Tri-fused ring type PI3K alpha inhibitor as well as preparation method and medical application thereof

Abstract

The invention discloses a tricyclic PI3K alpha inhibitor as well as a preparation method and medical application thereof. Specifically, the invention relates to a compound as shown in a general formula (1) and a preparation method thereof, and application of the compound as shown in the general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as PI3Kalpha inhibitors. The compound and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates of the compound can be used for preparing medicines for treating or preventing related diseases mediated by PI3K alpha. # imgabs0 #

Description

Tricyclic PI3Kα inhibitors and their preparation method and medical use

[0001] This application claims priority to Chinese Patent Application No. 202211457330.4, filed on November 17, 2022, Chinese Patent Application No. 202310546509.5, filed on May 15, 2023, and Chinese Patent Application No. 202311275481.2, filed on September 28, 2023. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and more specifically, relates to a class of novel compounds having phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitory effects, a preparation method thereof, and the use of such compounds in the preparation of anti-tumor drugs. Background Art

[0003] The phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt / PKB)-mammalian target of rapamycin (mTOR) pathway is an important signaling pathway in mammalian tumor immunity, closely related to cell proliferation, cell cycle progression, cell survival, cell growth, and angiogenesis. Activation of this pathway is closely related to tumor cell apoptosis, migration, tumor development, and drug resistance. The PI3K protein family is divided into four major categories: I, II, III, and IV. These four categories of proteins have different structures and functions. The most widely studied is class I PI3K, which is further divided into four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. PI3Kα undergoes activating mutations and amplifications in a variety of tumors, and is closely related to the development and progression of tumors.

[0004] PI3Kα is activated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). Upon activation, it catalyzes the conversion of phosphatidylinositol 2-phosphate (PIP2) to phosphatidylinositol 3-phosphate (PIP3). PIP3 further activates protein kinase B (Akt / PKB) and its downstream signaling pathways. PI3Kα consists of the catalytic subunit p110α and the regulatory subunit p85. The Cancer Genome Atlas Project, which has studied mutations in over 3,000 cancers, has ranked the gene encoding PI3Kα, PIK3CA, as the second most commonly mutated oncogene. Hotspot mutations are primarily concentrated in the helical region and kinase domain, including E542K, 545K, and H1047R. Mutations in PI3Kα not only aberrantly activate PI3Kα but also inhibit expression of the tumor suppressor gene PTEN, leading to rapid cell proliferation and tumorigenesis. Therefore, PI3Kα remains a crucial target in the development of various anticancer drugs.

[0005] PI3K inhibitors primarily include pan-PI3K inhibitors and selective PI3K inhibitors. Pan-PI3K inhibitors act on all isoforms, but lack specificity for a single isoform, resulting in varying degrees of potential toxicity. Inhibition of PI3Kβ can lead to thrombocytopenia and thrombosis, while inhibition of PI3Kδ can cause immune system abnormalities, autoimmunity, and frequent infections. PI3Kγ is closely linked to blood pressure stability and smooth muscle contraction, and inhibition of PI3Kγ can lead to hypertension. Therefore, developing highly active and selective PI3Kα inhibitors could avoid off-target toxicity and hold significant clinical value.

[0006] Currently, only one PI3Kα selective inhibitor is on the market: Novartis's Alpelisib, approved in 2019 for use in combination with fulvestrant for the treatment of postmenopausal women and men with PIK3CA mutations and HR+ / HER2- advanced or metastatic breast cancer whose disease has progressed during or after endocrine therapy. In addition, several PI3Kα selective inhibitors, such as GDC-0077 and CYH33, are in clinical development.

[0007] Summary of the Invention

[0008] The present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0009] In the general formula (1):

[0010] CLM is a group that can covalently bind to the PI3Kα protein;

[0011] L is a group connecting CLM and the three-ring structure;

[0012] R1 and R2 are independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, carbamoyl, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, -(CH2) nl R a 、-(CH2) nl OR a or -(CH2) nl NR a R bwherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amino, carbamoyl, mercapto, hydroxy, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally further selected from deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylhaloalkyl, halogen, substituted or unsubstituted cycloalkylamino, mercapto, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted cycloalkylhaloalkoxy, substituted or unsubstituted cycloalkylhydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, -(CH2) nl R c 、-(CH2) nl OR c and -(CH2) nl NR c R d is substituted by one or more substituents in;

[0013] Alternatively, any two adjacent or non-adjacent R2 form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl;

[0014] R a 、R b 、R c and R d each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, carbamoyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;

[0015] R3 is H, halogen, (C1-C3) alkyl or cyclopropyl;

[0016] R4 is a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S, and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, S, and O, wherein the 4- to 6-membered heterocycloalkyl group, the phenyl group, or the 5- to 6-membered heteroaryl group is optionally further substituted with one or more substituents selected from deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocycloalkyl, oxoheterocycloalkyl, thioheterocycloalkyl, oxo, and thio; and

[0017] n is 0, 1, 2, or 3;

[0018] m is 0, 1, 2, 3 or 4;

[0019] n1 is 0, 1, 2 or 3.

[0020] In another preferred embodiment, the general formula (1) has a structure as shown in the general formula (2):

[0021] wherein CLM, L, R1, R2, R3, R4, m and n are as defined above.

[0022] In another preferred embodiment, in the general formula (1) or (2), CLM is a group comprising a carbon-carbon double bond or a carbon-carbon triple bond that can covalently bind to the cysteine ​​residue (Cys) in the PI3Kα protein.

[0023] In another preferred embodiment, wherein in the general formula (1) or general formula (2), CLM is -NHCN, -CN,

[0024] R e is H, substituted or unsubstituted (C1-C6) alkyl, or substituted or unsubstituted (C3-C6) cycloalkyl;

[0025] R f 、R g and R h are each independently H, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -(CH2) w R, -(CH2) w OR, -(CH2) w N(R)2, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from N, S and O;

[0026] or R e and R f 、R f and R g 、R g and R h 、R e and R h It may form a substituted or unsubstituted 4- to 7-membered saturated or partially unsaturated ring containing 0 to 2 heteroatoms independently selected from N, S and O; wherein two hydrogen atoms on the same carbon of the 4- to 7-membered saturated or partially unsaturated ring may be replaced by oxygen to form an oxo group;

[0027] Each R is independently H, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, or substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from N, S and O;

[0028] w is 0, 1, or 2.

[0029] In another preferred embodiment, wherein in the general formula (1) or general formula (2), CLM is -NHCN, -CN, CLM is preferably -NHCN, -CN, CLM is more preferably

[0030] In another preferred embodiment, wherein in the general formula (1) or (2), L is wherein L1, L2, L3, L4, and L5 are independently selected from a chemical bond, O, S, NH, C(=O), C(=O)NH, S(=O), S(=O)2, (C1-C6)alkylene, -(C1-C6)alkylene-O-, (C2-C3)alkenylene, (C2-C3)alkynylene, (C3-C10)cycloalkylene, phenylene, a 5-11 membered cyclyl group, a 3-10 membered saturated or partially unsaturated alkylene group containing 1-4 heteroatoms independently selected from N, S, and O, heterocycloalkyl, 7-11 membered heterospirocyclic group, 5-11 membered heterobridged cyclic group or 5-9 membered heteroaryl group, the (C1-C6) alkylene, -(C1-C6) alkylene-O-, (C2-C3) alkenylene, (C2-C3) alkynylene, (C3-C10) cycloalkylene, 3-10 membered saturated or partially unsaturated heterocycloalkylene, phenylene, 7-11 membered heterospirocyclic group, 5-11 membered heterobridged cyclic group or 5-9 membered heteroaryl group are optionally substituted by 1, 2 or 3 R L replace;

[0031] Each R L are independently selected from H, halogen, OH, NH2, CN, -CONH2, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkyl-C(=O)-, (C1-C6) alkoxy, (C1-C6) alkylthio or (C1-C6) alkylamino, wherein the (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkyl-C(=O)-, (C1-C6) alkoxy, (C1-C6) alkylthio or (C1-C6) alkylamino is optionally substituted by 1, 2 or 3 R LL replace;

[0032] Each R LL Each is independently selected from H, halogen, (C1-C6) alkyl, OH, NH2, MeNH-, Me2N-, CH3, CH2F, CHF2 or CF3; wherein * indicates connection with CLM.

[0033] In another preferred embodiment, in the general formula (1) or the general formula (2), each L1, L2, L3, L4, and L5 are independently a chemical bond, O, S, NH, C(=O), C(=O)NH, S(=O), S(=O)2, CH2,

[0034] In another preferred embodiment, wherein in the general formula (1) or the general formula (2),

[0035] L1 is a chemical bond, (C2-C3) alkenylene, (C2-C3) alkynylene, (C3-C10) cycloalkylene, 3-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocyclylene, 5-11 membered heterobridged cyclylene, said (C2-C3) alkenylene, (C2-C3) alkynylene, (C3-C10) cycloalkylene, 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene or 5-11 membered heterobridged cyclylene being optionally substituted by 1, 2 or 3 R L replace;

[0036] L2 is a chemical bond, C(=O), C(=O)NH, (C1-C6)alkylene, or -(C1-C6)alkylene-O-;

[0037] L3 is a chemical bond, a 3-10 membered saturated or partially unsaturated heterocycloalkylene group containing 1 to 4 heteroatoms independently selected from N, S and O, a 7-11 membered heterospirocyclic group, or a 5-11 membered heterobridged cyclic group, wherein the 3-10 membered saturated or partially unsaturated heterocycloalkylene group, the 7-11 membered heterospirocyclic group or the 5-11 membered heterobridged cyclic group is optionally substituted by 1, 2 or 3 R L replace;

[0038] L4 is a chemical bond, C(=O), C(=O)NH, (C1-C6)alkylene, or -(C1-C6)alkylene-O-;

[0039] L5 is phenylene, 5-9 membered heteroarylene, 3-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocyclic group, 5-11 membered heterobridged ring group, and the phenylene, 5-9 membered heteroarylene, 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclic group or 5-11 membered heterobridged ring group is optionally substituted by 1, 2 or 3 R L replace.

[0040] In another preferred embodiment, wherein in the general formula (1) or the general formula (2),

[0041] L1 is a 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene containing 1-4 heteroatoms independently selected from N, S, and O, wherein the 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene is optionally substituted by 1, 2, or 3 R L replace;

[0042] L2 is a chemical bond;

[0043] L3 is a 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene containing 1-4 heteroatoms independently selected from N, S, and O, wherein the 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene is optionally substituted by 1, 2, or 3 R L replace;

[0044] L4 is a chemical bond;

[0045] L5 is phenylene, 5-9 membered heteroaryl, 3-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the phenylene, 5-9 membered heteroaryl, 3-10 membered saturated or partially unsaturated heterocycloalkylene is optionally substituted by 1, 2 or 3 R L replace.

[0046] In another preferred embodiment, wherein the structural unit in the general formula (1) or the general formula (2) is Selected from * indicates connection to CLM.

[0047] In another preferred embodiment, wherein in the general formula (1) or the general formula (2), each R1 and R2 are independently selected from H, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, halogen, amino, carbamoyl, -(CH2) nl R a 、-(CH2) nl OR a and -(CH2) nl NR a R b wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amino and carbamoyl groups are optionally further selected from deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylhaloalkyl, halogen, substituted or unsubstituted cycloalkylamino, mercapto, oxo, cyano, hydroxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, -(CH2) nl R c 、-(CH2) nl OR c and -(CH2) nl NR c R d is substituted by one or more substituents in;

[0048] Alternatively, any two adjacent or non-adjacent R2 groups are linked to form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group and the heterocycloalkyl group are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo and hydroxy;

[0049] R a 、R b 、R c and R d are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, hydroxy, amino, carbamoyl, cycloalkyl or heterocycloalkyl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, cycloalkyl and heterocycloalkyl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl;

[0050] R3 is H, halogen, cyclopropyl or CH3;

[0051] R4 is a 4- to 6-membered saturated heterocycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S, and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, S, and O, wherein the 4- to 6-membered saturated heterocycloalkyl group, the phenyl group, or the 5- to 6-membered heteroaryl group is optionally further substituted with one or more substituents selected from deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, oxoheterocycloalkyl, thioheterocycloalkyl, oxo, or thio; and

[0052] n is 0, 1, or 2;

[0053] m is 0, 1, or 2;

[0054] n1 is 0 or 1.

[0055] In another preferred embodiment, wherein in the general formula (1) or the general formula (2), each R1 and R2 are independently selected from H, deuterium, methyl, deuterated methyl, halogenated alkyl, methoxy, hydroxyl, halogenated methoxy, F, Cl, amino, carbamoyl,

[0056] Or when m is 2, two R2 connected to the same carbon atom may form a cyclopropyl group.

[0057] In another preferred embodiment, in the general formula (1) or (2), R3 is H, F, Cl, cyclopropyl or CH3.

[0058] In another preferred embodiment, the general formula (1) or the general formula (2) has a structure as shown in the general formula (3):

[0059] in,

[0060] L1 is a 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene containing 1-4 heteroatoms independently selected from N, S, and O, wherein the 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene is optionally substituted by 1, 2, or 3 R L replace;

[0061] L3 is a 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene containing 1-4 heteroatoms independently selected from N, S, and O, wherein the 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene is optionally substituted by 1, 2, or 3 R L replace;

[0062] L5 is phenylene, 5-9 membered heteroaryl, 3-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the phenylene, 5-9 membered heteroaryl, 3-10 membered saturated or partially unsaturated heterocycloalkylene is optionally substituted by 1, 2 or 3 R L replace;

[0063] Each R L Independently selected from H, F, Cl, hydroxy, amino, cyano, amide, methyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, methylamino, dimethylamino;

[0064] CLM is

[0065] R1 is independently selected from hydrogen, deuterium, (C1-C3) alkyl, (C1-C3) deuterated alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, amino, methylamino, hydroxy, cyano, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, n is 0, 1 or 2;

[0066] R3 is H, halogen, (C1-C3) alkyl or cyclopropyl;

[0067] R4 is a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the 4- to 6-membered heterocycloalkyl group, the phenyl group or the 5- to 6-membered heteroaryl group is optionally further substituted by one or more substituents selected from deuterium, (C1-C3) alkyl, (C1-C3) deuterated alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, amino, nitro, hydroxy, cyano, (C3-C6) cycloalkyl, (3-6-membered) heterocycloalkyl, (3-6-membered) oxoheterocycloalkyl, (3-6-membered)thioheterocycloalkyl, oxo and thioxo.

