Condensed ring compound and application thereof

Abstract

The invention relates to a fused ring compound and application thereof. Specifically, the compound disclosed by the invention has a structure as shown in a formula (I), the definitions of all groups and substituent groups are described in the specification, and the compound has excellent selective activity on mutant PI3Kalpha. The invention also discloses a preparation method of the compound and an application of the compound in an anti-tumor aspect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to fused ring compounds used as PI3Kα inhibitors, to pharmaceutical compositions containing such compounds or their salts, and to applications of such compounds in regulating PI3Kα activity or treating PI3Kα-related diseases. Background Art

[0002] Phosphatidylinositol 3-kinases (PI3Ks) are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositol or phospholipid inositol. They play a key role in many fundamental biological processes, including proliferation, survival, differentiation, and metabolism. PI3Ks are currently divided into class IA, class IB, class II, and class III. Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are usually activated by tyrosine kinases or G protein-coupled receptors to produce PIP3, which binds to downstream effectors such as Akt / PDK1, mTOR, Tec family kinases, and effectors in the Rho family GTPases pathway. Class II and class III PI3Ks play a key role in intracellular transport by synthesizing PI(3)P and PI(3,4)P2. Among them, the class IA family consists of three subtypes: α, β, and δ. The class IB family includes only the γ subtype. Among the different PI3K subfamily proteins, PI3Kα is a heterodimer containing a p110α catalytic subunit and a p85α regulatory subunit. The gene encoding the p110α subunit, PIK3CA, is mutated at a rate of nearly 30% in human cancers, including colorectal cancer, glioblastoma, and gastric cancer. Importantly, overactivation of PI3Kα is directly associated with resistance to current therapeutic drugs and poor prognosis.

[0003] Mutations in the gene encoding PI3Kα occur primarily as point mutations in several hot spots in the helical and kinase domains, such as E542K, E545K, and H1047R. These mutations have been shown to be oncogenic gain-of-function mutations. Due to the high incidence of PI3Kα mutations, targeting this pathway may provide valuable therapeutic opportunities. Other PI3K isoforms such as PI3Kδ or PI3Kγ are primarily expressed in hematopoietic cells, whereas PI3Kα and PI3Kβ are constitutively expressed.

[0004] Due to the central role of PI3Kα in regulating glucose homeostasis, PI3K inhibition often results in hyperglycemia and / or hyperinsulinemia in patients. High levels of circulating insulin may promote cancer cell mitosis and / or anti-apoptosis, thereby attenuating the anti-proliferative effects of PI3K inhibitors.

[0005] In the setting of PI3Kα mutant cancers, one approach to overcoming the problem of insulin and / or glucose replacement after systemic inhibition of PI3Kα is to develop inhibitors that are more selective for mutant PI3Kα than for wild-type PI3Kα. This would create a larger window for drug doses to selectively inhibit the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα that controls systemic metabolism in host tissues, thereby limiting toxicity and allowing higher doses and more complete inhibition of the drug target.

[0006] Current PI3Kα inhibitors are nearly equivalent in wild-type and mutant forms. Because the PI3Kα mutation site is far from the active site, selective inhibitors of the mutation have been elusive. Therefore, inhibitors targeting allosteric binding pockets near known mutations (such as H1047R, E542K, E545K) may provide a new way to selectively inhibit PI3Kα. Therefore, targeting the allosteric binding pocket of PI3Kα mutations may in turn provide valuable therapeutic targets for drug development. Summary of the invention

[0007] The object of the present invention is to provide a compound represented by formula (I), a preparation method thereof and use thereof in selective PI3Kα inhibitor drugs.

[0008] The first aspect of the present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof,

[0009]

[0010] in:

[0011] X1 is selected from the group consisting of N, O, CH;

[0012] X2 and X3 are each independently selected from the following group: N, C;

[0013] Y and Z are each independently selected from the group consisting of N, C, and CH;

[0014] L is selected from the following group: C optionally substituted by 0-4 halogen and / or hydroxyl groups 1-4 Alkylene, wherein the C 1-4 Any methylene unit in the alkylene group is optionally replaced by a substituent selected from the group consisting of: -N(R a )-、-O-、-N(R a )C(O)-、-C(O)N(R a )-, -C(O)-, -OC(O)-, -S-, -S(O)-, -S(O)2-;

[0015] Ring A is selected from the following group: C 6-10Aryl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein the C 6-10 Aryl, 5-6 membered heteroaryl is optionally substituted by m R4;

[0016] Ring B is selected from the following group: C 6-10 Aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, saturated or partially saturated C 3-6 Cycloalkyl, saturated or partially saturated 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S; wherein the C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl is optionally substituted by n R5;

[0017] R1 is selected from the group consisting of H, deuterium, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy;

[0018] R2 and R3 are each independently selected from the following group: H, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 3-5 Cycloalkyl, halogenated C 3-5 Cycloalkyl;

[0019] Each R4 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R6, -C(O)OR6, -C(O)NR6R7, -SO2R6, -S(O)(NR6)R7, -SO2NR6R7, -P(O)R6R7, C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;

[0020] Each R5 is independently selected from the group consisting of H, deuterium, halogen, =O, -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、-L1-(saturated or partially saturated C 3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(saturated or partially saturated 3-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, -SO2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8R9,

[0021] Alternatively, the two R5 atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, or 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 0-6 substituents selected from the group consisting of H, deuterium, halogen, =O, -CN, -OH, =NR9, C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6Alkoxy, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR9R 10 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

[0022] R a Selected from the following group: H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 alkyl;

[0023] L1 is a bond or is selected from the following group: C 1-6 Alkylene, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkylene, -NR6-, -O-, -C(O)-, -C(O)NR6-, -NR6C(O)-;

[0024] Each R6, R7, R8, R9, R 10 Each independently selected from the following group: H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 0-6 substituents selected from the group consisting of halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl;

[0025] Alternatively, R6, R7 and the heteroatoms to which they are connected together form a 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; Alternatively, R8, R9 and the heteroatoms to which they are connected together form a 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; Alternatively, R9, R 10 Together with the heteroatoms to which it is attached, it forms a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S;

[0026] each are independently a single bond or a double bond;

[0027] Each m and n are independently selected from the following group: 0, 1, 2, 3, 4, 5.

[0028] In another preferred embodiment, X1 is selected from the following group: N, O, CH.

[0029] In another preferred embodiment, X1 is N.

[0030] In another preferred embodiment, X2 is selected from the following group: N, C.

[0031] In another preferred embodiment, X2 is C.

[0032] In another preferred embodiment, X3 is selected from the following group: N, C.

[0033] In another preferred embodiment, X3 is N.

[0034] In another preferred embodiment, Y is selected from the following group: N, C, CH.

[0035] In another preferred embodiment, Y is C.

[0036] In another preferred embodiment, Z is selected from the following group: N, C, CH.

[0037] In another preferred embodiment, Z is C.

[0038] In another preferred embodiment, L is selected from the following group: C optionally substituted by 0-4 halogens and / or hydroxyl groups 1-4 Alkylene, wherein the C 1-4 Any methylene unit in the alkylene group is optionally replaced by a substituent selected from the group consisting of: -N(R a )-、-O-、-N(R a )C(O)-、-C(O)N(R a )-, -C(O)-, -OC(O)-, -S-, -S(O)-, -S(O)2-.

[0039] In another preferred embodiment, L is selected from the following group: C 1-4 Alkylene, wherein the C 1-4 Any methylene unit in the alkylene group is optionally replaced by a substituent selected from the group consisting of -O-, -C(O)-, and -S-.

[0040] In another preferred embodiment, L is selected from the following group: -CH2-O-, -O-CH2-, -CH2-, -(C=O)-.

[0041] In another preferred embodiment, L is selected from the following group: -CH2-O-, -O-CH2-.

[0042] In another preferred embodiment, R1 is C 1-3 alkyl.

[0043] In another preferred embodiment, R2 is selected from the following group: halogen, C 1-3 Alkyl, halogenated C 1-3 alkyl.

[0044] In another preferred embodiment, R2 is selected from the following group: halogen, C 1-3 alkyl.

[0045] In another preferred embodiment, R3 is selected from the following group: H, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 3-5 Cycloalkyl, halogenated C 3-5 Cycloalkyl.

[0046] In another preferred embodiment, R3 is H.

[0047] In another preferred embodiment, each are independently a single bond or a double bond.

[0048] In another preferred embodiment, each m is independently selected from the following group: 0, 1, 2, 3, 4, 5.

[0049] In another preferred embodiment, m is 1.

[0050] In another preferred embodiment, each m and n are independently selected from the following group: 0, 1, 2, 3, 4, 5.

[0051] In another preferred embodiment, n is 1.

[0052] In another preferred embodiment, the compound has a structure selected from the following group:

[0053]

[0054] Wherein, R1, R2, R3, L, Y, Z, Ring A, and Ring B are as defined in claim 1;

[0055] structure Contains the following configurations:

[0056] In another preferred embodiment, ----- is a linking site.

[0057] In another preferred embodiment, ring A has a structure selected from the following group:

[0058]

[0059] wherein each R4 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R6, -

[0060] C(O)OR6, -C(O)NR6R7, -SO2R6, -S(O)(NR6)R7, -SO2NR6R7, -P(O)R6R7, C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;

[0061] m is selected from the following group: 0, 1, 2, 3, 4, 5.

[0062] In another preferred embodiment, ring A has a structure selected from the following group:

[0063]

[0064] wherein R4 is as defined above.

[0065] In another preferred embodiment, ring A has a structure selected from the following group:

[0066]

[0067] wherein R4 is as defined above.

[0068] In another preferred embodiment, ring A is R4 is as defined above.

[0069] In another preferred embodiment, ring A is In another preferred embodiment, the B ring has a structure selected from the following group:

[0070]

[0071]

[0072] wherein each R5 is independently selected from the group consisting of H, deuterium, halogen, =O, -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、-L1-(C 3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(3-10 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, -SO2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8R9,

[0073] Alternatively, the two R5 atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, or 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 0-6 substituents selected from the group consisting of H, deuterium, halogen, =O, -CN, -OH, =NR9, C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR9R 10 , C 3-6Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S;

[0074] n is selected from the following group: 0, 1, 2, 3, 4, 5.

[0075] In another preferred embodiment, ring B is R5 is as defined above.

[0076] In another preferred embodiment, the B ring is selected from the following group: In another preferred embodiment, the compound has a structure selected from the following group:

[0077]

[0078] Wherein, R1, R2, R3, L, Y, Z, and Ring B are as defined in claim 1;

[0079] Each R4 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R6, -C(O)OR6, -C(O)NR6R7, -SO2R6, -S(O)(NR6)R7, -SO2NR6R7, -P(O)R6R7, C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S;

[0080] X4 is CR4 or N;

[0081] m is selected from the following group: 0, 1, 2, 3, 4.

[0082] In another preferred embodiment, the compound is selected from the following group:

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] In another preferred embodiment, the compound is not a compound selected from the following group:

[0096]

[0097] In another preferred embodiment, the compound is not a compound selected from the following group:

[0098]

[0099] The second aspect of the present invention provides a pharmaceutical composition comprising a safe and effective amount of one or more compounds described in the first aspect of the present invention and a pharmaceutically acceptable carrier.

[0100] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing a selective PI3Kα inhibitor.

[0101] The fourth aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing a drug for regulating PI3Kα activity or treating PI3Kα-related diseases.

[0102] In another preferred embodiment, the PI3Kα has one or more mutations selected from the following group: H1047R, E542K, E545K.

[0103] In another preferred embodiment, the PI3Kα-related disease is cancer or tumor.

[0104] In another preferred embodiment, the cancer or tumor is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid, unknown primary cancer, cardiac (heart) tumor, atypical teratoma / rhabdoid tumor, primary central nervous system lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia ( CML), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, fungal disease, S-cell lymphoma, syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, sensory blastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid, malignant gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma, kidney cancer, laryngeal cancer, white Blood disease, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic carcinoma, metastatic squamous neck carcinoma, midline duct carcinoma with nut gene alteration, oral cancer, multiple endocrine neoplasms syndrome, multiple myeloma / plasma cell neoplasms, myelodysplastic syndrome, myelodysplastic tumors, myeloproliferative tumors, chronic myeloproliferative tumors, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma Tumors, sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell tumor, multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, skin squamous cell carcinoma, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic cancer, thyroid cancer, tracheobronchial tumors, renal pelvis and ureteral transitional cell carcinoma, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, Wilms' tumor.

