; and dosage forms suitable for topical administration, such as creams, ointments, lotions, pastes, sprays, foams, and gels. These dosage forms can be prepared by conventional methods in the pharmaceutical art.

[0093] In a third aspect of the application, 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, in the manufacture of a medicament for the prevention and / or treatment of a disease mediated by PI3Kα, especially cancer.

[0094] In a fourth aspect of the application, 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, especially cancer.

[0095] In a fifth aspect of the application, 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 prevention and / or treatment of a disease mediated by PI3Kα, especially cancer.

[0096] In a sixth aspect of the application, there is provided a method of preventing and / or treating a disease mediated by PI3Kα, especially 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.

[0097] The compounds of the present application are inhibitors of PI3Kα and are therefore useful in the treatment of diseases mediated by PI3Kα. The term "disease mediated by PI3Kα" refers to a disease associated with the activity of PI3Kα or in which PI3Kα plays a role. Such diseases include, but are not limited to, cancer. The cancer includes, 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's lymphoma, head and neck cancer, bone cancer, skin cancer, testicular cancer, and the like.

[0098] In some embodiments, the PI3Ka is a mutant PI3Ka. In some embodiments, the PI3Ka has at least one mutation selected from the group consisting of E542K, E545K, and H1047R. In some embodiments, the PI3Ka has a H1047R mutation.

[0099] The compounds and pharmaceutical compositions of the present application can 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.

[0100] Example 1

[0101] The compounds of the present application can be prepared by a variety of methods, some of which are illustrated in the following examples. It is to be understood that these particular methods do not constitute any limitation of the scope of the present application. The reagents and starting materials used in the following examples were obtained from commercial suppliers or readily prepared by one of ordinary skill in the art.

[0102] Common Abbreviation Notes:

[0103] Abbreviations: PE = petroleum ether; EA = ethyl acetate; MeOH = methanol; DCM = dichloromethane; DCE = dichloroethane; CH3CN = acetonitrile; 1,4-dioxane = 1,4-dioxane; DMSO = dimethyl sulfoxide; HFIP = hexafluoroisopropanol; DMF = N,N-dimethylformamide; Hex = n-hexane; IPA = isopropyl alcohol; NMP = N-methylpyrrolidinone; NMO = N-methylmorpholine-N-oxide; TEA = triethylamine; DIEA = diisopropylethylamine; CuI = copper iodide; CuCN = copper cyanide; triphosgene = triphosgene; p-TsOH = p-toluenesulfonic acid; T3P = 1- propylphosphonic anhydride; TsN3 = p-toluenesulfonyl azide; PPA = polyphosphoric acid.

[0104] Preparation of key intermediates

[0105] Preparation of intermediate a1:

[0106]

[0107] First step: In a 100 mL reaction flask, dissolve methylmalonic acid a1-1 (1.0 g, 8.47 mmol) and 2,4,6-trichlorophenol a1-2 (3.5 g, 17.8 mmol) in 13 mL of phosphorus oxychloride, and react at 90 °C for 12 hours, and cool to room temperature. Remove the solvent under reduced pressure, add 50 mL of ice water to the mixture, and adjust the pH to about 8 by adding saturated aqueous sodium bicarbonate solution, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 1 / 1) to obtain compound a1-3 (1.4 g), with a yield of 35%.

[0108] Second step: Under nitrogen protection, dissolve the intermediate a1-3 (1.3 g, 2.73 mmol) from the previous step in 30 mL of anhydrous toluene, add compound 2-amino-3-bromo-5-methylpyridine a1-4 (423 mg, 2.27 mmol), and react at 105 °C for 2 hours, stop the reaction, and cool to room temperature. Add 100 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 1 / 2) to obtain intermediate a1-5 (500 mg), with a yield of 82%. LCMS: ESI-MS (m / z): 269 [M+H] + .