[0068] In another preferred embodiment, wherein in the general formula (3),

[0069] L1 is a 4-10 membered saturated or partially unsaturated heterocycloalkylene group or a 5-11 membered heterobridged cyclic group containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the 4-10 membered saturated or partially unsaturated heterocycloalkylene group or the 5-11 membered heterobridged cyclic group is optionally substituted by 1, 2 or 3 R L Substituted; L1 is preferably More preferably

[0070] L3 is a 4-10 membered saturated or partially unsaturated heterocycloalkylene group or a 5-11 membered heterobridged cyclic group containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the 4-10 membered saturated or partially unsaturated heterocycloalkylene group or the 5-11 membered heterobridged cyclic group is optionally substituted by 1, 2 or 3 R L Substituted; L3 is preferably More preferably

[0071] L5 is phenylene, 5-6 membered heteroaryl, 4-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the phenylene, 5-6 membered heteroaryl, 4-10 membered saturated or partially unsaturated heterocycloalkylene is optionally substituted by 1, 2 or 3 R L Substituted; L5 is preferably

[0072] CLM is

[0073] R e is H or Me;

[0074] R fis H, F, Me or CN;

[0075] R g and R h are each independently H, halogen, -CN, -(CH2) w R, -(CH2) w OR, -(CH2) w N(R)2, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C3-C6)cycloalkyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, wherein the substituted or unsubstituted (C1-C6)alkyl is preferably The substituted or unsubstituted (C3-C6) cycloalkyl group is preferably Each R is independently H, (C1-C6) alkyl, (C3-C6) cycloalkyl, 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocycloalkyl or 5-11 membered heterobridged cycloalkyl, wherein the (C1-C6) alkyl, (C3-C6) cycloalkyl, 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocycloalkyl or 5-11 membered heterobridged cycloalkyl The 1-membered heterobridged cycloalkyl group is optionally further substituted by one or more substituents selected from deuterium, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, a 3-7 membered saturated or partially unsaturated heterocycloalkyl group containing 1-2 heteroatoms independently selected from N, S and O, a 7-11 membered heterospirocyclic group, a 5-11 membered heterobridged cyclic group, an oxo group, -C(O)Me, -C(O)OMe, -C(O)OBu-t, -F, Cl, -OH, and -NH2;

[0076] w is 0, 1 or 2;

[0077] R1 is independently selected from hydrogen, deuterium, -Me, -OMe, -OCD3, -CD3, -CHF2, -CF3, F, Cl, -NH2, -NHMe, hydroxy, cyano, cyclopropyl, n is 0, 1 or 2;

[0078] R3 is H, F, Cl, -Me or cyclopropyl;

[0079] R4 is a 5-membered heterocycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S and O, or a 5-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N, S and O, wherein the 5-membered heterocycloalkyl group or the 5-membered heteroaryl group is optionally further substituted by one or more substituents selected from deuterium, (C1-C3) alkyl, (C1-C3) deuterated alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, amino, nitro, hydroxy, cyano, (C3-C6) cycloalkyl, (3-6-membered) heterocycloalkyl, (3-6-membered) oxoheterocycloalkyl, (3-6-membered)thioheterocycloalkyl, oxo and thioxo.

[0080] In another preferred embodiment, wherein in the general formula (3),

[0081] L1 is a 4-10 membered saturated or partially unsaturated heterocycloalkylene group or a 5-11 membered heterobridged cyclic group containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the 4-10 membered saturated or partially unsaturated heterocycloalkylene group or the 5-11 membered heterobridged cyclic group is optionally substituted by 1, 2 or 3 R L L1 is preferably a 4-7 membered saturated or partially unsaturated heterocycloalkylene containing 1-2 N atoms, a 6-9 membered hetero-bridged cyclic group containing 1-2 N atoms, the 4-7 membered saturated or partially unsaturated heterocycloalkylene or 6-9 membered hetero-bridged cyclic group optionally substituted by 1-2 R L Substituted; L1 is preferably

[0082] L3 is a 4-10 membered saturated or partially unsaturated heterocycloalkylene group or a 5-11 membered heterobridged cyclic group containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the 4-10 membered saturated or partially unsaturated heterocycloalkylene group or the 5-11 membered heterobridged cyclic group is optionally substituted by 1, 2 or 3 R L L3 is preferably a 4-7 membered saturated or partially unsaturated heterocycloalkylene containing 1-2 N atoms, a 6-9 membered hetero-bridged cyclic group containing 1-2 N atoms, the 4-7 membered saturated or partially unsaturated heterocycloalkylene or 6-9 membered hetero-bridged cyclic group optionally substituted by 1-2 R L Substituted; L3 is preferably

[0083] L5 is phenylene, 5-6 membered heteroarylene containing 1-2 heteroatoms independently selected from N, S and O, 4-10 membered saturated or partially unsaturated heterocycloalkylene containing 1-4 heteroatoms independently selected from N, S and O, and the phenylene, 5-6 membered heteroarylene, 4-10 membered saturated or partially unsaturated heterocycloalkylene is optionally substituted by 1, 2 or 3 R LL5 is preferably phenylene, 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, S and O, 8-10 membered partially unsaturated bicyclic heterocycloalkylene containing 1-3 heteroatoms independently selected from N, S and O, the phenylene, 5-6 membered heteroaryl, 8-10 membered partially unsaturated bicyclic heterocycloalkylene may be optionally substituted by 1-2 R L Substituted; L5 is preferably

[0084] Each R L Independently selected from H, F, Cl, hydroxy, amino, cyano, amide, methyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, methylamino, dimethylamino;

[0085] CLM is

[0086] R e is H or Me;

[0087] R f is H, F, Me or CN;

[0088] R g and R h are each independently H, halogen, -CN, -(CH2) w R, -(CH2) w OR, -(CH2) w N(R)2, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C3-C6)cycloalkyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, wherein the substituted or unsubstituted (C1-C6)alkyl is preferably The substituted or unsubstituted (C3-C6) cycloalkyl group is preferably

[0089] Each R is independently H, -C(O)R m 、-C(O)OR m 、-S(O)2R m 、-CH2OC(O)R n 、

[0090] R m and R nEach of them is independently H, (C1-C18) alkyl, (C3-C6) cycloalkyl, 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocycloalkyl or 5-11 membered heterobridged cycloalkyl, wherein the (C1-C18) alkyl, (C3-C6) cycloalkyl, 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocycloalkyl or 5-11 membered heterobridged cycloalkyl The 1-membered heterobridged cycloalkyl group is optionally further substituted by one or more substituents selected from deuterium, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, a 3-7 membered saturated or partially unsaturated heterocycloalkyl group containing 1-2 heteroatoms independently selected from N, S and O, a 7-11 membered heterospirocyclic group, a 5-11 membered heterobridged cyclic group, an oxo group, -C(O)Me, -C(O)OMe, -C(O)OBu-t, -F, Cl, -OH, -NH2; R m and R n Each is independently preferably H, methyl, ethyl, tert-butyl, isopropyl, cyclopropyl or cyclobutyl;

[0091] w is 0, 1 or 2;

[0092] R1 is independently selected from hydrogen, deuterium, -Me, -OMe, -OCD3, -CD3, -CHF2, -CF3, F, Cl, -NH2, -NHMe, hydroxy, cyano, cyclopropyl, n is 0, 1 or 2;

[0093] R3 is H, F, Cl, -Me or cyclopropyl;

[0094] R4 is a 5-membered heterocycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S and O, or a 5-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N, S and O, wherein the 5-membered heterocycloalkyl group or the 5-membered heteroaryl group is optionally further substituted by one or more substituents selected from deuterium, (C1-C3) alkyl, (C1-C3) deuterated alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, amino, nitro, hydroxy, cyano, (C3-C6) cycloalkyl, (3-6-membered) heterocycloalkyl, (3-6-membered) oxoheterocycloalkyl, (3-6-membered)thioheterocycloalkyl, oxo and thioxo.

[0095] In another preferred embodiment, in the general formula (1)-(3), R4 is preferably a 5-membered heterocycloalkyl group containing 1 N atom, a 5-membered heterocycloalkyl group containing 1 N and 1 S or O, or a 5-membered heteroaryl group containing 1, 2 or 3 groups independently selected from N, S or O, wherein the 5-membered heterocycloalkyl group or the 5-membered heteroaryl group is optionally further substituted by 1 or 2 substituents independently selected from -D, -Me, -CD3, -CH2F, -CHF2, -CF3, -OMe, -OCD3, oxo and thio.

[0096] In another preferred embodiment, wherein in the general formula (1)-(3), R4 is selected from

[0097] In another specific embodiment of the present invention, the compound of the present invention has one of the following structures:

[0098] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and / or excipient, and a compound of the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0099] Another object of the present invention is to provide the use of the compound represented by general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, or the pharmaceutical composition thereof, for preparing a medicament for treating, regulating, or preventing a disease associated with PI3Kα. The disease is preferably cancer, and the cancer is a hematological cancer or a solid tumor.

[0100] Another object of the present invention is to provide a method for treating, regulating or preventing diseases mediated by PI3Kα, comprising administering to a subject a therapeutically effective amount of a compound represented by the general formula (1) of the present invention, or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition.

[0101] It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0102] Synthesis of compounds

[0103] The following specifically describes the preparation methods of the compound of general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0104] The compounds of formula (1) described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials used in the synthesis of the compounds can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulae provided herein.

[0105] In one aspect, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of the compounds used, reaction temperatures, reaction times, etc., are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art. In one aspect, the present invention also provides a method for preparing the compound of formula (1), wherein the compound of formula (1) can be prepared using the following general reaction scheme 1:

[0106] General reaction scheme 1

[0107] Compounds of formula (1) can be prepared according to general reaction scheme 1, wherein R1, R2, R3, R4, L, CLM, n, and m are as defined above. As shown in general reaction scheme 1, compound 1-1 undergoes a coupling reaction with an intermediate R4 (NH or boronic ester) to produce compound 1-2. Compound 1-2 then undergoes a coupling reaction with each structural unit of L (L1 to L5) in sequence, and the structure is then extended step by step to produce compound 1-3. Compound 1-3 is then reacted with the corresponding acyl chloride or acid to produce the target compound of formula (1).

[0108] Further forms of compounds

[0109] "Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a substance that does not cause undesirable biological effects or interact in a deleterious manner with any of its components when administered to a subject.

[0110] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of the formula with an acid or base, wherein the acid or base includes, but is not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1. st Acids and Bases in Ed., (Wiley, 2002).

[0111] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystal forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water / organic solvent, using organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, solvated forms are considered equivalent to unsolvated forms.

[0112] In other embodiments, the compound of formula (1) is prepared in different forms, including but not limited to, amorphous, crushed and nano-particle forms. In addition, the compound of formula (1) includes crystalline forms and can also be polymorphic. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs generally have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.

[0113] In another aspect, compounds of formula (1) may have chiral centers and / or axial chirality and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially purified compounds are included within the scope of the present invention. The present invention is intended to include all such isomeric forms of these compounds.

[0114] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) and C-14( 14 C). For example, deuterated compounds can be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0115] Unless otherwise specified, any reference to an atom in the compounds of the present invention refers to its stable atomic isotope. Unless otherwise specified, when a position in a molecular structure is designated as "H" or "hydrogen," such position should be understood to have the natural abundance of the hydrogen isotope. Similarly, when a position is designated as "D" or "deuterium," such position should be understood to have a deuterium isotope abundance at least 3000 times its natural abundance (the natural abundance of the deuterium isotope is 0.015%).

[0116] More preferably, the deuterium atom abundance at each deuterated site of the deuterated compound of the present invention is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, it is at least 4500 times (67.5% deuterium atom enrichment). More preferably, it is at least 5000 times (75% deuterium atom enrichment). More preferably, it is at least 6000 times (90% deuterium atom enrichment). More preferably, it is at least 6333 times (95% deuterium atom enrichment). More preferably, it is at least 6466.7 times (97% deuterium atom enrichment). More preferably, it is at least 6600 times (99% deuterium atom enrichment). More preferably, it is at least 6633.3 times (99.5% deuterium atom enrichment).

[0117] the term

[0118] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. It should be noted that, throughout the specification and the appended claims, the singular forms "a," "an," and "an" include plural referents unless the context clearly indicates otherwise. Conventional methods, such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology, are employed unless otherwise indicated. Throughout this application, the use of "or" or "and" means "and / or," unless otherwise indicated.

[0119] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. Preferred are lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl. More preferred are lower alkyl groups containing 1 to 3 carbon atoms, such as methyl, ethyl, propyl, and 2-propyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t Bu.

[0120] Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

[0121] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups of 1 to 14 carbon atoms. Preferred are lower alkenyl groups containing 1 to 4 carbon atoms, such as ethenyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl. More preferred are lower alkenyl groups containing 1 to 2 carbon atoms.

[0122] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl group as defined above.

[0123] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Preferred are lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl. More preferred are lower alkynyl groups containing 1 to 2 carbon atoms.

[0124] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl group as defined above.

