TWI793704B - SOS1 inhibitors, pharmaceutical compositions comprising them and uses thereof - Google Patents

Abstract

本發明涉及式(I)的SOS1抑制劑、包含其的藥物組合物、及其用於預防或治療疾病的用途。

The present invention relates to SOS1 inhibitors of formula (I), pharmaceutical compositions containing them, and their use for preventing or treating diseases.

Description

SOS1 inhibitors, pharmaceutical compositions comprising them and uses thereof

The present invention relates to SOS1 inhibitors, pharmaceutical compositions containing them, and uses thereof for preventing or treating diseases.

RAS family proteins are small GTPases encoded by RAS genes, including KRAS (Kirsten murine sarcoma virus oncogene homolog), HRAS (Harvey murine sarcoma virus oncogene homolog), and NRAS (neuroblastoma RAS virus oncogene homolog ) and any mutant thereof. Inside the cell, the RAS protein transitions between an inactive state and an active state, when bound to guanosine diphosphate (GDP), the RAS protein is in an inactive state, and when bound to guanosine triphosphate (GTP) , the RAS protein is activated. The inherent GTPase activity of RAS protein is weak, and the intrinsic GDP-GTP nucleotide exchange rate is low, and the transition between its inactivation and activation state is regulated by two types of factors: GTPase activating protein (GTPase activating protein, GAP), which can catalyze the hydrolysis of GTP bound to RAS protein into GDP, and inactivate RAS protein; Guanine nucleotide exchange factor (Guanine nucleotide exchange factor, GEF), including SOS1 protein (Son of Sevenless 1), etc., can catalyze The combination of RAS protein and GTP promotes the activation of RAS protein. The RAS protein in the activated state can initiate multiple signal transductions such as the RAF/MEK/ERK (MAPK) pathway and the PI3K/AKT/mTOR pathway by activating a series of downstream effector proteins (including RAF and phosphoinositide kinase PI3K, etc.) pathways, thereby regulating a variety of cellular processes such as cell proliferation, survival, metabolism, motility, angiogenesis, immunity, and growth. Mutations in RAS family proteins can inhibit their intrinsic GTPase activity and GAP-induced GTPase activity, leading to the continuous activation of RAS protein, which in turn leads to the continuous activation of the downstream effector pathway of RAS protein. RAS is the most frequently mutated oncogene in human cancers. KRAS mutations (such as G12, G13 and Q61, etc.) are widely found in many human cancers, including lung cancer, colorectal cancer and pancreatic cancer. HRAS mutations and NRAS mutations also appear in different human cancer types. RAS protein mutations, overexpression, and gene amplification are potential resistance mechanisms to a variety of anticancer drugs (such as the EGFR antibodies cetuximab and panitumumab, and the EGFR tyrosine kinase inhibitor osimertinib).

The SOS protein was first discovered in Drosophila, and SOS1 is the human homologue of the Drosophila SOS protein. SOS1 protein is a multi-domain protein composed of 1333 amino acids, which consists of N-terminal domain, Dbl homology domain (Dbl homology, DH), Pleckstrin substrate protein homology domain (Pleckstrin homology, PH), RAS exchange motif (Ras exchanger motif, REM), CDC25 homology domain and C-terminal domain, in which REM and CDC25 homology domain together constitute the catalytic domain, which is the guanine nucleotide exchange factor of SOS1 protein Indispensable part of catalytic function. Studies have shown that SOS1 plays a key role in the initiation and signal transduction of mutant RAS proteins in RAS-mutant cancers, SOS1 knockout inhibits the survival and proliferation of KRAS-mutant tumor cells, and re-expresses the catalytic site in SOS1-knockout KRAS-mutant tumor cells In point-mutated SOS1, tumor cells were unable to resume survival and proliferation, proving that the guanine nucleotide exchange catalytic activity of SOS1 plays a key role in the survival and proliferation of KRAS mutant tumor cells. In addition to regulating the mutant RAS protein, SOS1 can also participate in the signal initiation and transduction process of tumor cells through other mechanisms. SOS1 can bind to the growth factor receptor binding protein Grb2 to form a SOS1-Grb2 complex, and then bind to activated receptor tyrosine kinases (such as EGFR, ErbB2/3/4, VEGFR1/2/3, PDGFR-A/B, FGFR1 /2/3, IGF1R, ALK, ROS1, TRK-A/B/C, RET, c-MET, AXL, etc.), or by other cell surface membrane receptors (such as TCR, BCR, CSF1R). SOS1 acts as a guanine nucleotide exchange factor to activate the GTPase RAC1, which is associated with various human cancers and other diseases. Studies have shown that SOS1 mutations are present in embryonal rhabdomyosarcoma, Sertoli cell tumor, cutaneous granulosa cell tumor, and lung adenocarcinoma, and overexpression of SOS1 protein has also been found in bladder cancer and prostate cancer.

SOS2 is a homologue of SOS1 in mammalian cells, which also functions as a guanine nucleotide exchange factor. Studies on mouse gene knockout models have shown that SOS1 germline knockout can cause mouse embryos to die in the second trimester, while adult mice can continue to survive after SOS1 knockout, in contrast, SOS2 knockout has no effect on embryos or mature mice. Clear phenotypic changes, whereas adult SOS1/2 double-knockout mice die rapidly, suggest that selective targeting of SOS1 may achieve a high therapeutic index for RAS-mutant tumors regulated by SOS1.

Inhibiting the binding of SOS1 catalytic site to RAS protein can block the initiation of RAS protein mediated by SOS1, and then inhibit the downstream signal transduction of RAS protein (such as the phosphorylation initiation of ERK, etc.). Protein-dependent tumor cells such as KRAS mutant tumor cell lines have inhibitory effects (such as inhibition of proliferation, survival, metastasis, etc.).

The present invention provides compounds useful as SOS1 inhibitors, which have excellent inhibitory activity against SOS1. The SOS1 inhibitor of the present invention can inhibit the interaction and initiation of SOS1 and RAS proteins, especially have a significant inhibitory effect on the interaction between SOS1 and KRAS mutant proteins, and can be proteins carrying RAS and upstream and downstream proteins (including KRAS, NRAS, HRAS, Receptor tyrosine kinases (eg, EGFR, ErbB2/3/4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, TrkA/B/C, RET, c-MET, VEGFR1/ 2/3, AXL), GAP (such as NF1) and SOS1) mutations in cancer patients provide pharmacological benefit. In addition, SOS1 inhibitors are effective in RAC1-dependent cancers and other diseases associated with dysregulation of RAS signaling pathways such as neurofibromatosis, Noonan syndrome (NS), heart-facial-skin syndrome (CFC) and hereditary gingival type 1 Pharmacological benefit will also be provided in fibroids.

The compounds of the present invention also have better physicochemical properties (such as solubility, physical and/or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, suitable half-life and duration of action), improved Safety (lower toxicity and/or less side effects, wider therapeutic window) and other more excellent properties.

式(I) 其中： X ¹、X ²、X ³及X ⁴各自獨立地選自C=O、CH ₂、CHR、C(R) ₂及N-L-R ²，較佳地，X ¹、X ²、X ³及X ⁴中至少一個為N-L-R ²； L選自直接鍵、C _1-6亞烷基、C(=O)、O、S(=O)、S(=O) ₂及NR ⁴； 環B選自C _3-10烴環、3-10員雜環、C _6-10芳環及5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)； R及R ¹在每次出現時各自獨立地選自鹵素、-NH ₂、-CN、-NO ₂、-OH、-O-C _1-6烷基、C _1-6烷基、鹵代C _1-6烷基、C _1-6亞烷基-OH、鹵代C _1-6亞烷基-OH、C _2-6烯基、C _2-6炔基、飽和或部分不飽和的C _3-10環烴基、飽和或部分不飽和的3-10員雜環基、C _6-10芳基、5-14員雜芳基及C _6-12芳烷基，該環烴基及雜環基中至多2個環成員為C(=O)，當m大於1及/或n大於1時，兩個R ¹及/或兩個R連同其所連接的原子視情況共同構成C _3-10烴環、3-10員雜環、C _6-10芳環或5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)； R ²選自H、C _1-6烷基、鹵代C _1-6烷基、C _1-6亞烷基-OH、鹵代C _1-6亞烷基-OH、C _2-6烯基、C _2-6炔基、飽和或部分不飽和的C _3-10環烴基、飽和或部分不飽和的3-10員雜環基、C _6-10芳基、5-14員雜芳基、C _6-12芳烷基、-C(=O)R ⁵、-OC(=O)R ⁵、-C(=O)OR ⁵、-OR ⁵、-SR ⁵、-S(=O)R ⁵、-S(=O) ₂R ⁵、-S(=O) ₂NR ⁵R ⁶、-NR ⁵R ⁶、-C(=O)NR ⁵R ⁶、-NR ⁵-C(=O)R ⁶、-NR ⁵-C(=O)OR ⁶、-NR ⁵-S(=O) ₂-R ⁶、-NR ⁵-C(=O)-NR ⁵R ⁶、-C _1-6亞烷基-NR ⁵R ⁶、-C _1-6亞烷基-O(P=O)(OH) ₂及-O-C _1-6亞烷基-NR ⁵R ⁶； R ³及R ⁴各自獨立地選自H、鹵素、-NH ₂、-CN、-NO ₂、-OH、-O-C _1-6烷基、-O-(3-10員雜環基)、C _1-6烷基、鹵代C _1-6烷基、C _1-6亞烷基-OH、鹵代C _1-6亞烷基-OH、C _2-6烯基、C _2-6炔基、飽和或部分不飽和的C _3-10環烴基、飽和或部分不飽和的3-10員雜環基、C _6-10芳基、5-14員雜芳基、C _6-12芳烷基、-C(=O)R ⁵、-OC(=O)R ⁵、-C(=O)OR ⁵、-OR ⁵、-SR ⁵、-S(=O)R ⁵、-S(=O) ₂R ⁵、-S(=O) ₂NR ⁵R ⁶、-NR ⁵R ⁶、-C(=O)NR ⁵R ⁶、-NR ⁵-C(=O)R ⁶、-NR ⁵-C(=O)OR ⁶、-NR ⁵-S(=O) ₂-R ⁶、-NR ⁵-C(=O)-NR ⁵R ⁶、-C _1-6亞烷基-NR ⁵R ⁶、-C _1-6亞烷基-O(P=O)(OH) ₂及-O-C _1-6亞烷基-NR ⁵R ⁶； 上述基團在每次出現時各自視情況經一個或多個獨立地選自下列的取代基取代：鹵素、-OH、氧代、-NH ₂、-CN、-NO ₂、C _1-6烷基、C _2-6烯基、C _2-6炔基、C _3-6環烴基、3-10員雜環基、C _6-10芳基、5-14員雜芳基、C _6-12芳烷基、=N-OR ⁵、-C(=NH)NH ₂、-C(=O)R ⁵、-OC(=O)R ⁵、-C(=O)OR ⁵、-OR ⁵、-SR ⁵、-S(=O)R ⁵、-S(=O) ₂R ⁵、-S(=O) ₂NR ⁵R ⁶、-NR ⁵R ⁶、-C(=O)NR ⁵R ⁶、-NR ⁵-C(=O)R ⁶、-NR ⁵-C(=O)OR ⁶、-NR ⁵-S(=O) ₂-R ⁶、-NR ⁵-C(=O)-NR ⁵R ⁶、-C _1-6亞烷基-NR ⁵R ⁶及-O-C _1-6亞烷基-NR ⁵R ⁶，該烷基、環烴基、雜環基、芳基、雜芳基及芳烷基進一步視情況經一個或多個獨立地選自下列的取代基取代：鹵素、-OH、氧代、-NH ₂、-CN、-NO ₂、C _1-6烷基、C _3-6環烴基、3-10員雜環基、C _6-10芳基、5-14員雜芳基及C _6-12芳烷基； R ⁵及R ⁶在每次出現時各自獨立地選自H、C _1-6烷基、C _3-10環烴基、3-10員雜環基、C _6-10芳基、5-14員雜芳基及C _6-12芳烷基；並且 m為選自0、1、2、3及4的整數。 One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the The compound has the structure of formula (I):

