TW202229291A - Sos1 inhibitor, pharmaceutical composition comprising same, and use thereof - Google Patents

Abstract

An SOS1 inhibitor of formula (I) or formula (I'), a pharmaceutical composition comprising same, and a use thereof for preventing or treating diseases.

Description

SOS1 inhibitors, pharmaceutical compositions containing the same and uses thereof

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

RAS family proteins are small GTPases encoded by the RAS gene, including KRAS (Kirsten murine sarcoma virus oncogene homolog), HRAS (Harvey murine sarcoma virus oncogene) and NRAS (neuroblastoma RAS virus oncogene homolog) ) and any mutants thereof. Inside the cell, the RAS protein transitions between inactive and activated states, when bound to guanosine diphosphate (GDP), the RAS protein is in an inactive state, when bound to guanosine triphosphate (GTP) , the RAS protein is activated. The intrinsic GTPase activity of RAS protein is weak, and the intrinsic GDP-GTP nucleotide exchange rate is low, and the transition between its inactive and activated states 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 to GDP, inactivating RAS protein; Guanine nucleotide exchange factor (GEF), including SOS1 protein (Son of Sevenless 1), etc., can catalyze Binding of RAS protein to GTP, thereby promoting the initiation 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 initiating a series of downstream effector proteins (including RAF and phosphatidylinositol kinase PI3K, etc.). pathways, thereby regulating a variety of cellular processes such as cell proliferation, survival, metabolism, motility, angiogenesis, immunity, and growth. Mutation of RAS family proteins can inhibit their intrinsic GTPase activity and GAP-induced GTPase activity, resulting in the continuous activation of RAS proteins, which in turn leads to the continuous activation of downstream effector pathways of RAS proteins. RAS is the most frequently mutated oncogene in human cancers. KRAS mutations (such as G12, G13, and Q61, etc.) are widely present in a variety of human cancers, including lung, colorectal, and pancreatic cancer. HRAS mutations and NRAS mutations also appear in in different human cancer types. RAS protein mutation, overexpression and gene amplification are potential mechanisms of resistance to various anticancer drugs (eg, EGFR antibodies cetuximab and panitumumab, EGFR tyrosine kinase inhibitor osimertinib).

The SOS protein was first discovered in Drosophila, and SOS1 is the human homolog of the Drosophila SOS protein. SOS1 protein is a multi-domain protein composed of 1333 amino acids, consisting of N-terminal domain, Dbl homology (DH), Pleckstrin substrate protein homology domain (Pleckstrin homology, PH), Ras exchanger motif (REM), CDC25 homology domain and C-terminal domain are composed of REM and CDC25 homology domain together to form a catalytic functional domain, which is the SOS1 protein to play a guanine nucleotide exchange factor A necessary part of the catalytic function. Studies have shown that SOS1 plays a critical role in the initiation and signal transduction of mutant RAS proteins in RAS-mutated cancers, SOS1 depletion inhibits the survival and proliferation of KRAS-mutant tumor cells, and the catalytic site is re-expressed in SOS1-depleted KRAS-mutant tumor cells. In point mutant SOS1, tumor cells could not resume survival and proliferation, demonstrating that the guanine nucleotide exchange catalytic activity of SOS1 is critical for the survival and proliferation of KRAS mutant tumor cells. In addition to regulating mutant RAS proteins, SOS1 can also participate in the signal initiation and transduction process of tumor cells through other mechanisms. SOS1 can bind to growth factor receptor-binding protein Grb2 to form a SOS1-Grb2 complex, which in turn binds 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 recruited 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 a variety of human cancers and other diseases. Studies have shown that SOS1 mutations are present in embryonal rhabdomyosarcoma, testicular Sertoli cell tumor, granulosa cell tumor of the skin, and lung adenocarcinoma, and overexpression of the SOS1 protein has also been found in bladder and prostate cancers.

SOS2 is the homologue of SOS1 in mammalian cells and also functions as a guanine nucleotide exchange factor. Mouse knockout model studies have shown that germline knockout of SOS1 can cause mouse embryos to die in the second trimester, while adult mice continue to survive after SOS1 knockout. In contrast, SOS2 knockout has no effect on embryos and mature mice. Significant phenotypic changes, while SOS1/2 double-knockout adult mice died rapidly, suggesting that selective targeting of SOS1 may achieve a high therapeutic index for SOS1-regulated RAS-mutant tumors.

Inhibiting the binding of SOS1 catalytic site to RAS protein can block SOS1-mediated RAS protein initiation, thereby inhibiting RAS protein downstream signaling (such as ERK phosphorylation initiation, etc.). SOS1 inhibitors with such a mechanism of action can inhibit mutant RAS. Protein-dependent tumor cells such as KRAS mutant tumor cell lines have inhibitory effects (eg, 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 protein, especially has a significant inhibitory effect on the interaction between SOS1 and KRAS mutant protein, and can be used for 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 (eg, NF1) and SOS1) mutated cancer patients provide pharmacological benefit. In addition, SOS1 inhibitors in RAC1-dependent cancers and other diseases associated with dysregulation of RAS signaling pathway such as neurofibromas, Noonan syndrome (NS), cardio-facial-cutaneous syndrome (CFC) and hereditary gingival type 1 Pharmacological benefits will also be provided in fibroids.

The compounds of the present invention also have better physicochemical properties (eg solubility, physical and/or chemical stability), improved pharmacokinetic properties (eg improved bioavailability, suitable half-life and duration of action), improved better safety properties (lower toxicity and/or fewer side effects, wider therapeutic window), etc.

或

式(I)                                式(I’) 其中： 環A及環B各自獨立地選自C _3-10烴環、3-10員雜環、C _6-10芳環和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，該烴環和雜環中至多2個環成員為C(=O)； R ²、R ²’、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和-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； m為選自0、1、2、3及4的整數；並且 n為選自0、1、2或3的整數。 One aspect of 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 The compound has the structure of formula (I) or formula (I'):

or

Formula (I) Formula (I') wherein: Ring A and Ring B are each independently selected from C _3-10 hydrocarbon rings, 3-10-membered heterocycles, C _6-10 -membered aromatic rings and 5-14-membered heteroaromatic rings, At most 2 ring members in the hydrocarbon ring and heterocycle 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 alkene base, C _2-6 alkynyl, saturated or partially unsaturated C _3-10 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl, at most 2 ring members in the cyclic hydrocarbon group 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 to which it is attached collectively constitutes a _C3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring, a _C6-10 membered aromatic ring or a 5-14 membered heteroaromatic ring, as the case may be, with at most 2 of the hydrocarbon ring and the heterocyclic ring Ring member is C(=O); R ² , R ² ', R ³ and R ⁴ are each independently selected from H, halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6alkane group, -O-(3-10 membered heterocyclyl), 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 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl group , 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 ; The above groups are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: 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 membered 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, cyclohydrocarbyl, heterocyclyl, aryl radical, heteroaryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, _-NH2 , -CN, _-NO2 , _C1-6 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 appear in each are independently selected from H, C _1-6 alkyl group, C _3-10 cyclic hydrocarbon group, 3-10 membered heterocyclic group, C _6-10 aryl group, 5-14 membered heteroaryl group and C _6-12 aryl group alkyl; m is an integer selected from 0, 1, 2, 3, and 4; and n is an integer selected from 0, 1, 2, or 3.

Another aspect of 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, polymorph, solvate, N- Oxides, isotopically-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 pro- 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 pro- A drug or a pharmaceutical composition of the present invention for use as an SOS1 inhibitor.

Another aspect of the present invention provides a method of preventing or treating an SOS1-related disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polyimide thereof Crystalline forms, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the present invention.

definition

Unless otherwise defined hereinafter, all technical and scientific terms used herein are intended to 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 refer to techniques commonly understood in the art, including those variations or substitutions of equivalent techniques to those of ordinary skill in the art to which this invention belongs. While the following terms are believed to be well understood by those of ordinary skill in the art to which this invention pertains, the following definitions are set forth to better explain the invention.

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

As used herein, the term "alkylene" refers to 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 " _C1-6 alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) , 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 (where the group is referred to as a "haloalkyl" _{) (} eg _CH2F , _CHF2 , _CF3 , _CCl3 , _C2F5 , _C2Cl5 , _{CH2CF3 , CH2Cl} or -CH ₂ CH ₂ CF ₃ etc.). The term "C _1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, 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 ("C _2-6 alkenyl"). The alkenyl group 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 pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as 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, decalinyl, etc.)), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group 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 (eg, cyclopropyl, cyclobutyl, cyclopentyl, or cyclopentyl) of 3 to 6 ring carbon atoms hexyl), optionally substituted with 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.

As used herein, the terms "cyclohydrocarbylene", "cyclohydrocarbyl" and "hydrocarbon ring" refer to rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms saturated (ie, "cycloalkylene" and "cycloalkyl") or unsaturated (ie having one or more double and/or triple bonds in the ring) monocyclic or polycyclic (including spirocycles) , fused or bridged systems) hydrocarbon rings including, but not limited to ()cyclopropylidene (ring), ()cyclobutylidene (ring), ()cyclopentylene (ring), ()cyclopentylene Hexyl (ring), ()cycloheptylidene (ring), ()cyclooctyl (ring), ()cyclononyl (ring), ()cyclohexenyl (ring) and the like.

As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" mean having, for example, 3-10 (suitably 3-8, more suitably 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 (ie, heterocycloalkyl) or partially unsaturated (ie, having one or more double bond and/or triple bond) cyclic group. For example, a "3-10 membered (sub)heterocycle (radical)" is one having 2-9 (eg, 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and is independently selected from N A saturated or partially unsaturated (sub)heterocycle (radical) of one or more (eg 1, 2, 3 or 4) heteroatoms of , O and S. Examples of heterocyclylenes and heterocycle(radicals) include, but are not limited to: ()oxiranyl, ()aziridinyl, (azetidinyl), ()oxygenide Heterocyclobutyl (oxetanyl), ()tetrahydrofuranyl, ()dioxolinyl (dioxolinyl), ()pyrrolidine, ()pyrrolidone, ()imidazolidinylene, () ) Pyrazolidine, () Pyrrolidene, () Tetrahydropyranyl, () Piperidinyl, () Morpholinyl, () Dithianyl (dithianyl), () Thiomorpholinyl, ()piperazinylidene or (trithianylidene)trithianyl. The groups also encompass bicyclic ring systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-nitrogen Heterobicyclo[2.2.2]octane, etc.). Heterocyclylene and heterocycle(groups) are 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 pi 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 ()naphthylene (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, _-NO2 , _C1-6 alkyl, etc.). The ()arylene group and the aromatic ring 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 "()heteroarylidene" and "heteroaromatic ring" refer to monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one heteroatom (such as oxygen, nitrogen, etc.) which may be the same or different or sulfur) and, in addition, can be benzo-fused in each case. In particular, "()heteroarylene" or "heteroaromatic ring" is selected from ()thienylene, ()furanyl, ()pyrrolidene, ()oxazolylylene, ()thiazolylylene, ()imidazolylidene, ()pyrazolylidene, ()isoxazolylidene, ()isothiazolylidene, ()oxadiazolylidene, ()triazolylidene, ()thiadiazolylidene etc., and their benzo derivatives; or ()pyridylene, ()pyridazinylene, ()pyrimidinylene, ()pyrazinylene, ()triazinylene, etc., and their benzos derivative. The "()heteroarylidene group" and "heteroaromatic ring" may optionally be combined with another ring (such as a _C3-10 hydrocarbon ring, a 3-10-membered heterocyclic ring, a _C6-10 aromatic ring, or a 5-14-membered ring). Heteroaromatic ring) is fused, and the fused group is, for example,

.

As used herein, the term "aralkyl" preferably refers to 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 in the ring , 12 or 13 carbon atoms and at least one nitrogen atom, which optionally also contains one or more (eg one, two, three or four) selected from N, O, C=O, S, S=O and a ring member of S(=O) ₂ , which is connected to the rest of the molecule through a nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, optionally benzo-fused, and relatively The attachment to the remainder of the molecule is preferably through a nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

The term "substituted" means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the designated group, provided that no more than the designated atom is present at the normal valences in the case and this substitution forms stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form 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 hydrogens present) may be independently selected individually and/or together of optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optional Substituent substitution.

If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, 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.

Unless indicated, as used herein, the point of attachment of a substituent can be from any suitable position on the substituent.