[0125] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), preferably containing 3 to 14 ring carbon atoms (C 3-14 In some embodiments, the cycloalkyl group has 3-10 ring carbon atoms (C 3-10 In some embodiments, a cycloalkyl group has 3-8 ring carbon atoms (C 3-8 In some embodiments, the cycloalkyl group has 3-7 ring carbon atoms (C 3-7 In some embodiments, the cycloalkyl group has 3-6 ring carbon atoms (C 3-6 In some embodiments, the cycloalkyl group has 4-6 ring carbon atoms (C 4-6 In some embodiments, the cycloalkyl group has 5-6 ring carbon atoms (C 5-6 In some embodiments, a cycloalkyl group has 5-10 ring carbon atoms (C 5-10Cycloalkyl). If the carbocyclic ring contains at least one double bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl group," or if the carbocyclic ring contains at least one triple bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl group." Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is tricyclic. The ring-forming carbon atoms of the cycloalkyl group may optionally be oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl groups). In some embodiments, the cycloalkyl group may be fused with an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, the cycloalkyl group may be fused with an aryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, cycloalkyl groups can be fused with aryl groups and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl groups and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.

[0126] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

[0127] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0128] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group. Aryl is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

[0129] Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.

[0130] Unless otherwise specified, "arylene" refers to a divalent aromatic radical as defined above. Examples of arylene radicals include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.

[0131] Unless otherwise specified, "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms, the heteroatoms being independently selected from O, N or S, preferably 1, 2, 3 or 4 heteroatoms, preferably a 5-14 membered aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, more preferably a 5-9 membered aromatic group containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen, more preferably a 5-6 membered aromatic group containing 1-3 heteroatoms selected from oxygen, sulfur or nitrogen. The heteroaryl group is monocyclic or polycyclic. The monocyclic heteroaryl group is preferably a 5-6 membered aromatic group containing 1-3 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6 membered aromatic group containing 1-2 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6 membered aromatic group containing 1 heteroatom selected from oxygen, nitrogen or sulfur. In some embodiments, the monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,

[0132] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0133] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and selenium, preferably a saturated or partially unsaturated ring containing 1-4 heteroatoms selected from oxygen, sulfur or nitrogen, more preferably a saturated or partially unsaturated ring containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen. In some embodiments, heterocycloalkyl is a 5-8 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-8 membered heterocycloalkyl). Heterocycloalkyl is a 5-6 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-6 membered heterocycloalkyl). In some embodiments, 5-6 membered heterocycloalkyl contains 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocycloalkyl contains 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocycloalkyl contains 1 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. If heterocycloalkyl contains at least one double bond, then partially unsaturated heterocycloalkyl can be referred to as "heterocycloalkenyl", or if heterocycloalkyl contains at least one triple bond, then partially unsaturated heterocycloalkyl can be referred to as "heterocycloalkynyl". Heterocycloalkyl can include monocyclic, bicyclic, spirocyclic or polycyclic (e.g., having two fused or bridged rings) ring systems. In certain embodiments, heterocycloalkyl is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl can be optionally oxidized to form oxo or thioxo or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl can be connected via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains 0 to 2 double bonds. The definition of heterocycloalkyl also includes a portion (also referred to as partially unsaturated heterocycle) of an aromatic ring having one or more fused to the heterocycloalkyl ring (i.e., sharing a key therewith), such as a benzo derivative of piperidine, morpholine, azacycloheptatriene or thienyl. The heterocycloalkyl containing a fused aromatic ring can be connected via any ring-forming atom, including the ring-forming atom of the fused aromatic ring.Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanediyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazole , 4-nitro-2-nitro-1-pyridine, 4 ...1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine,

[0134] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

[0135] Unless otherwise specified, "heterocyclospiroalkyl" / "heterospiroalkyl" / "heterospirocyclyl" refers to a polycyclic hydrocarbon group formed by two or more saturated or partially unsaturated monocyclic rings sharing a carbon atom (called a spiro atom), wherein one or more (such as 1, 2 or 3) ring atoms are selected from nitrogen, oxygen or S(O) p(wherein p is 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom can be substituted or unsubstituted (i.e. N or NR, R is hydrogen or other substituents defined herein). Each monocycle can contain one or more double bonds, but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are divided into single spiro heterocyclic groups, double spiro heterocyclic groups or multi-spiro heterocyclic groups according to the number of shared spiro atoms between the rings. The term "(5-15 yuan) heterocyclic spiroalkyl" refers to a heterocyclic spiroalkyl group with 5 to 15 ring atoms, wherein the monocycle with shared spiro atoms is a 3 to 8 yuan monocycle, and at least one monocycle is a heterocyclic alkyl ring. Preferably, it is a (6-18 yuan) heterocyclic spiroalkyl group with 6 to 18 ring atoms, wherein 1-3 ring atoms are heteroatomic, more preferably a (7-15 yuan) heterocyclic spiroalkyl group with 7 to 15 ring atoms, wherein 1-3 ring atoms are heteroatomic. Most preferably, it is a 9-membered (4-membered monocyclic (heterocyclic) base ring / 6-membered monocyclic (heterocyclic) base ring, a 5-membered monocyclic (heterocyclic) base ring / 5-membered monocyclic (heterocyclic) base ring), a 10-membered (5-membered monocyclic (heterocyclic) base ring / 6-membered monocyclic (heterocyclic) base ring) or an 11-membered (6-membered monocyclic (heterocyclic) base ring / 6-membered monocyclic (heterocyclic) base ring) monospiro heterocyclic group. Specific examples of heterocyclic spiroalkyl groups include, but are not limited to

[0136] Unless otherwise specified, "heterobridged cycloalkyl" / "heterobridged cyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic.

[0137] Unless otherwise specified, "oxo" refers to =0; for example, a carbonyl group substituted with an oxo group is a "carbonyl group." The group formed by sulfur being replaced by an oxo group is called "sulfinyl" The group formed by sulfur being substituted by two oxo groups is called "sulfonyl".

[0138] Unless otherwise specified, "thio" refers to =S.

[0139] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group indicates that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0140] Unless otherwise specified, the term "substituted" refers to a substituent group other than one or more hydrogen atoms on a specified atom or group that is substituted by one or more hydrogen atoms, without exceeding the normal valence of the specified atom. For example, one or more hydrogen atoms of an alkyl, alkylene, alkenyl, alkynyl, hydroxyl or amido group can be substituted by one or more substituent groups. Wherein the substituent group includes but is not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or its combination. The definition of "substituted" does not include similar indefinite structures obtained by defining a substituent group having a further substituent group attached to infinity (for example, a substituted aryl group itself substituted by a substituted aryl group with a substituted alkyl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, a substituted aryl group is continuously substituted by two other substituted aryls to an aryl group substituted by ((substituted aryl) substituted aryl). Similarly, the above definition does not include substitution patterns that are not allowed (for example, a methyl group substituted by 5 fluorines or a heteroaryl group with two adjacent oxygen ring atoms). This substitution pattern that is not allowed is well known to those skilled in the art. Whenever used to modify a chemical group, "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes but is not limited to "alkyl aryl". Unless otherwise specified, if a group is described as optionally substituted, any substituent of the group itself is unsubstituted.

[0141] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0142] Unless otherwise specified, it will be understood that the word "comprise", or variations such as "comprises" or "comprising", imply the inclusion of a stated element or integer, or group of elements or integers, but not the exclusion of any other element or integer, or group of elements or integers.

[0143] The substituent "-O-CH2-O-" refers to the substituent in which two oxygen atoms are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, for example:

[0144] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0145] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0146] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thiopyranyl are six-membered rings, while cyclopentyl, pyrrolyl, furanyl, and thiophenyl are five-membered rings.

[0147] The term "fragment" refers to a specific part or functional group of a molecule. A chemical fragment is generally considered to be a chemical entity contained in or attached to a molecule.

[0148] The term "isomer" means any tautomer, stereoisomer, atropisomer, isotopomer, enantiomer or diastereomer of any compound of the present invention. The compounds of the present invention may have one or more chiral centers or double bonds and therefore exist in stereoisomeric forms, for example, double bond isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). Therefore, the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) forms as well as enantiomers and stereoisomer mixtures, such as racemates. Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can be separated into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, and crystallization of the compounds as chiral salt complexes or crystallization of the compounds in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

[0149] The term "isotopomers" refers to different molecules whose structures differ only in one isotope but are otherwise identical.

[0150] The term "atropisomer" refers to a conformational stereoisomer produced when rotation about a single bond within a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule and the substituents at either end of the single bond are asymmetric, i.e., atropisomers do not require a stereocenter. When the barrier to rotation about the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation of the individual isomers is permitted (LaPlante et al., J. Med. Chem. 2011, 54, 20, 7005), preferably by chiral resolution.

[0151] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0152] Unless otherwise stated, Indicates a single bond or a double bond.

[0153] Unless otherwise stated, Indicates the E or Z form of carbon-carbon double bonds, or a mixture of the two. express Or a mixture of both.

[0154] Specific pharmaceutical and medical terms

[0155] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0156] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0157] "Active ingredient" refers to the compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0158] The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0159] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0160] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0161] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0162] Therapeutic uses

[0163] The present invention provides methods for treating diseases using the compounds of formula (1) or pharmaceutical compositions of the present invention, including but not limited to conditions involving PI3Kalpha (eg, cancer).

[0164] In some embodiments, a method for treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of formula (1). In some embodiments, the cancer is mediated by PI3Kalpha. In other embodiments, the cancer is a blood cancer and a solid tumor, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.

[0165] Route of administration

[0166] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0167] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0168] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0169] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0170] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0171] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0172] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0173] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0174] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0175] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0176] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compounds of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, all of which are within the skill of a skilled physician.

[0177] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features. DETAILED DESCRIPTION

[0178] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0179] In all embodiments, 1 H-NMR was recorded on a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were by volume.

[0180] Example 1 Synthesis of Compound 1

[0181] Step 1: Synthesis of compound int_1-2:

[0182] Dissolve 5-bromo-2-hydroxybenzaldehyde (20.0 g, 99.5 mmol) in methanol (200 mL), add glyoxal (72.2 g, 1.24 mol) and aqueous ammonia (89.7 g, 716 mmol). Stir the reaction mixture at 30°C for 12 hours. Filter the reaction mixture, and concentrate the filtrate under reduced pressure to obtain the crude product, int_1-2, as a black solid.

[0183] LCMS m / z(ESI):238.9[M+H] + .

[0184] Step 2: Synthesis of compound int_1-3:

[0185] Compound int_1-2 (31.0 g, 130 mmol) was dissolved in N,N-dimethylformamide (300 mL), and 1,2-dibromoethane (97.4 g, 519 mmol) and cesium carbonate (169 g, 519 mmol) were added. The reaction solution was stirred at 85°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The intermediate int_1-3 was then separated and purified by silica gel chromatography.

[0186] LCMS m / z(ESI):265.1[M+H] + .

[0187] Step 3: Synthesis of compound int_1-4:

[0188] Intermediate int_1-3 (19.0 g, 71.7 mmol) was dissolved in N,N-dimethylformamide (200 mL). N-iodosuccinimide (48.4 g, 215 mmol) was added at 25°C, and the reaction mixture was stirred at 60°C for 12 hours. Water (500 mL) was added to the reaction mixture, causing a large amount of solid to precipitate. The solid was filtered under reduced pressure, and the filter cake was dissolved in ethyl acetate (1.0 L) and washed with saturated aqueous sodium hydroxide (1.0 L x 2) and then with saturated ammonium chloride (1.0 L x 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product, int_1-4, as a yellow solid.

[0189] LCMS m / z(ESI):516.9[M+H] + .

[0190] 1H NMR (400MHz, DMSO-d6) δ8.36 (d, J = 2.6 Hz, 1H), 7.44 (dd, J = 2.6, 8.7 Hz, 1H), 7.02-6.96 (m, 1H), 4.49-4.44 (m, 2H), 4.38-4.34 (m, 2H).

[0191] Step 4: Synthesis of compound int_1-5:

[0192] Compound int_1-4 (28.0 g, 54.2 mmol) was dissolved in anhydrous tetrahydrofuran (280 mL). Ethylmagnesium bromide (3 M, 27.1 mL) was added at -20°C, and the reaction mixture was stirred at -20°C for 3 hours. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (300 mL). The mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then isolated and purified by silica gel chromatography to obtain intermediate int_1-5.

[0193] LCMS m / z(ESI):392.1[M+H] + .

[0194] 1 H NMR (400MHz, DMSO-d6) δ 8.38 (d, J = 2.5 Hz, 1H), 7.57 (s, 1H), 7.43 (dd, J = 2.6, 8.7 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.43 (s, 4H).

[0195] Step 5: Synthesis of compound int_1-7:

[0196] Compound int_1-5 (1.43 g, 3.65 mmol) and (4S)-4-(difluoromethyl)-1,3-oxazolidin-2-one (500 mg, 3.65 mmol) were dissolved in dimethyltetrahydrofuran (30 mL). Copper acetate (132.50 mg, 729.48 μmol), N,N-dimethyl-1,2-cyclohexanediamine (156.06 mg, 1.10 mmol), and cesium carbonate (2.38 g, 7.31 mmol) were added under nitrogen. The reaction mixture was stirred at 80°C for 16 hours. After cooling, saturated aqueous ammonium chloride (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then purified by silica gel chromatography to obtain intermediate int_1-7.

[0197] LCMS m / z(ESI):399.9[M+H] + .

[0198] 1 H NMR (400MHz, DMSO-d6) δ8.41 (d, J = 2.5 Hz, 1H), 7.45-7.39 (m, 2H), 7.00 (d, J = 8. 8Hz,1H),6.85-6.49(m,1H),5.15-4.97(m,1H),4.66-4.55(m,2H),4.46(s,4H).

[0199] Step 6: Synthesis of compound int_1-8:

[0200] Compound int_1-7 (300 mg, 749.67 μmol) and N-BOC piperazine (418.88 mg, 2.25 mmol) were dissolved in tetrahydrofuran (8 mL). Cesium carbonate (732.77 mg, 2.25 mmol) and (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (62.70 mg, 74.97 μmol) were added under nitrogen. The reaction mixture was stirred at 80°C for 16 hours. After cooling, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then isolated and purified by silica gel chromatography to obtain intermediate int_1-8.

[0201] LCMS m / z(ESI):506.1[M+H] + .

