Sos1 inhibitors, pharmaceutical compositions comprising the same, and uses thereof

Abstract

SOS1 inhibitors of Formula (I) or Formula (I'), pharmaceutical compositions comprising the same, and uses thereof for preventing or treating diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to SOS1 inhibitors, pharmaceutical compositions comprising the same, and uses thereof for preventing or treating diseases. BACKGROUND

[0003] RAS family proteins are small GTPases encoded by RAS genes, including KRAS (Kirsten rat sarcoma viral oncogene homolog), HRAS (Harvey rat sarcoma viral oncogene) and NRAS (neuroblastoma RAS viral oncogene homolog) and any mutants thereof. In cells, RAS proteins shift between inactivated and activated states, when bound to guanine nucleotide diphosphate (GDP), RAS proteins are in inactivated state, when bound to guanine nucleotide triphosphate (GTP), RAS proteins are activated. The intrinsic GTPase activity of RAS proteins is weak, and the intrinsic GDP-GTP nucleotide exchange rate is low, and the shift between inactivated and activated states of RAS proteins is regulated by two types of factors: GTPase activating proteins (GAPs) that can catalyze the hydrolysis of GTP bound to RAS proteins to GDP, inactivating RAS proteins; Guanine nucleotide exchange factors (GEFs) including SOS1 proteins (Son of Sevenless 1) and the like, which can catalyze the binding of RAS proteins to GTP, thereby promoting the activation of RAS proteins. Activated RAS proteins can activate multiple signal transduction pathways such as the RAF / MEK / ERK (MAPK) pathway and the PI3K / AKT / mTOR pathway by activating a series of downstream effector proteins including RAF and phosphatidylinositol kinase PI3K, etc., thereby regulating multiple cellular processes such as cell proliferation, survival, metabolism, motility, angiogenesis, immunity, and growth. Mutations in RAS family proteins can inhibit their intrinsic GTPase activity and GAP-induced GTPase activity, leading to persistent activation of RAS proteins, and further leading to persistent activation of the 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 multiple human cancers including lung cancer, colorectal cancer and pancreatic cancer, and HRAS mutations and NRAS mutations also occur in different human cancer types. Mutations, overexpression and gene amplification of RAS proteins are potential resistance mechanisms against multiple anticancer drugs such as EGFR antibodies cetuximab and panitumumab, and EGFR tyrosine kinase inhibitor osimertinib.

[0004] SOS protein was first discovered in Drosophila, and SOS1 is the human homolog of Drosophila SOS protein. SOS1 protein is a multi-domain protein composed of 1333 amino acids, which is composed of N-terminal domain, Dbl homology domain (DH), Pleckstrin homology domain (PH), Ras exchange motif (REM), CDC25 homology domain and C-terminal domain. REM and CDC25 homology domain together constitute the catalytic domain, which is essential for the catalytic function of SOS1 protein as a guanine nucleotide exchange factor. Studies have shown that SOS1 plays a key role in the activation and signal transduction of mutant RAS protein in RAS mutant cancer. SOS1 knockout can inhibit the survival and proliferation of KRAS mutant tumor cells. In SOS1 knockout KRAS mutant tumor cells, re-expression of catalytic site mutant SOS1 cannot restore the survival and proliferation of tumor cells, which proves that the guanine nucleotide exchange catalytic activity of SOS1 plays a key role in the survival and proliferation of KRAS mutant tumor cells. In addition to regulating mutant RAS protein, SOS1 can also participate in the activation and transmission of tumor cell signals through other mechanisms. SOS1 can bind to growth factor receptor binding protein Grb2 to form SOS1-Grb2 complex, and then bind to activated receptor tyrosine kinase (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 be recruited by other cell surface membrane receptors (such as TCR, BCR, CSF1R). SOS1 can activate GTPase RAC1 as a guanine nucleotide exchange factor, and RAC1 is associated with various human cancers and other diseases. Studies have shown that SOS1 mutations exist in embryonal rhabdomyosarcoma, Sertoli cell tumors, cutaneous granular cell tumors and lung adenocarcinoma, and overexpression of SOS1 protein has also been found in bladder cancer and prostate cancer.

[0005] SOS2 is the homolog of SOS1 in mammalian cells, also has the function of guanine nucleotide exchange factor. Studies on mouse knockout models have shown that SOS1 germline knockout can cause mouse embryos to die in the middle of pregnancy, while adult mice can continue to survive after SOS1 knockout. In contrast, SOS2 knockout has no obvious phenotype changes in embryos and adult mice, and SOS1 / 2 double knockout adult mice die rapidly, which indicates that selective targeting of SOS1 may achieve a higher therapeutic index for RAS mutant tumors regulated by SOS1.

[0006] Inhibition of the binding of the catalytic site of SOS1 to RAS protein can block SOS1 -mediated activation of RAS protein, and thus inhibit downstream signaling of RAS protein (such as phosphorylation activation of ERK, etc.). SOS1 inhibitors with such mechanism of action have inhibitory effects (such as inhibiting proliferation, survival, metastasis, etc.) on tumor cells dependent on mutant RAS protein, such as KRAS mutant tumor cell lines. SUMMARY

[0007] The present application provides compounds for use as SOS1 inhibitors, which have superior inhibitory activity on SOS1. The SOS1 inhibitors of the present application can inhibit the interaction and activation of SOS1 with RAS protein, especially have significant inhibitory effect on the interaction of SOS1 and KRAS mutant protein, and can provide pharmacological benefits for cancer patients carrying mutations in RAS and upstream and downstream proteins, including KRAS, NRAS, HRAS, receptor tyrosine kinases (such as EGFR, ErbB2 / 3 / 4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1R, INSR, ALK, ROS, TrkA / B / C, RET, c-MET, VEGFR1 / 2 / 3, AXL), GAP (such as NF1) and SOS1. In addition, SOS1 inhibitors will also provide pharmacological benefits in RAC1-dependent cancers and other diseases related to dysregulation of the RAS signaling pathway, such as neurofibromas, Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC) and type 1 hereditary gingival fibromas.

