PI3kα modulator

Abstract

Disclosed in the present invention is a PI3Kα modulator. Specifically, the present invention relates to a compound represented by general formula (1), a preparation method therefor, and the use of the compound represented by general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof in the preparation of drugs for treating or preventing related diseases involving PI3Kα.

Description

PI3Kα regulator

[0001] This application claims priority to Chinese patent application 2024118018357, filed on December 9, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of medicinal chemistry, and more specifically, relates to a new class of compounds with inhibitory and degradative effects on phosphatidylinositol 3-kinase alpha (PI3Kα), their preparation methods, and the use of such compounds in the preparation of drugs for PI3Kα-related diseases, including but not limited to tumors and non-tumor diseases such as vascular abnormalities. Background Technology

[0003] The phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt / PKB)-mammalian target of rapamycin (mTOR) pathway is an important signaling pathway in mammals, closely related to cell proliferation, survival, and angiogenesis. The PI3K protein family is divided into four major classes: I, II, III, and IV, each with distinct structures and functions. Class I PI3K is further divided into four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. Among these, PI3Kα undergoes activating mutations and amplification in tumors and certain genetic diseases, and is closely related to the occurrence and development of these diseases.

[0004] PI3Kα consists of the catalytic subunit p110α and the regulatory subunit p85. PI3Kα is activated by receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs). Upon activation, it catalyzes the conversion of phosphatidylinositol 2-phosphate (PIP2) to phosphatidylinositol 3-phosphate (PIP3). PIP3 then recruits and activates various protein kinases, including PDK and AKT, thereby activating downstream signaling pathways.

[0005] Cancer genome sequencing results have revealed the important role of PI3Kα in cancer occurrence and development. PIK3CA, encoding 110α, is the second most frequently mutated gene, with a mutation frequency of 13% [Cancer Biol Ther, 2004.3(8):p.772-5]. Mutations in PI3Kα are mainly concentrated in the helical region and kinase domain of the catalytic subunit p110α, including E542 / 545K and H1047R / L mutations, also known as PI3Kα hotspot mutations. In addition to cancer, PI3Kα hotspot mutations are also present in PI3CA-related disorder, characterized by abnormal blood vessels and abnormal tissue proliferation [Gene Reviews ((R)), MP Adam, et al., Editors. 1993: Seattle (WA)]. These hotspot mutations lead to abnormal activation of PI3Kα. In addition, PI3Kα amplification is also present in various tumors, participating in tumor occurrence and development.

[0006] PI3Kα inhibitors are clinically used to treat advanced or metastatic breast cancer carrying PI3Kα gene mutations. However, existing drugs cannot efficiently and sustainably inhibit PI3Kα, and severe toxic side effects limit their dosage and frequency of administration [Cancer Discov, 2019.9(4):p.482-491]. Studies have shown that a significant portion of toxic side effects stem from the non-selective effects of drugs on different PI3K subtypes. For example, inhibition of PI3Kβ leads to hyperglycemia and thrombocytopenia, inhibition of PI3Kδ leads to elevated transaminases, enteritis, and bone marrow suppression, and inhibition of PI3Kγ leads to hypertension. Improving the selectivity of drugs for PI3Kα and sustaining PI3Kα inhibition is an important goal in the development of PI3Kα inhibitors. The FDA-approved PI3Kα inhibitor alpelisib failed to sustain PI3Kα inhibition in clinical trials, exhibiting only a 6-fold selectivity for PI3Kδ, and 78.5% of patients required discontinuation or dose reduction due to toxic side effects [multiple disciplinary review 212526Orig1s000 2016]. Therefore, developing a new generation of highly effective and selective PI3Kα inhibitors has significant clinical application value. Summary of the Invention

[0007] This invention provides a novel class of PI3Kα inhibitors that exhibit high selectivity for other isoforms such as PI3Kβ, PI3Kδ, and PI3Kγ, with a safety window significantly superior to existing drugs. Surprisingly, in addition to inhibiting kinase function, these compounds also induce ubiquitination and degradation of the PI3Kα protein, thus demonstrating a stronger and more sustained inhibitory effect.

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

[0009] A compound of general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0010] in:

[0011] PTM (PI3Ka targeting moiety) is a group that targets and binds to the PI3Kα protein;

[0012] Ring A is a substituted or unsubstituted 5- to 9-membered saturated or partially unsaturated heterocyclic alkyl group or a substituted or unsubstituted 5- to 9-membered heteroaryl group;

[0013] L is a group that connects PTM and ring A.

[0014] In another preferred embodiment, wherein in the general formula (1), PTM is

[0015] in:

[0016] X is either O or S;

[0017] X1 is N or CR X1 ;

[0018] X2 is N or CR X2 ;

[0019] X3 is N or CR X3 ;

[0020] R X1 R X2 R X3 R2 is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, carbamoyl, mercapto, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and oxoyl.

[0021] Alternatively, any two adjacent or non-adjacent R2s may together with all the atoms between them to form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group may optionally be 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 alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

[0022] R3 is H, deuterium, halogen, (C1-C3) alkyl, or (C3-C6) cycloalkyl;

[0023] R4 is a 4- to 6-membered heterocyclic alkyl, phenyl, or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms independently selected from N, S, and O, wherein the 4- to 6-membered heterocyclic alkyl, phenyl, or 5- to 6-membered heteroaryl is optionally further substituted by one or more substituents selected from deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic alkyl, oxoheterocyclic alkyl, thioheterocyclic alkyl, oxo, and thio.

[0024] m can be 0, 1, 2, 3, or 4.

[0025] In another preferred embodiment, in the general formula (1), A is

[0026] in,

[0027] Z can be NR8, O, or S independently;

[0028] m can be 0, 1, 2, 3, or 4;

[0029] R5 and R6 are each independently selected from halogens, H, deuterium, substituted or unsubstituted (C1-C6) alkyl, phenyl or heteroaryl groups, or R5 and R6 together with the commonly linked atoms form (C3-C6) cycloalkyl, 3- to 10-membered saturated or partially unsaturated heterocycloalkyl, 7- to 11-membered heterospirocycloalkyl, or 5- to 11-membered heterobridged cycloalkyl.

[0030] R7 and R8 are independently selected from H, (C1-C6)alkyl, (C3-C12)cycloalkyl, (C1-C6)alkoxy, -OH, and -OR. k -SR k -C(S)SR k -C(S)OR k -NR k R l -CN, -C(O)R k -C(O)OR k -S(O)2R k -S(O)R k -CH2OC(O)R k -CH2OC(O)OR k -C(S)R k -C(S)OR k -C(O)SR k -C(O)NR k Rl -C(S)NR k R l -C(O)ONR k R l -(C1-C6)alkyl-OR k -(C1-C6)alkyl NR k R l -S(O)2NR k R l The (C1-C6) alkyl, (C3-C12) cycloalkyl, (C1-C6) alkoxy, 3-12 saturated or partially unsaturated heterocyclic alkyl, 7-12 heterospirocyclic alkyl or 5-12 heterobridged cycloalkyl, 6-10 aryl, 5-15 heteroaryl, wherein the (C1-C6) alkyl, (C3-C12) cycloalkyl, (C1-C6) alkoxy, 3-12 saturated or partially unsaturated heterocyclic alkyl, 7-12 heterospirocyclic alkyl or 5-12 heterobridged cycloalkyl, 6-10 aryl, 5-15 heteroaryl are optionally further surrounded by 1, 2, 3, 4 or 5 R's. m Substitution; two hydrogen atoms on the same carbon atom can be replaced by oxygen to form an oxo group or by... The replaced, or two Rs m Together with the atoms between the two, they form substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted 3- to 10-membered saturated or partially unsaturated heterocycloalkyl, substituted or unsubstituted 7- to 11-membered heterospirocycloalkyl, and substituted or unsubstituted 5- to 11-membered heterobridged cycloalkyl.

[0031] Alternatively, R6 and R7 together with the atoms between them can form substituted or unsubstituted 4- to 10-membered saturated or partially unsaturated heterocyclic alkyl groups, 7- to 11-membered heterospirocyclic groups, or 5- to 11-membered heterobridged cyclic groups.

[0032] Alternatively, an R5 and R7 together with the atoms between them can form a substituted or unsubstituted 4- to 10-membered saturated or partially unsaturated heterocyclic alkyl, 7- to 11-membered heterospirocyclic, or 5- to 11-membered heterobridged cyclic group.

[0033] Alternatively, an R7 and a Z together with the atoms between them can form a substituted or unsubstituted 4- to 10-membered partially unsaturated heterocyclic alkyl group, a 7- to 11-membered heterospirocyclic group, or a 5- to 11-membered heterobridged cyclic group;

[0034] R k and R lEach of the following is independently H, -C(O)R, -C(O)OR, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C12)cycloalkyl, 3- to 12-membered saturated or partially unsaturated heterocyclic alkyl, 7- to 12-membered heterospirocycloalkyl or 5- to 12-membered heterobridged cycloalkyl, phenyl, 5- to 12-membered heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C12)cycloalkyl, 3- to 12-membered saturated or partially unsaturated heterocyclic alkyl, 7- to 12-membered heterospirocycloalkyl or 5- to 12-membered heterobridged cycloalkyl, phenyl, 5- to 12-membered heteroaryl is optionally further surrounded by 1, 2, 3, 4 or 5 Rs. m Substitution; two hydrogen atoms on the same carbon atom can be replaced by oxygen to form an oxo group or by... Replaced;

[0035] Or R k and R l Together with the atoms that are connected together, they form substituted or unsubstituted 3- to 10-membered saturated or partially unsaturated heterocyclic alkyl groups, substituted or unsubstituted 7- to 11-membered heterospirocyclic groups, and substituted or unsubstituted 5- to 11-membered heterobridged cyclic groups;

[0036] R a and R b Each is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cycloalkyl, or heterocycloalkyl; or R a and R b Together with the atoms they are connected to, they form 3- to 10-membered cycloalkyl or heterocycloalkyl groups;

[0037] R mSelected from deuterium, H, halogen, OH, SH, NH2, -CN, -NC, -NCS, -N3, NO2, -CONH2, (C1-C6)alkyl, (C1-C6)alkyl-(C3-C6)cycloalkyl, (C1-C6)alkyl-(C3-C6)heterocyclicalkyl, (C1-C6)haloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, -N=S(O)(R)2, -S(O)=(NH)R, -SCN, -S(O)2CN, -SNC, -S(O)2NC, -S(O)2N(R)2, -SF5, -P(O)(R)2, -P(S)(R)2, -P(O)( OR)R, -P(O)(OR)2, -N(R)2, -N(R)OR, -C(O)NR(OR), -C(O)NRCN, -SR, -B(OR)2, -B(R)2, -BH(OR), -SeR, -SeCN, -NCSe, -Si(R)3, -Si(OR)3, -SiR( OR)2, -Si(R)2(OR), -C(O)R, -C(O)OR, -C(O)CH2R, -S(O)2R, -S(O)R, -CH2OC(O)R, -CH2OC(O)OR, -C(S)R, -C(S)OR, -C(O)SR, -C(O)N(R)2, -(CH2) 1～3 OR, -(CH2) 1～3 N(R)2、-(CH2) 1～3 S(O)R、-(CH2) 1～3 S(O)2R、-(CH2) 1～3NS(O)(R)2, -OC(O)R, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamine, -NHC(O)OR, -NHC(O)N(R)2, -NHC(O)R, -NRS(O)2R, -NRCN, 3-12 saturated or partially unsaturated heterocyclic alkyl, 7-12 heterospirocyclic alkyl or 5-12 heterobridged cycloalkyl, 6-10 aryl, 5-12 heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)alkyl-(C3-C6)cycloalkyl, (C1-C6)alkyl-(C 3-C6) heterocyclic alkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C2-C6) alkenyl, (C3-C6) cycloalkyl, -OC(O)-(C1-C6) alkyl, -OC(O)-(C3-C6) cycloalkyl, (C1-C6) haloalkyl, (C1-C6) alkyl-C(=O)-, (C1-C6) alkoxy, (C1-C6) alkylthio or (C1-C6) alkylamine, 3- to 12-membered saturated or partially unsaturated heterocyclic alkyl, 7- to 12-membered heterospirocyclic alkyl or 5- to 12-membered heterobridged cycloalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, optionally surrounded by 1, 2, 3, 4 or 5 Rs. n replace;

[0038] Each R n Each of the following is independently selected from H, halogen, (C1-C6)alkyl, -P(O)(OR)2, (C1-C6)alkoxy, cyclopropyl, OH, NH2, CN, MeNH-, Me2N-, CH3, CH2F, CHF2 or CF3;

[0039] Each R is independently H, a substituted or unsubstituted (C1-C6) alkyl, a substituted or unsubstituted (C3-C6) cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted 3- to 7-membered saturated or partially unsaturated heterocyclic alkyl, or a substituted or unsubstituted 5- to 10-membered heteroaryl; or each of the two independently selected Rs can form a 3- to 10-membered saturated or partially unsaturated heterocyclic alkyl, a 7- to 11-membered heterospirocyclic, or a 5- to 11-membered heterobridged cycloalkyl.

[0040] In another preferred embodiment, in the general formula (1), L is Where * indicates that this end is connected to A;

[0041] L1, L2, L3, L4, L5, and L6 are independently selected from chemical bonds, O, S, NR, C(=O), C(=O)NR, S(=O), S(=O)NR, S(=O)2, S(=O)2NR, (C1-C6)alkylene, -(C1-C6)alkylene-O-, (C2-C6)alkenyl, (C2-C6)ynylene, (C3-C10)cycloalkylene, 6-10 arylene, 5-11 bridged cycloalkyl, 3-10 saturated or partially unsaturated heterocyclic alkylene. 7-11 member heterospirocyclic, 5-11 member heterobridged cyclic, or 5-10 member heteroaryl, wherein the (C1-C6) alkylene, -(C1-C6) alkylene-O-, (C2-C6) alkenyl, (C2-C6) ynylene, (C3-C10) cycloalkylene, 3-10 member saturated or partially unsaturated heterocycloalkylene, 6-10 member aryl, 7-11 member heterospirocyclic, 5-11 member heterobridged cyclic, or 5-10 member heteroaryl are each independently and optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 Rs. L replace;

[0042] Each R L Selected independently from R m H, deuterium, halogen, OH, SH, NH2, CN, -CONH2, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkylamine, oxo group, The (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkylamine groups are optionally surrounded by 1, 2 or 3 R groups. LL replace;

[0043] Each R LL Each of the following is independently selected from H, halogen, (C1-C6)alkyl, cyclopropyl, (C1-C6)alkoxy, OH, NH2, MeNH-, Me2N-, CH3, CH2F, CHF2 or CF3;

[0044] Or two R atoms respectively connected to the same or different atoms in L1, L2, L3, L4, L5, and L6. L It can be formed together with all the atoms in between to form a (C3-C20) saturated or partially unsaturated cycloalkyl or a 3- to 20-membered saturated or partially unsaturated heterocycloalkyl, wherein each of the (C3-C20) saturated or partially unsaturated cycloalkyl or the 3- to 20-membered saturated or partially unsaturated heterocycloalkyl can be independently and optionally replaced by one or more substituents.

[0045] In another preferred embodiment, in the general formula (1), L1, L2, L3, L4, L5, and L6 are respectively independently chemical bonds, O, S, NH, NMe, C(=O), C(=O)NH, C(=O)NMe, S(=O), S(=O)2, S(=O)2NH, CH2,

[0046] In another preferred embodiment, wherein the general formula (1) is,

[0047] L1 is a chemical bond, (C2-C3)-eneyl, (C2-C3)-ynyl, (C3-C10)-cycloalkyl, 3-10 saturated or partially unsaturated heterocyclic alkyl, 7-11 spirocyclic, or 5-11 heterobridged cycloalkyl, wherein the (C2-C3)-eneyl, (C2-C3)-ynyl, (C3-C10)-cycloalkyl, 3-10 saturated or partially unsaturated heterocyclic alkyl, 7-11 spirocyclic, or 5-11 heterobridged cycloalkyl are optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 Rs. L replace;

[0048] L2 represents chemical bonds, C(=O), C(=O)NH, (C1-C6)alkylene, and -(C1-C6)alkylene-O-.

[0049] L3 is a chemical bond, a 3-10 member saturated or partially unsaturated heterocyclic alkyl group, a 7-11 member heterospirocyclic group, or a 5-11 member heterobridged cyclic group, wherein the 3-10 member saturated or partially unsaturated heterocyclic alkyl group, the 7-11 member heterospirocyclic group, or the 5-11 member heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 Rs. L replace;

[0050] L4 represents chemical bonds, C(=O), C(=O)NH, (C1-C6)alkylene, and -(C1-C6)alkylene-O-.

[0051] L5 is a phenylene, a 5-9-membered heteroaryl group, a 3-10-membered saturated or partially unsaturated heterocyclic alkyl group, a 7-11-membered heterospirocyclic group, or a 5-11-membered heterobridged cyclic group, wherein the phenylene, 5-9-membered heteroaryl group, 3-10-membered saturated or partially unsaturated heterocyclic alkyl group, 7-11-membered heterospirocyclic group, or 5-11-membered heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R groups. L replace;

[0052] L6 is C(=O), C(=O)NMe or C(=O)NH.

[0053] In another preferred embodiment, wherein the general formula (1) is,

[0054] L1 is a 3-10 member saturated or partially unsaturated heterocyclic alkyl group, a 7-11 member heterocyclic spirocyclic group, or a 5-11 member heterobridged cyclic group containing 1-4 heteroatoms, wherein the 3-10 member saturated or partially unsaturated heterocyclic alkyl group, the 7-11 member heterocyclic spirocyclic group, or the 5-11 member heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace;

[0055] L2 is a chemical bond;

[0056] L3 is a 3-10 member saturated or partially unsaturated heterocyclic alkyl group, a 7-11 member heterocyclic spirocyclic group, or a 5-11 member heterobridged cyclic group containing 1-4 heteroatoms, wherein the 3-10 member saturated or partially unsaturated heterocyclic alkyl group, the 7-11 member heterocyclic spirocyclic group, or the 5-11 member heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace;

[0057] L4 is a chemical bond;

[0058] L5 is a phenylene, a 5-9-membered heteroaryl group, or a 3-10-membered saturated or partially unsaturated heterocyclic alkyl group containing 1-4 heteroatoms, wherein the phenylene, 5-9-membered heteroaryl group, or 3-10-membered saturated or partially unsaturated heterocyclic alkyl group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace;

[0059] L6 is C(=O)NH, C(=O)NMe, or C(=O).

[0060] In another preferred embodiment, wherein in the general formula (1), each R X1 R X2 R X3 R2 is independently selected from H, deuterium, methyl, deuterated methyl, halomethyl, methoxy, hydroxy, halomethoxy, halogen, amino, and carbamoyl;

[0061] Or, when m is 2, adjacent or non-adjacent R2 can form cycloalkyl or heteroalkyl groups together with all the atoms between them.

[0062] In another preferred embodiment, in the general formula (1), R3 is H, F, Cl, cyclopropyl or CH3.

[0063] In another preferred embodiment, the general formula (1) has the structure shown in general formulas (2) to (5):

[0064] in,

[0065] X is either O or S;

[0066] L1 is a 3-10 member saturated or partially unsaturated heterocyclic alkyl group, a 7-11 member heterocyclic spirocyclic group, or a 5-11 member heterobridged cyclic group containing 1-4 heteroatoms, wherein the 3-10 member saturated or partially unsaturated heterocyclic alkyl group, the 7-11 member heterocyclic spirocyclic group, or the 5-11 member heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace;

[0067] L3 is a 3-10 member saturated or partially unsaturated heterocyclic alkyl group, a 7-11 member heterocyclic spirocyclic group, or a 5-11 member heterobridged cyclic group containing 1-4 heteroatoms, wherein the 3-10 member saturated or partially unsaturated heterocyclic alkyl group, the 7-11 member heterocyclic spirocyclic group, or the 5-11 member heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace;

[0068] L5 is a phenylene, a 5-9-membered heteroaryl group, or a 3-10-membered saturated or partially unsaturated heterocyclic alkyl group containing 1-4 heteroatoms, wherein the phenylene, 5-9-membered heteroaryl group, or 3-10-membered saturated or partially unsaturated heterocyclic alkyl group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace;

[0069] L6 is Where * represents the end and Connected;

[0070] Each R L Independently selected from H, deuterium, F, Cl, hydroxyl, mercapto, amino, cyano, amide, methyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, methylamino, dimethylamino, oxo, Vinyl, acetylene;

[0071] 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, hydroxyl, mercapto, cyano, (C3-C6)cycloalkyl, and (3-6)heterocyclic alkyl.

