Pyrazolopyrimidine compound and application thereof

Abstract

The invention belongs to the field of medicine synthesis, provides a pyrazolopyrimidine compound and application thereof, and particularly relates to a pyrazolopyrimidine compound shown as a formula (I) and / or an acceptable salt of the pyrazolopyrimidine compound in claim 1, a medicine composition containing the compound and / or the acceptable salt of the pyrazolopyrimidine compound in claim 1, a method for preparing the compound, and a preparation method of the compound. The invention also discloses application of the compound in preparation of medicines for treating PI3K-mediated related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and relates to a pyrazolopyrimidine compound as shown in formula (I) and / or its desired chemically acceptable salt, a pharmaceutical composition comprising the compound and / or its desired chemically acceptable salt, a method for preparing the compound, and use of the compound in preparing drugs for treating PI3K-mediated related diseases.

[0002] Background Art

[0003] Phosphoinositides (PI) play a key role as second messengers in a variety of cellular functions, including cell survival, signal transduction, and regulation of membrane trafficking and transport (Di Paolo, G. et al Nature, 2006, 443, 651-657; Schaeffer, EM et al Curr. Opin. Immunol., 2000, 12, 282-288). Dysfunction of various phosphoinositides is associated with a variety of diseases, including cancer, autoimmune diseases, and inflammation. Phosphoinositides are lipids containing two layers of fatty acids, whose fatty acids can be connected to cytoplasmic 1-inositol through glycerol phosphate bonds. Lipid kinase PI3K converts PI phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-triphosphate (PIP3) by ATP phosphorylation of the 3-OH of the inositol ring part (Parker, PJ Biochem. Soc. Trans., 2004, 32, 893-898). PIP3 acts as an anchoring point for protein kinases containing highly conserved pleckstrin homology (PH) domains (Hawkins, PT et al. Biochem. Soc. Trans., 2006, 34, 647-662), and can bind to signal proteins containing PH domains in cells, such as serine / threonine kinase Akt and PDK1 (3-phosphoinositide-dependent protein kinase), prompting PDK1 to phosphorylate Akt protein, leading to Akt activation. After these kinases are activated (phosphorylated or dephosphorylated), they can regulate a large number of important cellular functions, such as controlling most of the growth, survival and proliferation functions of cells by regulating downstream proteins such as mTOR, GSK3β, Foxo3a, p70S6K and NF-κB. Moreover, calcium mobilization and gene transcription are also controlled by the Tec family tyrosine kinases BTK, ETK and ITK of the PH domain (Fruman, DA et al Immunol. Rev. 2009, 228, 253-272.). Therefore, phosphoinositide metabolic enzymes such as PI3K have become attractive targets for modulating the functions of these second messengers.

[0004] The most studied PI3K is class I, which can be divided into two subclasses (class 1A and class 1B). Among them, class 1A (PI3Kα, PI3Kβ and PI3Kδ) is located downstream of receptor tyrosine kinases (RTKs), while class 1B (PI3Kγ) is located downstream of G protein-coupled receptors (GPCRs). These four homologous kinases exist as heterodimers of regulatory and catalytic subunits. Regulatory subunits contain domains that allow anchoring to cell surface receptors and other regulatory proteins. Catalytic subunits (p110α, p110β, p110γ, p110δ) contain ATP binding domains. The catalytic subunit, especially its ATP binding site, is currently the focus of research on PI3K small molecule inhibitors. Small molecule compounds can block the phosphorylation of PIP2 and the formation of PIP3 by competitively inhibiting the ATP binding site. Therefore, important regulatory proteins such as AKT will not be anchored to the cell membrane, and their functions will be inhibited.

[0005] PI3Kα and PI3Kβ are ubiquitously expressed in the body, while PI3Kγ and PI3Kδ are mainly present in leukocytes, and PI3Kδ is almost confined to the spleen, thymus, and peripheral blood leukocytes (Eicholt, BJ et al PLoS One, 2007, 9, e869). Dysregulation of PI3Kα and PI3Kβ is associated with the occurrence and development of solid tumor diseases; while dysregulation of PI3Kγ and PI3Kδ is associated with inflammatory and immune system diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lung diseases such as chronic obstructive pulmonary disease COPD and asthma, and hematological malignancies. Data obtained from transgenic mice and two successful B cell-targeted biologics have demonstrated the strict expression pattern of PI3Kδ, driving researchers in the field to develop new PI3Kδ small molecule inhibitors. These biologics, such as rituximab and belimumab, have been shown to be effective against RA and SLE, respectively. Since PI3Kδ has a unique role in B cell maturation and function (Vallerskog, T. et al Clin. Immunol., 2007, 122, 62-74), inhibiting PI3K should have similar effects to these two biological products. In addition to the regulatory effect of B cells, PI3Kδ also plays a partial role in T cell activation (Soond, R. et al; Blood, 2010, 115, 2203-3313) and neutrophil transport (Ali, K. et al Nature, 2004, 431, 1007-1011), and also helps to activate other white blood cells related to autoimmune diseases such as macrophages, dendritic cells and NK T cells (Fung-Leung, WP Cell. Signalling 2011, 23, 603-608). The role of PI3Kδ in leukocyte function can be supported by two recent documents. These two papers describe several major functional gain-of-function PI3Kδ mutations from several different families in Europe. PI3Kδ mutants show lymphoproliferation and immunodeficiency, which makes them susceptible to lung and ear infections (Angulo, I. et al Science 2013, 342, 866-871). The mechanism of immunodeficiency associated with this mutation is not very clear. According to the literature, it is speculated that the overactive p110δ-AKT-mTOR pathway promotes aerobic glycolysis, limits the function and survival of lymphocytes and causes them to age prematurely, impairing the appropriate immune response to pathogens (Lucas, CL et al, Nat. Immunol. 2014, 15, 88-97). Chronic inflammation is not unique to autoimmune diseases, but is also related to long-term exposure to stress or physical damage. These are all likely to lead to sustained signaling of the PI3Kδ pathway in responsive leukocytes.For example, in chronic obstructive pulmonary disease (COPD), continuous exposure to cigarette smoke is associated with high levels of PI3Kδ and phosphorylated AKT in the lungs (To, Y. et al, Am. J. Respir. Crit. Care Med. 2010, 182, 897-904). Like individuals with gain-of-function PI3Kδ mutations, COPD patients are more susceptible to recurrent bacterial respiratory infections, including Haemophilus influenzae and Streptococcus pneumoniae. Similar immune deficiencies in patients with gain-of-function gene mutations may be related to persistently activated PI3Kδ signaling in COPD. Leukocyte defects in patients with gain-of-function mutations can be improved by rapamycin treatment. Rapamycin is an inhibitor of mTOR, a downstream protein of PI3Kδ. Therefore, it is speculated that inhibiting PI3Kδ is also a potential feasible treatment option for diseases related to the PI3Kδ signaling pathway, not only for APDS (activated PI3K syndrome), complex autoimmune diseases such as SLE and RA, but also for pathological diseases caused by the activity of B cells and other leukocyte subsets driven by PI3Kδ (Palanki, M. et al, J. Med. Chem. 2007, 50, 4279-4294; Pei, Z. et al, ACSMed. Chem. Lett. 2013, 4, 103-107; Cushing, TD et al, J. Med. Chem. 2012, 55, 8559-8581; Shukla, MR. et al J. Med. Chem. 2020, 63, 14700-14723, Methot, JL, et al. al, J.Med.Chem.2021,64,5137-5156), and is also suitable for chronic non-autoimmune diseases such as respiratory disease COPD.

[0006] Oral PI3Kδ inhibitors, such as Idelalisib, Duvelisib, and the recently approved Umbralisib, have been approved for the treatment of B-cell lymphoma, but dose-limiting toxicity limits their clinical application and they are only used for second-line and later treatment of patients. Among them, Umbralisib has relatively good safety compared to the other two marketed drugs, and relatively less colorectal inflammation and immune liver toxicity. According to the latest review summary of Nature journal, one of the reasons is that the drug has the highest selectivity for other PI3K subtypes besides PI3Kδ (Nat Rev Drug Discov. 2021Oct; 20(10):741-769.).

[0007] In addition, the application of existing PI3Kδ inhibitors in the field of cancer is still limited to blood cancer, and its exploration and research results in solid tumors are limited. Studies have shown that PI3Kδ can also be used in combination with anti-PD1 antibodies for hot tumors (J Mol Med (Berl). 2016Jan; 94(1): 5-11.). Therefore, although there are more than 5 PI3Kδ inhibitors on the market or in late clinical development, they are all for blood cancer research and have not yet been marketed in China. Therefore, there is still a need for a PI3Kδ inhibitor with higher selectivity and less toxicity for clinical application, especially for expansion into first-line lymphoma, or expansion into solid tumors, and for non-cancer fields such as inflammatory diseases.

[0008] It is worth noting that none of the currently marketed drugs have been approved for inflammatory diseases. Except for two small studies, Duvelisib has not been further studied for inflammatory diseases. Inhalation administration has been explored for targeted lung treatment, because systemic administration may cause intolerable toxicity. In the prior art, patent documents WO2005113556, US20130071212, US20140179718, WO2016045591, CN108017641, and US2021046075 disclose a series of selective PI3Kδ inhibitor compounds, as well as their medical uses in the fields of PI3Kδ gene gain-of-function mutations, autoimmune diseases, chronic inflammatory diseases, and cancer.

[0009] Considering that there are two main types of PI3Kδ inhibitor structures, flat type and propeller-type with chiral groups, the flat type structure usually has many mutually conjugated aromatic groups and high structural planarity, which has the problems of poor solubility and poor selectivity.

[0010] In order to solve the above-mentioned defects and shortcomings in the prior art, the inventors and their team of the present invention application hope to select a propeller-type skeleton, design and synthesize a new class of compounds with pyrazolopyrimidine as the parent core, so as to obtain PI3Kδ inhibitors with high solubility and better selectivity.

[0011] Although developing compounds into salts is an effective method to improve solubility, the compounds of the present invention cannot form salts with all organic acids or inorganic acids, and their salt-forming properties are unpredictable. The solubility, stability, crystallinity and other physical and chemical properties of different salts are even more unpredictable. Summary of the invention

[0012] In a first aspect of the present invention, there is provided a compound represented by formula (I) and / or a pharmaceutically acceptable salt thereof,

[0013]

[0014] in:

[0015] R1 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, amino, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 3-6 Heterocycloalkyl, -C 3-6 Cycloalkoxy, -C 3-6 Heterocycloalkoxy, -C 1-6 Alkyl(O)C 1-6 Alkyl, -COOH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR 1a , aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy; wherein the thiol, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, aryl, aralkyl, -C(O)NH2, -S(O)2NH2, -S(O)(NH)NH2, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy can be optionally replaced by one or more R 1a replace.

[0016] R 1a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, -COOH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR a wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, heteroaryl, -C(O)NH2, -S(O)2NH2, -S(O)(NH)NH2 are selectively replaced by halogen, cyano, -OR a 、-SR a NR b R c , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocyclooxy, any one or more of which may be substituted or unsubstituted;

[0017] Preferably, R1 is independently selected from hydrogen, deuterium, halogen, cyano, amino, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 1-6 Alkoxy, -C 1-6 Haloalkyl, -C 1-6 Haloalkoxy, -C 1-6 Deuterated alkyl, -C 1-6 deuterated alkoxy; R2 is selected from hydrogen, halogen, deuterium, hydroxyl, cyano, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 3-6 Heterocycloalkyl, -C 3-6 Cycloalkoxy, -C 3-6 Heterocycloalkoxy, -COOH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl)2, -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR 2a , -C(O)NH2, aryl, heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, heteroaryl, -C(O)NH2, -S(O)2NH2, -S(O)(NH)NH2 can be optionally replaced by one or more R 2a replace;

[0018] R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, -COOH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR a wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, -C(O)NH2, -S(O)2NH2, -S(O)(NH)NH2 are selectively selected from halogen, cyano, -OR a 、-SR a NR b R c , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocyclooxy or one or more thereof may be substituted or unsubstituted;

[0019] Preferably, R2 is selected from hydrogen, halogen, cyano;

[0020] and / or, R1 and R2 selectively form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered heterocycloalkenyl, aryl, heteroaryl with the carbon atoms to which they are attached, and may be selectively replaced by one or more R 1a or R 2a Substitution; and the carbon atoms or sulfur atoms in the above-mentioned cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl groups may be selectively oxidized to form a part of an intra-ring carbonyl group, an amide group, an ester group, a sulfone group (-S(O)2-), or a sulfonamide group (-S(O)2NH-);

[0021] Preferably, and / or, R1 and R2 selectively form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group with the carbon atoms to which they are respectively connected, and the carbon atoms in the above cycloalkyl group or heterocycloalkyl group may be selectively oxidized to form a part of the intracyclic carbonyl group or ester group.

[0022] R3 is selected from hydrogen, deuterium, C 1-6 Alkyl, deuterated alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyanoalkyl, -C 3-6 Cycloalkyl, -C 3-6 Heterocycloalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl;

[0023] Preferably, R3 is selected from C 1-6 Alkyl, deuterated alkyl, halogenated C 1-6 Alkyl, -C 3-6 Cycloalkyl.