[0008] The compounds of the present application also have more superior physicochemical properties (e.g. solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g. improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0009] One aspect of the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound has the structure of Formula (I) or Formula (I’):

[0010]

[0011] wherein:

[0012] each of ring A and ring B is independently selected from C 3-10 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring and 5-14 membered heteroaromatic ring, up to 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O);

[0013] R and R 1independently at each occurrence selected from halogen, -NH2, -CN, -NO2, -OH, -O-C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkylene-OH, haloC 1-6 alkylene-OH, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl, up to two ring members of said cycloalkyl and heterocyclyl are C(=O), two R 1 and / or two R together with the atoms to which they are attached optionally collectively form a C 3-10 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring, up to two ring members of said hydrocarbon ring and heterocyclic ring are C(=O);

[0014] R 2 , R 2 , R 3 and R 4 are each independently selected from H, halogen, -NH2, -CN, -NO2, -OH, -O-C 1-6 alkyl, -O-(3-10 membered heterocyclyl), C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkylene-OH, haloC 1-6 alkylene-OH, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, 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)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R6 -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 Alkylenes -O(P=O)(OH)2 and -OC 1-6 Alkylene-NR 5 R 6 ;

[0015] Each of the above groups is optionally substituted by one or more substituents independently selected from the following: halogen, -OH, oxo, -NH2, -CN, -NO2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl group, =N-OR 5 -C(=NH)NH2, -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 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 R6 and -O-C 1-6 alkylene-NR 5 R 6 , said alkyl, cycloalkyl, heterocyclyl, aryl, 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, C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;

[0016] R 5 and R 6 are each independently at each occurrence selected from the group consisting of H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;

[0017] m is an integer selected from 0, 1, 2, 3 and 4; and

[0018] n is an integer selected from 0, 1, 2 or 3.

[0019] Another aspect of the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof and one or more pharmaceutically acceptable carriers, said pharmaceutical composition preferably being a solid, semi-solid, liquid or gaseous preparation.

[0020] Another aspect of the present application provides the use of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof or a pharmaceutical composition of the present application for the manufacture of a medicament for use as a SOS1 inhibitor.

[0021] Another aspect of the present application provides a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof or a pharmaceutical composition of the present application for use as a SOS1 inhibitor.

[0022] Another aspect of the present application provides a method of preventing or treating a SOS1 -related disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application. DETAILED DESCRIPTION

[0023] Definitions

[0024] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. References herein to technical terms used herein are intended to refer to the technical terms as commonly understood by those in the art, including variations or replacements of those technical terms that would be apparent to one of ordinary skill in the art. Although it is believed that the following terms are well understood by one of ordinary skill in the art, the following definitions are set forth to better define the present application.

[0025] The terms "comprising", "containing", "having", "including", or "involving" and other variants thereof are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0026] As used herein, the term "alkylene" denotes 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.

[0027] 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, for example 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 "alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, or n-hexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (when the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1-4 "alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

[0028] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group which contains one double bond and has 2-6 carbon atoms ("C 2-6Alkynyl"). The alkenyl group is, for example, ethenyl, 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 the compounds of the application contain alkenylene groups, the compounds can exist in pure E (entgegen) form, pure Z (zusammen) form, or in any mixture thereof.

[0029] As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl or propynyl.

[0030] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused, or bridged systems (such as bicyclo[l. l. l]pentyl, bicyclo[2.2. l]heptyl, bicyclo[3.2. l]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like)), which is 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 of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0031] As used herein, the terms "cycloalkylene", "cycloalkyl", and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic (including spiro, fused, or bridged systems) hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including, but not limited to, (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring), and the like.

[0032] As used herein, the terms "heterocyclyl," "heterocyclyl ene," and "heterocycle" refer to saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) cyclic groups having, for example, 3-10 (suitably having 3-8, more suitably having 3-6) ring atoms, at least one of which is a heteroatom selected from N, O, and S, and the remainder of which are C. For example, a "3-10 membered (hetero)cycloalkyl" is a saturated or partially unsaturated ring having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. Examples of heterocyclyl ene and heterocyclyl groups include, but are not limited to, (hetero)cyclooxanyl, (hetero)cycloaziridinyl, (hetero)cycloazetidinyl, (hetero)cyclooxetanyl, (hetero)cyclofuryl, (hetero)cyclotetrahydrofuranyl, (hetero)cyclooxepinyl, (hetero)cyclopyrrolidinyl, (hetero)cyclopyrrolonyl, (hetero)cycloimidazolidinyl, (hetero)cyclopyrazolidinyl, (hetero)cyclopyrrolinyl, (hetero)cyclotetrahydropyranyl, (hetero)cyclopipecolyl, (hetero)cyclomorpholinyl, (hetero)cyclo-dithianyl, (hetero)cyclothiomorpholinyl, (hetero)cyclo-piperazinyl, or (hetero)cyclo-trithianyl. The groups also encompass bicyclic systems, including spiro, fused, or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, and the like). The heterocyclyl ene and heterocyclyl groups can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0033] As used herein, the terms "(hetero)aryl" and "aromatic ring" refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated pi-electron system. For example, as used herein, the terms "C 6-10 (hetero)aryl" and "C 6-10 aromatic ring" mean aromatic groups containing 6 to 10 carbon atoms, such as (hetero)phenyl (benzene ring) or (hetero)naphthyl (naphthalene ring). The (hetero)aryl and aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, and the like). The (hetero)aryl and aromatic ring are optionally fused to another ring (e.g., C 3-10 hydrocarbon ring, 3-10 membered heterocycle, or 5-14 membered heteroaromatic ring), such as