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

The present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass number. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of ^hydrogen (eg, deuterium (2H), tritium ( ^3H )); isotopes of carbon (eg, ^11C , ^13C , ^and14C ) ; isotopes of chlorine (eg ³⁶ Cl); isotopes of fluorine (eg ¹⁸ F); isotopes of iodine (eg ¹²³ I and ¹²⁵ I); isotopes of nitrogen (eg ¹³ N and ¹⁵ N); isotopes of oxygen (eg ¹⁵ O) , ¹⁷ O and ¹⁸ O); isotopes of phosphorus (eg ³² P); and isotopes of sulfur (eg ³⁵ S). Certain isotopically-labeled compounds of the invention (eg, those incorporating radioisotopes) are useful in drug and/or substrate tissue distribution studies (eg, assays). The radioisotopes tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) are particularly useful for this purpose due to their ease of incorporation and ease of detection. Substitution with positron emitting isotopes such ^as11C , ^18F , ^15O , ^and13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. 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 previously employed non-labeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, _D2O , acetone- _d6 , or DMSO- _d6 .

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

), solid wedge (

) or imaginary wedge (

) depict the chemical bonds of the compounds of the present invention. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, racemic mixture, etc.). The use of real or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomer exists. When present in a racemic mixture, real 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 available as stereoisomers (which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereomers).

The present invention encompasses 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 ratio.

It will also be appreciated that certain compounds of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives. 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 After administration, the compounds of the invention or their metabolites or residues can be provided directly or indirectly. Accordingly, references herein to "a compound of the present invention" are also intended to encompass the various derivative forms of the compound described above.

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, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camphorsulphonate, citric acid salt, cyclohexylamine sulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, sea Benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodate/iodide, isethionate, lactate, malate, maleate, malonate acid salt, mesylate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxy Naphthate, Phosphate/Hydrogen Phosphate/Dihydrogen Phosphate, Pyroglutamate, Saccharate, Stearate, Succinate, Tannin, Tartrate, Tosylate, Trifluoroacetate and xinofoate.

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 salts, potassium salts, sodium salts, tromethamine salts and zinc salts.

For a review of suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those of ordinary skill in the art to which the present 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 (which can be hydrolyzed under physiological conditions to release free acid or alcohol forms of the present invention) compound). The compounds of the present invention may themselves also 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 as a structural element of the crystal lattice of the compound, in particular, for example, water, methanol or ethanol. 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 understand 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; The general knowledgeable person will identify 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 the preparation of N- oxides of heterocycles and tertiary amines are well known to those of ordinary skill in the art to which this invention pertains and include 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 e.g.: 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 the body upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like, of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.

The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity when administered into or onto the body can be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compound that are readily converted in vivo to 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 what is known as a "pro-moiety" by those of ordinary skill in the art to which the present invention pertains (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 present invention.

The present invention also encompasses compounds of the present invention that contain protecting groups. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule of interest, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished by conventional protecting groups, such as 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 can be removed at an appropriate subsequent stage using methods known in the art.

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

或

式(I)                                式(I’) 其中： 環A及環B各自獨立地選自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、R ²’、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和-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； m為選自0、1、2、3及4的整數；並且 n為選自0、1、2或3的整數。 In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein the compound has the structure of formula (I) or formula (I'):

or

Formula (I) Formula (I') wherein: Ring A and Ring B are each independently selected from a C _3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C _6-10 membered aromatic ring and a 5-14 membered heteroaromatic ring, At most 2 ring members in the hydrocarbon ring and heterocycle 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 alkene base, C _2-6 alkynyl, saturated or partially unsaturated C _3-10 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl, at most 2 ring members in the cyclic hydrocarbon group 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 to which it is attached collectively form a C _3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C _6-10 membered aromatic ring or a 5-14 membered heteroaromatic ring as the case may be, at most 2 of the hydrocarbon ring and the heterocyclic ring Ring member is C(=O); R ² , R ² ', R ³ and R ⁴ are each independently selected from H, halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6alkane group, -O-(3-10 membered heterocyclyl), 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 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl group , 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 ; The above groups are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: 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 membered 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, cyclohydrocarbyl, heterocyclyl, aryl radical, heteroaryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, _-NH2 , -CN, _-NO2 , _C1-6 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 appear in each are independently selected from H, C _1-6 alkyl group, C _3-10 cyclic hydrocarbon group, 3-10 membered heterocyclic group, C _6-10 aryl group, 5-14 membered heteroaryl group and C _6-12 aryl group alkyl; m is an integer selected from 0, 1, 2, 3, and 4; and n is an integer selected from 0, 1, 2, or 3.

In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein each occurrence of R is independently C _1-6 alkyl or C _1-6 alkylene-OH; preferably, each occurrence of R is independently methyl or -CH ₂ CH ₂ -OH.

為

、

或

；最佳地，

為

、

或

。 In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein Ring A is a 3-10-membered heterocyclic ring or a 5-14-membered heteroaromatic ring, and the heterocyclic or heteroaromatic ring contains one or more ring members selected from -O-, -NR- and -N=; good place,

for

,

or

; optimally,

for

,

or

.

In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein ring B is a bicyclo[1.1.1]pentane ring, a 2-oxabicyclo[2.1.1]hexane ring, a benzene ring or a thiophene ring, preferably a benzene ring or a thiophene ring.

；並且m為1或2。 In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs 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 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl group and 5-14 membered heteroaryl group, The alkylene, alkyl, cyclohydrocarbyl, heterocyclyl, aryl, and heteroaryl groups are optionally one or more independently selected from halogen, -OH, C _3-6 cyclohydrocarbyl, 3-10 membered heterocycle Substituent substitution of C _6-10 aryl group and 5-14-membered heteroaryl group; when m is greater than 1, the two R ¹ together with the atoms to which they are attached 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 with 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 compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof ,in

selected from

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

.

。 In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein R ² and R ² ' are each independently selected from H, -OC _1-6 alkyl and -O-(3-10 membered heterocyclyl); preferably, one of R ² and R ² ' is H, the other is H, -OCH ₃ or

.

In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein R ³ and R ⁴ are each independently selected from H and C _1-6 alkyl; preferably, R ³ is methyl, and R ⁴ is H.

、

、

或

式(II)                         式(III)                          式(IV)                           式(V)。 In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein the compound has the structure of formula (II), formula (III), formula (IV) or formula (V):

,

,

or

Formula (II) Formula (III) Formula (IV) Formula (V).

The present invention encompasses compounds resulting from any combination of the various embodiments.

101a、

101b、

102、

105、

106、

201、

203、

506及

507。 In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein the compound is selected from:

101a,

101b,

102.

105.

106.

201.

203.

506 and

507.

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 compound, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, semi-solid preparation, liquid preparation or Gaseous preparations. In some embodiments, the pharmaceutical composition may further comprise one or more other therapeutic agents.

In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites thereof Or prodrug or use of the pharmaceutical composition of the present invention in the preparation of a medicament for use as an inhibitor of SOS1.

In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites thereof or a prodrug or a pharmaceutical composition of the present invention, which acts as a SOS1 inhibitor.

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

In some embodiments, the SOS1-related disease includes cancer (eg, pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid Leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical 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, renal cancer, and sarcoma), RAS diseases (eg, neurofibromatosis type 1 (NF1), Noonan's syndrome (NS), Noonan's syndrome with multiple spots (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facial-Skin Syndrome (CFC), Leggers Syndrome and Hereditary Gingival Fibromatosis).

"Pharmaceutically acceptable carrier" in the present invention refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or tissue from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present 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 injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerin, propylene glycol, water, Ethanol etc. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as desired. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, 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 present invention may act systemically and/or locally. For this purpose they may be administered by a suitable route, for example by injection (eg intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasal, transmucosal, topical, in the form of ophthalmic formulations or administered by inhalation.

For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.

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

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

The dosing regimen can be adjusted to provide the best 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 noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.

The amount of the compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, effective doses range from about 0.0001 to about 50 mg per kg of body weight per day, eg, from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up 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, dose levels not higher than the lower end of the foregoing ranges may be sufficient, while in other cases larger doses may be employed without causing any deleterious side effects, provided that the larger dose 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, the term "treating", unless otherwise specified, means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term is applied, or one or more symptoms of such disorder or condition Such a disorder or condition or one or more symptoms of such a disorder or condition.

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

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

The present invention is further described below in conjunction with the examples, but these examples are 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 spectrometry (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 nuclear magnetic instrument, and the test solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ) or hexadeuterated dimethyl sulfite (DMSO- d ₆ ). Labeled as tetramethylsilane (TMS).

The measurement of LC-MS was performed on a Shimadzu LC-MS-2020 liquid mass spectrometer (manufacturer: Shimadzu, model: Shimadzu LC-MS-2020).

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

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

The reaction was detected by thin layer chromatography (TLC) or LC-MS, and the developing solvent systems used included dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system. Different polarities adjust the developing agent system (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

Microwave reactions were performed using a BiotageInitiator + (400 W, RT ~ 300°C) microwave reactor.

Column chromatography is generally used in the chemical industry with 200-300 mesh silica gel as the stationary phase. 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 compounds to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.) ).

Unless otherwise specified in the examples, the reaction temperature 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 Bide Pharmaceutical Technology Co., Ltd.

Abbreviations in the present invention have the following meanings: abbreviation meaning ACN Acetonitrile AcOH/ _CH3COOH Acetic acid/acetic acid n-Bu n-butyl Cs ₂ CO ₃ Cesium carbonate DIEA/DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMS Dimethyl sulfate DMSO dimethyl sulfoxide EtOH Ethanol Fe iron HCl hydrochloric acid _HNO3 Nitric acid H ₂ O water H ₂ SO ₄ sulfuric acid IPA/i-PrOH isopropyl alcohol K ₂ CO ₃ Potassium carbonate MeOH methanol N ₂ nitrogen NaBH ₄ Sodium borohydride Na ₂ B ₄ O ₇ Sodium tetraborate _NH4Cl Ammonium chloride _{NH4HCO3 _} Ammonium bicarbonate Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)dipalladium Pd(PPh ₃ ) ₄ Tetrakis(triphenylphosphine)palladium Pd(PPh ₃ ) ₂ Cl ₂ Bis(triphenylphosphine)palladium dichloride POCl ₃ Phosphorus oxychloride rt room temperature t-BuONa Sodium tert-butoxide TEA triethylamine TFA Trifluoroacetate THF tetrahydrofuran Ti(OEt) ₄ Tetraethyl titanate TLC thin layer chromatography

第一步：將 101a-3(0.50 g，2.0 mmol)加入到三氯氧磷(15 mL)中。將反應物加熱至100℃，攪拌10小時，將反應物直接減壓濃縮，將濃縮物溶於二氯甲烷(50 mL)中，用飽和碳酸氫鈉水溶液洗滌(3 x 50 mL)，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓快速矽膠管柱層析法(洗脫劑：乙酸乙酯:石油醚=0-30%)分離純化，得到化合物 101a-4(0.3 g)，其為白色固體。收率57%。ESI-MS: 267 [M+H] ⁺. 第二步：將 101a-4(60 mg，0.2 mmol)溶於異丙醇(4 mL)，加入( R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺鹽酸鹽(81 mg，0.3 mmol)和N,N-二異丙基乙胺(77 mg，0.6 mmol)，將反應液於110℃回流攪拌16小時。將反應物冷卻，減壓濃縮，將濃縮物通過製備TLC (洗脫劑：100%的乙酸乙酯)分離純化，得化合物 101a-5(44 mg)，其為淡黃色固體，收率47%。ESI-MS: 465 [M+H] ⁺. 第三步：將 101a-5(44 mg，0.1 mmol)溶於乙醇(5 mL)和水(2 mL)，加入鐵粉(50 mg，0.9 mmol)和氯化銨(48 mg，2.0 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)-10-甲氧基-2-甲基-7,8-二氫-[1,4]二噁英并[2,3-g]喹唑啉-4-胺(化合物 101a) (14.04 mg)，其為白色固體，收率27%。ESI-MS: 435 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.01 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 6.87 (s, 1H), 6.82 (s, 1H), 6.68 (s, 1H), 5.54-5.48 (m, 3H), 4.39-4.33 (m, 4H), 3.88 (s, 3H), 2.37 (s, 3H), 1.51 (d, J = 8.0 Hz, 3H)。 Example 1 : ( R )-N-(1-(3 - amino -5-( trifluoromethyl ) phenyl ) ethyl )-10 -methoxy- 2- methyl -7,8- di Preparation of Hydro- [1,4] dioxino [2,3-g] quinazolin - 4 - amine ( Compound 101a)

First step: 101a-3 (0.50 g, 2.0 mmol) was added to phosphorus oxychloride (15 mL). The reaction was heated to 100 °C and stirred for 10 hours. The reaction was directly concentrated under reduced pressure, the concentrate was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (3 x 50 mL), and then Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-30%) to obtain Compound 101a-4 (0.3 g) as a white solid. Yield 57%. ESI-MS: 267 [M+H] ⁺ . Second step: Dissolve 101a-4 (60 mg, 0.2 mmol) in isopropanol (4 mL) and add ( R )-1-(3-nitro- 5-(Trifluoromethyl)phenyl)ethan-1-amine hydrochloride (81 mg, 0.3 mmol) and N,N-diisopropylethylamine (77 mg, 0.6 mmol), the reaction solution was added at 110 The mixture was stirred at reflux for 16 hours. The reactant was cooled, concentrated under reduced pressure, and the concentrate was separated and purified by preparative TLC (eluent: 100% ethyl acetate) to obtain compound 101a-5 (44 mg) as a pale yellow solid, yield 47% . ESI-MS: 465 [M+H] ⁺ . Step 3: Dissolve 101a-5 (44 mg, 0.1 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (50 mg, 0.9 mmol) ) and ammonium chloride (48 mg, 2.0 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), and 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)-10-methoxy -2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine (Compound 101a ) (14.04 mg) as a white solid, Yield 27%. ESI-MS: 435 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.01 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 6.87 (s, 1H), 6.82 (s, 1H), 6.68 (s, 1H), 5.54-5.48 (m, 3H), 4.39-4.33 (m, 4H), 3.88 (s, 3H), 2.37 (s, 3H), 1.51 (d, J = 8.0 Hz, 3H).