[0072] R2 is independently selected from hydrogen, deuterium, (C1-C3)alkyl, (C1-C3)deuteratedalkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, and halogen;

[0073] Alternatively, any two adjacent or non-adjacent R2 atoms can form a (C3-C6) cycloalkyl or heterocycloalkyl group together with all the atoms between them;

[0074] R3 is H, deuterium, halogen, (C1-C3) alkyl, or cyclopropyl;

[0075] R4 is a 4- to 6-membered heterocyclic alkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclic alkyl, phenyl, or 5- to 6-membered heteroaryl 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, hydroxyl, cyano, (C3-C6)cycloalkyl, (3- to 6-membered) heterocyclic alkyl, (3- to 6-membered) oxoheterocyclic alkyl, (3- to 6-membered) thioheterocyclic alkyl, oxo, and thio.

[0076] m can be 0, 1, 2, 3, or 4;

[0077] n can be 0, 1, 2, or 3.

[0078] In another preferred embodiment, in the general formulas (2), (3), (4), and (5),

[0079] L1 is a 4-10 member saturated or partially unsaturated heterocyclic alkyl group containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, or a 5-11 member heterobridged cycloalcoside containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O. The 4-10 member saturated or partially unsaturated heterocyclic alkyl group and the 5-11 member heterobridged cycloalcoside are optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L Replacement; L1 is preferred More preferably More preferably The left end of the group can be connected to L3 or PTM, preferably to L3;

[0080] L3 is a 4-10 member saturated or partially unsaturated heterocyclic alkyl group containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, or a 5-11 member heterobridged cycloalcoside containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, wherein the 4-10 member saturated or partially unsaturated heterocyclic alkyl group or the 5-11 member heterobridged cycloalcoside is optionally surrounded by 1, 2, 3, or 4 R atoms. L Replacement; L3 is preferred More preferably The left end of the group can be connected to L5 or L1, preferably to L5;

[0081] L5 is a phenylene, a 5-6-membered heteroaryl group, or a 4-10-membered saturated or partially unsaturated heterocyclic alkyl group containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, wherein the phenylene, 5-6-membered heteroaryl group, or 4-10-membered saturated or partially unsaturated heterocyclic alkyl group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L Replacement; L5 is preferred More preferably More preferably More preferably The left end of the group can be connected to L6 or L3, preferably to L6;

[0082] R1 is independently selected from hydrogen, deuterium, -Me, -OMe, -OCD3, -CD3, -CHF2, -CF3, F, Cl, -NH2, -NHMe, hydroxyl, mercapto, cyano, and cyclopropyl.

[0083] R3 is hydrogen, deuterium, F, Cl, -Me, or cyclopropyl;

[0084] R4 is a 5-membered heterocyclic alkyl 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 heterocyclic alkyl group or 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, hydroxyl, mercapto, cyano, (C3-C6)cycloalkyl, (3-6-membered)heterocyclic alkyl, (3-6-membered)oxoheterocyclic alkyl, (3-6-membered)thioheterocyclic alkyl, oxo, and thio.

[0085] In another preferred embodiment, in the general formulas (1) to (5), R4 is preferably a 5-membered heterocyclic alkyl group containing one N atom, a 5-membered heterocyclic alkyl group containing one N and one S or O, or a 5-membered heteroaryl group containing one, two or three independently selected from N, S or O, wherein the 5-membered heterocyclic alkyl group or 5-membered heteroaryl group is optionally further replaced by one or two substituents independently selected from -D, -Me, -CD3, -CH2F, -CHF2, -CF3, -OMe, -OCD3, oxo and thio groups.

[0086] In another preferred embodiment, in the general formulas (1) to (5), R4 is selected from...

[0087] In another preferred embodiment, the general formula (1) has the structure shown in general formulas (6) to (9):

[0088] in,

[0089] Z is NR8, O, or S;

[0090] L5 is a phenylene group, a 5-6 membered heteroaryl group containing one or two heteroatoms independently selected from N, S, and O, and a 9-10 membered partially unsaturated heterocyclic alkyl group containing one, two, three, or four heteroatoms independently selected from N, S, and O, wherein the phenylene group, the 5-6 membered heteroaryl group, and the 9-10 membered partially unsaturated heterocyclic alkyl group are each independently optionally surrounded by one, two, three, four, five, six, seven, or eight R atoms. L replace;

[0091] L6 is Where * represents the end and Connected;

[0092] o can be 0, 1, 2, 3, 4, or 5;

[0093] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0094] Each R L Each of the following is independently selected from H, deuterium, halogen, OH, NH2, SH, CN, -CONH2, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkylamine, oxo group, etc. Vinyl, ethynyl, wherein the (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkylamine group is optionally surrounded by 1, 2 or 3 R groups. LL replace;

[0095] Each R LL Each of the following is independently selected from H, halogen, (C1-C6) alkyl, OH, NH2, -NHCH3, -N(CH3)2, -CH3, -CH2F, -CHF2 or -CF3.

[0096] In another preferred embodiment, the general formula (1) has a structure as shown in general formula (10):

[0097] in,

[0098] Z is NR8 or O;

[0099] L5 is a 5-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, S, and O, wherein the 5-membered heteroaryl group is optionally surrounded by 1 or 2 R atoms. L replace.

[0100] In another preferred embodiment, in the general formula (10), L5 is preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazinyl, imidazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrrolyl, furanyl, thiaphenyl, more preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazinyl, pyrrolyl.

[0101] In another preferred embodiment, in the general formulas (6) to (9), R5 and R6 are phenyl, methyl, trifluoromethyl or ethyl; or R5 and R6 together with the atoms they are connected to form (C3-C6) cycloalkyl, 3-6 membered heterocyclic alkyl, preferably cyclopropyl or cyclobutyl; or R5 is substituted or unsubstituted phenyl, methyl, trifluoromethyl or ethyl, and R6 and R7 together with the atoms between them form substituted or unsubstituted 5-10 membered saturated or partially unsaturated heterocyclic alkyl, preferably 5-6 membered saturated heterocyclic alkyl or 9 membered partially unsaturated heterocyclic alkyl.

[0102] In another preferred embodiment, wherein the general formulas (6) to (9) and general formula (10) are:

[0103] Z is either NH or O;

[0104] R7 is a phenyl group, a 5- to 7-membered monocyclic heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, Se, and O, or an 8- to 10-membered bicyclic heteroaryl group containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from N, S, Se, and O, wherein the phenyl or heteroaryl group is optionally further surrounded by 1, 2, 3, 4, or 5 R7 atoms. m replace;

[0105] R mThe following are the possible values ​​for hydrogen, deuterium, F, Cl, Br, I, OH, NO2, NH2, CN, -N(CH3)2, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -SCN, -S(O)2CN, -S(O)2N(CH3)2, -SF5, -P(O)(CH3)2, -P(S)(CH3) 2, -P(O)(OH)CH3, -P(O)(OH)2, -NHOCH3, -C(O)NH(OMe), -C(O)NHCN, -C(O)N(CH3)2, -NHS(O)2CH3, -NHCN, -C(O)OH, -C(O)OCH3, (C1-C6)alkyl, (C2-C3)alkynyl, (C2-C3)alkenyl, (C1-C3)alkoxy (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C3-C6) cycloalkyl, -NHC(O)OR, -NHC(O)N(R)2, -NHC(O)R, 3- to 6-membered saturated or partially unsaturated heterocyclic alkyl, phenyl, 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from N, S, Se and O, wherein the alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic alkyl, phenyl, and heteroaryl are each optionally substituted by 1, 2 or 3 H, F, Cl, -CH3, cyclopropyl, OH, NH2, CN, -OCH3, -CH2OCH3, -NHCH3, -N(CH3)2, -CH2N(CH3)2, -CH3, -CH2F, -CHF2 or -CF3.

[0106] In another preferred embodiment, in the general formulas (6) to (9) and general formula (10), R7 is a number of 1, 2, 3, 4 or 5 R7s. m The substituted phenyl group, or a 5- to 6-membered monocyclic heteroaryl group containing one, two, three, or four heteroatoms independently selected from N, S, Se, and O, preferably surrounded by one, two, three, four, or five R atoms. m Substituted phenyl, pyrrolyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,5-thiadiazolyl, 1,2,5-oxadiazolyl.

[0107] In another preferred embodiment, in the general formulas (6) to (9) and general formula (10), R7 is a number of 1, 2, 3, 4 or 5 R7s. mThe substituted 8- to 10-membered bicyclic heteroaryl group containing one, two, three, four, five, or six heteroatoms independently selected from N, S, and O is preferred.

[0108] In another preferred embodiment, in the general formulas (6) to (9) and general formula (10), R m For H, F, Cl, Br, OH, NO2, NH2, CN, -NHCH3, -N(CH3)2, -NHC(O)OC(CH3)3, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -SCN, -S(O)2CN, -S(O)2 N(CH3)2, -SF5, -P(O)(CH3)2, -P(S)(CH3)2, -P(O)(OH)CH3, -P(O)(OH)2, -NHOCH3, -C(O)NH(OMe), -C(O)NHCN, -C(O)N(CH3)2, -NHS(O)2CH3, -NHCN, -C(O)OH, -C (O)OCH3, -C(O)OC(CH3)3, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, -OCHF2, -OCH2F, -CH=CH2, -CH2CH=CH2, -CH=CH2CH3, -CH=CH2CH2OCH3, -CH=CH2CH2N(CH3)2, -C≡CH, -C≡CHCH3, -CH2C≡CH, -C≡CHCH2OCH3, -C≡CHCH2N(CH3)2, cyclopropyl, cyclobutyl, oxacyclobutane, azacyclobutane.

[0109] In another preferred embodiment, wherein the general formulas (6) to (9) and general formula (10) are:

[0110] Z is either NH or O;

[0111] R7 is -C(O)R k or -C(O)OR k ;

[0112] R kThe (C1-C3) alkyl, (C3-C6) cycloalkyl, or 3- to 6-membered saturated or partially unsaturated heterocyclic alkyl containing 1 to 2 heteroatoms independently selected from N, S, and O, wherein the (C1-C3) alkyl, (C3-C6) cycloalkyl, or 3- to 6-membered saturated or partially unsaturated heterocyclic alkyl containing 1 to 2 heteroatoms independently selected from N, S, and O is optionally further surrounded by 1, 2, 3, 4, or 5 R atoms. m Substitution; two hydrogen atoms on the same carbon atom can be replaced by oxygen to form an oxo group or by... Replaced; R a and R b Each can be H or F independently;

[0113] R m The following are the possible values: H, F, Cl, OH, NH2, CN, -N(CH3)2, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -C(O)OH, -C(O)OCH3, (C1-C3)alkyl, (C1-C3)alkoxy, cyclopropyl, (C1-C3)haloalkyl, (C1-C3)haloalkoxy.

[0114] In another preferred embodiment, wherein the general formulas (6) to (9) and general formula (10) are:

[0115] Z is either NH or O;

[0116] R7 is -C(O)R k or -C(O)OR k ;

[0117] R k The phenyl group is a 5- to 6-membered monocyclic heteroaryl group containing one, two, three, or four heteroatoms independently selected from N, S, and O; or an 8- to 10-membered bicyclic heteroaryl group containing one, two, three, or four heteroatoms independently selected from N, S, and O, wherein the phenyl or heteroaryl group is optionally further surrounded by one, two, three, four, or five R atoms. m replace;

[0118] R m The derivatives are H, F, Cl, OH, NH2, CN, -N(CH3)2, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -C(O)OH, -C(O)OCH3, -CH3, -OCH3, -CF3, -CH2F, -CHF2, -OCF3, and cyclopropyl.

[0119] In another preferred embodiment, wherein the general formulas (6) to (9) and general formula (10) are:

[0120] Z is either NH or O;

[0121] R7 is -C(O)NR k R l ;

[0122] R k and R l Each of the following is independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C6)cycloalkyl, 3-6 member saturated or partially unsaturated heterocyclic alkyl, 7-12 member heterospirocyclic alkyl or 5-12 member heterobridged cycloalkyl, phenyl, 5-12 member heteroaryl containing 1-4 heteroatoms independently selected from N, S and O; the two hydrogens on the same carbon may be replaced by oxygen to form an oxo group or by... Replaced; R a and R b Each can be H or F independently.

[0123] In another preferred embodiment, wherein the general formulas (6) to (9) and general formula (10) are:

[0124] Z is either NH or O;

[0125] R7 is H, (C1-C3)alkyl, or (C3-C6)cycloalkyl, wherein the (C1-C3)alkyl or (C3-C6)cycloalkyl is further surrounded by 1, 2, 3, 4, or 5 R7 groups. m Substitution; two hydrogen atoms on the same carbon atom can be replaced by oxygen to form an oxo group or by... Replaced; R a and R b Each can be H or F independently;

[0126] R m The following are the possible values: hydrogen, deuterium, F, Cl, OH, NH2, CN, -N(CH3)2, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -C(O)OH, -C(O)OCH3, (C1-C3)alkyl, cyclopropyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy.

[0127] In another preferred embodiment, wherein the general formulas (6) to (9) and general formula (10) are:

[0128] Z is either NH or O;

[0129] R7 is a 3- to 12-membered saturated or partially unsaturated heterocyclic alkyl group, a 7- to 12-membered heterospirocyclic alkyl group, or a 5- to 12-membered heterobridged cycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S, O, and P, wherein the 3- to 12-membered saturated or partially unsaturated heterocyclic alkyl group, a 7- to 12-membered heterospirocyclic alkyl group, or a 5- to 12-membered heterobridged cycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S, O, and P is optionally further surrounded by 1, 2, 3, 4, or 5 R7 atoms. m Substitution; two hydrogen atoms on the same carbon atom can be replaced by oxygen to form an oxo group or by... Replaced; R a and R b Each can be H or F independently;

[0130] R m Hydrogen, deuterium, F, Cl, OH, NO2, NH2, CN, -N(CH3)2, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -C(O)OH, -C(O)OCH3, (C1-C3)alkyl, cyclopropyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, -NHC(O)OR, -NHC(O)R, containing The alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, heterocyclic alkyl group, phenyl group, and 5-6-membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N, S and O, wherein each of the alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, heterocyclic alkyl group, phenyl group, and heteroaryl group is independently and optionally substituted by one, two or three H, F, Cl, -CH3, OH, NH2, CN, -NHCH3, -N(CH3)2, -CH3, -CH2F, -CHF2 or -CF3.

[0131] In another preferred embodiment, wherein the general formulas (6) to (9) and general formula (10) are:

[0132] R7 is

[0133] In another specific embodiment of the present invention, the compound of general formula (1) has one of the following structures:

[0134] This invention also provides a method for preparing compounds with structures as shown in general formula (11).

[0135] L6 is Where * represents the end and Linked; Compounds of general formula (11) can be prepared by the following methods:

[0136] PG is a protecting group, which can be deprotected under certain conditions to reveal the exposed α-position NH.

[0137] This invention also provides a method for preparing a class of compounds with structures as shown in general formula (11):

[0138] Compounds of general formula (11) can be obtained by a condensation reaction between intermediate acid int_3 and L5 on intermediate int_4. In this case, intermediate acid int_3 can also be first prepared as an active ester and then reacted with intermediate int_4.

[0139] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a diluent and / or an excipient, and a compound of the general formula of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0140] Another object of the present invention is to provide the use of the compounds of the general formula of the present invention, or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical compositions thereof, in the preparation of medicaments for treating, regulating or preventing diseases related to PI3Kα. The diseases are preferably cancers, specifically hematologic malignancies and solid tumors.

[0141] Another object of the present invention is to provide a method for treating, modulating or preventing diseases associated with PI3Kα, comprising administering to a subject a therapeutically effective amount of a compound of the general formula of the present invention, or any isomer thereof, crystal form thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof.

[0142] It should be understood that the foregoing general description of the invention and the following detailed description are exemplary and illustrative, and are intended to provide further explanation of the claimed invention.

[0143] Compound Synthesis

[0144] The preparation method of the compound of general formula (1) of the present invention is described in detail below, but these specific methods do not constitute any limitation on the present invention.

[0145] The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with the methods described herein. Furthermore, the solvents, temperatures, and other reaction conditions mentioned herein can be varied. Starting materials used in the synthesis of the compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using known techniques and starting materials, including those discovered 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 The method described in Ed. (Wiley 1999) can be used to prepare compounds by employing appropriate reagents and by introducing different groups into the molecular formulas provided herein.

[0146] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the explanations below. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art. On the other hand, the present invention also provides a method for preparing the compound of general formula (2), wherein the compound of general formula (2) can be prepared by the following general reaction process 1 or 2:

[0147] General reaction process 1

[0148] When Z is NH, the compound of general formula (2) can be prepared according to general reaction procedure 1, where X, R1, R2, R3, R4, R5, R6, R7, L1, L3, L5, L6, n, and m are as defined above. As shown in general reaction procedure 1, compound 1-1 undergoes a coupling reaction with intermediate R4 (NH or boron ester) to generate compound 1-2. Compound 1-2 then undergoes a coupling reaction with each structural unit of L1, L3, L5, and so on, and then the structure is extended step by step to obtain compound 1-3. Compound 1-3 and The reaction produces compound 1-4-1 (reacting with the -NH2 substituent on L) or 1-4-2 (reacting with NH on L), and compound 1-4-1 or compound 1-4-2 then reacts with the corresponding aldehyde to produce the target general formula compound (2).

[0149] General reaction process 2

[0150] Compounds of general formula (2) can also be prepared according to general reaction procedure 2, where compounds 1-3 react directly with the corresponding acids to generate the target compound of general formula (2).

[0151] General reaction process 3

[0152] When Z is NH, the compound of general formula (3) can be prepared according to general reaction procedure 1, wherein X, R3, R4, R5, R6, R7, L1, L3, L5 and L6 are as defined above. As shown in general reaction procedure 1, compound 3-1 undergoes a coupling reaction with intermediate R4 (NH or boron ester) to generate compound 3-2. Compound 3-2 then undergoes a coupling reaction with each structural unit of L1, L3, L5, and L6 in sequence, and then the structure is extended step by step to obtain compound 3-3. Compound 3-3 and The reaction produces compound 3-4-1 (reacting with the -NH2 substituent on L) or 3-4-2 (reacting with NH on L), and compound 3-4-1 or compound 3-4-2 then reacts with the corresponding aldehyde to produce the target general formula compound (3).

[0153] Further forms of the compound

[0154] "Pharmaceutical acceptable" here means that a substance, such as a carrier or diluent, will not destroy the biological activity or properties of a compound and is relatively non-toxic. For example, when given to an individual, a substance will not cause unwanted biological effects or interact with any of its components in a harmful manner.

[0155] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the administered organism and does not diminish the compound's biological activity and properties. In some specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of a general formula with an acid or base, wherein said 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).

[0156] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is ethanol. Solvates of compounds of general formula (1) are readily prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are readily prepared by recrystallization from a mixture of water and organic solvents, including but not limited to tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds mentioned herein can exist in both solvated and non-solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0157] In other specific embodiments, compounds of general formula (1) are prepared in various forms, including but not limited to amorphous, pulverized, and nano-particle forms. Furthermore, compounds of general formula (1) include crystalline forms and can also be polymorphic. Polymorphs comprise different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvents, crystallization rates, and storage temperatures may cause a single crystal form to dominate.

[0158] In another aspect, compounds of general formula (1) may possess a chiral center and / or axial chirality, and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, 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 diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of this invention. This invention means including all such isomeric forms of these compounds.