[0034] As used herein, the terms "(hetero)aryi" and "heteroaromatic" mean a monocyclic, bicyclic or tricyclic aromatic ring system 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 contains at least one heteroatom which can be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and, in addition, can be benzo-fused in each case. In particular, the "(hetero)aryi" or "heteroaromatic" is selected from (hetero)thiophenyl, (hetero)furyl, (hetero)pyrrolyl, (hetero)oxazolyl, (hetero)thiazolyl, (hetero)imidazolyl, (hetero)pyrazolyl, (hetero)isoxazolyl, (hetero)isothiazolyl, (hetero)oxadiazolyl, (hetero)thiadia- zolyl, and the like, as well as their benzo derivatives; or (hetero)pyridyl, (hetero)pyridazinyl, (hetero)pyrimidinyl, (hetero)pyrazinyl, (hetero)triazinyl, and the like, as well as their benzo derivatives. The "(hetero)aryi" and "heteroaromatic" can also optionally be fused to another ring (for example a C 3-10 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring) fused, the fused group being for example

[0035] As used herein, the term "aralkyl" preferably means an aryl or heteroaryl substituted alkyl group, wherein the 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.

[0036] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.

[0037] As used herein, the term "nitrogen-containing heterocycle" means a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which can also optionally contain one or more (for example one, two, three or four) ring members selected from N, O, C=0, S, S=0 and S(=0)2, which is attached to the remainder of the molecule through the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atom, the nitrogen-containing heterocycle optionally being benzo-fused, and preferably through the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring to the remainder of the molecule.

[0038] The term "substituted" means that one or more (e.g., one, two, three or four) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0039] If a substituent is described as "optionally substituted" then the substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with a selection of one or more of a list of substituents, then one or more hydrogens on the carbon (to the extent there are any hydrogens present) can be replaced with independently selected optional substituents, alone or in combination. If a nitrogen of a substituent is described as being optionally substituted with a selection of one or more of a list of substituents, then one or more hydrogens on the nitrogen (to the extent there are any hydrogens present) can each be replaced with an independently selected optional substituent.

[0040] If a substituent is described as being "independently selected from" a group, then each substituent is selected independently of the other(s). Thus, each substituent can be the same or different from the other (other) substituent(s).

[0041] As used herein, the term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, or 10, under reasonable conditions.

[0042] Unless indicated, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0043] When a bond to a substituent is shown as a dashed line passing through a ring, then such substituent can be bonded to any atom in the ring which can be substituted.

[0044] The present application also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the present application except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present application include, but are not limited to, isotopes of hydrogen, such as deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon, such as 11 C, 13 C and 14 C); isotopes of chlorine, such as 36 Cl); isotopes of fluorine, such as 18 F); isotopes of iodine, such as 123 I and 125 I); isotopes of nitrogen, such as 13 N and 15N); isotopes of oxygen (e.g. 15 O, 17 O and 18 O); isotopes of phosphorus (e.g. 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotopically-labeled compounds of the application (for example, those into which radioactive isotopes are incorporated) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotopes tritium, i.e., 3 H), and carbon-14, i.e., 14 C), are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N), provide markers which can be used in Positron Emission Topography (PET) studies. Compounds of the application labeled with isotopes can be prepared by carrying out the procedures described in the Schemes and / or Examples and Preparations below by substituting the appropriate isotopically labeled reagents for the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the application include those wherein the solvent of crystallization can be isotopically substituted, e.g., D2O, acetone-d6 or DMSO-d6.

[0045] The term "stereoisomers" denotes isomers having the same molecular formula but different structures, resulting from a difference in the arrangement of atoms or groups in space. In compounds with one or more asymmetric centers, racemates of the compounds, single enantiomers, and mixtures of enantiomers can be formed. Particular individual molecules can also exist as geometric isomers (cis / trans). Similarly, compounds of the application can exist as mixtures of two or more different structural forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the application encompasses all such isomers and mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0046] A solid line a solid wedge or a dashed wedge Chemical bonds of the compounds of the present application are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) including at that carbon atom. The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate the presence of the depicted stereoisomer. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present application are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present application can exhibit more than one type of isomerism, and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0047] The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0048] It is also to be understood that certain compounds of the present application can exist in free form for treatment, or, where appropriate, as a pharmaceutically acceptable derivative thereof. In the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs which, upon administration to a patient in need thereof, are capable of providing, directly or indirectly, a compound of the present application or a metabolite or residue thereof. Accordingly, as referenced herein, reference to "a compound of the present application" is intended to encompass all such derivative forms of the compound.

[0049] Pharmaceutically acceptable salts of the compounds of the present application include both acid addition salts and base addition salts.

[0050] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, heptanoate, hexanoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / diphosphate / hydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0051] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc.

[0052] A review of suitable salts is given in Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing the pharmaceutically acceptable salts of the compounds of this application are known to those skilled in the art.

[0053] As used herein, the term "ester" means an ester derived by reaction of the carboxyl group of a compound of the respective general formula in this application with an alcohol under ester-forming conditions. The compounds of the present application can also be esters themselves.

[0054] The compounds of the present application can exist in the form of solvates, preferably hydrates, wherein the compound of the present application contains as a structural element of the crystal lattice of said compound a polar solvent, in particular, for example, water, methanol or ethanol. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0055] One skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires an available lone pair of electrons to oxidize to an oxide; one skilled in the art will recognize which nitrogen-containing heterocycles are capable of forming N-oxides. One skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of the heterocycle or tertiary amine with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[0056] Also included within the scope of the application are metabolites of the compounds of the application, i.e., substances formed in vivo from the administered compound. Such products can result, for example, from oxidation, reduction, hydrolysis, am idation, deam idation, esterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the present application includes metabolites of compounds of the application, whether prepared biochemically, or by means of chemical synthesis, including compounds prepared by contacting a compound of the application with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0057] The present application further includes within its scope prodrugs of the compounds of the application, which are certain derivatives of the compounds of the application that possess little or no pharmacological activity themselves but, upon administration, are converted into compounds of the present application that are pharmacologically active in vivo. Typically such prodrugs will be functional derivatives of the compounds that are readily transformed in vivo into the desired therapeutically active compound. For more information on prodrugs see "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series; T. Higuchi and V. Stella. Prodrugs of the present application can be prepared by replacing appropriate functionalities present in the compounds of the application with certain moieties known to those skilled in the art as "pro-moieties" (for example as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985).