[0105] In another preferred embodiment, the cancer is selected from the following group: endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophageal gastric cancer, neurothecoma, head and neck squamous cell carcinoma, melanoma, esophageal gastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenal cortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymoma, pheochromocytoma, other neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma.

[0106] In another preferred embodiment, the cancer is breast cancer, prostate cancer or brain cancer.

[0107] In another preferred embodiment, the cancer is breast ductal carcinoma.

[0108] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0109] After long-term and in-depth research, the inventor unexpectedly prepared a class of compounds with excellent PI3Kα mutation selective inhibitory activity and a preparation method thereof. Specifically, through structural optimization, the inventor obtained a class of compounds with excellent PI3Kα mutation selective inhibitory activity. On this basis, the inventor completed the present invention.

[0110] the term

[0111] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0112] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0113] In the present invention, “C 1-6 "Alkyl" refers to a straight or branched chain alkyl group comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like. Other similar terms have similar meanings.

[0114] In the present invention, the term "C 1-6 "Alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy. Preferably, C 1-3 Alkoxy. Other similar terms have similar meanings.

[0115] In the present invention, the term "deuterated C 1-6 "Alkyl" refers to an alkyl group having a straight or branched chain of 1 to 6 carbon atoms, wherein the hydrogen atoms on the carbon atoms are optionally replaced by one, more or all deuterium atoms, such as -CD3, -CH2CD3, -CH(CH3)CD3, etc. The term "deuterated C 1-3 "Alkyl" has a similar meaning.

[0116] In the present invention, the term "deuterated C 1-6 "Alkoxy" refers to an alkoxy group in which the hydrogen atoms on a straight or branched chain of 1 to 6 carbon atoms are optionally replaced by one, more or all deuterium, such as -OCD3, -OCH2CD3, -OCH(CH3)CD3, etc. The term "deuterated C 1-3 "Alkoxy" has a similar meaning.

[0117] In the present invention, the term "C 1-6 “Heteroalkyl” refers to a straight or branched alkyl group having 1 to 6 carbon atoms containing 1 to 4 heteroatoms selected from N, O or S, including but not limited to methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, -CH2OH, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2, and the like.

[0118] In the present invention, the term "saturated or partially saturated C 3-10 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including: 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl, C 3-8 Monocyclic alkyl, C 4-12 Cycloalkyl, wherein some of the carbon atoms on the ring can form an unsaturated structure with the adjacent carbon atoms in the form of double bonds, includes but is not limited to:

[0119]

[0120] wait.

[0121] In the present invention, the term "C 3-6 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring, including but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term "C 3-5 "Cycloalkyl" has a similar meaning.

[0122] In the present invention, the term "saturated or partially saturated 3-12 membered heterocycloalkyl" refers to a cyclic alkyl group containing 1-4 heteroatoms selected from N, O or S, which may be a saturated ring or a partially unsaturated ring, including: a 5-12 membered spirocycloalkyl group containing 1-4 heteroatoms selected from N, O or S, a 5-12 membered bridged cycloalkyl group containing 1-4 heteroatoms selected from N, O or S, a 3-8 membered monocycloalkyl group containing 1-4 heteroatoms selected from N, O or S, a 4-12 membered cycloalkyl group containing 1-4 heteroatoms selected from N, O or S, including but not limited to:

[0123] The terms "3-6 membered heterocycloalkyl" and "4-6 membered heterocycloalkyl" have similar meanings.

[0124] In the present invention, the term "C 1-6 “Alkylene” refers to a straight or branched alkylene structure comprising 1 to 6 carbon atoms, including, but not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-. The term “C 1-4 "Alkylene" has a similar meaning.

[0125] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning. 6-10 "Aryl" refers to an aromatic structure containing 6-10 carbon atoms without heteroatoms, including: monocyclic C6 aromatic, bicyclic C 8-10 Aryl; including but not limited to: etc. The aryl group may be optionally substituted or unsubstituted. The part connected to the parent is an aromatic ring.

[0126] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning, referring to a monocyclic or polycyclic heteroaromatic group containing 1 to 4 heteroatoms selected from N, O or S. For example, "5-10 membered heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from N, O or S and 1 to 9 carbon atoms, which includes: 5-6 membered monocyclic heteroaryl, 8-10 membered polycyclic heteroaryl. Among them, "5-6 membered monocyclic heteroaryl" includes, but is not limited to: furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.; "8-10 membered polycyclic heteroaryl" includes, but is not limited to:

[0127]

[0128] The heteroaryl group may be optionally substituted or unsubstituted, wherein the portion attached to the parent group is an aromatic ring.

[0129] In the present invention, the term "halo" means substituted with halogen.

[0130] In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those that are stable or chemically feasible. The substituents include, but are not limited to, halogen, hydroxyl, carboxyl (-COOH), C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C 1-6 Alkoxy, C1-C10 sulfonyl, etc.

[0131] In the present invention, the term "0-6" means 0, 1, 2, 3, 4, 5 or 6. Other similar terms have similar meanings.

[0132] It should be understood that when a group is present in multiple different positions of a compound at the same time, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the following group:" has the same meaning as the term "each independently selected from the following group:" and the term "independently selected from the following group:".

[0133] Compound

[0134] The present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof,

[0135]

[0136] Wherein, R1, R2, R3, X1, X2, X3, L, Y, Z, Ring A and Ring B are as defined above.

[0137] In another preferred embodiment, in the compound, any one of R1, R2, R3, X1, X2, X3, L, Y, Z, A ring, and B ring is independently a corresponding specific group in the specific compound.

[0138] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0139] Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0140] The term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0141] It should be understood that the specific preparation method of the compound of formula (I) of the present invention does not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combination can be easily performed by a person skilled in the art to which the present invention belongs.

[0142] Typically, the compounds of the present invention can be prepared by the process described in the examples, wherein the raw materials and reagents used can be purchased from commercial sources unless otherwise specified.

[0143] Pharmaceutical compositions and methods of administration

[0144] The present invention also provides a pharmaceutical composition comprising a safe and effective amount of one or more of the compounds and a pharmaceutically acceptable carrier.

[0145] Since the compounds of the present invention have excellent anti-tumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0146] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0147] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0148] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0149] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0150] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0151] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0152] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0153] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0154] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0155] Compositions for parenteral injection may include 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.

[0156] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0157] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0158] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0159] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0160] Compared with the prior art, the present invention has the following main advantages:

[0161] (1) The compound has excellent activity selective for PI3Kα mutation.

[0162] (2) The compound has excellent pharmacokinetic properties and excellent safety.

[0163] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0164] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0165] Example Synthesis Route

[0166] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is defined as follows. Compounds marked with (or) or (rel) are single enantiomers with arbitrarily specified absolute stereochemistry (e.g., based on chiral SFC elution described in the Examples section). Compounds marked with (&) or (rac) are mixtures of enantiomers with relative stereochemistry as shown in the text. Compounds marked with (abs) are single enantiomers with absolute stereochemistry as shown in the text.

[0167] Example 1

[0168] Compounds of the present invention

[0169]

[0170] The synthetic route and experimental process are as follows:

[0171]

[0172] 1. Synthesis of compound C1-2:

[0173] Compound C1-1 (2 g, 10.48 mmol) was dissolved in 20 mL of acetone, and 2,4,6-trichlorophenyl maleic acid diester (5.8 g, 12.56 mmol) was added at 60°C under nitrogen protection, and the mixture was stirred under reflux for 1.5 h. The reaction was completed. The mixture was cooled and filtered, and the filter cake was washed twice with petroleum ether / ethyl acetate and dried to obtain 1.9 g of the product.

[0174] 2. Synthesis of compound C1-3:

[0175] Under nitrogen protection, phosphorus oxychloride (0.92 g, 6 mmol) was added dropwise to N, N-dimethylformamide (10 mL) at 0°C. Under this condition, the reaction was stirred for 40 min. Then, C1-2 (510 mg, 2 mmol) was dissolved in N, N-dimethylformamide (1 mL) and added dropwise to the above reaction solution. The reaction was stirred at 80°C for 1 h. The reaction was completed. After cooling, saturated brine was added, and the mixture was extracted with ethyl acetate three times. The organic phase was washed three times with saturated brine, dried and spun to obtain 450 mg of the product. 1 HNMR: (CDCl3, 400Hz), δ10.44(s,1H), 9.14~9.12(m,1H), 8.32~8.30(m,1H).

[0176] 3. Synthesis of compound C1-4:

[0177] Compound C1-3 (400 mg, 1.31 mmol) was dissolved in methanol / dichloromethane (16 mL / 16 mL), and NaBH4 (25 mg, 0.65 mmol) was added at 0°C under nitrogen protection and stirred for 10 min. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench, and dichloromethane was extracted three times, spin-dried, and separated on a preparative plate to obtain 260 mg of the product. 1 HNMR: (CDCl3, 400Hz), δ8.94~8.92(m,1H), 8.14~8.12(m,1H), 4.90(s,2H), 3.08(m,1H).

[0178] 4. Synthesis of compound C1-5:

[0179] Compound C1-4 (500 mg, 1.63 mmol) and triethylamine (330 mg, 3.26 mmol) were dissolved in dichloromethane (18 mL). Acetyl chloride (200 mg, 2.45 mmol) was added at 0°C. The mixture was reacted for 20 min at 0°C under nitrogen protection. TLC showed that the reaction was complete. Saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with dichloromethane three times. The mixture was dried, spin-dried, and purified by column chromatography to obtain 300 mg of the product. 1 HNMR: (CDCl3, 400Hz), δ8.97~8.95(m,1H), 8.16~8.14(m,1H), 5.31(s,2H), 2.72(s,3H), 2.08(s,3H).

[0180] 5. Synthesis of Compound C1-6:

[0181] Compound C1-5 (400 mg, 1.15 mmol) and tributyl (1-ethoxyethylene) tin (580 mg, 1.6 mmol), Pd (PPh3) 2Cl2 (100 mg, 0.115 mmol) were dissolved in dry dioxane (15 mL) and stirred at 80°C for 12 h. Then, potassium fluoride solution was added at room temperature, stirred for 0.5 h, filtered, and the mother liquor was extracted with ethyl acetate three times. The organic phase was separated and dried by rotation. 2 ml of dioxane and 6M H2SO4 (2 mL) were added, and stirred at 25°C for 1 h. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added, extracted with ethyl acetate, dried by rotation, and separated on a preparative plate to obtain 320 mg of the product. 1 HNMR: (CDCl3, 400Hz), δ9.04~9.02(m,1H),8.20~8.18(m,1H),4.90(s,2H),3.08~3.06(m,1H),2.90(s,3H)

[0182] 6. Synthesis of Compound C1-7:

[0183] Compound C1-6 (100 mg, 0.28 mmol), 2-hydroxyphenylboronic acid (152 mg, 0.86 mmol), Pd(dppf)Cl2 (20 mg, 0.028 mmol), and sodium carbonate (60 mg, 0.56 mmol) were dissolved in dioxane (10 mL) and water (1 mL). Under nitrogen protection, the mixture was stirred at 80 °C for 12 h. After the reaction was completed, the mixture was dried and purified by column chromatography to obtain 80 mg of the product. 1 HNMR: (CDCl3, 400Hz), δ9.93 (s, 1H), 9.10~9.08 (m, 1H), 8.04~8.02 (m, 1H), 7.64~7.62 (m, 1H), 7.40~7 .38(m,1H),7.11~7.09(m,1H),7.02~6.98(m,1H),4.83~4.81(m,2H),3.22~3.18(m,1H),2.77(s,3H).

[0184] 7. Synthesis of Compound C1-8:

[0185] Compound C1-7 (150 mg, 0.45 mmol) was dissolved in dry tetrahydrofuran (5 mL), and triphenylphosphine (160 mg, 0.6 mmol) was added under nitrogen protection at 0°C and stirred for 0.5 h. Then diisopropyl azodicarboxylate (120 mg, 0.6 mmol) was added, the temperature was raised to room temperature, stirred for 1 h, and dried by spin drying. 80 mg of the product was obtained by separation on a preparative plate. 1 HNMR: (CDCl3, 400Hz) δ9.06~9.04(m,1H),8.08~8.00(m,2H),7.42~7.38(m,1H),7.09~7.07(m,1H),6.99~6.97(m,1H),5.41(s,2H),3.00(s,3H)

[0186] 8. Synthesis of Compound C1-9:

[0187] Compound C1-8 (55.8 mg, 0.18 mmol) was dissolved in methanol / dichloromethane (10 mL / 10 mL), and NaBH4 (14 mg, 0.36 mmol) was added at room temperature under nitrogen protection and stirred at 25°C for 10 min. After the reaction was completed, 1 drop of water was added to quench, and the mixture was spin-dried and separated on a preparative plate to obtain 38 mg of the product.