[0159] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Oxygen-18 ( 18 O), Iodine-125 ( 125 I) and C-14 14 C). For example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs generally have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0160] Unless otherwise specified, any atom in the compounds described in this invention refers to its stable-state isotope. Unless otherwise specified, when a site on the molecular structure is chosen as "H" or "hydrogen", that site should be understood as having a natural abundance of hydrogen isotopes. Similarly, unless otherwise specified, when a site is chosen as "D" or "deuterium", that site should be understood as having a deuterium isotope abundance of at least 3000 times its natural abundance (the natural abundance of deuterium isotopes is 0.015%).

[0161] More preferably, the deuterium abundance at each deuteration site of the deuterated compound in this invention is at least 3500 times its natural abundance (52.2% deuterium enrichment). More preferably, at least 4500 times (67.5% deuterium enrichment). More preferably, at least 5000 times (75% deuterium enrichment). More preferably, at least 6000 times (90% deuterium enrichment). More preferably, at least 6333 times (95% deuterium enrichment). More preferably, at least 6466.7 times (97% deuterium enrichment). More preferably, at least 6600 times (99% deuterium enrichment). More preferably, at least 6633.3 times (99.5% deuterium enrichment).

[0162] the term

[0163] Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, unless otherwise clearly indicated, the singular form "a" includes the plural meaning. Unless otherwise specified, substituents (such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.) in this application are optionally substituted, i.e., they can be substituted or unsubstituted. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0164] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl. Lower alkyl groups containing 1 to 3 carbon atoms are more preferred, 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, etc. i Pr、 n Pr、 i Bu、 n Bu or t Bu.

[0165] Unless otherwise specified, "alkylene" means a divalent alkyl group as defined above. Examples of alkylene include, but are not limited to, methylene and ethylene.

[0166] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight-chain or branched groups with 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms are preferred, such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl. Lower alkenyl groups containing 1 to 2 carbon atoms are more preferred.

[0167] Unless otherwise specified, “alkenyl” refers to a divalent alkenyl group as defined above.

[0168] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight-chain and branched groups with 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, such as ethynyl, 1-propynyl, or 1-butynyl. Lower alkynyl groups containing 1 to 2 carbon atoms are more preferred.

[0169] Unless otherwise specified, “ethynyl” means a divalent ethynyl group as defined above.

[0170] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), preferably containing 3-14 ring carbon atoms (C14-C24). 3-14 A non-aromatic hydrocarbon ring system (cycloalkyl). In some embodiments, the cycloalkyl group has 3-10 ring carbon atoms (C60-C70). 3-10 (Cycloalkyl). In some embodiments, the cycloalkyl group has 3-8 cyclic carbon atoms (C60-C85). 3-8 (Cycloalkyl). In some embodiments, the cycloalkyl group has 3-7 cyclic carbon atoms (C60-C75). 3-7 (Cycloalkyl). In some embodiments, the cycloalkyl group has 3-6 cyclic carbon atoms (C66-C66). 3-6 (Cycloalkyl). In some embodiments, the cycloalkyl group has 4-6 cyclic carbon atoms (C66-C66). 4-6 (Cycloalkyl). In some embodiments, the cycloalkyl group has 5-6 cyclic carbon atoms (C66-C66). 5-6 (Cycloalkyl). In some embodiments, the cycloalkyl group has 5-10 cyclic carbon atoms (C10-C20). 5-10 Cycloalkyl groups. A partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl" if the carbide ring contains at least one double bond, or as a "cycloynyl" if the carbide ring contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is either monocyclic or bicyclic. In some embodiments, the cycloalkyl group is tricyclic. The cycloforming carbon atom 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). In some embodiments, the cycloalkyl group may be fused with aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl groups. In some embodiments, the cycloalkyl group may be fused with aryl, cycloalkyl, and heterocyclic alkyl groups. In some embodiments, the cycloalkyl group may be fused with aryl and heterocyclic alkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norcamphenyl, norpinel, norcarel, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and so on.

[0171] Unless otherwise specified, “cycloalkylene” means a divalent cycloalkyl group as defined above.

[0172] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1-6 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, particularly those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, etc. i- PrO, n- PrO, i- BuO、 n- BuO or t- BuO.

[0173] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, which can be monocyclic or polycyclic, such as a monocyclic aryl ring fused with one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrene.

[0174] Unless otherwise specified, "aryloxy group" refers to an aryl group bonded to the rest of the molecule via an ether oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy groups.

[0175] Unless otherwise specified, "arylene" refers to a divalent aryl group as defined above. Examples of arylene groups include, but are not limited to, 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, naphthylene, and phenanthrene.

[0176] Unless otherwise specified, "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms, wherein the heteroatoms are independently selected from O, N, P, Se, or S, and the number of heteroatoms is preferably 1, 2, 3, or 4. It is more 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 optionally selected from oxygen, sulfur, or nitrogen, and even more preferably a 5-6-membered aromatic group containing 1-3 heteroatoms optionally selected from oxygen, sulfur, or nitrogen. The heteroaryl group can be monocyclic or polycyclic. Monocyclic heteroaryl groups are preferably 5-6-membered aromatic groups containing 1-3 heteroatoms optionally selected from oxygen, nitrogen, or sulfur. More preferably, they are 5-6-membered aromatic groups containing 1-2 heteroatoms optionally selected from oxygen, nitrogen, or sulfur. Even more preferably, they are 5-6-membered aromatic groups containing 1 heteroatom optionally 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 heterocyclic alkyl groups. In some embodiments, the nitrogen on the heteroaryl ring can be oxidized to an N-oxide, such as... Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, furanyl, thiopheneyl, isoxazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isothiazolyl, pyrroloyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiaphenyl, benzooxazolyl, benzopyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolo[3,2-c]pyridyl, 1H-pyrrolo[2,3-b]pyridyl.

[0177] Unless otherwise specified, “hybrid aryl” refers to a divalent heteroaryl group as defined above.

[0178] Unless otherwise specified, "heterocyclic alkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenyl groups as part of a ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, selenium, and silicon, preferably containing 1-4 heteroatoms selected from oxygen, sulfur, or nitrogen, and more preferably containing 1-2 heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments, the heterocyclic alkyl is a 5-14 membered non-aromatic ring containing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (5-14 membered heterocyclic alkyl). In some embodiments, the heterocyclic alkyl is a 3-9 membered non-aromatic ring containing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (3-9 membered heterocyclic alkyl). In some embodiments, the heterocyclic alkyl group is a 5-8 membered non-aromatic ring containing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (5-8 membered heterocyclic alkyl group). In some embodiments, the heterocyclic alkyl group is a 5-6 membered non-aromatic ring containing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (5-6 membered heterocyclic alkyl group). In some embodiments, the 5-6 membered heterocyclic alkyl group contains 1-3 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic alkyl group contains 1-2 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic alkyl group contains 1 cyclic heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl group is a 10-13 membered non-aromatic ring containing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (10-13 membered heterocyclic alkyl group). In some embodiments, the 10-13 membered heterocyclic alkyl group contains 1-3 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 10-13 membered heterocyclic alkyl group contains 1-2 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 10-13 membered heterocyclic alkyl group contains 1 cyclic heteroatom independently selected from nitrogen, oxygen, and sulfur. If the heterocyclic alkyl group contains at least one double bond, then the partially unsaturated heterocyclic alkyl group may be referred to as a "heterocyclic alkenyl group," or if the heterocyclic alkyl group contains at least one triple bond, then the partially unsaturated heterocyclic alkyl group may be referred to as a "heterocyclic ynyl group." Heterocyclic alkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (e.g., having two fused or bridging rings) ring systems. In some embodiments, the heterocyclic alkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The cyclic carbon atoms and heteroatoms of the heterocyclic alkyl group may optionally be oxidized to form oxo or thio groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O)2, N-oxides, etc.), or the nitrogen atom may be quaternized. The heterocyclic alkyl group may be linked via cyclic carbon atoms or cyclic heteroatoms. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds.In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. The definition of heterocyclic alkyl also includes portions of an aromatic ring (also called partially unsaturated heterocycles) having one or more aromatic rings fused to (i.e., sharing bonds with) the heterocyclic alkyl ring, such as benzo[a] derivatives of piperidine, morpholine, aziridine, or tetrahydrothiophene, and pyrido[a] derivatives of piperidine, morpholine, aziridine, or tetrahydrothiophene. Heterocyclic alkyl groups containing fused aromatic rings can be linked via any cyclizing atom, including the cyclizing atom of the fused aromatic ring. Examples of heterocyclic alkyl groups include, but are not limited to, azirrobutyl, azirroheptyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxoperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazo[5,4-c]pyridinyl, and 4,5,6,7-tetrahydro-1H-imidazolium. [4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolyl, butyrolactam, valproic acid, imidazolinone, hydantoin, dioxolane, phthalimide, pyrimidin-2,4(1H,3H)-diketoyl, 1,4-dioxane, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S,S-oxide, piperazine, pyranyl, pyridinone, 3-pyrrololinyl, thiaranyl, pyranone, tetrahydrothiophene, 2-azaspiro[3.3]heptyl, indololinyl.

[0179] Unless otherwise specified, "heterocyclic alkylene" refers to a divalent heterocyclic alkylene group as defined above, and specific examples of heterocyclic alkylene groups include, but are not limited to, those that are not limited to, heterocyclic alkylene groups.

[0180] Unless otherwise specified, "heterocyclic spirocyclic alkyl" / "heterocyclic alkyl" / "heterocyclic group" refers to a polycyclic cyclic hydrocarbon group formed by two or more saturated or partially unsaturated monocyclic rings sharing a single carbon atom (called a spiro atom), wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S(O). pThe heteroatom (where p is 0, 1, or 2) is a carbon atom, 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, where R is hydrogen or other substituents defined herein). Each monocycle may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Spirocycloheterocyclic groups are classified as monospirocycloheterocyclic, bispirocycloheterocyclic, or polyspirocycloheterocyclic groups based on the number of shared spiro atoms between rings. The term "(5-15-membered) heterocyclic spirocycloalkyl" refers to a heterocyclic spirocycloalkyl having 5 to 15 ring atoms, wherein the monocycles sharing the spiro atom are 3 to 8-membered monocycles, and at least one monocycle is a heterocyclic alkyl ring. Preferably, it is a (6-18-membered) heterocyclic spirocycloalkyl having 6 to 18 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, more preferably a (7-15-membered) heterocyclic spirocycloalkyl having 7 to 15 ring atoms, wherein 1 to 3 ring atoms are heteroatoms. The most preferred are 9-membered (4-membered monocyclic (heterocyclic) alkyl groups / 6-membered monocyclic (heterocyclic) alkyl groups, 5-membered monocyclic (heterocyclic) alkyl groups / 5-membered monocyclic (heterocyclic) alkyl groups, 10-membered (5-membered monocyclic (heterocyclic) alkyl groups / 6-membered monocyclic (heterocyclic) alkyl groups, or 11-membered (6-membered monocyclic (heterocyclic) alkyl groups / 6-membered monocyclic (heterocyclic) alkyl groups. Specific examples of heterocyclic spirocyclic alkyl groups include, but are not limited to, those listed below.

[0181] Unless otherwise specified, "subheterospirocyclic" refers to a divalent heterospirocyclic group as defined above. Specific examples of subheterospirocyclic groups include, but are not limited to, those described above.

[0182] Unless otherwise specified, "heterobridged cycloalkyl" or "heterobridged cycloyl group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where 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 bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic.

[0183] Unless otherwise specified, "hybridized cycloalkylene" refers to a divalent heterobridged cycloalkylene group as defined above, and specific examples of hybridized cycloalkylene groups include, but are not limited to, those that are not limited to, heterobridged cycloalkylene groups.

[0184] Unless otherwise specified, "oxo" refers to =O; for example, a group formed by substituting carbon with an oxo group is a "carbonyl". The group formed by the substitution of sulfur with one oxo group is called "thionyl". The group formed by the substitution of sulfur with two oxo groups is called a sulfonyl group. ".

[0185] Unless otherwise specified, "halogen" (or halogenated group) means fluorine, chlorine, bromine or iodine. The term "halogenated" (or "halogen substituted") appearing before the group name indicates that the group is partially or completely halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0186] Unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on a specified atom or group are substituted by one or more substituents other than hydrogen atoms, without exceeding the normal valence of the specified atom. For example, one or more hydrogen atoms of alkyl, alkylene, alkenyl, alkynyl, hydroxyl, or amino groups may be substituted by one or more substituents. The substituents mentioned include, but are not limited to, alkyl, alkenyl, alkynyl, acyl, amino, amide, amidyl, aryl, azide, carbamoyl, carboxyl, carboxylic acid ester, cyano, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazyl, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. The definition of "substituted" does not include similar indeterminate structures obtained by defining substituents having further substituents attached to infinity (e.g., a substituted aryl group having a substituted alkyl group itself substituted by a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise specified, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of a substituted aryl group by two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definition does not include disallowed substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art. Whenever used to modify a chemical group, “substituted” may describe other chemical groups as defined herein. For example, the term “substituted aryl” includes, but is not limited to, “alkylaryl.” Unless otherwise specified, if a group is described as optionally substituted, any substituted elements of that group are themselves unsubstituted.

[0187] "Optional" or "optionally" means that the event or condition described below may, but is not required, occur, and the description includes both the scenario in which the event or condition occurs and the scenario in which the event or condition does not occur.

[0188] The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl is optionally substituted”). It is not intended to imply that the characteristic “X” (e.g., alkyl) itself is optional. As described in this specification, certain target compounds may contain one or more “optionally substituted” moieties. Generally, the term “substituted”, whether or not preceded by the term “optionally”, means that one or more hydrogens of the specified moiety are replaced by suitable substituents, such as any of the substituents or groups described in this specification. Unless otherwise specified, the “optionally substituted” group may have suitable substituents at each substituted position of said group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. For example, in the term “optionally substituted (C1-C6)alkyl-(5-9-membered)heteroaryl”, the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The combinations of substituents in this disclosure are preferably combinations of substituents that form stable or chemically viable compounds. As used in this specification, the term "stable" means that a compound remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0189] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group can independently be deuterium; halogen; -(CH2). 0-4 R o ;-(CH2) 0-4 OR o ;-O(CH2) 0-4 R o -O-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 CH(OR o )2;-(CH2) 0-4 SR o ;R o Substituted -(CH2) 0-4 Ph;R o Substituted -(CH2) 0-4 O(CH2) 0-1 Ph;R o Substituted -CH=CHPh; R o Substituted -(CH2) 0-4 O(CH2) 0-1-(5-9) heteroaryl; 4-8 saturated or unsaturated heterocyclic alkyl (e.g., pyridyl); 3-8 saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0-4 N(R o )C(O)NR o 2; -N(R) o )C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2; -N(R) o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 -C(O)-N(R o )2;-(CH2) 0-4 -C(O)-N(R o )-S(O)2-R o ;-C(NCN)NR o 2;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR o ;-SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NRo 2; -C(S)NR o 2;-C(S)SR o ;-(CH2) 0-4 OC(O)NR o 2; -C(O)N(OR) o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR) o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2; -N(R) o )S(O)2R o ;-N(OR) o )R o ;-C(NOR) o )NR o 2;-C(NH)NR o 2; -P(O)2R o ;-P(O)R o 2; -P(O)(OR o )2;-OP(O)R o 2; -OP(O)(OR o )2;-OP(O)(OR o )R o ;-SiR o 3; -(C 1-4 )alkylene-ON(R o )2; or -(C 1-4 )alkylene-C(O)ON(R o )2, where each R o It can be substituted and independently of hydrogen, -C as defined below. 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1Ph, -CH2-(5-6-membered) heteroaryl, or a 3-6-membered saturated, partially unsaturated, or aryl ring having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur, or, despite the above definitions, two independently existing R... o Together with the atoms connected thereto, they form 3-12 saturated or partially unsaturated cycloalkyl or heterocycloalkyl groups having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; 3-12 aryl or heteroaryl groups having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and may be substituted as defined below.

[0190] R o (or two independently existing R) o Suitable monovalent substituents on the ring formed together with the atoms it is attached to can be halogens, -(CH2), or other similar substances independently. 0-2 R o1 -(halogenated R) o1 -(CH2) 0-2 OH, -(CH2) 0-2 OR o1 -(CH2) 0-2 CH(OR o1 )2、-O(halogenated R o1 -CN, -N3, -(CH2) 0-2 C(O)R o1 -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR o1 -(CH2) 0-2 SR o1 -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR o1 -(CH2) 0-2 NR o1 2, -NO2, -SiR o1 3. -OSiR o1 3. -C(O)SR o1 -(C 1-4 )alkylene-C(O)OR o1 or -SSR o1 , where each R o1 Unsubstituted, or substituted by one or more halogens when preceded by "halogenated", and each R o1 Selected independently from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1Ph, a 3-6 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl group having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and a 5-6 membered aryl or heteroaryl group having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. R o Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0191] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include: =O, =S, =NNR. o2 2、=NNHC(O)R o2 =NNHC(O)OR o2 =NNHS(O)2R o2 =NR o2 =NOR o2 -O(C(R) o2 2)) 2-3 O- or -S(C(R) o2 2)) 2-3 S-, where R o2 Each time it appears, it is independently selected from hydrogen; the C that can be substituted can be defined as follows. 1-6 Aliphatic group; or 5-6 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl groups having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or 5-6 membered aryl or heteroaryl groups having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the adjacent substituted carbon of the "optionally substituted" group include: -O(CR o2 2) 2-3 O-, where R o2 Each time it appears, it is independently selected from hydrogen; the C that can be substituted can be defined as follows. 1-6 Aliphatic group; or 3-6 saturated or partially unsaturated cycloalkyl or heterocycloalkyl groups having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6 aryl or heteroaryl groups having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0192] R o2 Suitable substituents on aliphatic groups include halogens, -R o3 -(halogenated R) o3 -OH, -OR o3 -O (halogenated R) o3 -CN, -C(O)OH, -C(O)OR o3 -NH2, -NHR o3 -NR o3 2 or -NO2, where each R o3 Unsubstituted, or substituted by one or more halogens when preceded by "halogenated", and each R o3Selected independently from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, a 3-6 saturated or partially unsaturated cycloalkyl or heterocycloalkyl group having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 aryl or heteroaryl group having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0193] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R o4 -NR o4 2. -C(O)R o4 -C(O)OR o4 -C(O)C(O)R o4 -C(O)CH2C(O)R o4 -S(O)2R o4 -S(O)2NR o4 2. -C(S)NR o4 2. -C(NH)NR o4 2 or -N(R) o4 )S(O)2R o4 ; where each R o4 It is hydrogen on its own; the C that can be substituted can be defined as follows. 1-6 Aliphatic group; unsubstituted -OPh; 3-6 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl groups having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 5-6 membered aryl or heteroaryl groups having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Or, despite the above definitions, two independently existing R groups. o4 Together with the atoms attached thereto, they form 3-12 saturated or partially unsaturated cycloalkyl or heterocycloalkyl groups having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or 3-12 aryl or heteroaryl groups having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0194] R o4 Suitable substituents on the aliphatic group are independently halogens, -R o5 -(halogenated R) o5 -OH, -OR o5 -O (halogenated R) o5 -CN, -C(O)OH, -C(O)OR o5 -NH2, -NHR o5 -NR o5 2 or -NO2, where each R o5 Unsubstituted, or substituted by one or more halogens when preceded by "halogenated", and each R o5 C is independent 1-4Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, a 3-6 membered saturated or partially unsaturated cycloalkyl or heterocycloalkyl group having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and a 5-6 membered aryl or heteroaryl group having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. R o4 Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0195] Unless otherwise specified, "acyl" means -C(=O)-R, where R is selected from optionally substituted alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl or heterocycloalkyl.

[0196] Unless otherwise specified, the word “comprising”, or variations thereof such as “including” or “containing”, may be understood to mean including the stated element or integer, or a group of elements or integers, but does not exclude any other element or integer, or a group of elements or integers.

[0197] The substituent "-O-CH2-O-" indicates that the two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocyclic alkyl, aryl, or heteroaryl group. For example:

[0198] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a single bond.