[0058] The present application also encompasses compounds of the present application containing protecting groups. During any of the processes for preparation of the compounds of the present application, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned, and thereafter to remove the protecting groups. This can be achieved by means of conventional protecting groups, for example those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference. The protecting groups can be removed at a suitable subsequent stage using methods known from the art.

[0059] The term "about" refers to ± 10% of the stated value, preferably ± 5%, more preferably ± 2%.

[0060] Compounds

[0061] In some embodiments, the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of Formula (I) or Formula (I’):

[0062]

[0063] wherein:

[0064] each of ring A and ring B is independently selected from C 3-10 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10C(=O), and up to two ring members of the aryl and heteroaryl groups are C(=O);

[0065] R and R 1 are each independently at each occurrence selected from the group consisting of H, halogen, -NH2, -CN, -NO2, -OH, -O-C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkylene-OH, haloC 1-6 alkylene-OH, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl, up to two ring members of the cycloalkyl and heterocyclyl groups are C(=O), and two R 1 and / or two R together with the atoms to which they are attached optionally collectively form a C 3-10 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring, up to two ring members of the hydrocarbon ring and heterocyclic ring are C(=O);

[0066] R 2 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, halogen, -NH2, -CN, -NO2, -OH, -O-C 1-6 alkyl, -O-(3-10 membered heterocyclyl), C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkylene-OH, haloC 1-6 alkylene-OH, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, 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)2R 5 , -S(=O)2NR 5 R6 , -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)2and -O-C 1-6 alkylene-NR 5 R 6 ;

[0067] each of the above groups is optionally substituted with one or more substituents independently selected from halogen, -OH, oxo, -NH2, -CN, -NO2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, =N-OR 5 , -C(=NH)NH2, -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 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)-NR5 R 6 , -C 1-6 alkylene-NR 5 R 6 , and -O-C 1-6 alkylene-NR 5 R 6 , said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl further optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, -NH2, -CN, -NO2, C 1-6 alkyl, C 3-6 ycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;

[0068] R 5 and R 6 are each independently at each occurrence selected from the group consisting of H, C 1-6 alkyl, C 3-10 ycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;

[0069] m is an integer selected from 0, 1, 2, 3 and 4; and

[0070] n is an integer selected from 0, 1, 2 or 3.

[0071] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R is, at each occurrence, independently C 1-6 alkyl or C 1-6 alkylene-OH; preferably, R is, at each occurrence, independently methyl or -CH2CH2-OH.

[0072] In some embodiments, the present application provides a compound, 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, said heterocyclic or heteroaromatic ring comprising one or more ring members selected from -O-, -NR- and -N=; preferably, is most preferably, is

[0073] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein Ring B is a bicyclo[l. l. l]pentane ring, a 2-oxabicyclo[2. l. l]hexane ring, a phenyl ring, or a thiophene ring, most preferably a phenyl ring or a thiophene ring.

[0074] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 1 each occurrence is independently selected from the group consisting of halogen, -NH2, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkylene-OH, haloC 1-6 alkylene-OH, saturated or partially unsaturated C 3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl, said alkylene, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl;

[0075] when m is greater than 1, two R 1 together with the atoms to which they are attached optionally collectively form a C 3-10 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring, up to 2 ring members of said hydrocarbon and heterocyclic rings being C(=0), and said hydrocarbon, heterocyclic, aromatic and heteroaromatic rings being optionally substituted with one or more halogens;

[0076] preferably, R 1 each occurrence is independently selected from the group consisting of CF3, NH2and and m is 1 or 2.

[0077] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein is selected from the group consisting of

[0078] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R2 and R 2 each independently is selected from the group consisting of H, -O-C 1-6 alkyl and -O-(3-10 membered heterocyclyl); preferably, R 2 and R 2 one of R

[0079] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 3 and R 4 each independently is selected from the group consisting of H and C 1-6 alkyl; preferably, R 3 is methyl, and R 4 is H.

[0080] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of Formula (II), Formula (III), Formula (IV), or Formula (V):

[0081]

[0082] The present application encompasses compounds resulting from any combination of the various embodiments.

[0083] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:

[0084]

[0085] Pharmaceutical compositions and methods of treatment

[0086] In some embodiments, the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers, preferably in a solid, semi-solid, liquid, or gaseous formulation. In some embodiments, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0087] In some embodiments, the present application provides the use of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application, in the manufacture of a medicament for use as a SOS1 inhibitor.

[0088] In some embodiments, the present application provides a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application, for use as a SOS1 inhibitor.

[0089] In some embodiments, the present application provides a method of preventing or treating a SOS1 -related disease, comprising administering to an individual in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application.

[0090] In some embodiments, the SOS1 -related disease comprises cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial 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), RASopathy (e.g., neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome, and hereditary gingival fibromatosis).

[0091] A "pharmaceutically acceptable carrier" of the present application means a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered, and which is suitable for contact with the tissue of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio as defined in the art.

[0092] Pharmaceutically acceptable carriers that can be employed in the pharmaceutical compositions of the application include, but are not limited to, sterile aqueous, such as water and oils, including those of amphibian, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Saline and glycerol waters are also exemplarily liquid carriers, especially for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, white

[0093] The pharmaceutical compositions of the application can act systemically and / or topically. For this purpose, they can be administered by suitable routes, such as by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip infusion) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0094] For these routes of administration, the pharmaceutical compositions of the application can be administered in suitable dosage forms.

[0095] The 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.

[0096] The term "effective amount" as used herein refers to the amount of a compound that, when administered, will relieve to some extent one or more of the symptoms of the disorder being treated.