[0109] Third step: Under nitrogen protection, dissolve the intermediate a1-5 (500 mg, 1.87 mmol) from the previous step and phosphorus oxychloride (2.0 mL) in 3 mL of dichloroethane, slowly add 1.0 mL of DIEA, after the dropwise addition is complete, react at 105 °C for 24 hours. Add 2.0 mL of phosphorus oxychloride and 0.5 mL of DIEA to the system, continue stirring for 16 hours, stop the reaction, and cool to room temperature. Remove the solvent under reduced pressure, add 50 mL of ice water to the mixture, adjust the pH to about 8 by adding saturated aqueous sodium bicarbonate solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 3 / 1) to obtain intermediate a1 (200 mg), with a yield of 37%. LCMS: ESI-MS (m / z): 287 [M+H] + .

[0110] Preparation of intermediate a2:

[0111]

[0112] First Step: Under nitrogen protection, dissolve the starting material 2-amino-3-bromo-5-methylbenzoic acid a2-1 (2.0 g, 8.7 mmol) and triethylamine (3.5 g, 24.8 mmol) in 20 mL of ethanol, add methyl isothiocyanate (950 mg, 13.0 mmol), and react at 65 °C for 3 hours. Stop the reaction, cool to room temperature, and precipitate the solid. Extract with ethanol, dry the filter cake, and dry to obtain yellow solid a2-2 (1.8 g), yield: 73%. LCMS: ESI-MS (m / z): 286 [M+H] + .

[0113] Second Step: Under nitrogen protection, dissolve the intermediate a2-2 (1.8 g, 6.36 mmol) and DIEA (0.2 mL) in 10 mL of phosphorus oxychloride, and react at 105 °C for 12 hours. Remove the solvent under reduced pressure, add 50 mL of ice water to the mixture, and adjust the pH to about 8 by adding saturated aqueous sodium bicarbonate solution. Extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 3 / 1) to obtain intermediate a2 (1.2 g), yield: 67%. LCMS: ESI-MS (m / z): 288 [M+H] + .

[0114] Preparation of intermediate a3:

[0115]

[0116] First Step: Under nitrogen protection, dissolve the starting material 3-bromo-5-methylbenzene-1,2-diamine a3-1 (4.0 g, 20.0 mmol) and ethyl pyruvate a3-2 (11.6 g, 100.0 mmol) in 20 mL of methanol, and react at room temperature for 1 hour. Stop the reaction, precipitate the solid. Extract with ethanol, dry the filter cake, and dry to obtain yellow solid a3-2 (3.0 g), yield: 59%. LCMS: ESI-MS (m / z): 253 [M+H] + .

[0117] Second Step: Under nitrogen protection, dissolve the intermediate a3-2 (3.0 g, 11.9 mmol) in 60 mL of dichloroethane, add phosphorus oxychloride (1.18 g, 77.4 mmol), and react at 105 °C for 1 hour. Remove the solvent under reduced pressure, add 80 mL of ice water to the mixture, and adjust the pH to about 8 by adding saturated aqueous sodium bicarbonate solution. Extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 2 / 1) to obtain intermediate a3 (3.0 g), yield: 93%. LCMS: ESI-MS (m / z): 271 [M+H] + .

[0118] Preparation of intermediates b1-b4, b7-b8, b11-b12:

[0119]

[0120] First step: Intermediate a1 (200 mg, 0.70 mmol) and compound 5-fluoroisoindoline b1-1 (142 mg, 1.04 mmol) were dissolved in 4 mL of anhydrous acetonitrile, DIEA (360 mg, 2.76 mmol) was added, and the reaction was allowed to proceed at 80 °C for 3 hours. The reaction was stopped, and the reaction solution was poured into 50 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (PE / EA, 2 / 1) to obtain intermediate b1-2 (130 mg) with a yield of 48%. LCMS: ESI-MS (m / z): 388 [M+H] + .