[0202] Step 7: Synthesis of compound int_1-9:

[0203] Compound int_1-8 (330 mg, 652.80 μmol) was dissolved in dichloromethane (12 mL), followed by the addition of trifluoroacetic acid (1.5 mL, 15.98 mmol). The reaction mixture was stirred at 30°C for 1 hour. N,N-diisopropylethylamine (2 mL) was slowly added to the reaction mixture at 0°C to adjust the pH to 8. The mixture was then concentrated to dryness under reduced pressure to yield the crude product, int_1-9, as a yellow solid.

[0204] LCMS m / z(ESI):406.1[M+H] + .

[0205] Step 8: Synthesis of compound int_1-10:

[0206] Compound int_1-9 (80.0 mg, 197 μmol) and 4-Boc-aminophenylacetic acid (59.5 mg, 237 μmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (76.51 mg, 592 μmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (90.0 mg, 237 μmol) were added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (6 mL) and extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then purified by silica gel chromatography to obtain intermediate int_1-10.

[0207] LCMS m / z(ESI):639.2[M+H] + .

[0208] Step 9: Synthesis of compound int_1-11:

[0209] Compound int_1-10 (120 mg, 188 μmol) was dissolved in anhydrous dichloromethane (3 mL), and trifluoroacetic acid (643 mg, 5.64 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain crude compound int_1-11 as a brown oil.

[0210] LCMS m / z(ESI):539.1[M+H] + .

[0211] Step 10: Synthesis of Compound 1:

[0212] Compound int_1-11 (100 mg, 186 μmol) was dissolved in anhydrous dichloromethane (3 mL), and N,N-diisopropylethylamine (56.1 mg, 434 μmol) was added. Acryloyl chloride (16.8 mg, 186 μmol) was then added at 0°C. The reaction mixture was stirred at 25°C for 0.2 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (6 mL), and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The mixture was purified by preparative liquid chromatography to obtain Compound 1 as a white solid.

[0213] LCMS m / z(ESI):593.5[M+H] + .

[0214] 1H NMR (400MHz, DMSO-d6) δ10.11(s,1H),7.76(d,J=2.8Hz,1H),7.59(d,J=8.5Hz,2H),7.34(s,1H),7.19(d,J=8.5Hz,2H),7.01-6.88(m,2H),6.85-6. 50(m,1H),6.48-6.36(m,1H),6.31-6.18(m,1H),5.78-5.69(m,1H),5.09 -4.93(m,1H),4.68-4.52(m,2H),4.42-4.36(m,4H),3.72(s,2H),3.65(br s,4H),3.05-4.97(m,4H).

[0215] Example 2 Synthesis of Compound 2

[0216] Step 1: Synthesis of compound int_2-1:

[0217] Compound int_1-9 (148.30 mg) was dissolved in N,N-dimethylformamide (8 mL), and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (371.42 mg, 976.82 μmol) and tert-butyl (2-oxo-2-(piperazin-1-yl)ethyl)carbamate (264 mg) were added. Finally, N,N-diisopropylethylamine (907 μL, 5.21 mmol) was added. The reaction mixture was stirred at 30°C for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then purified by silica gel chromatography to obtain the intermediate int_2-1.

[0218] LCMS m / z(ESI):563.1[M+H] + .

[0219] Step 2: Synthesis of compound int_2-2:

[0220] Compound int_2-1 (321 mg, 570.60 μmol) was dissolved in dichloromethane (12 mL), followed by the addition of trifluoroacetic acid (1.3 mL, 17.12 mmol). The reaction mixture was stirred at 30°C for 1 hour. N,N-diisopropylethylamine (2 mL) was slowly added to the reaction mixture at 0°C to adjust the pH to 8. The mixture was then concentrated to dryness under reduced pressure to obtain a crude yellow solid, compound int_2-2.

[0221] LCMS m / z(ESI):463.1[M+H] + .

[0222] Step 3: Synthesis of compound int_2-4:

[0223] (R)-1-N-BOC-β-proline (27.9 mg, 129.7 μmol) was dissolved in N,N-dimethylformamide (2 mL). O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (61.7 mg, 162.2 μmol), N,N-diisopropylethylamine (41.9 mg, 324.4 μmol), and compound int_2-2 (50.0 mg, 108.1 μmol) were added. The reaction mixture was stirred at 25°C for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude compound int_2-4 as a yellow oil.

[0224] LCMS m / z(ESI):660.2[M+H] + .

[0225] Step 4: Synthesis of compound int_2-5:

[0226] Compound int_2-4 (60.0 mg, 91.0 μmol) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (622.3 mg, 5.46 mmol) was added. The reaction mixture was stirred at 30°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain compound int_2-5 as a yellow oil.

[0227] LCMS m / z(ESI):560.1[M+H] + .

[0228] Step 5: Synthesis of compound 2:

[0229] Compound int_2-5 (50.0 mg, 89.4 μmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (34.7 mg, 268.1 μmol) and acryloyl chloride (8.1 mg, 89.4 μmol) were added. The reaction solution was ultrasonically shaken at 25°C for 5 minutes. Saturated aqueous sodium carbonate solution (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography to obtain Compound 2 as a white solid.

[0230] LCMS m / z(ESI):614.3[M+H] + .

[0231] 1 H NMR(400MHz, DMSO-d6)δ8.12-8.28(m,1H)7.79(d,J=2.76Hz,1H)7.35(s,1H)6.91-7.03(m,2H)6.52-6.85 (m,2H)6.08-6.17(m,1H)5.61-5.68(m,1H)4.96-5.09(m,1H)4.51-4.71(m,2H)4.31-4.45(m,4H)4.02(br d, J=5.52Hz,2H)3.42-3.81(m,8H)3.00-3.15(m,5H)1.88-2.14(m,2H).

[0232] Example 3 Synthesis of Compound 3

[0233] Step 1: Synthesis of compound int_3-2:

[0234] S-1-Boc-pyrrolidine-3-carboxylic acid (22.3 mg, 103.8 μmol) was dissolved in N,N-dimethylformamide (1 mL). O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (49.3 mg, 129.7 μmol), N,N-diisopropylethylamine (33.5 mg, 259.5 μmol), and compound int_2-2 (40.0 mg, 86.5 μmol) were added. The reaction mixture was stirred at 25°C for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude compound int_3-2 as a yellow oil.

[0235] LCMS m / z(ESI):660.2[M+H] + .

[0236] Step 2: Synthesis of compound int_3-3:

[0237] Compound int_3-2 (60.0 mg, 91.0 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (622.3 mg, 5.46 mmol) was added. The reaction mixture was stirred at 30°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude compound int_3-3 as a yellow oil.

[0238] LCMS m / z(ESI):560.1[M+H] + .

[0239] Step 3: Synthesis of compound 3:

[0240] Compound int_3-3 (50.0 mg, 89.4 μmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (34.7 mg, 268.1 μmol) and acryloyl chloride (8.1 mg, 89.4 μmol) were added. The reaction solution was ultrasonically shaken at 25°C for 5 minutes. Saturated sodium carbonate solution (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by preparative liquid chromatography to obtain compound 3 as a white solid.

[0241] LCMS m / z(ESI):614.1[M+H] + .

[0242] 1 H NMR(400MHz, DMSO-d6)δ8.19(br d,J=2.76Hz,1H)7.79(d,J=2.51Hz,1H)7.35(s,1H)6.92-7.02(m,2H)6.51-6.83(m,2H)6.12(br d,J=16.56Hz,1H)5.65(br d,J=11.29Hz,1H)4.96-5.08(m,1H)4.54-4.67(m,2H)4.35-4.44(m,4H)4.02(br d,J=5.52Hz,2H)3.47-3.79(m,8H)3.00-3.14(m,5H)1.89-2.12(m,2H).

[0243] Example 4 Synthesis of Compound 4

[0244] Step 1: Synthesis of compound int_4-1:

[0245] Compound int_1-9 (200 mg, 493 μmol) and N-Boc-3-formylazetidine (137 mg, 740 μmol) were dissolved in anhydrous tetrahydrofuran (4 mL). Triethylamine (150 mg, 1.48 mmol) and sodium triacetoxyborohydride (209 mg, 987 μmol) were added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (6 mL) and extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then purified by silica gel chromatography to obtain intermediate int_4-1.

[0246] LCMS m / z(ESI):575.2[M+H] + .

[0247] Step 2: Synthesis of compound int_4-2:

[0248] Compound int_4-1 (230 mg, 400 μmol) was dissolved in anhydrous dichloromethane (3 mL), and trifluoroacetic acid (1.37 g, 12.0 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain crude compound int_4-2 as a brown oil.

[0249] LCMS m / z(ESI):475.1[M+H] + .

[0250] Step 3: Synthesis of compound int_4-3:

[0251] Compound int_4-2 (100 mg, 211 μmol) and p-fluoronitrobenzene (59.5 mg, 421 μmol) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (87.4 mg, 632 μmol) was added. The reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was diluted with water (6 mL), and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by silica gel chromatography to obtain the intermediate int_4-3.

[0252] LCMS m / z(ESI):596.1[M+H] + .

[0253] Step 4: Synthesis of compound int_4-4:

[0254] Compound int_4-3 (100 mg, 168 μmol) was dissolved in anhydrous ethanol (5 mL) and water (1 mL). Ammonium chloride (135 mg, 2.52 mmol) and iron powder (93.8 mg, 1.68 mmol) were added, and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (6 mL), and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound int_4-4 as a yellow solid.

[0255] LCMS m / z(ESI):565.1[M+H] + .

[0256] Step: Synthesis of compound 4:

[0257] Compound int_4-4 (90 mg, 159 μmol) was dissolved in anhydrous dichloromethane (3 mL), and N,N-diisopropylethylamine (61.7 mg, 477 μmol) was added. Acryloyl chloride (14.4 mg, 159.1 μmol) was then added at 0°C. The reaction mixture was stirred at 25°C for 0.2 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (6 mL), and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The mixture was purified by preparative liquid chromatography to obtain compound 4 as a white solid.

[0258] LCMS m / z(ESI):620.3[M+H] + .

[0259] 1 H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.46 (d, J = 8.8 Hz,2H),7.34(s,1H),6.98-6.88(m,2H),6.84-6.51(m,1H),6.43-6.33(m,3 H),6.23-6.13(m,1H),5.72-5.62(m,1H),5.11-4.96(m,1H),4.66-4.53(m ,2H),4.45-4.33(m,4H),3.90(t,J=7.4Hz,2H),3.49-3.39(m,4H),3.08(br s,4H), 2.99-2.88(m,1H),2.69-2.56(m,4H).

[0260] Example 5 Synthesis of Compound 5

[0261] Step 1: Synthesis of compound int_5-1:

[0262] Compound int_4-2 (100 mg, 211 μmol) and N-tert-butyloxycarbonyl-4-piperidone (63.0 mg, 316 μmol) were dissolved in anhydrous tetrahydrofuran (3 mL). N,N-diisopropylethylamine (81.7 mg, 632 μmol) and sodium triacetoxyborohydride (89.3 mg, 422 μmol) were added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (6 mL) and extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then purified by silica gel chromatography to obtain the intermediate int_5-1.

[0263] LCMS m / z(ESI):658.3[M+H] + .

[0264] Step 2: Synthesis of compound int_5-2:

[0265] Compound int_5-1 (130 mg, 198 μmol) was dissolved in anhydrous dichloromethane (3 mL), and trifluoroacetic acid (451 mg, 3.95 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain crude compound int_5-2 as a brown oil.

[0266] LCMS m / z(ESI):558.2[M+H] + .

[0267] Step 3: Synthesis of compound 5:

[0268] Compound int_5-2 (110 mg, 197 μmol) was dissolved in anhydrous dichloromethane (3 mL), and N,N-diisopropylethylamine (76.5 mg, 592 μmol) was added. Acryloyl chloride (17.9 mg, 197 μmol) was then added at 0°C. The reaction mixture was stirred at 25°C for 0.2 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (6 mL), and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography to yield compound 5 as a white solid.

[0269] LCMS m / z(ESI):612.3[M+H] + .

[0270] 1 H NMR (400MHz, DMSO-d6) δ7.75 (d, J=2.5Hz, 1H), 7.34 (s, 1H), 6.96-6.88 (m, 2H), 6.82-6.50 (m, 2H), 6.05 (dd, J=2.4, 16.7Hz, 1H), 5.66-5 .60(m,1H),5.09-4.95(m,1H),4.66-4.53(m,2H),4.43-4.33(m,4H),4.04-3.75(m,2H),3.34-3.29(m,7H),3.22-2.90(m,6H),2.73(br t,J=6.4Hz,2H),2.59-2.53(m,2H),2.21(br s,1H),1.59(br s,2H),1.05(br s,2H).

[0271] Example 6 Synthesis of Compound 6

[0272] Step 1: Synthesis of compound int_6-1:

[0273] 1-Boc-4-piperidinic acid (169.51 mg, 739.32 μmol) was dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (324.36 mg, 853.07 μmol) and compound int_2-2 (263 mg, 568.71 μmol) were added. Finally, N,N-diisopropylethylamine (792.47 μL, 5.21 mmol) was added. The reaction mixture was stirred at 30°C for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The intermediate int_6-1 was then isolated and purified by silica gel chromatography.

[0274] LCMS m / z(ESI):674.2[M+H] + .

[0275] Step 2: Synthesis of compound int_6-2:

[0276] Compound int_6-1 (170 mg, 252.34 μmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (561 μL, 7.57 mmol). The reaction mixture was stirred at 30°C for 2 hours. N,N-diisopropylethylamine (2 mL) was slowly added to the reaction mixture at 0°C to adjust the pH to 8. The mixture was then concentrated to dryness under reduced pressure to obtain a crude yellow solid, compound int_6-2.

[0277] LCMS m / z(ESI):574.2[M+H] + .