[0097] Dosage regimens can be adjusted to provide the optimum desired response. For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is important that dosage values be taken as being typical of the conditions under which treatment is carried out, and that dosage values can vary according to the type and severity of the condition being treated. It is further to be understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0098] The amount of the compounds of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compounds, and the prescribing physician's judgment. Generally, the effective dose is from about 0.0001 to about 50 mg per kg of body weight per day, for example, from about 0.01 to about 10 mg / kg / day (single or divided doses). For a 70 kg person, this would total from about 0.007 mg / day to about 3500 mg / day, for example, from about 0.7 mg / day to about 700 mg / day. In some cases, dose levels not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses administered throughout the day.

[0099] The content or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, preferably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0100] Unless otherwise stated, as used herein, the term “treating” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0101] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0102] In some embodiments, the pharmaceutical compositions of the present invention may also contain one or more additional therapeutic or preventative agents.

[0103] Example

[0104] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0105] The structure of the compound was determined by nuclear magnetic resonance spectroscopy (NMR). 1 Confirmation was performed using 1H NMR or mass spectrometry (MS).

[0106] Chemical shift (δ) is given in parts per million (ppm). 1HNMR was measured on a Bruker BioSpin GmbH 400 NMR spectrometer, and the test solvent was deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or hexadeuterated dimethyl sulfoxide (DMSO-d6), and tetramethylsilane (TMS) was used as an internal standard.

[0107] LC-MS was measured on a Shimadzu LC-MS-2020 liquid chromatograph-mass spectrometer (manufacturer: Shimadzu, model: Shimadzu LC-MS-2020).

[0108] Preparation of high performance liquid chromatography was performed using a waters 2767 (waters sunfire, C18, 19x250mm 10um column).

[0109] Thin layer chromatography (TLC) was performed using a yellow sea HSGF 254 (5x20cm) silica gel plate, and thin layer preparation chromatography was performed using a Yantai GF 254 (0.4-0.5nm) silica gel plate.

[0110] Thin layer chromatography (TLC) or LC-MS was used to detect the reaction, and the developing agent system included dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system, which was adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

[0111] Microwave reaction used Biotage Initiator+ (400W, RT-300℃) microwave reactor.

[0112] Column chromatography generally used 200-300 mesh silica gel as the stationary phase. The eluent system included dichloromethane and methanol system and n-hexane and ethyl acetate system, which was adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

[0113] Unless otherwise specified in the examples, the reaction temperature was room temperature (20-30℃).

[0114] The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company or Shanghai Bide Pharmaceutical Technology Co., Ltd. and other companies.

[0115] The abbreviations in the present application have the following meanings:

[0116] Abbreviations Meanings ACN acetonitrile AcOH / CH3COOH acetic acid / ethanoic acid n-Bu n-butyl Cs2CO3 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 H2O water H2SO4 sulfuric acid IPA / i-PrOH isopropanol [K2CO3] potassium carbonate MeOH methanol [N2] nitrogen NaBH4 sodium borohydride Na2B4O7 sodium tetraborate NH4Cl ammonium chloride NH4HCO3 ammonium bicarbonate [Pd2(dba)3] tris(dibenzylideneacetone)dipalladium [Pd(PPh3)4] tetrakis(triphenylphosphine)palladium [Pd(PPh3)2Cl2] bis(triphenylphosphine)palladium dichloride POCl3 phosphorus oxychloride rt room temperature t-BuONa sodium tert-butoxide TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran [Ti(OEt)4] tetraethyl titanate TLC thin layer chromatography

[0117] Example 1: Preparation of (R)-N-(l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-10- methoxy-2-methyl-7,8-dihydro-[l,4]dioxino[2,3-g]quinolin-4-amine (Compound 101a)

[0118]

[0119] 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 solution (3 x 50 mL), then saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography on a medium-pressure flash silica gel column (eluent: ethyl acetate: petroleum ether = 0-30%) to give compound 101a-4 (0.3 g) as a white solid. Yield 57%. ESI-MS: 267 [M+H] + .

[0120] Second Step: 101a-4 (60 mg, 0.2 mmol) was dissolved in isopropanol (4 mL), (R)-l-(3- nitro-5-(trifluoromethyl)phenyl)ethan-l -amine hydrochloride (81 mg, 0.3 mmol) and N,N- diisopropylethylamine (77 mg, 0.6 mmol) were added, and the reaction was stirred at 110 °C for 16 hours. The reaction was cooled and concentrated under reduced pressure. The concentrate was purified by preparative TLC (eluent: 100% ethyl acetate) to give compound 101a-5 (44 mg) as a light yellow solid. Yield 47%. ESI-MS: 465 [M+H] + .

[0121] Third Step: 101a-5 (44 mg, 0.1 mmol) was dissolved in ethanol (5 mL) and water (2 mL), iron powder (50 mg, 0.9 mmol) and ammonium chloride (48 mg, 2.0 mmol) were added, and the reaction was stirred at 90 °C for 2 hours. The reaction was cooled, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, 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 purified by high-pressure preparative liquid chromatography to give (R)-N-(l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-10-methoxy-2-methyl-7,8- dihydro-[l,4]dioxino[2,3-g]quinolin-4-amine (Compound 101a) (14.04 mg) as a white solid. Yield 27%. ESI-MS: 435 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) 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).

[0122] Example 2: Preparation of (R)-N-(l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6- methoxy-2-methyl-8,9-dihydro-[l,4]dioxino[2,3-h]quinazolin-4-amine (Compound 101b)

[0123]

[0124] First Step: Dissolve sodium tetraborate (30.0 g, 78.7 mmol) in water (300 mL), add methyl gallate (5.0 g, 27.2 mmol). Stir the reaction at room temperature for 1 hour. Dissolve sodium hydroxide (4.4 g, 110.0 mmol) in water (15 mL), slowly add to the reaction at room temperature, after the addition is complete, stir the reaction at room temperature for 15 minutes. Slowly add dimethyl sulfate (13.3 g, 105.4 mmol) at 0 °C. Stir the reaction at room temperature for 15 hours. Add sulfuric acid to the reaction to pH 6. Extract the reaction with dichloromethane (3 x 200 mL), wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give compound 101b-1 (3.6 g) as a light yellow oil. Yield 67%. ESI-MS: 199 [M+H] + .