[0199] When one of the variables is selected as a chemical bond, it means that the two groups connected are directly linked. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0200] The term "membered ring" includes any ring structure. The term "membered" refers to the number of skeleton atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thioranyl are six-membered rings, while cyclopentyl, pyrroleyl, furanyl, and thiophenyl are five-membered rings.

[0201] The term "fragment" refers to a specific part or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to a molecule.

[0202] The term "isomer" refers to any tautomer, stereoisomer, transisomer, isotopic isomer, 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 thus exist in stereoisomeric form, such as double-bonded 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 mixtures of enantiomers and stereoisomers, such as racemates. The enantiomers and stereoisomers of the compounds of this invention can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high-performance liquid chromatography, and by crystallizing the compounds as chiral salt complexes or by crystallizing the compounds in chiral solvents. The enantiomers and stereoisomers can also be obtained by well-known asymmetric synthetic methods using stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts.

[0203] The term "isotope isomers" refers to different molecules that are identical in structure except for their isotopes.

[0204] The term "restricted transisomer" refers to a conformational stereoisomer that arises when rotation around a single bond within a molecule is prevented or significantly slowed by spatial interactions with other parts of the molecule, and when the substituents at the ends of the single bond are asymmetrical; that is, a restricted transisomer does not require a stereocenter. When the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, the separation of individual isomers is permissible (LaPlante et al., J.Med.Chem. 2011, 54, 20, 7005), preferably by chiral resolution.

[0205] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be linked to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds being connected, resulting in a group with a corresponding valence. For example, "pyridyl" indicates... "Oxazolyl" indicates

[0206] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0207] Unless otherwise stated, use Indicates a single bond or a double bond.

[0208] Unless otherwise stated, use The E-type or Z-type, or a mixture of both, represent carbon-carbon double bonds, such as... express Or a mixture of the two.

[0209] Unless otherwise stated, use The E-type or Z-type, or a mixture of both, represent carbon-carbon double bonds, such as... express Or a mixture of the two.

[0210] Unless otherwise stated, the structures of amidines in this invention all include their tautomers, such as:

[0211] Specific pharmaceutical and medical terms

[0212] The term “acceptable,” as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for general therapeutic purposes.

[0213] The terms “treatment,” “treatment process,” or “therapy” as used herein include alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndromes; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; alleviating a disease or symptom; reducing complications arising from a disease or symptom; or preventing or treating signs arising from a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, may improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether administered regularly or intermittently, continuously or intermittently, it may be attributable to or related to the administration.

[0214] "Active ingredient" refers to the compound represented by general formula (1), and pharmaceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers. The asymmetric centers that may exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention means including all such isomeric forms of these compounds.

[0215] The terms “compound,” “composition,” “agent,” or “medicine or medicament” may be used interchangeably here, and all refer to a compound or composition that, when applied to an individual (human or animal), can induce a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0216] The term “administered, administering, or administration” here refers to the direct application of the compound or composition described herein, or the application of a prodrug, derivative, or analog of the active compound.

[0217] While the numerical ranges and parameters used to define the broader scope of this invention are approximate values, the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any value inevitably contains standard deviations due to individual test methods. Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "approximately" may mean that the actual value falls within the acceptable standard error of the mean, as determined by those skilled in the art. Except for experimental examples, or unless explicitly stated otherwise, it is understood that all ranges, quantities, values, and percentages used herein (e.g., to describe material usage, duration, temperature, operating conditions, quantity ratios, and others similar) are modified with "approximately". Therefore, unless otherwise stated, the numerical parameters disclosed in this specification and the accompanying claims are approximate values ​​and are subject to change as needed. At a minimum, these numerical parameters should be understood as the indicated significant digits and values ​​obtained using general rounding.

[0218] Unless otherwise defined in this specification, scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. Furthermore, unless conflicting with the context, singular nouns used herein include their plural forms, and vice versa.

[0219] Therapeutic uses

[0220] The present invention provides a method for treating diseases using compounds or pharmaceutical compositions of general formula (1) of the present invention, including but not limited to conditions involving PI3Kalpha (e.g., cancer, vascular abnormalities, and tissue hyperplasia).

[0221] In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of general structural formula (1). In some embodiments, the cancer is mediated by PI3Kalpha. In other embodiments, the cancer is a hematologic malignancy and a solid tumor, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial carcinoma, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all metastatic cancers.

[0222] route of administration

[0223] The compounds of this invention and their pharmaceutically acceptable salts can be formulated into various preparations, comprising, within a safe and effective range, the compounds of this invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective range of the compound is determined based on the age, condition, and duration of treatment of the patient.

[0224] "Pharmaceutically acceptable excipients or carriers" refers to one or more compatible solid or liquid fillers or gelling substances that 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 and with the compounds of the present invention without significantly reducing the efficacy of the compounds. 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0225] When applying the compounds of this invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0226] 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 components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0227] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0228] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0229] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0230] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0231] 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.

[0232] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0233] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of this invention is applied to the mammal (e.g., human) requiring treatment, wherein the dose administered is a pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 2–1000 mg, and more preferably 2–200 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0234] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features. Attached Figure Description

[0235] Figure 1 shows the effect of the ubiquitination inhibitor TAK243 on the inhibition of compound 7 induced by compound 7 in SW948 cells in biological example 1;

[0236] Figure 2 shows the reduction of P110α in SW948 cells induced by compound 7 induced by the proteasome inhibitor MG132 in biological example 1;

[0237] Figure 3 shows that, compared with the control compounds GDC-0077 and Alpelisib, compounds 7, 64, 142, 183, and 187 inhibited the levels of P110α protein, pAKT, pS6, and pRAS40 in SW948 cells in Biological Example 1.

[0238] Figure 4 shows the level of P110α protein in SKOV3 tumor tissue in vivo by compound 142 in biological example 13. Detailed Implementation

[0239] The following description will elaborate on the specific aspects, characteristics, and advantages of the aforementioned compounds, methods, and pharmaceutical compositions, making the content of this invention readily apparent. It should be understood that the detailed descriptions and examples described below are specific embodiments and are for reference only. After reading this description, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by this application.

[0240] In all embodiments, 1 H-NMR was recorded using a Varian Mercury 400 NMR spectrometer, and chemical shifts are expressed as δ (ppm). Unless otherwise specified, the silica gel used for separation was 200-300 mesh, and all eluent ratios were by volume.

[0241] Example 1: Synthesis of Compound 11

[0242] Step 1: Synthesis of compound int_11-2:

[0243] 5-Bromo-2-hydroxybenzaldehyde (20.0 g, 99.5 mmol) was dissolved in methanol (200 mL), and glyoxal (72.2 g, 1.24 mol) and ammonia (89.7 g, 716 mmol) were added. The reaction mixture was stirred at 30 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude black solid compound int_11-2.

[0244] LCMS m / z(ESI): 238.9 [M+H] + .

[0245] Step 2: Synthesis of compound int_11-3:

[0246] Compound int_11-2 (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 mixture was stirred at 85 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Then, the intermediate int_11-3 was obtained by silica gel chromatography.

[0247] LCMS m / z(ESI): 265.1 [M+H] + .

[0248] Step 3: Synthesis of compound int_11-4:

[0249] Intermediate int_11-3 (19.0 g, 71.7 mmol) was dissolved in N,N-dimethylformamide (200 mL), and N-iodosuccinimide (48.4 g, 215 mmol) was added at 25 °C. The reaction mixture was stirred at 60 °C for 12 hours. Water (500 mL) was added to the reaction mixture, during which a large amount of solid precipitated. The mixture was filtered under reduced pressure, and the filter cake was dissolved in ethyl acetate (1.0 L). The mixture was washed with saturated sodium hydroxide aqueous solution (1.0 L × 2), and then with saturated ammonium chloride (1.0 L × 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give crude yellow solid product int_11-4.

[0250] LCMS m / z(ESI): 516.9 [M+H] + .

[0251] 1 H 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).

[0252] Step 4: Synthesis of compound int_11-5:

[0253] Compound int_11-4 (28.0 g, 54.2 mmol) was dissolved in anhydrous tetrahydrofuran (280 mL), and ethyl magnesium bromide (3 M, 27.1 mL) was added at -20 °C. The reaction mixture was stirred at -20 °C for 3 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (300 mL), and extracted with ethyl acetate (300 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Then, the intermediate int_11-5 was obtained by silica gel chromatography.

[0254] LCMS m / z(ESI): 392.1 [M+H] + .

[0255] 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).

[0256] Step 5: Synthesis of compound int_11-7:

[0257] Compound int_11-5 (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). Under nitrogen protection, 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. The reaction mixture was stirred at 80 °C for 16 hours. After cooling, saturated ammonium chloride aqueous solution (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (100 mL × 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_11-7 was then purified by silica gel chromatography.

[0258] LCMS m / z(ESI): 399.9 [M+H] + .

[0259] 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).

[0260] Step 6: Synthesis of compound int_11-8:

[0261] Compound int_11-7 (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 protection. The reaction mixture was stirred at 80 °C for 16 hours. After cooling, water (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (100 mL × 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_11-8 was then purified by silica gel chromatography.

[0262] LCMS m / z(ESI): 506.1 [M+H] + .

[0263] Step 7: Synthesis of compound int_11-9:

[0264] Compound int_11-8 (330 mg, 652.80 μmol) was dissolved in dichloromethane (12 mL), and then trifluoroacetic acid (1.5 mL, 15.98 mmol) was added. 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, and then the solution was concentrated to dryness under reduced pressure to obtain the crude yellow solid product int_11-9.

[0265] LCMS m / z(ESI): 406.1 [M+H] + .

[0266] Step 8: Synthesis of compound int_11-10:

[0267] Compound int_11-9 (600 mg) and 1-Boc-3-azacyclobutanone (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 ammonium chloride aqueous solution (200 mL), extracted with dichloromethane (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound int_11-10 was then purified by silica gel chromatography.

[0268] LCMS m / z(ESI): 561.3 [M+H] + .

[0269] Step 9: Synthesis of compound int_11-11:

[0270] Compound int_11-10 (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. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture to adjust the pH to 9. The mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude yellow oily product int_11-11.

[0271] LCMS m / z(ESI): 461.0 [M+H] + .

[0272] Step 10: Synthesis of compound int_11-12:

[0273] Compound int_11-11 (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 the mixture was stirred at 100 °C for 1 hour. After cooling, the reaction solution was quenched with ice water (200 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound int_11-12 was then purified by silica gel chromatography.

[0274] LCMS m / z(ESI): 582.1 [M+H] + .

[0275] Step 11: Synthesis of compound int_11-13:

[0276] Compound int_11-12 (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 reacted at 60 °C with stirring for 2 hours. The reaction mixture was filtered through a diatomaceous earth filter, washed with ethanol, and the filtrate was concentrated to dryness under reduced pressure. Saturated sodium bicarbonate solution was added to adjust the pH to 9. The mixture was 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 to give a yellow solid compound int_11-13.

[0277] LCMS m / z(ESI): 551.8 [M+H] + .

[0278] 1 H 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,2H),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).

[0279] Step 12: Synthesis of compound int_11-14:

[0280] Compound int_11-13 (400 mg), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (331 mg, 0.87 mmol), and cyanoacetic acid (68 mg, 0.80 mmol) were dissolved in N,N-dimethylformamide (30 mL), and diisopropylethylamine (281 mg, 2.18 mmol) was added. The reaction mixture was stirred at 25 °C for 16 hours. Water (300 mL) was added to the reaction mixture, 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 purified by slurrying with ethyl acetate (20 mL) to obtain a white solid compound int_11-14.

[0281] LCMS m / z(ESI): 619.3 [M+H] + .

[0282] Step 13: Synthesis of compound int_11-16:

[0283] 2-Bromo-2-methylpropanal (20 g, 132.45 mmol) was dissolved in dichloromethane (250 mL). The reaction solution was cooled to 0 °C, and then 3,3-difluorocyclobutylamine (14.19 g, 132.45 mmol) was added. The mixture was heated to 30 °C and stirred for 36 hours. The reaction solution was concentrated to dryness under reduced pressure, and then purified by silica gel chromatography to obtain the oily compound int_11-16.

[0284] LC-MS m / z (ESI): 178.0 [M+H] + .

[0285] Step 14: Synthesis of Compound 11:

[0286] Compound int_11-16 (4.6 g) was dissolved in dichloromethane (50 mL). The reaction solution was cooled to 0 °C, and pyrrolidine (4 mL) and trimethylchlorosilane (2 mL) were added. The mixture was heated to 25 °C and stirred for 0.5 hours. Then, compound int_11-14 (900 mg, 1.45 mmol) was added, and the mixture was stirred at 25 °C for another hour. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound 11 was then purified by silica gel chromatography.

[0287] LC-MS m / z (ESI): 778.1 [M+H] + .

[0288] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),7.73(d,J=2.9Hz,1H),7.57(s,1H),7.44-7.39(m,2H),7.31(s,1H) ,6.93(dd,J=9.0,2.9Hz,1H),6.88(d,J=8.9Hz,1H),6.83-6.53(m,1H),6.44-6.36(m,2H),5.05-4.92(m,1 H),4.58(m,1H),4.53(m,1H),4.38-4.32(m,4H),4.05(t,J=8.1Hz,1H),3.90(t,J=7.1Hz,2H),3.57(dd,J= 7.4,5.4Hz,2H),3.31-3.28(m,1H),3.14-3.07(m,4H),2.89-2.76(m,2H),2.51-2.46(m,6H),1.34(s,6H).

[0289] Example 2 Synthesis of Compound 94

[0290] Step 1: Synthesis of compound int_94-1:

[0291] Compound int_11-15 (1.3 g, 8.6 mmol) was dissolved in 10 mL of dichloromethane. The reaction solution was cooled to 0 °C, and cyclopropylamine (735.5 mg, 12.9 mmol) was added. After the addition was complete, the temperature was raised to 25 °C and stirred for 20 hours. The reaction solution was quenched with hydrochloric acid aqueous solution (1 N, 30 mL), extracted with dichloromethane (30 mL × 3), and the aqueous phase was retained. The pH of the aqueous phase was adjusted to 10–11 with potassium hydroxide aqueous solution, and then 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 to give a yellow oily compound int_94-1.

[0292] Step 2: Synthesis of Compound 94:

[0293] Compound int_94-1 (61 mg) was dissolved in dichloromethane (8 mL). The reaction solution was cooled to 0 °C, and pyrrolidine (170 mg, 2.41 mmol) and trimethylchlorosilane (87 mg, 1.45 mmol) were added. The mixture was heated to 25 °C and stirred for 0.5 hours. Then, compound int_11-14 (100 mg, 0.16 mmol) was added, and the reaction was stirred at 25 °C for 12 hours. The reaction solution was quenched with water (30 mL), extracted with dichloromethane (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound 94 was then purified by silica gel chromatography.

[0294] LC-MS m / z (ESI): 728.5 [M+H] + .

[0295] 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 8.05 (s, 1H), 7.73 (d, J = 2.9Hz, 1H), 7.48-7.42 (m, 2H), 7.3 0(s,1H),6.96-6.85(m,2H),6.78-6.50(m,1H),6.42(d,J=8.8Hz,2H),5.04-4.91(m,1H),4.64-4. 49(m,2H),4.40-4.30(m,4H),3.91(t,J=7.1Hz,2H),3.59(dd,J=7.5,5.3Hz,2H),3.30(m,1H),3. 08(dd,J=7.2,3.8Hz,4H),2.50(s,4H),2.23(m,1H),1.45(s,6H),1.00-0.93(m,2H),0.86(m,2H).

[0296] Example 3: Synthesis of Compounds 97A and 97B

[0297] Step 1: Synthesis of compound int_97-3:

[0298] At 12 °C, 2,2-difluoroethanol (200 mg, 2.44 mmol), pyridine (578 mg, 7.31 mmol), and 4-dimethylaminopyridine (30 mg, 0.24 mmol) were mixed in a reaction flask, and dichloromethane (4 mL) was added to dissolve and stir for 10 minutes. Then, p-nitrophenyl chloroformate (491 mg, 2.44 mmol) was added, and stirring was continued for 1 hour. The compound int_97-3 was obtained by direct separation and purification by silica gel chromatography.

[0299] Step 2: Synthesis of compound int_97-5:

[0300] (1,1-Dimethyl-2-oxoethyl) tert-butyl carbamate (272 mg, 1.45 mmol) was dissolved in dichloromethane (8 mL). The reaction solution was cooled to 0 °C, and pyrrolidine (517 mg, 7.27 mmol) and trimethylchlorosilane (263 mg, 1.45 mmol) were added. The mixture was heated to 25 °C and stirred for 0.5 hours. Then, compound int_11-14 (300 mg, 0.49 mmol) was added, and the reaction was continued at 25 °C with stirring for 1 hour. The reaction solution was quenched with water (30 mL), extracted with dichloromethane (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Then, compound int_97-5 was obtained by silica gel chromatography.

[0301] LC-MS m / z (ESI): 788.4 [M+H] + .

[0302] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),9.37(s,1H),7.77(d,J=2.9Hz,1H),7.73(d,J=1.6Hz,1H),7.4 6(d,J=8.8Hz,2H),7.34(s,1H),6.96(dd,J=8.9,2.9Hz,1H),6.91(d,J=8.9Hz,1H),6.81-6.53(m,1H ),6.45(d,J=8.8Hz,2H),4.62(t,J=9.1Hz,1H),4.99(m,1H),4.56(m,2H),4.42-4.36(m,4H),3.94(t ,J=7.1Hz,2H),3.64-3.60(m,2H),3.32(m,1H),3.11(m,4H),2.51(m,4H),1.55(s,9H),1.51(s,6H).

[0303] Step 3: Synthesis of compound int_97-6:

[0304] Compound int_97-5 (386 mg, 0.49 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred at 25 °C for 1.5 hours. Under ice-water bath cooling, saturated sodium bicarbonate aqueous solution was added to adjust the pH to 8. The mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Then, compound int_97-6 was obtained by silica gel chromatography.

[0305] LC-MS m / z (ESI): 688.4 [M+H] + .

[0306] 1 H NMR (400MHz, DMSO-d6) δ10.50 (s, 1H), 8.24 (s, 1H), 7.77 (d, J = 2.9Hz, 1H), 7.53-7.46 (m, 2H),7.34(s,1H),6.99-6.90(m,2H),6.83-6.52(m,1H),6.48-6.41(m,2H),5.07-4.95(m, 1H),4.62-4.56(m,2H),4.42-4.39(m,2H),4.38-4.35(m,2H),3.94(t,J=7.1Hz,2H),3.6 2(dd,J=7.5,5.4Hz,2H),3.33-3.27(m,1H),3.14-3.09(m,4H),2.53(m,4H),1.44(s,6H).

[0307] Step 4: Synthesis of compounds 97A and 97B:

[0308] Compounds int_97-3 (36 mg, 0.145 mmol) and int_97-6 (100 mg, 0.145 mmol) were dissolved in acetonitrile (2 mL) at 20 °C and stirred for 2 hours. The reaction solution was directly purified by preparative liquid chromatography to obtain compounds 97A and 97B.

[0309] Compound 97A:

[0310] LC-MS m / z (ESI): 796.3 [M+H] + Rt: 0.932 min.

[0311] 1H NMR (400MHz, DMSO-d6) δ11.49(s,1H),9.41(s,1H),7.75(m,2H),7.43(d,J=8.4Hz, 2H),7.31(s,1H),6.96-6.85(m,2H),6.78-6.50(m,1H),6.43-6.26(m,3H),5.05-4 .92(m,1H),4.63-4.49(m,4H),4.40-4.30(m,4H),3.90(t,J=7.1Hz,2H),3.59(dd, J=7.5,5.3Hz,2H),3.27-3.25(m,1H),3.13-3.01(m,4H),2.50(s,4H),1.51(s,6H).

[0312] Compound 97B:

[0313] LC-MS m / z (ESI): 796.3 [M+H] + Rt: 1.121 min.