[0024] R4 is independently selected from heteroaryl, which is a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, which contains 1 or 2 N ring heteroatoms in the ring, the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group having 9 or 10 ring atoms, which contains 1, 2, 3 or 4 N ring heteroatoms in the ring, the remaining ring atoms are carbon atoms, wherein at least one ring is aromatic, and the heteroaryl group includes those heteroaryl groups in which the N ring heteroatoms are in the form of N-oxides, and the heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, deuterium, cyano, hydroxyl, mercapto, C 1-6 Alkyl, haloalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -COOH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C1-6 Alkyl)(C 1-6 alkyl), -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR a 、-NHC(O)(C 1-6 Alkyl), -NHC(O)(C 1-6 Cycloalkyl), -NHC(O)O(C 1-6 alkyl), -NHC(O)O(C 1-6 cycloalkyl), phenyl and 5 or 6 membered heteroaryl; wherein C 1-6 Alkyl, haloalkyl, -NH2, -COOH, -C(O)NH2, cycloalkyl, heterocycloalkyl may be replaced by one or more R 1a wherein the 5- or 6-membered heteroaryl as a substituent of R4 is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, which contains 1, 2 or 3 ring heteroatoms independently selected from N, O or S in the ring, and the remaining ring atoms are carbon atoms, and when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein the phenyl or 5- or 6-membered heteroaryl as a substituent of the heteroaryl is optionally substituted by one or more substituents selected from the following: halogen, amino, hydroxyl, mercapto, C1-6 alkyl and -O(C 1-6 Alkyl), haloalkyl;

[0025] R5 is independently selected from hydrogen, C 1-6 Alkyl, hydroxy substituted alkyl, deuterated alkyl, hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, cycloalkylalkyl or cycloalkoxyalkyl, wherein the alkyl group may be optionally replaced by one or more R 5a Replacement; R 5a is selected from deuterium, halogen, CN, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be halogen, CN, -OR a 、-SR a 、-NR b R c , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl substitution;

[0026] And / or, R4 and R5 selectively form a nitrogen-containing heterocyclic group or heteroaryl group with the N atom to which they are connected, wherein the nitrogen-containing heterocyclic group and heteroaryl group may be selectively substituted by one or more substituents, including but not limited to halogen, deuterium, amino, hydroxyl, thiol, cyano, alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aromatic, aromatic oxy, heteroaromatic, heteroaromatic oxy, -COOH, -C(O)NH2, -C(O)NH(C1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR a 、-OR a 、-SR a NR b R c ;

[0027] Among them, R a , R b and R c are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 3-6 Heterocycloalkyl, hydroxy substituted C 1-6 Alkyl, -C 1-6 Alkyl(O)C 1-6 Alkyl, aryl, heteroaryl;

[0028] and / or R b and R c Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group or are substituted by 1 to 3 R a replace.

[0029] R6 is selected from aryl, heteroaryl or heterocyclic, wherein the heteroaryl or heterocyclic contains 1 to 3 heteroatoms selected from N, O or S;

[0030] The R6 may be further optionally substituted by hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, amino, alkyl, alkoxy, haloalkyl, haloalkoxy, oxo, cycloalkyl, -NH(C 1-6 Alkyl), -O - 、-N(C 1-6 Alkyl)(C 1-6 Alkyl), -SO2(C 1-6 alkyl).

[0031] Further, the R6 is selected from 5-6 membered aryl, 5-6 membered heteroaryl, 4-6 membered heterocyclic group, 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; the R6 may be further substituted by hydrogen, deuterium, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3Haloalkyl, oxo, C 3-6 The invention can be substituted by one or more of cycloalkyl, -N(CH3)2.

[0032] Preferably, the R6 is selected from the following groups:

[0033]

[0034] Wherein, m, n or p is 1, 2 or 3;

[0035] More preferably, the R6 is selected from the following groups:

[0036]

[0037] The R6 may be further optionally substituted with hydrogen, deuterium, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, oxo, C 3-6 The invention can be substituted by one or more of cycloalkyl, -N(CH3)2.

[0038] Preferably, the compound is selected from the following formula (Ia) or (Ib):

[0039]

[0040] Wherein, R1 is selected from hydrogen, deuterium, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl;

[0041] R2 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl;

[0042] Alternatively, R1 and R2 form a C 3-6 Cycloalkyl, 3-6 membered heterocyclic group;

[0043] R3 is selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C1-6 Deuterated alkoxy or C 3-6 Cycloalkyl;

[0044] R6 is selected from 5-6 membered heteroaryl, 4-6 membered heterocyclyl, 8-10 membered bicyclic heteroaryl, wherein the heteroaryl or heterocyclyl contains 1 to 3 heteroatoms selected from N, O or S;

[0045] Preferably, R6 is selected from the following groups:

[0046]

[0047] Wherein, m, n or p is 1, 2 or 3;

[0048] More preferably, R6 is selected from the following groups:

[0049]

[0050] The R6 may be further optionally substituted with hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, oxo, C 3-6 Cycloalkyl, -NH(C 1-3 Alkyl), -O, -

[0051] N(C 1-3 Alkyl)(C 1-3 Alkyl), -SO2(C 1-3 alkyl) in one or more substitutions;

[0052] R7, R8 or R9 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy.

[0053] Further, R4 is selected from a heteroaryl group, or R4 and R5 form a heteroaryl group;

[0054] wherein the heteroaryl group is a monocyclic aromatic hydrocarbon group having 6 ring atoms, which contains 1 or 2 N ring heteroatoms in the ring, and the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group having 9 ring atoms, which contains 3 or 4 N ring heteroatoms in the ring, and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring and the heteroaryl group is optionally substituted by one or more substituents selected from the following: halogen, cyano, hydroxyl, mercapto, C 1-6 Alkyl, haloalkyl, cycloalkyl, -O(C 1-6 Alkyl) and -O(C 1-6 haloalkyl), -NH2, NH(C 1-6 Alkyl), N(C1-6 Alkyl)(C 1-6 alkyl), -CO2H, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), phenyl and 5- or 6-membered heteroaryl.

[0055] Further, R4 is selected from a heteroaryl group, or R4 and R5 form a heteroaryl group;

[0056] wherein the heteroaryl is a monocyclic aromatic hydrocarbon group having 6 ring atoms, which contains 1 or 2 N ring heteroatoms in the ring, and the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group having 9 ring atoms, which contains 3 or 4 N ring heteroatoms in the ring, and the remaining ring atoms are carbon atoms, wherein at least one ring is aromatic and the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, bromine, cyano, hydroxyl, mercapto, haloalkyl, C 1-6 Alkyl, -NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)(C 1-6 alkyl), -CO2H, -C(O)NH2, -C(O)NH(C 1-6 alkyl), phenyl, pyridyl, pyrimidinyl, piperazinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl.

[0057] Further, the phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl in R4 are optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, thiol, amino, C 1-6 Alkyl, haloalkyl, cycloalkyl, -O(C 1-6 Alkyl) and -O(C 1-6 haloalkyl).

[0058] Furthermore, the aryl group in the heteroaryl group is selected from pyrimidine, purine, pyrazolopyrimidine, and pyrrolopyrimidine.

[0059] Furthermore, R4, or the heteroaryl formed by R4 and R5 is selected from the following substituents

[0060]

[0061] wherein the substituent is optionally substituted by one or more of the following substituents: fluorine, chlorine, bromine, cyano, hydroxyl, mercapto, haloalkyl, C 1-6 Alkyl, -NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)(C 1-6alkyl), -CO2H, -CONH2, -C(O)NH(C 1-6 alkyl), phenyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl and tetrazolyl, wherein the phenyl, pyridyl, pyrimidinyl, piperazinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl as R4 substituents are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, mercapto, C 1-6 Alkyl, haloalkyl, cycloalkyl, -O(C 1-6 Alkyl) and -O(C 1-6 haloalkyl).

[0062] Further, R4 is selected from Any substituent in, R4 is optionally substituted by one or more substituents selected from the following substituents: fluorine, chlorine, bromine, cyano, haloalkyl, C 1-6 Alkyl, -NH2, NH(C 1-6 alkyl), -CO2H, -CONH2, phenyl, pyridyl, pyrazolyl, triazolyl and tetrazolyl,

[0063] Wherein phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl as R4 substituents are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-6 Alkyl and -O(C 1-6 alkyl).

[0064] Furthermore, R3 is C 1-4 Alkyl, C 1-4 Deuterated alkyl and C 1-4 Halogenated alkyl.

[0065] Further, R3 is methyl, deuterated methyl, ethyl, deuterated ethyl and trifluoromethyl.

[0066] Furthermore, the compound represented by formula (I) is selected from:

[0067]

[0068]

[0069]

[0070]

[0071] The second aspect of the present invention is the use of any of the compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of drugs for treating diseases mediated by PI3K.

[0072] Furthermore, diseases mediated by PI3K include diseases responsive to inhibition of PI3K, including autoinflammatory diseases, respiratory diseases, infectious diseases, autoimmune diseases and cancer.

[0073] Furthermore, the invention provides a use in a drug for treating a disease mediated by PI3K, wherein the PI3K is PI3Kδ.

[0074] Furthermore, the disease is selected from cancer, inflammation, respiratory disease, infectious disease, bone marrow-related disease and autoimmune disease.

[0075] Further, cancer is solid tumor, leukemia, lymphoma and multiple myeloma.Leukemia can be selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML); the lymphoma is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, -cell lymphoma and diffuse large B-cell lymphoma; the autoimmune disease, inflammatory disease, respiratory disease, bone marrow-related disease and infectious disease can be selected from skin inflammation, rheumatoid arthritis, allergic rhinitis, asthma, Kras disease, chronic obstructive pulmonary disease (COPD), systemic lupus erythematosus, psoriasis, multiple sclerosis, activated PI3K syndrome, Sjogren's syndrome, myelofibrosis and / or leishmaniasis.

[0076] Further, the cancer is a solid tumor, including breast cancer, melanoma, head and neck cancer, lung cancer, thymic carcinoma and hematological malignancies.

[0077] The third aspect of the present invention provides a pharmaceutical composition, which comprises a compound of any one of the above formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0078] Furthermore, the pharmaceutical composition is also used in combination with small molecule compounds and / or large molecule antibodies to treat cancer, inflammation, bone marrow-related diseases and autoimmune diseases.

[0079] Furthermore, the small molecule compound includes BTK inhibitor and Bcl2 inhibitor.

[0080] Furthermore, the macromolecular antibodies include anti-CD20, anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies.

[0081] The fourth aspect of the present invention provides use of any of the above pharmaceutical compositions in treating diseases mediated by PI3K, wherein the disease is selected from cancer, inflammation, respiratory disease, infectious disease, bone marrow-related disease and autoimmune disease.

[0082] The fifth aspect of the present invention provides a solvate, a racemic mixture, an enantiomer, a diastereomer, a tautomer or a mixture of any proportion thereof including a racemic mixture of any of the above compounds of formula (I), wherein each substituent of R1, R2, R3, R4 and R5 is as defined above.

[0083]

[0084] In a sixth aspect, the present invention provides a prodrug of any one of the compounds of formula (I) above.

[0085] In the seventh aspect of the present invention, a method for inhibiting PI3K activity in vivo or in vitro using any of the above compounds of formula (I) is provided, which comprises contacting an effective dose of any of the above compounds of formula (I) and / or a pharmaceutically acceptable salt thereof with PI3K kinase.

[0086] Further, the PI3K kinase is any one or more of PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ. Further, the PI3K kinase is PI3Kδ.

[0087] In an eighth aspect, the present invention provides a combined therapeutic system for treating cancer, inflammation and autoimmune diseases, which comprises at least any one of the compounds of formula (I) above or a pharmaceutically acceptable salt thereof, and a small molecule compound or a macromolecular antibody.

[0088] The compounds of the present invention may be asymmetric, for example, having one or more stereocenters. Unless otherwise specified, all stereoisomers, for example, enantiomers and diastereomers. Containing asymmetrically substituted carbon atoms. The compounds of the present invention may be isolated into optically pure or racemic forms. Optically pure forms may be prepared by resolution of racemates, or by using chiral synthons or chiral reagents.

[0089] The compounds of the present invention may also include tautomeric forms. Tautomeric forms are generated by the interchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0090] The compounds of the present invention may also include all isotopic forms of atoms present in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

[0091] The present invention also includes pharmaceutically acceptable salts of compounds of formula (I). Pharmaceutically acceptable salts refer to derivatives of compounds of formula (I) wherein the parent compound is modified by conversion of the base moiety present into its salt form, or derivatives of compounds of formula (I) wherein the parent compound is modified by conversion of the acid moiety present into its salt form.

[0092] Specifically, examples of pharmaceutically acceptable salts include, but are not limited to, salts of inorganic or organic acids of basic groups (such as amines), or salts of inorganic or organic bases of acidic groups (such as carboxylic acids). The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound of formula (I) by reacting the free base forms of these compounds with 1-4 equivalents of an appropriate acid in a solvent system. Suitable salts are listed in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).

[0093] Compounds of the present invention and pharmaceutically acceptable salts thereof also include solvate forms or hydrate forms. Generally speaking, solvate forms or hydrate forms are equivalent to non-solvate forms or non-hydrate forms, and are all included in the scope of the present invention. Some compounds of the present invention can exist in multiple crystal forms or amorphous forms. Generally speaking, all physical forms of compounds are included in the scope of the present invention.