[0188] 9. Synthesis of Compound C1-10:

[0189] Compound C1-9 (31 mg, 0.1 mmol) was dissolved in dry dichloromethane (5 mL), phosphorus tribromide (90 mg, 0.3 mmol) was added at room temperature under nitrogen protection, and stirred at 25°C for 12 h. Then the mixture was spin-dried and directly used for the next step.

[0190] 10. Synthesis of Compound C1-11:

[0191] Compound C1-10 (120 mg crude product) was dissolved in dry N,N-dimethylformamide (1 mL), added to tert-butyl 2-aminobenzoate (115 mg, 0.6 mmol) in N,N-dimethylformamide at 25°C, and stirred at 60°C for 12 h. When TLC showed the reaction was complete, saturated brine was added, extracted three times with ethyl acetate, and the mixture was spin-dried. 20 mg of the product was obtained by separation on a preparative plate.

[0192] 11. Synthesis of Compound C1-12:

[0193] Compound C1-11 (70 mg, 0.14 mmol) was dissolved in dichloromethane (4 mL) / trifluoroacetic acid (2 mL), stirred at 23°C under nitrogen protection for 12 h, TLC showed the reaction was complete, and the product was dried to give 70 mg.

[0194] 12. Synthesis of compounds C1 and C2:

[0195] Compound C1-12 (50 mg, 0.16 mmol) was chirally resolved to obtain:

[0196] C1(9.3mg)[M+H] + :432.2 1 HNMR: (DMSO-d6, 400Hz), δ12.77(m,1H),8.87~8.85(m,1H),8.51~8.50(m,1H),8.25(d,J=8.0Hz,1H),7.93(d,J=8.4Hz,1H),7.83(d,J=7.6Hz,1H), 7.48~7.44(m,1H),7.22~7.14(m,2H),7.04(m,1H),6.59~6.55(m,1H),6. 45(m,1H),5.54~5.51(m,1H),5.34(d,J=8.4Hz,1H),1.71(d,J=7.8Hz,2H)

[0197] C2 (8.7 mg) [M+H] + :432.1 1HNMR: (DMSO-d6, 400Hz), δ12.77(m,1H),8.87~8.85(m,1H),8.51~8.50(m,1H),8.25(d,J=8.0Hz,1H),7.93(d,J=8.4Hz,1H),7.83(d,J=7.6Hz,1H), 7.48~7.44(m,1H),7.22~7.14(m,2H),7.04(m,1H),6.59~6.55(m,1H),6. 45(m,1H),5.54~5.51(m,1H),5.34(d,J=8.4Hz,1H),1.71(d,J=7.8Hz,2H)

[0198] Example 2

[0199] Compounds of the present invention

[0200]

[0201] The synthetic route and experimental process are as follows:

[0202]

[0203] 1. Synthesis of compound C3-2:

[0204] Dissolve C3-1 (33 g, 0.17 mol) in acetone (350 ml), heat to 60°C, add 2,4,6-trichlorophenyl maleate (96.5 g, 0.21 mol) in batches. React at 60°C for 3 hours until the reaction is complete. Cool to room temperature, filter, wash the filter cake with petroleum ether / ethyl acetate = 5 / 1, spin dry the solid, and obtain 34 g of the product. 1 H NMR (400MHz, DMSO-d6) δ11.91(m,1H),8.90(dd,J=4.7,2.8Hz,1H),8.66(dd,J=7.2,2.8Hz,1H),5.56(s,1H).

[0205] 2. Synthesis of compound C3-3:

[0206] C3-2 (22 g) was added to a reaction flask, and 220 ml of phosphorus oxychloride was added. The reaction was carried out at 120°C for 36 h. The reaction was completed by liquid chromatography-mass spectrometry. The reaction mixture was cooled to room temperature, concentrated, diluted with dichloromethane, quenched with sodium carbonate solution, adjusted to alkalinity, extracted with dichloromethane three times, dried and concentrated, and column chromatography was performed to obtain 15 g of the product.

[0207] 3. Synthesis of compound C3-4:

[0208] Dissolve C3-3 (14 g, 50.7 mmol) in toluene (140 ml), add tributyl (1-ethoxyethylene) tin (22.0 g, 60.9 mmol), Pd (PPh3) Cl2 (3.56 g, 5.07 mmol), and react at 70 ° C overnight under nitrogen protection. After the reaction is completed, the reaction is cooled to room temperature, potassium fluoride solution is added to quench, ethyl acetate is added to dilute, stirred at room temperature for 0.5 h, filtered, and the filter cake is washed with ethyl acetate. The mother liquor is extracted twice with ethyl acetate, the organic phases are combined, concentrated to 100 ml, 10 ml of concentrated hydrochloric acid is added, stirred at room temperature for 0.5 h, plated, hydrolysis is completed, liquid separation is performed, the aqueous phase is extracted once with ethyl acetate, the organic phase is dried, concentrated, and column chromatography is performed to obtain 8 g of the product.

[0209] 4. Synthesis of compound C3-5:

[0210] Compound C3-4 (5.3 g, 22.08 mmol) was dissolved in dioxane / H2O (10 / 1, 110 mL), and 2-(hydroxymethyl)phenylboronic acid cyclic monoester (8.9 g, 66.25 mmol), Pd(dppf)Cl2 (1.6 g, 2.20 mmol), and sodium carbonate (7.0 g, 66.25 mmol) were added. The mixture was reacted at 80°C overnight under nitrogen protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed twice with saturated brine, and the organic phase was dried, concentrated, and column chromatography was performed to obtain 5 g of the product. 1 H NMR(400MHz,Chloroform-d)δ9.17–9.12(m,1H),7.93(dd,J=6.4,2.8Hz,1H),7.60–7.48(m,3 H),7.40-7.46(m,1H),6.74(s,1H),4.64(d,J=6.0Hz,2H),3.33(t,J=6.4Hz,1H),2.76(s,3H).

[0211] 5. Synthesis of compound C3-6:

[0212] Dissolve compound C3-5 (5 g, 16.0 mmol) in acetic acid (100 ml), add iodine (2.44 g, 9.6 mmol), cerium ammonium nitrate (4.39 g, 8.0 mmol). React at room temperature overnight. The reaction is complete. Dilute the reaction solution with 300 ml of ethyl acetate, wash twice with sodium thiosulfate solution, adjust the alkalinity of the organic phase with sodium carbonate solution, extract three times with ethyl acetate, combine the organic phases, dry, concentrate, and obtain 2.1 g of the product by column chromatography. 1H NMR (400MHz, Chloroform-d) δ9.14(m,1H),8.03(dd,J=6.8,2.8Hz,1H),7.59(m,1H),7.51(m,1H),7.43(m,1H),7.31(m,1H),4.54(s,2H),2.71(s,3H).

[0213] 6. Synthesis of compound C3-7:

[0214] Dissolve C3-6 (219 mg, 0.5 mmol) in dioxane (7.5 ml), add Pd2(dba)3 (45.8 mg, 0.05 mmol), Xantphos (57.8 mg, 0.10 mmol), Cs2CO3 (244.5 mg, 0.75 mmol), and react at 90°C for 1.5 h under nitrogen protection. The reaction is complete. The reaction solution is diluted with ethyl acetate, filtered, and the mother liquor is washed twice with saturated brine, dried, and concentrated to obtain 89 mg of the product separated by the preparation plate. 1 HNMR(400MHz,Chloroform-d)δ9.02(m,1H),8.13–8.08(m,1H),7.85(dd,J=6. 8,2.8Hz,1H),7.53–7.46(m,2H),7.24–7.19(m,1H),5.41(s,2H),3.02(s,3H).

[0215] 7. Synthesis of compound C3-8:

[0216] C3-7 (180 mg, 0.58 mmol) was dissolved in dichloromethane / methanol (10 / 1, 5 ml), and sodium borohydride (26.5 mg, 0.70 mmol) was added. The reaction was incubated at room temperature for 10 min. After completion of the reaction, the mixture was quenched with aqueous ammonium chloride solution, extracted twice with dichloromethane, and the organic phases were combined, dried, concentrated, and slurried (petroleum ether / ethyl acetate 1 / 1) to obtain 150 mg of the product.

[0217] 8. Synthesis of compound C3-9:

[0218] Dissolve C3-8 (150 mg, 0.48 mmol) in dichloromethane (5 ml), add phosphorus tribromide (156 mg, 0.57 mmol), and react at room temperature for 12 h. Liquid chromatography-mass spectrometry was performed to determine the completion of the reaction. Concentrate the reaction solution and use it directly in the next step.

[0219] 9. Synthesis of compound C3-10:

[0220] Dissolve C3-9 (0.48 mmol) in 5 ml of N,N-dimethylformamide, add tert-butyl 2-aminobenzoate (463.2 mg, 2.4 mmol), and react at 60°C overnight. Liquid mass spectrometry shows that the reaction is complete. Dilute with ethyl acetate, wash three times with saturated ammonium chloride solution, dry, and concentrate to obtain 120 mg of the product separated by a preparative plate.

[0221] 10. Synthesis of compound C3-11:

[0222] Compound C3-10 was dissolved in 5 ml of dichloromethane, and 2.5 ml of trifluoroacetic acid was added at room temperature. The mixture was reacted for 12 h at room temperature. After the reaction was completed, the mixture was directly concentrated and dried by oil pump. 71 mg of the product was separated by preparative plate. The product was separated by chiral preparative chromatography to obtain:

[0223] C3 (27.69 mg), 1 H NMR (400MHz, DMSO-d6) δ12.78(m,1H),8.77(m,1H),8.52(m,1H),8.30–8.16(m,1H),7.83(dd,J=8.0,1.6Hz,1H),7.73(dd,J=8.0,2.8Hz,1H),7.61 –7.50(m,2H),7.45–7.33(m,1H),7.21(m,1H),6.64–6.52(m,1H),6.44(d ,J=8.4Hz,1H),5.52(t,J=6.4Hz,1H),5.38(s,2H),1.72(d,J=6.4Hz,3H).

[0224] C4 (26.04 mg) 1 H NMR (400MHz, DMSO-d6) δ12.78(m,1H),8.77(m,1H),8.52(m,1H),8.30–8.16(m,1H),7.83(dd,J=8.0,1.6Hz,1H),7.73(dd,J=8.0,2.8Hz,1H),7.61 –7.50(m,2H),7.45–7.33(m,1H),7.21(m,1H),6.64–6.52(m,1H),6.44(d ,J=8.4Hz,1H),5.52(t,J=6.4Hz,1H),5.38(s,2H),1.72(d,J=6.4Hz,3H).

[0225] Example 3

[0226] Compounds of the present invention

[0227]

[0228] The synthetic route and experimental process are as follows:

[0229]

[0230] 1. Synthesis of compound C5-1:

[0231] Compound C3-4 (3.5 g, 14.6 mmol), 2-ethoxycarbonylphenylboronic acid (8.48 g, 43.8 mmol), Pd(dppf)Cl2 (1.06 g, 1.46 mmol), and sodium carbonate (3 g, 25.2 mmol) were dissolved in dioxane (100 mL) and water (10 mL). Under nitrogen protection, the mixture was stirred at 80 °C for 12 h. After the reaction was completed, the mixture was spin-dried and purified by column chromatography to obtain 4 g of the product. 1 H NMR(400MHz,Chloroform-d)δ9.17–9.09(m,1H),8.00(dd,J=6.8,3.2Hz,1H),7.86(dd,J=7.6,1.6 Hz,1H),7.65–7.52(m,3H),6.72(s,1H),4.16(q,J=7.2Hz,2H),2.78(s,3H),1.15(t,J=7.2Hz,3H).