第一步 ：將四硼酸鈉(30.0 g，78.7 mmol)溶解在水(300 mL)中，加入沒食子酸甲酯(5.0 g, 27.2 mmol)。將反應物在室溫下攪拌1小時。將氫氧化鈉(4.4 g, 110.0 mmol)溶解在水(15 mL)中，室溫下，緩慢滴加至反應液中，滴加完畢後，將反應物在室溫下攪拌15分鐘。0 ℃下，緩慢滴加硫酸二甲酯(13.3 g，105.4 mmol)。將反應物在室溫下攪拌15小時。滴加硫酸至反應液pH值為6。將反應液用二氯甲烷(3 x 200 mL)萃取，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，得到化合物 101b-1(3.6 g)，其為淺黃色油狀物。收率67%。ESI-MS: 199 [M+H] ⁺. 第二步 ：將 101b-1(3.6 g，21.8 mmol)和碳酸鉀(12.0 g，86.8 mmol)溶解在N,N-二甲基甲醯胺(30 mL)中。在室溫攪拌下，緩慢滴加1,2-二溴乙烷(6.1 g，32.5 mmol)。將反應物在室溫下攪拌18小時。將反應液用乙酸乙酯/水(1:1，400 mL)萃取，然後將有機相用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓快速矽膠管柱層析法(洗脫劑：乙酸乙酯:石油醚=0-20%)分離純化，得到化合物 101b-2(2.6 g)，其為白色固體。收率53%。ESI-MS: 225 [M+H] ⁺. 第三步：將 101b-2(2.6 g，11.6 mmol)溶解在醋酸(20 mL)中。在室溫下，緩慢滴加硝酸(68%，10.0 mL)。將反應物加熱至60℃，攪拌10小時。將反應液傾倒至冰水(200 mL)中，然後用乙酸乙酯(2 x 200 mL)萃取，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓快速矽膠管柱層析法(洗脫劑：乙酸乙酯:石油醚=0-20%)分離純化，得到化合物 101a-1和 101b-3混合物 (2.0 g)，其為淺黃色固體。收率64%。ESI-MS: 270 [M+H] ⁺. 第四步：將 101a-1和 101b-3混合物(2.0 g，7.4 mmol)溶解在乙醇/水(20 mL/20 mL)中。在室溫攪拌下，加入鐵粉(100目，2.3 g，41 mmol)和氯化銨(2.2 g，41 mmol)，加熱至90℃，攪拌8小時。將反應物冷卻，通過矽藻土過濾，將濾餅用乙酸乙酯(50 mL)洗滌，將濾液減壓濃縮，用乙酸乙酯/水(1:1，200 mL)萃取，然後將有機相用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓快速矽膠管柱層析法(洗脫劑：乙酸乙酯:石油醚=0-30%)分離純化，得到化合物 101a-2和 101b-4混合物(1.4 g)，其為淺黃色固體。收率79%。ESI-MS: 240 [M+H] ⁺. 第五步：將 101a-2和 101b-4混合物(1.4 g，5.8 mmol)加入到乙腈(30 mL)中。在室溫攪拌下，加入鹽酸的二氧六環溶液(4N, 25 mL)。將反應物加熱至90℃，攪拌6小時，產生大量固體。將反應物冷卻，過濾，將濾餅用水(20 mL)洗滌，烘乾。得到化合物 101b-5(0.49 g)，其為淺黃色固體。收率34%。ESI-MS: 249 [M+H] ⁺. 將濾液減壓濃縮，濃縮物經反相色譜純化得到化合物 101a-3(0.50 g)，其為類白色固體。收率34.5%。ESI-MS: 249 [M+H] ⁺. 第六步：將 101b-5(0.49 g，2.0 mmol)加入到三氯氧磷(15 mL)中。將反應物加熱至100℃，攪拌10小時，將反應物直接減壓濃縮，將濃縮物溶於二氯甲烷(50 mL)中，用飽和碳酸氫鈉水溶液洗滌(3 x 50 mL)，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓快速矽膠管柱層析法(洗脫劑：乙酸乙酯:石油醚=0-30%)分離純化，得到化合物 101b-6(0.34 g)為白色固體。收率64%。ESI-MS: 267 [M+H] ⁺. 第七步：將 101b-6(60 mg，0.2 mmol)溶於異丙醇(4 mL)，加入( R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺鹽酸鹽(81 mg，0.3 mmol)和N,N-二異丙基乙胺(77 mg，0.6 mmol)，將反應液於110℃回流攪拌16小時。將反應物冷卻，減壓濃縮，將濃縮物通過製備TLC (洗脫劑：100%的乙酸乙酯)分離純化，得化合物 101b-7(40 mg)，其為淡黃色固體，收率43%。ESI-MS: 465 [M+H] ⁺. 第八步：將 101b-7(40 mg，0.1 mmol)溶於乙醇(5 mL)和水(2 mL)，加入鐵粉(50 mg，0.9 mmol)和氯化銨(48 mg，2.0 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-甲氧基-2-甲基-8,9-二氫-[1,4]二噁英并[2,3- h]喹唑啉-4-胺(化合物 101b) (10.11 mg)，其為白色固體，收率26%。ESI-MS: 435 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 7.96 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 6.87 (s, 1H), 6.84 (s, 1H), 6.69 (s, 1H), 5.59-5.51 (m, 3H), 4.32-4.31 (m, 4H), 3.89 (s, 3H), 2.35 (s, 3H), 1.54 (d, J = 8.0 Hz, 3H)。 Example 2 : ( R )-N-(1-(3 - amino -5-( trifluoromethyl ) phenyl ) ethyl )-6- methoxy- 2- methyl- 8,9 -di Preparation of Hydro- [1,4] dioxino [2,3 - h ] quinazolin- 4 - amine ( Compound 101b)

First step : Sodium tetraborate (30.0 g, 78.7 mmol) was dissolved in water (300 mL) and methyl gallate (5.0 g, 27.2 mmol) was added. The reaction was stirred at room temperature for 1 hour. Sodium hydroxide (4.4 g, 110.0 mmol) was dissolved in water (15 mL), and slowly added dropwise to the reaction solution at room temperature. After the dropwise addition, the reaction was stirred at room temperature for 15 minutes. At 0 °C, dimethyl sulfate (13.3 g, 105.4 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 15 hours. Sulfuric acid was added dropwise until the pH value of the reaction solution was 6. The reaction solution was extracted with dichloromethane (3 x 200 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 101b-1 (3.6 g) as a pale yellow oil . Yield 67%. ESI-MS: 199 [M+H] ⁺ . Second step : 101b-1 (3.6 g, 21.8 mmol) and potassium carbonate (12.0 g, 86.8 mmol) were dissolved in N,N-dimethylformamide ( 30 mL). 1,2-Dibromoethane (6.1 g, 32.5 mmol) was slowly added dropwise with stirring at room temperature. The reaction was stirred at room temperature for 18 hours. The reaction solution was extracted with ethyl acetate/water (1:1, 400 mL), then the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was passed through a medium pressure fast silica gel column. Chromatography (eluent: ethyl acetate: petroleum ether=0-20%) was separated and purified to obtain compound 101b-2 (2.6 g) as a white solid. Yield 53%. ESI-MS: 225 [M+H] ⁺ . Third step: Dissolve 101b-2 (2.6 g, 11.6 mmol) in acetic acid (20 mL). Nitric acid (68%, 10.0 mL) was slowly added dropwise at room temperature. The reaction was heated to 60°C and stirred for 10 hours. The reaction solution was poured into ice water (200 mL), then extracted with ethyl acetate (2 x 200 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to medium pressure Separation and purification by flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-20%) gave a mixture of compounds 101a-1 and 101b-3 (2.0 g) as a pale yellow solid. Yield 64%. ESI-MS: 270 [M+H] ⁺ . Fourth step: A mixture of 101a-1 and 101b-3 (2.0 g, 7.4 mmol) was dissolved in ethanol/water (20 mL/20 mL). Under stirring at room temperature, iron powder (100 mesh, 2.3 g, 41 mmol) and ammonium chloride (2.2 g, 41 mmol) were added, heated to 90° C., and stirred for 8 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethyl acetate (50 mL), the filtrate was concentrated under reduced pressure, extracted with ethyl acetate/water (1:1, 200 mL), and the organic phase was then Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-30%), A mixture of compounds 101a-2 and 101b-4 (1.4 g) was obtained as a pale yellow solid. Yield 79%. ESI-MS: 240 [M+H] ⁺ . Fifth step: A mixture of 101a-2 and 101b-4 (1.4 g, 5.8 mmol) was added to acetonitrile (30 mL). With stirring at room temperature, hydrochloric acid in dioxane (4N, 25 mL) was added. The reaction was heated to 90°C and stirred for 6 hours, resulting in a large amount of solid. The reaction was cooled, filtered, and the filter cake was washed with water (20 mL) and dried. Compound 101b-5 (0.49 g) was obtained as a pale yellow solid. Yield 34%. ESI-MS: 249 [M+H] ⁺ . The filtrate was concentrated under reduced pressure, and the concentrate was purified by reverse phase chromatography to give compound 101a-3 (0.50 g) as an off-white solid. Yield 34.5%. ESI-MS: 249 [M+H] ⁺ . Sixth step: 101b-5 (0.49 g, 2.0 mmol) was added to phosphorus oxychloride (15 mL). The reaction was heated to 100 °C and stirred for 10 hours. The reaction was directly concentrated under reduced pressure, the concentrate was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (3 x 50 mL), and then Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-30%) to obtain Compound 101b-6 (0.34 g) was a white solid. Yield 64%. ESI-MS: 267 [M+H] ⁺ . Seventh step: Dissolve 101b-6 (60 mg, 0.2 mmol) in isopropanol (4 mL) and add ( R )-1-(3-nitro- 5-(Trifluoromethyl)phenyl)ethan-1-amine hydrochloride (81 mg, 0.3 mmol) and N,N-diisopropylethylamine (77 mg, 0.6 mmol), the reaction solution was added at 110 The mixture was stirred at reflux for 16 hours. The reactant was cooled, concentrated under reduced pressure, and the concentrate was separated and purified by preparative TLC (eluent: 100% ethyl acetate) to obtain compound 101b-7 (40 mg) as a pale yellow solid, yield 43% . ESI-MS: 465 [M+H] ⁺ . Step 8: Dissolve 101b-7 (40 mg, 0.1 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (50 mg, 0.9 mmol) ) and ammonium chloride (48 mg, 2.0 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), and 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-methoxy -2-methyl-8,9-dihydro-[1,4]dioxino[2,3- h ]quinazolin-4-amine (compound 101b ) (10.11 mg) as a white solid, Yield 26%. ESI-MS: 435 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 7.96 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 6.87 (s, 1H), 6.84 (s, 1H), 6.69 (s, 1H), 5.59-5.51 (m, 3H), 4.32-4.31 (m, 4H), 3.89 (s, 3H), 2.35 (s, 3H), 1.54 (d, J = 8.0 Hz, 3H).