[0094] The present invention also includes prodrugs of the compounds of formula (I). Prodrugs are pharmacological substances (i.e., drugs) derived from parent drugs. Once administered, the prodrugs are metabolized in vivo to become parent drugs. Prodrugs can be prepared by replacing one or more functional groups present in the compound, wherein the substituents in the prodrug are removed in vivo in such a way as to be converted into the parent compound. The preparation and use of prodrugs are described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems" Vol. 14 of the ACSSymposium Series and Bioreversible. DETAILED DESCRIPTION

[0095] The present invention is further described below by examples, which are only used to more specifically illustrate the preferred embodiments of the present invention and are not used to limit the technical solutions of the present invention. The above-mentioned solutions of the present invention are all technical solutions that can achieve the purpose of the present invention. The temperatures and reagents used in the following examples can be replaced by the above-mentioned corresponding temperatures and reagents to achieve the purpose of the present invention.

[0096] definition

[0097] As used in this application, the following terms, phrases and symbols have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0098] A hyphen ("-") between two letters or symbols indicates the point of attachment of a substituent. For example, -O(C 1-4 Alkyl) refers to a C group attached to the rest of the molecule through an oxygen atom. 1-4 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0099] Unless expressly stated otherwise, terms such as "a" or "1" refer to one or more.

[0100] The term "alkyl" as used herein refers to a straight or branched saturated hydrocarbon group containing 1-18 carbon atoms, such as 1-12 carbon atoms, such as 1-6 carbon atoms, and such as 1-4 carbon atoms. For example, "C1-6 alkyl" is within the scope of "alkyl" and represents the alkyl group having 1-6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n-Pr"), isopropyl ("i-Pr"), n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("sBu"), and tert-butyl ("t-Bu").

[0101] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon group containing 2-10 carbon atoms, such as 2-6 carbon atoms, and 2-4 carbon atoms, containing one or more, such as 1, 2 or 3 carbon-carbon double bonds (C=C). For example, "C2-6 alkenyl" is within the scope of "alkenyl" and means an alkenyl group having 2-6 carbon atoms. Examples of alkenyl include, but are not limited to, vinyl, 2-propenyl and 2-butenyl.

[0102] The term "alkynyl" as used herein refers to a straight or branched hydrocarbon group containing one or more, such as 1, 2 or 3, carbon-carbon triple bonds (C≡C) and containing 2-10 carbon atoms, such as 2-6 carbon atoms, and further such as 2-4 carbon atoms. 2-6 "Alkynyl" refers to an alkynyl group containing one carbon-carbon triple bond (C≡C) and having 2-6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl and 2-butynyl.

[0103] As used herein, the term "halo" refers to fluoro, chloro, bromo and iodo, and "halogen" refers to fluorine, chlorine, bromine and iodine.

[0104] The term "haloalkyl" as used herein refers to an alkyl defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be identical or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, wherein the halogen atoms are identical to each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl include, but are not limited to, -CF3, -CHF2, -CH2CF3, etc.

[0105] The term "alkoxy" as used herein refers to the group -O-alkyl, wherein alkyl is as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy, including isomers thereof.

[0106] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated cyclic hydrocarbon group containing 3-12 ring carbon atoms, such as 3-8 ring carbon atoms, and 3-6 ring carbon atoms, which may have one or more rings, such as 1 or 2 rings. For example, "C3-8 cycloalkyl" represents a cycloalkyl group having 3-8 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and similar groups.

[0107] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a 4- to 12-membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated ring selected from the group consisting of at least one, e.g., 1-4, further e.g., 1-3, or further e.g., 1 or 2, heteroatoms selected from O, S, and N, and at least one carbon atom. The point of attachment of the heterocyclyl group may be on a heteroatom or on carbon. "Heterocyclyl" or "heterocyclic" also refers to a monocyclic ring containing at least one heteroatom selected from O, S, and N; or a fused ring wherein at least one ring contains at least one heteroatom selected from O, S, and N and the other ring is not a heteroaryl or aryl group, and the point of attachment may be on the heterocyclic ring or on the other ring.

[0108] The term "cycloalkoxy" as used herein refers to the group -O-cycloalkyl, wherein cycloalkyl is as defined above. Examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, including isomers thereof.

[0109] The term "heterocycloalkoxy" as used herein refers to the group -O-heterocycloalkyl, wherein heterocycloalkyl is as defined above. Examples of cycloalkoxy include, but are not limited to, aziridineoxy, epoxypropaneoxy, azetidinyloxy, oxetanyloxy, including isomers thereof.

[0110] The "cycloalkenyl" described herein refers to a non-aromatic cyclic hydroxyl group containing one or more, for example, 1, 2 or 3 carbon-carbon double bonds, 3-12 ring carbon atoms, preferably 3-8 ring carbon atoms, more preferably 3-6 ring carbon atoms, which may have one or more rings, preferably 1 or 2 rings. For example, C 3-8 ring carbon atoms and cycloalkenyl, preferably "C 3-6 "Cycloalkenyl" refers to a cycloalkenyl group having 3-6 ring carbon atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0111] The "heterocycloalkenyl" described herein means that one or more carbon atoms in the above-mentioned "cycloalkenyl" are replaced by N, O, or S. For example, C 3-8 The heterocyclic alkenyl group is preferably a "C 3-6 "Heterocycloalkenyl" means a heterocycloalkenyl having 3-6 ring atoms. Examples of heterocycloalkenyl include, but are not limited to, azetidinyl, oxetinyl, azocyclopentyl, oxolyl, and oxenyl.

[0112] The term "aryl (Ar)" as used herein, unless otherwise specifically defined, refers to a carbocyclic hydrocarbon group consisting of one or more rings fused together containing 6-14 ring carbon atoms, for example 6-12 ring carbon atoms, wherein at least one ring is an aromatic ring and the other rings are not heteroaryl as defined below, and the point of attachment may be on the aromatic ring or on the other rings. Examples of aryl (Ar) include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl. As used herein, "aryl" or "aromatic" follows Hückel's rule, where the number of π electrons is equal to 4n+2, and n is zero or any positive integer up to 6.

[0113] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a 4- to 12-membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated ring selected from the group consisting of at least one, e.g., 1-4, further e.g., 1-3, or further e.g., 1 or 2, heteroatoms selected from O, S, and N, and at least one carbon atom. The point of attachment of the heterocyclyl group may be on a heteroatom or on carbon. "Heterocyclyl" or "heterocyclic" also refers to a monocyclic ring containing at least one heteroatom selected from O, S, and N; or a fused ring wherein at least one ring contains at least one heteroatom selected from O, S, and N and the other ring is not a heteroaryl or aryl group, and the point of attachment may be on the heterocyclic ring or on the other ring.

[0114] The term "heteroaryl (Ar)" as used herein, unless otherwise specifically defined, refers to: a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, for example, a monocyclic aromatic hydrocarbon group having 6 ring atoms, which contains one or more, for example, 1, 2 or 3, for example, 1 or 2 ring heteroatoms independently selected from N, O and S (for example, N) in the ring, and the remaining ring atoms are carbon atoms; and a bicyclic aromatic hydrocarbon group having 8-12 ring atoms, for example, a bicyclic aromatic hydrocarbon group having 9 or 10 ring atoms, which contains one or more, for example, 1, 2, 3 or 4, for example, 1 or 2 ring heteroatoms independently selected from N, O and S (for example, N) in the ring, and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring. For example, a bicyclic heteroaryl group includes a 5-6-membered heteroaryl ring fused to a 5-6-membered cycloalkyl ring, a heterocyclyl ring or an aryl ring, wherein the point of attachment may be on the heteroaryl ring or on the cycloalkyl ring / heterocyclyl ring / aryl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other. Heteroaryl groups also include those heteroaryl groups in which the N ring heteroatoms are in the form of N-oxides, such as N-oxidized pyrimidinyl. In some embodiments, the ring heteroatoms in the above heteroaryl groups are N atoms, and such heteroaryl groups are referred to as "nitrogen-containing heteroaryl groups". Nitrogen-containing heteroaryl groups also include those heteroaryl groups in which the N ring heteroatoms are in the form of N-oxides, such as N-oxidized pyridinyl.

[0115] Examples of heteroaryl (Ar) include, but are not limited to, pyridyl, pyridyl N-oxide; pyrazinyl; pyrimidinyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; tetrazolyl; triazolyl; thienyl; furanyl; pyranyl; pyrrolyl; pyridazinyl; benzo[d]thiazolyl; benzodioxolyl, such as benzo[d][1,3]dioxolyl; benzoxazolyl, such as benzo[d]oxazolyl; imidazopyridinyl, such as imidazo[1,2-a]pyridinyl; triazolopyridinyl, such as Such as [1,2,4]triazolo[4,3-a]pyridinyl and [1,2,4]triazolo[1,5-a]pyridinyl; indazolyl; 2H-indazolyl; pyrrolopyrimidinyl, such as pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; pyrazolopyrimidinyl, such as pyrazolo[1,5-a]pyrimidinyl; tetrazolopyridinyl, such as tetrazolopyridinyl; benzothienyl; benzofuranyl; benzimidazolinyl; indolyl; indolyl; purinyl, such as 9H-purinyl and 7H-purinyl

[0116] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyrrolyl; pyrazolyl; imidazolyl; pyridinyl; pyrazinyl; pyrimidinyl, N-oxidized pyrimidinyl; pyridazinyl; pyrrolopyrimidinyl, such as pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; purinyl, such as 9H-purinyl and 7H-purinyl; quinolyl; indolyl; and indazolyl.

[0117] The term "hydroxyl" as used herein refers to an -OH group.

[0118] As used herein, the term "thiol" refers to a -SH group.

[0119] As used herein, the term "oxo" refers to a =0 group.

[0120] The term "carboxy" as used herein refers to a -C(O)-OH group.

[0121] As used herein, the term "cyano" refers to a -CN group.

[0122] The term "amino" as used herein refers to a -NH2 group.

[0123] As used herein, "group" and "radical" are synonymous and are used to indicate a functional group or a molecular fragment that can be linked to other molecular fragments.

[0124] If a structural formula herein contains an asterisk "*", the compound represented by the structural formula is a chiral compound, that is, the compound is in the R-configuration or the S-configuration. The configuration of the compound can be determined by a person skilled in the art using a variety of analytical techniques, such as single crystal X-ray crystallography and / or optical polarimetry and according to conventional protocols.

[0125] As used herein, the terms "selective", "selective", "selectively", "optional", "optional" or "optionally" mean that the subsequently described substitution pattern, event or situation may occur once or more than once, or may not occur, and that the description includes instances where the substitution pattern occurs as well as instances where the substitution pattern does not occur. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined herein. It should be understood by those skilled in the art that for any group containing one or more substituents, the group does not include any substitution pattern that is sterically impractical, chemically incorrect, synthetically infeasible and / or inherently unstable.

[0126] As used herein, the term "including but not limited to" means that the selected scope takes precedence over the subsequently listed groups, but groups not listed may also be used.

[0127] As used herein, the term "substituted" or "substituted by" means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given substituent group, provided that the normal valence of the given atom is not exceeded. When the substituent is oxo (i.e., =O), then two hydrogen atoms on a single atom are replaced by oxygen. Combinations of substituents and / or variables are permitted only if they result in chemically correct and stable compounds. A chemically correct and stable compound means that the compound is sufficiently stable to be isolated from a reaction mixture and the chemical structure of the compound can be determined, and then formulated into a formulation that at least has practical utility.

[0128] Unless otherwise indicated, substituents are named into the core structure. For example, it is understood that when (cycloalkyl)alkyl is listed as a possible substituent, it means that the point of attachment of the substituent to the core structure is at the alkyl portion.

[0129] The term "substituted with one or more substituents" as used herein means that one or more hydrogen atoms on a given atom or group are independently replaced with one or more substituents selected from a given group. In some embodiments, "substituted with one or more substituents" means that a given atom or group is replaced with 1, 2, 3 or 4 substituents independently selected from a given group.

[0130] It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers, and therefore there are two or more stereoisomers. Racemic mixtures of these isomers, single isomers and mixtures enriched in one enantiomer, and diastereomers and mixtures partially enriched in specific diastereomers when there are two chiral centers are within the scope of the present invention. It will also be appreciated by those skilled in the art that the present invention includes all single stereoisomers (e.g., enantiomers), racemic mixtures or partially resolved mixtures of compounds of formula (I), and, where appropriate, single tautomers thereof.

[0131] In other words, in some embodiments, the present invention provides compounds containing various degrees of stereoisomeric purity, i.e., diastereomeric or enantiomeric purity expressed as different "ee" or "de" values. In some embodiments, the compounds of Formula (I) (e.g., as described herein) have an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any value between these recited values). In some embodiments, the compounds of Formula (I) (e.g., as described herein) have an enantiomeric purity of greater than 99.9% ee, up to 100% ee. In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity of at least 60% de (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any value between these recited values). In some embodiments, the compound of formula (I) (e.g., as described herein) has a diastereomeric purity of greater than 99.9% de.

[0132] The term "enantiomeric excess" or "ee" refers to the amount of one enantiomer relative to the other. For a mixture of R and S enantiomers, the percentage of enantiomeric excess is defined as |RS|*100, where R and S are the mole or weight fractions of each enantiomer in the mixture, and R+S=1. If the optical rotation of a chiral substance is known, the percentage of enantiomeric excess is defined as ([a]obs / [a]max)*100, where [a]obs is the optical rotation of the enantiomeric mixture and [a]max is the optical rotation of the pure enantiomer.