[0232] 2. Synthesis of compound C5-2:

[0233] Compound C5-1 (4 g, 11.3 mmol) was dissolved in methanol / dichloromethane (16 mL / 80 mL), and sodium borohydride (210 mg, 5.65 mmol) was added under nitrogen protection at room temperature and stirred at 25°C for 10 min. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench, and dichloromethane was extracted and dried, and column chromatography was performed to obtain 2 g of the product. 1 H NMR(400MHz,Chloroform-d)δ8.96(m,1H),7.89(m,1H),7.69(dd,J=7.6,2.8Hz,1H),7.65–7.51(m,3 H), 6.66 (s, 1H), 5.30 (m, 1H), 4.27 (s, 1H), 4.21 (q, J = 7.2Hz, 2H), 1.63 (m, 3H), 1.16 (t, J = 7.2Hz, 3H).

[0234] 3. Synthesis of compound C5-3:

[0235] Compound C5-2 (2 g, 5.6 mmol) was dissolved in dry 1,2-dichloroethane (60 mL), and phosphorus tribromide (4.55 g, 16.8 mmol) was added at room temperature under nitrogen protection and stirred at 50°C for 5 h. A small amount of methanol was added to quench the mixture, and 1.2 g of the product was purified by column chromatography. 1HNMR(400MHz,Chloroform-d)δ8.97(m,1H),7.99(dd,J=7.6,2.8Hz,1H),7.86(d,J=7.6Hz,1H),7.65–7.52( m,3H),6.70(s,1H),6.11(q,J=7.2Hz,1H),4.22(q,J=7.2Hz,2H),2.05–1.94(m,3H),1.14(t,J=7.2Hz,3H).

[0236] 4. Synthesis of compound C5-4:

[0237] Compound C5-3 (1.2 g, 2.87 mmol) was dissolved in dry N,N-dimethylformamide (10 mL), added to tert-butyl 2-aminobenzoate (1.67 g, 8.61 mmol) at 25°C, and stirred at 80°C for 12 h. After the reaction was completed, saturated brine was added, extracted three times with ethyl acetate, dried by spin drying, and separated by column chromatography to obtain 740 mg of the product.

[0238] 5. Synthesis of compound C5-5:

[0239] Compound C5-4 (100 mg, 0.188 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium diisopropylamide (2M) (0.3 mL, 1.13 mmol) was added at room temperature and stirred at 25°C for 30 s. After the reaction was completed, 30 mg of the product was obtained by direct separation on a preparative plate. 1 H NMR(400MHz,Chloroform-d)δ9.19(m,1H),8.45(d,J=5.6Hz,1H),8.04–7.93(m,3H),7.81(d,J=7.2Hz,1H),7.61(m,2 H),7.16(m,1H),6.66–6.58(m,1H),6.25(d,J=8.4Hz,1H),5.66(p,J=6.4Hz,1H),1.78(d,J=6.8Hz,3H),1.64(s,9H).

[0240] 6. Synthesis of compounds C5-6 and C5-7:

[0241] Compound C5-5 (300 mg, 0.617 mmol) was chirally resolved to obtain:

[0242] C5-6 (120 mg), C5-7 (120 mg)

[0243] 7. Synthesis of compounds C5 and C6:

[0244] Compound C5-6 (40 mg, 0.082 mmol) was dissolved in a mixed solvent of trifluoroacetic acid / dichloromethane (2 mL / 2 mL) and stirred at 25°C for 12 h. After the reaction was completed, the mixture was spin-dried and separated on a preparative plate to obtain product C5 (34 mg). 1 H NMR (400MHz, DMSO-d6) δ13.13-12.37(m,1H),9.20(dd,J=4.4,2.8Hz,1H),8.67-8.53(m,1H),8.31(dd,J=7.6,2.8Hz,1H), 8.02(d,J=7.2Hz,1H),7.87–7.62(m,4H),7.26-7.16(m,1H),6.63–6.46(m,2H),5.62-5.51(m,1H),1.73(d,J=6.8Hz,3H).

[0245] 8. Synthesis of compound C6:

[0246] Compound C5-7 (40 mg, 0.082 mmol) was dissolved in a mixed solvent of trifluoroacetic acid / dichloromethane (2 mL / 2 mL) and stirred at 25°C for 12 h. After the reaction was completed, the mixture was spin-dried and separated on a preparative plate to obtain product C6 (30 mg). 1 H NMR (400MHz, DMSO-d6) δ13.13-12.37(m,1H),9.20(dd,J=4.4,2.8Hz,1H),8.67-8.53(m,1H),8.31(dd,J=7.6,2.8Hz,1H), 8.02(d,J=7.2Hz,1H),7.87–7.62(m,4H),7.26-7.16(m,1H),6.63–6.46(m,2H),5.62-5.51(m,1H),1.73(d,J=6.8Hz,3H).

[0247] Example 4

[0248] Compounds of the present invention

[0249]

[0250] The synthetic route and experimental process are as follows:

[0251]

[0252]

[0253] 1. Synthesis of compound C7:

[0254] Compound C5 (24 mg, 0.56 mmol) was dissolved in methanol / dichloromethane (0.2 mL / 2 mL), and sodium borohydride (1.1 mg, 0.28 mmol) was added under nitrogen protection at room temperature and stirred at 25°C for 10 min. After the reaction was completed, saturated ammonium chloride aqueous solution was added to quench, and dichloromethane was extracted and dried, and the product 10 mg was obtained by separation on a preparative plate. 1 H NMR (400MHz, DMSO-d6) δ12.99–12.53(m,1H),9.06-8.99(m,1H),8.77–8.61(m,1H),8.09-7.95(m,2H),7.82(dd,J=8.0,1.6Hz,1H),7.70 (d,J=7.2Hz,1H),7.64–7.50(m,2H),7.19(m,1H),6.62–6.42(m,2H),5.85–5.65(m,2H),5.60-5.49(m,1H),1.72(dd,J=6.4,2.8Hz,3H).

[0255] 2. Synthesis of compound C8:

[0256] Compound C6 (24 mg, 0.56 mmol) was dissolved in methanol / dichloromethane (0.2 mL / 2 mL), and sodium borohydride (1.1 mg, 0.28 mmol) was added under nitrogen protection at room temperature and stirred at 25°C for 10 min. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench, and dichloromethane was extracted and dried, and the product 12 mg was obtained by separation on a preparative plate. 1 H NMR (400MHz, DMSO-d6) δ12.99–12.53(m,1H),9.06-8.99(m,1H),8.77–8.61(m,1H),8.09-7.95(m,2H),7.82(dd,J=8.0,1.6Hz,1H),7.70 (d,J=7.2Hz,1H),7.64–7.50(m,2H),7.19(m,1H),6.62–6.42(m,2H),5.85–5.65(m,2H),5.60-5.49(m,1H),1.72(dd,J=6.4,2.8Hz,3H).

[0257] Example 5

[0258] Compounds of the present invention

[0259]

[0260] The synthetic route and experimental process are as follows:

[0261]

[0262] 1. Synthesis of compound C9-1:

[0263] Compound C5-7 (100 mg, 0.21 mmol) was dissolved in methanol / dichloromethane (0.2 mL / 2 mL), and sodium borohydride (4 mg, 0.11 mmol) was added under nitrogen protection at room temperature and stirred at 25°C for 10 min. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench, and dichloromethane was extracted and dried, and 80 mg of the product was obtained by separation on a preparative plate. 1 H NMR(400MHz,Chloroform-d)δ8.95(m,1H),8.33(m,1H),7.99-7.94(m,1H),7.84(m,1H),7.77–7.67(m,2H),7.55–7.43(m,2H),7.10-7.03(m, 1H), 6.52 (m, 1H), 6.19 (d, J = 8.4Hz, 1H), 5.92 (d, J = 2.0Hz, 1H), 5.59 (q, J = 6.8Hz, 1H), 3.13 (m, 1H), 1.69 (dd, J = 6.8, 3.6Hz, 3H), 1.57 (s, 9H).

[0264] 2. Synthesis of compound C9-2:

[0265] Compound C9-1 (80 mg, 0.164 mmol) was dissolved in trifluoroacetic acid (5 mL), and triethylsilane (95 mg, 0.82 mmol) was added. The mixture was stirred at 25°C for 12 h. After the reaction was completed, the mixture was spin-dried and separated on a preparation plate to obtain 40 mg of the product.

[0266] 3. Synthesis of compounds C9 and C10:

[0267] Compound C9-2 (40 mg) was chirally resolved to obtain:

[0268] C9 (5.3 mg) [M+H] + :416.2 1H NMR(400MHz,DMSO-d6)δ12.74(m,1H),9.00(dd,J=4.8,2.8Hz,1H),8.68-8 .55(m,1H),8.15–8.06(m,1H),8.01-7.94(m,1H),7.85-7.79(m,1H),7.74( d,J=7.2Hz,1H),7.62–7.52(m,2H),7.23–7.14(m,1H),6.56(t,J=7.6Hz,1 H),6.49(d,J=8.4Hz,1H),5.58(m,1H),3.98(s,2H),1.74(d,J=6.4Hz,3H).

[0269] C10 (6.1 mg) [M+H] + :416.2 1 H NMR(400MHz,DMSO-d6)δ12.74(m,1H),9.00(dd,J=4.8,2.8Hz,1H),8.84-8.66 (m,1H),8.15–8.06(m,1H),8.01-7.94(dd,J=7.6,2.8Hz,1H),7.85-7.79(m,1H ),7.74(d,J=7.2Hz,1H),7.62–7.52(m,2H),7.23–7.14(m,1H),6.54(t,J=7.6H z,1H),6.46(d,J=8.4Hz,1H),5.58(m,1H),3.98(s,2H),1.73(d,J=6.4Hz,3H).

[0270] Example 6

[0271] Compounds of the present invention

[0272]

[0273] The synthetic route and experimental process are as follows:

[0274]

[0275] 1. Synthesis of compound s1-2:

[0276] Compound s1-1 (3 g, 15.1 mmol) was dissolved in dry dichloromethane (30 mL). Acetyl chloride (1.54 g, 19.6 mmol) was added to the reaction solution at 0°C. The temperature was naturally raised and stirred for reaction for 12 h. After the reaction was completed, saturated brine was added, and the mixture was extracted with dichloromethane three times. The mixture was spin-dried and separated by column chromatography to obtain 3 g of the product.

[0277] 2. Synthesis of compound s1:

[0278] Compound s1-2 (1 g, 4.2 mmol) and pinacol borate (1.27 g, 5 mmol), potassium acetate (1.24 g, 12.6 mmol), Pd(dppf)Cl2 (5 mg, 0.025 mmol) were dissolved in dry 2-methyltetrahydrofuran (20 mL) and stirred at 80 degrees for 12 h. After the reaction was completed, the mixture was filtered at room temperature, rinsed with methyl tert-butyl ether, concentrated to 5 ml, methyl tert-butyl ether was added, stirred, filtered, the filter cake was rinsed with methyl tert-butyl ether, dried, and purified by column chromatography to obtain 620 mg of the product. 1 H NMR (400MHz, Chloroform-d) δ8.58(m,1H),7.81(dd,J=7.4,1.8Hz,1H),7.63(dd,J=7.7,1.8Hz,1H),6.95(t,J=7.6Hz,1H),1.38(s,12H).

[0279] 3. Synthesis of compound C11-1:

[0280] Compound C1-6 (1.5 g, 5.6 mmol), 2-hydroxy-3-cyanophenylborane (2 g, 8.3 mmol), Xphos-Pd-G3 (510 mg, 0.56 mmol), potassium phosphate (3.56 g, 16.8 mmol) were dissolved in dioxane (150 mL) and water (15 mL), stirred at 80 ° C for 1 h under nitrogen protection, and the reaction was completed. The mixture was spin-dried and purified to obtain 780 mg of the product. 1 HNMR: (DMSO-d6, 400Hz) δ9.16 (dd, J=4.5, 2.8Hz, 1H), 8.46 (dd, J=7.4, 2.9Hz, 1H), 7.94 (dd, J= 7.7, 1.7Hz, 1H), 7.79 (dd, J=7.7, 1.7Hz, 1H), 7.10 (t, J=7.7Hz, 1H), 4.39 (s, 2H), 2.70 (s, 3H).