[0278] Step 3: Synthesis of compound 6:

[0279] Compound int_6-2 (145 mg, 252.79 μmol) was dissolved in dichloromethane (6 mL), and N,N-diisopropylethylamine (132 μL, 758 μmol) was added. Acryloyl chloride (21 μL, 253 μmol) was then added at 0°C, and the reaction mixture was stirred at 30°C for 5 minutes. Saturated aqueous sodium carbonate (15 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography afforded compound 6 as a white solid.

[0280] LCMS m / z(ESI):628.2[M+H] + .

[0281] 1 H NMR(400MHz,DMSO-d6)δ7.98(t,J=5.4Hz,1H),7.79(d,J=2.8Hz,1H),7.35(s,1H),7.02-6.9 0(m,2H),6.85-6.75(m,1H),6.73-6.48(m,1H),6.20-6.01(m,1H),5.75-5.57(m,1H),5.10- 4.94(m,1H),4.67-4.51(m,2H),4.46-4.31(m,5H),4.09-3.93(m,3H),3.67-3.53(m,4H),3. 17-2.98(m,5H),2.77-2.65(m,1H),2.58-2.54(m,1H),1.81-1.56(m,2H),1.59-1.32(m,2H).

[0282] Example 7 Synthesis of Compound 7

[0283] Step 1: Synthesis of compound int_7-1:

[0284] 1-N-BOC-4-piperidinepropionic acid (67.03 mg, 260.48 μmol) was dissolved in N,N-dimethylformamide (3 mL). 2-(7-Azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (123.81 mg, 325.61 μmol) and compound int_1-9 (88 mg) were added, followed by N,N-diisopropylethylamine (113 μL, 651 μmol). The reaction mixture was stirred at 30°C for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting product was then purified by silica gel chromatography to obtain the intermediate int_7-1.

[0285] LCMS m / z(ESI):645.2[M+H] + .

[0286] Step 2: Synthesis of compound int_7-2:

[0287] Compound int_7-1 (120 mg, 186.13 μmol) was dissolved in dichloromethane (4 mL), followed by the addition of trifluoroacetic acid (413 μL, 5.58 mmol). The reaction mixture was stirred at 30°C for 2 hours. N,N-diisopropylethylamine (2 mL) was slowly added to the reaction mixture at 0°C to adjust the pH to 8. The mixture was then concentrated to dryness under reduced pressure to obtain a crude yellow solid, compound int_7-2.

[0288] LCMS m / z(ESI):545.2[M+H] + .

[0289] Step 3: Synthesis of compound 7:

[0290] Compound int_7-2 (100 mg, 183.62 μmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (160 μL, 918 μmol) was added. Acryloyl chloride (7 μL, 90 μmol) was then added at 0°C, and the reaction mixture was stirred at 30°C for 5 minutes. Saturated aqueous sodium carbonate (15 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography afforded compound 7 as a white solid.

[0291] LCMS m / z(ESI):599.2[M+H] + .

[0292] 1 H NMR (400MHz, DMSO-d6) δ7.79(d,J=2.8Hz,1H),7.35(s,1H),7.07-6.90(m,2H),6.85-6.77(m,1H),6.76-6.51( m,1H),6.20-6.01(m,1H),5.70-5.63(m,1H),5.12-4.93(m,1H),4.68-4.53(m,2H),4.48-4.31(m,5H),4.02(br d,J=13.7Hz,1H),3.69-3.55(m,4H),3.15-2.92(m,5H),2.43-2.35(m,3H),1.72(br d,J=12.5Hz,2H),1.58-1.39(m,3H),1.10-0.90(m,2H).

[0293] Example 8 Synthesis of Compound 11

[0294] Step 1: Synthesis of compound int_11-1:

[0295] Compound int_1-9 (80.0 mg, 197 μmol) and p-nitrophenylpropionic acid (46.2 mg, 237 μmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (51.0 mg, 395 μmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (90.0 mg, 237 μmol) were added. The reaction mixture was stirred at 25°C for 2 hours. Water (6 mL) was added to dilute the reaction mixture, and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then purified by silica gel chromatography to obtain the intermediate int_11-1.

[0296] LCMS m / z(ESI):583.1[M+H] + .

[0297] Step 2: Synthesis of compound int_11-2:

[0298] Compound int_11-1 (110 mg, 189 μmol) was dissolved in anhydrous ethanol (3 mL) and water (0.5 mL). Ammonium chloride (152 mg, 2.83 mmol) and iron powder (158 mg, 2.83 mmol) were added, and the reaction mixture was stirred at 60°C for 1 hour. After cooling, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Saturated aqueous sodium bicarbonate (6 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude yellow solid compound int_11-2.

[0299] LCMS m / z(ESI):553.1[M+H] + .

[0300] Step 3: Synthesis of compound 11:

[0301] Compound int_11-2 (100 mg, 181 μmol) was dissolved in anhydrous dichloromethane (2 mL), and N,N-diisopropylethylamine (56.1 mg, 434 μmol) was added. Acryloyl chloride (16.4 mg, 181 μmol) was then added at 0°C. The reaction mixture was stirred at 25°C for 0.2 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (6 mL), and the mixture was extracted with ethyl acetate (6 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The mixture was purified by preparative liquid chromatography to obtain compound 11 as a white solid.

[0302] LCMS m / z(ESI):607.2[M+H] + .

[0303] 1 H NMR(400MHz,DMSO-d6)δ10.08(br s,1H),7.83(br s,1H),7.57(d,J=8.3Hz,2H),7.36(s,1H),7.21(d,J=8.3Hz,2H),7.05-6.92(m,2H),6.87-6.53(m,1H),6.49-6.3 6(m,1H),6.32-6.19(m,1H),5.79-5.68(m,1H),5.11-4.94(m,1H),4.69-4.54(m,2H),4.47-4.34(m,4H),3.61(br s,4H),3.04(br s,4H),2.86-2.76(m,2H),2.71-2.62(m,2H).

[0304] Example 9 Synthesis of Compound 12

[0305] Step 1: Synthesis of compound int_12-1:

[0306] Compound int_1-9 (230 mg, 567.34 μmol) and 1-BOC-4-piperidinecarboxaldehyde (363.00 mg, 1.70 mmol) were dissolved in tetrahydrofuran (8 mL). Sodium acetate borohydride (1.20 g, 5.67 mmol) and triethylamine (790 μL, 5.67 mmol) were added. The reaction mixture was stirred at 30°C for 1 hour. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then purified by silica gel chromatography to obtain the intermediate int_12-1.

[0307] LCMS m / z(ESI):603.2[M+H] + .

[0308] Step 2: Synthesis of compound int_12-2:

[0309] Compound int_12-1 (200 mg, 331.86 μmol) was dissolved in dichloromethane (6 mL), followed by the addition of trifluoroacetic acid (737 μL, 9.96 mmol). The reaction mixture was stirred at 30°C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to obtain the crude product, int_12-2, as a yellow oil.

[0310] LCMS m / z(ESI):503.2[M+H] + .

[0311] Step 3: Synthesis of compound int_12-3:

[0312] Compound int_12-2 (140.38 mg, 994.91 μmol) and p-fluoronitrobenzene (100 mg, 198.98 μmol) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (1.00 g, 7.24 mmol) was added. The reaction mixture was stirred at 100°C for 1 hour. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then purified by silica gel chromatography to obtain the intermediate int_12-3.

[0313] LCMS m / z(ESI):624.2[M+H] + .

[0314] Step 4: Synthesis of compound int_12-4:

[0315] Compound int_12-3 (100 mg, 160.35 μmol) was dissolved in ethanol (5 mL) and water (1 mL), followed by the addition of iron powder (89.55 mg, 1.60 mmol) and ammonium chloride (85.77 mg, 1.60 mmol). The reaction mixture was stirred at 60°C for 1 hour. After cooling, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Saturated aqueous sodium carbonate (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude yellow solid compound int_12-4.

[0316] LCMS m / z(ESI):594.2[M+H] + .

[0317] Step 5: Synthesis of compound int_12-5:

[0318] Compound int_12-4 (50 mg, 84.22 μmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (74 μL, 421 μmol) was added. Acryloyl chloride (7 μL, 84.22 μmol) was then added at 0°C, and the reaction mixture was stirred at 30°C for 5 minutes. Saturated aqueous sodium carbonate solution (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography afforded compound 12 as a white solid.

[0319] LCMS m / z(ESI):648.2[M+H] + .

[0320] 1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.37(s,0.349H),7.77(br s,1H),7.50(br d,J=9.0Hz,2H),7.34(s,1H),7.06-6.84(m,4H),6.83-6.50(m,1H),6.48-6.39(m,1H),6.25-6.14(m,1H),5.68(br d,J=9.8Hz,1H),5.12-4.95(m,1H),4.68-4.52(m,2H),4.49-4.32(m,4H),3.62(br d,J=11.0Hz,2H),3.09(br s,4H),2.61-2.52(m,5H),2.60-2.30(m,3H),1.85-1.75(m,2H),1.70-1.60(m,1H),1.25-1.20(m,2H).

[0321] Example 10 Synthesis of Compound 15

[0322] Step 1: Synthesis of compound int_15-2:

[0323] N-Boc-piperazine (10 g, 53.69 mmol) and N,N-diisopropylethylamine (13.85 g, 107.38 mmol) were dissolved in tetrahydrofuran (200 ml), followed by the addition of methyl 4-chlorobutyrate (8.8 g, 64.43 mmol). The reaction mixture was heated to 60°C and stirred for 12 hours. After cooling to room temperature, the reaction mixture was poured into ice water (100 mL), and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by silica gel chromatography to obtain intermediate int_15-2.

[0324] 1 H NMR (400MHz, CDCl3) δ3.65 (s, 3H), 3.42–3.35 (m, 4H), 2.34 (td, J = 7.2, 3.1Hz, 8H), 1.79 (p, J = 7.3Hz, 2H), 1.68 (s, 2H), 1.44 (s, 9H).

[0325] Step 2: Synthesis of compound int_15-3:

[0326] Compound int_15-2 (1.7 g, 5.94 mmol) was dissolved in tetrahydrofuran (20 mL), followed by the addition of an aqueous solution (10 mL) of lithium hydroxide (1.42 g, 59.36 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove the tetrahydrofuran, and water (20 mL) was added. The mixture was extracted with dichloromethane (20 mL x 2). The aqueous phase was retained and the pH was adjusted to 5-6 with hydrochloric acid (0.1 N). The system was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound int_15-3 as a yellow solid.

[0327] Step 3: Synthesis of compound int_15-4:

[0328] Compounds int_1-9 (150 mg, 370 μmol) and int_15-3 (151.15 mg, 555 μmol) were dissolved in N,N-dimethylformamide (50 mL). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (168.72 mg, 444 μmol) and N,N-diisopropylethylamine (143.19 mg, 1.11 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 50 mL of ice water, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then purified by silica gel chromatography to obtain the intermediate int_15-4.

[0329] LCMS m / z(ESI):660.4[M+H] + .

[0330] Step 4: Synthesis of compound int_15-5:

[0331] Compound int_15-4 (110 mg, 166.73 μmol) was dissolved in dichloromethane (3 mL), and a solution of hydrogen chloride in dioxane (2 mL, 4 N) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to obtain a crude yellow solid compound int_15-5.

[0332] Step 5: Synthesis of compound 15:

[0333] Compound int_15-5 (80 mg) was dissolved in dichloromethane (5 mL), followed by the addition of N,N-diisopropylethylamine (36.88 mg, 285.9 μmol). The mixture was cooled to 0°C in an ice-water bath, and acryloyl chloride (14.23 mg, 157.25 μmol) was added. The ice-bath was removed and the mixture was stirred for 0.1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by preparative liquid chromatography to obtain compound 15 as a white solid.

[0334] LCMS m / z(ESI):614.3[M+H] + .

[0335] 1 H NMR (400MHz, DMSO-d6) δ7.82-783 (d, J=4.0Hz 1H), 7.26 (s, 1H), 6.95-6.97 (br d,J=8.0Hz,1H),6.87-6.90(dd,J=8.0Hz,2H),6.46-6.61(m,2H),6.26-6.30(m,1H),5.69-5.72(br d,J=12.0Hz,1H),4.85-4.95(m,1H),4.70-4.74(m,1H),4.51-4.56(br t,J=16.0Hz,1H),4.39-4.42(m,2H),4.33-4.35(m,2H),3.74-3.80(m,4H ),3.63-3.66(m,4H),3.08-3.13(m,4H),2.53-2.60(m,5H),2.42-2.45(br t,J=12.0Hz,2H),1.87-1.95(m,2H).

[0336] Example 11 Synthesis of Compound 16

[0337] Step 1: Synthesis of compound int_16-1:

[0338] Compound int_1-9 (200 mg) and p-aminoBoc-phenylacetaldehyde (139.25 mg, 0.592 mmol) were dissolved in a 1:1 mixture of dichloromethane and methanol (5 mL) at room temperature. Triethylamine (50.0 mg, 0.494 mmol) was added, and the reaction mixture was stirred at 25°C for 0.5 hours. Sodium cyanoborohydride (93.13 mg, 1.482 mmol) was then added, and stirring continued at 25°C for 2 hours. The reaction mixture was poured into ice water (8 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting mixture was then purified by silica gel chromatography to afford the intermediate int_16-1.

[0339] LCMS m / z(ESI):625.40[M+H] + .

[0340] Step 2: Synthesis of compound int_16-2:

[0341] Compound int_16-1 (220 mg, 0.55 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and a 1,4-dioxane solution of hydrogen chloride (4N, 3 mL) was added. The reaction mixture was stirred at 25°C for 2 hours and concentrated to dryness under reduced pressure to obtain crude compound int_16-2 as a yellow solid.

[0342] LCMS m / z(ESI):525.30[M+H] + .

[0343] Step 3: Synthesis of compound int_16-3:

[0344] Compound int_16-2 (150 mg) was dissolved in anhydrous dichloromethane (3 mL), and N,N-diisopropylethylamine (69.0 mg, 0.534 mmol) was added. Acryloyl chloride (24.2 mg, 0.267 mmol) was then added at 0°C. The reaction mixture was stirred at 25°C for 0.1 hour. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (6 mL), and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by silica gel chromatography to obtain compound 16.