[0121] Second step: Under nitrogen protection, intermediate b1-2 (130 mg, 0.34 mmol) and tributyl(1-ethoxyvinyl)tin b1-3 (182 mg, 0.50 mmol) were dissolved in 3 mL of 1,4-dioxane, and a catalyst Pd(PPh3)2Cl2 (24 mg, 0.034 mmol) was added. The reaction was allowed to proceed at 90 °C for 16 hours, and then cooled to room temperature. To the reaction solution, an aqueous potassium fluoride solution was added to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by flash column chromatography (EA) to obtain intermediate b1 (70 mg) with a yield of 59%. LCMS: ESI-MS (m / z): 352 [M+H] + .

[0122] Referring to the synthesis route of compound b1, the following molecules were synthesized using similar backbone structures.

[0123]

[0124] Preparation of intermediates b5-b6, b13-b14:

[0125]

[0126] First Step: ice bath, dissolve raw material b5-1 (1.0 g, 3.82 mmol) in 10 mL of a mixed solution of methanol and dichloromethane (v / v, 1 / 1), add NaBH4 (460 mg, 11.5 mmol), react at room temperature for 3 hours, stop the reaction. Add 30 mL of water to the reaction solution, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 1 / 1) to obtain compound b5-2 (500 mg), yield: 50%. LCMS: ESI-MS (m / z): 265 [M+H] + .

[0127] Second Step: ice bath, dissolve the intermediate b5-2 (500 mg, 1.89 mmol) in 6 mL of dichloromethane, add PBr3 (1.0 g, 3.78 mmol) dropwise, after dropping, react at room temperature for 2 hours, stop the reaction. Add 20 mL of water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 2 / 1) to obtain compound b5-3 (500 mg), yield: 81%. LCMS: ESI-MS (m / z): 327 [M+H] + .

[0128] Third Step: dissolve the intermediate b5-3 (500 mg, 1.53 mmol) and DIEA (597 mg, 4.6 mmol) in 5 mL of acetonitrile, add raw material 2-aminobenzoic acid methyl ester b5-4 (347 mg, 2.29 mmol), warm to 90°C and react for 12 hours, cool to room temperature. Add 50 mL of water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (PE / EA, 1 / 1) to obtain compound b5 (200 mg), yield: 39%. LCMS: ESI-MS (m / z): 398 [M+H] + .

[0129] Referring to the synthesis route of compound b5, the following molecules are synthesized using similar backbone structures.

[0130]

[0131] Preparation of intermediate b9:

[0132]

[0133] Step 1: Dissolve the starting material b9-1 (10.3 g, 49 mmol) in ethylenediamine (13.8 g, 230 mmol), add catalyst P2S5 (100 mg), and warm to 85 °C for 12 h. Cool to room temperature. Add 200 mL water to the reaction mixture, and precipitate the solid. Filter to obtain compound b9-2 (11.0 g). Yield: 89%. LCMS: ESI-MS (m / z): 254 [M+H] + .

[0134] Step 2: Cool the intermediate b9-2 (11.0 g, 43.5 mmol) from the previous step and KOH (550 mg) in 100 mL ethanol. Add carbon disulfide (16.5 g, 217 mmol) dropwise. After the addition is complete, warm to 70 °C for 12 h. Cool to room temperature. Remove the solvent under reduced pressure. Add dilute hydrochloric acid to the reaction mixture to adjust the pH to about 3. Extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain compound b9-3 (12.8 g). LCMS: ESI-MS (m / z): 296 [M+H] + .

[0135] Step 3: Dissolve the intermediate b9-3 (12.8 g, 43.4 mmol) and potassium carbonate (7.2 g, 52.0 mmol) in 100 mL acetone. Add MeI (9.2 g, 65.0 mmol) dropwise. After the addition is complete, warm to 60 °C for 2 h. Cool to room temperature. Remove the solvent under reduced pressure. Add 50 mL water to the reaction mixture. Extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. Purify the crude product by flash reverse column chromatography (acetonitrile / water, 4 / 5) to obtain compound b9 (9.2 g). Yield: 95%. LCMS: ESI-MS (m / z): 310 [M+H] + .