[0281] 4. Synthesis of compound C11-2:

[0282] Compound C11-1 (780 mg, 2.2 mmol) was dissolved in dry tetrahydrofuran (90 mL), triphenylphosphine (750 mg, 2.8 mmol) was added under nitrogen protection at 0°C, and stirred at 0°C for 0.5 h. Then diisopropyl azodicarboxylate (579 mg, 2.8 mmol) was added, the temperature was raised to room temperature, stirred for 1 h, and dried by spin drying. 0.6 g of the product was obtained by column chromatography. 1HNMR: (CDCl3, 400Hz) δ9.07 (dd, J=3.9, 2.9Hz, 1H), 8.28 (dd, J=7.8, 1.7Hz, 1H), 8.04 (dd, J=6 .9, 3.0Hz, 1H), 7.66 (dd, J = 7.7, 1.7Hz, 1H), 7.17 (t, J = 7.8Hz, 1H), 5.59 (s, 2H), 2.98 (s, 3H).

[0283] 5. Synthesis of compound C11-3:

[0284] Compound C11-2 (100 mg, 0.3 mmol) was dissolved in methanol / dichloromethane (10 mL / 10 mL), and sodium borohydride (11 mg, 0.3 mmol) was added under nitrogen protection at room temperature, and stirred at 25°C for 10 min. After the reaction was completed, saturated ammonium chloride aqueous solution was added to quench, and the product was treated and purified to obtain 60 mg.

[0285] 6. Synthesis of compound C11-4:

[0286] Compound C11-3 (26 mg, 0.08 mmol) was dissolved in dry dichloromethane (5 mL), phosphorus tribromide (62 mg, 0.24 mmol) was added under nitrogen protection at room temperature, and stirred at 25°C for 12 h. Then the mixture was spin-dried and directly used for the next step.

[0287] 7. Synthesis of compound C11-5:

[0288] Compound C11-4 (36 mg crude product) was dissolved in dry N,N-dimethylformamide (1 mL), added to tert-butyl 2-aminobenzoate (88 mg, 0.48 mmol) in N,N-dimethylformamide at 25°C, and stirred at 60°C for 12 h. After the reaction was completed, saturated brine was added, and the mixture was extracted three times with ethyl acetate, dried by rotation, and separated on a preparation plate to obtain 18 mg of the product.

[0289] 8. Synthesis of Compounds C11-6 & C11-7

[0290] Compound C11-5 (18 mg, 0.035 mmol) was chirally separated to obtain: C11-6 (4.8 mg) and C11-7 (5.0 mg)

[0291] 9. Synthesis of Compound C11:

[0292] Compound C11-6 (4.8 mg) was dissolved in dichloromethane (2 mL) / trifluoroacetic acid (1 mL), stirred at 23 °C under nitrogen protection for 12 h, and the reaction was completed and the product was dried to obtain 2 mg, [M+H] + :457.1.

[0293] 10. Synthesis of compound C12:

[0294] Compound C11-7 (5 mg) was dissolved in dichloromethane (2 mL) / trifluoroacetic acid (1 mL), stirred for 12 h at 23 °C under nitrogen protection, and the reaction was completed. The product was dried to obtain 1.8 mg, [M+H] + :457.1 1 HNMR: (DMSO-d6, 400Hz), δ9.05-8.77(m,2H),8.53(dd,J=7.8,1.7Hz,1H),7.99-7.88(m,2H),7.83(dd,J=7.9,1.7Hz,1H),,7.31(t,J= 7.7Hz,1H),7.13(t,J=7.8Hz,1H),6.54(t,J=7.5Hz,1H),6.38(d,J=8.4Hz,1H),5.56(s,2H),5.52-5.49(m,1H),1.69(d,J=7.8Hz,3H).

[0295] Example 7

[0296] Compounds of the present invention

[0297]

[0298] The synthetic route and experimental process are as follows:

[0299]

[0300] 1. Synthesis of compound C13-2:

[0301] Compound C13-1 (6 g, 30.3 mmol) was dissolved in 280 mL of anhydrous dichloromethane, and triethylamine (9.2 g, 90.9 mmol) and acetyl chloride (3.57 g, 45.45 mmol) in 20 mL of anhydrous dichloromethane were slowly added at 0°C, and the temperature was slowly raised to 25°C for 12 h to react until the raw materials reacted completely. Saturated sodium bicarbonate aqueous solution was slowly added to adjust the pH to 8, and then extracted with dichloromethane, the organic phase was separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified to obtain 7.3 g of product. 1 H NMR (400MHz, Chloroform-d) δ7.92 (d, J = 12.0Hz, 1H), 7.64 (dd, J = 8.4, 2.0Hz, 1H), 7.27 (d, J = 8.4Hz, 1H), 2.39 (s, 3H).

[0302] 2. Synthesis of compound C13-3:

[0303] C13-2 (7.3 g, 30.4 mmol) and bis-pinacol borate (9.27 g, 36.5 mmol), potassium acetate (9 g, 91.2 mmol) and Pd(dppf)Cl2·DCM (1.24 g, 1.52 mmol) were dissolved in 150 mL of anhydrous dioxane. Under nitrogen protection, the reaction solution was slowly heated to 80°C and stirred for 12 h. After the reaction of the raw materials was complete, the reaction solution was cooled to room temperature, diluted with saturated brine, and then extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 5.5 g of the product. 1 H NMR (400MHz, Chloroform-d) δ8.28(s,1H),7.93(d,J=2.2Hz,1H),7.61(dd,J=8.6,2.2Hz,1H),6.93(d,J=8.6Hz,1H),1.38(s,12H).

[0304] 3. Synthesis of compound C13-4:

[0305] C13-3 (2.04 g, 8.33 mmol) and C1-6 (1.5 g, 5.56 mmol), potassium phosphate (3.5 g, 16.7 mmol) and XphosPdG3 (470 mg, 0.56 mmol) were dissolved in a mixed solvent consisting of 150 mL of dioxane and 15 mL of water. Under nitrogen protection, the reaction solution was slowly heated to 80 ° C and stirred for 2 h. After the reaction of the raw materials was complete, the reaction solution was cooled to room temperature, diluted with saturated brine, and then extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 630 mg of the product. 1 H NMR(400MHz,Chloroform-d)δ11.41-10.76(m,1H),9.19–9.09(m,1H),8.16–8.05(m,2H),7.6 7(dd,J=8.4,2.0Hz,1H),7.18(d,J=8.4Hz,1H),4.78(s,2H),3.18-2.90(m,1H),2.77(s,3H).

[0306] 4. Synthesis of compound C13-5:

[0307] Compound C13-4 (630 mg, 1.78 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran. Under nitrogen protection, the reaction solution was cooled to 0°C, triphenylphosphine (606 mg, 2.31 mmol) was slowly added, and the temperature was maintained and stirred for 1 h. Then diisopropyl azodicarboxylate (468 mg, 2.31 mmol) was added, and the temperature was raised to room temperature. After the raw materials reacted completely, the reaction solution was diluted with saturated brine, and then extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 430 mg of the product. 1 H NMR(400MHz,Chloroform-d)δ9.06(t,J=3.6Hz,1H),8.34(d,J=2.0Hz,1H),8.05(dd,J=6.8 ,3.2Hz,1H),7.66(dd,J=8.4,2.0Hz,1H),7.06(d,J=8.4Hz,1H),5.51(s,2H),2.99(s,3H).

[0308] 8. Synthesis of compound C13-6:

[0309] Compound C13-5 (400 mg, 1.2 mmol) was dissolved in a mixed solvent consisting of 50 mL of dichloromethane and 50 mL of methanol. Sodium borohydride (45.2 mg, 1.2 mmol) was slowly added under nitrogen protection, and the reaction solution was stirred at room temperature for 10 min. After the reaction of the raw materials was complete, the reaction solution was diluted with water, and then extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 300 mg of the product. 1 H NMR (400MHz, DMSO-d6) δ8.89(dd,J=4.8,3.2Hz,1H),8.48(d,J=2.0Hz,1H),8.06(dd,J=8.4,2.8Hz,1H),7.90(dd,J=8. 4,2.0Hz,1H),7.20(d,J=8.4Hz,1H),5.70(d,J=4.8Hz,1H),5.60(d,J=5.6Hz,1H),5.46(s,2H),1.53(d,J=6.4Hz,3H).

[0310] 9. Synthesis of compound C13-7:

[0311] Compound C13-6 (300 mg, 0.89 mmol) was dissolved in 60 mL of anhydrous dichloromethane. Under nitrogen protection, phosphorus tribromide (721 mg, 2.66 mmol) was slowly added. The mixture was stirred at room temperature for 12 h. After the reaction of the raw materials was complete, the mixture was concentrated under reduced pressure to obtain 300 mg of the product, which was directly used for the next step.

[0312] 10. Synthesis of compound C13-8:

[0313] Compound C13-7 (300 mg, 0.75 mmol) was dissolved in 20 mL of anhydrous N,N-dimethylformamide. At room temperature, tert-butyl 2-aminobenzoate (873 mg, 4.51 mmol) was slowly added. The temperature was slowly raised to 60°C and the reaction was stirred for 12 h. After the reaction of the raw materials was complete, the reaction solution was diluted with water and then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 60 mg of the product.

[0314] 11. Synthesis of compounds C13-9 and C13-10:

[0315] Compound C13-8 was chiral resolved to obtain:

[0316] C13-9(25mg)[M+H] + :513.3

[0317] C13-10(25mg)[M+H] + :513.3

[0318] 12. Synthesis of compound C13:

[0319] Compound C13-9 (25 mg, 0.049 mmol) was dissolved in 10 mL of anhydrous dichloromethane and 5 mL of trifluoroacetic acid, stirred at room temperature for 12 h, and after the reaction of the raw materials was complete, the mixture was concentrated under reduced pressure and purified to obtain 14 mg of the product. Ms[M+H] + 457.2, 1 HNMR(400MHz,DMSO-d6)δ13.20-12.40(m,1H),8.89(dd,J=4.4,2.8Hz,1H),8.66(d,J=2.0Hz,1H),8.59-8.46(s,1H),7.99–7.80 (m,3H),7.26-7.16(m,2H),6.58(t,J=7.6Hz,1H),6.47(d,J=8.4Hz,1H),5.72–5.63(m,1H),5.48(s,2H),1.70(d,J=6.4Hz,3H).

[0320] 13. Synthesis of Compound C14:

[0321] Compound C13-10 (25 mg, 0.049 mmol) was dissolved in 10 mL of anhydrous dichloromethane and 5 mL of trifluoroacetic acid, stirred at room temperature for 12 h, and after the reaction of the raw materials was complete, the mixture was concentrated under reduced pressure and purified to obtain 14 mg of the product. Ms[M+H] + 457.2,1 H NMR(400MHz, DMSO-d6)δ13.20-12.40(m,1H),8.89(dd,J=4.4,2.8Hz,1H),8.66(d,J=2.0Hz,1H),8.59-8.46(m,1H),7.99–7.80 (m,3H),7.26-7.16(m,2H),6.58(t,J=7.6Hz,1H),6.47(d,J=8.4Hz,1H),5.72–5.63(m,1H),5.48(s,2H),1.70(d,J=6.4Hz,3H).

[0322] Example 8

[0323] Compounds of the present invention

[0324]

[0325] The synthetic route and experimental process are as follows:

[0326]

[0327] 1. Synthesis of compound C15-2:

[0328] Compound C15-1 (2.0 g, 7.5 mmol), cerium ammonium nitrate (2.06 g, 3.7 mmol), and I2 (1.15 g, 4.0 mmol) were dissolved in acetic acid (20 mL) and stirred at room temperature for 16 h. After the reaction was completed, sodium sulfite aqueous solution was added to quench, extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography to obtain 2.3 g of the product.

[0329] 2. Synthesis of compound C15-3:

[0330] C15-2 (1.3 g, 3.3 mmol), vinylboronic acid pinacol ester (1.53 g, 9.9 mmol), Pd(dppf)Cl2 (243 mg, 0.33 mmol), sodium carbonate (703 mg, 6.6 mmol) were added to a mixed solvent of dioxane (20 mL) and water (2 mL). The mixture was stirred at 90°C overnight and the reaction was complete. 400 mg of the product was obtained by column chromatography purification.

[0331] 3. Synthesis of compound C15-4:

[0332] C15-3 (1.05 g, 3.5 mmol), 6-methoxypyridine-2-boronic acid pinacol ester (1.27 g, 5.3 mmol), thiophene-2-carboxylic acid copper (I) (1.02 g, 5.3 mmol), Pd (PPh 3) 4 (415 mg, 0.35 mmol), Cs 2 CO 3 (2.34 g, 7.19 mmol) were added to dioxane (20 mL) and stirred overnight at 90 ° C. After the reaction was completed, the product was treated and purified by column chromatography to obtain 400 mg. 1 H NMR(400MHz,Chloroform-d)δ8.12(dd,J=7.5,3.3Hz,1H),7.88(dd,J=8.2,3.3Hz,1H),7.82-7.69(m,1H),7.43(d,J=7.3Hz,1H),6.91 (d,J=8.4Hz,1H),6.68(dd,J=17.6,11.8Hz,1H),6.41(dd,J=17.6,2.1Hz,1H),5.56(dd,J=11.8,2.1Hz,1H),3.97(s,3H),2.81(s,3H).