Formula (I) wherein: X ¹ , X ² , X ³ and X ⁴ are each independently selected from C=O, CH ₂ , CHR, C(R) ₂ and NLR ² , preferably, X ¹ , X ² , At least one of X ³ and X ⁴ is NLR ² ; L is selected from direct bonds, C _1-6 alkylene, C(=O), O, S(=O), S(=O) ₂ and NR ⁴ ; Ring B is selected from C _3-10 hydrocarbon ring, 3-10 membered heterocyclic ring, C _6-10 aromatic ring and 5-14 membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O ); R and R ¹ are each independently selected from halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _{3 -10} cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl, the cyclohydrocarbyl and heterocyclic At most 2 ring members are C(=O), when m is greater than 1 and/or n is greater than 1, two R ¹ and/or two R together with the atoms connected to them form a C _3-10 hydrocarbon ring as appropriate , 3-10 membered heterocyclic ring, C _6-10 membered heteroaromatic ring or 5-14 membered heteroaromatic ring, at most 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O); R ² is selected from H, C _{1 -6} alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl, C _2-6 alkynyl, Saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C (=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 alkylene-O(P=O)(OH) ₂ and -OC _1-6 alkylene-NR ⁵ R ⁶ ; R ³ and R ⁴ are each independently selected from H, halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6 alkyl, -O-(3-10 membered heterocyclyl), C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 Alkyl-OH, C _2-6 alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)- NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 alkylene-O(P=O)(OH) ₂ and -OC _1-6 alkylene-NR ⁵ R ⁶ ; each occurrence of the above groups is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, oxo, -NH ₂ , -CN, -NO ₂ , C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, =N-OR ⁵ , -C(=NH)NH ₂ , -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , - OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O) NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(= O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ and -OC _1-6 alkylene-NR ⁵ R ⁶ , the alkyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl and aralkyl are further optionally substituted by one or more substituents independently selected from: halogen, -OH, oxo, -NH ₂ , -CN, -NO ₂ , C _1-6 alkyl , C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl; R ⁵ and R ⁶ are each present Independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl and m is an integer selected from 0, 1, 2, 3 and 4.

Another aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N- Oxides, isotope-labeled compounds, metabolites or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.

Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or precursor thereof Use of the medicament or the pharmaceutical composition of the present invention in the preparation of a medicament for use as an SOS1 inhibitor.

Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or precursor thereof A drug or a pharmaceutical composition of the present invention, which is used as a SOS1 inhibitor.

Another aspect of the present invention provides a method for preventing or treating SOS1-related diseases, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph Crystal forms, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the present invention.

definition

Unless defined otherwise hereinafter, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. References to techniques used herein are intended to mean techniques commonly understood in the art, including those technical changes or substitutions of equivalent techniques that would be obvious to those having ordinary skill in the art to which this invention pertains. While the following terms are believed to be well understood by those having ordinary skill in the art to which this invention pertains, the following definitions are set forth to better explain the present invention.

The terms "comprising", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements or method steps.

As used herein, the term "alkylene" means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene , propylene or butylene.

As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms. For example, as used herein, the term "C _1-6 alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as Halogen substitution (in which case the group is referred to as "haloalkyl") (for example CH ₂ F, CHF ₂ , CF ₃ , CCl ₃ , C ₂ F ₅ , C ₂ Cl ₅ , CH ₂ CF ₃ , CH ₂ Cl or _{-CH2CH2CF3 , etc.} ). The term "C _1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group containing one double bond and having 2-6 carbon atoms (" _C2-6 alkenyl"). The alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2- Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When a compound of the present invention contains an alkenylene group, the compound may exist in the pure E (entgegen) form, in the pure Z (zusammen) form, or any mixture thereof.

As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg ethynyl or propynyl.

As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.)), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15 carbon atoms. For example, the term "C _3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclopropyl) of 3 to 6 ring-forming carbon atoms. hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.

As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" mean ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Saturated (ie, "cycloalkylene" and "cycloalkyl") or unsaturated (ie, having one or more double and/or triple bonds within the ring) monocyclic or polycyclic (including spirocyclic) atoms , fused or bridged system) hydrocarbon rings, including but not limited to (ylidene)cyclopropyl (ring), (ylidene)cyclobutyl (ring), ((ylidene)cyclopentyl (ring), (sub)cyclo Hexyl (ring), (ylidene) cycloheptyl (ring), (ylidene) cyclooctyl (ring), (ylidene) cyclononyl (ring), (ylidene) cyclohexenyl (ring) and the like.

As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" mean having, for example, 3-10 (suitably having 3-8, more suitably having 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., with one or more double bond and/or triple bond) cyclic group. For example, a "3-10 membered (sub)heterocyclic (group)" has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N A saturated or partially unsaturated (sub)heterocyclic ring (group) of one or more (for example, 1, 2, 3 or 4) heteroatoms of , O and S. Examples of heterocyclylene and heterocycle (base) include, but are not limited to: (sub)oxirane, (sub)aziridinyl, (sub)azetidinyl (azetidinyl), (sub)oxo Heterocyclobutyl (oxetanyl), (sub)tetrahydrofuranyl, (sub)dioxolinyl (dioxolinyl), (sub)pyrrolidinyl, (sub)pyrrolidinyl, (sub)imidazolidinyl, (sub) ) pyrazolidinyl, (sub)pyrrolinyl, (sub)tetrahydropyranyl, (sub)piperidinyl, (sub)morpholinyl, (sub)dithianyl (dithianyl), (sub) Thiomorpholinyl, piperazinyl or trithianyl. The groups also encompass bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[5.5]undecane, Heterobicyclo[2.2.2]octane, etc.). Heterocyclylene and heterocycl(yl) may be optionally substituted with one or more (eg 1, 2, 3 or 4) suitable substituents.

。 As used herein, the terms "()arylene" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the terms "C _6-10 ()arylene" and "C _6-10 aromatic ring" mean an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or (ylidene) naphthyl (naphthalene ring). The ()arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.). (Arylene) groups and aromatic rings are optionally fused with another ring (such as a C _3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring or a 5-14 membered heteroaromatic ring), and the fused group is, for example,

.

。 As used herein, the terms "(heteroarylene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and, additionally, in each case may be benzo-fused. In particular, "(y)heteroaryl" or "heteroaromatic ring" is selected from (y)thienyl, (y)furyl, (y)pyrrolyl, (y)oxazolyl, (y)thiazolyl, (Yellow) imidazolyl, (lower) pyrazolyl, (lower) isoxazolyl, (lower) isothiazolyl, (lower) oxadiazolyl, (lower) triazolyl, (lower) thiadiazolyl etc., and their benzo derivatives; or (sub)pyridyl, (sub)pyridazinyl, (sub)pyrimidinyl, (sub)pyrazinyl, (sub)triazinyl, etc. derivative. The "heteroaryl group" and "heteroaromatic ring" may also be combined with another ring (such as a C _3-10 hydrocarbon ring, a 3-10 member heterocycle, a C _6-10 aromatic ring or a 5-14 member Heteroaryl ring) fused, the fused group is for example

.

As used herein, the term "aralkyl" preferably denotes an aryl or heteroaryl substituted alkyl group, wherein said aryl, heteroaryl and alkyl groups are as defined herein. Typically, the aryl group can have 6-14 carbon atoms, the heteroaryl group can have 5-14 ring atoms, and the alkyl group can have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.

As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 or 13 carbon atoms and at least one nitrogen atom, which may also optionally contain one or more (for example, one, two, three or four) selected from N, O, C=O, S, S=O and a ring member of S(=0) ₂ , which is connected to the rest of the molecule through the nitrogen atom and any remaining ring atoms in the nitrogen-containing heterocycle, which is optionally benzofused, and relatively The linkage to the rest of the molecule is preferably via the nitrogen atom of the nitrogen-containing heterocycle and any carbon atom of the fused benzene ring.

The term "substituted" means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present The normal valence of the case and the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently selected individually and/or together of optional substituents. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected by the optional Substituent substitution.

If substituents are described as being "independently selected from" a group, each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.

As used herein, unless otherwise indicated, the point of attachment of a substituent may be from any suitable position of the substituent.

When a bond for a substituent is shown as being through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring-forming atom in such a substitutable ring.

The present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( ^2H ), tritium ( ^3H )); isotopes of carbon (e.g. ^{, 11C} , ^13C , and ^14C ). ; isotopes of chlorine (such as ³⁶ Cl); isotopes ^of fluorine (such as ¹⁸ F); isotopes of iodine (such as ¹²³ I and ¹²⁵ I); isotopes of nitrogen (such as ¹³ N and ¹⁵ N); , ¹⁷ O and ¹⁸ O); phosphorus isotopes (eg ³² P); and sulfur isotopes (eg ³⁵ S). Certain isotopically-labeled compounds of the invention (eg, those incorporating radioactive isotopes) are useful in drug and/or substrate tissue distribution studies (eg, assays). The radioisotopes tritium ( ^ie3H ) and carbon-14 ( ^ie14C ) are particularly useful for this purpose due to their ease of incorporation and ease of detection. Substitution with positron-emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, for example, _D2O , acetone- _d6 or DMSO- _d6 .

The term "stereoisomer" means isomers formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three or four) asymmetric centers, which may give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of this application encompasses all such ratios in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) isomers or mixtures thereof.

)、實楔形(

)或虛楔形(

)描繪本發明的化合物的化學鍵。使用實線以描繪鍵連至不對稱碳原子的鍵欲表明，包括該碳原子處的所有可能的立體異構體(例如，特定的對映異構體、外消旋混合物等)。使用實或虛楔形以描繪鍵連至不對稱碳原子的鍵欲表明，存在所示的立體異構體。當存在於外消旋混合物中時，使用實及虛楔形以定義相對立體化學，而非絕對立體化學。除非另外指明，否則本發明的化合物意欲可以立體異構體(其包括順式及反式異構體、光學異構體(例如R及S對映異構體)、非對映異構體、幾何異構體、旋轉異構體、構象異構體、阻轉異構體及其混合物)的形式存在。本發明的化合物可表現一種以上類型的異構現象，且由其混合物(例如外消旋混合物及非對映異構體對)組成。 In this paper, the solid line (

), solid wedge (

) or imaginary wedge (

) depicts the chemical bonds of the compounds of the invention. The use of a solid line to delineate a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and imaginary wedges are used to define relative rather than absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof). The compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and pairs of diastereoisomers.

The present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

It will also be understood that certain compounds of the present invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to patients in need thereof Following administration, the compound of the invention or its metabolites or residues can be provided directly or indirectly. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.

The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citric acid salt, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, sea Benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate salt, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxy Naphthalate, Phosphate/Hydrogen Phosphate/Dihydrogen Phosphate, Pyroglutamate, Saccharate, Stearate, Succinate, Tannin, Tartrate, Tosylate, Trifluoroacetate and xinafoate.

Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salt, potassium salt, sodium salt, tromethamine salt and zinc salt.

For a review of suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of compounds of the present invention are known to those having ordinary skill in the art to which this invention pertains.

As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound). The compounds of the invention may also themselves be esters.

The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention comprise a polar solvent such as water, methanol or ethanol in particular as a structural element of the crystal lattice of the compound. The amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.

Those skilled in the art to which the present invention pertains will appreciate that not all nitrogen-containing heterocycles are capable of forming N- oxides because nitrogen requires available lone pairs of electrons to be oxidized to oxides; Usually the knowledgeable will recognize nitrogen-containing heterocycles capable of forming N- oxides. Those of ordinary skill in the art to which this invention pertains will also recognize that tertiary amines are capable of forming N- oxides. Synthetic methods for preparing N- oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), Hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines. These methods for preparing N- oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis , vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press and GWH Cheeseman and ESG Werstiuk, Advances in Heterocyclic Chemistry , vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.

The present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be obtained, for example, by using those known to those skilled in the art to which the present invention pertains as "pro-moiety" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985) )" are prepared in place of appropriate functional groups present in the compounds of the invention.

The invention also encompasses compounds of the invention which contain protecting groups. During any of the preparations of the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming chemically protected forms of the compounds of the invention. This can be accomplished by conventional protecting groups, for example, those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.