[0345] LCMS m / z(ESI):579[M+H] + .

[0346] 1H NMR (400MHz, CDCl3) δ7.85(d,J=2.9Hz,1H),7.50(d,J=8.1Hz,2H),7.25(m,1H),7.19(d,J=8.3Hz,3H),6.95(d,J =8.9Hz,1H),6.89(dd,J=8.9,2.8Hz,1H),6.51–6.37(m,1H),6.22(dd,J=16.8,10.2Hz,1H),5.76(dd,J=10.2,1. 3Hz,1H),4.93(d,J=6.5Hz,1H),4.87(d,J=8.9Hz,1H),4.72(dd,J=9.3,4.0Hz,1H),4.52(t,J=9.3Hz,1H),4.43– 4.37(m,2H),4.36–4.30(m,2H),3.22(t,J=5.0Hz,4H),2.89–2.81(m,2H),2.80–2.73(m,4H),2.73–2.65(m,2H).

[0347] Example 12 Synthesis of Compound 27

[0348] Step 1: Synthesis of compound int_27-1:

[0349] Compound int_1-9 (600 mg) and 1-Boc-3-azetidinone (930 mg, 5.43 mmol) were dissolved in dichloromethane (25 mL), and sodium triacetoxyborohydride (1.15 g, 5.43 mmol) was added. The mixture was stirred at 25°C for 16 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by silica gel chromatography to obtain compound int_27-1.

[0350] LCMS m / z(ESI):561.3[M+H] + .

[0351] Step 2: Synthesis of compound int_27-2:

[0352] Compound int_27-1 (559 mg, 1.00 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred at 25°C for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 9. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain crude int_27-2 as a yellow oil.

[0353] LCMS m / z(ESI):461.0[M+H] + .

[0354] Step 3: Synthesis of compound int_27-3:

[0355] Compound int_27-2 (310 mg), p-fluoronitrobenzene (190 mg, 1.35 mmol), and anhydrous potassium carbonate (279 mg, 2.02 mmol) were dissolved in N,N-dimethylformamide (25 mL) and stirred at 100°C for 1 hour. The reaction solution was cooled and quenched with ice water (200 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by silica gel chromatography to obtain compound int_27-3.

[0356] LCMS m / z(ESI):582.1[M+H] + .

[0357] Step 4: Synthesis of compound int_27-4:

[0358] Compound int_27-3 (386 mg, 0.66 mmol), reduced iron powder (394 mg, 6.64 mmol), and ammonium chloride (355 mg, 6.64 mmol) were dissolved in ethanol and water (6:1, 100 mL) and stirred at 60°C for 2 hours. The reaction mixture was hot filtered through a pad of celite, rinsed with ethanol, and the filtrate was concentrated to dryness under reduced pressure. Saturated aqueous sodium bicarbonate was added to pH = 9, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound int_27-4 as a yellow solid.

[0359] LCMS m / z(ESI):551.8[M+H] + .

[0360] 1H NMR (400MHz, DMSO-d6) δ7.73(d,J=2.9Hz,1H),7.30(s,1H),6.96-6.84(m,2H),6.88-6.50(m,1H),6.47-6.40(m,2H),6.23-6.17(m,2 H),5.02-4.94(m,1H),4.62-4.49(m,2H),4.39-4.29(m,4H),3.78(t,J=6.8Hz,2H),3.39(t,J=6.3Hz,2H),3.20(m,5H),3.06(m,4H).

[0361] Step 5: Synthesis of compound int_27:

[0362] Compound int_27-4 (360 mg, 0.65 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (169 mg, 1.31 mmol) was added. The reaction solution was cooled to 0°C, and acryloyl chloride (59 mg, 0.65 mmol) was slowly added. The reaction solution was stirred at 0°C for 15 minutes. The reaction solution was quenched by the addition of saturated sodium bicarbonate aqueous solution (50 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by beating with ethyl acetate (20 mL) to obtain white compound 27.

[0363] LCMS m / z(ESI):605.8[M+H] + .

[0364] 1 H NMR (400MHz, DMSO-d6) δ9.84 (s, 1H), 7.73 (d, J = 2.9Hz, 1H), 7.47-7.41 (m, 2H), 7.31(s,1H),6.96-6.84(m,2H),6.78-6.50(m,1H),6.41-6.29(m,3H),6.15(dd, J=17.0,2.2Hz,1H),5.64(dd,J=10.1,2.2Hz,1H),4.96(m,1H),4.65-4.47(m,2H ),4.40-4.29(m,4H),3.88(m,2H),3.59-3.52(m,2H),3.25(m,5H),3.06(m,4H).

[0365] Example 13 Synthesis of Compound 28 and Compound 29

[0366] Step 1: Synthesis of compound int_28-1:

[0367] Compound int_1-9 (3.30 g) and 1-tert-butoxycarbonyl-3-pyrrolidone (2.07 g, 11.2 mmol) were dissolved in anhydrous methanol (100 mL). Triethylamine (776 mg, 7.47 mmol) and glacial acetic acid (45 mg, 0.75 mmol) were added, and the mixture was stirred at 40°C for 1 hour. Sodium cyanoborohydride (1.41 g, 22.41 mmol) was then added, and the mixture was stirred at 40°C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The mixture was then separated and purified by silica gel chromatography to obtain compound int_28-1.

[0368] LCMS m / z(ESI):575.3[M+H] + .

[0369] Step 2: Synthesis of compound int_28-2:

[0370] Compound int_28-1 (3.9 g, 6.79 mmol) was dissolved in dichloromethane (200 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred at 25°C for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction solution until the pH reached 9. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain crude compound int_28-2 as a yellow oil.

[0371] LCMS m / z(ESI):475.2[M+H] + .

[0372] Step 3: Synthesis of compound int_28-3:

[0373] Compound int_28-2 (3.2 g), p-fluoronitrobenzene (1.90 g, 13.49 mmol), and anhydrous potassium carbonate (2.80 g, 20.23 mmol) were dissolved in N,N-dimethylformamide (250 mL) and stirred at 100°C for 1 hour. After cooling, the reaction solution was added with water (2 L) and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by silica gel chromatography to obtain compound int_28-3.

[0374] LCMS m / z(ESI):596.2[M+H] +.

[0375] Step 4: Synthesis of compound int_28-4:

[0376] Compound int_28-3 (2 g, 3.36 mmol), reduced iron powder (1.88 g, 33.58 mmol), and ammonium chloride (1.80 g, 33.58 mmol) were dissolved in ethanol and water (6:1, 500 mL) and stirred at 60°C for 2 hours. The reaction mixture was hot filtered through a pad of Celite, rinsed with ethanol, and the filtrate was concentrated to dryness under reduced pressure. Saturated aqueous sodium bicarbonate was added to pH = 9, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound int_28-4 as a yellow solid.

[0377] LCMS m / z(ESI):566.20[M+H] + .

[0378] Step 5: Synthesis of compound int_28-5:

[0379] Compound int_28-4 (1.69 g, 2.75 mmol) was dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (709.71 mg, 5.49 mmol) was added. The reaction solution was cooled to 0°C, and acryloyl chloride (254 mg, 2.75 mmol) was slowly added. The reaction solution was stirred at 0°C for 0.5 hours. The reaction solution was quenched by the addition of saturated aqueous sodium bicarbonate (50 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by beating with ethyl acetate (20 mL) to obtain the white compound int_28-5.

[0380] LCMS m / z(ESI):620.3[M+H] + .

[0381] 1H NMR (400MHz, DMSO-d6) δ9.78 (s, 1H), 7.75 (d, J = 2.8Hz, 1H), 7.48-7.41 (m, 2H), 7.31 (s, 1H), 6.96-6.85 (m, 2H), 6. 79-6.52(m,1H),6.50-6.46(m,2H),6.35(dd,J=17.0,10.1Hz,1H),6.14(dd,J=17.0,2.2Hz,1H),5.63(dd,J=10.1, 2.2Hz,1H),5.00(m,1H),4.60(d,J=9.3Hz,1H),4.56-4.50(m,1H),4.40-4.29(m,4H),3.44(dd,J=9.0,7.1Hz,1H), 3.36-3.26(m,1H),3.18(m,1H),3.06(m,5H),2.94(m,1H),2.61(m,4H),2.17(dd,J=11.4,5.7Hz,1H),1.82(m,1H).

[0382] Step 6: Synthesis of Compound 28 and Compound 29:

[0383] Compound int_28-5 was subjected to chiral separation to give compound 28 (Rt=3.561 min) and compound 29 (Rt=5.252 min).

[0384] Chiral analysis method:

[0385] Instrument: Waters UPCC with PDA Detector and QDa Detector

[0386] Column: Chiralcel OJ-3, 100 × 4.6 mm ID, 3 μm

[0387] Mobile phase: A: Carbon dioxide B: Methanol (0.05% diethylamine)

[0388] Elution gradient: 40% B

[0389] Flow rate: 2.8 mL / min

[0390] Column temperature: 35°C

[0391] Back pressure: 1500psi

[0392] Detection wavelength: 254nm

[0393] Example 14 Synthesis of Compound 99

[0394] Compound int_27-4 (130 mg, 0.236 mmol) and 2-fluoroacrylic acid (32 mg, 0.353 mmol) were dissolved in N,N-dimethylacetamide (5 mL). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (134 mg, 0.353 mmol) and N,N-diisopropylethylamine (91 mg, 0.708 mmol) were added, and the reaction solution was stirred at 25°C for 2 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml × 3). The organic phases were combined and washed with saturated brine (20 ml × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The mixture was then slurried with N,N-dimethylformamide to obtain compound 99 as a yellow solid.

[0395] LCMS m / z(ESI):624.0[M+H] + .

[0396] 1 H NMR (400MHz, DMSO-d6) δ10.07-9.97(m,1H),7.77(d,J=2.8Hz,1H),7.54-7.46(m,2H) ,7.34(s,1H),6.98-6.89(m,2H),6.85-6.51(m,1H),6.47-6.38(m,2H),5.77-5.54(m ,1H),5.34(dd,J=15.7,3.5Hz,1H),5.09-4.94(m,1H),4.66-4.53(m,2H),4.43-4.35 (m, 4H), 3.93 (t, J = 7.1Hz, 2H), 3.61 (dd, J = 7.5, 5.4Hz, 2H), 3.32 (m, 5H), 3.11 (s, 4H).

[0397] Example 15 Synthesis of Compound 100

[0398] Compound int_27-4 (130 mg, 0.235 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of N,N-diisopropylethylamine (91 mg, 0.707 mmol). The mixture was cooled to 0°C in an ice-water bath, and methacryloyl chloride (25 mg, 0.235 mmol) was added and stirred for 1 hour. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (25 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The mixture was then purified by preparative liquid chromatography to afford Compound 100 as a white solid.

[0399] LCMS m / z(ESI):620.0[M+H] + .

[0400] 1 H NMR (400MHz, DMSO-d6) δ9.48(s,1H),7.77(d,J=2.8Hz,1H),7.45(d,J=8.3Hz,2H),7.34(s, 1H),6.98-6.89(m,2H),6.82-6.52(m,1H),6.40(d,J=8.3Hz,2H),5.74(s,1H),5.43(s,1H), 5.07-4.96(m,1H),4.64-4.54(m,2H),4.40(d,J=5.6Hz,2H),4.37(d,J=5.2Hz,2H),3.92(t, J=7.0Hz,2H),3.59(t,J=6.4Hz,2H),3.30(t,J=6.2Hz,5H),3.13-3.08(m,4H),1.93(s,3H).

[0401] Example 16 Synthesis of Compound 106

[0402] Step 1: Synthesis of compound int_106-1:

[0403] Intermediate int_1-7 (2.00 g, 5.00 mmol) was dissolved in anhydrous toluene (70 mL), and Lawesson's reagent (20.21 g, 49.98 mmol) was added. The reaction mixture was stirred at 130°C for 12 hours. The reaction mixture was concentrated to obtain a pale yellow crude product, which was then purified by silica gel chromatography to obtain compound int_106-1.

[0404] Step 2: Synthesis of compound int_106-2:

[0405] Compound int_106-1 (150 mg, 0.360 mmol) was dissolved in anhydrous toluene (8 mL). 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (45 mg, 0.109 mmol) and dichlorobis(4-methylisopropylphenyl)ruthenium(II) (67 mg, 0.109 mmol) were added. The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was concentrated to dryness to obtain a black crude product, which was then separated and purified by silica gel chromatography to obtain compound int_106-2.

[0406] Step 3: Synthesis of compound int_106-3:

[0407] Compound int_106-2 (450 mg, 1.08 mmol) was dissolved in 1,4-dioxane (10 mL). Tert-butyl piperazine-1-carboxylate (403 mg, 2.16 mmol), cesium carbonate (704 mg, 2.16 mmol), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (136 mg, 0.324 mmol) were added. The reaction mixture was stirred at 105°C for 16 hours. The reaction mixture was concentrated to dryness to obtain a brown crude product, which was separated and purified by silica gel chromatography to obtain compound int_106-3.

[0408] LCMS m / z(ESI):522.2[M+H] + .

[0409] Step 4: Synthesis of compound int_106-4:

[0410] Compound int_106-3 (375 mg, 0.72 mmol) was dissolved in dichloromethane (5 mL), and a solution of hydrogen chloride in dioxane (4 M, 5 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain a crude white solid compound int_106-4.

[0411] LCMS m / z(ESI):421.90[M+H] + .

[0412] Step 5: Synthesis of compound int_106-5:

[0413] Compound int_106-4 (312 mg) and 1-Boc-3-azetidinone (507 mg, 2.96 mmol) were dissolved in dichloromethane (25 mL), and sodium acetate borohydride (628 mg, 2.96 mmol) was added. The reaction solution was stirred at 25°C for 2 hours. Water (25 mL) was added to the reaction solution to quench it, and the mixture was extracted with dichloromethane (25 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The mixture was then separated and purified by silica gel chromatography to obtain compound int_106-5.