[0333] 4. Synthesis of compound C15-5:

[0334] C15-4 (400 mg, 1.0 mmol), NaI (307 mg, 2.0 mmol), TMS-Cl (223 mg, 2.0 mmol) were added to acetonitrile (20 mL) and the reaction was continued at 50°C overnight. After the reaction was completed, ethyl acetate and aqueous sodium bicarbonate solution were added and purified by column chromatography to obtain 90 mg of the product. 1 H NMR(400MHz,Chloroform-d)δ8.15(dd,J=7.3,3.3Hz,1H),7.92(dd,J=7.9,3.3Hz,1H),7.56(d d,J=9.2,6.8Hz,1H),6.86-6.67(m,2H),5.68-5.56(m,1H),2.88(s,3H),1.91(d,J=6.6Hz,3H).

[0335] 5. Synthesis of compound C15-6:

[0336] Compound C15-5 (100 mg) was dissolved in methanol / dichloromethane (4 mL / 4 mL), and NaBH4 (9 mg) was added at room temperature under nitrogen protection, and stirred at 25°C for 10 min. After the reaction was completed, saturated aqueous ammonium chloride solution was added to quench, the mixture was spin-dried, and purified by column chromatography to obtain 50 mg of the product.

[0337] 6. Synthesis of compound C15-7:

[0338] Compound C15-6 (100 mg, 0.3 mmol) was dissolved in dry dichloromethane (5 mL), phosphorus tribromide (448 mg, 0.9 mmol) was added under nitrogen protection at room temperature, and stirred at 25°C for 12 h. The mixture was then concentrated and used directly in the next reaction.

[0339] 7. Synthesis of compound C15-8:

[0340] Compound C15-7 (100 mg crude product) was dissolved in dry N,N-dimethylformamide (1 mL), added to tert-butyl 2-aminobenzoate (115 mg, 0.6 mmol) in N,N-dimethylformamide at 25°C, and stirred at 60°C for 12 h. After the reaction was completed, saturated brine was added, extracted with ethyl acetate three times, concentrated, and purified by column chromatography to obtain 50 mg of the product.

[0341] 8. Synthesis of Compound C15-9

[0342] Compound C15-8 (50 mg) was added to a mixed solvent of trifluoroacetic acid (2 mL) and dichloromethane (4 mL), and stirred at 25°C for 16 h. After the reaction was completed, the mixture was concentrated and purified by column chromatography to obtain 30 mg of the product.

[0343] 9. Synthesis of compounds C15, C16, C17, and C18

[0344] C15-9 was separated by the following splitting method:

[0345] Instrument: Agilent 1260 InfinityⅡ, chromatographic column: phenomenex 5μmcellulose-4 (250×21.2mm), mobile phase: n-hexane: ethanol = 8:2, column temperature: 25°C. Separation: C15 (3.5mg) Ms[M+H]+457.2, C16 (3.7mg) Ms[M+H]+457.2, C17 (3.2mg) Ms[M+H]+457.2, C18 (3.6mg) Ms[M+H]+457.2.

[0346] Example 9

[0347] Compounds of the present invention

[0348]

[0349] The synthetic route and experimental process are as follows:

[0350]

[0351] 1. Synthesis of compound C19-2:

[0352] Add 2-amino-3-bromo-5-methylpyridine (10 g, 53.5 mmol) to acetone (100 ml), heat to 60°C, add 2,4,6-trichlorophenyl maleate (29.7 g, 64.2 mmol) in batches. After adding, react at 60°C for 3 hours until the reaction is complete. Cool to room temperature, filter, rinse the filter cake with petroleum ether / ethyl acetate, and dry the filter cake to obtain 8.5 g of the product.

[0353] 2. Synthesis of compound C19-3:

[0354] Add phosphorus oxychloride (8 ml) dropwise to N,N-dimethylformamide (120 ml) under ice bath, and stir at 0°C for 40 min. Add N,N-dimethylformamide solution of C19-2 (8 g / 16 ml) to the reaction solution, and heat to 80°C for 2 h. The reaction is complete. Cool the reaction mixture to room temperature, pour into water to quench, filter, wash the filter cake three times with water, dissolve with dichloromethane, dry to remove water, and concentrate to obtain 8 g of product.

[0355] 3. Synthesis of compound C19-4:

[0356] C19-3 (8 g, 26.7 mmol) was dissolved in dichloromethane / methanol (250 / 25 ml), and sodium borohydride (506 mg, 13.38 mmol) was slowly added in batches under an ice bath. The reaction was allowed to react at room temperature for 10 min, and the reaction was completed. The mixture was quenched with aqueous ammonium chloride solution, extracted twice with dichloromethane, and the organic phases were combined, dried, concentrated, and slurried (petroleum ether / ethyl acetate) to obtain 5.2 g of the product.

[0357] 4. Synthesis of compound C19-5:

[0358] Dissolve C19-4 (5.4 g, 17.9 mmol) in toluene (80 ml), add tributyl (1-ethoxyethylene) tin (7.7 g, 21.5 mmol), Pd (PPh3) Cl2 (1.3 g, 1.80 mmol), and react at 70 ° C overnight under nitrogen protection. After the reaction is completed, cool to room temperature, add potassium fluoride solution to quench, dilute with ethyl acetate, stir at room temperature for 0.5 h, filter, and wash the filter cake with ethyl acetate. The mother liquor is extracted twice with ethyl acetate, the organic phases are combined, concentrated to 100 ml, 6N hydrochloric acid 6 ml is added, and stirred at room temperature for 2 min. After hydrolysis is completed, adjust the pH to alkaline with sodium bicarbonate solution, separate the liquids, extract the aqueous phase with ethyl acetate once, dry the organic phase, concentrate, and slurry (petroleum ether / ethyl acetate) to obtain 3.2 g of the product.

[0359] 5. Synthesis of compound C19-6:

[0360] Compound C19-5 (1 g, 3.76 mmol) was dissolved in dioxane / H2O (10 / 1, 20 mL), and 2-hydroxy-4-nitrile phenyl borate (1.1 g, 4.51 mmol), Xphos-Pd-G3 (318.8 mg, 0.38 mmol), and potassium phosphate (2.39 g, 11.28 mmol) were added. The mixture was reacted at 80°C for 1 h under nitrogen protection. After the reaction was completed, the reaction solution was diluted with ethyl acetate and water, filtered, separated, and the aqueous phase was extracted with ethyl acetate once. The aqueous phase was acidified with 2N hydrochloric acid, filtered, concentrated, and slurried with ethyl acetate to obtain 500 mg of the product.

[0361] 5. Synthesis of compound C19-7:

[0362] Dissolve compound C19-6 (170 mg, 0.49 mmol) in dry tetrahydrofuran (5 ml), add triphenylphosphine (166 mg, 0.63 mmol), protect with nitrogen, and stir for 0.5 h in an ice bath. Then add diisopropyl azodicarboxylate (128 mg, 0.63 mmol). React for 0.5 h in an ice bath, then warm to room temperature and react for 1 h. The reaction is complete. Filter and dry to obtain 140 mg of the product.

[0363] 6. Synthesis of compound C19-8:

[0364] C19-7 (140 mg, 0.42 mmol) was dissolved in dichloromethane / methanol (10 / 1, 5.5 ml), sodium borohydride (16.1 mg, 0.42 mmol) was added under ice bath, and the reaction was carried out at room temperature for 10 min. After the reaction was completed, aqueous ammonium chloride solution was added to quench, and dichloromethane was extracted twice. The organic phases were combined, dried, concentrated, and slurried (petroleum ether / ethyl acetate) to obtain 130 mg of the product.

[0365] 7. Synthesis of compound C19-9:

[0366] Dissolve C19-8 (130 mg, 0.39 mmol) in dichloromethane (5 ml), add phosphorus tribromide (317 mg, 1.17 mmol), and react at room temperature overnight. After the reaction is complete, concentrate the reaction solution and use it directly in the next step.

[0367] 8. Synthesis of Compound C19-10:

[0368] Dissolve C19-9 in N,N-dimethylformamide, add tert-butyl 2-aminobenzoate (527 mg, 2.73 mmol), and react overnight at 60°C. After the reaction is completed, cool the reaction solution to room temperature, dilute with ethyl acetate, wash three times with saturated ammonium chloride solution, dry the organic phase, concentrate, and purify by column chromatography to obtain 50 mg of the product.

[0369] 9. Synthesis of compounds C19 and C20:

[0370] Dissolve C19-10 (50 mg) in dichloromethane (2 ml), add trifluoroacetic acid (1 ml), and react at room temperature for 24 hours. After the reaction is complete, concentrate the reaction solution and separate using the following separation method:

[0371] Instrument: Agilent 1260 InfinityⅡ, chromatographic column: phenomenex 5μmcellulose-4 (250×21.2mm), mobile phase: n-hexane:ethanol=6:4, column temperature: 25℃.

[0372] C20 (10.1 mg), 1 H NMR (400MHz, DMSO) δ12.72(br,1H),8.72(s,1H),8.61(d,J=4.0Hz,1H),8.49(d,J=8.0Hz,1H),7.88–7.79(m,3H),7.22–7. 15(m,2H),6.55(t,J=8.0Hz,1H),6.47(d,J=12Hz,1H),5.67-5.61(m,1H),5.45(s,2H),2.36(s,3H),1.67(d,J=4.0Hz,3H).

[0373] C19 (10.4 mg), 1 H NMR (400MHz, DMSO) δ12.75(br,1H),8.73(s,1H),8.61(d,J=4.0Hz,1H),8.49(d,J=8.0Hz,1H),7.89–7.80(m,3H),7.23–7.1 6(m,2H),6.55(t,J=8.0Hz,1H),6.47(d,J=8.0Hz,1H),5.67-5.61(m,1H),5.45(s,2H),2.36(s,3H),1.67(d,J=8.0Hz,3H).

[0374] Example 10

[0375] Compounds of the present invention

[0376]

[0377] The synthetic route and experimental process are as follows:

[0378]

[0379] 1. Synthesis of compound C21-2:

[0380] Dissolve 7-bromo-3,4-dihydro-2H-isoquinolin-1-one (5g, 22.22mmol) in N,N-dimethylacetamide (50ml), add Pd2(dba)3 (203mg, 0.22mmol), dppf (122mg, 0.22mmol), zinc powder (57.2mg, 0.88mmol), zinc cyanide (2.7g, 22.22mmol). The reaction temperature was raised to 120℃ under nitrogen protection for 4h. Cool to room temperature and purify by column chromatography to obtain 3g of product.

[0381] 2. Synthesis of compound C21-3:

[0382] C21-2 (2 g, 11.63 mmol) and 2-amino-3-bromo-5-fluorobenzoic acid (5.42 g, 23.26 mmol) were added to a reaction flask, phosphorus oxychloride (50 ml) was added, the temperature was raised to 110°C, and the reaction was continued for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, treated, and purified by column chromatography to obtain 1.5 g of the product.

[0383] 3. Synthesis of compound C21-4:

[0384] Dissolve C21-3 (530 mg, 1.43 mmol) in dioxane (10 ml), add Pd(PPh3)2Cl2 (100.8 mg, 0.14 mmol), tributyl(1-ethoxyethylene)tin (622 mg, 1.72 mmol). React at 70°C for 12 h under nitrogen protection. The reaction is complete. The reaction solution is cooled to room temperature and treated to obtain 500 mg of crude product.

[0385] 4. Synthesis of compound C21-5:

[0386] C21-4 (500 mg, 1.43 mmol) was dissolved in a mixed solvent of dichloromethane / methanol (10 / 1, 22 ml), sodium borohydride (55 mg, 1.43 mmol) was added under ice bath, and the mixture was reacted at room temperature for 20 min. After the reaction was completed, aqueous ammonium chloride solution was added to quench the mixture, and the mixture was extracted twice with dichloromethane. The organic phases were combined, dried, concentrated, and slurried to obtain 260 mg of the product.