The term "about" means within ±10%, preferably within ±5%, more preferably within ±2% of the stated value.

式(I) 其中： X ¹、X ²、X ³及X ⁴各自獨立地選自C=O、CH ₂、CHR、C(R) ₂及N-L-R ²，較佳地，X ¹、X ²、X ³及X ⁴中至少一個為N-L-R ²； L選自直接鍵、C _1-6亞烷基、C(=O)、O、S(=O)、S(=O) ₂及NR ⁴； 環B選自C _3-10烴環、3-10員雜環、C _6-10芳環及5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)； R及R ¹在每次出現時各自獨立地選自鹵素、-NH ₂、-CN、-NO ₂、-OH、-O-C _1-6烷基、C _1-6烷基、鹵代C _1-6烷基、C _1-6亞烷基-OH、鹵代C _1-6亞烷基-OH、C _2-6烯基、C _2-6炔基、飽和或部分不飽和的C _3-10環烴基、飽和或部分不飽和的3-10員雜環基、C _6-10芳基、5-14員雜芳基及C _6-12芳烷基，該環烴基及雜環基中至多2個環成員為C(=O)，當m大於1及/或n大於1時，兩個R ¹及/或兩個R連同其所連接的原子視情況共同構成C _3-10烴環、3-10員雜環、C _6-10芳環及5-14員雜芳環，該烴環及雜環中至多2個環成員為C(=O)； R ²選自H、C _1-6烷基、鹵代C _1-6烷基、C _1-6亞烷基-OH、鹵代C _1-6亞烷基-OH、C _2-6烯基、C _2-6炔基、飽和或部分不飽和的C _3-10環烴基、飽和或部分不飽和的3-10員雜環基、C _6-10芳基、5-14員雜芳基、C _6-12芳烷基、-C(=O)R ⁵、-OC(=O)R ⁵、-C(=O)OR ⁵、-OR ⁵、-SR ⁵、-S(=O)R ⁵、-S(=O) ₂R ⁵、-S(=O) ₂NR ⁵R ⁶、-NR ⁵R ⁶、-C(=O)NR ⁵R ⁶、-NR ⁵-C(=O)R ⁶、-NR ⁵-C(=O)OR ⁶、-NR ⁵-S(=O) ₂-R ⁶、-NR ⁵-C(=O)-NR ⁵R ⁶、-C _1-6亞烷基-NR ⁵R ⁶、-C _1-6亞烷基-O(P=O)(OH) ₂及-O-C _1-6亞烷基-NR ⁵R ⁶； R ³及R ⁴各自獨立地選自H、鹵素、-NH ₂、-CN、-NO ₂、-OH、-O-C _1-6烷基、-O-(3-10員雜環基)、C _1-6烷基、鹵代C _1-6烷基、C _1-6亞烷基-OH、鹵代C _1-6亞烷基-OH、C _2-6烯基、C _2-6炔基、飽和或部分不飽和的C _3-10環烴基、飽和或部分不飽和的3-10員雜環基、C _6-10芳基、5-14員雜芳基、C _6-12芳烷基、-C(=O)R ⁵、-OC(=O)R ⁵、-C(=O)OR ⁵、-OR ⁵、-SR ⁵、-S(=O)R ⁵、-S(=O) ₂R ⁵、-S(=O) ₂NR ⁵R ⁶、-NR ⁵R ⁶、-C(=O)NR ⁵R ⁶、-NR ⁵-C(=O)R ⁶、-NR ⁵-C(=O)OR ⁶、-NR ⁵-S(=O) ₂-R ⁶、-NR ⁵-C(=O)-NR ⁵R ⁶、-C _1-6亞烷基-NR ⁵R ⁶、-C _1-6亞烷基-O(P=O)(OH) ₂及-O-C _1-6亞烷基-NR ⁵R ⁶； 上述基團在每次出現時各自視情況經一個或多個獨立地選自下列的取代基取代：鹵素、-OH、氧代、-NH ₂、-CN、-NO ₂、C _1-6烷基、C _2-6烯基、C _2-6炔基、C _3-6環烴基、3-10員雜環基、C _6-10芳基、5-14員雜芳基、C _6-12芳烷基、=N-OR ⁵、-C(=NH)NH ₂、-C(=O)R ⁵、-OC(=O)R ⁵、-C(=O)OR ⁵、-OR ⁵、-SR ⁵、-S(=O)R ⁵、-S(=O) ₂R ⁵、-S(=O) ₂NR ⁵R ⁶、-NR ⁵R ⁶、-C(=O)NR ⁵R ⁶、-NR ⁵-C(=O)R ⁶、-NR ⁵-C(=O)OR ⁶、-NR ⁵-S(=O) ₂-R ⁶、-NR ⁵-C(=O)-NR ⁵R ⁶、-C _1-6亞烷基-NR ⁵R ⁶及-O-C _1-6亞烷基-NR ⁵R ⁶，該烷基、環烴基、雜環基、芳基、雜芳基及芳烷基進一步視情況經一個或多個獨立地選自下列的取代基取代：鹵素、-OH、氧代、-NH ₂、-CN、-NO ₂、C _1-6烷基、C _3-6環烴基、3-10員雜環基、C _6-10芳基、5-14員雜芳基及C _6-12芳烷基； R ⁵及R ⁶在每次出現時各自獨立地選自H、C _1-6烷基、C _3-10環烴基、3-10員雜環基、C _6-10芳基、5-14員雜芳基及C _6-12芳烷基；並且 m為選自0、1、2、3及4的整數。 Compounds In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or precursors thereof Drug, wherein the compound has the structure of formula (I):

Formula (I) wherein: X ¹ , X ² , X ³ and X ⁴ are each independently selected from C=O, CH ₂ , CHR, C(R) ₂ and NLR ² , preferably, X ¹ , X ² , At least one of X ³ and X ⁴ is NLR ² ; L is selected from direct bonds, C _1-6 alkylene, C(=O), O, S(=O), S(=O) ₂ and NR ⁴ ; Ring B is selected from C _3-10 hydrocarbon ring, 3-10 membered heterocyclic ring, C _6-10 aromatic ring and 5-14 membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O ); R and R ¹ are each independently selected from halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _{3 -10} cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl, the cyclohydrocarbyl and heterocyclic At most 2 ring members are C(=O), when m is greater than 1 and/or n is greater than 1, two R ¹ and/or two R together with the atoms connected to them form a C _3-10 hydrocarbon ring as appropriate , 3-10 membered heterocyclic ring, C _6-10 membered heteroaromatic ring and 5-14 membered heteroaromatic ring, at most 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O); R ² is selected from H, C _{1 -6} alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl, C _2-6 alkynyl, Saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C (=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 alkylene-O(P=O)(OH) ₂ and -OC _1-6 alkylene-NR ⁵ R ⁶ ; R ³ and R ⁴ are each independently selected from H, halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6 alkyl, -O-(3-10 membered heterocyclyl), C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 Alkyl-OH, C _2-6 alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)- NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 alkylene-O(P=O)(OH) ₂ and -OC _1-6 alkylene-NR ⁵ R ⁶ ; each occurrence of the above groups is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, oxo, -NH ₂ , -CN, -NO ₂ , C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, =N-OR ⁵ , -C(=NH)NH ₂ , -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , - OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O) NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(= O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ and -OC _1-6 alkylene-NR ⁵ R ⁶ , the alkyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl and aralkyl are further optionally substituted by one or more substituents independently selected from: halogen, -OH, oxo, -NH ₂ , -CN, -NO ₂ , C _1-6 alkyl , C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl; R ⁵ and R ⁶ are each present Independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl and m is an integer selected from 0, 1, 2, 3 and 4.

式(II) 環A為

、

或

；並且 n為選自0、1、2或3的整數。 In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof , wherein the compound has the structure of formula (II):

Formula (II) Ring A is

,

or

and n is an integer selected from 0, 1, 2 or 3.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof , wherein L is a direct bond, -CH ₂ - or C(=O).

、

、

、

、

及

。 In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof , wherein, R ² is a saturated or partially unsaturated C _3-10 cycloalkyl or a saturated or partially unsaturated 3-10 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally selected from one or more Substituents of -C(=O)R ⁵ and -C(=O)NR ⁵ R ⁶ are substituted; preferably, R ² is cyclobutanyl, cyclohexane, piperidinyl or tetrahydropyranyl , which is optionally substituted by one or more substituents selected from -C(=O)CH ₃ and -C(=O)N(CH ₃ ) ₂ ; more preferably, -LR ² is selected from

,

,

,

,

and

.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof , wherein ring B is bicyclo[1.1.1]pentane ring, 2-oxabicyclo[2.1.1]hexane ring, benzene ring or thiophene ring, preferably benzene ring or thiophene ring.

及

；並且m為1或2。 In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof , wherein each occurrence of R ¹ is independently selected from halogen, -NH ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _{1 -6} alkylene-OH, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl and 5-14 membered heteroaryl, The alkylene group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally selected from one or more independently selected from halogen, -OH, C _3-6 cycloalkyl group, 3-10 membered heterocycle Substituents of C _6-10 aryl and 5-14 membered heteroaryl; When m is greater than 1, two R ¹ and the atoms connected to them together form a C _3-10 hydrocarbon ring, 3- 10-membered heterocyclic ring, C _6-10 aromatic ring or 5-14 membered heteroaromatic ring, at most 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O), and the hydrocarbon ring, heterocyclic ring, aromatic ring and The heteroaromatic ring is optionally substituted by one or more halogens; preferably, each occurrence of R ¹ is independently selected from CF ₃ , NH ₂ ,

and

; and m is 1 or 2.

選自

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

及

。 In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof ,in

selected from

,

,

,

,

,

,

,

,

,

,

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,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof , wherein R ³ is selected from H and C _1-6 alkyl; preferably, R ³ is methyl.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof , wherein R ⁴ is selected from H and C _1-6 alkyl; preferably, R ⁴ is H.

式(III)。 本發明涵蓋對各個實施方案進行任意組合所得的化合物。 In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof , wherein the compound has the structure of formula (III):

Formula (III). The present invention encompasses compounds resulting from any combination of the various embodiments.

301、

302、

303、

304、

305、

306、

307、

308、

309、

310、

311及

312。 In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof , wherein the compound is selected from:

301、

302、

303、

304、

305、

306、

307、

308、

309、

310、

311 and

312.

Pharmaceutical Compositions and Methods of Treatment In some embodiments, the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorphic form thereof Compounds, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or gaseous preparations. In some embodiments, the pharmaceutical composition may also include one or more additional therapeutic agents.

In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or prodrug or the pharmaceutical composition of the present invention is used in the purposes in the preparation of the medicine of SOS1 inhibitor.

In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or a prodrug or a pharmaceutical composition of the invention for use as a SOS1 inhibitor.

In some embodiments, the present invention provides a method for preventing or treating SOS1-related diseases, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, or stereoisomer thereof to an individual in need thereof , polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.

In some embodiments, the SOS1-associated disease includes cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid Leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, squamous cell carcinoma of the head and neck, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate carcinoma, glioblastoma, renal carcinoma, and sarcoma), RAS disorders (e.g., neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with mottling (NSML), Capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), heart-facial-cutaneous syndrome (CFC), Legers syndrome and hereditary gingival fibromatosis).

"Pharmaceutically acceptable carrier" in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil , sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol etc. The composition, if desired, can also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasally, transmucosally, topically, in the form of an ophthalmic formulation or by inhalation.

For these routes of administration, the pharmaceutical composition of the present invention can be administered in an appropriate dosage form.

The dosage forms include but are not limited to tablets, capsules, lozenges, hard lozenges, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions , Injectable solutions, elixirs, syrups.

The term "effective amount" as used herein refers to the amount of a compound which, when administered, alleviates to some extent one or more symptoms of the condition being treated.

Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician. Generally, the effective dosage is about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg human this would amount to about 0.007 mg/day to about 3500 mg/day, eg about 0.7 mg/day to about 700 mg/day. In some cases dosage levels not exceeding the lower limit of the aforementioned ranges may be sufficient, while in other cases larger dosages may still be employed without causing any deleterious side effects, provided that the larger dosage is first The dose is divided into several smaller doses to be administered throughout the day.