[0414] LCMS m / z(ESI):576.90[M+H] + .

[0415] Step 6: Synthesis of compound int_106-6:

[0416] Compound int_106-5 (290 mg, 0.506 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added dropwise, and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude white solid compound int_106-6.

[0417] LCMS m / z(ESI):476.90[M+H] + .

[0418] Step 7: Synthesis of compound int_106-7:

[0419] Compound int_106-6 (220 mg), p-fluoronitrobenzene (130 mg, 0.824 mmol), and potassium phosphate (197 mg, 1.428 mmol) were dissolved in NN-dimethylformamide (25 mL). The reaction solution was heated to 100°C and stirred for 2 hours. After cooling to room temperature, water (25 mL) was added and the mixture was extracted with ethyl acetate (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by silica gel chromatography to obtain compound int_106-7.

[0420] LCMS m / z(ESI):597.90[M+H] + .

[0421] Step 8: Synthesis of compound int_106-8:

[0422] Compound int_106-7 (240 mg, 0.402 mmol), reduced iron powder (224 mg, 4.02 mmol), and ammonium chloride (215 mg, 4.02 mmol) were mixed in water (2 mL) and ethanol (12 mL). The mixture was heated to 80°C and stirred for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude white solid compound int_106-8.

[0423] LCMS m / z(ESI):567.9[M+H] + .

[0424] Step 9: Synthesis of compound 106:

[0425] Compound int_106-8 (180 mg) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.5 mL) was added. Acryloyl chloride (29 mg, 0.322 mmol) was added dropwise with stirring at 0°C. The reaction solution was stirred at 25°C for 1 hour. Water (25 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by silica gel chromatography to obtain compound 106.

[0426] LCMS m / z(ESI):622.0[M+H] + .

[0427] 1 H NMR(400MHz, DMSO-d6)δ9.86(d,J=2.5Hz,1H),7.77(t,J=2.8Hz,1H),7.51-7.44(m,3H),6.99 -6.89(m,2H),6.73-6.34(m,4H),6.22-6.14(m,1H),5.77-5.64(m,1H),5.26(d,J=22.2Hz,1H),4.42- 4.33(m,4H),3.95-3.84(m,3H),3.62-3.50(m,3H),3.31-3.28(m,1H),3.10(s,4H),2.72-2.52(m,4H).

[0428] Example 17 Synthesis of Compound 95

[0429] Step 1: Synthesis of compound int_95-1:

[0430] Compound int_27-4 (400 mg), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (331 mg, 0.87 mmol), and cyanoacetic acid (68 mg, 0.80 mmol) were dissolved in N,N-dimethylformamide (30 mL). Diisopropylethylamine (281 mg, 2.18 mmol) was added, and the reaction solution was stirred at 25°C for 16 hours. Water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and then purified by slurrying with ethyl acetate (20 mL) to obtain compound int_95-1 as a white solid.

[0431] LCMS m / z(ESI):619.3[M+H] + .

[0432] Step 2: Synthesis of compound 95:

[0433] 2-Methyl-2-(methyl(oxetane-3-yl)amino)propanal (508 mg, 3.23 mmol) was dissolved in dichloromethane (30 mL). After replacing the atmosphere with nitrogen, the reaction solution was cooled to 0°C. Pyrrolidine (0.4 mL) and trimethylsilyl chloride (0.4 mL) were added, and the temperature was raised to 25°C with stirring for 1 hour. Compound int_95-1 (400 mg, 0.65 mmol) was then added, and stirring continued at 25°C for 1 hour. The reaction solution was quenched with water (30 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The mixture was then purified by preparative liquid chromatography to afford Compound 95 as a white solid.

[0434] LCMS m / z(ESI):758.4[M+H] + .

[0435] 1 H NMR (400MHz, DMSO-d6) δ9.90(s,1H),7.77(d,J=2.9Hz,1H),7.40(d,J=8.6Hz,2H),7.34(s,1H),7.30( s,1H),6.99-6.89(m,2H),6.83-6.52(m,1H),6.43(d,J=8.8Hz,2H),5.07-4.96(m,1H),4.67-4.59(m,3 H),4.56(dd,J=9.4,3.8Hz,1H),4.51(t,J=6.9Hz,2H),4.40–4.37(m,4H),4.19-4.09(m,1H),3.94(t, J=7.0Hz,2H),3.61(t,J=6.5Hz,2H),3.29(m,1H),3.11(s,4H),2.53(m,4H),2.33(s,3H),1.18(s,6H).

[0436] Example 18 Synthesis of Compound 96

[0437] Compound int_27-4 (200 mg), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (166 mg, 0.44 mmol), and trans-4-dimethylaminocrotonate hydrochloride (66 mg, 0.40 mmol) were dissolved in N,N-dimethylformamide (30 mL). Diisopropylethylamine (187.45 mg, 1.45 mmol) was added, and the mixture was stirred at 25°C for 16 hours. Water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was then slurried with ethyl acetate to obtain compound 96 as a white solid.

[0438] LCMS m / z(ESI):663.4[M+H] + .

[0439] 1 H NMR(400MHz,DMSO-d6)δ9.76(s,1H),7.79–7.69(m,1H),7.45–7.43(m,2H), 7.34–7.28(m,1H),6.96–6.84(m,2H),6.81–6.48(m,2H),6.42–6.33(m,2H) ,6.19(m,1H),4.98(m,1H),4.63–4.51(m,2H),4.34(m,4H),3.88(m,2H),3. 60–3.53(m,2H),3.26(m,2H),3.23-3.02(m,5H),2.52(m,4H),2.21(s,6H).

[0440] Using a similar synthesis method as in Examples 1-18 above, with different starting materials, the target compound 8-344 in Table 1 can be obtained.

[0441] Table 1

[0442] Table 2 NMR data of some compounds of the present invention

[0443] Biological Example 1 In vitro inhibition of PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ kinase activity by the compounds of the present invention

[0444] The ADP-Glo ​​Kinase Assay Kit was used according to the manufacturer's instructions. The following buffer solution was prepared: 50 mM HEPES, pH 7.5, 3 mM MgCl2, 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS, and 2 mM DTT. Test compound samples were dissolved in DMSO and diluted three-fold to a specific starting concentration, such as 10 μM, before being added to the screening system. A DMSO control and a no-kinase control were also established. Optimal concentrations of PI3Kα, PI3Kδ, PI3Kβ, and PI3Kγ enzymes, substrate (PIP2), and ATP were prepared using the buffer. The enzyme reaction system consisted of: buffer, 25 μM ATP, kinase substrate (PIP2, 50 μg / mL), and kinases PI3Kα (0.15 μg / mL), PI3Kδ (1.2 μg / mL), PI3Kβ (0.3 μg / mL), and PI3Kγ (2.5 μg / mL). The reaction system was reacted at room temperature for 1 hour. The reaction was terminated by adding the stop reagent (ADP-Glo ​​reagent, 5 μL) and the ADP content in the system was detected using the detection reagent (Kinase Detection Reagent, 10 μL). The signal data was collected using the Envision instrument. The inhibition rate was calculated according to the following formula: % inhibition rate = (DMSO control signal value - sample signal value) / (DMSO control signal value - no kinase added control signal value). Use Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)^HillSlope) formula is fitted into a curve to obtain IC 50 The results are shown in Table 3 below.

[0445] Table 3 Inhibitory activity of the compounds of the present invention on PI3K kinase (IC 50 , nM)

[0446] Biological Example 2 In vitro inhibition of HCC1954 cell proliferation by the compounds of the present invention

[0447] HCC1954 (PI3Kα H1047R mutation) cells were seeded in 384-well plates (Fisher 142762) with 2000 cells per well. A serial dilution of the compound was added on the second day. 144 hours after compound addition, the ATP content in the cells was measured using CellTiter-Lumi (Biyuntian C0068XL). Cell growth was evaluated and the IC50 of the compound for inhibiting cell growth was calculated. 50 The results are shown in Table 4 below.

[0448] Table 4 Inhibitory activity of the compounds of the present invention on HCC1954 cells (IC 50 ,nM) <50nM:++++ 50~100nM:+++ 100~1000nM:++ >1000nM:+

[0449] Biological Example 3 In vitro inhibition of MCF-7 cell proliferation by the compounds of the present invention

[0450] MCF-7 (PI3Kα E545K mutation) cells were seeded in 384-well plates (Fisher 142762) with 2000 cells per well. A serial dilution of the compound was added on the second day. 144 hours after the addition of the compound, the ATP content in the cells was measured by CellTiter-Lumi (Biyuntian C0068XL). Cell growth was evaluated and the IC value of the compound for inhibiting cell growth was calculated. 50 The results are shown in Table 5 below.

[0451] Table 5 Inhibitory activity of the compounds of the present invention on MCF-7 cells (IC 50 ,nM) <50nM:++++ 50~100nM:+++ 100~1000nM:++ >1000nM:+

[0452] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: In the general formula (1): CLM is a group that can covalently bind to the PI3Kα protein; L is a group connecting CLM and the three-ring structure; R1 and R2 are independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, carbamoyl, mercapto, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, -(CH2) nl R a 、-(CH2) nl OR a or -(CH2) nl NR a R b wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amino, carbamoyl, mercapto, hydroxy, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally further selected from deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylhaloalkyl, halogen, substituted or unsubstituted cycloalkylamino, mercapto, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkylalkoxy, substituted or unsubstituted cycloalkylhaloalkoxy, substituted or unsubstituted cycloalkylhydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, -(CH2) nl R c 、-(CH2) nl OR c and -(CH2) nl NR c R d is substituted by one or more substituents; Alternatively, any two adjacent or non-adjacent R2 form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; R a 、R b 、R c and R d each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, carbamoyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; R3 is H, halogen, (C1-C3) alkyl or cyclopropyl; R4 is a 4-6 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, a phenyl group or a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from N, S and O, wherein the 4-6 membered heterocycloalkyl, phenyl group or 5-6 membered heteroaryl group is optionally further selected from deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, is substituted by one or more substituents selected from heterocycloalkyl, oxoheterocycloalkyl, thioheterocycloalkyl, oxo and thio; and n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; n1 is 0, 1, 2 or 3.

2. The compound according to claim 1 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the general formula (1) has a structure as shown in the general formula (2): wherein CLM, L, R1, R2, R3, R4, m and n are as defined in claim 1.

3. The compound according to claim 1 or 2, or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) or (2), CLM is a group comprising a carbon-carbon double bond or a carbon-carbon triple bond that can covalently bind to a cysteine ​​residue (Cys) in the PI3Kα protein.

4. The compound according to claim 3 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) or (2), CLM is -NHCN, -CN, R e is H, substituted or unsubstituted (C1-C6) alkyl, or substituted or unsubstituted (C3-C6) cycloalkyl; R f 、R g and R h are each independently H, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -(CH2) w R, -(CH2) w OR, -(CH2) w N(R)2, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from N, S and O; or R e and R f 、R f and R g 、R g and R h 、R e and R h It may form a substituted or unsubstituted 4- to 7-membered saturated or partially unsaturated ring containing 0 to 2 heteroatoms independently selected from N, S and O; wherein two hydrogen atoms on the same carbon of the 4- to 7-membered saturated or partially unsaturated ring may be replaced by oxygen to form an oxo group; Each R is independently H, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated heterocycloalkane containing 1-2 heteroatoms independently selected from N, S and O substituted or unsubstituted 5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, S and O; w is 0, 1, or 2.

5. The compound according to claim 4 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) or (2), CLM is -NHCN, -CN, CLM is preferably -NHCN, -CN, CLM is more preferably 6. The compound according to any one of claims 1 to 5 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) or (2), L is wherein L1, L2, L3, L4, and L5 are independently selected from a chemical bond, O, S, NH, C(=O), C(=O)NH, S(=O), S(=O)2, (C1-C6)alkylene, -(C1-C6)alkylene-O-, (C2-C3)alkenylene, (C2-C3)alkynylene, (C3-C10)cycloalkylene, phenylene, a 5-11 membered cyclyl group, a 3-10 membered saturated or partially alkylene group containing 1-4 heteroatoms independently selected from N, S, and O unsaturated heterocycloalkylene, 7-11 membered heterospirocyclic group, 5-11 membered heterobridged cyclic group or 5-9 membered heteroarylene, the (C1-C6)alkylene, -(C1-C6)alkylene-O-, (C2-C3)alkenylene, (C2-C3)alkynylene, (C3-C10)cycloalkylene, 3-10 membered saturated or partially unsaturated heterocycloalkylene, phenylene, 7-11 membered heterospirocyclic group, 5-11 membered heterobridged cyclic group or 5-9 membered heteroarylene are optionally substituted by 1, 2 or 3 R L replace; Each R L are independently selected from H, halogen, OH, NH2, CN, -CONH2, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkyl-C(=O)-, (C1-C6) alkoxy, (C1-C6) alkylthio or (C1-C6) alkylamino, wherein the (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkyl-C(=O)-, (C1-C6) alkoxy, (C1-C6) alkylthio or (C1-C6) alkylamino is optionally substituted by 1, 2 or 3 R LL replace; Each R LL Each is independently selected from H, halogen, (C1-C6) alkyl, OH, NH2, MeNH-, Me2N-, CH3, CH2F, CHF2 or CF3; wherein * indicates connection with CLM.