[0125] Second Step: Dissolve 101b-1 (3.6 g, 21.8 mmol) and potassium carbonate (12.0 g, 86.8 mmol) in N,N-dimethylformamide (30 mL). Slowly add 1,2-dibromoethane (6.1 g, 32.5 mmol) dropwise with stirring at room temperature. Stir the reaction at room temperature for 18 hours. Extract the reaction with ethyl acetate / water (1:1, 400 mL), then wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, separate and purify the concentrate by medium pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 0-20%) to give compound 101b-2 (2.6 g) as a white solid. Yield 53%. ESI-MS: 225 [M+H] + .

[0126] Third step: Dissolve 101b-2 (2.6 g, 11.6 mmol) in acetic acid (20 mL). At room temperature, slowly add nitric acid (68%, 10.0 mL). Heat the reaction to 60 °C and stir for 10 hours. Pour the reaction into ice water (200 mL) and then extract with ethyl acetate (2 x 200 mL), wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the concentrate by column chromatography on medium pressure silica gel (eluent: ethyl acetate: petroleum ether = 0-20%) to give a mixture of compounds 101a-1 and 101b-3 (2.0 g) as a light yellow solid. Yield 64%. ESI-MS: 270 [M+H] + .

[0127] Fourth step: Dissolve the mixture of 101a-1 and 101b-3 (2.0 g, 7.4 mmol) in ethanol / water (20 mL / 20 mL). At room temperature, add iron powder (100 mesh, 2.3 g, 41 mmol) and ammonium chloride (2.2 g, 41 mmol) with stirring, heat to 90 °C, and stir for 8 hours. Cool the reaction, filter through celite, wash the filter cake with ethyl acetate (50 mL), concentrate the filtrate under reduced pressure, extract with ethyl acetate / water (1:1, 200 mL), then wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the concentrate by column chromatography on medium pressure silica gel (eluent: ethyl acetate: petroleum ether = 0-30%) to give a mixture of compounds 101a-2 and 101b-4 (1.4 g) as a light yellow solid. Yield 79%. ESI-MS: 240 [M+H] + .

[0128] Fifth step: Add the mixture of 101a-2 and 101b-4 (1.4 g, 5.8 mmol) to acetonitrile (30 mL). At room temperature, add hydrochloric acid in dioxane (4N, 25 mL) with stirring. Heat the reaction to 90 °C and stir for 6 hours, producing a large amount of solid. Cool the reaction, filter, wash the filter cake with water (20 mL), and dry in an oven. Compound 101b-5 (0.49 g) is obtained as a light yellow solid. Yield 34%. ESI-MS: 249 [M+H] + . Concentrate the filtrate under reduced pressure, and purify the concentrate by reverse phase chromatography to give compound 101a-3 (0.50 g) as a white-like solid. Yield 34.5%. ESI-MS: 249 [M+H] + .

[0129] Step 6: 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 h. The reaction was directly concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (3 x 50 mL), then saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography on a medium-pressure silica gel column (eluent: ethyl acetate: petroleum ether = 0-30%) to give compound 101b-6 (0.34 g) as a white solid. Yield 64%. ESI-MS: 267 [M+H] + .

[0130] Step 7: 101b-6 (60 mg, 0.2 mmol) was dissolved in isopropanol (4 mL), (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) were added, and the reaction was stirred at 110 °C for 16 h. The reaction was cooled and concentrated under reduced pressure. The concentrate was purified by preparative TLC (eluent: 100% ethyl acetate) to give compound 101b-7 (40 mg) as a light yellow solid. Yield 43%. ESI-MS: 465 [M+H] + .

[0131] Step 8: 101b-7 (40 mg, 0.1 mmol) was dissolved in ethanol (5 mL) and water (2 mL), iron powder (50 mg, 0.9 mmol) and ammonium chloride (48 mg, 2.0 mmol) were added, and the reaction was stirred at 90 °C for 2 h. The reaction was cooled, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic phase was concentrated under reduced pressure, and the concentrate was purified by high-pressure preparative liquid chromatography to give (R)-N-(1-(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] + . 1H-NMR (400 MHz, DMSO-d6) δ: ppm 7.96 (d, J = 8.0 Hz, 1 H), 7.35 (s, 1 H), 6.87 (s, 1 H), 6.84 (s, 1 H), 6.69 (s, 1 H), 5.59-5.51 (m, 3 H), 4.32-4.31 (m, 4 H), 3.89 (s, 3 H), 2.35 (s, 3 H), 1.54 (d, J = 8.0 Hz, 3 H).

[0132] Example 3: Preparation of 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]quinolin-4-amine (Compound 102a)

[0133]

[0134] First Step: 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). Stir the reaction at 90 °C for 10 h, cool and filter, wash the filter cake with ethyl acetate (100 mL), add water to the filtrate, separate the layers, extract the aqueous phase with ethyl acetate (3 x 100 mL), wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, purify the concentrate by column chromatography on a medium pressure flash silica gel column (eluent: ethyl acetate: petroleum ether = 30-60%) to give compound 102-1 (12.24 g) as a white solid. Yield 54%. ESI-MS: 211 [M+H] + .

[0135] Second Step: Dissolve 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) in N,N-dimethylformamide (80 mL), stir at 60 °C for 3 h. Cool the reaction, filter through celite, wash the filter cake with ethyl acetate (100 mL), add water to the filtrate, separate the layers, extract the aqueous phase with ethyl acetate (3 x 100 mL), wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, purify the concentrate by trituration with ethyl acetate to give compound 102-2 (8.9 g) as a white solid. Yield 67%. ESI-MS: 281 [M+H] + .