[0136] Preparation of intermediate b10:

[0137]

[0138] Step: Dissolve the intermediate b9 (120 mg, 0.44 mmol) and manganese dioxide (76 mg, 0.88 mmol) in 10 mL toluene. React at room temperature for 72 h. Filter, remove the solvent under reduced pressure, add 50 mL water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. Purify the crude product by flash reverse column chromatography (acetonitrile / water, 2 / 5) to obtain compound b10 (60 mg). Yield: 50%. LCMS: ESI-MS (m / z): 308 [M+H] + .

[0139] Preparation of intermediates c1-c5:

[0140]

[0141] First Step: Dissolve the starting material c1-1 (3.0 g, 13.6 mmol) and tetrahydropyrrole c1-2 (1.0 g, 13.6 mmol) in 30 mL of DMSO, add potassium carbonate (2.8 g, 20.5 mmol), and warm to 120 °C for 3 hours. Cool to room temperature. Add 100 mL of water to the reaction, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by flash reverse column chromatography (acetonitrile / water, 4 / 5) to obtain compound c1-3 (2.0 g) with a yield of 54%. LCMS: ESI-MS (m / z): 271 [M+H] + .

[0142] Second Step: Dissolve the intermediate c1-3 (2.0 g, 7.4 mmol) from the previous step and iron powder (2.1 g, 36.9 mmol) in a mixture of 20 mL of ethanol and water (v / v, 9 / 1), and add acetic acid (0.7 g, 11.1 mmol) dropwise. After the dropwise addition is complete, warm to 80 °C for 4 hours. Cool to room temperature. Add 100 mL of water to the reaction, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by flash reverse column chromatography (acetonitrile / water, 4 / 5) to obtain compound c1-4 (1.0 g) with a yield of 56%. LCMS: ESI-MS (m / z): 241 [M+H] + .

[0143] Third Step: Dissolve the intermediate c1-4 (1.0 g, 4.1 mmol) from the previous step in 10 mL of ethyl acetate, and add H2O2 (30%, 2.8 g, 82.9 mmol) dropwise. After the dropwise addition is complete, warm to 80 °C for 72 hours. Cool to room temperature. Add 50 mL of water to the reaction, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by flash reverse column chromatography (acetonitrile / water, 4 / 5) to obtain compound c1 (500 mg) with a yield of 51%. LCMS: ESI-MS (m / z): 237 [M+H] + .

[0144] The following intermediates were synthesized according to the above synthetic route using the corresponding starting materials / similar skeletons:

[0145]

[0146] Preparation of intermediates c6-c8:

[0147]

[0148] Step: Under nitrogen protection, dissolve the starting material c6-1 (200 mg, 0.80 mmol) and hexamethyl ditin c6-2 (293 mg, 1.2 mmol) in 3 mL of 1,4-dioxane, add catalyst Pd(PPh3)4 (92 mg, 0.08 mmol), and heat to 80 °C for 3 hours. Cool to room temperature and filter. Remove the solvent under reduced pressure, and separate the crude product by flash column chromatography (PE / EA, 4 / 1) to obtain intermediate c6 (100 mg) with a yield of 41%. LCMS: ESI-MS (m / z): 338 [M+H] + .

[0149] According to the above synthesis route, using the corresponding starting materials / similar skeletons, the following intermediates were synthesized:

[0150]

[0151] Example 2

[0152] Preparation of target molecules P1-P2, H1

[0153]

[0154] First step: Under ice bath and nitrogen protection, dissolve intermediate b1 (70 mg, 0.20 mmol) in 1 mL of a mixture of methanol and dichloromethane, and add NaBH4 (23 mg, 0.6 mmol). Heat to room temperature for 1 hour, and stop the reaction. Pour the reaction solution into 20 mL of ice water, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (DCM / MeOH, 20 / 1) to obtain compound P1-1 (70 mg). LCMS: ESI-MS (m / z): 354 [M+H] + .