[0133] The term "diastereomeric excess" or "de" refers to the amount of one diastereomer relative to the other diastereomer and is defined by analogy to enantiomeric excess. Thus, for a mixture of diastereomers D1 and D2, the percentage of diastereomeric excess is defined as |D1–D2|*100, where D1 and D2 are the mole or weight fractions of the respective diastereomers in the mixture and D1+D2=1.

[0134] Determination of diastereomers and / or enantiomeric excess may be accomplished using a variety of analytical techniques, including nuclear magnetic resonance spectroscopy, chiral column chromatography, and / or optical polarimetry, and according to conventional protocols familiar to those skilled in the art.

[0135] The racemic mixture can be used in its own form or resolved into individual isomers. Resolution can yield a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known and include physical methods, such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then freeing one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers that are substantially free of the other isomer, i.e., the desired stereoisomers with an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as is well known to those skilled in the art, the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers, which can be separated by chromatography or fractional crystallization, followed by chemical removal of the chiral auxiliary to obtain the pure enantiomers.

[0136] The "pharmaceutically acceptable salt" of the present invention refers to a salt of a free acid or base of a compound of formula (I) that is non-toxic, biologically tolerable or other biologically suitable for administration to a subject for treatment.

[0137] "Pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed by compounds of formula (I) with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed by compounds of formula (I) with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts formed with alkanedicarboxylic acids of formula HOOC-(CH2)n-COOH (wherein n is 0-4), etc. "Pharmaceutically acceptable salts" also include base addition salts formed by compounds of formula (I) with acidic groups and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium. The molar ratio of the compound of formula (I) to the acid or cation in the resulting pharmaceutically acceptable salt includes, but is not limited to, 1:1, 1:2, 1:3 and 1:4.

[0138] The "prodrug" of the present invention refers to a pharmacological substance (i.e., drug) derived from a parent drug. Once administered, the prodrug is metabolized into the parent drug in vivo. The prodrug can be prepared by replacing one or more functional groups present in the compound, wherein the substituent in the prodrug is removed in vivo in such a way as to be converted into the parent compound. The preparation and use of prodrugs can be found in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACSSymposium Series and Bioreversible. "Prodrugs" include, but are not limited to: esters of compounds of formula (I) such as phosphates, formates, and carbamates; amides such as formamide and acetamide.

[0139] In addition, if the compounds described herein are obtained in the form of acid addition salts, their free base forms can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of a free base, its acid addition salt, especially a pharmaceutically acceptable acid addition salt, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art can determine various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts without undue experimentation.

[0140] The term "solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to entrain a fixed molar ratio of solvent molecules in the solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more molecules of water with one molecule of the substance, wherein the water retains its molecular state of H2O, and such a combination can form one or more hydrates, such as hemihydrates, monohydrates and dihydrates, as well as variable hydrates.

[0141] As used herein, the terms "group" and "radical" are synonymous and are used to indicate a functional group or a molecular fragment that can be attached to other molecular fragments.

[0142] The term "active ingredient" is used to refer to a chemical substance with biological activity. In some embodiments, an "active ingredient" is a chemical substance with pharmaceutical use. In the United States, actual drug activity can be determined by appropriate preclinical tests, whether in vitro or in vivo. However, drug activity that is sufficient to be accepted by regulatory agencies (such as the FDA in the United States) must have higher standards than preclinical tests. Whether such a higher standard of drug activity can be successfully obtained generally cannot be reasonably expected from preclinical test results, but can be established through appropriate and effective randomized, double-blind, controlled clinical trials conducted in humans.

[0143] The term "treating" or "treatment" of a disease or disorder, in the context of achieving a beneficial therapeutic effect, refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) and / or pharmaceutically acceptable salts thereof as described herein, to an individual, such as a human, suffering from the disease or disorder, or having symptoms of the disease or disorder, or having a predisposition to the disease or disorder, in order to cure, heal, alleviate, relieve, alter, cure, improve, ameliorate or affect the disease or disorder, symptoms of the disease or disorder, or a predisposition to the disease or disorder. In some embodiments, the disease or disorder is cancer.

[0144] When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction that produces the indicated and / or desired product may not necessarily come directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0145] The term "effective amount" as used herein refers to an amount or dosage of a PI3K inhibitor that is generally sufficient to produce a beneficial therapeutic effect on a patient who needs treatment for a disease or disorder mediated by PI3K activity. The effective amount or dosage of the active ingredient in the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., the mode or route of administration or administration, the pharmacokinetics of the drug ingredient, the severity and course of the disease or disorder, the individual's previous or ongoing treatment, the individual's health status and response to the drug, and the judgment of the attending physician). In the United States, the determination of the effective dose is generally difficult to predict from preclinical trials. In fact, the dose is completely unpredictable, and new unpredictable dosage regimens will develop after the dose is originally used in randomized, double-blind, controlled clinical trials.

[0146] Typical dosage range is from about 0.0001 to about 200 mg of active ingredient per kg of individual body weight per day, for example, from about 0.001 to 100 mg / kg / day, or about 0.01 to 35 mg / kg / day, or about 0.1 to 10 mg / kg, once a day or in divided dose units (for example, twice a day, three times a day, four times a day). For a 70 kg person, a suitable dosage range can be about 0.05 to about 7 grams / day, or about 0.2 to about 5 grams / day. Once the patient's disease or disorder improves, the dosage can be adjusted to maintain treatment. For example, the dosage or the number of administrations can be adjusted according to the change of symptoms, or the dosage and the number of administrations can be reduced to the level of the desired therapeutic effect. Of course, if the symptoms are alleviated to an appropriate level, treatment can be stopped. However, for the recurrence of symptoms, the patient may need intermittent long-term treatment.

[0147] The term "inhibit" refers to a reduction in the baseline activity of a biological activity or process. The term "inhibit PI3K activity" is the actual drug activity for the purposes of the present invention and refers to a reduction in PI3K activity caused by a direct or indirect response to the presence of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof as described herein, relative to the activity of PI3K in the absence of the compound of formula (I) and / or a pharmaceutically acceptable salt thereof. The reduction in activity may be caused by a direct interaction between the compound of formula (I) and / or a pharmaceutically acceptable salt thereof as described herein and PI3K, or by an interaction between the compound of formula (I) and / or a pharmaceutically acceptable salt thereof as described herein and one or more other factors that affect the activity of PI3K. For example, the presence of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof as described herein may reduce the activity of PI3K by directly binding to PI3K, may reduce the activity of PI3K by directly or indirectly affecting another factor, or may reduce the activity of PI3K by directly or indirectly reducing the amount of PI3K present in a cell or organism.

[0148] As used herein, the term "individual" refers to mammals and non-mammals. Mammals refer to any member of the class mammals, including but not limited to humans; non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, and pigs; livestock, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds, etc. The term "individual" does not limit a particular age or sex. In some embodiments, the individual is a human.

[0149] In general, the term "about" is used herein to modify a stated numerical value by 20% above or below that value.

[0150] General synthesis method of the compound of formula (I)

[0151] Reaction Scheme 1

[0152]

[0153] As shown in route 1, the compound of formula i-1 reacts with NCS to obtain a compound of formula i-2. The compound of formula i-2 reacts with ethyl 3-ethoxyacrylate to obtain a compound of formula i-3. The compound of formula i-3 reacts with NIS to obtain a compound of formula i-4. The compound of formula i-4 reacts with POCl3 to obtain a compound of formula i-5. The compound of formula i-5 reacts with a tin reagent under the catalysis of an appropriate palladium reagent to obtain a compound of formula i-6. The compound of formula i-6 is reduced with a chiral reagent (+)-DIPCl to obtain a compound of formula i-7. The compound of formula i-7 is subjected to Mitsunobu reaction to obtain a compound of formula i-8. The compound of formula i-8 of ArB(OH)2 (Ar is as defined herein) is subjected to Suzuki coupling reaction under the catalysis of an appropriate palladium reagent to obtain a compound of formula i-9. The palladium-catalyzed carbon-carbon coupling reaction can be carried out under appropriate conditions: such as in a suitable polar solvent such as DMF, ACN, THF or DMSO, etc.; in a suitable base such as TEA, DIEPA, Cs2CO3, KOAc, etc.; using a catalyst such as Pd(OAc)2, Pd(dppf)2Cl2, Pd(PPh3)4 or Pd2(dba)3, etc. The following reaction can be carried out as follows. The compound of formula i-9 is treated with water and hydrazine to obtain a compound of formula i-10. The compound of formula i-10 is reacted with R4-Cl in the presence of a base (such as DIEPA, etc.) and under appropriate conditions, and / or further derivatized (R5-x) to obtain a compound of formula (I).

[0154] Reaction Scheme 2

[0155]

[0156] As shown in route 2, the compound of formula i-11 reacts with ethyl acetate under alkaline conditions to obtain a compound of formula i-12. The compound of formula i-12 is refluxed with DMF-DMA in toluene, and then the concentrated reaction is further reacted with the compound of formula i-1 under acidic conditions to generate a compound of formula i-13. The compound of formula i-13 is subjected to ester hydrolysis to obtain the compound acid of formula i-14. The compound acid of formula i-14 reacts with N,O-dimethylhydroxylamine to obtain an amide compound of formula i-15. Halogen is introduced into the compound of formula i-15 under appropriate conditions to obtain a compound of formula i-16, or the obtained halide is further modified to obtain a compound of formula i-16. The compound of formula i-16 reacts with a reducing agent (LiAlH, Dibal-H) under appropriate conditions to generate a compound of formula i-17. The compound of formula i-17 is condensed with (S)-2-methylpropane-2-sulfenamide, and then reacted with an appropriate Grignard reagent to obtain a compound of formula i-19. The compound of formula i-19 is deprotected to obtain a compound of formula i-20. The compound of formula i-20 is reacted with R4-Cl in the presence of a base (such as DIEPA, etc.) and under appropriate conditions, and / or further derivatized (R5-x) to obtain a compound of formula (I).

[0157] Pharmaceutical compositions and uses

[0158] The compounds of formula (I) described herein (e.g., any compound herein) and / or pharmaceutically acceptable salts thereof can be formulated into pharmaceutical compositions alone or in combination with one or more additional active ingredients. The pharmaceutical composition comprises: (a) an effective amount of a compound of formula (I) described herein and / or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0159] A pharmaceutically acceptable carrier is one that is compatible with the active ingredient in the composition (in some embodiments, stabilizes the active ingredient) and is not harmful to the individual being treated. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts) can be used as pharmaceutical excipients to deliver the active ingredient. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are disclosed in a standard reference book in the art (Remington's Pharmaceutical Sciences, A. Osol).

[0160] The pharmaceutical composition comprising a compound of formula (I) as described herein (e.g., any compound herein) and / or a pharmaceutically acceptable salt thereof can be administered in various known ways, such as oral, topical, rectal, parenteral, inhalation or implantation. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intralesional and intracranial injection or infusion.

[0161] The pharmaceutical composition described herein can be prepared in the form of tablets, capsules, bagged granules, dragees, powders, granules, lozenges, powder injections, liquid preparations or suppositories. In some embodiments, the pharmaceutical composition comprising the compound of formula (I) and / or its pharmaceutically acceptable salt can be formulated for intravenous infusion, topical administration or oral administration.

[0162] The composition for oral administration can be in any oral acceptable dosage form, including but not limited to: tablets, capsules, emulsions and aqueous suspensions, dispersants and solutions. Commonly used tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also often added to tablets. When administered orally in capsule form, useful diluents include lactose and dried corn starch. When administered orally in the form of an aqueous suspension or emulsion, an emulsifier or suspending agent can be used to suspend or dissolve the active ingredient in the oil phase. If necessary, certain sweeteners, flavoring agents or pigments can also be added.

[0163] In some embodiments, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt in tablets can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg. In some embodiments, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt in capsules can be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg.

[0164] Sterile injectable compositions (such as aqueous or oily suspensions) can be prepared according to techniques known in the art using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable intermediates can also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Pharmaceutically acceptable carriers and solvents can be used, in particular, mannitol, water, Ringer's solution, and physiological saline. In addition, sterile, non-volatile oils such as synthetic mono- or diglycerides are commonly used as solvents or suspending media. Fatty acids such as oleic acid and its glyceride derivatives and natural pharmaceutically acceptable oils such as olive oil or castor oil (especially its polyoxyethylated form) are commonly used as injectable intermediates. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants.

[0165] The inhalation composition may be prepared according to techniques well known in the art of pharmaceutical formulation using benzyl alcohol or other suitable preservatives, using absorption promoters to improve bioavailability, using fluorocarbons and / or other solubilizing or dispersing agents known in the art, or it may be prepared as a solution in saline.

[0166] Topical compositions can be formulated into forms such as oils, creams, lotions, ointments, etc. Suitable carriers for compositions include vegetable oils or mineral oils, white vaseline (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (i.e., alcohols with carbon atoms greater than 12). In some embodiments, a pharmaceutically acceptable carrier is a carrier in which the active ingredient can be dissolved. If necessary, the composition may also include an emulsifier, a stabilizer, a wetting agent, and an antioxidant, as well as a substance that imparts color or fragrance. In addition, a transdermal penetration enhancer may also be added to the topical preparation. Examples of such enhancers are found in U.S. Patents US No. 3,989,816 and 4,444,762.