第一步 ：將沒食子酸甲酯(20 g，106.61 mmol)溶解在N,N-二甲基甲醯胺(100 mL)中，加入1,2-二溴乙烷(30.6 g, 162.91 mmol)和碳酸鉀(30 g，217.22 mmol)。將反應物在90℃下攪拌10h，冷卻過濾，將濾餅用乙酸乙酯(100 mL)洗滌，向濾液中加入水，分液，將水相用乙酸乙酯(3 x 100 mL)萃取，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓快速矽膠管柱層析法(洗脫劑：乙酸乙酯:石油醚=30-60%)分離純化，得到化合物 102-1(12.24 g)，其為類白色固體。收率54%。ESI-MS: 211 [M+H] ⁺. 第二步 ：將 1 02 -1(10 g，47.62 mmol)、( R)-四氫呋喃-3-基4-甲基苯磺酸酯(13.9 g，57.14 mmol)和碳酸銫(23.3g，71.43 mmol)溶解在N,N-二甲基甲醯胺(80 mL)中，在60℃下攪拌3小時。將反應物冷卻，通過矽藻土過濾，將濾餅用乙酸乙酯(100 mL)洗滌，向濾液中加入水，分液，將水相用乙酸乙酯(3 x 100 mL)萃取，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物用乙酸乙酯打漿純化，得到化合物 102-2(8.9 g)，其為類白色固體。收率67%。ESI-MS: 281 [M+H] ⁺. 第三步：將 102-2(3 g，10.71 mmol)溶解在冰乙酸(15 mL)。在室溫下，緩慢滴加硝酸(3 ml)，升溫至60℃，攪拌10小時。將反應物冷卻，然後倒入水中，用二氯甲烷(3 x 50 mL)萃取，水洗，飽和碳酸氫鈉水溶液洗，無水硫酸鈉乾燥，過濾，濃縮，得到化合物 102-3(3.3 g)，其為棕色油狀物。收率94%。ESI-MS: 326 [M+H] ⁺. 第四步：將 102-3(3.3g，10.02 mmol)溶解在乙醇(25 ml)中，在室溫攪拌下，加入鐵粉(100目，5.2 g，100.22 mmol)、氯化銨(5.4 g，100.22 mmol)和水(25 ml)，將反應物在90℃下攪拌2小時。將反應物冷卻，通過矽藻土過濾，將濾餅用乙醇(100 mL)和乙酸乙酯(100 mL)洗滌，將濾液減壓濃縮，剩餘水相用乙酸乙酯(3 x 100 mL)萃取，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，得到化合物 102-4(3.7g，粗品)，其為棕色固體。ESI-MS: 296 [M+H] ⁺. 第五步：N ₂氛圍下，將 102-4 (3.7 g)、鹽酸的二氧六環溶液(4M)(20 ml)溶解在乙腈(20 mL)中。將反應物在室溫下攪拌2h，升溫至90℃下攪拌10h。將反應物冷卻，過濾，二氧六環淋洗，將濾餅用水溶解，飽和碳酸氫鈉溶液調節至中性，乙酸乙酯萃取(3 x 50 mL)，濃縮後用中壓快速矽膠管柱層析法(洗脫劑：二氯甲烷:甲醇=0-20%)分離純化，得到化合物 102-5(1g)，其為類白色固體。兩步的總收率為33%。ESI-MS: 305 [M+H] ⁺. 第六步：將 102-5 (120 mg，0.39 mmol)溶解在三氯氧磷(3 ml)中。將反應物加熱至100℃，攪拌4小時。體系減壓濃縮後用二氯甲烷(20 ml)稀釋後，滴加到冷的飽和碳酸氫鈉溶液中，分液，將水相用二氯甲烷(3x 20 mL)萃取，合併有機相，無水硫酸鈉乾燥，濃縮，中壓快速矽膠管柱層析法(洗脫劑：二氯甲烷:甲醇=0-20%)分離純化，得到化合物 102-6(50 mg)，其為淺棕色固體。收率40%。ESI-MS: 323 [M+H] ⁺. 第七步：將 102-6(50 mg，0.16 mmol)、( R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺鹽酸鹽(44 mg，0.16 mmol)溶解在異丙醇(2 mL)中，滴加N,N-二異丙基乙胺(103 mg，0.8 mmol)，110℃回流反應10h。將反應物冷卻、濃縮，加入水和乙酸乙酯，分液，乙酸乙酯(3 x 20 mL)萃取，將有機相用無水硫酸鈉乾燥，濃縮，中壓快速矽膠管柱層析法(洗脫劑：二氯甲烷:甲醇=0-20%)分離純化，得到化合物 102-7(44 mg)，其為白色固體。收率53%。ESI-MS: 521 [M+H] ⁺ 第八步：將 102-7(44 mg，0.084 mmol)溶解在乙醇(2 ml)中，在室溫攪拌下，加入鐵粉(100目，47 mg，0.85 mmol)、氯化銨(45g，0.85 mmol)和水(2 ml)，將反應物在90℃下攪拌2小時。將反應物冷卻，通過矽藻土過濾，將濾餅用乙醇(100 mL)和乙酸乙酯(100 mL)洗滌，將濾液減壓濃縮，剩餘水相用乙酸乙酯(3 x 100 mL)萃取，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，濃縮物用二甲基亞碸(2 mL)溶解後，用C18逆相層析管柱進行純化(洗脫劑：ACN:5 mmol/L NH ₄HCO ₃水溶液=0-40%)。凍乾得到 N-(( R)-1-(3-胺基-5-(三氟甲基)苯基)乙基)-2-甲基-6-(((S)-四氫呋喃-3-基)氧基)-8,9-二氫-[1,4]二噁英并[2,3- h]喹唑啉-4-胺(16 mg)，其為白色固體。收率39%。ESI-MS: 491 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆)：δ 7.89 (s, 1H), 7.29 (s, 1H), 6.82 (s, 2H), 6.65 (s, 1H), 5.52 (s, 3H), 5.12 (s, 1H), 4.29 (s, 4H), 3.93 (d, J= 8.1 Hz, 1H), 3.87-3.75 (m, 3H), 2.31 (s, 3H), 2.25 (td, J= 8.0, 6.0 Hz, 1H), 2.03-1.95 (m, 1H), 1.50 (d, J= 6.0 Hz, 3H)。 Example 3 : N -(( R )-1-(3- amino -5-( trifluoromethyl ) phenyl ) ethyl )-2- methyl- 6-(((S) -tetrahydrofuran -3 Preparation of -yl ) oxy ) -8,9 -dihydro- [1,4] dioxino [2,3- h ] quinazolin- 4 - amine ( compound 102a)

Step 1: Dissolve methyl gallate (20 g, 106.61 mmol) in N,N-dimethylformamide (100 mL), add 1,2-dibromoethane (30.6 g, 162.91 mmol) and potassium carbonate (30 g, 217.22 mmol). The reactant was stirred at 90 °C for 10 h, cooled and filtered, the filter cake was washed with ethyl acetate (100 mL), water was added to the filtrate, the layers were separated, and the aqueous phase was extracted with ethyl acetate (3 x 100 mL), Then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure fast silica gel column chromatography (eluent: ethyl acetate: petroleum ether=30-60%). to give compound 102-1 (12.24 g) as an off-white solid. Yield 54%. ESI-MS: 211 [M+H] ⁺ . Second step : 102-1 (10 g, 47.62 mmol), ( R )-tetrahydrofuran- 3 - yl 4-methylbenzenesulfonate (13.9 g, 57.14 mmol) and cesium carbonate (23.3 g, 71.43 mmol) were dissolved in N,N-dimethylformamide (80 mL) and stirred at 60°C for 3 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethyl acetate (100 mL), water was added to the filtrate, the layers were separated, the aqueous phase was extracted with ethyl acetate (3 x 100 mL), and the Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was purified by beating with ethyl acetate to obtain compound 102-2 (8.9 g) as an off-white solid. Yield 67%. ESI-MS: 281 [M+H] ⁺ . Third step: 102-2 (3 g, 10.71 mmol) was dissolved in glacial acetic acid (15 mL). At room temperature, nitric acid (3 ml) was slowly added dropwise, the temperature was raised to 60°C, and the mixture was stirred for 10 hours. The reaction was cooled, then poured into water, extracted with dichloromethane (3 x 50 mL), washed with water, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 102-3 (3.3 g), It was a brown oil. Yield 94%. ESI-MS: 326 [M+H] ⁺ . Fourth step: Dissolve 102-3 (3.3 g, 10.02 mmol) in ethanol (25 ml), add iron powder (100 mesh, 5.2 g, 100.22 mmol), ammonium chloride (5.4 g, 100.22 mmol) and water (25 ml), the reaction was stirred at 90 °C for 2 h. The reaction was cooled, filtered through celite, the filter cake was washed with ethanol (100 mL) and ethyl acetate (100 mL), the filtrate was concentrated under reduced pressure, and the remaining aqueous phase was extracted with ethyl acetate (3 x 100 mL). , washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 102-4 (3.7 g, crude product) as a brown solid. ESI-MS: 296 [M+H] ⁺ . Fifth step: 102-4 ( 3.7 g), hydrochloric acid in dioxane (4M) (20 ml) was dissolved in acetonitrile ( ₂₀ mL) under N atmosphere )middle. The reaction was stirred at room temperature for 2 h, then warmed to 90 °C and stirred for 10 h. The reactant was cooled, filtered, rinsed with dioxane, the filter cake was dissolved in water, the saturated sodium bicarbonate solution was adjusted to neutrality, extracted with ethyl acetate (3 x 50 mL), concentrated and concentrated with a medium pressure fast silica gel column Chromatography (eluent: dichloromethane: methanol = 0-20%) was separated and purified to obtain compound 102-5 (1 g) as an off-white solid. The overall yield for the two steps was 33%. ESI-MS: 305 [M+H] ⁺ . Sixth step: 102-5 ( 120 mg, 0.39 mmol) was dissolved in phosphorus oxychloride (3 ml). The reaction was heated to 100°C and stirred for 4 hours. The system was concentrated under reduced pressure, diluted with dichloromethane (20 ml), added dropwise to a cold saturated sodium bicarbonate solution, separated, the aqueous phase was extracted with dichloromethane (3 x 20 mL), the organic phases were combined and anhydrous Dry over sodium sulfate, concentrate, and separate and purify by medium pressure flash silica gel column chromatography (eluent: dichloromethane: methanol = 0-20%) to obtain compound 102-6 (50 mg) as a light brown solid. Yield 40%. ESI-MS: 323 [M+H] ⁺ . Seventh step: 102-6 (50 mg, 0.16 mmol), ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl ) Ethane-1-amine hydrochloride (44 mg, 0.16 mmol) was dissolved in isopropanol (2 mL), N,N-diisopropylethylamine (103 mg, 0.8 mmol) was added dropwise, and refluxed at 110 °C Reaction for 10h. The reaction was cooled, concentrated, water and ethyl acetate were added, the layers were separated, extracted with ethyl acetate (3 x 20 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to medium pressure flash silica gel column chromatography (washed). Removal agent: dichloromethane: methanol = 0-20%) was separated and purified to obtain compound 102-7 (44 mg) as a white solid. Yield 53%. ESI-MS: 521 [M+H] ⁺ Step 8: Dissolve 102-7 (44 mg, 0.084 mmol) in ethanol (2 ml), add iron powder (100 mesh, 47 mg) under stirring at room temperature , 0.85 mmol), ammonium chloride (45 g, 0.85 mmol) and water (2 ml) and the reaction was stirred at 90 °C for 2 h. The reaction was cooled, filtered through celite, the filter cake was washed with ethanol (100 mL) and ethyl acetate (100 mL), the filtrate was concentrated under reduced pressure, and the remaining aqueous phase was extracted with ethyl acetate (3 x 100 mL). , washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was dissolved in dimethylsulfite (2 mL), and purified by C18 reverse phase chromatography column (eluent: ACN : 5 mmol/L NH ₄ HCO ₃ aqueous solution = 0-40%). Lyophilization to give N -(( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-3- (yl)oxy)-8,9-dihydro-[1,4]dioxino[2,3- h ]quinazolin-4-amine (16 mg) as a white solid. Yield 39%. ESI-MS: 491 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 7.89 (s, 1H), 7.29 (s, 1H), 6.82 (s, 2H), 6.65 (s, 1H), 5.52 (s, 3H), 5.12 (s, 1H), 4.29 (s, 4H), 3.93 (d, J = 8.1 Hz, 1H), 3.87-3.75 (m, 3H), 2.31 (s, 3H), 2.25 (td, J = 8.0, 6.0 Hz, 1H), 2.03-1.95 (m, 1H), 1.50 (d, J = 6.0 Hz, 3H).