[0136] Step 3: Dissolve 102-2 (3 g, 10.71 mmol) in glacial acetic acid (15 mL). At room temperature, slowly add nitric acid (3 ml), warm up to 60 °C, stir for 10 h. Cool the reaction, then pour into water, extract with dichloromethane (3 x 50 mL), wash with water, saturated aqueous sodium bicarbonate solution, dry over anhydrous sodium sulfate, filter, concentrate to give compound 102-3 (3.3 g) as a brown oil. Yield 94%. ESI-MS: 326 [M+H] + .

[0137] Step 4: Dissolve 102-3 (3.3 g, 10.02 mmol) in ethanol (25 ml), at room temperature, add iron powder (100 mesh, 5.2 g, 100.22 mmol), ammonium chloride (5.4 g, 100.22 mmol) and water (25 ml), stir the reaction at 90 °C for 2 h. Cool the reaction, filter through celite, wash the filter cake with ethanol (100 mL) and ethyl acetate (100 mL), concentrate the filtrate under reduced pressure, extract the remaining aqueous phase with ethyl acetate (3 x 100 mL), wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give compound 102-4 (3.7 g, crude) as a brown solid. ESI-MS: 296 [M+H] + .

[0138] Step 5: Dissolve 102-4 (3.7 g), hydrochloric acid in dioxane (4 M) (20 ml) in acetonitrile (20 mL) under N2 atmosphere. Stir the reaction at room temperature for 2 h, warm up to 90 °C for 10 h. Cool the reaction, filter, rinse with dioxane, dissolve the filter cake in water, adjust to neutral with saturated sodium bicarbonate solution, extract with ethyl acetate (3 x 50 mL), concentrate, purify by column chromatography on silica gel (eluent: dichloromethane:methanol = 0-20%) to give compound 102-5 (1 g) as a white solid. Overall yield for two steps 33%. ESI-MS: 305 [M+H] + .

[0139] Step 6: Dissolve 102-5 (120 mg, 0.39 mmol) in phosphorus oxychloride (3 ml). Heat the reaction to 100 °C, stir for 4 h. Concentrate the system under reduced pressure, dilute with dichloromethane (20 ml), add dropwise to cold saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase with dichloromethane (3 x 20 mL), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, purify by column chromatography on silica gel (eluent: dichloromethane:methanol = 0-20%) to give compound 102-6 (50 mg) as a light brown solid. Yield 40%. ESI-MS: 323 [M+H] +.

[0140] Seventh step: Dissolve 102-6 (50 mg, 0.16 mmol), (R)-1-(3-nitro-5- (trifluoromethyl)phenyl)ethan-1-amine hydrochloride (44 mg, 0.16 mmol) in isopropanol (2 mL), add N,N-diisopropylethylamine (103 mg, 0.8 mmol) dropwise, reflux the reaction at 110 °C for 10 h. Cool the reaction, concentrate, add water and ethyl acetate, separate the layers, extract with ethyl acetate (3 x 20 mL), dry the organic phase over anhydrous sodium sulfate, concentrate, purify by column chromatography on silica gel (eluent: dichloromethane:methanol = 0-20%) to give compound 102-7 (44 mg) as a white solid. Yield 53%. ESI-MS: 521 [M+H] +

[0141] Eighth step: Dissolve 102-7 (44 mg, 0.084 mmol) in ethanol (2 ml), at room temperature under stirring, add iron powder (100 mesh, 47 mg, 0.85 mmol), ammonium chloride (45 g, 0.85 mmol) and water (2 ml), stir the reaction at 90 °C for 2 h. Cool the reaction, filter through celite, wash the filter cake with ethanol (100 mL) and ethyl acetate (100 mL), concentrate the filtrate under reduced pressure, extract the remaining aqueous phase with ethyl acetate (3 x 100 mL), wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, dissolve the concentrate in dimethyl sulfoxide (2 mL) and purify by column chromatography on C18 reverse phase (eluent: ACN: 5 mmol / L NH4HCO3 in water = 0-40%). Lyophilize 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-d6): 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).

[0142] Example 4: Preparation of (R)-N-(l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2- yl)ethyl)-6-methoxy-2-methyl-8,9-dihydro-[l,4]dioxino[2,3-h]quinolin-4-amine (Compound 105)

[0143]

[0144] First step: Dissolve 101b-6 (110 mg, 0.41 mmol) and (R)-l-(5-bromothiophen-2-yl)ethan-l- amine hydrochloride (110 mg, 0.49 mmol) in dimethyl sulfoxide (1 mL), drop in N,N- diisopropylethylamine (265 mg, 2.05 mmol), and stir at 150 °C for 10 h. Cool the reaction, concentrate, add water and ethyl acetate, separate, extract with ethyl acetate (3 x 20 mL), dry the organic phase with anhydrous sodium sulfate, concentrate, dissolve the crude product in dimethyl sulfoxide (2 mL), and purify with a C18 reverse phase column (eluent: ACN: 5 mmol / L NH4HCO3 aqueous solution = 0-40%) to obtain Compound 105-1 (100 mg) as a white solid. Yield 67%. ESI-MS: 437 [M+H] +

[0145] Second step: Dissolve 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) in a mixed solution of dioxane and water (5:1) (3 ml) under nitrogen protection, add tetrakis(triphenylphosphine)palladium (27 mg, 0.02 mmol), and stir at 100 °C for 10 h. Cool the reaction, concentrate, add 10 ml of water, extract with ethyl acetate (3 x 20 mL), dry the organic phase with anhydrous sodium sulfate, concentrate, dissolve the crude product in N,N-dimethylformamide (2 mL), and purify with a C18 reverse phase column (eluent: ACN: 5 mmol / L NH4HCO3 aqueous solution = 40-60%). Concentrate the target fraction, freeze-dry to obtain (R)-N-(l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6-methoxy-2-methyl-8,9-dihydro-[l,4]dioxino[2,3-h]quinolin-4-amine (25 mg) with a yield of 22%. ESI-MS: 491 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) 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).