[0167] Creams can be prepared from a mixture of mineral oil, self-emulsifying beeswax and water, with the active ingredient dissolved in a small amount of fat, such as almond oil, mixed therein. An example of a cream comprises about 40 parts of water, about 20 parts of beeswax, about 40 parts of mineral oil, and about 1 part of almond oil by weight. Ointments can be prepared by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and cooling the mixture. An example of an ointment comprises about 30% almond oil and about 70% white soft paraffin by weight.

[0168] Suitable in vitro experiments can be used to evaluate the practical use of the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts in inhibiting PI3K activity. The other practical uses of the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts in treating cancer or autoimmune diseases can be further detected by in vivo experiments. For example, the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts can be administered to animals (such as mouse models) suffering from cancer or autoimmune diseases, and then the therapeutic effect can be evaluated. If the results of the preclinical trials are successful, the dosage range and administration route for animals such as humans can also be predicted.

[0169] The compounds of Formula (I) and / or pharmaceutically acceptable salts thereof described herein may show sufficient preclinical practical utility to warrant clinical trials and are expected to show beneficial therapeutic or prophylactic effects, for example, in individuals suffering from cancer.

[0170] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and / or the ability to establish new growth foci at other sites. The term "cancer" includes, but is not limited to, solid tumors and hematologic malignancies. The term "cancer" includes cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" includes both primary cancers and metastatic cancers.

[0171] Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial carcinoma or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, head and neck squamous cell carcinoma; skin cancer, including, for example, malignant melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, for example, gliomas, anaplastic oligodendrogliomas, adult glioblastoma multiforme, and adult anaplastic astrocytomas; bone cancer; soft tissue sarcomas; and thyroid cancer.

[0172] Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast phase (CML-BP); acute lymphocytic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's lymphoma; non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS), including refractory anemia (RA), refractory anemia with ringed siderblasts (RARS), refractory anemia with excess blasts ( excess blast, RAEB) and refractory anemia with excess blast in transformation (RAEB-T); and myeloproliferative syndrome.

[0173] In some embodiments, typical hematological malignancies include leukemias, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML); multiple myeloma (MM); and lymphomas, such as Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0174] The term "inflammatory disease" refers to a pathological state resulting in an inflammatory response, particularly due to chemotaxis of neutrophils. Examples of such diseases include inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (IBD) (e.g., Crohn's disease and ulcerative colitis); ischemia-reperfusion injury, including tissue reperfusion injury caused by surgery, myocardial ischemia such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery, and abnormal contractile responses of coronary vessels after percutaneous transluminal coronary angioplasty, tissue reperfusion injury after stroke and abdominal aortic aneurysm surgery; cerebral edema secondary to stroke; cranial trauma; hemorrhagic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behcet's disease; dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis; meningitis; brain Inflammation; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis (RA); Sjögren's syndrome; vasculitis; diseases involving leukocyte infiltration; central nervous system (CNS) inflammatory diseases secondary to sepsis or trauma, multiple organ injury syndrome; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated diseases, including glomerulonephritis; sepsis; sarcoidosis; immunopathological reactions caused by tissue / organ transplantation; lung inflammation, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF) and cystic fibrosis. Preferred indications include, but are not limited to, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other arthritic conditions, multiple sclerosis (MS), asthma, systemic lupus erythematosus, adult respiratory distress syndrome, Behcet's disease, psoriasis, chronic inflammatory lung disease, graft-versus-host disease, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease, and paralysis.

[0175] The term "infectious disease" refers to a pathological state caused by infection with viruses, bacteria, parasites, etc. Non-limiting examples of such diseases include leishmaniasis, pneumonia caused by the new coronavirus, and sepsis.

[0176] The term "pulmonary disease" refers to pathological conditions associated with the lung organ. Non-limiting examples of such diseases include bronchiectasis, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, pneumonia, acute lung injury, acute respiratory distress syndrome.

[0177] The term "bone marrow-related disease" refers to a pathological state associated with the bone marrow organ. Non-limiting examples of such diseases include myelofibrosis and polycythemia vera.

[0178] The compounds of formula (I) and / or pharmaceutically acceptable salts thereof described herein may be used to achieve beneficial therapeutic or prophylactic effects, for example, in individuals suffering from autoimmune diseases.

[0179] The term "autoimmune disease" refers to a disease or condition caused by an immune response to self-antigens that results in damage to one's own tissues or organs. Examples of autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), asthma, and idiopathic thrombocytopenic purpura, as well as myeloid proliferative disorders such as myelofibrosis, postpolycythemia vera / essential thrombocytosis myelofibrosis (PV / ET).

[0180] In some embodiments, inflammatory diseases and autoimmune diseases include rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus erythematosus, systemic lupus erythematosus, psoriasis, and multiple sclerosis.

[0181] In addition, the compounds of formula (I) described herein (e.g., any compound described herein) and / or a pharmaceutically acceptable salt thereof can be used in combination with another active ingredient for the treatment of cancer, inflammatory or autoimmune diseases. The additional active ingredient can be administered separately from the compound of formula (I) described herein and / or a pharmaceutically acceptable salt thereof, or can be included in a pharmaceutical composition according to the present disclosure, such as a fixed-dose combination drug. In a typical embodiment, the additional active ingredient is one that is known or has been found to be effective for treating a disease mediated by PI3K activity, such as another PI3K regulator or a compound that can effectively antagonize another target associated with the specific disease. Combination therapy can be used to improve the efficacy (e.g., by including a compound that can enhance the efficacy or effectiveness of the compound of formula (I) described herein and / or a pharmaceutically acceptable salt thereof into the combination therapy), reduce one or more side effects, or reduce the required dose of the compound of formula (I) described herein and / or a pharmaceutically acceptable salt thereof.

[0182] Example

[0183] The following examples are illustrative of the present invention and are not intended to limit the present invention in any way. Unless otherwise specified, all fractions are weight fractions and temperatures are in degrees Celsius. Pressure is atmospheric pressure or near atmospheric pressure. All data are measured by Agilent (Agilent 6120and / or 1100). Except for the synthetic intermediates, all reagents used in the present invention are obtained from commercial channels. The names of all compounds except reagents are generated by ChemDrew 20.0.

[0184] ACN Acetonitrile

[0185] Boc tert-Butyloxycarbonyl

[0186] (Boc)2O tert-Butyl pyrocarbonate

[0187] DAST Diethylaminosulfur trifluoride

[0188] DCM Dichloromethane

[0189] DEA Diethylamine

[0190] DMF N,N-Dimethylformamide

[0191] DMA Dimethylacetamide

[0192] DIBAL-H Diisobutylaluminum hydride

[0193] DIEPA N,N-Diisopropylethylamine

[0194] EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0195] EtOAc / EA Ethyl acetate

[0196] Et3N Triethylamine

[0197] HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0198] HBTU O-Benzotriazole-tetramethyluronium hexafluorophosphate

[0199] HOAc Acetic acid

[0200] HOBt 1-Hydroxybenzotriazole

[0201] ee enantiomeric excess

[0202] mL milliliters

[0203] g

[0204] mg milligram

[0205] ng

[0206] mol mole

[0207] mmol millimole

[0208] h hour

[0209] MeOH Methanol

[0210] NaH Sodium hydride

[0211] NCS N-chlorosuccinimide

[0212] NMP N-Methyl-2-pyrrolidone

[0213] PE Petroleum Ether

[0214] Pd(dppf)2Cl2 [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride

[0215] Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium

[0216] Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium

[0217] PMB p-Methoxybenzyl cyanide

[0218] PPh3 Triphenylphosphine

[0219] THF Tetrahydrofuran

[0220] TFA Trifluoroacetic acid

[0221] TFE Trifluoroethanol

[0222] TsOH 4-Toluenesulfonic acid

[0223] Xphos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0224] Embodiment 1:

[0225] Compound 19: (S)-4-amino-6-((1-(3-chloro-2-methyl-5-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethyl)amino)pyrimidine-5-carbonitrile

[0226]

[0227] 1) Synthesis of 4-chloro-5-methyl-1H-pyrazol-3-amine (19b)

[0228] 5-Methyl-1H-pyrazole-3-amine (40g, 412.4mmol) was dissolved in 1L dichloromethane. N-chlorosuccinimide was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, the mixture was concentrated in vacuo, the residue was diluted with water, and then extracted with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to dryness to obtain a crude product. Then, it was separated and purified by silica gel column (eluted with dichloromethane / methanol=10 / 1) to obtain a purple-red solid product 4-chloro-5-methyl-1H-pyrazole-3-amine (47g, yield 87%). LC-MS: m / z(ESI)=132.2[M+H] + .

[0229] 2) Synthesis of 3-chloro-2-methylpyrazolo[1,5-a]pyrimidine-5-ol (19c)

[0230] Dissolve 4-chloro-5-methyl-1H-pyrazol-3-amine (47g, 358.8mmol) and ethyl (E)-3-ethoxy acrylate (56.83g, 394.7mmol) in 500ml N,N-dimethylformamide. Add cesium carbonate (175.3g, 538.1mmol) at room temperature. Heat the mixture to 110°C and stir overnight under nitrogen protection. After the reaction solution is cooled, filter it and wash the filter cake with ethyl acetate. Concentrate the vacuum filtrate to obtain a crude product. Then separate and purify by silica gel column (eluted with dichloromethane / methanol=10 / 1) to obtain a brown solid product 3-chloro-2-methylpyrazolo[1,5-a]pyrimidine-5-ol (34g, yield 52%). LC-MS: m / z(ESI)=184.1[M+H] + .

[0231] 3) Synthesis of 3-chloro-6-iodo-2-methylpyrazolo[1,5-a]pyrimidine-5-ol (19d)

[0232] 3-Chloro-2-methylpyrazolo[1,5-a]pyrimidine-5-ol (34 g, 185.8 mmol) was dissolved in 500 ml of acetonitrile, and N-iodosuccinimide (62.7 g, 278.7 mmol) was added at 0°C. The mixture was heated to 70°C and stirred for 2 days. After the reaction was cooled, it was concentrated to dryness to obtain a crude product. Then, it was separated and purified by silica gel column (eluted with dichloromethane / methanol=10 / 1) to obtain a brown solid product 3-chloro-6-iodo-2-methylpyrazolo[1,5-a]pyrimidine-5-ol (33 g, yield 58%). LC-MS: m / z(ESI)=351.0[M+H+CH3CN] + .

[0233] 4) Synthesis of 3,5-dichloro-6-iodo-2-methylpyrazolo[1,5-a]pyrimidine (19e) Phosphorus oxychloride (100 mL) was added to 3-chloro-6-iodo-2-methylpyrazolo[1,5-a]pyrimidine-5-ol (33 g, 106.8 mmol), and the mixture was heated to 100°C and stirred for 6 hours. The reaction solution was cooled and concentrated to dryness to obtain a crude product. Then, it was separated and purified by silica gel column (eluted with petroleum ether / ethyl acetate = 10 / 1) to obtain a yellow solid product 3,5-dichloro-6-iodo-2-methylpyrazolo[1,5-a]pyrimidine (4.8 g, yield 14%). LC-MS: m / z (ESI) = 368.9 [M+H+CH3CN] + .

[0234] 5) Synthesis of 1-(3,5-dichloro-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethan-1-one (19f)

[0235] Dissolve 3,5-dichloro-6-iodo-2-methylpyrazolo[1,5-a]pyrimidine (4.8 g, 15 mmol) and tributyl(1-ethoxyvinyl)stannane (22 g, 60 mmol) in 1,4-dioxane (10 mL), add 1,1-(bis(diphenylphosphino)ferrocenepalladium chloride) (1.1 g, 1.5 mmol), and react at 80°C for 2 hours under nitrogen protection. After cooling, add 4N hydrochloric acid solution to the reaction solution. Stir the resulting mixture at 25°C for 0.5 hours, then dilute with water and extract with ethyl acetate. The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to dryness to obtain a crude product. The residue was separated and purified by silica gel column (eluted with petroleum ether / ethyl acetate=10 / 1) to give a black solid product, 1-(3,5-dichloro-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethan-1-one (1.6 g, yield 44%). 1 H NMR (400MHz, DMSO-d6): δ9.35 (s, 1H), 8.63 (d, J = 4.00Hz, 1H), 8.24 (d, J = 8.00 Hz,1H),8.06(t,J=8.00Hz,1H),7.57–7.54(m,1H),2.48(s,3H),2.40(s,3H).

[0236] 6) Synthesis of (R)-1-(3,5-dichloro-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-ol (19 g)

[0237] 1-(3,5-dichloro-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-one (1.6 g, 7 mmol) was dissolved in 30 ml of tetrahydrofuran, and (+)-B-diisopine camphenyl chloroborane solution (5.8 mL, 17.5 mmol, 3 M tetrahydrofuran solution) was added at 0 ° C under nitrogen protection, and the reaction solution was stirred at 25 ° C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a crude product. Then, it was separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1 elution) to obtain a yellow solid product (R)-1-(3,5-dichloro-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-ol (1 g, yield 58%). LC-MS: m / z (ESI) = 246.1 [M+H] + .