The content or amount of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg mg, such as 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

As used herein, unless otherwise stated, the term "treating" means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such a disorder or condition, or preventing Such a disorder or condition or one or more symptoms of such a disorder or condition.

"Individual" as used herein includes a human or a non-human animal. Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).

In some embodiments, the pharmaceutical compositions of the present invention may also comprise one or more additional therapeutic or prophylactic agents.

The present invention is further described below in conjunction with the examples, but the provision of these examples is not intended to limit the scope of the present invention.

The structures of the compounds were confirmed by nuclear magnetic resonance spectroscopy ( ¹ H NMR) or mass spectroscopy (MS).

Chemical shifts (δ) are given in parts per million (ppm). The determination of ¹ HNMR was carried out on a Bruker BioSpin GmbH 400 NMR instrument, and the test solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ) or hexadeuteriodimethylsulfone (DMSO- d ₆ ), and the inner Labeled as Tetramethylsilane (TMS).

The determination of LC-MS was carried out on Shimadzu LC-MS-2020 liquid mass spectrometer (manufacturer: Shimadzu, model: Shimadzu LC-MS-2020).

Preparative high performance liquid chromatography was performed using waters 2767 (waters sunfire, C18, 19×250 mm 10um column).

Thin-layer chromatography (TLC) was carried out using Huanghai brand HSGF 254 (5 × 20 cm) silica gel plates, and thin-layer preparative chromatography was carried out using GF 254 (0.4-0.5 nm) silica gel plates produced in Yantai.

Adopt thin-layer chromatography (TLC) or LC-MS to detect reaction, and the developer system that uses comprises dichloromethane and methanol system, normal hexane and ethyl acetate system and sherwood oil and ethyl acetate system, according to the compound to be separated Adjust the developer system with different polarities (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

Microwave reaction using BiotageInitiator + (400 W, RT ~ 300 ℃) microwave reactor.

Column chromatography generally uses 200-300 mesh silica gel as the stationary phase in Chenghua Chemical Industry. The eluent system includes dichloromethane and methanol system and n-hexane and ethyl acetate system, and the eluent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.) ).

Unless otherwise specified in the examples, the temperature of the reaction is room temperature (20° C. to 30° C.).

The reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Shanghai Beide Pharmaceutical Technology Co., Ltd.

Abbreviations in the present invention have the following meanings: abbreviation meaning _CCl4 carbon tetrachloride DIEA/DIPEA N,N-Diisopropylethylamine DMSO DMSO EDC 1,2-Dichloroethane Fe iron HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCl hydrochloric acid H ₂ O water K ₂ CO ₃ potassium carbonate MeOH Methanol MeONa Sodium methoxide NaBH ₃ CN Sodium cyanoborohydride NH ₄ Cl ammonium chloride Pd(PPh ₃ ) ₄ Tetrakis(triphenylphosphine)palladium PPh ₃ Triphenylphosphine TLC TLC rt/rt room temperature _ZnCl2 Zinc chloride

第一步 ：將乙脒(2.4 g，23.1 mmol)溶解在甲醇(50 mL)中，加入甲醇鈉(3.2 g，58.4 mmol)及1-(叔丁基)3-甲基4-氧代哌啶-1,3-二甲酸酯(5.0 g，19.5 mmol)。將反應液於60℃攪拌6小時。將反應物冷卻，減壓濃縮，加水稀釋(100 mL)，向體系中加入鹽酸(2M)調pH值到中性，乙酸乙酯萃取(2 x 100 mL)，將有機相減壓濃縮，得到化合物 301-1(5.0 g)，其為白色固體，收率96%。ESI-MS: 266 [M+H] ⁺. 第二步 ：將 30 1-1(5.0 g，18.9 mmol)溶於1,2-二氯乙烷(70 mL)，加入四氯化碳(3.2 g，21.1 mmol)及三苯基膦(5.5 g，21.1 mmol)，將反應物在70℃下反應8小時。將反應物冷卻，將反應液減壓濃縮，將濃縮物通過管柱層析法(乙酸乙酯:石油醚=0-60%)分離純化，得到化合物 301-2(4.7 g)，其為淡黃色固體，收率89%。ESI-MS: 284 [M+H] ⁺. 第三步：將 301-2 (2.0 g, 7.1 mmol)溶於二甲基亞碸(20 mL)，加入( R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺鹽酸鹽(2.3 g，8.5 mmol)及N,N-二異丙基乙胺(2.7 g，21.3  mmol)，將反應液於150℃下攪拌16小時。將反應物冷卻，加水稀釋(50 mL)，乙酸乙酯萃取(100 mL)，將有機相減壓濃縮，將濃縮物通過管柱層析法(甲醇:二氯甲烷=0-8%)分離純化，得到化合物 301-3(1.7 g)，其為淡黃色固體，收率50%。ESI-MS: 482 [M+H] ⁺. 第四步：將 301-3(1.7 g，3.5 mmol)溶於二氧六環(20 mL)，加入鹽酸(4M，二氧六環中的溶液)(5 mL)，將反應液在室溫下攪拌，TLC監控原料反應完全，減壓濃縮去除溶劑得化合物 301-4(1.3 g)，其為白色固體，收率90%。ESI-MS: 382 [M+H] ⁺. 第五步：將 301-4(150 mg，0.4 mmol)溶於甲醇(5 mL)，加入環丁酮(50 mg，0.7 mmol)、無水氯化鋅(145 mg，1.0 mmol)及氰基硼氫化鈉(68 mg，1.0 mmol)，將反應液於室溫下攪拌15小時。加水淬冷反應，減壓濃縮，加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，得化合物 301-5(120 mg)，其為黃色固體，收率76%。ESI-MS: 436 [M+H] ⁺. 第六步：將 301-5(120 mg，0.3 mmol)溶於乙醇(5 mL)及水(2 mL)，加入鐵粉(157 mg，2.8 mmol)及氯化銨(150 mg，2.8 mmol)，將反應液於90℃下攪拌2小時。將反應物冷卻，過濾，將濾餅用乙酸乙酯洗滌，將濾液減壓濃縮，將濃縮物用水(10 mL)稀釋，用乙酸乙酯萃取(2 x 10 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法分離純化，得( R)- N-(1-(3-胺基-5-(三氟甲基)苯基)乙基)-6-環丁基-2-甲基-5,6,7,8-四氫吡啶并[4,3- d]嘧啶-4-胺(53.79 mg)，其為白色固體，收率49%。ESI-MS: 406 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 6.83 (s, 1H), 6.79-6.77 (m, 2H), 6.67 (s, 1H), 5.52-5.50 (m, 2H), 5.40-5.34 (m, 1H), 3.34-3.31 (m, 2H), 3.18 (s, 3H), 2.98-2.94 (m, 2H), 2.92 (s, 3H), 2.10-2.07 (m, 2H), 1.92-1.87 (m, 2H), 1.72-1.66 (m, 2H), 1.45 (d, J = 4.0 Hz, 3H)。 Example 1 : ( R ) -N- (1-(3- amino -5-( trifluoromethyl ) phenyl ) ethyl )-6- cyclobutyl -2- methyl -5,6,7 , Preparation of 8- tetrahydropyrido [4,3- d ] pyrimidin -4- amine ( compound 301)

Step 1 : Dissolve acetamidine (2.4 g, 23.1 mmol) in methanol (50 mL), add sodium methoxide (3.2 g, 58.4 mmol) and 1-(tert-butyl) 3-methyl-4-oxopiper Pyridine-1,3-dicarboxylate (5.0 g, 19.5 mmol). The reaction solution was stirred at 60°C for 6 hours. The reactant was cooled, concentrated under reduced pressure, diluted with water (100 mL), added hydrochloric acid (2M) to the system to adjust the pH to neutral, extracted with ethyl acetate (2 x 100 mL), and concentrated the organic phase under reduced pressure to obtain Compound 301-1 (5.0 g), which is a white solid, yield 96%. ESI-MS: 266 [M+H] ⁺ . The second step : dissolve 30 1-1 (5.0 g, 18.9 mmol) in 1,2-dichloroethane (70 mL), add carbon tetrachloride (3.2 g, 21.1 mmol) and triphenylphosphine (5.5 g, 21.1 mmol), the reactants were reacted at 70°C for 8 hours. The reactant was cooled, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (ethyl acetate:petroleum ether=0-60%) to obtain compound 301-2 (4.7 g), which was light Yellow solid, yield 89%. ESI-MS: 284 [M+H] ⁺ . The third step: Dissolve 301-2 ( 2.0 g, 7.1 mmol) in dimethylsulfoxide (20 mL), add ( R )-1-(3-nitrate Base-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (2.3 g, 8.5 mmol) and N,N-diisopropylethylamine (2.7 g, 21.3 mmol), the reaction solution Stir at 150°C for 16 hours. The reactant was cooled, diluted with water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was separated by column chromatography (methanol:dichloromethane=0-8%) Purification afforded compound 301-3 (1.7 g) as a light yellow solid with a yield of 50%. ESI-MS: 482 [M+H] ⁺ . The fourth step: Dissolve 301-3 (1.7 g, 3.5 mmol) in dioxane (20 mL), add hydrochloric acid (4M, solution in dioxane ) (5 mL), the reaction solution was stirred at room temperature, TLC monitored the complete reaction of the raw materials, and concentrated under reduced pressure to remove the solvent to obtain compound 301-4 (1.3 g), which was a white solid with a yield of 90%. ESI-MS: 382 [M+H] ⁺ .The fifth step: Dissolve 301-4 (150 mg, 0.4 mmol) in methanol (5 mL), add cyclobutanone (50 mg, 0.7 mmol), anhydrous chlorination Zinc (145 mg, 1.0 mmol) and sodium cyanoborohydride (68 mg, 1.0 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 301-5 (120 mg) as a yellow solid, Yield 76%. ESI-MS: 436 [M+H] ⁺ . Step 6: Dissolve 301-5 (120 mg, 0.3 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (157 mg, 2.8 mmol ) and ammonium chloride (150 mg, 2.8 mmol), and the reaction solution was stirred at 90° C. for 2 hours. The reaction was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2 x 10 mL), the organic phase was concentrated under reduced pressure , the concentrate was separated and purified by high-pressure preparative liquid chromatography to obtain ( R ) -N- (1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-cyclobutyl - 2-methyl-5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidin-4-amine (53.79 mg), which is a white solid, yield 49%. ESI-MS: 406 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 6.83 (s, 1H), 6.79-6.77 (m, 2H), 6.67 (s, 1H), 5.52-5.50 (m, 2H), 5.40- 5.34 (m, 1H), 3.34-3.31 (m, 2H), 3.18 (s, 3H), 2.98-2.94 (m, 2H), 2.92 (s, 3H), 2.10-2.07 (m, 2H), 1.92- 1.87 (m, 2H), 1.72-1.66 (m, 2H), 1.45 (d, J = 4.0 Hz, 3H).