[0314] 1 H NMR (400MHz, DMSO-d6) δ11.61(s,1H),10.40(s,1H),8.03(s,1H),7.74(d,J=2.8Hz,1H) ,7.38(d,J=8.5Hz,2H),7.31(s,1H),6.97-6.85(m,2H),6.78-6.50(m,1H),6.44-6.42( m,3H),5.01-4.96(m,1H),4.63-4.49(m,2H),4.36-4.32(m,6H),3.90(t,J=7.1Hz,2H), 3.59(t,J=6.3Hz,2H),3.27-3.25(m,1H),3.13-3.04(m,4H),2.50(s,4H),1.39(s,6H).

[0315] Example 4: Synthesis of Compounds 102A and 102B

[0316] Compound int_97-6 (100 mg, 0.145 mmol) was dissolved in N,N-dimethylformamide (5 mL) at 5 °C. Triethylamine (74 mg, 0.727 mmol) and methylaminoformyl chloride (68 mg, 0.727 mmol) were added, and the mixture was heated to 14 °C and stirred for 4 hours. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography to obtain compounds 102A and 102B.

[0317] Compound 102A:

[0318] LC-MS m / z (ESI): 745.1 [M+H] + Rt = 0.983 min.

[0319] 1 H NMR (400MHz, DMSO-d6) δ11.58(s,1H),9.87(d,J=2.2Hz,1H),7.83(d,J=2.1Hz,1H),7.74(d,J=2.9Hz,1H),7. 64–7.58(m,2H),7.31(s,1H),7.28(d,J=4.8Hz,1H),6.93(dd,J=9.0,2.9Hz,1H),6.88(d,J=8.9Hz,1H),6.79 –6.49(m,1H),6.44–6.35(m,2H),5.04–4.93(m,1H),4.65–4.49(m,2H),4.40–4.30(m,4H),3.91(t,J=7.0Hz, 2H), 3.59 (dd, J = 7.4, 5.4Hz, 2H), 3.30 (m, 1H), 3.08 (m, 4H), 2.63 (d, J = 4.7Hz, 3H), 2.50 (m, 4H), 1.34 (s, 6H).

[0320] Compound 102B:

[0321] LC-MS m / z (ESI): 745.1 [M+H] + Rt = 0.938 min.

[0322] 1H NMR (400MHz, DMSO-d6) δ10.03(s,1H),9.88(d,J=4.8Hz,1H),8.85(s,1H),7.74(d,J=2.9Hz,1H),7.61(s, 1H),7.45–7.39(m,2H),7.31(s,1H),6.93(dd,J=9.0,2.9Hz,1H),6.88(d,J=8.8Hz,1H),6.79–6.49(m,1H ),6.44–6.38(m,2H),5.04–4.93(m,1H),4.61–4.50(m,2H),4.42–4.30(m,4H),3.91(t,J=7.1Hz,2H),3.5 9(dd,J=7.5,5.3Hz,2H),3.30(m,1H),3.13–3.04(m,4H),2.71(d,J=4.6Hz,3H),2.50(s,4H),1.55(s,6H).

[0323] Example 5 Synthesis of Compound 171

[0324] Step 1: Synthesis of compound int_171-1:

[0325] Compound int_11-15 (1.3 g, 8.6 mmol) was dissolved in dichloromethane (20 mL). The reaction solution was cooled to 0 °C, and aniline (1.6 g, 17.21 mmol) was added. After the addition was complete, the mixture was stirred at 25 °C for 20 hours. The reaction solution was quenched with 1 N hydrochloric acid aqueous solution (30 mL), and then extracted with dichloromethane (30 mL × 3). The aqueous phase was collected, and the pH of the aqueous phase was adjusted to 10–11 with potassium hydroxide aqueous solution. The mixture was then 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 to obtain a yellow oily compound int_171-1 (crude product, directly added to the next reaction).

[0326] LC-MS m / z (ESI): 164.2 [M+H] + .

[0327] Step 2: Synthesis of Compound 171:

[0328] Compound int_171-1 (132 mg) was dissolved in dichloromethane (8 mL). The reaction solution was cooled to 0 °C, and pyrrolidine (171 mg, 2.4 mmol) and trimethylchlorosilane (176 mg, 1.61 mmol) were added. The mixture was heated to 25 °C and stirred for 0.5 hours. Then, compound int_11-14 (100 mg, 0.16 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution (30 mL), extracted with dichloromethane (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound 171 was then purified by silica gel chromatography.

[0329] LC-MS m / z (ESI): 764.4 [M+H] + .

[0330] 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),7.91(s,1H),7.74(d,J=2.9Hz,1H),7.65-7.52(m,2H ),7.52-7.40(m,3H),7.33-7.25(m,3H),6.96-6.85(m,2H),6.78-6.50(m,1H),6.46-6.38(m ,2H),5.04-4.92(m,1H),4.65-4.49(m,2H),4.40-4.29(m,4H),3.90(t,J=7.1Hz,2H),3.58 (dd,J=7.5,5.4Hz,2H),3.27-3.25(m,1H),3.07(d,J=6.2Hz,4H),2.49(m,4H),1.30(s,6H).

[0331] Example 6 Synthesis of Compound 179

[0332] Compound int_97-6 (100 mg, 0.145 mmol) was dissolved in N,N-dimethylformamide (5 mL) at 5 °C. 2-pyridinecarboxylic acid (35.8 mg, 0.291 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (66 mg, 0.174 mmol) were added dropwise, followed by the addition of N,N-diisopropylethylamine (38 mg, 0.291 mmol). The mixture was heated to 40 °C and stirred for 2 hours. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative liquid chromatography to obtain compound 179.

[0333] LC-MS m / z (ESI): 793.4 [M+H] + .

[0334] 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),11.03(s,1H),8.82(d,J=4.5Hz,1H),8.14(d,J=7.8Hz,1H), 8.06(s,1H),8.04-7.95(m,1H),7.88(d,J=8.6Hz,2H),7.74(d,J=2.8Hz,1H),7.61(s,1H),7.30(s ,1H),6.97-6.85(m,2H),6.78–6.50(m,3H),5.01(m,1H),4.66-4.48(m,2H),4.35(d,J=8.2Hz,4H) ,3.93(t,J=7.0Hz,2H),3.61(t,J=6.5Hz,2H),3.31(m,1H),3.08(s,4H),2.50(s,4H),1.44(s,6H).

[0335] Example 7 Synthesis of Compounds 152A and 152B

[0336] Step 1: Synthesis of compound int_152-2:

[0337] Compound int_11-9 (3.6 g) and tert-butyl 2-methyl-3-oxozyracyclobutane-1-carboxylic acid (2.0 g, 10.81 mmol) were dissolved in methanol (200 mL). Triethylamine (3.0 g, 29.70 mmol) and acetic acid (2.9 g, 48.33 mmol) were added, and the mixture was stirred at 25 °C for 40 min. Sodium cyanoborohydride (1.87 g, 29.68 mmol) was then added, and the reaction mixture was heated to 40 °C and stirred for 16 h. The reaction mixture was quenched in cold water, and the aqueous phase was extracted with dichloromethane (60 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound int_152-2 was then purified by silica gel chromatography.

[0338] LC-MS m / z (ESI): 575.1 [M+H] + .

[0339] Step 2: Synthesis of compound int_152-3:

[0340] Compound int_152-2 (2.6 g, 4.53 mmol) was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (8 mL) was added. The mixture was stirred at 25 °C for 3 hours. The reaction solution was poured into cold water (100 mL), and saturated sodium bicarbonate solution was added to adjust the pH to approximately 8. The aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude solid compound int_152-3.

[0341] LC-MS m / z (ESI): 475.0 [M+H] + .

[0342] Step 3: Synthesis of compound int_152-4:

[0343] Compound int_152-3 (2.2 g) was dissolved in N,N-dimethylformamide (100 mL), and p-fluoronitrobenzene (1.5 g, 10.64 mmol) and potassium carbonate (2.28 g, 16.52 mmol) were added. The mixture was heated to 100 °C and stirred for 1 hour under nitrogen protection. After cooling, the reaction solution was poured into ice water (200 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Then, compound int_152-4 was obtained by silica gel chromatography.

[0344] LC-MS m / z (ESI): 596.1 [M+H] + .

[0345] Step 4: Synthesis of compound int_152-5:

[0346] Compound int_152-4 (1.0 g, 1.68 mmol) was dissolved in ethanol / water (6 / 1, 120 mL), and reduced iron powder (939 mg, 16.77 mmol) and ammonium chloride (1.3 g, 24.30 mmol) were added. The mixture was heated to 60 °C and stirred for 1 hour. The reaction solution was filtered while hot, concentrated, and then saturated sodium bicarbonate aqueous solution (120 mL) was added. The aqueous phase was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give crude solid compound int_152-5.

[0347] LC-MS m / z (ESI): 566.0 [M+H] + .

[0348] Step 5: Synthesis of compound int_152-6:

[0349] Compound int_152-5 (1.0 g) was dissolved in N,N-dimethylformamide (100 mL), followed by the addition of cyanoacetic acid (230 mg, 2.71 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (810 mg, 2.13 mmol) and N,N-diisopropylethylamine (600 mg, 4.65 mmol). The mixture was stirred at 30 °C for 2 hours under nitrogen protection. The reaction solution was poured into cold water (200 mL), and a solid precipitated. After filtration, the solid was washed with ethyl acetate and concentrated to dryness under reduced pressure to give a yellow solid compound int_152-6.

[0350] LC-MS m / z (ESI): 633.0 [M+H] + .

[0351] Step 6: Synthesis of Compound 152A and Compound 152B:

[0352] 2-Methyl-2-(oxetane-3-ylamino)propionaldehyde (491 mg, 3.43 mmol) was dissolved in dichloromethane (70 mL). Under nitrogen protection, pyrrolidine (610 mg, 8.59 mmol) was added, the mixture was cooled to 0 °C, and trimethylchlorosilane (464 mg, 4.30 mmol) was added. The mixture was stirred at 25 °C for 0.5 hours, and then compound int_152-6 (500 mg, 0.859 mmol) was added. The mixture was stirred for another 12 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (100 mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was purified by preparative liquid chromatography (column: waters Xbridge Prep OBDTM C18, 150 × 19 mm × 5 μm, 12 nm; mobile phase A: 0.2% NH3.H2O in waters; mobile phase B: CAN) to give a yellow solid compound 152A (a 1:1 mixture of isomers) and compound 152B (a 1:1 mixture of isomers).

[0353] LC-MS analysis method:

[0354] Instruments: LC (Agilent 1290Infinity II) + MS (Agilent G6125B)

[0355] Column: Agilent Poroshell 120EC-C18 (2.1mm*50mm, 1.9μm)

[0356] Mobile phase: A: 0.05% FA in H2O; B: 0.05% FA in ACN

[0357] Elution gradient: 5% B to 100% B in 1.8 min; then to 95% B in 0.6 min.

[0358] Flow rate: 0.8 mL / min

[0359] Column temperature: 40℃

[0360] Detection wavelength: 220nm / 254nm

[0361] Chiral analysis methods:

[0362] Instrument: Agilent 1260Ⅱ

[0363] Column: Chiralpak IC (4.6 mm I.D. * 250 mm L, 5 μm)

[0364] Mobile phase: HEX-IPA-EtOH-DCM-EDA = 10:30:50:25:0.1

[0365] Elution gradient: isocratic elution

[0366] Flow rate: 0.8 mL / min

[0367] Column temperature: 30℃

[0368] Detection wavelength: 220nm / 254nm

[0369] Compound 152A:

[0370] LC-MS m / z (ESI): 758.1 [M+H] + Rt: 0.921 min.

[0371] Chiral HPLC Rt:20.94min,22.27min.

[0372] 1H NMR (400MHz, DMSO-d6) δ12.42(s,1H),7.73(d,J=2.7Hz,1H),7.56(s,1H),7.43(d,J=8.6Hz,3H),7. 30(s,1H),6.95-6.85(m,2H),6.82-6.45(m,3H),5.07-4.98(m,1H),4.98-4.79(m,3H),4.74-4.71( m,1H),4.64-4.50(m,2H),4.42-4.29(m,4H),3.97(t,J=6.9Hz,1H),3.83-3.79(m,1H),3.27-3.25( m,1H),3.09-3.06(m,4H),2.81-2.78(m,1H),2.47-2.41(m,4H),1.42(d,J=6.0Hz,3H),1.21(s,6H).

[0373] Compound 152B:

[0374] LC-MS m / z (ESI): 758.1 [M+H] + Rt: 1.035 min.

[0375] Chiral HPLC Rt:25.15min,27.64min.

[0376] 1 H NMR(400MHz,DMSO-d6)δ12.37(s,1H),7.75(d,J=2.8Hz,1H),7.56(s,1H),7.48-7.39(m,3H),7 .31(s,1H),6.97-6.85(m,2H),6.78-6.50(m,1H),6.43-6.36(m,2H),5.02(s,1H),4.90(s,3H), 4.74-4.70(m,1H),4.63-4.51(m,2H),4.41-4.32(m,4H),4.32-4.21(m,1H),3.68(p,J=7.3Hz, 2H),3.21(d,J=6.8Hz,1H),3.13-3.06(m,4H),2.45(s,4H),1.25(d,J=6.2Hz,3H),1.21(s,6H).

[0377] Example 8 Synthesis of Compound 203

[0378] Step 1: Synthesis of compound int_203-1:

[0379] Compound int_11-15 (2 g, 13.33 mmol) was dissolved in dichloromethane (60 mL), and 3-aminopyridine (1.4 g, 14.89 mmol) was added. The mixture was stirred at 25 °C for 48 hours under nitrogen protection. The reaction solution was quenched in ice water, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to finally obtain compound int_203-1.

[0380] LC-MS m / z (ESI): 164.9 [M+H] + .

[0381] Step 2: Synthesis of compound int_203-3:

[0382] Compound int_203-1 (600 mg, 3.65 mmol) was dissolved in dichloromethane (20 mL). Under nitrogen protection, pyrrolidine (5.2 g, 73 mmol) was added, followed by diethyl malonate (580 mg, 3.65 mmol). The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated and purified by C18 reverse-phase column chromatography to obtain compound int_203-3.

[0383] LC-MS m / z (ESI): 261.1 [M+H] + .

[0384] Step 3: Synthesis of compound int_203-4:

[0385] Compound int_203-3 (430 mg, 1.65 mmol) was dissolved in methanol (5 mL), water (5 mL) was added, and then lithium hydroxide (346 mg, 8.25 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, the pH was adjusted to 3-4 with dilute hydrochloric acid, and purified by C18 reverse-phase column chromatography to obtain compound int_203-4.

[0386] LC-MS m / z (ESI): 233.1 [M+H] + .

[0387] Step 4: Synthesis of compound 203:

[0388] Compound int_203-4 (62 mg, 0.267 mmol) was dissolved in dichloromethane (20 mL) under nitrogen protection. Compound int_11-13 (147 mg, 0.267 mmol) was added, followed by triethylamine (81 mg, 0.801 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (203 mg, 0.534 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and purified sequentially by C18 reversed-phase column chromatography and silica gel chromatography to obtain compound 203.

[0389] LC-MS m / z (ESI): 766.4 [M+H] + .

[0390] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.64(dd,J=4.8,1.6Hz,1H),8.52(d,J=2.5Hz,1H),8.16(s,1H ),7.86–7.69(m,2H),7.56(dd,J=8.2,4.8Hz,1H),7.45(d,J=8.5Hz,2H),7.32(s,1H),6.98–6.83(m, 2H),6.79–6.52(m,1H),6.43(d,J=8.4Hz,2H),5.10–4.85(m,1H),4.67–4.48(m,2H),4.46–4.25(m,4 H),3.92(t,J=7.1Hz,2H),3.60(t,J=6.5Hz,2H),3.27(m,1H),3.09(s,4H),2.52(m,4H),1.37(s,6H).

[0391] Example 9 Synthesis of Compound 241

[0392] Step 1: Synthesis of compound int_241-2:

[0393] Compound int_241-1 (1.4 g, 4.036 mmol), (4S)-4-(difluoromethyl)-1,3-oxazolidin-2-one (608 mg, 4.439 mmol), copper acetate (366 mg, 2.018 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (342 mg, 2.421 mmol), and cesium carbonate (2.6 g, 8.072 mmol) were mixed in 2-methyltetrahydrofuran (50 mL) and heated to 80 °C and stirred for 16 hours under argon protection. After cooling, the reaction solution was quenched with ammonium chloride aqueous solution (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound int_241-2.

[0394] LC-MS m / z (ESI): 357.1 [M+H] + .

[0395] Step 2: Synthesis of compound int_241-3:

[0396] Compound int_241-2 (1.33 g, 3.72 mmol), N-tert-butoxycarbonylpiperazine (763 mg, 4.09 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (488 mg, 0.56 mmol), and cesium carbonate (2.4 g, 7.45 mmol) were mixed in dioxane (30 mL) and heated to 100 °C and stirred for 16 hours under argon protection. After cooling, the reaction solution was filtered, the filtrate was evaporated to dryness, and purified by C18 reversed-phase column chromatography to obtain compound int_241-3.

[0397] LC-MS m / z (ESI): 507.3 [M+H] + .

[0398] Step 3: Synthesis of compound int_241-4:

[0399] Compound int_241-3 (1.6 g, 3.16 mmol) was dissolved in dichloromethane (10 mL), and 1,4-dioxane hydrochloride solution (4 M, 10 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was directly evaporated to dryness to obtain crude yellow solid compound int_241-4, which was used directly in the next reaction.

[0400] LC-MS m / z (ESI): 407.2 [M+H]+ .

[0401] Step 4: Synthesis of compound int_241-5:

[0402] Compound int_241-4 (1.3 g) and tert-butyl 3-oxozylidene-1-carboxylic acid (809 mg, 4.74 mmol) were added to methanol (20 mL), followed by acetic acid (0.1 mL) and sodium cyanoborohydride (400 mg, 6.32 mmol). The mixture was heated to 60 °C and stirred for 5 hours. After cooling, the reaction solution was concentrated to remove some of the methanol, and water (60 mL) was added. The solution was extracted with dichloromethane (60 mL × 3). The organic phases were combined, concentrated, and purified by C18 reversed-phase column chromatography to obtain compound int_241-5.

[0403] LC-MS m / z (ESI): 562.3 [M+H] + .

[0404] Step 5: Synthesis of compound int_241-6:

[0405] Compound int_241-5 (1.48 g, 2.63 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (4 mL) was added. The mixture was stirred at room temperature for 1 hour. The solution was then concentrated to dryness to obtain crude yellow oily compound int_241-6, which was used directly in the next reaction.

[0406] LC-MS m / z (ESI): 462.2 [M+H] + .

[0407] Step 6: Synthesis of compound int_241-7:

[0408] Compound int_241-6 (1.21 g) was added to N,N-dimethylformamide (15 mL), and potassium carbonate (3.26 g, 23.67 mmol) was added in portions under ice-water bath cooling. Then p-fluoronitrobenzene (400 mg, 2.89 mmol) was added, and the mixture was heated to 60 °C and stirred for 10 hours. After cooling, water (80 mL) was added, the mixture was filtered, and the filter cake was collected and dried to give a yellow solid compound int_241-7.

[0409] LC-MS m / z (ESI): 583.3 [M+H] + .

[0410] Step 7: Synthesis of compound int_241-8:

[0411] Compound int_241-7 (1.3 g, 2.233 mmol) was dissolved in methanol (65 mL), and acetic acid (1 mL) and zinc powder (4.3 g, 67.010 mmol) were added. The mixture was stirred at room temperature for 2 hours. After dilution with dichloromethane, the mixture was filtered. The pH of the filtrate was adjusted to 9–10 with saturated sodium bicarbonate solution. The filtrate was concentrated to remove some methanol, and extracted with dichloromethane (60 mL × 3). The organic phases were combined, concentrated, and purified by C18 reversed-phase column chromatography to obtain compound int_241-8.

[0412] LC-MS m / z (ESI): 553.3 [M+H] + .