7. The compound according to claim 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) or (2), each L1, L2, L3, L4, and L5 are independently a chemical bond, O, S, NH, C(=O), C(=O)NH, S(=O), S(=O)2, CH2, 8. The compound according to claim 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) or (2), L1 is a chemical bond, (C2-C3) alkenylene, (C2-C3) alkynylene, (C3-C10) cycloalkylene, 3-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocyclylene, 5-11 membered heterobridged cyclylene, said (C2-C3) alkenylene, (C2-C3) alkynylene, (C3-C10) cycloalkylene, 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene or 5-11 membered heterobridged cyclylene being optionally substituted by 1, 2 or 3 R L replace; L2 is a chemical bond, C(=O), C(=O)NH, (C1-C6)alkylene, or -(C1-C6)alkylene-O-; L3 is a chemical bond, a 3-10 membered saturated or partially unsaturated heterocycloalkylene group containing 1 to 4 heteroatoms independently selected from N, S and O, a 7-11 membered heterospirocyclic group, or a 5-11 membered heterobridged cyclic group, wherein the 3-10 membered saturated or partially unsaturated heterocycloalkylene group, the 7-11 membered heterospirocyclic group or the 5-11 membered heterobridged cyclic group is optionally substituted by 1, 2 or 3 R L replace; L4 is a chemical bond, C(=O), C(=O)NH, (C1-C6)alkylene, or -(C1-C6)alkylene-O-; L5 is phenylene, 5-9 membered heteroarylene, 3-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocyclic group, 5-11 membered heterobridged ring group, and the phenylene, 5-9 membered heteroarylene, 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclic group or 5-11 membered heterobridged ring group is optionally substituted by 1, 2 or 3 R L replace.

9. The compound according to claim 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) or (2), L1 is a 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene containing 1-4 heteroatoms independently selected from N, S, and O, wherein the 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene is optionally substituted by 1, 2, or 3 R L replace; L2 is a chemical bond; L3 is a 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene containing 1-4 heteroatoms independently selected from N, S, and O, wherein the 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene is optionally substituted by 1, 2, or 3 R L replace; L4 is a chemical bond; L5 is phenylene, 5-9 membered heteroaryl, 3-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the phenylene, 5-9 membered heteroaryl, 3-10 membered saturated or partially unsaturated heterocycloalkylene is optionally substituted by 1, 2 or 3 R L replace.

10. The compound according to claim 6 or 7 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) or (2), the structural unit Selected from * indicates connection to CLM.

11. The compound according to any one of claims 1 to 10, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1) or general formula (2), each R1 and R2 are independently selected from H, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, amino, carbamoyl, -(CH2) nl R a 、-(CH2) nl OR a and -(CH2) nl NR a R b wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amino and carbamoyl groups are optionally further selected from deuterium, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkylhaloalkyl, halogen, substituted or unsubstituted cycloalkylamino, mercapto, oxo, cyano, hydroxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, -(CH2) nl R c 、-(CH2) nl OR c and -(CH2) nl NR c R d is substituted by one or more substituents; Alternatively, any two adjacent or non-adjacent R2 groups are linked to form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group and the heterocycloalkyl group are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo and hydroxy; R a 、R b 、R c and R d are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, hydroxy, amino, carbamoyl, cycloalkyl or heterocycloalkyl, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, cycloalkyl and heterocycloalkyl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl; R3 is H, halogen, cyclopropyl or CH3; R4 is a 4- to 6-membered saturated heterocycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S, and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, S, and O, wherein the 4- to 6-membered saturated heterocycloalkyl group, the phenyl group, or the 5- to 6-membered heteroaryl group is optionally further substituted with one or more substituents selected from deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, oxoheterocycloalkyl, thioheterocycloalkyl, oxo, or thio; and n is 0, 1, or 2; m is 0, 1, or 2; n1 is 0 or 1.

12. The compound according to claim 11 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) or (2), each R1 and R2 are independently selected from H, deuterium, methyl, deuterated methyl, haloalkyl, methoxy, hydroxy, halomethoxy, F, Cl, amino, carbamoyl, Or when m is 2, two R2 connected to the same carbon atom may form a cyclopropyl group.

13. The compound according to claim 11 or 12, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) or (2), R3 is H, F, Cl, cyclopropyl or CH3.

14. The compound according to claim 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the general formula (1) or (2) has a structure as shown in the general formula (3): in, L1 is a 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene containing 1-4 heteroatoms independently selected from N, S, and O, wherein the 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene is optionally substituted by 1, 2, or 3 R L replace; L3 is a 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene containing 1-4 heteroatoms independently selected from N, S, and O, wherein the 3-10 membered saturated or partially unsaturated heterocycloalkylene, 7-11 membered heterospirocyclylene, or 5-11 membered heterobridged cyclylene is optionally substituted by 1, 2, or 3 R L replace; L5 is phenylene, 5-9 membered heteroaryl, 3-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the phenylene, 5-9 membered heteroaryl, 3-10 membered saturated or partially unsaturated heterocycloalkylene is optionally substituted by 1, 2 or 3 R L replace; Each R L Independently selected from H, F, Cl, hydroxy, amino, cyano, amide, methyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, methylamino, dimethylamino; CLM is R1 is independently selected from hydrogen, deuterium, (C1-C3) alkyl, (C1-C3) deuterated alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, amino, methylamino, hydroxy, cyano, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, n is 0, 1 or 2; R3 is H, halogen, (C1-C3) alkyl or cyclopropyl; R4 is a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S and O, a phenyl group, or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the 4- to 6-membered heterocycloalkyl group, the phenyl group or the 5- to 6-membered heteroaryl group is optionally further substituted by one or more substituents selected from deuterium, (C1-C3) alkyl, (C1-C3) deuterated alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, amino, nitro, hydroxy, cyano, (C3-C6) cycloalkyl, (3-6-membered) heterocycloalkyl, (3-6-membered) oxoheterocycloalkyl, (3-6-membered)thioheterocycloalkyl, oxo and thioxo.

15. The compound according to claim 14 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), L1 is a 4-10 membered saturated or partially unsaturated heterocycloalkylene group or a 5-11 membered heterobridged cyclic group containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the 4-10 membered saturated or partially unsaturated heterocycloalkylene group or the 5-11 membered heterobridged cyclic group is optionally substituted by 1, 2 or 3 R L Substituted; L1 is preferably More preferably L3 is a 4-10 membered saturated or partially unsaturated heterocycloalkylene group or a 5-11 membered heterobridged cyclic group containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the 4-10 membered saturated or partially unsaturated heterocycloalkylene group or the 5-11 membered heterobridged cyclic group is optionally substituted by 1, 2 or 3 R L Substituted; L3 is preferably More preferably L5 is phenylene, 5-6 membered heteroaryl, 4-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the phenylene, 5-6 membered heteroaryl, 4-10 membered saturated or partially unsaturated heterocycloalkylene is optionally substituted by 1, 2 or 3 R L Substituted; L5 is preferably CLM is R e is H or Me; R f is H, F, Me or CN; R g and R h are each independently H, halogen, -CN, -(CH2) w R, -(CH2) w OR, -(CH2) w N(R)2, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted heteroatoms containing 1 to 2 independently selected from N, S and O The 3-7 membered saturated or partially unsaturated heterocyclic alkyl group, the substituted or unsubstituted (C1-C6) alkyl group is preferably The substituted or unsubstituted (C3-C6) cycloalkyl group is preferably Each R is independently H, (C1-C6) alkyl, (C3-C6) cycloalkyl, 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocycloalkyl or 5-11 membered heterobridged cycloalkyl, wherein the (C1-C6) alkyl, (C3-C6) cycloalkyl, 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocycloalkyl or 5-11 membered heterobridged cycloalkyl The 1-membered heterobridged cycloalkyl group is optionally further substituted by one or more substituents selected from deuterium, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, a 3-7 membered saturated or partially unsaturated heterocycloalkyl group containing 1-2 heteroatoms independently selected from N, S and O, a 7-11 membered heterospirocyclic group, a 5-11 membered heterobridged cyclic group, an oxo group, -C(O)Me, -C(O)OMe, -C(O)OBu-t, -F, Cl, -OH, and -NH2; w is 0, 1 or 2; R1 is independently selected from hydrogen, deuterium, -Me, -OMe, -OCD3, -CD3, -CHF2, -CF3, F, Cl, -NH2, -NHMe, hydroxy, cyano, cyclopropyl, n is 0, 1 or 2; R3 is H, F, Cl, -Me or cyclopropyl; R4 is a 5-membered heterocycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S and O, or a 5-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N, S and O, wherein the 5-membered heterocycloalkyl group or the 5-membered heteroaryl group is optionally further substituted by one or more substituents selected from deuterium, (C1-C3) alkyl, (C1-C3) deuterated alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, amino, nitro, hydroxy, cyano, (C3-C6) cycloalkyl, (3-6-membered) heterocycloalkyl, (3-6-membered) oxoheterocycloalkyl, (3-6-membered)thioheterocycloalkyl, oxo and thioxo.

16. The compound according to claim 14 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), L1 is a 4-10 membered saturated or partially unsaturated heterocycloalkylene group or a 5-11 membered heterobridged cyclic group containing 1 to 4 heteroatoms independently selected from N, S and O, wherein the 4-10 membered saturated or partially unsaturated heterocycloalkylene group or the 5-11 membered heterobridged cyclic group is optionally substituted by 1, 2 or 3 R L L1 is preferably a 4-7 membered saturated or partially unsaturated heterocycloalkylene containing 1-2 N atoms, a 6-9 membered hetero-bridged cyclic group containing 1-2 N atoms, the 4-7 membered saturated or partially unsaturated heterocycloalkylene or 6-9 membered hetero-bridged cyclic group optionally substituted by 1-2 R L Substituted; L1 is preferably L3 is a 4-10 membered saturated or partially unsaturated heterocycloalkylene containing 1 to 4 heteroatoms independently selected from N, S and O, a 5-11 membered Heterobridged ring group, the 4-10 membered saturated or partially unsaturated heterocycloalkylene group, the 5-11 membered heterobridged ring group is optionally substituted by 1, 2 or 3 R L L3 is preferably a 4-7 membered saturated or partially unsaturated heterocycloalkylene containing 1-2 N atoms, a 6-9 membered hetero-bridged cyclic group containing 1-2 N atoms, the 4-7 membered saturated or partially unsaturated heterocycloalkylene or 6-9 membered hetero-bridged cyclic group optionally substituted by 1-2 R L Substituted; L3 is preferably L5 is phenylene, 5-6 membered heteroarylene containing 1-2 heteroatoms independently selected from N, S and O, 4-10 membered saturated or partially unsaturated heterocycloalkylene containing 1-4 heteroatoms independently selected from N, S and O, and the phenylene, 5-6 membered heteroarylene, 4-10 membered saturated or partially unsaturated heterocycloalkylene is optionally substituted by 1, 2 or 3 R L L5 is preferably phenylene, 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, S and O, 8-10 membered partially unsaturated bicyclic heterocycloalkylene containing 1-3 heteroatoms independently selected from N, S and O, the phenylene, 5-6 membered heteroaryl, 8-10 membered partially unsaturated bicyclic heterocycloalkylene may be optionally substituted by 1-2 R L Substituted; L5 is preferably Each R L Independently selected from H, F, Cl, hydroxy, amino, cyano, amide, methyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, methylamino, dimethylamino; CLM is R e is H or Me; R f is H, F, Me or CN; R g and R h are each independently H, halogen, -CN, -(CH2) w R, -(CH2) w OR, -(CH2) w N(R)2, substituted or unsubstituted (C1-C6)alkyl, substituted or unsubstituted (C3-C6)cycloalkyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, wherein the substituted or unsubstituted (C1-C6)alkyl is preferably The substituted or unsubstituted (C3-C6) cycloalkyl group is preferably Each R is independently H, -C(O)R m 、-C(O)OR m 、-S(O)2R m 、-CH2OC(O)R n 、 R m and R n Each of them is independently H, (C1-C18) alkyl, (C3-C6) cycloalkyl, 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocycloalkyl or 5-11 membered heterobridged cycloalkyl, wherein the (C1-C18) alkyl, (C3-C6) cycloalkyl, 3-7 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, 7-11 membered heterospirocycloalkyl or 5-11 membered heterobridged cycloalkyl The 1-membered heterobridged cycloalkyl group is optionally further substituted by one or more substituents selected from deuterium, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, a 3-7 membered saturated or partially unsaturated heterocycloalkyl group containing 1-2 heteroatoms independently selected from N, S and O, a 7-11 membered heterospirocyclic group, a 5-11 membered heterobridged cyclic group, an oxo group, -C(O)Me, -C(O)OMe, -C(O)OBu-t, -F, Cl, -OH, -NH2; R m and R n Each is independently preferably H, methyl, ethyl, tert-butyl, isopropyl, cyclopropyl or cyclobutyl; w is 0, 1 or 2; R1 is independently selected from H, -D, -Me, -OMe, -OCD3, -CD3, -CHF2, -CF3, F, Cl, -NH2, -NHMe, -OH, -CN, cyclopropyl, n is 0, 1 or 2; R3 is H, F, Cl, -Me or cyclopropyl; R4 is a 5-membered heterocycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S and O, or a 5-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N, S and O, wherein the 5-membered heterocycloalkyl group or the 5-membered heteroaryl group is optionally further selected from deuterium, (C1-C3) alkyl, (C1-C3) deuterated alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, amino, nitro, hydroxy, cyano, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, (3-6 membered) oxoheterocycloalkyl, R4 is preferably substituted by one or more substituents selected from -D, -Me, -CD3, -CH2F, -CHF2, -CF3, -OMe, -OCD3, oxo and thioxo; R4 is preferably a 5-membered heterocycloalkyl containing 1 N atom, a 5-membered heterocycloalkyl containing 1 N and 1 S or O, or a 5-membered heteroaryl containing 1, 2 or 3 independently selected from N, S or O, wherein the 5-membered heterocycloalkyl or 5-membered heteroaryl is optionally further substituted by 1 or 2 substituents independently selected from -D, -Me, -CD3, -CH2F, -CHF2, -CF3, -OMe, -OCD3, oxo and thioxo.

17. The compound according to any one of claims 1 to 16, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), general formula (2) or general formula (3), R4 is selected from 18. The compound according to any one of claims 1 to 17, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:

18. A pharmaceutical composition, characterized in that It contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1 to 17 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

19. Use of the compound according to any one of claims 1 to 17 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to claim 18 in the preparation of a drug for treating diseases associated with PI3Kα.

20. The use according to claim 19, wherein the disease is cancer, and the cancer is a blood cancer and a solid tumor.

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