[0238] 7) Synthesis of (S)-2-(1-(3,5-dichloro-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)isoindoline-1,3-dione (19h)

[0239] In reaction flask A, (R)-1-(3,5-dichloro-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-ol (1g, 4.1mmol) and isoindoline-1,3-dione (1.2g, 8.2mmol) were dissolved in 20ml tetrahydrofuran. In reaction flask B, triphenylphosphine (4.3g, 16.4mmol) was dissolved in 50ml tetrahydrofuran. Diisopropyl azodicarboxylate (3.3g, 16.4mmol) was added dropwise at 0℃ under nitrogen protection. Then, the mixture in reaction flask B was added to reaction flask A at 0℃ under nitrogen protection. The reaction mixture was stirred at 25℃ for 4 hours. Diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product. Then, the product was separated and purified by silica gel column (petroleum ether / ethyl acetate = 5 / 1) to obtain a light yellow solid product (S)-2-(1-(3,5-dichloro-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)isoindoline-1,3-dione (754 mg, yield 49%). LC-MS: m / z (ESI) = 375.1 [M+H] + .

[0240] 8) Synthesis of (S)-2-(1-(3-chloro-2-methyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethyl)isoindoline-1,3-dione (19i)

[0241] (S)-2-(1-(3,5-dichloro-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)isoindoline-1,3-dione (70.0 mg, 0.19 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (92.3 mg, 0.29 mmol) were dissolved in 1,4-dioxane (6 mL), and 1,1-(bisdiphenylphosphino)ferrocenepalladium chloride (145.1 mg, 0.2 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (190.7 mg, 0.4 mmol) and sodium carbonate (423.6 mg, 4 mmol) were added. The mixture was stirred at 80°C for 12 hours under nitrogen protection. After cooling, the mixture was diluted with water and then extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was then separated and purified by silica gel column (petroleum ether / ethyl acetate = 5 / 1 elution) to obtain the product (S)-2-(1-(3-chloro-2-methyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethyl)isoindoline-1,3-dione (80.0 mg, yield 78%). LC-MS: m / z(ESI)=537.3[M+H] + .

[0242] 9) Synthesis of (S)-1-(3-chloro-2-methyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-amine (19j)

[0243] (S)-2-(1-(3-chloro-2-methyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethyl)isoindoline-1,3-dione (80.0 mg, 0.16 mmol) was dissolved in ethanol (3 mL), and hydrazine hydrate (80 mg, 1.6 mmol) was added at room temperature. The reaction solution was stirred at 100°C for 0.5 hours. After cooling, it was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was then separated and purified by silica gel column (eluted with dichloromethane / methanol=10 / 1) to obtain (S)-1-(3-chloro-2-methyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-amine (53.0 mg, yield 82%). LC-MS: m / z(ESI)=407.3[M+H] + .

[0244] 10) Synthesis of (S)-4-amino-6-((1-(3-chloro-2-methyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethyl)amino)pyrimidine-5-carbonitrile (19k)

[0245] (S)-1-(3-chloro-2-methyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-amine (53 mg, 0.13 mmol) and 4,6-diaminopyrimidine-5-carbonitrile (30 mg, 0.20 mmol) were added with potassium fluoride (9.6 mg, 0.17 mmol) and N,N-diisopropylethylamine (71.1 mg, 0.55 mmol) in dimethyl sulfoxide (1 mL) at room temperature, and the mixture was heated to 130°C and stirred for 12 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was then separated and purified by preparative high performance liquid chromatography (acetonitrile / water (0.5% ammonia water): 20-50%) to obtain (S)-4-amino-6-((1-(3-chloro-2-methyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethyl)amino)pyrimidine-5-carbonitrile (30 mg, yield 46%). LC-MS: m / z(ESI)=525.3[M+H] + .

[0246] 11) Synthesis of (S)-4-amino-6-((1-(3-chloro-2-methyl-5-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethyl)amino)pyrimidine-5-carbonitrile (19)

[0247] (S)-4-amino-6-((1-(3-chloro-2-methyl-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethyl)amino)pyrimidine-5-carbonitrile (30 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL), trifluoroformic acid (0.5 mL) was added at room temperature, and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was then separated and purified by preparative high performance liquid chromatography (acetonitrile / water (0.5% ammonia water): 20-50%) to obtain a yellow solid product (S)-4-amino-6-((1-(3-chloro-2-methyl-5-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethyl)amino)pyrimidine-5-carbonitrile (11.8 mg, yield 50%). LC-MS: m / z(ESI)=395.4[M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ8.95 (s, 1H), 7.85 (d, J = 8.00Hz, 2H), 6.95 (s, 1H), 6.24 (dd, J = 12.00, 8.00Hz, 1H), 2.37 (s, 3H), 1.52 (d, J = 4.00Hz, 3H).

[0248] Compound 1-4 can be synthesized by a method similar to that of compound 19.

[0249] Embodiment 2:

[0250] Compound 5: (S)-4-amino-6-((1-(3-chloro-5-imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-ethyl)amino)pyrimidine-5-carbonitrile

[0251]

[0252] 1) Synthesis of ethyl 3-(imidazo[1,2-a]pyridin-6-yl)-3-oxopropanoate (5b)

[0253] In reaction flask A, imidazo[1,2-a]pyridine-6-carboxylic acid (5 g, 30.8 mmol) and N,N'-carbonyldiimidazole (6.65 g, 41 mmol) were dissolved in 100 ml of tetrahydrofuran, heated to 65 ° C and stirred for 6 hours. In reaction flask B, ethyl malonate monopotassium salt (17.4 g, 102 mmol) and magnesium chloride (4.9 g, 51.5 mmol) were dissolved in 200 ml of tetrahydrofuran, triethylamine (10.4 g, 102 mmol) was added, and stirred at room temperature for 6 hours. Then the mixture in reaction flask B was added to reaction flask A, and the reaction mixture was stirred at 65 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product. Then, the product was separated and purified by silica gel column (petroleum ether / ethyl acetate = 5 / 1) to obtain a yellow solid product, ethyl 3-(imidazo[1,2-a]pyridin-6-yl)-3-oxopropanoate (6 g, yield 84%). LC-MS: m / z (ESI) = 233.1 [M+H] + .

[0254] 2) Synthesis of 3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester 4-chloro-5-methylpyrazol-3-amine (5c)

[0255] Dissolve 3-(imidazo[1,2-a]pyridin-6-yl)-3-oxopropionic acid ethyl ester (6g, 25.86mmol) and N,N-dimethylformamide dimethyl acetal (3.7g, 31mmol) in 100ml toluene and reflux for 2 hours. After the reaction is completed, remove the toluene by distillation under reduced pressure. The residue is dissolved in 100ml ethanol, and 4-chloro-5-methylpyrazole-3-amine (3.4g, 25.86mmol) and 20ml glacial acetic acid are added under stirring, and react at room temperature for 12 hours. After the reaction is completed, remove the ethanol by distillation under reduced pressure, add water to the residue, and extract with dichloromethane. The obtained organic phase was washed with saturated sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1 elution) to obtain a yellow solid product 3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester 4-chloro-5-methylpyrazol-3-amine (3.5 g, yield 38%). LC-MS: m / z (ESI) = 356.1 [M+H] + .

[0256] 3) Synthesis of 3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (5d)

[0257] 3-Chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester 4-chloro-5-methylpyrazol-3-amine (3.5 g, 9.83 mmol) was dissolved in 100 ml of tetrahydrofuran and 100 ml of water, and lithium hydroxide monohydrate (0.825 g, 19.66 mmol) was added. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, tetrahydrofuran was removed by distillation under reduced pressure, the residue was diluted with water, and the solid was removed by filtration. The filtrate was adjusted to pH = 3 with 4N hydrochloric acid, and the solid precipitated. The solid was filtered, the filter cake was washed with water, and dried to obtain a yellow solid product 3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (2 g, yield 62%). LC-MS: m / z (ESI) = 328.1 [M+H] + .

[0258] 4) Synthesis of 3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-N-methoxy-N,2-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide (5e)

[0259] 3-Chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (2g, 6.1mmol) and N,N-diisopropylethylamine (1.57g, 12.2mmol) were dissolved in 200ml of dichloromethane, and N,O-dimethylhydroxylamine hydrochloride (0.648g, 6.7mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (2.55g, 6.7mmol) were added under stirring, and stirred at room temperature for 12 hours. After the reaction was completed, it was diluted with water and extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain a crude product. The yellow solid product 3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-N-methoxy-N,2-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide (1.5 g, yield 66%) was obtained by separation and purification on a silica gel column (petroleum ether / ethyl acetate = 1 / 1 elution). LC-MS: m / z (ESI) = 371.1 [M+H] + .

[0260] 5) Synthesis of 3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (5f)

[0261] 3-Chloro-5-(imidazo[1,2-a]pyridin-6-yl)-N-methoxy-N,2-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide (1.5 g, 4 mmol) was dissolved in 100 ml of tetrahydrofuran, and lithium aluminum tetrahydride solution (4 mL, 4 mmol, 1 M tetrahydrofuran solution) was added dropwise at -78 °C under nitrogen protection, and the reaction solution was stirred at -78 °C for 1 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a crude product. Then, it was separated and purified by silica gel column (eluted with petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow solid product 3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxaldehyde (0.6 g, yield 48%). LC-MS: m / z (ESI) = 312.1 [M+H] + .

[0262] 6) Synthesis of (S, Z)-N-((3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)methylene)-2-methylpropane-2-sulfenamide (5 g)

[0263] 3-Chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (0.6 g, 1.92 mmol) and (S)-tert-butylsulfenamide (696 mg, 5.76 mmol) were dissolved in 100 ml of tetrahydrofuran, tetraethyl titanate (1.74 g, 7.65 mmol) was added, and the mixture was heated to 65°C and stirred for 12 hours. After cooling, the mixture was diluted with water and then extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was then separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1 elution) to obtain a yellow solid product (S, Z)-N-((3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)methylene)-2-methylpropane-2-sulfinamide (420 mg, yield 52%). LC-MS: m / z(ESI)=415.1[M+H] + .

[0264] 6) Synthesis of (S)-N-(S)-1-(3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)-2-methylpropane-2-sulfenamide (5h)

[0265] (S, Z)-N-((3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)methylene)-2-methylpropane-2-sulfenamide (420 mg, 1.01 mmol) was dissolved in 10 ml of tetrahydrofuran, and methylmagnesium iodide tetrahydrofuran solution (2 mL, 2 mmol, 1 M tetrahydrofuran solution) was added dropwise at -78°C under nitrogen protection, and the reaction solution was stirred at -78°C for 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a crude product. Then, the product was separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1 elution) to obtain a yellow solid product (S)-N-(S)-1-(3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)-2-methylpropane-2-sulfenamide (280 mg, yield 64%). LC-MS: m / z(ESI)=431.1[M+H] + .

[0266] 8) Synthesis of (S)-1-(3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-amine (5i)

[0267] Dissolve (S)-N-(S)-1-(3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)-2-methylpropane-2-sulfinamide (280 mg, 0.65 mmol) in 5 ml of methanol and add 1 ml of hydrochloric acid 1,4-dioxane solution. Stir at room temperature for 1 hour. Remove methanol by distillation under reduced pressure, dilute with water, adjust pH to 7 with saturated sodium carbonate solution, and extract with ethyl acetate. The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo to obtain a yellow solid product (S)-1-(3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-amine (100 mg, yield 47%). LC-MS: m / z (ESI) = 327.1 [M+H] + .

[0268] 9) Synthesis of (S)-4-amino-6-((1-(3-chloro-5-imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-ethyl)amino)pyrimidine-5-carbonitrile (5)

[0269] (S)-1-(3-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-amine (100 mg, 0.305 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (94 mg, 0.61 mmol) were dissolved in dimethyl sulfoxide (5 mL), potassium fluoride (26 mg, 0.46 mmol) and N,N-diisopropylethylamine (196 mg, 1.51 mmol) were added at room temperature, heated to 90°C and stirred for 12 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was then separated and purified by preparative high performance liquid chromatography (solvent A: water + 0.5% ammonia water; solvent B: acetonitrile; gradient: 20-50%), followed by SFC separation to obtain a yellow solid product (S)-4-amino-6-((1-(3-chloro-5-imidazo[1,2-a]pyridin-6-yl)-2-methylpyrazolo[1,5-a]pyrimidine-6-ethyl)amino)pyrimidine-5-carbonitrile (17 mg, yield 12%). LC-MS: m / z(ESI)=445.2[M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ8.97(s,1H),8.94(brs,1H),8.08(s,1H),7.90(d,J=8.00Hz,1H),7.76(d,J =12.00Hz,1H),7.70(s,1H),7.39(d,J=8.00Hz,1H),5.14–5.09(m,1H),2.33(s,3H),1.59(brs,3H).

[0270] Compounds 6-18, 20-45, and 47-58 can be synthesized by a method similar to that of compound 5.