[0413] Step 8: Synthesis of compound int_241-9:

[0414] Compound int_241-8 (1.1 g, 1.993 mmol), 2-cyanoacetic acid (185 mg, 2.192 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (960 mg, 2.989 mmol) were dissolved in N,N-dimethylformamide (12 mL), followed by the addition of N,N-diisopropylethylamine (760 mg, 5.978 mmol). The mixture was stirred at room temperature for 1 hour. Water (60 mL) was added to the reaction solution, and the mixture was filtered. The filter cake was dried to obtain compound int_241-9.

[0415] LC-MS m / z (ESI): 620.3 [M+H] + .

[0416] Step 9: Synthesis of compound int_241-11:

[0417] 5-(trifluoromethyl)thiazol-2-amine (1.2 g, 7.136 mmol) and potassium carbonate (2.9 g, 21.411 mmol) were mixed in acetonitrile (25 mL), and then compound int_11-15 (1.6 g, 10.700 mmol) was added. The tube was sealed and stirred at 50 °C for 16 hours. The potassium carbonate was removed by filtration, the mixture was concentrated to dryness, and purified by silica gel chromatography to obtain compound int_241-11.

[0418] LC-MS m / z (ESI): 239.1 [M+H] + .

[0419] Step 10: Synthesis of Compound 241:

[0420] Compounds int_241-9 (250 mg, 0.403 mmol) and int_499-911 (125 mg, 0.605 mmol) were mixed in dichloromethane (12 mL), and pyrrolidine (573 mg, 8.060 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to dryness and purified by C18 reversed-phase column chromatography and silica gel chromatography to obtain compound 241.

[0421] LC-MS m / z (ESI): 840.6 [M+H] + .

[0422] 1 H NMR (400MHz, DMSO-d6) δ10.16 (s, 1H), 9.27 (s, 1H), 8.08 (q, J = 1.5Hz, 1H), 7.97 (s,1H),7.81(s,1H),7.54–7.39(m,4H),6.86–6.53(m,1H),6.48–6.37(m,2H), 5.12–4.94(m,1H),4.64–4.52(m,2H),4.41(m,4H),3.92(t,J=7.0Hz,2H),3.60 (m,2H),3.41(t,J=4.9Hz,4H),3.27(m,1H),2.45(d,J=5.1Hz,4H),1.72(s,6H).

[0423] Example 10 Synthesis of Compound 420

[0424] Step 1: Synthesis of compound int_420-2:

[0425] Compound int_11-11 (31.4 g, 0.0682 mol) was dissolved in dioxane (1 L), and 5-iodo-1-methyl-3-nitro-1H-pyrazole (20.41 g, 0.0807 mol), cesium carbonate (44 g, 0.135 mol), and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene palladium dichloride (2.57 g, 3.391 mmol) were added. The mixture was refluxed under nitrogen protection for 24 hours. After cooling, the reaction solution was filtered, the filtrate was concentrated, and the compound int_420-2 was obtained by silica gel chromatography.

[0426] LC-MS m / z (ESI): 586 [M+H] + .

[0427] Step 2: Synthesis of compound int_420-3:

[0428] Compound int_420-2 (30 g, 0.0512 mol) was dissolved in tetrahydrofuran / methanol (300 mL / 300 mL), and palladium on carbon (3 g, 10% wt) was added. The mixture was hydrogenated at atmospheric pressure for 24 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain compound int_420-3.

[0429] LC-MS m / z (ESI): 556 [M+H] + .

[0430] Step 3: Synthesis of compound int_420-4:

[0431] Compound int_420-3 (25.2 g, 0.0453 mol) was dissolved in N,N-dimethylformamide (250 mL), and cyanoacetic acid (5.82 g, 0.0685 mol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (25.8 g, 0.0679 mol) were added. The reaction mixture was cooled to 0 °C under nitrogen protection, and then triethylamine (9.16 g, 0.0907 mol) was added with stirring. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched dropwise in water (3 L), resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was dried under vacuum to obtain compound int_420-4.

[0432] LC-MS m / z(ESI): 623 [M+H] + .

[0433] Step 4: Synthesis of compound int_420-6:

[0434] 5-(trifluoromethyl)oxazol-2-amine (900 mg, 5.918 mmol), compound int_11-15 (1.34 g, 8.877 mmol), potassium carbonate (2.45 g, 17.754 mmol), and acetonitrile (30 mL) were added to a sealed tube, heated to 50 °C, and stirred for 16 hours. The reaction solution was concentrated to dryness and purified by C18 reverse-phase column chromatography to obtain compound int_420-6.

[0435] LC-MS m / z (ESI): 223.1 [M+H] + .

[0436] Step 5: Synthesis of Compound 420:

[0437] Compounds int_420-6 (571 mg, 2.57 mmol) and int_420-4 (800 mg, 1.286 mmol) were added to dichloromethane (20 mL), followed by tetrahydropyrrole (2.74 g, 38.58 mmol). The mixture was stirred at room temperature for 1 hour. Water (30 mL) and dichloromethane (30 mL) were added, the organic phase was separated, concentrated to dryness, and purified by C18 reversed-phase column chromatography to obtain compound 420.

[0438] LC-MS m / z (ESI): 827.3 [M+H] + .

[0439] 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H),9.47–9.33(m,1H),8.76(q,J=1.7Hz,1H),7.91(d,J=1 .6Hz,1H),7.76(d,J=2.9Hz,1H),7.33(s,1H),7.00–6.87(m,2H),6.66(dd,J=57.1,54.2Hz,1 H),5.93(s,1H),5.12–4.92(m,1H),4.64–4.53(m,2H),4.43–4.32(m,4H),3.97(t,J=7.1Hz, 2H),3.71(t,J=6.6Hz,2H),3.47(s,3H),3.27(m,1H),3.10(s,4H),2.50(m,4H),1.60(s,6H).

[0440] Using a similar synthesis method to that of Examples 1-10 above, and with different raw materials, the target compounds in Table 1 can be obtained.

[0441] Table 1

[0442] Biological Example 1: In vitro pharmacodynamic experiments of some compounds of the present invention in HCC1954 and SW948 cells—detection of P110α ubiquitination, protein level changes, and pathway-related markers induced by the compounds.

[0443] HCC1954 cells were cultured in adherent medium at 37°C with 10% fetal bovine serum and 1% P / S, using 1640 medium supplemented with 10% fetal bovine serum and 1% P / S. When cell saturation reached 80%-90%, cells were digested, counted, and a cell suspension was prepared. 3 x 10⁵ cells were seeded per well in a 24-well cell culture plate. Multiple dilutions of the compound were added to the cell culture plate. After treatment at the corresponding time points, samples were collected and lysed at 4°C for 20 min using lysis buffer. The cells were centrifuged at 12000 rpm for 10 min, and the supernatant was used for Western blotting to detect P110α ubiquitination, protein level changes, and pathway-related markers.

[0444] SW948 cells were cultured in adherent DMEM medium supplemented with 10% fetal bovine serum, 1% P / S, and 5 μg / mL insulin, at 37°C and 5% CO2. When cell saturation reached 80%-90%, cells were digested, counted, and a cell suspension was prepared. Cells were then seeded at 3 x 1024 wells in 24-well cell culture plates. 5 Cells were treated with either a proteasome inhibitor (MG132) or a ubiquitinase inhibitor (TAK243) at multiple dilutions. After treatment for the corresponding time points, the cells were collected and lysed at 4°C for 20 min. The cells were then centrifuged at 12000 rpm for 10 min, and the supernatant was used for Western blotting to detect P110α ubiquitination, protein level changes, and pathway-related markers. The results are shown in Figures 1 and 2.

[0445] As shown in Figure 1, the compounds of the present invention induce distinct double bands for P110α in Western blotting in a dose-dependent manner. The double bands induced by the compounds of the present invention can be dose-dependently prevented using ubiquitin inhibitors, demonstrating that the compound-induced double bands are caused by protein ubiquitination. As shown in Figure 2, the compounds of the present invention can induce P110α degradation in a dose-dependent manner, and proteasome inhibitors can prevent the degradation of P110α induced by the compounds of the present invention. As shown in Figure 3, the compounds of the present invention can induce P110α ubiquitination and degradation in a dose-dependent manner even at low concentrations, and inhibit the phosphorylation of downstream related proteins.

[0446] Biological Example 2: In vitro experiment to inhibit the activity of PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ kinases by the compounds of the present invention.

[0447] The ADP-Glo ​​Kinase Assay kit was used in the experiment, and the procedure was followed according to the instructions. The following buffer solutions were prepared: 50 mM HEPES, pH 7.5, 3 mM MgCl2, 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS, and 2 mM DTT. The test compound samples were dissolved in DMSO, diluted 3-fold at a predetermined starting concentration (e.g., 10 μM), and added to the screening system. A DMSO control and a control without kinase were also included. The optimal concentrations of PI3Kα, PI3Kδ, PI3Kβ, and PI3Kγ enzymes, substrate (PIP2), and ATP were prepared using buffer solutions. The enzyme reaction system included: buffer solution, 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 allowed to react at room temperature for 1 hour. The reaction was terminated by adding a stop reagent (ADP-Glo ​​reagent, 5 μL), and the ADP content in the system was detected using a detection reagent (Kinase Detection Reagent, 10 μL). Signal data were collected using an Envision instrument. The inhibition rate was calculated using the following formula: % Inhibition rate = (DMSO control signal value - Sample signal value) / (DMSO control signal value - Untreated control signal value). Y = Bottom + (Top - Bottom) / (1 + (IC50) 50 The formula / X)^HillSlope) is fitted to a curve to obtain IC. 50 Values. The results are shown in Table 2 below.

[0448] Table 2. Inhibitory activity of the compounds of this invention against PI3K kinase (IC50) 50 (nM)

[0449] Biological Example 3: In vitro inhibition of HCC1954 cell proliferation by the compound of the present invention.

[0450] HCC1954 (PI3KαH1047R mutant) cells were seeded in 384-well plates (Fisher 142762) with 2000 cells per well. On the second day, serially diluted compounds were added. 144 hours after compound addition, CellTiter-Lumi (Beyotime C0068XL) was added to measure ATP levels in the cells, assess cell growth, and calculate the IC50 of the compound in inhibiting cell growth. 50 The results are shown in Table 3 below.

[0451] Table 3. Inhibitory activity of the compounds of the present invention against HCC1954 cells (IC50) 50 ,nM)

[0452] <50nM:++++

[0453] 50~100nM:+++

[0454] 100~500nM:++

[0455] >500nM:+

[0456] Biological Example 4: In vitro inhibition of MCF-7 cell proliferation by the compound of the present invention.

[0457] MCF-7 (PI3KαE545K mutant) cells were seeded in 384-well plates (Fisher 142762) with 2000 cells per well. On the second day, serially diluted compounds were added. 144 hours after compound addition, CellTiter-Lumi (Beyotime C0068XL) was added to measure ATP levels in the cells, assess cell growth, and calculate the IC50 of the compound in inhibiting cell growth. 50 The results are shown in Table 4 below.

[0458] Table 4. Inhibitory activity of the compounds of the present invention against MCF-7 cells (IC50) 50 ,nM)

[0459] <10nM:++++

[0460] 10~50nM:++

[0461] 50~100nM:++

[0462] >100nM:+

[0463] Biological Example 5: In vitro inhibition of SKOV3 cell proliferation by some compounds of the present invention.

[0464] SKOV3 (PI3KαH1047R mutant) cells were cultured in McCoy's 5A medium supplemented with 10% fetal bovine serum and 1% P / S, at 37°C and 5% CO2. When cell saturation reached 80%-90%, cells were digested, counted, and a cell suspension was prepared. 1500 cells were seeded per well in 96-well plates. Five 5-fold dilutions of the compound were added to the cell culture plates. After 7 days of incubation at 37°C and 5% CO2, cell viability was assessed using CellTiter-Glo 3D Reagent (Promega) to evaluate cell growth and calculate the IC50 (inhibition rate) of the compound on cell growth. 50 The results are shown in Table 5 below.

[0465] Table 5. Inhibitory activity of the compounds of the present invention against SKOV3 cells (IC50) 50 ,nM)

[0466] Biological Example 6: In vitro inhibition of T47D cell proliferation by some compounds of the present invention.

[0467] T47D cells were cultured in adherent medium at 37°C with 10% fetal bovine serum, 1% P / S, and 10 μg / mL insulin, under the following conditions: 1640 medium. When cell saturation reached 80%-90%, cells were digested, counted, and a cell suspension was prepared. 1000 cells were seeded per well in 96-well plates. Five 5-fold dilutions of the compound were added to the cell culture plates. After 7 days of incubation at 37°C with 5% CO2, cell viability was assessed using CellTiter-Glo Reagent (Promega). The results are shown in Table 6 below.

[0468] Table 6. Inhibitory activity of the compounds of the present invention against T47D cells (IC50) 50 ,nM)

[0469] Biological Example 7: Inhibitory effect of some compounds of the present invention on pAKT(S473) in HCC1954 cells.

[0470] HCC1954 cells were cultured adherently in 1640 medium supplemented with 10% fetal bovine serum and 1% P / S, at 37°C and 5% CO2. When cell saturation reached 80%-90%, cells were digested, counted, and a cell suspension was prepared. 8000 cells were seeded per well in a 96-well permeable plate. Five 5-fold dilutions of the compound were added to the cell culture plates, which were then incubated at 37°C for 0.5h, 6h, and 24h in a 5% CO2 incubator. After fixation, pAKT (S473) antibody was added and incubated overnight at 4°C. Cells were washed, and HRP secondary antibody was added and incubated at room temperature for 2h. Cells were washed again, and ECL staining was performed for 30min. Lum fluorescence signal was detected using a microplate reader.

[0471] Table 7. Inhibition of pAKT(S473) in HCC1954 cells by the compounds of this invention (IC50). 50 ,nM)

[0472] <5nM:++++

[0473] 5~50nM:++

[0474] 50~100nM:++

[0475] >100nM:+

[0476] Biological Example 8: In vivo pharmacokinetic experiments of the compounds of the present invention

[0477] Female CD-1 mice aged 7 to 10 weeks were selected, and the intravenous and oral doses were 1 mg / kg and 10 mg / kg, respectively. Mice were fasted for at least 12 hours before administration, and were given food 4 hours after administration. They had free access to water throughout the experiment.

[0478] Injectable formulation: 10% DMSO + 10% HS15 (30% aqueous solution) + 80% PBS.

[0479] Oral formulation prescription 1: 0.5% MC + 1% TWEEN.

[0480] Oral formulation 2: 5% DMSO + 95% HS15 (30% aqueous solution).

[0481] On the day of the experiment, animals in the intravenous group were administered the corresponding compound via a single tail vein injection at a volume of 2 ml / kg; animals in the oral group were administered the corresponding compound via a single gavage injection at a volume of 10 ml / kg. Animal weight was measured before administration, and the volume of administration was calculated based on body weight. Sample collection times were 0.083, 0.167, 0.5, 1, 2, 4, 8, and 24 hours. At each time point, approximately 200 μL of whole blood and plasma were collected via the orbital venous plexus for concentration determination using high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). All animals were subjected to CO2 asphyxiation after the last time point PK sample was collected. Plasma concentrations were processed using a non-compartmental model in Winnolin™ version 8.2 (Pharsight, Mountain View, CA) pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method. The results are shown in Table 8 below.

[0482] Table 8. In vivo pharmacokinetic evaluation results of the compounds of this invention

[0483] Biological Example 9: In vivo pharmacodynamic experiments of some compounds of the present invention in the SKOV3 xenograft model.

[0484] SKOV3 cells were cultured adherently in McCoy's 5A medium supplemented with 10% fetal bovine serum and 1% P / S, at 37°C and 5% CO2. Cells were passaged twice daily with trypsin digestion. When cells maintained an exponential growth phase and viability greater than 95%, cells were harvested, counted, and mixed 1:1 with Matrigel gel. SKOV3 cells were then inoculated into the right nape of 6-8 week old female BALB / c nude mice at a density of 8 × 10⁸ cells / mL. 6 Each cell is inoculated at a volume of 0.2 mL.

[0485] When the average tumor volume reaches 150-300 mm 3 Mice were randomly divided into groups of 6 or 8. The compound was administered orally according to the prescribed regimen. Tumor volume and mouse weight were measured twice weekly for 2–3 weeks. The inhibitory effect of the compound on SKOV3 tumors was then assessed. The tumor inhibition rate (TGI) was calculated as follows: TGI (%) = [(1 - (average tumor volume at the end of treatment in a given treatment group - average tumor volume at the start of treatment in that treatment group)) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%.

[0486] At the endpoint of the in vivo experiment (or 2 weeks after administration), blood glucose levels were measured in all groups using a Roche blood glucose meter by collecting tail blood from mice. Blood glucose levels were measured at the following times: 0 min before administration and 30 min, 60 min, 90 min, 3 h, 4 h, 7 h, and 24 h after administration. Insulin and time-series pharmacokinetic (PK) tests were also performed on mouse plasma samples collected from all groups at the following times: 0 min before administration, 30 min after administration, 4 h, and 7 h after administration.

[0487] After two weeks of continuous administration, a glucose tolerance test (GTT) was performed. Mice were fasted for 5 hours, then administered the drug orally. One hour after administration, 2 g / kg of glucose was injected intraperitoneally. Blood glucose levels were measured using tail blood samples from mice in all groups using a Roche blood glucose meter. Blood glucose was measured at the following times: before administration, 1 hour after administration, and 15 min, 30 min, 60 min, 90 min, 2 h, and 3 h after glucose injection.

[0488] Three animals were taken from each group, and the following samples were collected 3 hours and 24 hours after drug administration: tumor, liver, thigh skeletal muscle, fat, spleen, and 30 μL of plasma, 30 μL of whole blood, and 30 μL of serum.

[0489] Western blot (WB) detection in tumor tissues: 3 hours and 24 hours after the last day of drug administration, tumor tissues were collected, and 3 times the volume of RIPA lysis buffer containing protease inhibitors was added according to the tissue weight. The tissues were homogenized at 65 Hz and 4°C. After centrifugation at 12,000 rpm for 10 min, the supernatant was collected for Western blotting to detect the expression levels of proteins such as P110α in tumors and tissues.

[0490] Tissue distribution detection: Add homogenate at 3-5 times the tissue weight, homogenize at 65 Hz and 4℃, and then perform concentration determination by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS 5500plus). Plasma and whole blood sample detection: Winnolin was used. TM Version 8.2 (Pharsight, Mountain View, CA) pharmacokinetic software uses a non-compartmental model to process plasma concentrations and calculates pharmacokinetic parameters using the linear logarithmic trapezoidal method.

[0491] Serum ALT and AST levels in mice were measured using a blood biochemistry analyzer.

[0492] The specific results are shown in Table 9-10.

[0493] Table 9. Tumor inhibition rate and effect on blood glucose of the compounds of this invention in the SKOV3 model.

[0494] Table 10. Tumor inhibition rate and effects on blood glucose of the compounds of this invention in the SKOV3 model.

[0495] Biological Example 10: In vivo pharmacodynamic experiments of some compounds of the present invention in an MCF7 xenograft model.

[0496] MCF7 cells were cultured in adherent DMEM medium supplemented with 10% fetal bovine serum and 1% P / S at 37°C and 5% CO2. Cells were passaged twice daily with trypsin digestion. One week prior to inoculation, cells were cultured with 2 μM estrogen in the medium. When cells maintained exponential growth and viability was greater than 95%, cells were harvested, counted, and mixed 1:1 with Matrigel gel. One day before inoculation, estrogen-releasing probes were implanted into the left nape of mice. MCF7 cells were inoculated into the right nape of 6-8 week old female BALB / c nude mice at a density of 1 × 10⁶ cells / cm². 7 Each cell is inoculated at a rate of 0.2 mL. Inoculation continues until the average tumor volume reaches 150-300 mm². 3 Mice were randomly divided into groups of 5 (or 6) each. The compound was administered orally (or subcutaneously when combined with Fulvestrant) according to the appropriate regimen (single agent or combination). Tumor volume and mouse weight were measured twice weekly for 2–4 weeks. The inhibitory effect of the compound on MCF7 tumors was then assessed. The tumor inhibition rate (TGI) was calculated as follows: TGI (%) = [(1 - (mean tumor volume at the end of treatment in a given group - mean tumor volume at the start of treatment in that group)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0497] At the endpoint of the in vivo experiment (or 2 weeks after administration), blood glucose levels were measured in all groups using a Roche blood glucose meter by collecting tail blood from mice. Blood glucose levels were measured at the following times: 0 min before administration and 30 min, 60 min, 90 min, 3 h, 4 h, 7 h, and 24 h after administration. Insulin and time-series pharmacokinetic (PK) tests were also performed on mouse plasma samples collected from all groups at the following times: 0 min before administration, 30 min after administration, 4 h, and 7 h after administration.