第一步 ：將 301-4(130 mg，0.3 mmol)溶於甲醇(5 mL)，加入四氫-4 H-吡喃-4-酮(60 mg，0.6 mmol)、無水氯化鋅(121 mg，0.9 mmol)及氰基硼氫化鈉(61 mg，0.9 mmol)，將反應液於室溫下攪拌15小時。加水淬冷反應，減壓濃縮，加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，得化合物 302-1(110 mg)，其為黃色固體，收率76%。ESI-MS: 466 [M+H] ⁺. 第二步：將 302-1(110 mg，0.2 mmol)溶於乙醇(5 mL)及水(2 mL)，加入鐵粉(135 mg，2.4 mmol)及氯化銨(129 mg，2.4 mmol)，將反應液於90℃下攪拌2小時。將反應物冷卻，過濾，將濾餅用乙酸乙酯洗滌，將濾液減壓濃縮，將濃縮物用水(10 mL)稀釋，用乙酸乙酯萃取(2 x 10 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法分離純化，得( R)- N-(1-(3-胺基-5-(三氟甲基)苯基)乙基)-2-甲基-6-(四氫-2 H-吡喃-4-基)-5,6,7,8-四氫吡啶并[4,3- d]嘧啶-4-胺(38.11 mg)，其為白色固體，收率36%。ESI-MS: 436 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 6.83 (s, 1H), 6.79-6.76 (m, 2H), 6.68 (s, 1H), 5.53-5.51 (m, 2H), 5.41-5.33 (m, 1H), 3.97-3.93 (m, 2H), 3.39 (s, 2H), 3.36-3.30 (m, 2H), 2.76-2.73 (m, 2H), 2.67-2.61 (m, 1H), 2.58-2.56 (m, 2H), 2.23 (s, 3H), 1.83-1.80 (m, 2H), 1.63-1.54 (m,2H), 1.45 (d, J = 4.0 Hz, 3H)。 Example 2 : ( R ) -N- (1-(3- amino -5-( trifluoromethyl ) phenyl ) ethyl )-2- methyl -6-( tetrahydro -2 H - pyran Preparation of -4- yl )-5,6,7,8- tetrahydropyrido [4,3- d ] pyrimidin -4- amine ( compound 302)

Step 1 : Dissolve 301-4 (130 mg, 0.3 mmol) in methanol (5 mL), add tetrahydro- 4H -pyran-4-one (60 mg, 0.6 mmol), anhydrous zinc chloride (121 mg, 0.9 mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 302-1 (110 mg) as a yellow solid, Yield 76%. ESI-MS: 466 [M+H] ⁺ . Second step: Dissolve 302-1 (110 mg, 0.2 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (135 mg, 2.4 mmol ) and ammonium chloride (129 mg, 2.4 mmol), and the reaction solution was stirred at 90° C. for 2 hours. The reaction was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2 x 10 mL), the organic phase was concentrated under reduced pressure , the concentrate was separated and purified by high-pressure preparative liquid chromatography to obtain ( R ) -N- (1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl- 6-(tetrahydro- 2H -pyran-4-yl)-5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidin-4-amine (38.11 mg) as a white solid , yield 36%. ESI-MS: 436 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 6.83 (s, 1H), 6.79-6.76 (m, 2H), 6.68 (s, 1H), 5.53-5.51 (m, 2H), 5.41- 5.33 (m, 1H), 3.97-3.93 (m, 2H), 3.39 (s, 2H), 3.36-3.30 (m, 2H), 2.76-2.73 (m, 2H), 2.67-2.61 (m, 1H), 2.58-2.56 (m, 2H), 2.23 (s, 3H), 1.83-1.80 (m, 2H), 1.63-1.54 (m, 2H), 1.45 (d, J = 4.0 Hz, 3H).

第一步 ：將化合物 301-2(2.0 g, 7.1 mmol)溶於二甲基亞碸(20 mL)，加入( R)-1-(5-溴噻吩-2-基)乙-1-胺鹽酸鹽(2.0 g，8.5 mmol)及N,N-二異丙基乙胺(2.7 g，21.3  mmol)，將反應液於150℃下攪拌16小時。將反應物冷卻，加水稀釋(50 mL)，乙酸乙酯萃取(100 mL)，將有機相減壓濃縮，將濃縮物通過管柱層析法(甲醇:二氯甲烷=0-8%)分離純化，得到化合物 303-1(1.7 g)，其為淡黃色固體，收率53%。ESI-MS: 453 [M+H] ⁺. 第二步 ：將 303 -1 (1.7 g, 3.8 mmol)溶於二氧六環\水(5:1)(30 mL)，加入(2-((二甲基胺基)甲基)苯基)硼酸(1.0 g，5.7 mmol)、四(三苯基膦)鈀(462 mg，0.4 mmol)及碳酸鉀(1.6 g，11.4 mmol)，將反應液於100℃下攪拌16小時。將反應物冷卻，過濾，將濾液減壓濃縮，加水稀釋(50 mL)，乙酸乙酯萃取(100 mL)，將有機相減壓濃縮，將濃縮物通過管柱層析法(甲醇:二氯甲烷=0-8%)分離純化，得到化合物 303-2(1.5 g)，其為淡黃色固體，收率78%。ESI-MS: 508 [M+H] ⁺. 第三步：將 303-2(1.7 g，3.0 mmol)溶於二氧六環(20 mL)，加入鹽酸(4M，二氧六環的溶液)(5 mL)，將反應液在室溫下攪拌，TLC監控原料反應完全，減壓濃縮去除溶劑得化合物 303-3(1.0 g)，其為白色固體，收率83%。ESI-MS: 408 [M+H] ⁺. 第四步：將 303-3(120 mg，0.3 mmol)溶於甲醇(5 mL)，加入環丁酮(43 mg，0.6 mmol)、無水氯化鋅(130 mg，0.9 mmol)及氰基硼氫化鈉(61 mg，0.9 mmol)，將反應液於室溫下攪拌15小時。加水淬冷反應，減壓濃縮，加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法純化，得( R)-6-環丁基- N-(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-2-甲基-5,6,7,8-四氫吡啶并[4,3- d]嘧啶-4-胺(52.76 mg)，其為白色固體，收率38%。ESI-MS: 462 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 7.43 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.35-7.28 (m, 2H), 7.15 (d, J = 4.0 Hz, 1H), 7.00-6.96 (m, 2H), 5.79-5.76 (m, 1H), 3.37 (s, 2H), 3.31 (s, 2H), 3.19-3.11 (m, 2H), 2.97-2.90 (m, 1H), 2.52-2.51 (m, 2H), 2.31 (s, 3H), 2.13 (s, 6H), 2.07-2.05 (m, 2H), 1.90-1.83 (m, 2H), 1.70-1.64 (m, 2H), 1.61 (d, J = 4.0 Hz, 3H)。 Embodiment 3 : ( R )-6- cyclobutyl - N- (1-(5-(2-(( dimethylamino ) methyl ) phenyl ) thiophen -2- yl ) ethyl )-2 -Preparation of methyl -5,6,7,8- tetrahydropyrido [4,3- d ] pyrimidin -4- amine ( compound 303)

The first step : Dissolve compound 301-2 (2.0 g, 7.1 mmol) in dimethylsulfene (20 mL), add ( R )-1-(5-bromothiophen-2-yl) ethane-1-amine hydrochloride (2.0 g, 8.5 mmol) and N,N-diisopropylethylamine (2.7 g, 21.3 mmol), and the reaction solution was stirred at 150° C. for 16 hours. The reactant was cooled, diluted with water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was separated by column chromatography (methanol:dichloromethane=0-8%) Purification afforded compound 303-1 (1.7 g) as a light yellow solid with a yield of 53%. ESI-MS: 453 [M+H] ⁺ .Second step : 303 -1 ( 1.7 g, 3.8 mmol) was dissolved in dioxane\water (5:1) (30 mL), added (2-( (Dimethylamino)methyl)phenyl)boronic acid (1.0 g, 5.7 mmol), tetrakis(triphenylphosphine)palladium (462 mg, 0.4 mmol) and potassium carbonate (1.6 g, 11.4 mmol), the reaction The solution was stirred at 100°C for 16 hours. The reactant was cooled, filtered, the filtrate was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was passed through column chromatography (methanol:dichloro methane=0-8%), separated and purified to obtain compound 303-2 (1.5 g), which was a light yellow solid with a yield of 78%. ESI-MS: 508 [M+H] ⁺ . The third step: Dissolve 303-2 (1.7 g, 3.0 mmol) in dioxane (20 mL), add hydrochloric acid (4M, solution of dioxane) (5 mL), the reaction solution was stirred at room temperature, TLC monitored the complete reaction of the raw materials, and concentrated under reduced pressure to remove the solvent to obtain compound 303-3 (1.0 g), which was a white solid with a yield of 83%. ESI-MS: 408 [M+H] ⁺ . The fourth step: dissolve 303-3 (120 mg, 0.3 mmol) in methanol (5 mL), add cyclobutanone (43 mg, 0.6 mmol), anhydrous chloride Zinc (130 mg, 0.9 mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by high-pressure preparative liquid chromatography to give ( R )-6-cyclobutyl- N- (1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methyl-5, 6,7,8-Tetrahydropyrido[4,3- d ]pyrimidin-4-amine (52.76 mg), a white solid, yield 38%. ESI-MS: 462 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 7.43 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.35-7.28 (m, 2H), 7.15 (d, J = 4.0 Hz, 1H), 7.00-6.96 (m, 2H), 5.79-5.76 (m, 1H), 3.37 (s, 2H), 3.31 (s, 2H), 3.19-3.11 (m, 2H ), 2.97-2.90 (m, 1H), 2.52-2.51 (m, 2H), 2.31 (s, 3H), 2.13 (s, 6H), 2.07-2.05 (m, 2H), 1.90-1.83 (m, 2H ), 1.70-1.64 (m, 2H), 1.61 (d, J = 4.0 Hz, 3H).

第一步 ：將 301-4(130 mg，0.3 mmol)溶於甲醇(5 mL)，加入 N,N-二甲基-4-氧代環己烷-1-甲醯胺(101 mg，0.6 mmol)、無水氯化鋅(121 mg，0.9 mmol)及氰基硼氫化鈉(61 mg，0.9 mmol)，將反應液於室溫下攪拌15小時。加水淬冷反應，減壓濃縮，加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，得化合物 304-1(110 mg)，其為黃色固體，收率69%。ESI-MS: 535 [M+H] ⁺. 第二步：將 304-1(110 mg，0.2 mmol)溶於乙醇(5 mL)及水(2 mL)，加入鐵粉(135 mg，2.4 mmol)及氯化銨(129 mg，2.4 mmol)，將反應液於90℃下攪拌2小時。將反應物冷卻，過濾，將濾餅用乙酸乙酯洗滌，將濾液減壓濃縮，將濃縮物用水(10 mL)稀釋，用乙酸乙酯萃取(2 x 10 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法分離純化，得( R)-4-(4-((1-(3-胺基-5-(三氟甲基)苯基)乙基)胺基)-2-甲基-7,8-二氫吡啶并[4,3- d]嘧啶-6(5 H)-基)-N,N-二甲基環己烷-1-甲醯胺(52.33 mg)，其為白色固體，收率52%。ESI-MS: 505 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.01 (d, J = 8.0 Hz, 1H), 6.87 (s, 2H), 6.76 (s, 1H), 5.55-5.47 (m, 1H), 4.22 (s, 2H), 3.75-3.22 (m, 4H), 3.03 (s, 3H), 2.81 (s, 3H), 2.63-2.58 (m, 1H), 2.53 (s, 6H), 2.25-2.23 (m, 2H), 1.90-1.87 (m, 2H), 1.67-1.61 (m, 2H), 1.55 (d, J = 4.0 Hz, 3H), 1.50-1.47 (m, 2H)。 Example 4 : ( R )-4-(4-((1-(3- amino -5-( trifluoromethyl ) phenyl ) ethyl ) amino )-2- methyl -7,8- Preparation of Dihydropyrido [4,3- d ] pyrimidin -6(5 H )-yl ) -N,N- dimethylcyclohexane -1- carboxamide ( compound 304)

Step 1 : Dissolve 301-4 (130 mg, 0.3 mmol) in methanol (5 mL), add N,N -dimethyl-4-oxocyclohexane-1-formamide (101 mg, 0.6 mmol), anhydrous zinc chloride (121 mg, 0.9 mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 304-1 (110 mg) as a yellow solid, Yield 69%. ESI-MS: 535 [M+H] ⁺ . Second step: Dissolve 304-1 (110 mg, 0.2 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (135 mg, 2.4 mmol ) and ammonium chloride (129 mg, 2.4 mmol), and the reaction solution was stirred at 90° C. for 2 hours. The reaction was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2 x 10 mL), the organic phase was concentrated under reduced pressure , the concentrate was separated and purified by high-pressure preparative liquid chromatography to obtain ( R )-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino )-2-methyl-7,8-dihydropyrido[4,3- d ]pyrimidin-6(5 H )-yl)-N,N-dimethylcyclohexane-1-carboxamide ( 52.33 mg), which is a white solid with a yield of 52%. ESI-MS: 505 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.01 (d, J = 8.0 Hz, 1H), 6.87 (s, 2H), 6.76 (s, 1H), 5.55-5.47 (m, 1H) , 4.22 (s, 2H), 3.75-3.22 (m, 4H), 3.03 (s, 3H), 2.81 (s, 3H), 2.63-2.58 (m, 1H), 2.53 (s, 6H), 2.25-2.23 (m, 2H), 1.90-1.87 (m, 2H), 1.67-1.61 (m, 2H), 1.55 (d, J = 4.0 Hz, 3H), 1.50-1.47 (m, 2H).