第一步 ：將 101b-6(110 mg，0.41 mmol)和( R)-1-(5-溴噻吩-2-基)乙-1-胺鹽酸鹽(110 mg，0.49 mmol)溶解在二甲基亞碸(1 mL)中，滴加N,N-二異丙基乙胺(265 mg，2.05 mmol)，升溫至150℃下攪拌10h。將反應物冷卻、濃縮，加入水和乙酸乙酯，分液，乙酸乙酯(3x 20 mL)萃取，將有機相用無水硫酸鈉乾燥，濃縮，將所得粗品用二甲基亞碸(2 mL)溶解後，用C18逆相層析管柱柱進行純化(洗脫劑：ACN: 5 mmol/L NH ₄HCO ₃水溶液=0-40%)，得到化合物 105-1(100 mg)，其為白色固體。收率67%。ESI-MS: 437 [M+H] ⁺ 第二步：氮氣保護下，將 105-1(100 mg，0.23 mmol)、(2-((二甲基胺基)甲基)苯基)硼酸(82 mg，0.46 mmol)和碳酸鉀(96 mg，0.69 mmol)溶於二氧六環和水(5:1)的混合溶液(3 ml)，加入四(三苯基膦)鈀(27 mg，0.02 mmol)，100℃下攪拌10h，將反應物冷卻、濃縮，加入水10 ml，用乙酸乙酯(3x 20 mL)萃取，將有機相用無水硫酸鈉乾燥，濃縮，將所得粗製品用N,N-二甲基甲醯胺(2 mL)溶解後，用C18逆相層析管柱進行純化(洗脫劑：ACN:5 mmol/L NH ₄HCO ₃水溶液=40-60%)，將目標流分濃縮，凍乾，得到( R)- N-(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-6-甲氧基-2-甲基-8,9-二氫-[1,4]二噁英并[2,3- h]喹唑啉-4-胺(25 mg)，收率22%。ESI-MS: 491 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (d, J = 8.3 Hz, 1H), 7.45-7.41 (m, 1H), 7.39-7.35 (m, 1H), 7.34-7.27 (m, 3H), 7.18 (d, J = 3.6 Hz, 1H), 7.07 (d, J = 3.7, 1.1 Hz, 1H), 5.96 (t, J = 7.3 Hz, 1H), 4.31 (s, 4H), 3.86 (s, 3H), 3.34 (s, 2H), 2.43 (s, 3H), 2.11 (s, 6H), 1.71 (d, J = 6.9 Hz, 3H)。 Example 4 : ( R )-N-(1-(5-(2-( ( dimethylamino ) methyl ) phenyl ) thiophen -2- yl ) ethyl )-6- methoxy- 2 - Preparation of methyl- 8,9 -dihydro- [1,4] dioxino [2,3- h ] quinazolin- 4 - amine ( compound 105)

Step 1: Dissolve 101b-6 (110 mg, 0.41 mmol) and ( R )-1-(5-bromothiophen-2-yl)ethan-1-amine hydrochloride (110 mg, 0.49 mmol) in two N,N-diisopropylethylamine (265 mg, 2.05 mmol) was added dropwise to methyl sulfite (1 mL), and the temperature was raised to 150 °C and stirred for 10 h. The reaction was cooled, concentrated, water and ethyl acetate were added, the layers were separated, extracted with ethyl acetate (3×20 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the obtained crude product was washed with dimethylsulfite (2 mL). ) was dissolved, and purified with a C18 reverse phase chromatography column (eluent: ACN: 5 mmol/L NH ₄ HCO ₃ aqueous solution=0-40%) to obtain compound 105-1 (100 mg), which was White solid. Yield 67%. ESI-MS: 437 [M+H] ⁺ Second step: under nitrogen protection, 105-1 (100 mg, 0.23 mmol), (2-((dimethylamino)methyl)phenyl)boronic acid ( 82 mg, 0.46 mmol) and potassium carbonate (96 mg, 0.69 mmol) were dissolved in a mixed solution (3 ml) of dioxane and water (5:1), and tetrakis(triphenylphosphine)palladium (27 mg, 0.02 mmol), stirred at 100 °C for 10 h, cooled and concentrated the reactant, added 10 ml of water, extracted with ethyl acetate (3 x 20 mL), dried the organic phase with anhydrous sodium sulfate, concentrated, and the obtained crude product was washed with N , N-dimethylformamide (2 mL) was dissolved, and purified with a C18 reverse phase chromatography column (eluent: ACN: 5 mmol/L NH ₄ HCO ₃ aqueous solution=40-60%), the The target fractions were concentrated and lyophilized to give ( R )-N-(1-(5-(2-(( dimethylamino )methyl)phenyl)thiophen-2-yl)ethyl)-6- Methoxy-2-methyl-8,9-dihydro-[1,4]dioxino[2,3- h ]quinazolin-4-amine (25 mg), 22% yield. ESI-MS: 491 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (d, J = 8.3 Hz, 1H), 7.45-7.41 (m, 1H), 7.39-7.35 (m, 1H), 7.34-7.27 (m, 3H), 7.18 (d, J = 3.6 Hz, 1H), 7.07 (d, J = 3.7, 1.1 Hz, 1H), 5.96 (t, J = 7.3 Hz, 1H), 4.31 (s, 4H), 3.86 ( s, 3H), 3.34 (s, 2H), 2.43 (s, 3H), 2.11 (s, 6H), 1.71 (d, J = 6.9 Hz, 3H).

將 101b-6(100 mg，0.37 mmol)和( R)-1-(3-(三氟甲基)苯基)乙-1-胺鹽酸鹽(84 mg，0.37 mmol)溶解在異丙醇(4 mL)中，滴加N,N-二異丙基乙胺(480 mg，3.74 mmol)，升溫至回流反應10h。將反應物冷卻、濃縮，加入水和乙酸乙酯，分液，乙酸乙酯(3x 20 mL)萃取，將有機相用無水硫酸鈉乾燥，濃縮，將所得粗製品用二甲基亞碸(2 mL)溶解後，用C18逆相層析管柱進行純化(洗脫劑：ACN: 5 mmol/L NH ₄HCO ₃水溶液=0-40%)。凍乾得到標題化合物(28 mg)，其為白色固體。收率18%。ESI-MS: 420 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ )：δ 8.01 (s, 1H), 7.76 (s, 1H), 7.71 (s, 1H), 7.54 (s, 2H), 7.35 (s, 1H), 5.69-5.62 (m, 1H), 4.32 (s, 4H), 3.91 (s, 3H), 2.29 (s, 3H), 1.62 (d, J= 6.8 Hz, 3H)。 Example 5 : ( R )-6- Methoxy- 2- methyl - N- (1-(3-( trifluoromethyl ) phenyl ) ethyl )-8,9 -dihydro- [1, 4] Preparation of Dioxino [2,3- h ] quinazolin- 4 - amine ( Compound 106)

101b-6 (100 mg, 0.37 mmol) and ( R )-1-(3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (84 mg, 0.37 mmol) were dissolved in isopropanol (4 mL), N,N-diisopropylethylamine (480 mg, 3.74 mmol) was added dropwise, and the temperature was raised to reflux for 10 h. The reactant was cooled, concentrated, water and ethyl acetate were added, the layers were separated, extracted with ethyl acetate (3×20 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the obtained crude product was washed with dimethylsulfite (2 mL) was dissolved, and purified with a C18 reverse phase chromatography column (eluent: ACN: 5 mmol/L NH ₄ HCO ₃ aqueous solution=0-40%). Lyophilization gave the title compound (28 mg) as a white solid. Yield 18%. ESI-MS: 420 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ): δ 8.01 (s, 1H), 7.76 (s, 1H), 7.71 (s, 1H), 7.54 (s, 2H), 7.35 (s, 1H), 5.69-5.62 (m, 1H), 4.32 (s, 4H), 3.91 (s, 3H), 2.29 (s, 3H), 1.62 (d, J= 6.8 Hz, 3H).

第一步 ：1-溴-3-硝基-5-(三氟甲基)苯(20.0 g，74.1 mmol)溶解在二氧六環(300 mL)中，加入三丁基(1-乙氧基乙烯基)錫(32.1 g，88.9 mmol)、三乙胺(15.0 g，148.5 mmol)和Pd(PPh ₃) ₂Cl ₂(2.6 g, 3.7 mmol)，氮氣保護下80℃攪拌16小時。將反應物冷卻，向體系中加入鹽酸(4M)(20 mL)，室溫攪拌2小時，體系減壓濃縮，加水稀釋(100 mL)，乙酸乙酯萃取(2 x 100 mL)，將有機相減壓濃縮，將濃縮物通過管柱層析法(乙酸乙酯:石油醚=0-30%)分離純化，得到化合物 201-1(13.0 g)，其為淡黃色油狀物，收率75%。ESI-MS: 234 [M+H] ⁺. 第二步：將 201-1 (10.0 g，42.9 mmol)溶於四氫呋喃(150 mL)，加入( R)-2-甲基丙烷-2-亞磺醯胺(6.23 g，51.5 mmol)和鈦酸四乙酯(19.6 g，86.0 mmol)，回流反應8小時。將反應液冷卻，倒入水中，生成白色沉澱物，過濾去除，將濾餅用乙酸乙酯洗滌，濾液用乙酸乙酯萃取(2 x 100 mL)，將有機相減壓濃縮，將濃縮物通過管柱層析法(乙酸乙酯:石油醚=0-40%)分離純化，得到化合物 201-2(12.9 g)，其為淡黃色油狀物，收率90%。ESI-MS: 337 [M+H] ⁺. 第三步：將 201-2(12.9 g, 38.4 mmol)溶於四氫呋喃(150 mL)，-78℃下加入硼氫化鈉(2.6 g，69.1 mmol)，反應液緩慢升到室溫，TLC監控原料反應完全。加水淬冷反應，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(乙酸乙酯:石油醚=0-40%)分離純化，得到化合物 201-3，其為淡黃色固體，收率65%。ESI-MS: 339 [M+H] ⁺. 第四步：將 201-3(8.5 g，25.1 mmol)溶於二氧六環(100 mL)中，加入鹽酸(4M，二氧六環中的溶液)(15 mL)，將反應液在室溫下攪拌，TLC監控原料反應完全，過濾，將濾餅用乙酸乙酯洗滌，將產物烘乾，得化合物 201-4(5.3 g)，其為白色固體，收率78%。ESI-MS: 235 [M+H] ⁺. 第五步：將2,3-二氫苯并[ b][1,4]二噁英-6-羧酸甲酯(10.0 g，51.5 mmol)溶於醋酸(30 mL)，冰水浴下加入濃硝酸(8 mL)，將反應液於70℃下攪拌6小時。將反應物冷卻，並倒入冰水中，有固體生成，過濾，將濾餅用水洗滌，真空乾燥，得化合物 201-5(10.1 g)，其為淡黃色固體，收率(82%)。ESI-MS: 240 [M+H] ⁺. 第六步：將 201-5(2.2 g，9.2 mmol)溶於乙醇(15 mL)和水(4 mL)，加入鐵粉(5.2 g，92.1 mmol)和氯化銨(4.9 g，92.1 mmol)，將反應液於90℃下攪拌3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 20 mL)，將有機相減壓濃縮，得化合物 201-6(1.8 g)，其為棕色固體，收率94%。ESI-MS: 210 [M+H] ⁺. 第七步：將 201-6(1.8 g，8.6 mmol)溶於乙腈(15 mL)中，滴加濃鹽酸至固體全部溶解，然後將反應液於80℃攪拌16小時。將反應物冷卻，將生成的沉澱物過濾，將濾餅用乙腈洗滌，乾燥，得到化合物 201-7(460 mg)，其為白色固體，收率26%。ESI-MS: 219 [M+H] ⁺. 第八步：將 201-7(460 mg，2.1 mmol)溶於三氯氧磷(15 mL)中，將反應液於100℃攪拌4小時。將反應物冷卻，減壓濃縮，將粗產物用二氯甲烷溶解，將有機相用飽和碳酸氫鈉溶液洗滌，減壓濃縮，得化合物 201-8(350 mg)，其為黃色固體，收率71%。ESI-MS: 237 [M+H] ⁺. 第九步：將 201-8(120 mg，0.5 mmol)溶於異丙醇(4 mL)，加入( R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺鹽酸鹽( 1-4)(177 mg，0.7 mmol)和N,N-二異丙基乙胺(194 mg，1.5 mmol)，回流反應6小時。將反應物冷卻，減壓濃縮，將濃縮物通過管柱層析法(甲醇:二氯甲烷=0-10%)分離純化，得化合物 201-9(70 mg)，收率32%。ESI-MS: 435 [M+H] ⁺. 第十步：將 201-9(70 mg，0.2 mmol)溶於乙醇(6 mL)和水(2 mL)，加入鐵粉(112 mg，2.0 mmol)和氯化銨(107 mg，2.0 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-7,8-二氫-[1,4]二噁英并[2,3-g]喹唑啉-4-胺(26.7 mg)，其為白色固體，收率41%。ESI-MS: 405 [M+H] ⁺ 。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 7.96 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 6.83 (s, 1H), 6.68 (s, 1H), 5.52-5.48 (m, 3H), 4.35-4.33 (m, 4H), 2.32 (s, 3H), 1.51 (d, J = 8.0 Hz, 3H)。 Example 6 : ( R )-N-(1-(3 - amino -5-( trifluoromethyl ) phenyl ) ethyl )-2- methyl -7,8 -dihydro- [1,4 ] Preparation of dioxino [2,3-g] quinazolin- 4 - amine ( compound 201)