[0271] Embodiment 3:

[0272] Compound 46: (S)-4-amino-6-((1-(3-chloro-2-(methyl-d3)-5-phenylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)amino)pyrimidine-5-carbonitrile

[0273]

[0274] 1) Synthesis of ethyl 2-bromo-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylate (46b)

[0275] Ethyl benzoyl acetate (10g, 52mmol) and N,N-dimethylformamide dimethyl acetal (7.44g, 52.4mmol) were dissolved in 100ml toluene and refluxed for 2 hours. After the reaction was completed, toluene was removed by distillation under reduced pressure. The residue was dissolved in 100ml ethanol, and 5-bromo-1H-pyrazole-3-amine (8.4g, 52mmol) and 30ml glacial acetic acid were added under stirring, and the reaction was carried out at room temperature for 8 hours. After the reaction was completed, ethanol was removed by distillation under reduced pressure, and the residue was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was then separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow solid product 2-bromo-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester (6g, yield 33%). LC-MS: m / z (ESI) = 346.1 [M+H] + .

[0276] 2) Synthesis of ethyl 2-(methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylate (46c)

[0277] Dissolve 2-bromo-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester (5.5g, 15.89mmol) in 100 ml of tetrahydrofuran, add zinc powder (2g, 31.77mmol), iodomethane-D3 (6.9g, 47.66mmol), 1,3-bis(diphenylphosphinopropane) nickel dichloride (0.86g, 1.59mmol) and sodium iodide (4.7g, 31.77mmol) under nitrogen protection, and heat to 70°C and stir for 16 hours. After cooling, filter to remove solids, dilute the filtrate with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and vacuum concentrate the filtrate to obtain a crude product. Then separate and purify by silica gel column (petroleum ether / ethyl acetate = 1 / 1 elution) to obtain a yellow solid product 2-(methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester (2.9g, yield 64%). LC-MS: m / z (ESI) = 285.1 [M+H] + .

[0278] 3) Synthesis of 2-(methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (46d)

[0279] Dissolve 2-(methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester (2.9 g, 10.2 mmol) in 50 ml of tetrahydrofuran and 50 ml of water, and add lithium hydroxide monohydrate (0.85 g, 20.2 mmol). The mixture is stirred at 25°C for 1 hour. After the reaction is completed, tetrahydrofuran is removed by distillation under reduced pressure, the residue is diluted with water, and the solid is removed by filtration. The filtrate is adjusted to pH=3 with 4N hydrochloric acid, and the solid is precipitated. The solid is filtered, and the filter cake is washed with water and dried to obtain a yellow solid product 2-(methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1.3 g, yield 50%). LC-MS: m / z(ESI)=257.1[M+H] + .

[0280] 4) Synthesis of N-methoxy-N-methyl-2-methyl-D3-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxamide (46e)

[0281] 2-(Methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.7g, 2.7mmol) and N,N-diisopropylethylamine (1.05g, 8.15mmol) were dissolved in 100 ml of dichloromethane, and N,O-dimethylhydroxylamine hydrochloride (0.53g, 5.43mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (1.13g, 2.98mmol) were added under stirring, and stirred at room temperature for 12 hours. After the reaction was completed, it was diluted with water and extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain a crude product. The yellow solid product N-methoxy-N-methyl-2-methyl-D3-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxamide (0.42 g, yield 51%) was obtained by separation and purification on a silica gel column (petroleum ether / ethyl acetate = 1 / 1 elution). LC-MS: m / z (ESI) = 300.1 [M+H] + .

[0282] 5) Synthesis of 3-chloro-N-methoxy-N-methyl-2-methoxy-D3-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxamide (46f)

[0283] N-methoxy-N-methyl-2-methyl-D3-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxamide (0.42 g, 1.4 mmol) was dissolved in 100 ml of acetonitrile, N-chlorosuccinimide (186 mg, 1.4 mmol) was added, and the mixture was heated to 60°C and stirred for 12 hours. After cooling, the mixture was diluted with water and then extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was then separated and purified by silica gel column (eluted with petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow solid product 3-chloro-N-methoxy-N-methyl-2-methyl-D3-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxamide (350 mg, yield 75%). LC-MS: m / z (ESI) = 334.1 [M+H] + .

[0284] 6) Synthesis of 3-chloro-2-methyl-D3-5-phenylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (46 g)

[0285] 3-Chloro-N-methoxy-N-methyl-2-methyl-D3-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxamide (350mg, 1.05mmol) was dissolved in 100 ml of tetrahydrofuran, and lithium aluminum tetrahydride solution (1.05mL, 1.05mmol, 1M tetrahydrofuran solution) was added dropwise at -78°C under nitrogen protection, and the reaction solution was stirred at -78°C for 1 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a crude product. Then, it was separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1 elution) to obtain a yellow solid product 3-chloro-2-methyl-D3-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxaldehyde (190mg, yield 66%). LC-MS: m / z(ESI)=275.1[M+H] + .

[0286] 7) Synthesis of (R, Z)-N-(3-chloro-2-methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidine-6-methylene)-2-methylpropane-2-sulfinamide (46h)

[0287] 3-Chloro-2-methyl-D3-5-phenylpyrazolo[1,5-a]pyrimidine-6-carboxaldehyde (190 mg, 0.96 mmol) and (R)-tert-butylsulfenamide (0.25 g, 2.06 mmol) were dissolved in 20 ml of tetrahydrofuran, tetraethyl titanate (0.62 g, 2.75 mmol) was added, and the mixture was heated to 65 ° C and stirred for 12 hours. After cooling, the mixture was diluted with water and then extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum concentrated to obtain a crude product, which was then separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1 elution) to obtain a yellow solid product (R, Z)-N-(3-chloro-2-methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidine-6-methylene)-2-methylpropane-2-sulfenamide (300 mg, yield 82%). LC-MS: m / z (ESI) = 378.1 [M+H] + .

[0288] 8) Synthesis of (R)-N-(S)-1-(3-chloro-2-methyl-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)-2-methylpropane-2-sulfinamide (46i)

[0289] Dissolve (R, Z)-N-(3-chloro-2-methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidine-6-methylene)-2-methylpropane-2-sulfinamide (0.3 g, 0.79 mmol) in 10 ml of tetrahydrofuran, add methylmagnesium bromide tetrahydrofuran solution (1.6 mL, 1.6 mmol, 1M tetrahydrofuran solution) dropwise at -78 ° C under nitrogen protection, and stir the reaction solution at -78 ° C for 2 hours. The reaction is quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness to obtain a crude product. Then, the product was separated and purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1 elution) to obtain a yellow solid product (R)-N-(S)-1-(3-chloro-2-methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)-2-methylpropane-2-sulfenamide (280 mg, yield 90%). LC-MS: m / z (ESI) = 394.1 [M+H] + .

[0290] 9) Synthesis of (S)-1-(3-chloro-2-methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-amine (46j)

[0291] Dissolve (R)-N-(S)-1-(3-chloro-2-methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)-2-methylpropane-2-sulfinamide (280 mg, 0.71 mmol) in 5 ml of methanol and add 2 ml of hydrochloric acid 1,4-dioxane solution. Stir at room temperature for 1 hour. Remove methanol by distillation under reduced pressure, dilute with water, adjust pH to 7 with saturated sodium carbonate solution, and extract with ethyl acetate. The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo to obtain a yellow solid product (S)-1-(3-chloro-2-methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-amine (190 mg, yield 92%). LC-MS: m / z(ESI)=290.1[M+H] + .

[0292] 10) Synthesis of (S)-4-amino-6-((1-(3-chloro-2-(methyl-d3)-5-phenylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)amino)pyrimidine-5-carbonitrile (46)

[0293] (S)-1-(3-chloro-2-methyl-D3)-5-phenylpyrazolo[1,5-a]pyrimidin-6-yl)ethane-1-amine (100 mg, 0.345 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (106 mg, 0.69 mmol) were dissolved in dimethyl sulfoxide (5 mL), potassium fluoride (30 mg, 0.52 mmol) and N,N-diisopropylethylamine (222 mg, 1.71 mmol) were added at room temperature, heated to 90°C and stirred for 12 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was then separated and purified by preparative high performance liquid chromatography (solvent A: water + 0.1% formic acid; solvent B: acetonitrile; gradient: 49-59%) to obtain a yellow solid product (S)-4-amino-6-((1-(3-chloro-2-(methyl-d3)-5-phenylpyrazolo[1,5-a]pyrimidin-6-yl)ethyl)amino)pyrimidine-5-carbonitrile (54 mg, yield 38%). LC-MS: m / z(ESI)=408.1[M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ8.92 (s, 1H), 7.86 (s, 1H), 7.76–7.40 (m, 5H), 4.99–4.94 (m, 1H), 1.51 (d, J = 8.00Hz, 3H).

[0294] Table 1. Summary of spectral data of synthetic example compounds

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305] Example 4: Fluorescence measurement of PI3K enzyme activity

[0306] PI3K kinases including PIK3CG (p110 gamma) were purchased from Invitrogen, and p110α / p85α, p110β / p85α, and p110δ / p85α were purchased from BPS.

[0307] ADP-Glo TM Kinase Assay(ADP-Glo TM The Kinase Assay Kit (Promega, v9102) is a luminescent kinase assay that detects the ADP formed during the kinase reaction; ADP is converted to ATP, which is then quantified by Ultra-Glo TM Luciferase converts the luminescence signal into a light signal. The luminescence signal is positively correlated with the activity of the kinase. This kit is suitable for detecting the effect of compounds on the activity of a variety of purified kinases, making it an ideal tool for primary screening and studying the selectivity of kinase action. The operation of the kit has two steps: first, after the kinase reaction, add an equal volume of ADP-Glo ​​to the kinase reaction system. TM The first step is to add a kinase assay reagent, which simultaneously converts ADP to ATP and detects newly synthesized ATP using a coupled luciferase / luciferin reaction.

[0308] The detection process is as follows:

[0309] Kinase buffer contained 50 mM HEPES, pH 7.5; 3 mM MgCl2; 1 mM EGTA; 100 mM NaCl; 0.03% CHAPS; 2 mM DTT.

[0310] 1) Add 1 μL of compound diluent to 384 test plate (Corning, Cat#4512). (The final concentrations of the compound tested are 1000nM, 333.33nM, 111.11nM, 37.037nM, 12.345nM, 4.115nM, 1.372nM, 0.457nM, 0.1524nM and 0.0508nM, a total of 10 concentrations, duplicate wells. The final DMSO concentration is 1%)

[0311] 2) Add 2 μl of kinase solution to the corresponding positions of the 384 detection plate (the final concentration of PI3Kα is 0.25 μg / ml; the final concentration of PI3Kβ is 0.3 μg / ml; the final concentration of PI3Kγ is 1.2 μg / ml; the final concentration of PI3Kδ is 0.3 μg / ml).

[0312] 3) Add 2 μl of substrate solution (PI3Kα: PIP2 final concentration 20 μM, ATP final concentration 10 μM; PI3Kγ, β and δ: PIP2 final concentration 30 μM, ATP final concentration 20 μM) to the corresponding position of the 384 detection plate, and react at room temperature for 120 minutes.

[0313] 4) Equilibrate the ADP-Glo ​​reagent to room temperature. Add 5 μl of ADP-Glo ​​reagent to each well of the test plate to terminate the reaction. Centrifuge at 1000 rpm for 1 minute. Then shake slowly on a shaker and equilibrate at room temperature for 40 minutes.

[0314] 5) Add 10 μl of kinase detection reagent to each well, centrifuge for 1 minute, and read using Envision after equilibration for 30 minutes.

[0315] Data analysis: Copy the test values ​​from Envision and convert the test value data into percentage inhibition values. Inhibition rate = (Max-Sample) / (Max-Min)*100. Fit the data in the XLfit excel plug-in version to obtain the IC50 value. (Max: the reaction system contains kinase and substrate; Min: the reaction system contains only substrate; Sample: the reaction system contains kinase, substrate and compound).

[0316] Example 5: Evaluation of the inhibitory effect of the compound on PI3Kδ in the human lymphoma cell line RAJI and the mouse macrophage-like cell line Raw264.7

[0317] This example is to evaluate the effect of the compound on different PI3K isoforms at the cellular level by detecting the phosphorylation of AKT. In order to evaluate the effect of the compound on the PI3K-δ isoform, the human lymphoma cell line RAJI needs to be combined with anti-IgM antibody.

[0318] PI3K-δ isoforms: Raji cells were cultured in 96-well plates at 30 μL per well, 50,000 cells, and the cell culture medium was RPMI-1640 without serum. The cells were incubated overnight in a 5% CO2 and 37°C incubator. After 18 hours of serum starvation, 2s.5μL of compound (14X) was added to the cells and incubated in the incubator for 60 minutes. Then 2.5μL (14X, diluted with serum culture medium) of anti-human IgM (Jackson Immuno Research) was added and placed in the incubator for stimulation for 30 minutes (final concentration of 10μg / mL). 11.5μL of 4x lysis buffer was added to each well. Shake at room temperature for 45 minutes. 16μL of lysate was added to the 384 plate and 4μL of premixed antibodies from Cisbio's Phospho-AKT (Ser473) kit were added. The samples were centrifuged at 1000 rpm / min for 1 minute and incubated at 22°C for 4 hours before reading using Envision (665 nm / 615 nm).

[0319] Table 2 shows the inhibitory IC values ​​of the compounds of the present invention on PI3Kδ enzyme and cells 50 (nM)

[0320]

[0321]

[0322]

[0323] It can be seen from the above table that some compounds of the present invention have nM-level activity against PI3Kδ kinase and cells in in vitro cell tests.