將化合物 303-3(120 mg，0.3 mmol)溶於甲醇(5 mL)，加入 N,N-二甲基-4-氧代環己烷-1-甲醯胺(101 mg，0.6 mmol)、無水氯化鋅(130 mg，0.9 mmol)及氰基硼氫化鈉(61 mg，0.9 mmol)，將反應液於室溫下攪拌15小時。加水淬冷反應，減壓濃縮，加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法純化，得( R)-4-(4-((1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)胺基)-2-甲基-7,8-二氫吡啶并[4,3- d]嘧啶-6(5 H)-基)- N,N-二甲基環己烷-1-甲醯胺(135.88 mg)，其為白色固體，收率81%。ESI-MS: 561 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.03 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.56-7.49 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 5.94-5.87 (m, 1H), 4.43 (s, 2H), 4.17-4.16 (m, 2H), 3.42-3.41 (m, 2H), 3.08-3.00 (m, 6H), 2.81 (s, 3H), 2.78-2.66 (m, 6H), 2.55 (s, 3H), 2.15-1.91 (m, 2H), 1.93-1.86 (m, 3H), 1.71 (d, J = 4.0 Hz, 3H), 1.72-1.62 (m, 2H), 1.59-1.50 (m, 2H)。 Example 5 : ( R )-4-(4-((1-(5-(2-(( dimethylamino ) methyl ) phenyl ) thiophen -2- yl ) ethyl ) amino )- 2- Methyl -7,8- dihydropyrido [4,3- d ] pyrimidin -6( 5H )-yl ) -N ,N - dimethylcyclohexane - 1-carboxamide ( compound 305 ) preparation

Compound 303-3 (120 mg, 0.3 mmol) was dissolved in methanol (5 mL), and N,N -dimethyl-4-oxocyclohexane-1-formamide (101 mg, 0.6 mmol), Anhydrous zinc chloride (130 mg, 0.9 mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by high-pressure preparative liquid chromatography to give ( R )-4-(4-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-2-methyl-7 ,8-Dihydropyrido[4,3- d ]pyrimidin-6( 5H )-yl)-N ,N -dimethylcyclohexane-1-carboxamide (135.88 mg) as a white solid , yield 81%. ESI-MS: 561 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.03 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.56-7.49 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 5.94-5.87 (m, 1H), 4.43 (s, 2H) , 4.17-4.16 (m, 2H), 3.42-3.41 (m, 2H), 3.08-3.00 (m, 6H), 2.81 (s, 3H), 2.78-2.66 (m, 6H), 2.55 (s, 3H) , 2.15-1.91 (m, 2H), 1.93-1.86 (m, 3H), 1.71 (d, J = 4.0 Hz, 3H), 1.72-1.62 (m, 2H), 1.59-1.50 (m, 2H).

第一 步 ：將化合物 301-4(130 mg，0.3 mmol)溶於甲醇(5 mL)，加入1-乙醯基哌啶-4-酮(85 mg，0.6 mmol)、無水氯化鋅(121 mg，0.9 mmol)及氰基硼氫化鈉(61 mg，0.9 mmol)，將反應液於室溫下攪拌15小時。加水淬冷反應，減壓濃縮，加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，得化合物 306-1(130 mg)，其為黃色固體，收率86%。ESI-MS: 507 [M+H] ⁺. 第二步：將 306-1(130 mg，0.3 mmol)溶於乙醇(5 mL)及水(2 mL)，加入鐵粉(135 mg，2.4 mmol)及氯化銨(129 mg，2.4 mmol)，將反應液於90℃下攪拌2小時。將反應物冷卻，過濾，將濾餅用乙酸乙酯洗滌，將濾液減壓濃縮，將濃縮物用水(10 mL)稀釋，用乙酸乙酯萃取(2 x 10 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法分離純化，得( R)-1-(4-(4-((1-(3-胺基-5-(三氟甲基)苯基)乙基)胺基)-2-甲基-7,8-二氫吡啶并[4,3- d]嘧啶-6(5 H)-基)哌啶-1-基)乙-1-酮(88.72 mg)，其為白色固體，收率73%。ESI-MS: 477 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.82 (d, J = 8.0 Hz, 1H), 6.85 (s, 2H), 6.76 (s, 1H), 5.54-5.47 (m, 1H), 4.59-4.55 (m, 1H), 4.12 (s, 2H), 4.04-4.00 (m, 1H), 3.57-3.50 (m, 2H), 3.11-3.55 (m, 3H), 2.59-2.50 (m, 7H), 2.12-2.09 (m, 2H), 2.03 (s, 3H), 1.70-1.67 (m, 2H), 1.54 (d, J = 4.0 Hz, 3H)。 Embodiment 6 : ( R )-1-(4-(4-((1-(3- amino- 5-( trifluoromethyl ) phenyl ) ethyl ) amino )-2- methyl -7 , Preparation of 8- dihydropyrido [ 4,3- d ] pyrimidin -6( 5H ) -yl ) piperidin -1- yl ) ethan - 1- one ( compound 306)

Step 1 : Dissolve compound 301-4 (130 mg, 0.3 mmol) in methanol (5 mL), add 1-acetylpiperidin-4-one (85 mg, 0.6 mmol), anhydrous zinc chloride (121 mg, 0.9 mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 306-1 (130 mg) as a yellow solid, Yield 86%. ESI-MS: 507 [M+H] ⁺ . Second step: Dissolve 306-1 (130 mg, 0.3 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (135 mg, 2.4 mmol ) and ammonium chloride (129 mg, 2.4 mmol), and the reaction solution was stirred at 90° C. for 2 hours. The reaction was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2 x 10 mL), the organic phase was concentrated under reduced pressure , the concentrate was separated and purified by high-pressure preparative liquid chromatography to obtain ( R )-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) )amino)-2-methyl-7,8-dihydropyrido[4,3- d ]pyrimidin-6( 5H )-yl)piperidin-1-yl)ethan-1-one (88.72 mg ), which was a white solid with a yield of 73%. ESI-MS: 477 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.82 (d, J = 8.0 Hz, 1H), 6.85 (s, 2H), 6.76 (s, 1H), 5.54-5.47 (m, 1H) , 4.59-4.55 (m, 1H), 4.12 (s, 2H), 4.04-4.00 (m, 1H), 3.57-3.50 (m, 2H), 3.11-3.55 (m, 3H), 2.59-2.50 (m, 7H), 2.12-2.09 (m, 2H), 2.03 (s, 3H), 1.70-1.67 (m, 2H), 1.54 (d, J = 4.0 Hz, 3H).

將化合物 303-3(100 mg，0.3 mmol)溶於甲醇(5 mL)，加入1-乙醯基哌啶-4-酮(71 mg，0.5 mmol)、無水氯化鋅(116 mg，0.8 mmol)及氰基硼氫化鈉(54 mg，0.8 mmol)，將反應液於室溫下攪拌15小時。加水淬冷反應，減壓濃縮，加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法純化，得( R)-1-(4-(4-((1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)胺基)-2-甲基-7,8-二氫吡啶并[4,3- d]嘧啶-6(5 H)-基)哌啶-1-基)乙-1-酮(30.64 mg)，其為白色固體，收率23%。ESI-MS: 533 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.70 (br, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.56-7.49 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 7.08 (d, J = 4.0 Hz, 1H), 5.91-5.84 (m, 1H), 4.55-4.52 (m, 1H), 4.43 (s, 2H), 4.00-3.97 (m, 4H), 3.44-3.30 (m, 2H), 3.10-3.03 (m, 1H), 2.97 (s, 2H), 2.67-2.66 (m, 4H), 2.58-2.50 (m, 7H), 2.04-2.01 (m, 4H), 1.69 (d, J = 4.0 Hz, 3H), 1.66-1.52 (m, 2H)。 Embodiment 7 : ( R )-1-(4-(4-((1-(5-(2-(( dimethylamino ) methyl ) phenyl ) thiophen -2 - yl ) ethyl ) amine Base )-2- methyl - 7,8- dihydropyrido [ 4,3- d ] pyrimidin -6( 5H )-yl ) piperidin - 1- yl ) ethan -1- one ( compound 307) preparation

Dissolve compound 303-3 (100 mg, 0.3 mmol) in methanol (5 mL), add 1-acetylpiperidin-4-one (71 mg, 0.5 mmol), anhydrous zinc chloride (116 mg, 0.8 mmol ) and sodium cyanoborohydride (54 mg, 0.8 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by high-pressure preparative liquid chromatography to give ( R )-1-(4-(4-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-2-methyl yl-7,8-dihydropyrido[4,3- d ]pyrimidin-6( 5H )-yl)piperidin-1-yl)ethan-1-one (30.64 mg) as a white solid, yield The rate is 23%. ESI-MS: 533 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.70 (br, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.56-7.49 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 7.08 (d, J = 4.0 Hz, 1H), 5.91-5.84 (m, 1H), 4.55-4.52 (m, 1H), 4.43 ( s, 2H), 4.00-3.97 (m, 4H), 3.44-3.30 (m, 2H), 3.10-3.03 (m, 1H), 2.97 (s, 2H), 2.67-2.66 (m, 4H), 2.58- 2.50 (m, 7H), 2.04-2.01 (m, 4H), 1.69 (d, J = 4.0 Hz, 3H), 1.66-1.52 (m, 2H).

第一步 ：將四氫-2 H-吡喃-4-羧酸(40 mg，0.9 mmol)溶於N,N-二甲基甲醯胺(3 mL)，加入HATU (137 mg，0.4 mmol)、N,N-二異丙基乙胺(116 mg，0.9 mmol)及化合物 301-4(130 mg，0.3 mmol)，將反應液於室溫下攪拌15小時。加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，得化合物 308-1(110 mg)，其為黃色固體，收率74%。ESI-MS: 494 [M+H] ⁺. 第二步：將 308-1(110 mg，0.2 mmol)溶於乙醇(5 mL)及水(2 mL)，加入鐵粉(135 mg，2.4 mmol)及氯化銨(129 mg，2.4 mmol)，將反應液於90℃下攪拌2小時。將反應物冷卻，過濾，將濾餅用乙酸乙酯洗滌，將濾液減壓濃縮，將濃縮物用水(10 mL)稀釋，用乙酸乙酯萃取(2 x 10 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法分離純化，得( R)-(4-((1-(3-胺基-5-(三氟甲基)苯基)乙基)胺基)-2-甲基-7,8-二氫吡啶并[4,3- d]嘧啶-6(5 H)-基)(四氫-2 H-吡喃-4-基)甲酮(68.34 mg)，其為白色固體，收率67%。ESI-MS: 494 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.00 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 5.57-5.49 (m, 1H), 4.52-4.49 (m, 1H), 4.44 (s, 2H), 3.88-3.84 (m, 4H), 3.45-3.39 (m, 2H), 3.05-3.01 (m, 1H), 2.99-2.83 (m, 2H), 2.72-2.71 (m, 1H), 2.51 (s, 3H), 1.63-1.53 (m, 7H)。 Example 8 : ( R )-(4-((1-(3- amino -5-( trifluoromethyl ) phenyl ) ethyl ) amino )-2- methyl -7,8- dihydro Preparation of pyrido [4,3- d ] pyrimidin -6(5 H ) -yl )( tetrahydro -2 H - pyran -4- yl ) methanone ( compound 308)

Step 1 : Dissolve tetrahydro-2 H -pyran-4-carboxylic acid (40 mg, 0.9 mmol) in N,N-dimethylformamide (3 mL), add HATU (137 mg, 0.4 mmol ), N,N-diisopropylethylamine (116 mg, 0.9 mmol) and compound 301-4 (130 mg, 0.3 mmol), and the reaction solution was stirred at room temperature for 15 hours. It was diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 308-1 (110 mg) as a yellow solid with a yield of 74%. ESI-MS: 494 [M+H] ⁺ . The second step: dissolve 308-1 (110 mg, 0.2 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (135 mg, 2.4 mmol ) and ammonium chloride (129 mg, 2.4 mmol), and the reaction solution was stirred at 90° C. for 2 hours. The reaction was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2 x 10 mL), the organic phase was concentrated under reduced pressure , the concentrate was separated and purified by high-pressure preparative liquid chromatography to obtain ( R )-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)- 2-Methyl-7,8-dihydropyrido[4,3- d ]pyrimidin-6( 5H )-yl)(tetrahydro- 2H -pyran-4-yl)methanone (68.34 mg) , which is a white solid with a yield of 67%. ESI-MS: 494 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.00 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 5.57 -5.49 (m, 1H), 4.52-4.49 (m, 1H), 4.44 (s, 2H), 3.88-3.84 (m, 4H), 3.45-3.39 (m, 2H), 3.05-3.01 (m, 1H) , 2.99-2.83 (m, 2H), 2.72-2.71 (m, 1H), 2.51 (s, 3H), 1.63-1.53 (m, 7H).