Step 1 : 1-Bromo-3-nitro-5-(trifluoromethyl)benzene (20.0 g, 74.1 mmol) was dissolved in dioxane (300 mL), tributyl (1-ethoxy) was added vinyl)tin (32.1 g, 88.9 mmol), triethylamine (15.0 g, 148.5 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (2.6 g, 3.7 mmol), stirred at 80° C. for 16 hours under nitrogen protection. The reactant was cooled, hydrochloric acid (4M) (20 mL) was added to the system, stirred at room temperature for 2 hours, the system was concentrated under reduced pressure, diluted with water (100 mL), extracted with ethyl acetate (2 x 100 mL), and the organic phase was extracted with ethyl acetate (2 x 100 mL). Concentrated under reduced pressure, the concentrate was separated and purified by column chromatography (ethyl acetate:petroleum ether=0-30%) to obtain compound 201-1 (13.0 g) as a pale yellow oil, yield 75 %. ESI-MS: 234 [M+H] ⁺ . Second step: 201-1 ( 10.0 g, 42.9 mmol) was dissolved in tetrahydrofuran (150 mL), and ( R )-2-methylpropane-2-sulfinyl was added Amide (6.23 g, 51.5 mmol) and tetraethyl titanate (19.6 g, 86.0 mmol) were refluxed for 8 hours. The reaction solution was cooled and poured into water to form a white precipitate, which was removed by filtration, the filter cake was washed with ethyl acetate, the filtrate was extracted with ethyl acetate (2 x 100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was passed through Separation and purification by column chromatography (ethyl acetate:petroleum ether=0-40%) gave compound 201-2 (12.9 g) as a pale yellow oil with a yield of 90%. ESI-MS: 337 [M+H] ⁺ . Step 3: Dissolve 201-2 (12.9 g, 38.4 mmol) in tetrahydrofuran (150 mL), add sodium borohydride (2.6 g, 69.1 mmol) at -78°C , the reaction solution was slowly raised to room temperature, and the reaction of the raw materials was monitored by TLC. The reaction was quenched by adding water, extracted with ethyl acetate (100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (ethyl acetate: petroleum ether=0-40%) to obtain compound 201- 3 , which is a pale yellow solid, the yield is 65%. ESI-MS: 339 [M+H] ⁺ . Fourth step: Dissolve 201-3 (8.5 g, 25.1 mmol) in dioxane (100 mL), add hydrochloric acid (4M in dioxane) solution) (15 mL), the reaction solution was stirred at room temperature, TLC monitoring the raw material reaction was complete, filtered, the filter cake was washed with ethyl acetate, and the product was dried to obtain compound 201-4 (5.3 g), which was White solid, yield 78%. ESI-MS: 235 [M+H] ⁺ . Fifth step: 2,3-dihydrobenzo[ b ][1,4]dioxin-6-carboxylic acid methyl ester (10.0 g, 51.5 mmol) It was dissolved in acetic acid (30 mL), concentrated nitric acid (8 mL) was added under an ice-water bath, and the reaction solution was stirred at 70° C. for 6 hours. The reactant was cooled, poured into ice water, a solid was formed, filtered, the filter cake was washed with water, and dried in vacuo to give compound 201-5 (10.1 g) as a pale yellow solid, yield (82%). ESI-MS: 240 [M+H] ⁺ . Step 6: Dissolve 201-5 (2.2 g, 9.2 mmol) in ethanol (15 mL) and water (4 mL), add iron powder (5.2 g, 92.1 mmol) ) and ammonium chloride (4.9 g, 92.1 mmol), and the reaction solution was stirred at 90°C for 3 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 20 mL), and the organic phase was concentrated under reduced pressure , to obtain compound 201-6 (1.8 g) as a brown solid with a yield of 94%. ESI-MS: 210 [M+H] ⁺ . Step 7: Dissolve 201-6 (1.8 g, 8.6 mmol) in acetonitrile (15 mL), add concentrated hydrochloric acid dropwise until all the solids dissolve, and then place the reaction solution in acetonitrile (15 mL). Stir at 80°C for 16 hours. The reaction was cooled, the resulting precipitate was filtered, and the filter cake was washed with acetonitrile and dried to give compound 201-7 (460 mg) as a white solid with a yield of 26%. ESI-MS: 219 [M+H] ⁺ . Eighth step: 201-7 (460 mg, 2.1 mmol) was dissolved in phosphorus oxychloride (15 mL), and the reaction was stirred at 100° C. for 4 hours. The reactant was cooled, concentrated under reduced pressure, the crude product was dissolved in dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution, and concentrated under reduced pressure to obtain compound 201-8 (350 mg) as a yellow solid, yield 71%. ESI-MS: 237 [M+H] ⁺ . Step 9: Dissolve 201-8 (120 mg, 0.5 mmol) in isopropanol (4 mL), add ( R )-1-(3-nitro- 5-(Trifluoromethyl)phenyl)ethan-1-amine hydrochloride ( 1-4 ) (177 mg, 0.7 mmol) and N,N-diisopropylethylamine (194 mg, 1.5 mmol), The reaction was refluxed for 6 hours. The reactant was cooled, concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (methanol:dichloromethane=0-10%) to obtain compound 201-9 (70 mg) with a yield of 32%. ESI-MS: 435 [M+H] ⁺ . Step 10: Dissolve 201-9 (70 mg, 0.2 mmol) in ethanol (6 mL) and water (2 mL), add iron powder (112 mg, 2.0 mmol) ) and ammonium chloride (107 mg, 2.0 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), and 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- 7,8-Dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine (26.7 mg) as a white solid, 41% yield. ESI-MS: 405 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 7.96 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 6.83 (s, 1H), 6.68 (s, 1H), 5.52-5.48 (m, 3H), 4.35-4.33 (m, 4H), 2.32 (s, 3H), 1.51 (d, J = 8.0 Hz, 3H).

第一步 ：將化合物 201-8(300 mg，1.3 mmol)溶於異丙醇(6 mL)，加入( R)-1-(5-溴噻吩-2-基)乙-1-胺鹽酸鹽(470 mg，2.0 mmol)和N,N-二異丙基乙胺(516 mg，4.0 mmol)，反應液於110℃回流攪拌16h。冷卻，減壓濃縮，濃縮物經管柱層析法(甲醇:二氯甲烷=0~10%)分離純化，得(R)-N-(1-(5-溴噻吩-2-基)乙基)-2-甲基-7,8-二氫-[1,4]二噁英并[2,3-g]喹唑啉-4-胺( 203-1)(203 mg)，收率38%。ESI-MS: 406 [M+H] ⁺ 第二步：將 203-1(140 mg, 0.3 mmol)溶於1,4-二氧六環\水(5:1)(6 mL)，加入(2-((二甲胺基)甲基)苯基)硼酸(125 mg，0.7 mmol)、四(三苯基膦)鈀(35 mg，0.1 mmol)和碳酸鉀(138 mg，1.0 mmol)，氮氣保護下，反應液於100℃反應16小時。將反應液冷卻，過濾，濾液減壓濃縮，加水稀釋(10 mL)，乙酸乙酯萃取(10 mL)，有機相減壓濃縮，濃縮物經管柱層析法(甲醇:二氯甲烷=0~8%)和高壓製備液相色譜法分離純化，得到( R)- N-(1-(5-(2-((二甲基胺基)甲基)苯基)噻吩-2-基)乙基)-2-甲基-7,8-二氫-[1,4]二噁英并[2,3- g]喹唑啉-4-胺(化合物203) (30.43 mg)，白色固體，收率19%。ESI-MS: 461 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.13 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.55-7.48 (m, 3H), 7.44 (d, J = 4.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J = 4.0 Hz, 1H), 6.08~6.04 (m, 1H), 4.48-4.41 (m, 6H), 2.66 (s, 6H), 2.63 (s, 3H), 1.78 (d, J = 8.0 Hz, 3H)。 Example 7 : ( R )-N-(1-(5-(2-( ( dimethylamino ) methyl ) phenyl ) thiophen -2- yl ) ethyl )-2- methyl- 7, Preparation of 8 -dihydro- [1,4] dioxino [2,3- g ] quinazolin- 4 - amine ( Compound 203)

The first step : Compound 201-8 (300 mg, 1.3 mmol) was dissolved in isopropanol (6 mL), and ( R )-1-(5-bromothiophen-2-yl)ethan-1-amine hydrochloride was added Salt (470 mg, 2.0 mmol) and N,N-diisopropylethylamine (516 mg, 4.0 mmol), the reaction solution was stirred at 110 °C under reflux for 16 h. Cooled, concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (methanol:dichloromethane=0~10%) to obtain (R)-N-(1-(5-bromothiophen-2-yl)ethyl )-2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine ( 203-1 ) (203 mg), yield 38 %. ESI-MS: 406 [M+H] ⁺ Second step: dissolve 203-1 (140 mg, 0.3 mmol) in 1,4-dioxane\water (5:1) (6 mL), add ( 2-((dimethylamino)methyl)phenyl)boronic acid (125 mg, 0.7 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.1 mmol) and potassium carbonate (138 mg, 1.0 mmol), Under nitrogen protection, the reaction solution was reacted at 100°C for 16 hours. The reaction solution was cooled, filtered, the filtrate was concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (10 mL), the organic phase was concentrated under reduced pressure, and the concentrate was subjected to column chromatography (methanol:dichloromethane=0～ 8%) and high pressure preparative liquid chromatography to obtain ( R )-N-(1-(5-(2-(( dimethylamino )methyl)phenyl)thiophen-2-yl)ethyl yl)-2-methyl-7,8-dihydro-[1,4]dioxino[2,3- g ]quinazolin-4-amine (Compound 203) (30.43 mg), white solid, Yield 19%. ESI-MS: 461 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.13 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.55-7.48 (m, 3H), 7.44 (d, J = 4.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J = 4.0 Hz, 1H), 6.08~6.04 (m, 1H), 4.48-4.41 ( m, 6H), 2.66 (s, 6H), 2.63 (s, 3H), 1.78 (d, J = 8.0 Hz, 3H).