[0387] 5. Synthesis of compound C21-6:

[0388] Compound C21-5 (150 mg, 0.45 mmol) was dissolved in dichloromethane (5 ml), phosphorus tribromide (362.7 mg, 1.34 mmol) was added, and the mixture was reacted at room temperature overnight. After the reaction was completed, the reaction solution was dried and used directly in the next step.

[0389] 5. Synthesis of compound C21-7:

[0390] C21-6 was dissolved in DMF, tert-butyl 2-aminobenzoate (605 mg, 3.13 mmol) was added, and the mixture was reacted at 80°C for 4 h. After the reaction was completed by LC-MS, the reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed three times with saturated ammonium chloride solution. The organic phase was dried, concentrated, and purified by column chromatography to obtain 90 mg of the product.

[0391] 6. Synthesis of compounds C21 and C22:

[0392] C21-7 (90 mg) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (2 ml) was added, and the mixture was reacted at room temperature for 16 h. The reaction solution was concentrated and dried, and chiral separation was performed to obtain product C21 (10 mg). 1 HNMR(400MHz, CDCl3) δ8.82(d,J=1.6Hz,1H),8.32(m,1H),8.02(dd,J=8.0,1.6Hz,1H),7. 87(dd,J=8.0,3.2Hz,1H),7.79(dd,J=8.0,1.6Hz,1H),7.59(dd,J=9.2,3.2Hz,1H),7.49(d ,J=8.0Hz,1H),7.17-7.22(m,J=8.6,1H),6.57–6.65(m,1H),6.40(d,J=8.4Hz,1H),5.74( s,1H),4.33–4.59(m,1H),4.40–4.47(m,1H),3.26(t,J=6.4Hz,2H),1.76(d,J=6.8Hz,3H).

[0393] C22 (10 mg) 1 H NMR (400MHz, CDCl3) δ8.82 (d, J = 1.6Hz, 1H),

[0394] 8.32(m,1H),8.02(dd,J=8.0,1.6Hz,1H),7.87(dd,J=8.0,3.2Hz,1H),7.79(dd ,J=8.0,1.6Hz,1H),7.59(dd,J=9.2,3.2Hz,1H),7.49(d,J=8.0Hz,1H),7.17-7 .22(m,J=8.6,1H),6.57–6.65(m,1H),6.40(d,J=8.4Hz,1H),5.73(s,1H),4.53 –4.59(m,1H),4.40–4.47(m,1H),3.26(t,J=6.4Hz,2H),1.76(d,J=6.8Hz,3H)..

[0395] Embodiment 11

[0396] Compounds of the present invention

[0397]

[0398] The synthetic route and experimental process are as follows:

[0399]

[0400] 1. Synthesis of compound C23-1:

[0401] C3-4 (1.5 g, 5.4 mmol) was dissolved in dioxane (80 mL) and water (10 mL), and SM (3.3 g, 6.6 mmol), potassium phosphate (3.43 g, 16.2 mmol) and Xphos-Pd-G3 (0.46 g, 0.54 mmol) were added. The mixture was reacted at 80 °C for 1 h under nitrogen protection. After post-treatment, 1.9 g of the product was obtained by column chromatography.

[0402] 1 H NMR(400MHz,Chloroform-d)δ9.10(dd,J=4.0,3.2Hz,1H),8.03–7.94(m,2H),7.83(dd,J=8.0,1.6Hz,1H),7.73(d,J=1.6Hz, 1H),7.62–7.54(m,4H),7.44–7.38(m,2H),7.33(tt,J=6.4,1.2Hz,4H),6.54(s,1H),4.93(s,2H),2.54(s,3H),1.06(s,9H).

[0403] 2. Synthesis of compound C23-2:

[0404] Compound C23-1 (1.9 g, 3.3 mmol) was dissolved in 40 ml of acetic acid, and then ammonium cerium nitrate (0.91 g, 1.65 mmol) and elemental iodine (0.51 g, 1.98 mmol) were added, and the mixture was reacted overnight at room temperature. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with a saturated aqueous sodium sulfite solution, and then washed twice with a saturated aqueous sodium bicarbonate solution, dried, concentrated, and subjected to column chromatography to obtain 1.9 g of the product.

[0405] 1 H NMR(400MHz,Chloroform-d)δ9.09(dd,J=4.0,2.8Hz,1H),8.09–7.98(m,2H),7.85(dd,J=8.0, 1.6Hz,1H),7.62–7.51(m,5H),7.43–7.29(m,6H),4.80–4.63(m,2H),2.50(s,3H),1.04(s,9H).

[0406] 3. Synthesis of compound C23-3:

[0407] Compound C23-2 (1.9 g, 2.7 mmol) was dissolved in 75 ml of tetrahydrofuran, and triethylamine trihydrofluoride (2.17 g, 13.5 mmol) was added, and the mixture was reacted at room temperature overnight. Concentration and column chromatography were performed to obtain 1.1 g of the product.

[0408] 1 H NMR (400MHz, Chloroform-d) δ9.18(dd,J=4.0,2.8Hz,1H),8.08(dd,J=6.8,2.8Hz,1H),7.82(d,J=1.2Hz,2H),7.62(t,J=1.2Hz,1H),4.62(s,2H),2.72(s,3H).

[0409] 4. Synthesis of compound C23-4:

[0410] Compound C23-3 (1.1 g, 2.37 mmol) was dissolved in 60 ml of dioxane, and then Pd2(dba)3 (0.22 g, 0.24 mmol), Xantphos (0.27 g, 0.48 mmol) and cesium carbonate (1.16 g, 3.56 mmol) were added. The mixture was reacted at 90 °C for 1.5 h under nitrogen protection. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate and concentrated. The mixture was slurried with ethyl acetate / petroleum ether = 1:1 to obtain 600 mg of the product.

[0411] 1 H NMR(400MHz,Chloroform-d)δ9.04(dd,J=4.4,2.8Hz,1H),8.35(d,J=1.6Hz,1H),7.90(dd,J= 6.8, 2.8Hz, 1H), 7.80 (dd, J=7.6, 1.7Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 5.47 (s, 2H), 3.01 (s, 3H).

[0412] 5. Synthesis of compound C23-5:

[0413] Compound C23-4 (200 mg, 0.60 mmol) was dissolved in 20 ml of tetrahydrofuran, and then R-tert-butylsulfenamide (144 mg, 1.2 mmol) and tetraethyl titanate (543 mg, 2.4 mmol) were added and stirred at 70°C overnight. After the reaction was completed, water was added, filtered, the filter cake was washed with ethyl acetate, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, concentrated, and column chromatography was performed to obtain 150 mg of the product.

[0414] 6. Synthesis of compound C23-6:

[0415] Compound C23-5 (150 mg, 0.34 mmol) was dissolved in a mixed solvent of 5 ml dichloromethane and 5 ml methanol, and then sodium cyanoborohydride (64.5 mg, 1.02 mmol) and acetic acid (164 mg, 2.72 mmol) were added and stirred at room temperature overnight. After the reaction was completed, ammonia water was added, and dichloromethane was extracted, concentrated, and column chromatography was performed to obtain 100 mg of the product.

[0416] 1 H NMR(400MHz,Chloroform-d)δ8.87(dd,J=4.4,2.8Hz,1H),8.46(d,J=1.6Hz,1H),7.78(dd,J=7.6,1.6Hz,1H),7.62(dd,J=7.6 ,2.4Hz,1H),7.36(d,J=7.6Hz,1H),5.45(s,2H),5.12–5.05(m,1H),4.99(d,J=8.4Hz,1H),1.79(d,J=6.8Hz,3H),1.27(s,9H).

[0417] 7. Synthesis of compound C23-7:

[0418] Compound C23-6 (100 mg, 0.23 mmol) was added to 5 ml of dioxane hydrochloride, ultrasonicated for 5 min, and concentrated to obtain 100 mg of the product.

[0419] 8. Synthesis of compound C23:

[0420] Compound C23-7 (100 mg, 0.3 mmol) was dissolved in 20 ml of dichloromethane, and then triethylamine (150 mg, 1.5 mmol), copper acetate (108 mg, 0.6 mmol) and 2-carboxyphenylboronic acid (160 g, 0.9 mmol) were added, and stirred at room temperature overnight under oxygen. After the reaction was completed, ammonia water was added, and dichloromethane was extracted. The product 21.55 mg was obtained by high-efficiency preparative liquid separation. 1H NMR (400MHz, DMSO-d6) δ12.78(s,1H),8.79(dd,J=4.8,2.8Hz,1H),8.61(d,J=1.6Hz,1 H),8.52(s,1H),8.02(dd,J=7.6,1.6Hz,1H),7.83(dd,J=8.0,1.6Hz,1H),7.74(dd,J= 8.0,2.8Hz,1H),7.61(d,J=8.0Hz,1H),7.27–7.17(m,1H),6.58(t,J=7.6Hz,1H),6.47 (d,J=8.4Hz,1H),5.65(t,J=6.4Hz,1H),5.48(d,J=1.6Hz,2H),1.70(d,J=6.4Hz,3H).

[0421] Example 12

[0422] Compounds of the present invention

[0423]

[0424] The synthetic route and experimental process are as follows:

[0425]

[0426] 1. Synthesis of compound C24-2:

[0427] Dissolve compound C24-1 (5 g, 25.39 mmol) in 100 mL of anhydrous dichloromethane, slowly add triethylamine (7.69 g, 76.16 mmol) and acetyl chloride (2.99 g, 38.08 mmol) in 20 mL of anhydrous dichloromethane at 0°C, slowly heat to 25°C and react for 12 hours until the raw materials react completely. Saturated sodium bicarbonate aqueous solution is slowly added to adjust the pH to 8, then extracted with dichloromethane, the organic phase is separated, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure and purified to obtain 5.1 g of product. Ms[M+H] + 240.0

[0428] 1 H NMR (400MHz, DMSO-d6) δ7.98 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.73 (dd, J = 8.3, 2.0 Hz, 1H), 2.36 (s, 3H).

[0429] 2. Synthesis of compound C24-3:

[0430] C24-2 (5.1 g, 21.4 mmol), biboric acid pinacol ester (6.51 g, 25.61 mmol), potassium acetate (6.27 g, 64.03 mmol) and Pd (dppf) Cl2·DCM (1.74 g, 2.13 mmol) were dissolved in 150 mL of anhydrous dioxane. Under nitrogen protection, the reaction solution was slowly heated to 80 ° C and stirred for 12 h. After the reaction of the raw materials was complete, the reaction solution was cooled to room temperature, diluted with saturated brine, and then extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 5.4 g of product. 1 H NMR (400MHz, DMSO-d6) δ9.84(m,1H),7.60(d,J=7.6Hz,1H),7.20(dd,J=7.6,1.4Hz,1H),7.14(d,J=1.4Hz,1H),1.29(s,12H).

[0431] 3. Synthesis of compound C24-4:

[0432] C24-3 (3.0 g, 12.22 mmol) and C1-6 (1.1 g, 4.07 mmol), potassium phosphate (1.73 g, 8.15 mmol) and Xphos-Pd-G3 (345.66 mg, 0.41 mmol) were dissolved in a mixed solvent consisting of 100 mL of dioxane and 10 mL of water. Under nitrogen protection, the reaction solution was slowly heated to 80 ° C and stirred for 2 h. After the raw materials reacted completely, the reaction solution was cooled to room temperature, diluted with saturated brine, and then extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 750 mg of the product. Ms[M+H] + 354.1

[0433] 1 H NMR (400MHz, DMSO-d6) δ10.54(m,1H),9.10(dd,J=4.6,2.9Hz,1H),8.27(dd,J=7.3,2.9Hz,1H),7. 59 (d, J = 7.9 Hz, 1H), 7.40 (dd, J = 7.9, 1.6 Hz, 1H), 7.31 (d, J = 1.5 Hz, 1H), 4.35 (s, 2H), 2.67 (s, 3H).