將四氫-2 H-吡喃-4-羧酸(40 mg，0.9 mmol)溶於N,N-二甲基甲醯胺(3 mL)，加入HATU (137 mg，0.4 mmol)、N,N-二異丙基乙胺(116 mg，0.9 mmol)及化合物 303-3(100 mg，0.3 mmol)，將反應液於室溫下攪拌15小時。加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法純化，得( R)-(4-((1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)胺基)-2-甲基-7,8-二氫吡啶并[4,3- d]嘧啶-6(5 H)-基)(四氫-2 H-吡喃-4-基)甲酮(66.78 mg)，其為白色固體，收率51%。ESI-MS: 520 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.76 (br, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.51-7.48 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 7.09 (d, J = 4.0 Hz, 1H), 5.92-5.88 (m, 1H), 4.51-4.31 (m, 5H), 4.92-3.77 (m, 5H), 3.05-3.00 (m, 1H), 2.88-2.87 (m, 2H), 2.54 (s, 6H), 2.51 (s, 3H), 1.71 (d, J = 8.0 Hz, 3H), 1.63-1.57 (m, 4H)。 Example 9 : ( R )-(4-((1-(5-(2-(( dimethylamino ) methyl ) phenyl ) thiophen -2- yl ) ethyl ) amino )-2- Preparation of methyl -7,8- dihydropyrido [4,3- d ] pyrimidin -6( 5H ) -yl )( tetrahydro - 2H - pyran -4- yl ) methanone ( compound 309)

Dissolve tetrahydro- 2H -pyran-4-carboxylic acid (40 mg, 0.9 mmol) in N,N-dimethylformamide (3 mL), add HATU (137 mg, 0.4 mmol), N, N-Diisopropylethylamine (116 mg, 0.9 mmol) and compound 303-3 (100 mg, 0.3 mmol) were stirred at room temperature for 15 hours. Dilute with water (10 mL), extract with ethyl acetate (2 x 20 mL), concentrate the organic phase under reduced pressure, and purify the concentrate by high-pressure preparative liquid chromatography to give ( R )-(4-((1- (5-(2-((Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3 -d ] pyrimidin-6( 5H )-yl)(tetrahydro- 2H -pyran-4-yl)methanone (66.78 mg) as a white solid, yield 51%. ESI-MS: 520 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.76 (br, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.51-7.48 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 7.09 (d, J = 4.0 Hz, 1H), 5.92-5.88 (m, 1H), 4.51-4.31 (m, 5H), 4.92- 3.77 (m, 5H), 3.05-3.00 (m, 1H), 2.88-2.87 (m, 2H), 2.54 (s, 6H), 2.51 (s, 3H), 1.71 (d, J = 8.0 Hz, 3H) , 1.63-1.57 (m, 4H).

第一步 ：將化合物 301-4(130 mg，0.3 mmol)溶於甲醇(5 mL)，加入四氫-2 H-吡喃-4-甲醛(68 mg，0.6 mmol)、無水氯化鋅(121 mg，0.9 mmol)及氰基硼氫化鈉(61 mg，0.9 mmol)，將反應液於室溫下攪拌15小時。加水淬冷反應，減壓濃縮，加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，得化合物 310-1(110 mg)，其為黃色固體，收率76%。ESI-MS: 480 [M+H] ⁺. 第二步：將 310-1(110 mg，0.2 mmol)溶於乙醇(5 mL)及水(2 mL)，加入鐵粉(135 mg，2.4 mmol)及氯化銨(129 mg，2.4 mmol)，將反應液於90℃下攪拌2小時。將反應物冷卻，過濾，將濾餅用乙酸乙酯洗滌，將濾液減壓濃縮，將濃縮物用水(10 mL)稀釋，用乙酸乙酯萃取(2 x 10 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法分離純化，得( R)- N-(1-(3-胺基-5-(三氟甲基)苯基)乙基)-2-甲基-6-((四氫-2 H-吡喃-4-基)甲基)-5,6,7,8-四氫吡啶并[4,3- d]嘧啶-4-胺(66.47 mg)，其為白色固體，收率67%。ESI-MS: 450 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.96 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 5.53-5.49 (m, 1H), 4.14-4.13 (m, 2H), 3.89-3.85 (m, 2H), 3.46-3.30 (m, 4H), 3.11-3.04 (m, 4H), 2.52.2.50 (m, 4H), 2.14-2.13 (m, 1H), 1.73-1.64 (m, 2H), 1.54 (d, J = 8.0 Hz, 3H), 1.31-1.20 (m, 3H)。 Embodiment 10 : ( R ) -N- (1-(3- amino -5-( trifluoromethyl ) phenyl ) ethyl )-2- methyl -6-(( tetrahydro -2 H - pyridine Preparation of pyran -4- yl ) methyl )-5,6,7,8- tetrahydropyrido [4,3- d ] pyrimidin -4- amine ( compound 310)

Step 1 : Dissolve compound 301-4 (130 mg, 0.3 mmol) in methanol (5 mL), add tetrahydro-2 H -pyran-4-carbaldehyde (68 mg, 0.6 mmol), anhydrous zinc chloride ( 121 mg, 0.9 mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 310-1 (110 mg) as a yellow solid, Yield 76%. ESI-MS: 480 [M+H] ⁺ . Second step: Dissolve 310-1 (110 mg, 0.2 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (135 mg, 2.4 mmol ) and ammonium chloride (129 mg, 2.4 mmol), and the reaction solution was stirred at 90° C. for 2 hours. The reaction was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2 x 10 mL), the organic phase was concentrated under reduced pressure , the concentrate was separated and purified by high-pressure preparative liquid chromatography to obtain ( R ) -N- (1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl- 6-((tetrahydro- 2H -pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidin-4-amine (66.47 mg), It is a white solid with a yield of 67%. ESI-MS: 450 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.96 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 5.53 -5.49 (m, 1H), 4.14-4.13 (m, 2H), 3.89-3.85 (m, 2H), 3.46-3.30 (m, 4H), 3.11-3.04 (m, 4H), 2.52.2.50 (m, 4H), 2.14-2.13 (m, 1H), 1.73-1.64 (m, 2H), 1.54 (d, J = 8.0 Hz, 3H), 1.31-1.20 (m, 3H).

將化合物 303-3(100 mg，0.3 mmol)溶於甲醇(5 mL)，加入四氫-2 H-吡喃-4-甲醛(57 mg，0.5 mmol)、無水氯化鋅(116 mg，0.8 mmol)及氰基硼氫化鈉(54 mg，0.8 mmol)，將反應液於室溫下攪拌15小時。加水淬冷反應，減壓濃縮，加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法純化，得( R)- N-(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-2-甲基-6-((四氫-2 H-吡喃-4-基)甲基)-5,6,7,8-四氫吡啶并[4,3- d]嘧啶-4-胺(29.30 mg)，其為白色固體，收率23%。ESI-MS: 506 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 7.44 (d, J = 8.0 Hz, 1H), 7.38-7.37 (m, 1H), 7.36-7.30 (m, 2H), 7.15 (d, J = 4.0 Hz, 1H), 7.01-6.96 (m, 2H), 5.80-5.73 (m, 1H), 3.84-3.81 (m, 3H), 3.40-3.34 (m, 2H), 3.29-3.19 (m, 4H), 2.64-2.60 (m, 4H), 2.35-2.34 (m, 2H), 2.31 (s, 3H), 2.14-2.11 (m, 7H), 1.62-1.61 (m, 6H)。 Example 11 : ( R ) -N- (1-(5-(2-(( dimethylamino ) methyl ) phenyl ) thiophen -2- yl ) ethyl )-2- methyl -6- Preparation of (( tetrahydro -2 H - pyran -4- yl ) methyl )-5,6,7,8- tetrahydropyrido [4,3- d ] pyrimidin -4- amine ( compound 311)

Compound 303-3 (100 mg, 0.3 mmol) was dissolved in methanol (5 mL), tetrahydro-2 H -pyran-4-carbaldehyde (57 mg, 0.5 mmol), anhydrous zinc chloride (116 mg, 0.8 mmol) and sodium cyanoborohydride (54 mg, 0.8 mmol), the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by high-pressure preparative liquid chromatography to give ( R ) -N- (1-(5-(2-((Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methyl-6-((tetrahydro-2 H -pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidin-4-amine (29.30 mg) as a white solid, yield 23 %. ESI-MS: 506 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 7.44 (d, J = 8.0 Hz, 1H), 7.38-7.37 (m, 1H), 7.36-7.30 (m, 2H), 7.15 (d, J = 4.0 Hz, 1H), 7.01-6.96 (m, 2H), 5.80-5.73 (m, 1H), 3.84-3.81 (m, 3H), 3.40-3.34 (m, 2H), 3.29-3.19 (m, 4H), 2.64-2.60 (m, 4H), 2.35-2.34 (m, 2H), 2.31 (s, 3H), 2.14-2.11 (m, 7H), 1.62-1.61 (m, 6H).

第一步 ：將化合物 301-2(1.0 g, 3.5 mmol)溶於二甲基亞碸(20 mL)，加入( R)-1-(4-溴噻吩-2-基)乙-1-胺鹽酸鹽(1.0 g，4.2 mmol)及N,N-二異丙基乙胺(1.4 g，10.2 mmol)，將反應液於150℃下攪拌16小時。將反應物冷卻，加水稀釋(50 mL)，乙酸乙酯萃取(100 mL)，將有機相減壓濃縮，將濃縮物通過管柱層析法(甲醇:二氯甲烷=0~8%)分離純化，得到化合物 312-1(900 mg)，其為淡黃色固體，收率56%。ESI-MS: 453 [M+H] ⁺. 第二步 ：將 312 -1 (900 mg, 2.0 mmol)溶於二氧六環\水(5:1)(15 mL)，加入(2-((二甲基胺基)甲基)苯基)硼酸(534 mg，3.0 mmol)、四(三苯基膦)鈀(231 mg，0.2 mmol)及碳酸鉀(823 mg，6.0 mmol)，將反應液於100℃下攪拌16小時。將反應物冷卻，過濾，將濾液減壓濃縮，加水稀釋(50 mL)，乙酸乙酯萃取(100 mL)，將有機相減壓濃縮，將濃縮物通過管柱層析法(甲醇:二氯甲烷=0~8%)分離純化，得到化合物 312-2(450 mg)，其為淡黃色固體，收率45%。ESI-MS: 508 [M+H] ⁺. 第三步：將 312-2(450 mg，0.9 mmol)溶於二氧六環(5 mL)，加入鹽酸(4M，二氧六環中的溶液)(3 mL)，將反應液在室溫下攪拌，TLC監控原料反應完全，減壓濃縮去除溶劑得化合物 312-3(300 mg)，其為白色固體，收率82%。ESI-MS: 408 [M+H] ⁺. 第四步：將 312-3(100 mg，0.3 mmol)溶於甲醇(5 mL)，加入1-乙醯基哌啶-4-酮(71 mg，0.5 mmol)、無水氯化鋅(116 mg，0.8 mmol)及氰基硼氫化鈉(54 mg，0.8 mmol)，將反應液於室溫下攪拌15小時。加水淬冷反應，減壓濃縮，加水稀釋(10 mL)，用乙酸乙酯萃取(2 x 20 mL)，將有機相減壓濃縮，將濃縮物通過高壓製備液相色譜法純化，得( R)-1-(4-(4-((1-(4-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)胺基)-2-甲基-7,8-二氫吡啶并[4,3- d]嘧啶-6(5 H)-基)哌啶-1-基)乙-1-酮(58.03 mg)，其為白色固體，收率48%。ESI-MS: 533 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.45 (s, 1H), 7.42-7.40 (m, 1H), 7.39-7.29 (m, 3H), 7.25 (s, 1H), 6.95 (d, J = 6.0 Hz, 1H), 5.82-5.74 (m, 1H), 4.45-4.41 (m, 1H), 3.89-3.85 (m, 1H), 3.36-3.30 (m, 5H), 3.06-2.99 (m, 1H), 2.77-2.74 (m, 2H), 2.68-2.60 (m, 1H), 2.59-2.57 (m, 2H), 2.30 (s, 3H), 2.12 (s, 6H), 2.00 (s, 3H), 1.86-1.80 (m, 2H), 1.61 (d, J = 8.0 Hz, 3H), 1.53-1.51 (m, 2H)。 Embodiment 12 : ( R )-1-(4-(4-((1-(4-(2-(( dimethylamino ) methyl ) phenyl ) thiophen -2- yl ) ethyl ) amine Base )-2- methyl -7,8- dihydropyrido [ 4,3- d ] pyrimidin -6( 5H )-yl ) piperidin - 1- yl ) ethan -1- one ( compound 312) preparation