第一步 ：將1 H-吲唑-6-羧酸甲酯(5.0 g，28.4 mmol)溶解在硫酸\醋酸混合液(1:2，30 mL)中，冰浴下加入濃硝酸(8 mL)，室溫下攪拌16個小時。反應液倒入冰水中，乙酸乙酯萃取(2 x 100 mL)，有機相減壓濃縮，濃縮物經管柱層析法(乙酸乙酯:石油醚=0~60%)分離純化，得到5-硝基-1 H-吲唑-6-羧酸甲酯( 506-1)(5.6 g)，淡黃色油狀物，收率89%。ESI-MS: 222 [M+H] ⁺ 第二步：將 506-1(5.6 g，25.2 mmol)溶於乙腈(40 mL)，加入碳酸鉀(10.4 g，75.7 mmol)和((2-溴乙氧基)甲基)苯(6.0 g，27.7 mmol)，反應液於80℃反應4小時。將反應液冷卻，減壓濃縮，加水稀釋(100 mL)，乙酸乙酯萃取(2 x 100 mL)，將有機相減壓濃縮，濃縮物經管柱層析法(乙酸乙酯:石油醚=0~60%)分離純化，得到1-(2-(苄氧基)乙基)-5-硝基-1 H-吲唑-6-羧酸甲酯( 506-2)(4.0 g)，淡黃色固體，收率45%。ESI-MS: 356 [M+H] ⁺ 第三步：將( 506-2)(2.0 g，5.6 mmol)溶於甲醇(20 mL)，加入鐵粉(3.1 g，56.1 mmol)和氯化銨(3.0 g，56.1 mmol)溶於水中(5 mL)的溶液，反應液於80℃反應3小時。冷卻，過濾，濾餅用乙酸乙酯洗滌，濾液減壓濃縮，濃縮物加水(10 mL)稀釋，用乙酸乙酯萃取(2 x 20 mL)，有機相減壓濃縮，得1-(2-(苄氧基)乙基)-5-胺基-1 H-吲唑-6-羧酸甲酯( 506-3)(1.6 g)，棕色固體，收率89%。ESI-MS: 326 [M+H] ⁺ 第四步：將( 506-3)(1.6 g，4.9 mmol)溶於乙腈(15 mL)中，滴加濃鹽酸至生成的沉澱溶解，然後將反應液於80℃攪拌16小時。冷卻，生成的沉澱物過濾，濾餅用乙腈洗滌，乾燥，得到1-(2-(苄氧基)乙基)-6-甲基-1,7-二氫-8 H-吡唑并[3,4-g]喹唑啉-8-酮( 506-4)(400 mg)，白色固體，收率25%。ESI-MS: 335 [M+H] ⁺ 第五步：將( 506-4)(460 mg，1.4 mmol)溶於三氯氧磷(15 mL)中，反應液於100℃攪拌14個小時。冷卻，減壓濃縮，粗產物用二氯甲烷溶解，有機相用飽和碳酸氫鈉溶液洗滌，減壓濃縮，得1-(2-(苄氧基)乙基)-8-氯-6-甲基-1 H-吡唑并[3,4-g]喹唑啉( 506-5)(200 mg)，黃色固體，收率40%。ESI-MS: 353 [M+H] ⁺ 第六步：將( 506-5)(120 mg，0.3 mmol)溶於甲苯(5 mL)，加入( R)-1-(3-(三氟甲基)苯基)乙-1-胺鹽酸鹽(99 mg，0.4 mmol)、Pd ₂(dba) ₃(30 mg，0.1 mmol)和叔丁醇鈉(95 mg, 1.0 mmol)，氮氣保護下，於100℃反應13小時。冷卻，過濾，濾餅用乙酸乙酯洗滌，濾液減壓濃縮，濃縮物經管柱層析法(甲醇:二氯甲烷=0~5%)分離純化，得( R)-1-(2-(苄氧基)乙基)-6-甲基- N-(1-(3-(三氟甲基)苯基)乙基)-1 H-吡唑并[3,4-g]喹唑啉-8-胺( 506-6)(30 mg)，棕色固體，收率21%。ESI-MS: 506 [M+H] ⁺ 第七步：將( 506-6)(30 mg，0.1 mmol)溶於甲苯(2 mL)，加入三氟乙酸(1 mL)，反應液於70℃反應4小時。冷卻，減壓濃縮，粗產物用四氫呋喃溶解，加入氫氧化鈉水溶液，於40℃攪拌1小時，冷卻，用乙酸乙酯萃取(10 mL)，有機相減壓濃縮，濃縮物經高壓製備液相色譜法分離純化，得(R)-2-(6-甲基-8-((1-(3-(三氟甲基)苯基)乙基)胺基)-1 H-吡唑并[3,4-g]喹唑啉-1-基)乙-1-醇( 506) (2.0 mg)，白色固體，收率41%。ESI-MS: 416 [M+H] ⁺。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.74 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.62-7.56 (m, 2H), 5.76-5.72 (m, 1H), 4.98 (t, 1H), 4.57 (t, 2H), 3.93 (t, 2H), 2.39 (s, 3H), 1.68 (d, J = 8.0 Hz, 3H)。 Example 8 : ( R )-2-(6- methyl- 8-((1-(3-( trifluoromethyl ) phenyl ) ethyl ) amino ) -1H -pyrazolo [3, Preparation of 4- g ] quinazolin- 1 -yl ) ethan - 1 - ol (506)

The first step : 1 H -indazole-6-carboxylic acid methyl ester (5.0 g, 28.4 mmol) was dissolved in sulfuric acid\acetic acid mixture (1:2, 30 mL), and concentrated nitric acid (8 mL) was added under ice bath. ) and stirred at room temperature for 16 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (2 x 100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (ethyl acetate: petroleum ether=0~60%) to obtain 5- Nitro- 1H -indazole-6-carboxylic acid methyl ester ( 506-1 ) (5.6 g), pale yellow oil, yield 89%. ESI-MS: 222 [M+H] ⁺ Second step: 506-1 (5.6 g, 25.2 mmol) was dissolved in acetonitrile (40 mL), potassium carbonate (10.4 g, 75.7 mmol) and ((2-bromo) were added Ethoxy)methyl)benzene (6.0 g, 27.7 mmol), the reaction solution was reacted at 80°C for 4 hours. The reaction solution was cooled, concentrated under reduced pressure, diluted with water (100 mL), extracted with ethyl acetate (2 x 100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was subjected to column chromatography (ethyl acetate: petroleum ether=0 ~60%) was isolated and purified to obtain methyl 1-(2-(benzyloxy)ethyl)-5-nitro- 1H -indazole-6-carboxylate ( 506-2 ) (4.0 g), pale Yellow solid, yield 45%. ESI-MS: 356 [M+H] ⁺ Step 3: Dissolve ( 506-2 ) (2.0 g, 5.6 mmol) in methanol (20 mL), add iron powder (3.1 g, 56.1 mmol) and ammonium chloride (3.0 g, 56.1 mmol) dissolved in water (5 mL), and the reaction solution was reacted at 80°C for 3 hours. Cool, filter, wash the filter cake with ethyl acetate, concentrate the filtrate under reduced pressure, dilute the concentrate with water (10 mL), extract with ethyl acetate (2 x 20 mL), and concentrate the organic phase under reduced pressure to obtain 1-(2- (Benzyloxy)ethyl)-5-amino- 1H -indazole-6-carboxylate methyl ester ( 506-3 ) (1.6 g), brown solid, 89% yield. ESI-MS: 326 [M+H] ⁺ Step 4: ( 506-3 ) (1.6 g, 4.9 mmol) was dissolved in acetonitrile (15 mL), concentrated hydrochloric acid was added dropwise until the resulting precipitate was dissolved, and then the reaction was The solution was stirred at 80°C for 16 hours. After cooling, the resulting precipitate was filtered, and the filter cake was washed with acetonitrile and dried to give 1-(2-(benzyloxy)ethyl)-6-methyl-1,7-dihydro- 8H -pyrazolo[ 3,4-g]quinazolin-8-one ( 506-4 ) (400 mg), white solid, yield 25%. ESI-MS: 335 [M+H] ⁺ Step 5: ( 506-4 ) (460 mg, 1.4 mmol) was dissolved in phosphorus oxychloride (15 mL), and the reaction solution was stirred at 100° C. for 14 hours. Cooled, concentrated under reduced pressure, the crude product was dissolved in dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution, and concentrated under reduced pressure to obtain 1-(2-(benzyloxy)ethyl)-8-chloro-6-methane yl- 1H -pyrazolo[3,4-g]quinazoline ( 506-5 ) (200 mg), yellow solid, yield 40%. ESI-MS: 353 [M+H] ⁺ Step 6: Dissolve ( 506-5 ) (120 mg, 0.3 mmol) in toluene (5 mL), add ( R )-1-(3-(trifluoromethane) yl)phenyl)ethan-1-amine hydrochloride (99 mg, 0.4 mmol), Pd2(dba _{)3 (} 30 mg, 0.1 mmol) and sodium tert-butoxide (95 mg, 1.0 mmol) under nitrogen , and reacted at 100 °C for 13 hours. Cooling, filtering, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (methanol: dichloromethane=0~5%) to obtain ( R )-1-(2-( Benzyloxy)ethyl)-6-methyl- N- (1-(3-(trifluoromethyl)phenyl)ethyl) -1H -pyrazolo[3,4-g]quinazoline -8-amine ( 506-6 ) (30 mg), brown solid, 21% yield. ESI-MS: 506 [M+H] ⁺ Step 7: ( 506-6 ) (30 mg, 0.1 mmol) was dissolved in toluene (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction solution was heated at 70 °C The reaction was carried out for 4 hours. Cool, concentrate under reduced pressure, dissolve the crude product in tetrahydrofuran, add aqueous sodium hydroxide solution, stir at 40°C for 1 hour, cool, extract with ethyl acetate (10 mL), concentrate the organic phase under reduced pressure, and prepare the liquid phase from the concentrate under high pressure Chromatographic separation and purification to obtain (R)-2-(6-methyl-8-((1-(3-(trifluoromethyl)phenyl)ethyl)amino) -1H -pyrazolo[ 3,4-g]quinazolin-1-yl)ethan-1-ol ( 506 ) (2.0 mg), white solid, 41% yield. ESI-MS: 416 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.74 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.85 (s, 1H) , 7.80 (d, J = 8.0 Hz, 1H), 7.62-7.56 (m, 2H), 5.76-5.72 (m, 1H), 4.98 (t, 1H), 4.57 (t, 2H), 3.93 (t, 2H) ), 2.39 (s, 3H), 1.68 (d, J = 8.0 Hz, 3H).

第一步 ：將4-羥基-3-硝基苯甲酸甲酯(5.9 g，30.0 mmol)溶解在丙酮(200 mL)中，加入碳酸鉀(20.7 g，150.0 mmol)和溴乙酸甲酯(6.0 g, 39.0 mmol)。將反應物加熱至60℃，攪拌5小時。將反應物冷卻，過濾，將濾餅用丙酮(20 mL)洗滌。濾液減壓濃縮，置於石油醚(500 mL)中重結晶，過濾，將濾餅用石油醚(20 mL)洗滌，烘乾，得到化合物 507-1(6.7 g)，其為淺黃色固體。收率83%。ESI-MS: 270 [M+H] ⁺. 第二步：將 507-1(6.7 g，24.9 mmol)溶解在乙醇/水(100 mL/100 mL)中。在室溫攪拌下，加入鐵粉(100目，14.0 g，250 mmol)、氯化銨(13.4 g，250 mmol)和醋酸(68%，8 mL)。將反應物加熱至90℃，攪拌16小時。將反應物冷卻，通過矽藻土過濾，將濾餅用乙酸乙酯(50 mL)洗滌，將濾液減壓濃縮，用乙酸乙酯/水(1:1，800 mL)萃取，然後將有機相用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓快速矽膠管柱層析法(洗脫劑：乙酸乙酯:石油醚=0-50%)分離純化，得到化合物 507-2(3.7 g)，其為淺黃色固體。收率71%。ESI-MS: 208 [M+H] ⁺. 第三步：將 507-2(3.7 g，17.9 mmol)溶解在N,N-二甲基甲醯胺(40 mL)中。在室溫攪拌下，加入碳酸鉀(7.4 g，53.7 mmol)和碘甲烷(1.7 mL, 26.9 mmol)。將反應物加熱至60℃，攪拌10小時。將反應液傾倒至冰水(200 mL)中，然後用乙酸乙酯(2 x 200 mL)萃取，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，得到化合物 507-3(3.4 g)，其為淺黃色固體。收率85%。ESI-MS: 222 [M+H] ⁺. 第四步：將 507-3(3.4 g，15.4 mmol)溶解在醋酸(30 mL)中。在室溫下，緩慢滴加硝酸(68%，10.0 mL)。將反應物加熱至60℃，攪拌10小時。將反應液傾倒至冰水(200 mL)中，然後用乙酸乙酯(2 x 200 mL)萃取，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓快速矽膠管柱層析法(洗脫劑：乙酸乙酯:石油醚=0-50%)分離純化，得到化合物 507-4(2.6 g)，其為淺黃色固體。收率63%。ESI-MS: 267 [M+H] ⁺. 第五步：將 507-4(2.6 g，9.8 mmol)溶解在乙醇/水(20 mL/20 mL)中。在室溫攪拌下，加入鐵粉(100目，5.5 g，98 mmol)和氯化銨(5.2 g，98 mmol)，加熱至90℃，攪拌10小時。將反應物冷卻，通過矽藻土過濾，將濾餅用乙酸乙酯(50 mL)洗滌，將濾液減壓濃縮，用乙酸乙酯/水(1:1，200 mL)萃取，然後將有機相用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓快速矽膠管柱層析法(洗脫劑：乙酸乙酯:石油醚=0-50%)分離純化，得到化合物 507-5(1.7 g)，其為淺黃色固體。收率74%。ESI-MS: 237 [M+H] ⁺. 第六步：將 507-5(1.7g，7.2 mmol)加入到乙腈(20 mL)中。在室溫攪拌下，加入鹽酸的二氧六環溶液(4N, 20 mL)。將反應物加熱至90℃，攪拌12小時，產生大量固體。將反應物冷卻，過濾，將濾餅用水(20 mL)洗滌，烘乾，得到化合物 507-6(1.3 g)，其為灰白色固體。收率71%。ESI-MS: 246 [M+H] ⁺. 第七步：將 507-6(1.3 g，5.3 mmol)加入到三氯氧磷(25 mL)中。將反應物加熱至100℃，攪拌10小時，將反應物直接減壓濃縮，將濃縮物溶於二氯甲烷(80 mL)中，用飽和碳酸氫鈉水溶液洗滌(3 x 80 mL)，再用飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，將濃縮物經中壓快速矽膠柱色譜法(洗脫劑：乙酸乙酯:石油醚=0-30%)分離純化，得到化合物 507-7(0.91 g)，其為淺黃色固體。收率65%。ESI-MS: 264 [M+H] ⁺. 第八步：將 507-7(100 mg, 0.4 mmol)溶於二甲基亞碸(3 mL)，加入( R)-1-(3-(三氟甲基)苯基)乙-1-胺鹽酸鹽(126 mg，0.6 mmol)和N,N-二異丙基乙胺(2.7 g，21.3 mmol)，將反應液於130℃下攪拌16小時。將反應物冷卻，加水稀釋(10 mL)，乙酸乙酯萃取(20 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( R)-2,6-二甲基-4-((1-(3-(三氟甲基)苯基)乙基)胺基)-6 H-[1,4]噁嗪[3,2- g]喹唑啉-7(8 H)-酮(40.23 mg)，其為白色固體，收率50%。ESI-MS: 417 [M+H] ⁺ 。 ¹H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.33 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.61-7.55 (m, 2H), 7.09 (s, 1H), 5.72-5.65 (m, 1H), 4.78 (s, 2H), 3.43 (s, 3H), 2.34 (s, 3H), 1.64 (d, J = 8.0 Hz, 3H)。 生物學測定 Example 9 : ( R )-2,6 -Dimethyl- 4-((1-(3-( trifluoromethyl ) phenyl ) ethyl ) amino ) -6H- [1,4] oxa Preparation of oxazin [3,2- g ] quinazolin- 7( 8H ) -one ( compound 507)