[0155] Second step: Under nitrogen protection, dissolve compound P1-1 (70 mg, 0.198 mmol) from the previous step in 3 mL of anhydrous dichloromethane, and add PBr3 (160 mg, 0.59 mmol). React at room temperature for 3 hours, and stop the reaction. Pour the reaction solution into 50 mL of water, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by flash column chromatography (DCM / MeOH, 20 / 1) to obtain compound P1-2 (60 mg) with a yield of 73%. LCMS: ESI-MS (m / z): 416 [M+H] + .

[0156] Step 3: Under nitrogen, dissolve compound P1-2 (60 mg, 0.14 mmol), DIEA (70 mg, 0.54 mmol) and 2-aminobenzoic acid P1-3 (40 mg, 0.25 mmol) in 2 mL of acetonitrile, and react at room temperature for 2 hours. Add 10 mL of water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and separate the crude product by TLC thin layer chromatography to obtain the target compound P1 (20 mg). LCMS: ESI-MS (m / z): 473 [M+H] + .

[0157] 1 H NMR (400 MHz, DMSO-d6) δ 13.02 - 12.36 (m, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.47 - 7.41 (m, 1H), 7.26 (dd, J = 14.0 Hz, 8.0 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 6.57 (t, J = 8.0 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 5.39 - 5.33 (m, 1H), 5.19 (d, J = 12.0 Hz, 4H), 2.44 (s, 3H), 2.29 (s, 3H), 1.66 (d, J = 8.0 Hz, 3H).

[0158] Referring to the synthesis route of compound P1, the following target molecules were synthesized using similar backbone structures.

[0159]

[0160] Example 3

[0161] Preparation of target molecules H2-H5

[0162]

[0163] Step 1: Under nitrogen, dissolve intermediate c6 (110 mg, 0.33 mmol) and the previously prepared intermediate b5 (300 mg, 0.87 mmol) in 10 mL of tetrahydrofuran, add a catalyst Pd(PPh3)4 (92 mg, 0.08 mmol) and CuBr (84 mg, 0.64 mmol), and react at 70°C for 12 hours. Cool to room temperature and filter. Remove the solvent under reduced pressure, and separate the crude product by flash column chromatography (PE / EA, 1 / 1) to obtain compound H2-1 (30 mg) with a yield of 18%. LCMS: ESI-MS (m / z): 523 [M+H] + .

[0164] Second step: under nitrogen protection, the intermediate H2-1 (30 mg, 0.06 mmol) in step one was dissolved in 1 mL of methanol, 10% NaOH aqueous solution (1 mL) was added, and the reaction was heated to 40 °C for 1 hour, and then cooled to room temperature. The solvent was removed under reduced pressure, the crude product was dissolved in 3 mL of water, and the pH was adjusted to about 4 with dilute hydrochloric acid, extracted with dichloromethane, and separated by TLC thin layer chromatography (DCM / MeOH, 20 / 1) to obtain the target compound H2 (10 mg), yield: 33%. LCMS: ESI-MS (m / z): 509 [M+H] + .

[0165] HNMR (400 MHz, DMSO-d6) δ 12.5 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.78-7.75 (m, 2H), 7.54 (s, 1H), 7.50 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.23-7.18 (m, 2H), 6.55 (t, J = 8.0 Hz, 1H), 6.46 (d, J = 12.0 Hz, 1H), 5.14 (s, 1H), 3.31 (s, 3H), 2.39 (s, 3H), 2.12 (s, 3H), 1.71 (d, J = 8.0 Hz, 3H), 1.62-1.57 (m, 4H).

[0166] Referring to the synthesis route of compound H2, the following target molecules were synthesized using similar backbone structures.