[0498] Tissue distribution detection: Add homogenate at 3-5 times the tissue weight, homogenize at 65 Hz and 4℃, and then perform concentration determination by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS 5500plus). Plasma and whole blood sample detection: Winnolin was used. TM Version 8.2 (Pharsight, Mountain View, CA) pharmacokinetic software uses a non-compartmental model to process plasma concentrations and calculates pharmacokinetic parameters using the linear logarithmic trapezoidal method.

[0499] Serum ALT and AST levels in mice were measured using a blood biochemistry analyzer.

[0500] Western blot assay: Three volumes of RIPA lysis buffer containing protease inhibitors were added according to the tumor weight, and homogenized at 65 Hz and 4°C. After centrifugation at 12,000 rpm for 10 min, the supernatant was collected for Western blot analysis to detect target sites and pathway-related markers, and the inhibitory effects of various compounds on the markers were compared.

[0501] Biological Example 11: In vivo pharmacodynamic experiments of some compounds of the present invention in the SW948 xenograft tumor model.

[0502] SW948 cells were cultured in adherent DMEM medium supplemented with 10% fetal bovine serum, 1% P / S, and 5 μg / mL insulin, at 37°C and 5% CO2. Cells were passaged twice weekly using trypsin digestion. When cells maintained an exponential growth phase and viability greater than 95%, cells were harvested, counted, and mixed 1:1 with Matrigel. SW948 cells were inoculated into the right nape of 6-8 week old female BALB / c nude mice at a density of 8 × 10⁸ cells / mL. 6 Each cell is inoculated at a rate of 0.2 mL. Inoculation continues until the average tumor volume reaches 150-300 mm². 3 Mice were randomly divided into groups of 6. The compound was administered orally according to the corresponding protocol. Tumor volume and mouse weight were measured twice a week for 2-3 weeks. The inhibitory effect of the compound on SW948 tumors was then tested.

[0503] At the endpoint of the in vivo experiment (or 2 weeks after administration), blood glucose levels were measured in all groups using a Roche blood glucose meter by collecting tail blood from mice. Blood glucose levels were measured at the following times: 0 min before administration and 30 min, 60 min, 90 min, 3 h, 4 h, 7 h, and 24 h after administration. Insulin and time-series pharmacokinetic (PK) tests were also performed on mouse plasma samples collected from all groups at the following times: 0 min before administration, 30 min after administration, 4 h, and 7 h after administration.

[0504] After two weeks of continuous administration, a glucose tolerance test (GTT) was performed. Mice were fasted for 5 hours, then administered the drug orally. One hour after administration, 2 g / kg of glucose was injected intraperitoneally. Blood glucose levels were measured using tail blood samples from mice in all groups using a Roche blood glucose meter. Blood glucose was measured at the following times: before administration, 1 hour after administration, and 15 min, 30 min, 60 min, 90 min, 2 h, and 3 h after glucose injection.

[0505] Three animals were taken from each group, and the following samples were collected 3 hours and 24 hours after drug administration: tumor, liver, thigh skeletal muscle, fat, spleen, and 30 μL of plasma, 30 μL of whole blood, and 30 μL of serum.

[0506] Tissue distribution detection: Add homogenate at 3-5 times the tissue weight, homogenize at 65 Hz and 4℃, and then perform concentration determination by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS 5500plus). Plasma and whole blood sample detection: Winnolin was used. TM Version 8.2 (Pharsight, Mountain View, CA) pharmacokinetic software uses a non-compartmental model to process plasma concentrations and calculates pharmacokinetic parameters using the linear logarithmic trapezoidal method.

[0507] Serum ALT and AST levels in mice were measured using a blood biochemistry analyzer.

[0508] Biological Example 12: In vivo pharmacodynamic experiments of some compounds of the present invention in the HCC1954 xenograft tumor model.

[0509] HCC1954 cells were cultured adherently in 1640 medium supplemented with 10% fetal bovine serum and 1% P / S, at 37°C and 5% CO2. Cells were passaged twice daily with trypsin digestion. When cells maintained an exponential growth phase and viability greater than 95%, cells were harvested, counted, and mixed 1:1 with Matrigel. HCC1954 cells were inoculated into the right nape of 6-8 week old female BALB / c nude mice at a rate of 1 × 10⁷ cells per mouse, with an inoculation volume of 0.2 mL.

[0510] When the average tumor volume reaches 150-300 mm 3 Mice were randomly divided into groups of 6 or 8. The compound was administered orally according to the prescribed regimen. Tumor volume and mouse weight were measured twice weekly for 2–4 weeks. The inhibitory effect of the compound on HCC1954 tumors was then assessed. The tumor inhibition rate (TGI) was calculated as follows: TGI (%) = [(1 - (average tumor volume at the end of treatment in a given treatment group - average tumor volume at the start of treatment in that treatment group)) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%.

[0511] At the endpoint of the in vivo experiment (or 2 weeks after administration), blood glucose levels were measured in all groups using a Roche blood glucose meter by collecting tail blood from mice. Blood glucose levels were measured at the following times: 0 min before administration and 30 min, 60 min, 90 min, 3 h, 4 h, 7 h, and 24 h after administration. Insulin and time-series pharmacokinetic (PK) tests were also performed on mouse plasma samples collected from all groups at the following times: 0 min before administration, 30 min after administration, 4 h, and 7 h after administration.

[0512] After two weeks of continuous administration, a glucose tolerance test (GTT) was performed. Mice were fasted for 5 hours, then administered the drug orally. One hour after administration, 2 g / kg of glucose was injected intraperitoneally. Blood glucose levels were measured using tail blood samples from mice in all groups using a Roche blood glucose meter. Blood glucose was measured at the following times: before administration, 1 hour after administration, and 15 min, 30 min, 60 min, 90 min, 2 h, and 3 h after glucose injection.

[0513] Three animals were taken from each group, and the following samples were collected 3 hours and 24 hours after drug administration: tumor, liver, thigh skeletal muscle, fat, spleen, and 30 μL of plasma, 30 μL of whole blood, and 30 μL of serum.

[0514] A blood biochemistry analyzer was used to detect serum ALT, AST, and other indicators in mice. A blood cell analyzer was used to detect routine blood count indicators.

[0515] Western blot (WB) detection in tumor and other tissues: 3 hours and 24 hours after the last day of drug administration, tumor and other tissues were collected. Three volumes of RIPA lysis buffer containing protease inhibitors were added according to tissue weight, and homogenized at 65 Hz and 4°C. After centrifugation at 12000 rpm for 10 min, the supernatant was collected for Western blotting to detect the expression levels of proteins such as P110α in tumors and tissues. As shown in Figure 4, compared with the solvent control group, 2.5 mg / kg compound 142 significantly reduced the P110α protein level in mouse SKOV3 tumors.

[0516] Tissue distribution assay: Homogenize with 3-5 times the tissue weight of homogenate, homogenize at 65 Hz and 4°C, and then determine the concentration using high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS 5500plus). Plasma and whole blood sample assay: Plasma concentrations were processed using a non-compartmental model of Winnolin™ version 8.2 (Pharsight, Mountain View, CA) pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear logarithmic trapezoidal method.

[0517] Biological Example 13: Some compounds of the present invention reduced the expression levels of proteins such as P110α in subcutaneous xenografts of mice such as SKOV3.

[0518] SKOV3 xenograft tumor models were established. Mice were randomly divided into groups and administered the drug for 13 consecutive days. Three or 24 hours after the last day of administration, tumor tissues were harvested. Three volumes of RIPA lysis buffer containing protease inhibitors were added based on tissue weight, and the mixture was homogenized at 65 Hz and 4°C. After centrifugation at 12,000 rpm for 10 min, the supernatant was used for Western blotting to detect the expression levels of proteins such as P110α in the tumors and tissues. As shown in Figure 4, compared with the solvent control group, 2.5 mg / kg compound 142 significantly reduced the P110α protein level in mouse SKOV3 tumors.

[0519] Biological Example 14: Skin toxicity test of some compounds of the present invention in Brown Norway rats

[0520] Female Brown Norway rats aged 8-10 weeks were selected and administered the drug orally for 4 consecutive weeks to assess drug-related rash reactions. Rats were randomly divided into groups of 6, and each group received the corresponding compound via gavage daily at a volume of 10 mL / kg. Rash reactions were assessed weekly, including: 1. Hair loss: observation of hair loss throughout the rat's body; 2. After local hair removal, the skin inflammation status was scored, including skin discoloration, desquamation, crusting, scratching, and exudation; 3. Blood biochemistry: detection of changes in serum ALT / AST and TC / TG; 4. Complete blood count; 5. Detection of plasma inflammatory factors and chemokines; 6. Weekly assessment of blood glucose changes; 7. At the end of the 4-week experiment, histological changes in rat skin were examined: histological sections were used to assess epidermal hyperplasia, keratinization, immune cell infiltration, and detection of skin inflammatory factors in the skin tissue.

[0521] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can 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 of general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: in: PTM (PI3Ka targeting moiety) is a group that targets and binds to the PI3Kα protein; Ring A is a substituted or unsubstituted 5- to 9-membered saturated or partially unsaturated heterocyclic alkyl group or a substituted or unsubstituted 5- to 9-membered heteroaryl group; L is a group that connects PTM and ring A.

2. The compound of claim 1 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), PTM is in: X is either O or S; X1 is N or CR X1 ; X2 is N or CR X2 ; X3 is N or CR X3 ; R X1 R X2 R X3 R2 is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, carbamoyl, mercapto, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and oxoyl. Alternatively, any two adjacent or non-adjacent R2s may together with all the atoms between them to form a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group may optionally be 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 alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl. R3 is H, deuterium, halogen, (C1-C3) alkyl, or (C3-C6) cycloalkyl; R4 is a 4- to 6-membered heterocyclic alkyl, phenyl, or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms independently selected from N, S, and O, wherein the 4- to 6-membered heterocyclic alkyl, phenyl, or 5- to 6-membered heteroaryl is optionally further substituted by one or more substituents selected from deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic alkyl, oxoheterocyclic alkyl, thioheterocyclic alkyl, oxo, and thio. m can be 0, 1, 2, 3, or 4.

3. The compound as described in claim 1 or 2, or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein in the general formula (1), A is... in, Z can be NR8, O, or S independently; m can be 0, 1, 2, 3, or 4; R5 and R6 are each independently selected from halogens, H, deuterium, substituted or unsubstituted (C1-C6) alkyl, phenyl or heteroaryl groups, or R5 and R6 together with the commonly linked atoms form (C3-C6) cycloalkyl, 3- to 10-membered saturated or partially unsaturated heterocycloalkyl, 7- to 11-membered heterospirocycloalkyl, or 5- to 11-membered heterobridged cycloalkyl. R7 and R8 are independently selected from H, (C1-C6)alkyl, (C3-C12)cycloalkyl, (C1-C6)alkoxy, -OH, and -OR. k -SR k -C(S)SR k -C(S)OR k -NR k R l -CN, -C(O)R k -C(O)OR k -S(O)2R k -S(O)R k -CH2OC(O)R k -CH2OC(O)OR k -C(S)R k -C(S)OR k -C(O)SR k -C(O)NR k R l -C(S)NR k R l -C(O)ONR k R l -(C1-C6)alkyl-OR k -(C1-C6)alkyl NR k R l -S(O)2NR k R l The (C1-C6) alkyl, (C3-C12) cycloalkyl, (C1-C6) alkoxy, 3-12 saturated or partially unsaturated heterocyclic alkyl, 7-12 heterospirocyclic alkyl or 5-12 heterobridged cycloalkyl, 6-10 aryl, 5-15 heteroaryl, wherein the (C1-C6) alkyl, (C3-C12) cycloalkyl, (C1-C6) alkoxy, 3-12 saturated or partially unsaturated heterocyclic alkyl, 7-12 heterospirocyclic alkyl or 5-12 heterobridged cycloalkyl, 6-10 aryl, 5-15 heteroaryl are optionally further surrounded by 1, 2, 3, 4 or 5 R's. m Substitution; two hydrogen atoms on the same carbon atom can be replaced by oxygen to form an oxo group or by... The replaced, or two Rs m Together with the atoms between the two, they form substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted 3- to 10-membered saturated or partially unsaturated heterocycloalkyl, substituted or unsubstituted 7- to 11-membered heterospirocycloalkyl, and substituted or unsubstituted 5- to 11-membered heterobridged cycloalkyl. Alternatively, R6 and R7 together with the atoms between them can form substituted or unsubstituted 4- to 10-membered saturated or partially unsaturated heterocyclic alkyl groups, 7- to 11-membered heterospirocyclic groups, or 5- to 11-membered heterobridged cyclic groups. Alternatively, an R5 and R7 together with the atoms between them can form a substituted or unsubstituted 4- to 10-membered saturated or partially unsaturated heterocyclic alkyl, 7- to 11-membered heterospirocyclic, or 5- to 11-membered heterobridged cyclic group. Alternatively, an R7 and a Z together with the atoms between them can form a substituted or unsubstituted 4- to 10-membered partially unsaturated heterocyclic alkyl group, a 7- to 11-membered heterospirocyclic group, or a 5- to 11-membered heterobridged cyclic group; R k and R l Each of the following is independently H, -C(O)R, -C(O)OR, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C12)cycloalkyl, 3- to 12-membered saturated or partially unsaturated heterocyclic alkyl, 7- to 12-membered heterospirocycloalkyl or 5- to 12-membered heterobridged cycloalkyl, phenyl, 5- to 12-membered heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C12)cycloalkyl, 3- to 12-membered saturated or partially unsaturated heterocyclic alkyl, 7- to 12-membered heterospirocycloalkyl or 5- to 12-membered heterobridged cycloalkyl, phenyl, 5- to 12-membered heteroaryl is optionally further surrounded by 1, 2, 3, 4 or 5 Rs. m Substitution; two hydrogen atoms on the same carbon atom can be replaced by oxygen to form an oxo group or by... Replaced; Or R k and R l Together with the atoms that are connected together, they form substituted or unsubstituted 3- to 10-membered saturated or partially unsaturated heterocyclic alkyl groups, substituted or unsubstituted 7- to 11-membered heterospirocyclic groups, and substituted or unsubstituted 5- to 11-membered heterobridged cyclic groups; R a and R b Each is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cycloalkyl, or heterocycloalkyl; or R a and R b Together with the atoms they are connected to, they form 3- to 10-membered cycloalkyl or heterocycloalkyl groups; R m Selected from deuterium, H, halogen, OH, SH, NH2, -CN, -NC, -NCS, -N3, NO2, -CONH2, (C1-C6)alkyl, (C1-C6)alkyl-(C3-C6)cycloalkyl, (C1-C6)alkyl-(C3-C6)heterocyclicalkyl, (C1-C6)haloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, -N=S(O)(R)2, -S(O)=(NH)R, -SCN, -S(O)2CN, -SNC, -S(O)2NC, -S(O)2N(R)2, -SF5, -P(O)(R)2, -P(S)(R)2, -P(O)( OR)R, -P(O)(OR)2, -N(R)2, -N(R)OR, -C(O)NR(OR), -C(O)NRCN, -SR, -B(OR)2, -B(R)2, -BH(OR), -SeR, -SeCN, -NCSe, -Si(R)3, -Si(OR)3, -SiR( OR)2, -Si(R)2(OR), -C(O)R, -C(O)OR, -C(O)CH2R, -S(O)2R, -S(O)R, -CH2OC(O)R, -CH2OC(O)OR, -C(S)R, -C(S)OR, -C(O)SR, -C(O)N(R)2, -(CH2) 1～3 OR, -(CH2) 1～3 N(R)2、-(CH2) 1～3 S(O)R、-(CH2) 1～3 S(O)2R、-(CH2) 1～3 NS(O)(R)2, -OC(O)R, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamine, -NHC(O)OR, -NHC(O)N(R)2, -NHC(O)R, -NRS(O)2R, -NRCN, 3-12 saturated or partially unsaturated heterocyclic alkyl, 7-12 heterospirocyclic alkyl or 5-12 heterobridged cycloalkyl, 6-10 aryl, 5-12 heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)alkyl-(C3-C6)cycloalkyl, (C1-C6)... Alkyl-(C3-C6)heterocyclic alkyl, (C1-C6)haloalkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, -OC(O)-(C1-C6)alkyl, -OC(O)-(C3-C6)cycloalkyl, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkylamine, 3- to 12-membered saturated or partially unsaturated heterocyclic alkyl, 7- to 12-membered heterospirocyclic alkyl or 5- to 12-membered heterobridged cycloalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, optionally surrounded by 1, 2, 3, 4 or 5 Rs. n replace; Each R n Each of the following is independently selected from H, halogen, (C1-C6)alkyl, -P(O)(OR)2, (C1-C6)alkoxy, cyclopropyl, OH, NH2, CN, MeNH-, Me2N-, CH3, CH2F, CHF2 or CF3; Each R is independently H, a substituted or unsubstituted (C1-C6) alkyl, a substituted or unsubstituted (C3-C6) cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted 3- to 7-membered saturated or partially unsaturated heterocyclic alkyl, or a substituted or unsubstituted 5- to 10-membered heteroaryl; or each of the two independently selected Rs can form a 3- to 10-membered saturated or partially unsaturated heterocyclic alkyl, a 7- to 11-membered heterospirocyclic, or a 5- to 11-membered heterobridged cycloalkyl.

4. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1 to 3, wherein in the general formula (1), L is... Where * indicates that this end is connected to A; L1, L2, L3, L4, L5, and L6 are independently selected from chemical bonds, O, S, NR, C(=O), C(=O)NR, S(=O), S(=O)NR, S(=O)2, S(=O)2NR, (C1-C6)alkylene, -(C1-C6)alkylene-O-, (C2-C6)alkenyl, (C2-C6)ynylene, (C3-C10)cycloalkylene, 6-10 arylene, 5-11 bridged cycloalkyl, 3-10 saturated or partially unsaturated heterocyclic alkylene. 7-11 member heterospirocyclic, 5-11 member heterobridged cyclic, or 5-10 member heteroaryl, wherein the (C1-C6) alkylene, -(C1-C6) alkylene-O-, (C2-C6) alkenyl, (C2-C6) ynylene, (C3-C10) cycloalkylene, 3-10 member saturated or partially unsaturated heterocycloalkylene, 6-10 member aryl, 7-11 member heterospirocyclic, 5-11 member heterobridged cyclic, or 5-10 member heteroaryl are each independently and optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 Rs. L replace; Each R L Selected independently from R m H, deuterium, halogen, OH, SH, NH2, CN, -CONH2, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkylamine, oxo group, The (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkylamine groups are optionally surrounded by 1, 2 or 3 R groups. LL replace; Each R LL Each of the following is independently selected from H, halogen, (C1-C6)alkyl, cyclopropyl, (C1-C6)alkoxy, OH, NH2, MeNH-, Me2N-, CH3, CH2F, CHF2 or CF3; Or two R atoms respectively connected to the same or different atoms in L1, L2, L3, L4, L5, and L6. L It can be formed together with all the atoms in between to form a (C3-C20) saturated or partially unsaturated cycloalkyl or a 3- to 20-membered saturated or partially unsaturated heterocycloalkyl, wherein each of the (C3-C20) saturated or partially unsaturated cycloalkyl or the 3- to 20-membered saturated or partially unsaturated heterocycloalkyl can be independently and optionally replaced by one or more substituents.