Step 1: Dissolve methyl 4-hydroxy-3-nitrobenzoate (5.9 g, 30.0 mmol) in acetone (200 mL), add potassium carbonate (20.7 g, 150.0 mmol) and methyl bromoacetate (6.0 g, 39.0 mmol). The reaction was heated to 60°C and stirred for 5 hours. The reaction was cooled, filtered, and the filter cake was washed with acetone (20 mL). The filtrate was concentrated under reduced pressure, placed in petroleum ether (500 mL) for recrystallization, filtered, and the filter cake was washed with petroleum ether (20 mL) and dried to obtain compound 507-1 (6.7 g) as a pale yellow solid. Yield 83%. ESI-MS: 270 [M+H] ⁺ . Second step: 507-1 (6.7 g, 24.9 mmol) was dissolved in ethanol/water (100 mL/100 mL). With stirring at room temperature, iron powder (100 mesh, 14.0 g, 250 mmol), ammonium chloride (13.4 g, 250 mmol) and acetic acid (68%, 8 mL) were added. The reaction was heated to 90°C and stirred for 16 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethyl acetate (50 mL), the filtrate was concentrated under reduced pressure, extracted with ethyl acetate/water (1:1, 800 mL), and the organic phase was then Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-50%), Compound 507-2 (3.7 g) was obtained as a pale yellow solid. Yield 71%. ESI-MS: 208 [M+H] ⁺ . Third step: 507-2 (3.7 g, 17.9 mmol) was dissolved in N,N-dimethylformamide (40 mL). With stirring at room temperature, potassium carbonate (7.4 g, 53.7 mmol) and iodomethane (1.7 mL, 26.9 mmol) were added. The reaction was heated to 60°C and stirred for 10 hours. The reaction solution was poured into ice water (200 mL), then extracted with ethyl acetate (2 x 200 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 507-3 ( 3.4 g) as a pale yellow solid. Yield 85%. ESI-MS: 222 [M+H] ⁺ . Fourth step: 507-3 (3.4 g, 15.4 mmol) was dissolved in acetic acid (30 mL). Nitric acid (68%, 10.0 mL) was slowly added dropwise at room temperature. The reaction was heated to 60°C and stirred for 10 hours. The reaction solution was poured into ice water (200 mL), then extracted with ethyl acetate (2 x 200 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to medium pressure Separation and purification by flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-50%) gave compound 507-4 (2.6 g) as a pale yellow solid. Yield 63%. ESI-MS: 267 [M+H] ⁺ . Fifth step: 507-4 (2.6 g, 9.8 mmol) was dissolved in ethanol/water (20 mL/20 mL). Under stirring at room temperature, iron powder (100 mesh, 5.5 g, 98 mmol) and ammonium chloride (5.2 g, 98 mmol) were added, heated to 90° C., and stirred for 10 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethyl acetate (50 mL), the filtrate was concentrated under reduced pressure, extracted with ethyl acetate/water (1:1, 200 mL), and the organic phase was then Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-50%), Compound 507-5 (1.7 g) was obtained as a pale yellow solid. Yield 74%. ESI-MS: 237 [M+H] ⁺ . Sixth step: 507-5 (1.7 g, 7.2 mmol) was added to acetonitrile (20 mL). With stirring at room temperature, a solution of hydrochloric acid in dioxane (4N, 20 mL) was added. The reaction was heated to 90°C and stirred for 12 hours, resulting in a large amount of solid. The reaction was cooled, filtered, and the filter cake was washed with water (20 mL) and dried to give compound 507-6 (1.3 g) as an off-white solid. Yield 71%. ESI-MS: 246 [M+H] ⁺ . Seventh step: 507-6 (1.3 g, 5.3 mmol) was added to phosphorus oxychloride (25 mL). The reaction was heated to 100 °C and stirred for 10 hours. The reaction was directly concentrated under reduced pressure, the concentrate was dissolved in dichloromethane (80 mL), washed with saturated aqueous sodium bicarbonate (3 x 80 mL), and then Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was separated and purified by medium pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-30%) to obtain compound 507 -7 (0.91 g) as a pale yellow solid. Yield 65%. ESI-MS: 264 [M+H] ⁺ . Eighth step: Dissolve 507-7 (100 mg, 0.4 mmol) in dimethylsulfite (3 mL), add ( R )-1-(3-( Trifluoromethyl)phenyl)ethan-1-amine hydrochloride (126 mg, 0.6 mmol) and N,N-diisopropylethylamine (2.7 g, 21.3 mmol), the reaction was stirred at 130 °C 16 hours. The reaction was cooled, diluted with water (10 mL), extracted with ethyl acetate (20 mL), the organic phase was concentrated under reduced pressure, and the concentrate was separated by column chromatography (methanol:dichloromethane=0-8%) Purification to give ( R )-2,6-dimethyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino) -6H- [1,4]oxazine [3,2- g ]quinazolin-7( 8H )-one (40.23 mg) as a white solid in 50% yield. ESI-MS: 417 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ: ppm 8.33 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.75 (d, J = 8.0 Hz , 1H), 7.61-7.55 (m, 2H), 7.09 (s, 1H), 5.72-5.65 (m, 1H), 4.78 (s, 2H), 3.43 (s, 3H), 2.34 (s, 3H), 1.64 (d, J = 8.0 Hz, 3H). biological assay

Experimental Example 1. KRAS::SOS1 HTRF binding assay This assay can be used to examine the efficacy 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 the SOS1 inhibitor compound in this assay setup below. Reagents: • GST-SOS1 (aa564-1049), produced in-house • His-KRAS G12C (aa1-169), produced in-house • MAb Anti-6his-Tb cryptate Gold from Cisbio (Cat. No. 61HI2TLA) • MAb Anti-GST - XL665, from Cisbio (Cat. No. 61GSTXLA) Assay Plate: ProxiPlate-384Plus, from PerkinElmer (Cat. No. 6008280) Assay Buffer: PPI, from Cisbio (Cat. No. 61DB10RDF) Assay Protocol: • Dissolve test compounds in In DMSO, the concentration of the prepared stock solution was 10 mM, and the compound concentration was diluted with DMSO to 2 mM as the starting concentration of the assay, and the compound solution with the starting concentration of 2 mM was serially diluted 3-fold, and a total of 10 concentrations were diluted, and transferred by 0.1 using the Labcyte Echo instrument Add 5 μL of specific concentration of His-KRAS G12C to 0.1 μL of compound solution and centrifuge at 1000 rpm on an Eppendorf 5810R centrifuge for 1 min; • Then add 5 μL of specific concentration of GST-SOS1, 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 MAb Anti-6his - The mixture of Tb and MAb Anti-GST-XL665 was centrifuged at 1000 rpm for 1 min in an Eppendorf 5810R centrifuge; • 384-well assay plate was incubated at 25°C for 2 h; nm signal ratio. 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) 101a 46.5 101b 18.3 102 14.9 105 21.8 201 65.1 203 65.2 506 62.0 507 81.9

Various modifications of the invention, in addition to those described herein, will be apparent to those of ordinary skill 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 incorporated by reference in its entirety.

Claims (12)

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 formula (I ) or the structure of formula (I'):

or

Formula (I) Formula (I') wherein: Ring A and Ring B are each independently selected from a C _3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C _6-10 membered aromatic ring and a 5-14 membered heteroaromatic ring, At most 2 ring members in the hydrocarbon ring and heterocycle 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 alkene base, C _2-6 alkynyl, saturated or partially unsaturated C _3-10 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl, at most 2 ring members in the cyclic hydrocarbon group 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 to which it is attached collectively form a C _3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C _6-10 membered aromatic ring or a 5-14 membered heteroaromatic ring as the case may be, at most 2 of the hydrocarbon ring and the heterocyclic ring Ring member is C(=O); R ² , R ² ', R ³ and R ⁴ are each independently selected from H, halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6alkane group, -O-(3-10 membered heterocyclyl), 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 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl group , 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 ; The above groups are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: 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 membered 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, cyclohydrocarbyl, heterocyclyl, aryl radical, heteroaryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, _-NH2 , -CN, _-NO2 , _C1-6 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 appear in each are independently selected from H, C _1-6 alkyl group, C _3-10 cyclic hydrocarbon group, 3-10 membered heterocyclic group, C _6-10 aryl group, 5-14 membered heteroaryl group and C _6-12 aryl group alkyl; 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 a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R is Each occurrence is independently C _1-6 alkyl or C _1-6 alkylene-OH; preferably, R is independently at each occurrence methyl or -CH ₂ CH ₂ -OH. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein Ring A is a 3-10-membered heterocyclic ring or a 5-14-membered heteroaromatic ring, and the heterocyclic or heteroaromatic ring contains one or more ring members selected from -O-, -NR- and -N=; preferably ,

for

,

or

; optimally,

for

,

or

. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A prodrug, wherein ring B is a bicyclo[1.1.1]pentane ring, a 2-oxabicyclo[2.1.1]hexane ring, a benzene ring or a thiophene ring, preferably a benzene ring or a thiophene ring. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or A prodrug wherein each occurrence of R ¹ is independently selected from halogen, -NH ₂ , C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkylene-OH, halo C _1-6 alkylene-OH, saturated or partially unsaturated C _3-10 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl group and 5-14 membered heteroaryl group group, the alkylene, alkyl, cyclohydrocarbyl, heterocyclyl, aryl, and heteroaryl groups are optionally one or more independently selected from halogen, -OH, C _3-6 cyclohydrocarbyl, 3-10 membered Substituent substitution of heterocyclic group, C _6-10 aryl group and 5-14 membered heteroaryl group; when m is greater than 1, two R ¹ together with the atoms to which they are attached together form a C _3-10 hydrocarbon ring, 3-10-membered heterocyclic ring, C _6-10 -membered aromatic ring or 5-14-membered heteroaromatic ring, at most 2 ring members in the hydrocarbon ring and the heterocyclic ring are C(=O), and the hydrocarbon ring, heterocyclic ring, aromatic ring Rings and heteroaromatic rings are optionally substituted with one or more halogens; preferably, R ¹ at each occurrence is independently selected from CF ₃ , NH ₂ and

; and m is 1 or 2. The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrugs, of which

selected from

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A prodrug, wherein R ² and R ² ' are each independently selected from H, -OC _1-6 alkyl and -O-(3-10 membered heterocyclyl); preferably, among R ² and R ² ' One is H and the other is H, -OCH ₃ or

. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or ^A prodrug, wherein ^R3 and R4 are each independently selected from H and _C1-6 alkyl; preferably, ^R3 is methyl, and ^R4 is H. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A prodrug, wherein the compound has the structure of formula (II), formula (III), formula (IV) or formula (V):

,

,

or

Formula (II) Formula (III) Formula (IV) Formula (V). The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A prodrug, wherein the compound is selected from:

101a,

101b,

102.

105.

106.

201.

203.

506 and

507. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, and a pharmaceutically acceptable carrier, the pharmaceutical composition is preferably a solid preparation, semi-solid preparation, liquid preparation or gaseous preparation. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or prodrug or the use of the pharmaceutical composition of claim 11 in the preparation of a medicament for use as a SOS1 inhibitor, preferably, the medicament is used for the prevention or treatment of cancer (for example pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer) , multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical 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), RAS diseases such as neurofibromatosis type 1 (NF1) , Noonan's syndrome (NS), Noonan's syndrome with multiple spots (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio- Facial-cutaneous syndrome (CFC), Leggers syndrome and hereditary gingival fibromatosis).