The first step : Dissolve compound 301-2 (1.0 g, 3.5 mmol) in dimethylsulfene (20 mL), add ( R )-1-(4-bromothiophen-2-yl)ethan-1-amine hydrochloride (1.0 g, 4.2 mmol) and N,N-diisopropylethylamine (1.4 g, 10.2 mmol), and the reaction solution was stirred at 150° C. for 16 hours. The reactant was cooled, diluted with water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was separated by column chromatography (methanol:dichloromethane=0~8%) Purification gave compound 312-1 (900 mg) as a light yellow solid with a yield of 56%. ESI-MS: 453 [M+H] ⁺ .Second step : Dissolve 312 -1 ( 900 mg, 2.0 mmol) in dioxane\water (5:1) (15 mL), add (2-( (Dimethylamino)methyl)phenyl)boronic acid (534 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) and potassium carbonate (823 mg, 6.0 mmol), the reaction The solution was stirred at 100°C for 16 hours. The reactant was cooled, filtered, the filtrate was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was passed through column chromatography (methanol:dichloro methane=0~8%), separated and purified to obtain compound 312-2 (450 mg), which was a light yellow solid with a yield of 45%. ESI-MS: 508 [M+H] ⁺ . The third step: Dissolve 312-2 (450 mg, 0.9 mmol) in dioxane (5 mL), add hydrochloric acid (4M, solution in dioxane ) (3 mL), the reaction solution was stirred at room temperature, TLC monitored the complete reaction of the raw materials, and concentrated under reduced pressure to remove the solvent to obtain compound 312-3 (300 mg), which was a white solid with a yield of 82%. ESI-MS: 408 [M+H] ⁺ . The fourth step: 312-3 (100 mg, 0.3 mmol) was dissolved in methanol (5 mL), and 1-acetylpiperidin-4-one (71 mg , 0.5 mmol), anhydrous zinc chloride (116 mg, 0.8 mmol) and sodium cyanoborohydride (54 mg, 0.8 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by high-pressure preparative liquid chromatography to give ( R )-1-(4-(4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-2-methyl yl-7,8-dihydropyrido[4,3- d ]pyrimidin-6( 5H )-yl)piperidin-1-yl)ethan-1-one (58.03 mg) as a white solid, yield The rate is 48%. ESI-MS: 533 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 9.45 (s, 1H), 7.42-7.40 (m, 1H), 7.39-7.29 (m, 3H), 7.25 (s, 1H), 6.95 ( d, J = 6.0 Hz, 1H), 5.82-5.74 (m, 1H), 4.45-4.41 (m, 1H), 3.89-3.85 (m, 1H), 3.36-3.30 (m, 5H), 3.06-2.99 ( m, 1H), 2.77-2.74 (m, 2H), 2.68-2.60 (m, 1H), 2.59-2.57 (m, 2H), 2.30 (s, 3H), 2.12 (s, 6H), 2.00 (s, 3H), 1.86-1.80 (m, 2H), 1.61 (d, J = 8.0 Hz, 3H), 1.53-1.51 (m, 2H).

Biological Assay Experimental Example 1. KRAS::SOS1 HTRF Binding Assay This assay can be used to examine the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS ^G12C . This demonstrates the molecular mode of action of the compound. Low _IC50 values indicate high potency of SOS1 inhibitor compounds in following this assay setup.

Reagents: • GST-SOS1 (aa564-1049), produced in-house • His-KRAS G12C (aa1-169), produced in-house • MAb Anti-6his-Tb cryptate Gold, purchased from Cisbio (cat# 61HI2TLA) • MAb Anti-GST - XL665 from Cisbio (Cat# 61GSTXLA) Assay Plate: ProxiPlate-384Plus from PerkinElmer (Cat# 6008280) Assay Buffer: PPI from Cisbio (Cat# 61DB10RDF)

Determination scheme: • Dissolve the compound to be tested in DMSO, prepare a stock solution with a concentration of 10 mM, and dilute the compound concentration to 2 mM with DMSO as the initial concentration of the assay, and serially dilute the compound solution with an initial concentration of 2 mM 3 times, and co-dilution For 10 concentrations, use Labcyte Echo instrument to transfer 0.1 μL of the compound solution of each concentration to a 384-well assay plate (duplicate, duplicate hole); • Add 5 μL of specific concentration of His-KRAS G12C to 0.1 μL of the compound solution, in Centrifuge at 1000 rpm for 1 min in an Eppendorf 5810R centrifuge; • Add 5 μL of GST-SOS1 at a specific concentration, and centrifuge at 1000 rpm for 1 min in an Eppendorf 5810R centrifuge; • Incubate the 384-well assay plate at 25 °C for 15 min ; • Then add 10 μL of MAb Anti-6his-Tb and MAb Anti-GST-XL665 mixture, and centrifuge at 1000 rpm for 1 min on an Eppendorf 5810R centrifuge; • Incubate the 384-well assay plate at 25 ℃ for 2 h; • Finally use Perkin Elmer The Envision 2104 instrument reads the plate and obtains the signal ratio of 665/615 nm.

Each plate contains the following controls: • DMSO+KRAS+SOS1+ MAb Anti-6his-Tb + MAb Anti-GST-XL665

Calculation of results: _IC50 values were calculated and analyzed using a 4-parameter regression equation. The measurement results are shown in the table below. Compound number SOS1-KRAS ^G12C Interaction Assay (IC ₅₀ , nM) 301 247.4 302 116.5 303 136.6 304 83.3 305 86.7 306 54.3 307 32 309 124.1 311 117.7 312 85.4

Various modifications of the invention, in addition to those described herein, will become apparent to those skilled in the art to which the invention pertains from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, journal articles, books, and any other publications, is hereby incorporated by reference in its entirety.

Claims (20)

A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound thereof, wherein the compound has the structure of formula (II):

where: Ring A is

,

or

; L is selected from direct bonds, C _1-6 alkylene and C (=O); Ring B is selected from C _6-10 aromatic rings and 5-14 membered heteroaromatic rings; R and R ¹ are each present independently selected from halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene -OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3 -10-membered heterocyclic group, C _6-10 aryl group, 5-14-membered heteroaryl group and C _6-12 aralkyl group, at most 2 ring members of the cycloalkyl and heterocyclic group are C(=O), When m is greater than 1 and/or n is greater than 1, two R ¹ and/or two R together with the atoms connected to them form a C _3-10 hydrocarbon ring, a 3-10 membered heterocycle, a C _6-10 Aromatic ring or 5-14 membered heteroaromatic ring, at most 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O); R ² is selected from saturated or partially unsaturated C _3-10 cycloalkyl and saturated or partially Unsaturated 3-10 membered heterocyclic group; R ³ and R ⁴ are each independently selected from H and C _1-6 alkyl; each of the above groups is independently selected from one or more of The following substituents are substituted: halogen, -OH, oxo, -NH ₂ , -CN, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl group, 5-14 membered heteroaryl group, C _6-12 aralkyl group, =N-OR ⁵ , -C(=NH)NH ₂ , - C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C( =O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ and - OC _1-6 alkylene-NR ⁵ R ⁶ , the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl and aralkyl are further optionally replaced by one or more substituents independently selected from the following Substitution: halogen, -OH, oxo, -NH ₂ , -CN, -NO ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl; R ⁵ and R ⁶ are each independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 Member heterocyclyl, C _6-10 aryl, 5-14 member heteroaryl and C _6-12 aralkyl; m is an integer selected from 0, 1, 2, 3 and 4; and n is an integer selected from 0, 1, 2 or 3. The compound of claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound, wherein L is a direct bond, -CH ₂ - or C(=O ). The compound according to claim 1 or 2 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound, wherein R ² is saturated or partially unsaturated C _{3 -10} cycloalkyl or saturated or partially unsaturated 3-10 membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally selected from one or more of -C(=O)R ⁵ and -C(=O ) Substituents of NR ⁵ R ⁶ are substituted. Compounds as claimed in item 3 or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, hydrates or isotope-labeled compounds, wherein R ² is cyclobutanyl, cyclohexane, piperidine Pyridyl or tetrahydropyranyl, optionally substituted by one or more substituents selected from -C(=O)CH ₃ and -C(=O)N(CH ₃ ) ₂ . The compound of claim 1 or 2 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound, wherein -LR ² is selected from

,

,

,

,

and

. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound, wherein ring B is a benzene ring or a thiophene ring. The compound as claimed in item 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound thereof, wherein each occurrence of ^R is independently selected from Halogen, -NH ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl and 5-14 membered heteroaryl, the alkylene, alkyl, cycloalkyl, heterocyclic , aryl and heteroaryl are optionally selected from one or more independently selected from halogen, -OH, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl and 5-14 membered hetero The substituent of the aryl is substituted; when m is greater than 1, the two R ¹ together with the atoms connected to them form a C _3-10 hydrocarbon ring, a 3-10 membered heterocycle, a C _6-10 aromatic ring or a 5- 14-membered heteroaromatic ring, at most 2 ring members in the hydrocarbon ring and heterocycle are C(=O), and the hydrocarbon ring, heterocycle, aromatic ring and heteroaromatic ring are optionally substituted by one or more halogens. The compound as claimed in item 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound thereof, wherein each occurrence of ^R is independently selected from CF ₃ , NH ₂ ,

and

; and m is 1 or 2. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound, wherein

selected from

,

,

and

. The compound according to claim 1 or 2 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound, wherein R ³ is methyl. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound thereof, wherein R ⁴ is H. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound, wherein the compound has the structure of formula (III):

The compound of claim 1 or 2 or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound, wherein the compound is selected from:

A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound as claimed in any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope A labeled compound, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation. A compound as claimed in any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, hydrate or isotope-labeled compound or a pharmaceutical composition as claimed in claim 14 Use in the preparation of a medicament for use as an SOS1 inhibitor. The use according to claim 16, wherein the drug is used to prevent or treat cancer or RAS disease. The use of claim 17, wherein the cancer is selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial Carcinoma, gastric cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma. The use according to claim 17, wherein the cancer is selected from endometrial cancer and cervical cancer. Such as the use of claim 17, wherein the RAS disease is selected from neurofibromatosis type 1 (NF1), Noonan's syndrome (NS), Noonan's syndrome with spots (NSML), capillary malformation- Arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), heart-facial-cutaneous syndrome (CFC), Legers syndrome and hereditary gingival fibromatosis.