[0324] It should be understood that after reading the above disclosure of the present invention, without departing from the concept and spirit of the present invention, ordinary technicians in this field can make various changes, adjustments or combinations to the technical solutions of the present invention, and these equivalent forms also fall within the scope of protection required by this application.

Claims

1. A compound represented by formula (I) and / or a pharmaceutically acceptable salt thereof, characterized in that: in: R1 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, amino, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 3-6 Heterocycloalkyl, -C 3-6 Cycloalkoxy, -C 3-6 Heterocycloalkoxy, -C 1-6 Alkyl(O)C 1-6 Alkyl, -COOH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR 1a , aryl, aralkyl, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy; wherein the thiol, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, aryl, aralkyl, -C(O)NH2, -S(O)2NH2, -S(O)(NH)NH2, aralkyloxy, heteroaryl, heteroaralkyl, heteroaralkyloxy can be optionally replaced by one or more R 1a replace; R 1a is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, -COOH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR a wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, heteroaryl, - C(O)NH2, -S(O)2NH2, -S(O)(NH)NH2 are selectively substituted by halogen, cyano, -OR a 、-SR a NR b R c , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocyclooxy, or any one or more thereof may be substituted or unsubstituted; R2 is selected from hydrogen, halogen, deuterium, hydroxyl, cyano, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 3-6 Heterocycloalkyl, -C 3-6 Cycloalkoxy, -C 3-6 Heterocycloalkoxy, -COOH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)NH(C 1-6 alkyl)2, -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR 2a , -C(O)NH2, aryl, heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, heteroaryl, -C(O)NH2, -S(O)2NH2, -S(O)(NH)NH2 can be optionally replaced by one or more R 2a replace; R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, -COOH, -C(O)NH2, - C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR a wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, -C(O)NH2, -S(O)2NH2, -S(O)(NH)NH2 are selectively selected from halogen, cyano, -OR a 、-SR a NR b R c , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocyclooxy or one or more thereof may be substituted or unsubstituted; and / or, R1 and R2 selectively form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered heterocycloalkenyl, aryl, heteroaryl with the carbon atoms to which they are attached, and may be selectively replaced by one or more R 1a or R 2a Substitution; and the carbon atoms or sulfur atoms in the above-mentioned cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl groups may be selectively oxidized to form a part of an intra-ring carbonyl group, an amide group, an ester group, a sulfone group (-S(O)2-), or a sulfonamide group (-S(O)2NH-); R3 is selected from hydrogen, deuterium, C 1-6 Alkyl, deuterated alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyanoalkyl, -C 3-6 Cycloalkyl, -C 3-6 Heterocycloalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl; R4 is independently selected from heteroaryl, which is a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, which contains 1 or 2 N ring heteroatoms in the ring, the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group having 9 or 10 ring atoms, which contains 1, 2, 3 or 4 N ring heteroatoms in the ring, the remaining ring atoms are carbon atoms, wherein at least one ring is aromatic, and the heteroaryl group includes those heteroaryl groups in which the N ring heteroatoms are in the form of N-oxides, and the heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, deuterium, cyano, hydroxyl, mercapto, C 1-6 Alkyl, haloalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, -NH2, -NH(C 1-6 alkyl),- N(C 1-6 Alkyl)(C 1-6 alkyl), -COOH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR a 、-NHC(O)(C 1-6 Alkyl), -NHC(O)(C 1-6 Cycloalkyl), -NHC(O)O(C 1-6 alkyl), -NHC(O)O(C 1-6 cycloalkyl), phenyl and 5 or 6 membered heteroaryl; wherein C 1-6 Alkyl, haloalkyl, -NH2, -COOH, -C(O)NH2, cycloalkyl, heterocycloalkyl may be replaced by one or more R 1a Selectively substituted; wherein the 5- or 6-membered heteroaryl as a substituent of R4 is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, which contains 1, 2 or 3 ring heteroatoms independently selected from N, O or S in the ring, and the remaining ring atoms are carbon atoms, when the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other, wherein the phenyl or 5- or 6-membered heteroaryl as a substituent of the heteroaryl is optionally substituted with one or more substituents selected from the following: halogen, amino, hydroxyl, mercapto, C1-6 alkyl and -O(C1-6 alkyl), haloalkyl; R5 is independently selected from hydrogen, C 1-6 Alkyl, hydroxy substituted alkyl, deuterated alkyl, hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, cycloalkylalkyl or cycloalkoxyalkyl, wherein the alkyl group may be optionally replaced by one or more R 5a Replacement; R 5a is selected from deuterium, halogen, CN, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl may be halogen, CN, -OR a 、- SR a 、-NR b R c , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl substitution; And / or, R4 and R5 selectively form a nitrogen-containing heterocyclic group or heteroaryl group with the N atom to which they are connected, wherein the nitrogen-containing heterocyclic group and heteroaryl group may be selectively substituted by one or more substituents, including but not limited to halogen, deuterium, amino, hydroxyl, thiol, cyano, alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aromatic, aromatic oxy, heteroaromatic, heteroaromatic oxy, -COOH, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), -S(O)2NH2, -S(O)(NH)NH2, -C(O)OR a 、-OR a 、-SR a NR b R c ; Among them, R a , R b and R c are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 3-6 Heterocycloalkyl, hydroxy substituted C 1-6 Alkyl, -C 1-6 Alkyl(O)C 1-6 Alkyl, aryl, heteroaryl; and / or R b and R c Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered heterocycloalkyl group or are substituted by 1 to 3 R a replace; R6 is selected from aryl, heteroaryl or heterocyclic, wherein the heteroaryl or heterocyclic contains 1 to 3 heteroatoms selected from N, O or S; The R6 may be further optionally substituted by hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, amino, alkyl, alkoxy, haloalkyl, haloalkoxy, oxo, cycloalkyl, -NH(C 1-6 Alkyl), -O - 、-N(C 1-6 Alkyl)(C 1-6 Alkyl), -SO2(C 1-6 alkyl).

2. The compound of formula (I) and / or its pharmaceutically acceptable salt according to claim 1, characterized in that: The R6 is selected from 5-6 membered aryl, 5-6 membered heteroaryl, 4-6 membered heterocyclic group, 8-10 membered bicyclic heteroaryl or 8-10 membered bicyclic heterocyclic group, wherein the heteroaryl or heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; the R6 may be further substituted by hydrogen, deuterium, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, oxo, C 3-6 The invention can be substituted by one or more of cycloalkyl, -N(CH3)2.

3. The compound of formula (I) and / or its pharmaceutically acceptable salt according to claim 1, characterized in that: The R6 selection From the following groups: Wherein, m, n or p is 1, 2 or 3; The R6 may be further optionally substituted with hydrogen, deuterium, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, oxo, C 3-6 The invention can be substituted by one or more of cycloalkyl, -N(CH3)2.

4. The compound of formula (I) according to claim 1 and / or its pharmaceutically acceptable salt, characterized in that: The compound is selected from the following formula (Ia) or (Ib): Wherein, R1 is selected from hydrogen, deuterium, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl; R2 is selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl; Alternatively, R1 and R2 form a C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; R3 is selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy or C 3-6 Cycloalkyl; R6 is selected from 5-6 membered heteroaryl, 4-6 membered heterocyclyl, 8-10 membered bicyclic heteroaryl, wherein the heteroaryl or heterocyclyl contains 1 to 3 heteroatoms selected from N, O or S; Preferably, R6 is selected from the following groups: Wherein, m, n or p is 1, 2 or 3; The R6 may be further optionally substituted with hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, oxo, C 3-6 Cycloalkyl, -NH(C 1-3 alkyl), -O, -N(C 1-3 Alkyl)(C 1-3 Alkyl), -SO2(C 1-3 alkyl) in one or more substitutions; R7, R8 or R9 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy.

5. The compound of formula (I) according to claim 1 and / or its pharmaceutically acceptable salt, characterized in that: R4 is selected from heteroaryl, or R4 and R5 form a heteroaryl; wherein the heteroaryl group is a monocyclic aromatic hydrocarbon group having 6 ring atoms, which contains 1 or 2 N ring heteroatoms in the ring, and the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group having 9 ring atoms, which contains 3 or 4 N ring heteroatoms in the ring, and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring and the heteroaryl group is optionally substituted by one or more substituents selected from the following: halogen, cyano, hydroxyl, mercapto, C 1-6 Alkyl, haloalkyl, cycloalkyl, -O(C 1-6 Alkyl) and -O(C 1-6 haloalkyl), -NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)(C 1-6 alkyl), -CO2H, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl)(C 1-6 alkyl), phenyl and 5- or 6-membered heteroaryl.

6. The compound of formula (I) and / or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R4 is selected from heteroaryl, or R4 and R5 form a heteroaryl; wherein the heteroaryl is a monocyclic aromatic hydrocarbon group having 6 ring atoms, which contains 1 or 2 N ring heteroatoms in the ring, and the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group having 9 ring atoms, which contains 3 or 4 N ring heteroatoms in the ring, and the remaining ring atoms are carbon atoms, wherein at least one ring is aromatic and the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, bromine, cyano, hydroxyl, mercapto, haloalkyl, C 1-6 Alkyl, -NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)(C 1-6 alkyl), -CO2H, -C(O)NH2, -C(O)NH(C 1-6 alkyl), phenyl, pyridyl, pyrimidinyl, piperazinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl.

7. The compound of formula (I) and / or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that: The phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl in R4 are optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, thiol, amino, C 1-6 Alkyl, haloalkyl, cycloalkyl, -O(C 1-6 Alkyl) and - O(C 1-6 haloalkyl).

8. The compound of formula (I) and / or its pharmaceutically acceptable salt according to claim 6, characterized in that: The heteroaryl group is selected from pyrimidine, purinyl, pyrazolopyrimidine, and pyrrolopyrimidine.

9. The compound of formula (I) and / or a pharmaceutically acceptable salt thereof according to claim 5 or 6, characterized in that: R4, or the heteroaryl group formed by R4 and R5 is selected from the following substituents wherein the substituent is optionally substituted by one or more of the following substituents: fluorine, chlorine, bromine, cyano, hydroxyl, mercapto, haloalkyl, C 1-6 Alkyl, -NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)(C 1-6 alkyl),- CO2H、-CONH2、-C(O)NH(C 1-6 alkyl), phenyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl and tetrazolyl, wherein the phenyl, pyridyl, pyrimidinyl, piperazinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl as R4 substituents are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, mercapto, C 1-6 Alkyl, haloalkyl, cycloalkyl, -O(C 1-6 Alkyl) and -O(C 1-6 haloalkyl).

10. The compound of formula (I) and / or a pharmaceutically acceptable salt thereof according to claim 9, characterized in that: R4 is selected from Any substituent in, R4 is optionally substituted by one or more substituents selected from the following substituents: fluorine, chlorine, bromine, cyano, haloalkyl, C 1-6 Alkyl, -NH2, NH(C 1-6 alkyl), -CO2H, -CONH2, phenyl, pyridyl, pyrazolyl, triazolyl and tetrazolyl, Wherein phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl as R4 substituents are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-6 Alkyl and -O(C 1-6 alkyl).

11. The compound of formula (I) and / or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, characterized in that: R3 is C 1-4 Alkyl, C 1-4 Deuterated alkyl and C 1-4 Halogenated alkyl.

12. The compound of formula (I) and / or a pharmaceutically acceptable salt thereof according to any one of claims 11, characterized in that: R3 is methyl, deuterated methyl, ethyl, deuterated ethyl and trifluoromethyl.

13. The compound of formula (I) and / or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, characterized in that: The compound represented by formula (I) is selected from:

14. Use of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease mediated by PI3K.

15. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 14 in the preparation of a medicament for treating a disease mediated by PI3K, characterized in that: The PI3K is PI3Kδ.

16. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 14 in the preparation of a medicament for treating a disease mediated by PI3K, characterized in that: The disease is selected from the group consisting of cancer, inflammation, respiratory disease, infectious disease, bone marrow related disease and autoimmune disease.

17. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 16 in the preparation of a medicament for treating a disease mediated by PI3K, characterized in that: The cancers are solid tumors, including breast cancer, melanoma, head and neck cancer, lung cancer, thymic cancer, and hematological malignancies.

18. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

19. The pharmaceutical composition according to claim 18, characterized in that The pharmaceutical composition also includes use in combination with small molecule compounds and / or macromolecular antibodies to treat cancer, inflammation, bone marrow-related diseases and autoimmune diseases.

20. The pharmaceutical composition according to claim 19, characterized in that The small molecule compounds include kinase inhibitors and other non-kinase inhibitors.

21. The pharmaceutical composition according to claim 19, characterized in that The small molecule compounds include BTK inhibitors and Bcl2 inhibitors.

22. The pharmaceutical composition according to claim 19, characterized in that The macromolecular antibodies include anti-CD20, anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies.

23. Use of the composition according to claim 18 in treating diseases mediated by PI3K, wherein the disease is selected from cancer, inflammation, respiratory disease, infectious disease, bone marrow-related disease and autoimmune disease.

24. A solvate, racemic mixture, enantiomer, diastereomer, tautomer or a mixture thereof in any proportion including a racemic mixture of a compound of formula (I) according to any one of claims 1 to 13, characterized in that: As described in claim 1, each substituent of R1, R2, R3, R4 and R5

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