[0434] 4. Synthesis of compound C24-5:

[0435] Compound C24-4 (750 mg, 2.12 mmol) was dissolved in 50 mL of anhydrous tetrahydrofuran. Under nitrogen protection, the reaction solution was cooled to 0°C, triphenylphosphine (723.65 mg, 2.76 mmol) was slowly added, and the temperature was maintained and stirred for 1 h. Then diisopropyl azodicarboxylate (557.93 mg, 2.76 mmol) was added and the temperature was raised to room temperature for reaction. After the raw material reaction was complete, the reaction solution was diluted with saturated brine, and then extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 500 mg of the product. Ms[M+H] + 336.1

[0436] 8. Synthesis of compound C24-6:

[0437] Compound C24-5 (500 mg, 1.49 mmol) was dissolved in a mixed solvent consisting of 50 mL of dichloromethane and 50 mL of methanol. Under nitrogen protection, NaBH4 (56.62 mg, 1.49 mmol) was slowly added, and the reaction solution was stirred at room temperature for 10 min. After the reaction of the raw materials was complete, the reaction solution was diluted with water, and then extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 370 mg of the product. Ms[M+H] + 338.1

[0438] 1 H NMR (400MHz, DMSO-d6) δ8.87(dd,J=4.6,2.9Hz,1H),8.24(d,J=7.9Hz,1H),8.05(dd,J=8.3 ,2.8Hz,1H),7.59(dd,J=7.9,1.6Hz,1H),7.54(d,J=1.5Hz,1H),5.71(m,1H),5.56-5.48(m 1H),5.39(m,2H),1.52(d,J=6.4Hz,3H).

[0439] 9. Synthesis of compound C24-7:

[0440] Compound C24-6 (370 mg, 1.1 mmol) was dissolved in 80 mL of anhydrous dichloromethane. Under nitrogen protection, phosphorus tribromide (894.3 mg, 3.3 mmol) was slowly added. The mixture was stirred at room temperature for 12 h. After the reaction of the raw materials was complete, the mixture was concentrated under reduced pressure to obtain 300 mg of the product. Ms[M+H] + 400.0

[0441] 10. Synthesis of compound C24-8:

[0442] Compound C24-7 (300 mg, 0.75 mmol) was dissolved in 30 mL of anhydrous N,N-dimethylformamide. At room temperature, tert-butyl 2-aminobenzoate (870.68 mg, 4.51 mmol) was slowly added. The temperature was slowly raised to 60°C and stirred for 12 h. After the reaction of the raw materials was complete, the reaction solution was diluted with water and then extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 75 mg of the product. Ms[M+H] + 513.3

[0443] 11. Synthesis of compounds C24-9 and C24-10:

[0444] Compound C24-8 was subjected to high-efficiency preparative liquid phase chiral separation to obtain C24-9 (15 mg) [M+H] + :513.3,C24-10(15mg)[M+H] + :513.3:

[0445] 12. Synthesis of compound C24:

[0446] Compound C24-9 (70 mg, 0.14 mmol) was dissolved in 1.5 mL of anhydrous dichloromethane and 1.5 mL of trifluoroacetic acid, stirred at room temperature for 12 h, and after the reaction of the raw materials was complete, the mixture was concentrated under reduced pressure and purified to obtain 6 mg of the product. Ms[M+H] + 457.2

[0447] 1 H NMR (400MHz, DMSO-d6) δ8.91-8.86(m,1H),8.79-8.60(m,1H),8.39(d,J=8.0Hz,1H),8.00-7.92(m,1H),7.84(d,J=7.8Hz,1H),7.62- 7.54(m,2H),7.17(t,J=7.9Hz,1H),6.60-6.53(m,1H),6.42(d,J=8.5Hz,1H),5.58-5.48(m,1H),5.42(s,2H),1.70(d,J=6.6Hz,3H).

[0448] 13. Synthesis of compound C25:

[0449] Compound C24-10 (70 mg, 0.14 mmol) was dissolved in 1.5 mL of anhydrous dichloromethane and 1.5 mL of trifluoroacetic acid, stirred at room temperature for 12 h, and after the reaction of the raw materials was complete, the mixture was concentrated under reduced pressure and purified to obtain 6 mg of the product. Ms[M+H] + 457.2

[0450] 1 H NMR (400MHz, DMSO-d6) δ8.89(m,1H),8.81-8.63(m,1H),8.40(d,J=8.0Hz,1H),8.01-7.90(m,1H),7.83(d,J=7.9Hz,1H),7.64-7. 53(m,2H),7.16(t,J=7.7Hz,1H),6.54-6.45(m,1H),6.41(d,J=8.5Hz,1H),5.58-5.48(m,1H),5.43(s,2H),1.70(d,J=6.6Hz,3H).

[0451] Cell proliferation inhibition assay

[0452] 1. Experimental Materials

[0453] Cell Line Suppliers

[0454] SK-BR-3(WT) ATCC

[0455] T47D(H1047R) ATCC

[0456] The control compound Alpelisib (structural formula is ).

[0457] 2. Experimental plan

[0458] 1. Cell plating

[0459] a) Preparation of cell suspension

[0460] b) removing the culture medium from the culture flask;

[0461] c) Rinse the cells once with PBS;

[0462] d) digest with trypsin and collect by centrifugation;

[0463] e) Resuspend in culture medium, count and adjust to appropriate concentration.

[0464] f) Add the cell suspension to each well of a 96-well plate at a volume of 100 ul, place one plate for each cell type, and culture overnight in a 37° C., 5% CO 2 incubator.

[0465] 2. Compound treatment

[0466] Compound dilution

[0467] a) Prepare gradient dilution solutions of the tested compounds: Alpelisib and the compounds are stored at 10mM. Then 18ul of the stored solution is dissolved in 982ul of DMSO-free culture medium, and then 4-fold continuous gradient dilutions are performed with 0.5% DMSO culture medium, for a total of 9 concentrations. The compound concentrations after dilution are as follows:

[0468] 180000nM, 45000nM, 11250nM, 2812.5nM, 703.13nM, 175.78nM, 43.95nM, 10.99nM, 2.75nM

[0469] b) After thorough mixing, take 20ul of compound solution and add it to the cell culture plate containing 100ul of cells, with 3 replicates for each concentration. The final concentration of the compound is as follows:

[0470] 30000nM, 7500nM, 1875nM, 468.75nM, 117.188nM, 29.30nM, 7.32nM, 1.83nM, 0.46nM

[0471] c) Transfer the cells to an incubator and incubate for 3 days.

[0472] 3. CTG test

[0473] Take out the cell culture plate and add 25ul CTG to the 96-well plate, shake at room temperature for 10 minutes, and read the plate.

[0474] 4. Data Analysis

[0475] The survival rate (%Cell Survival) was calculated using the following formula:

[0476] %Cell Survival=100%×(OD_Sample-OD_LCave) / (OD_HC-OD_LCave)

[0477] OD_HC: 0.1‰ DMSO control group cell reading

[0478] OD_Sample: Cell reading after adding compound

[0479] OD_LC: Blank culture medium reading

[0480] Analyed by Prizm:Dose-response-Inhibition-Log(inhibitor)vs response(three parameters for the best fit)

[0481] The results of the cell proliferation inhibition test are shown in Table 1.

[0482] Table 1

[0483]

[0484] A stands for IC 50 ≤1000nM; B means 1000nM<IC 50 ≤3000nM;

[0485] C means 3000nM<IC 50 ≤5000nM; D means 5000nM<IC 50 ;

[0486] The experimental results show that the example compounds have a significant inhibitory effect on the H1047R mutant human breast ductal carcinoma cell line T47D, but have no significant inhibitory effect on the wild-type human breast adenocarcinoma cell line SK-BR-3, showing good selectivity.

[0487] The invention provides a series of compounds with PI3KαH1047R mutation activity and selectivity, and a synthesis method thereof, which have broad application prospects.

[0488] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound, characterized in that The compound is a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, in: X1 is selected from the group consisting of N, O, CH; X2 and X3 are each independently selected from the following group: N, C; Y and Z are each independently selected from the group consisting of N, C, and CH; L is selected from the following group: C optionally substituted by 0-4 halogen and / or hydroxyl groups 1-4 Alkylene, wherein the C 1-4 Any methylene unit in the alkylene group is optionally replaced by a substituent selected from the group consisting of: -N(R a )-、-O-、-N(R a )C(O)-、-C(O)N(R a )-, -C(O)-, -OC(O)-, -S-, -S(O)-, -S(O)2-; Ring A is selected from the following group: C 6-10 Aryl, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein the C 6-10 Aryl, 5-6 membered heteroaryl is optionally substituted by m R4; Ring B is selected from the following group: C 6-10 Aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, saturated or partially saturated C 3-6 Cycloalkyl, saturated or partially saturated 3-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S; wherein the C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl is optionally substituted by n R5; R1 is selected from the group consisting of H, deuterium, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy; R2 and R3 are each independently selected from the following group: H, halogen, -CN, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 3-5 Cycloalkyl, halogenated C 3-5 Cycloalkyl; Each R4 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R6, -C(O)OR6, -C(O)NR6R7, -SO2R6, -S(O)(NR6)R7, -SO2NR6R7, -P(O)R6R7, C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; Each R5 is independently selected from the group consisting of H, deuterium, halogen, =O, -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、-L1-(saturated or partially saturated C 3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(saturated or partially saturated 3-12 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, -SO2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8R9, Alternatively, the two R5 atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10 aryl, a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 0-6 substituents selected from the group consisting of H, deuterium, halogen, =O, -CN, -OH, =NR9, C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR9R 10 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; R a Selected from the following group: H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 alkyl; L1 is a bond or is selected from the following group: C 1-6 Alkylene, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkylene, -NR6-, -O-, -C(O)-, -C(O)NR6-, -NR6C(O)-; Each R6, R7, R8, R9, R 10 Each independently selected from the following group: H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 6-10 aryl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 0-6 substituents selected from the group consisting of halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl; Alternatively, R6, R7 and the heteroatoms to which they are connected together form a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S; Alternatively, R8, R9 and the heteroatoms to which they are connected together form a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S; Alternatively, R9, R 10 Together with the heteroatoms to which it is attached, it forms a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S; each are independently a single bond or a double bond; Each m and n are independently selected from the following group: 0, 1, 2, 3, 4, 5.

2. The compound according to claim 1, characterized in that The compound has a structure selected from the group consisting of: Wherein, R1, R2, R3, L, Y, Z, Ring A, and Ring B are as defined in claim 1; structure Contains the following configurations:

3. The compound according to claim 1, characterized in that Ring A has a structure selected from the group consisting of: wherein each R4 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R6, -C(O)OR6, -C(O)NR6R7, -SO2R6, -S(O)(NR6)R7, -SO2NR6R7, -P(O)R6R7, C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; m is selected from the following group: 0, 1, 2, 3, 4, 5.

4. The compound according to claim 1, characterized in that Ring B has a structure selected from the group consisting of: wherein each R5 is independently selected from the group consisting of H, deuterium, halogen, =O, -CN, -OH, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR8R9, =NR8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8C(O)R9, -SR8, -SO2R8, -NR8SO2R9, -SO2NR8R9, -NR8SO2NR9R 10 、-P(O)R8R9、-L1-(C 3-10 Cycloalkyl), -L1-(C 6-10 aryl), -L1-(3-10 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S), -L1-(5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, =O, -CN, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, -SO2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -NR8R9, Alternatively, the two R5 atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl, C 6-10 aryl, a 3-6 membered heterocycloalkyl group containing 1-4 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are optionally substituted by 0-6 substituents selected from the group consisting of H, deuterium, halogen, =O, -CN, -OH, =NR9, C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C containing 1-4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, -NR9R 10 , C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S; n is selected from the following group: 0, 1, 2, 3, 4, 5.

5. The compound according to claim 2, characterized in that The compound has a structure selected from the group consisting of: Wherein, R1, R2, R3, L, Y, Z, and Ring B are as defined in claim 1; Each R4 is independently selected from the group consisting of H, deuterium, halogen, -CN, -NO2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-3 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)R6, -C(O)OR6, -C(O)NR6R7, -SO2R6, -S(O)(NR6)R7, -SO2NR6R7, -P(O)R6R7, C 3-5 Cycloalkyl, 4-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; X4 is CR4 or N; m is selected from the following group: 0, 1, 2, 3, 4.

6. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

7. A pharmaceutical composition, characterized in that The invention comprises a safe and effective amount of the compound according to claim 1, and a pharmaceutically acceptable carrier.

8. A use of the compound according to claim 1, characterized in that: Used to prepare selective PI3Kα inhibitors.

9. A use of the compound according to claim 1, characterized in that: Used for preparing drugs for regulating PI3Kα activity or treating PI3Kα related diseases.

10. The use according to claim 9, characterized in that The PI3Kα-related disease is cancer or tumor.

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