[0167]

[0168]

[0169] Example 4

[0170] Preparation of target molecules P3-P

[0171]

[0172] First step: under nitrogen protection, intermediate b7 (100 mg, 0.4 mmol), potassium carbonate (165 mg, 1.2 mmol) and raw material P3-1 (106 mg, 0.6 mmol) were dissolved in 4 mL of a mixed solution of 1,4-dioxane and water (v / v, 4 / 1), a catalyst Pd(dppf)Cl2 (28 mg, 0.04 mmol) was added, and the reaction was heated to 90 °C for 2 hours, cooled to room temperature, and filtered. The solvent was removed under reduced pressure, and the crude product was separated by flash column chromatography (PE / EA, 5 / 1) to obtain compound P3-2 (90 mg), yield: 96%. LCMS: ESI-MS (m / z): 347 [M+H] + .

[0173] Second step: under nitrogen protection, the intermediate P3-2 (90 mg, 0.26 mmol) in step one was dissolved in 4 mL of a mixed solution of methanol and dichloromethane (v / v, 1 / 1), NaBH4 (30 mg, 0.78 mmol) was added, and the reaction was carried out at room temperature for 2 hours, and then stopped. The solvent was removed by evaporation under reduced pressure, the crude product was dissolved in 20 mL of water, extracted with dichloromethane, and the crude product was separated by column chromatography (PE / EA, 1 / 1) to obtain compound P3-3 (60 mg), with a yield of 67%. LCMS: ESI-MS (m / z): 349 [M+H] + .

[0174] Third step: under nitrogen protection, the intermediate P3-3 (60 mg, 0.17 mmol) in step two was dissolved in 4 mL of dichloromethane, PBr3 (90 mg, 0.34 mmol) was added, and the reaction was carried out at room temperature for 2 hours, and then stopped. The solvent was removed by evaporation under reduced pressure, the crude product was dissolved in 20 mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (PE / EA, 2 / 1) to obtain compound P3-4 (60 mg), with a yield of 67%. LCMS: ESI-MS (m / z): 411 [M+H] + .

[0175] Fourth step: under nitrogen protection, the intermediate P3-4 (60 mg, 0.15 mmol) and TEA (60 mg, 0.58 mmol) in step three were dissolved in 3 mL of tert-butyl alcohol, the raw material P3-5 (164 mg, 0.88 mmol) was added, and the reaction was carried out at 95°C for 12 hours, and then stopped. The solvent was removed by evaporation under reduced pressure, the crude product was dissolved in 30 mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography (DCM / MeOH, 20 / 1) to obtain compound P3-6 (30 mg), with a yield of 40%. LCMS: ESI-MS (m / z): 517 [M+H] + .

[0176] Fifth step: the intermediate P3-6 (30 mg, 0.06 mmol) in step four was dissolved in 1 mL of methanol, 10% NaOH aqueous solution (1 mL) was added, and the reaction was carried out at 40°C for 2 hours, and then cooled to room temperature. The solvent was removed by evaporation under reduced pressure, the crude product was dissolved in 3 mL of water, the pH was adjusted to about 4 with dilute hydrochloric acid, extracted with dichloromethane, and the crude product was separated by TLC thin layer chromatography (DCM / MeOH, 20 / 1) to obtain the target compound P3 (10 mg), with a yield of 33%. LCMS: ESI-MS (m / z): 503 [M+H] + .

[0177] 1H NMR (400 MHz, DMSO-d6) δ 9.37 - 9.25 (m, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 8.10 (s, 1H), 7.68 (d, J = 8.0 Hz, 3H), 7.11 (s, 1H), 6.78 (s, 1H), 5.36 (s, 1H), 4.24 (s, 3H), 2.34 (d, J = 16.0 Hz, 6H), 1.64 (s, 3H).

[0178] Referring to the synthesis route of compound P3, using similar backbone structure, the following target molecules were synthesized.