5. The compound of claim 4 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1) L1, L2, L3, L4, L5, L6 are independently chemical bonds, O, S, NH, NMe, C(=O), C(=O)NH, C(=O)NMe, S(=O), S(=O)2, S(=O)2NH, CH2, 6. The compound of claim 4 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), L1 is a chemical bond, (C2-C3)-eneyl, (C2-C3)-ynyl, (C3-C10)-cycloalkyl, 3-10 saturated or partially unsaturated heterocyclic alkyl, 7-11 spirocyclic, or 5-11 heterobridged cycloalkyl, wherein the (C2-C3)-eneyl, (C2-C3)-ynyl, (C3-C10)-cycloalkyl, 3-10 saturated or partially unsaturated heterocyclic alkyl, 7-11 spirocyclic, or 5-11 heterobridged cycloalkyl are optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 Rs. L replace; L2 represents chemical bonds, C(=O), C(=O)NH, (C1-C6)alkylene, and -(C1-C6)alkylene-O-. L3 is a chemical bond, a 3-10 member saturated or partially unsaturated heterocyclic alkyl group, a 7-11 member heterospirocyclic group, or a 5-11 member heterobridged cyclic group, wherein the 3-10 member saturated or partially unsaturated heterocyclic alkyl group, the 7-11 member heterospirocyclic group, or the 5-11 member heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 Rs. L replace; L4 represents chemical bonds, C(=O), C(=O)NH, (C1-C6)alkylene, and -(C1-C6)alkylene-O-. L5 is a phenylene, a 5-9-membered heteroaryl group, a 3-10-membered saturated or partially unsaturated heterocyclic alkyl group, a 7-11-membered heterospirocyclic group, or a 5-11-membered heterobridged cyclic group, wherein the phenylene, 5-9-membered heteroaryl group, 3-10-membered saturated or partially unsaturated heterocyclic alkyl group, 7-11-membered heterospirocyclic group, or 5-11-membered heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R groups. L replace; L6 is C(=O), C(=O)NMe or C(=O)NH.

7. The compound of claim 4 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), L1 is a 3-10 member saturated or partially unsaturated heterocyclic alkyl group, a 7-11 member heterocyclic spirocyclic group, or a 5-11 member heterobridged cyclic group containing 1-4 heteroatoms, wherein the 3-10 member saturated or partially unsaturated heterocyclic alkyl group, the 7-11 member heterocyclic spirocyclic group, or the 5-11 member heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace; L2 is a chemical bond; L3 is a 3-10 member saturated or partially unsaturated heterocyclic alkyl group, a 7-11 member heterocyclic spirocyclic group, or a 5-11 member heterobridged cyclic group containing 1-4 heteroatoms, wherein the 3-10 member saturated or partially unsaturated heterocyclic alkyl group, the 7-11 member heterocyclic spirocyclic group, or the 5-11 member heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace; L4 is a chemical bond; L5 is a phenylene, a 5-9-membered heteroaryl group, or a 3-10-membered saturated or partially unsaturated heterocyclic alkyl group containing 1-4 heteroatoms, wherein the phenylene, 5-9-membered heteroaryl group, or 3-10-membered saturated or partially unsaturated heterocyclic alkyl group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace; L6 is C(=O)NH, C(=O)NMe, or C(=O).

8. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1-7, wherein in the general formula (1), each R X1 R X2 R X3 R2 is independently selected from H, deuterium, methyl, deuterated methyl, halomethyl, methoxy, hydroxy, halomethoxy, halogen, amino, and carbamoyl; Or, when m is 2, adjacent or non-adjacent R2 can form cycloalkyl or heteroalkyl groups together with all the atoms between them.

9. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1-8, wherein in the general formula (1), R3 is H, F, Cl, cyclopropyl or CH3.

10. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1-9, wherein the general formula (1) has the structure shown in general formulas (2) to (5): in, X is either O or S; L1 is a 3-10 member saturated or partially unsaturated heterocyclic alkyl group, a 7-11 member heterocyclic spirocyclic group, or a 5-11 member heterobridged cyclic group containing 1-4 heteroatoms, wherein the 3-10 member saturated or partially unsaturated heterocyclic alkyl group, the 7-11 member heterocyclic spirocyclic group, or the 5-11 member heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace; L3 is a 3-10 member saturated or partially unsaturated heterocyclic alkyl group, a 7-11 member heterocyclic spirocyclic group, or a 5-11 member heterobridged cyclic group containing 1-4 heteroatoms, wherein the 3-10 member saturated or partially unsaturated heterocyclic alkyl group, the 7-11 member heterocyclic spirocyclic group, or the 5-11 member heterobridged cyclic group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace; L5 is a phenylene, a 5-9-membered heteroaryl group, or a 3-10-membered saturated or partially unsaturated heterocyclic alkyl group containing 1-4 heteroatoms, wherein the phenylene, 5-9-membered heteroaryl group, or 3-10-membered saturated or partially unsaturated heterocyclic alkyl group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L replace; L6 is Where * represents the end and Connected; Each R L Independently selected from H, deuterium, F, Cl, hydroxyl, mercapto, amino, cyano, amide, methyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, methylamino, dimethylamino, oxo, Vinyl, acetylene; 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, hydroxyl, mercapto, cyano, (C3-C6)cycloalkyl, and (3-6)heterocyclic alkyl. R2 is independently selected from hydrogen, deuterium, (C1-C3)alkyl, (C1-C3)deuteratedalkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, and halogen; Alternatively, any two adjacent or non-adjacent R2 atoms can form a (C3-C6) cycloalkyl or heterocycloalkyl group together with all the atoms between them; R3 is H, deuterium, halogen, (C1-C3) alkyl, or cyclopropyl; R4 is a 4- to 6-membered heterocyclic alkyl, phenyl, or 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclic alkyl, phenyl, or 5- to 6-membered heteroaryl 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, hydroxyl, cyano, (C3-C6)cycloalkyl, (3- to 6-membered) heterocyclic alkyl, (3- to 6-membered) oxoheterocyclic alkyl, (3- to 6-membered) thioheterocyclic alkyl, oxo, and thio. m can be 0, 1, 2, 3, or 4; n can be 0, 1, 2, or 3.

11. The compound of claim 10 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formulas (2), (3), (4), (5), L1 is a 4-10 member saturated or partially unsaturated heterocyclic alkyl group containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, or a 5-11 member heterobridged cycloalcoside containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O. The 4-10 member saturated or partially unsaturated heterocyclic alkyl group and the 5-11 member heterobridged cycloalcoside are optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L Replacement; L1 is preferred More preferably More preferably The left end of the group can be connected to L3 or PTM, preferably to L3; L3 is a 4-10 member saturated or partially unsaturated heterocyclic alkyl group containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, or a 5-11 member heterobridged cycloalcoside containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, wherein the 4-10 member saturated or partially unsaturated heterocyclic alkyl group or the 5-11 member heterobridged cycloalcoside is optionally surrounded by 1, 2, 3, or 4 R atoms. L Replacement; L3 is preferred More preferably The left end of the group can be connected to L5 or L1, preferably to L5; L5 is a phenylene, a 5-6-membered heteroaryl group, or a 4-10-membered saturated or partially unsaturated heterocyclic alkyl group containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, wherein the phenylene, 5-6-membered heteroaryl group, or 4-10-membered saturated or partially unsaturated heterocyclic alkyl group is optionally surrounded by 1, 2, 3, 4, 5, 6, 7, or 8 R atoms. L Replacement; L5 is preferred More preferably More preferably More preferably The left end of the group can be connected to L6 or L3, preferably to L6; R1 is independently selected from hydrogen, deuterium, -Me, -OMe, -OCD3, -CD3, -CHF2, -CF3, F, Cl, -NH2, -NHMe, hydroxyl, mercapto, cyano, and cyclopropyl. R3 is hydrogen, deuterium, F, Cl, -Me, or cyclopropyl; R4 is a 5-membered heterocyclic alkyl 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 heterocyclic alkyl group or 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, hydroxyl, mercapto, cyano, (C3-C6)cycloalkyl, (3-6-membered)heterocyclic alkyl, (3-6-membered)oxoheterocyclic alkyl, (3-6-membered)thioheterocyclic alkyl, oxo, and thio.

12. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1-11, wherein in the general formulas (1) to (5), R4 is preferably a 5-membered heterocyclic alkyl group containing one N atom, a 5-membered heterocyclic alkyl group containing one N and one S or O atom, or a 5-membered heteroaryl group containing one, two or three independently selected from N, S or O, wherein the 5-membered heterocyclic alkyl group or 5-membered heteroaryl group is optionally further substituted by one or two substituents independently selected from -D, -Me, -CD3, -CH2F, -CHF2, -CF3, -OMe, -OCD3, oxo and thio groups.

13. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1-12, wherein in the general formulas (1) to (5), R4 is selected from...

14. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1-13, wherein the general formula (1) has the structure shown in general formulas (6) to (9): in, Z is NR8, O, or S; L5 is a phenylene group, a 5-6 membered heteroaryl group containing one or two heteroatoms independently selected from N, S, and O, and a 9-10 membered partially unsaturated heterocyclic alkyl group containing one, two, three, or four heteroatoms independently selected from N, S, and O, wherein the phenylene group, the 5-6 membered heteroaryl group, and the 9-10 membered partially unsaturated heterocyclic alkyl group are each independently optionally surrounded by one, two, three, four, five, six, seven, or eight R atoms. L replace; L6 is Where * represents the end and Connected; o can be 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; Each R L Each of the following is independently selected from H, deuterium, halogen, OH, NH2, SH, CN, -CONH2, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkylamine, oxo group, etc. Vinyl, ethynyl, wherein the (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-C(=O)-, (C1-C6)alkoxy, (C1-C6)alkylthio or (C1-C6)alkylamine group is optionally surrounded by 1, 2 or 3 R groups. LL replace; Each R LL Each of the following is independently selected from H, halogen, (C1-C6) alkyl, OH, NH2, -NHCH3, -N(CH3)2, -CH3, -CH2F, -CHF2 or -CF3.

15. The compound or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof as described in any one of claims 1-13, wherein the general formula (1) has a structure as shown in general formula (10): in, Z is NR8 or O; L5 is a 5-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, S, and O, wherein the 5-membered heteroaryl group is optionally surrounded by 1 or 2 R atoms. L replace.

16. The compound of claim 15 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (10), L5 is preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazinyl, imidazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrrolyl, furanyl, thiaphenyl, more preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazinyl, pyrrolyl.

17. The compound of claim 14 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein in the general formulas (6) to (9), R5 and R6 are phenyl, methyl, trifluoromethyl or ethyl; or R5 and R6 together with the atoms they are connected to form (C3-C6) cycloalkyl, 3-6 membered heterocyclic alkyl, preferably cyclopropyl or cyclobutyl; or R5 is substituted or unsubstituted phenyl, methyl, trifluoromethyl or ethyl, and R6 and R7 together with the atoms between them form substituted or unsubstituted 5-10 membered saturated or partially unsaturated heterocyclic alkyl, preferably 5-6 membered saturated heterocyclic alkyl or 9 membered partially unsaturated heterocyclic alkyl.

18. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 14-17, wherein the general formulas (6) to (10) are: Z is either NH or O; R7 is a phenyl group, a 5- to 7-membered monocyclic heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from N, S, Se, and O, or an 8- to 10-membered bicyclic heteroaryl group containing 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from N, S, Se, and O, wherein the phenyl or heteroaryl group is optionally further surrounded by 1, 2, 3, 4, or 5 R7 atoms. m replace; R m The following are the possible values ​​for hydrogen, deuterium, F, Cl, Br, I, OH, NO2, NH2, CN, -N(CH3)2, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -SCN, -S(O)2CN, -S(O)2N(CH3)2, -SF5, -P(O)(CH3)2, -P(S)(CH3) 2, -P(O)(OH)CH3, -P(O)(OH)2, -NHOCH3, -C(O)NH(OMe), -C(O)NHCN, -C(O)N(CH3)2, -NHS(O)2CH3, -NHCN, -C(O)OH, -C(O)OCH3, (C1-C6)alkyl, (C2-C3)alkynyl, (C2-C3)alkenyl, (C1-C3)alkoxy (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C3-C6) cycloalkyl, -NHC(O)OR, -NHC(O)N(R)2, -NHC(O)R, 3- to 6-membered saturated or partially unsaturated heterocyclic alkyl, phenyl, 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from N, S, Se and O, wherein the alkyl, alkynyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic alkyl, phenyl, and heteroaryl are each optionally substituted by 1, 2 or 3 H, F, Cl, -CH3, cyclopropyl, OH, NH2, CN, -OCH3, -CH2OCH3, -NHCH3, -N(CH3)2, -CH2N(CH3)2, -CH3, -CH2F, -CHF2 or -CF3.

19. The compound of claim 18 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formulas (6) to (10), R7 is a compound surrounded by 1, 2, 3, 4 or 5 R7 groups. m The substituted phenyl group, or a 5- to 6-membered monocyclic heteroaryl group containing one, two, three, or four heteroatoms independently selected from N, S, Se, and O, preferably surrounded by one, two, three, four, or five R atoms. m Substituted phenyl, pyrrolyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,5-thiadiazolyl, 1,2,5-oxadiazolyl.

20. The compound of claim 18 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formulas (6) to (10), R7 is a compound surrounded by 1, 2, 3, 4 or 5 R7 groups. m The substituted 8- to 10-membered bicyclic heteroaryl group containing one, two, three, four, five, or six heteroatoms independently selected from N, S, and O is preferred.

21. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 14-20, wherein in the general formulas (6) to (10), R m For H, F, Cl, Br, OH, NO2, NH2, CN, -NHCH3, -N(CH3)2, -NHC(O)OC(CH3)3, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -SCN, -S(O)2CN, -S(O)2 N(CH3)2, -SF5, -P(O)(CH3)2, -P(S)(CH3)2, -P(O)(OH)CH3, -P(O)(OH)2, -NHOCH3, -C(O)NH(OMe), -C(O)NHCN, -C(O)N(CH3)2, -NHS(O)2CH3, -NHCN, -C(O)OH, -C (O)OCH3, -C(O)OC(CH3)3, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, -OCHF2, -OCH2F, -CH=CH2, -CH2CH=CH2, -CH=CH2CH3, -CH=CH2CH2OCH3, -CH=CH2CH2N(CH3)2, -C≡CH, -C≡CHCH3, -CH2C≡CH, -C≡CHCH2OCH3, -C≡CHCH2N(CH3)2, cyclopropyl, cyclobutyl, oxacyclobutane, azacyclobutane.

22. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 14-17, wherein the general formulas (6) to (10) are: Z is either NH or O; R7 is -C(O)R k or -C(O)OR k ; R k The (C1-C3) alkyl, (C3-C6) cycloalkyl, or 3- to 6-membered saturated or partially unsaturated heterocyclic alkyl containing 1 to 2 heteroatoms independently selected from N, S, and O, wherein the (C1-C3) alkyl, (C3-C6) cycloalkyl, or 3- to 6-membered saturated or partially unsaturated heterocyclic alkyl containing 1 to 2 heteroatoms independently selected from N, S, and O is optionally further surrounded by 1, 2, 3, 4, or 5 R atoms. m Substitution; two hydrogen atoms on the same carbon atom can be replaced by oxygen to form an oxo group or by... Replaced; R a and R b Each can be H or F independently; R m The following are the possible values: H, F, Cl, OH, NH2, CN, -N(CH3)2, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -C(O)OH, -C(O)OCH3, (C1-C3)alkyl, (C1-C3)alkoxy, cyclopropyl, (C1-C3)haloalkyl, (C1-C3)haloalkoxy.

23. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 14-17, wherein the general formulas (6) to (10) are: Z is either NH or O; R7 is -C(O)R k or -C(O)OR k ; R k The phenyl group is a 5- to 6-membered monocyclic heteroaryl group containing one, two, three, or four heteroatoms independently selected from N, S, and O; or an 8- to 10-membered bicyclic heteroaryl group containing one, two, three, or four heteroatoms independently selected from N, S, and O, wherein the phenyl or heteroaryl group is optionally further surrounded by one, two, three, four, or five R atoms. m replace; R m The derivatives are H, F, Cl, OH, NH2, CN, -N(CH3)2, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -C(O)OH, -C(O)OCH3, -CH3, -OCH3, -CF3, -CH2F, -CHF2, -OCF3, and cyclopropyl.

24. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 14-17, wherein the general formulas (6) to (10) are: Z is either NH or O; R7 is -C(O)NR k R l ; R k and R l Each of the following is independently H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C6)cycloalkyl, 3-6 member saturated or partially unsaturated heterocyclic alkyl, 7-12 member heterospirocyclic alkyl or 5-12 member heterobridged cycloalkyl, phenyl, 5-12 member heteroaryl containing 1-4 heteroatoms independently selected from N, S and O; the two hydrogens on the same carbon may be replaced by oxygen to form an oxo group or by... Replaced; R a and R b Each can be H or F independently.

25. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 14-17, wherein the general formulas (6) to (10) are: Z is either NH or O; R7 is H, (C1-C3)alkyl, or (C3-C6)cycloalkyl, wherein the (C1-C3)alkyl or (C3-C6)cycloalkyl is further surrounded by 1, 2, 3, 4, or 5 R7 groups. m Substitution; two hydrogen atoms on the same carbon atom can be replaced by oxygen to form an oxo group or by... Replaced; R a and R b Each can be H or F independently; R m The following are the possible values: hydrogen, deuterium, F, Cl, OH, NH2, CN, -N(CH3)2, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -C(O)OH, -C(O)OCH3, (C1-C3)alkyl, cyclopropyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy.

26. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 14-17, wherein the general formulas (6) to (10) are: Z is either NH or O; R7 is a 3- to 12-membered saturated or partially unsaturated heterocyclic alkyl group, a 7- to 12-membered heterospirocyclic alkyl group, or a 5- to 12-membered heterobridged cycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S, O, and P, wherein the 3- to 12-membered saturated or partially unsaturated heterocyclic alkyl group, a 7- to 12-membered heterospirocyclic alkyl group, or a 5- to 12-membered heterobridged cycloalkyl group containing 1 to 2 heteroatoms independently selected from N, S, O, and P is optionally further surrounded by 1, 2, 3, 4, or 5 R7 atoms. m Substitution; two hydrogen atoms on the same carbon atom can be replaced by oxygen to form an oxo group or by... Replaced; R a and R b Each can be H or F independently; R m Hydrogen, deuterium, F, Cl, OH, NO2, NH2, CN, -N(CH3)2, -S(O)2CH3, -CH2OCH3, -S(O)2CH3, -NS(O)(CH3)2, -S(O)(NH)CH3, -C(O)OH, -C(O)OCH3, (C1-C3)alkyl, cyclopropyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, -NHC(O)OR, -NHC(O)R, containing The alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, heterocyclic alkyl group, phenyl group, and 5-6-membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N, S and O, wherein each of the alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, heterocyclic alkyl group, phenyl group, and heteroaryl group is independently and optionally substituted by one, two or three H, F, Cl, -CH3, OH, NH2, CN, -NHCH3, -N(CH3)2, -CH3, -CH2F, -CHF2 or -CF3.

27. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 14-26, wherein the general formulas (6) to (10) are: R7 is 28. The compound of any one of claims 1-27, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound has one of the following structures:

29. A pharmaceutical composition, characterized in that, It contains pharmaceutically acceptable excipients or carriers, and the compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as any one of claims 1-28 as active ingredients.

30. Use of a compound as described in any one of claims 1-28, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described in claim 29, in the preparation of a medicament for treating diseases related to PI3Kα.

31. The use as described in claim 30, wherein the disease is cancer, and the cancer is a hematologic malignancy or a solid tumor.

32. A method for preparing a class of compounds with structures as shown in general formula (11), L6 is Where * represents the end and Connected; Compounds of general formula (11) can be prepared by the following methods: or, PG is a protecting group, which can be deprotected under certain conditions to reveal the exposed α-position NH.

33. A method for preparing a class of compounds with structures as shown in general formula (11): Compounds of general formula (11) can be obtained by a condensation reaction between intermediate acid int_3 and L5 on intermediate int_4; wherein, The intermediate acid int_3 can also be first made into an active ester and then reacted with the intermediate int_4.

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