[0179]

[0180]

[0181] Example 5

[0182] Intracellular inhibition experiment of the compound of the present application on mutant PI3Kα (H1047R) HCC1954 cells:

[0183] HCC1954 cells cultured in RPMI1640 (Gibco, Cat. No. A10491-01) containing 10% fetal bovine serum and 1% penicillin-streptomycin were seeded in 384-well microplates and incubated at 37°C, 5% carbon dioxide for 12 hours. Echo550 (Labcyte, Echo550) was used to add 200 microliters of different concentrations of compounds (dimethyl sulfoxide final concentration of 0.5%) to each well and incubated at 37°C for 2 hours. Then, the cells were fixed in 8% fixative (Solarbio, Cat. No. P1112) and washed once with phosphate buffer (PBS). After washing, blocking solution (LI-COR, Cat. No. 927-40000) was added to each well at room temperature for 1 hour. After removing the blocking solution, anti-phospho-Akt (S473) Rabbit mAb (CST, Cat. No. 4060S) and GAPDH (D4C6R) Mouse mAb (CST, Cat. No. 97166S) antibody working solution were added to each well, and incubated at 4°C for 12 hours. The microplate was washed three times with PBS containing 0.1% Tween-80 (PBST), and IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR, Cat. No. 926-32211) and IRDye 680RD Goat anti Mouse IgG (H+L) (LI-COR, Cat. No. 926-68070) antibody working solution were added, and the microplate was incubated at room temperature in the dark. After washing the microplate three times with PBST, the microplate was centrifuged at 1000 rpm for 1 minute, and the plate was scanned using an Odyssey CLx (LI-COR) instrument, the signal value was recorded, and the IC 50 value was calculated.

[0184] The results of the pAKT inhibition of the compounds for H1047R mutant breast cancer cells HCC1954 are shown in Table 1 below:

[0185] Table 1 Inhibition results of compounds for pAKT

[0186]

[0187] N.D. = not tested

[0188] The above results show that the molecules of the present application have good inhibitory effect on PI3Kα H1047R mutant cells.

[0189] Intracellular inhibition experiment of the compound of the present application for mutant PI3Kα (H1047R) MDA-MB-453 cells:

[0190] MDA-MB-453 cells cultured in RPMI1640 (Gibco, Cat. No. A10491-01) containing 10% fetal bovine serum and 1% penicillin-streptomycin were seeded in 384-well microplates and incubated at 37°C, 5% carbon dioxide for 12 hours. Echo550 (Labcyte, Echo550) was used to add 200 microliters of different concentrations of compounds (dimethyl sulfoxide final concentration of 0.5%) to each well and incubated at 37°C for 2 hours. Then, the cells were fixed in 8% fixative (Solarbio, Cat. No. P1112) and washed once with phosphate buffer (PBS). After washing, blocking solution (LI-COR, Cat. No. 927-40000) was added to each well at room temperature for 1 hour. After removing the blocking solution, anti-phospho-Akt (S473) Rabbit mAb (CST, Cat. No. 4060S) and GAPDH (D4C6R) Mouse mAb (CST, Cat. No. 97166S) antibody working solution were added to each well, and incubated at 4°C for 12 hours. The microplate was washed three times with PBS containing 0.1% Tween-80 (PBST), and IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR, Cat. No. 926-32211) and IRDye 680RD Goat anti Mouse IgG (H+L) (LI-COR, Cat. No. 926-68070) antibody working solution were added, and the microplate was incubated at room temperature in the dark. After washing the microplate three times with PBST, the microplate was centrifuged at 1000 rpm for 1 minute, and the plate was scanned using an Odyssey CLx (LI-COR) instrument, the signal value was recorded, and the IC 50 value was calculated.

[0191] The results of pAKT inhibition of the compounds for MDA-MB-453 breast cancer cells with H1047R mutation are shown in Table 2 below:

[0192] Table 2 Inhibition results of compounds for pAKT

[0193]

[0194] N.D. = not tested

[0195] The above results show that the molecules of the present application have good inhibitory effect on PI3Kα H1047R mutant cells.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, selected from the following compounds:

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