[0146] Example 5: Preparation of (R)-6-methoxy-2-methyl-N-(l-(3-(trifluoromethyl)phenyl)ethyl)- 8,9-dihydro-[l,4]dioxino[2,3-h]quinazolin-4-amine (Compound 106)

[0147]

[0148] Dissolve 101b-6 (100 mg, 0.37 mmol) and (R)-l-(3-(trifluoromethyl)phenyl)ethan-l- amine hydrochloride (84 mg, 0.37 mmol) in isopropanol (4 mL), add N,N- diisopropylethylamine (480 mg, 3.74 mmol) dropwise, and warm to reflux for 10 h. Cool the reaction, concentrate, add water and ethyl acetate, separate, extract with ethyl acetate (3 x 20 mL), dry the organic phase over anhydrous sodium sulfate, concentrate, and purify the resulting crude product using a C18 reverse phase column (eluent: ACN: 5 mmol / L NH4HCO3 in water = 0-40%) after dissolving in dimethyl sulfoxide (2 mL). Lyophilize to give the title compound (28 mg) as a white solid. Yield 18%. ESI-MS: 420 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): 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).

[0149] Example 6: Preparation of (R)-N-(l-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl- 7,8-dihydro-[l,4]dioxino[2,3-g]quinazolin-4-amine (Compound 201)

[0150]

[0151] First step: 1 -Bromo-3-nitro-5-(trifluoromethyl)benzene (20.0 g, 74.1 mmol) was dissolved in dioxane (300 mL), tributyl(l-ethoxyvinyl)tin (32.1 g, 88.9 mmol), triethylamine (15.0 g, 148.5 mmol) and Pd(PPh3)2Cl2(2.6 g, 3.7 mmol) were added, and the mixture was stirred at 80 °C under nitrogen for 16 h. The reaction was cooled, hydrochloric acid (4 M) (20 mL) was added to the system, and the mixture was stirred at room temperature for 2 h. 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 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 light yellow oil in a yield of 75%. ESI-MS: 234 [M+H] + .

[0152] Second step: 201-1 (10.0 g, 42.9 mmol) was dissolved in tetrahydrofuran (150 mL), (R)-2-methylpropane-2-sulfmide (6.23 g, 51.5 mmol) and tetraethyl titanate (19.6 g, 86.0 mmol) were added, and the mixture was refluxed for 8 h. The reaction was cooled, poured into water, and a white precipitate was formed. The precipitate was removed by filtration, the filter cake was washed with ethyl acetate, the filtrate was extracted with ethyl acetate (2 x 100 mL), and the organic phase was concentrated under reduced pressure. The concentrate was separated and purified by column chromatography (ethyl acetate: petroleum ether = 0-40%) to obtain compound 201-2 (12.9 g) as a light yellow oil in a yield of 90%. ESI-MS: 337 [M+H] + .

[0153] Third step: 201-2 (12.9 g, 38.4 mmol) was dissolved in tetrahydrofuran (150 mL), and sodium borohydride (2.6 g, 69.1 mmol) was added at -78 °C. The reaction was slowly warmed to room temperature, and TLC was used to monitor the completion of the reaction. The reaction was quenched with water, extracted with ethyl acetate (100 mL), and the organic phase was concentrated under reduced pressure. The concentrate was separated and purified by column chromatography (ethyl acetate: petroleum ether = 0-40%) to obtain compound 201-3 as a light yellow solid in a yield of 65%. ESI-MS: 339 [M+H] + .

[0154] Fourth Step: Dissolve 201-3 (8.5 g, 25.1 mmol) in dioxane (100 mL), add hydrochloric acid (4 M solution in dioxane) (15 mL), stir the reaction at room temperature, monitor the reaction by TLC until the starting material is consumed, filter, wash the filter cake with ethyl acetate, and dry the product to obtain compound 201-4 (5.3 g) as a white solid in 78% yield. ESI-MS: 235 [M+H] + .

[0155] Fifth Step: Dissolve methyl 2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylate (10.0 g, 51.5 mmol) in acetic acid (30 mL), add concentrated nitric acid (8 mL) under ice water bath, stir the reaction at 70 °C for 6 hours. Cool the reaction and pour into ice water, a solid is formed, filter, wash the filter cake with water, and dry under vacuum to obtain compound 201-5 (10.1 g) as a light yellow solid in 82% yield. ESI-MS: 240 [M+H] + .

[0156] Sixth Step: 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), stir the reaction at 90 °C for 3 hours. Cool the reaction, 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 compound 201-6 (1.8 g) as a brown solid in 94% yield. ESI-MS: 210 [M+H] + .

[0157] Seventh Step: Dissolve 201-6 (1.8 g, 8.6 mmol) in acetonitrile (15 mL), add concentrated hydrochloric acid dropwise until the solid is completely dissolved, then stir the reaction at 80 °C for 16 hours. Cool the reaction, filter the precipitate, wash the filter cake with acetonitrile, and dry to obtain compound 201-7 (460 mg) as a white solid in 26% yield. ESI-MS: 219 [M+H] + .

[0158] Eighth Step: Dissolve 201-7 (460 mg, 2.1 mmol) in phosphorus oxychloride (15 mL), stir the reaction at 100 °C for 4 hours. Cool the reaction, concentrate under reduced pressure, dissolve the crude product in dichloromethane, wash the organic phase with saturated sodium bicarbonate solution, and concentrate under reduced pressure to obtain compound 201-8 (350 mg) as a yellow solid in 71% yield. ESI-MS: 237 [M+H] + .

[0159] Ninth step: 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), and reflux the reaction for 6 hours. Cool the reaction, concentrate under reduced pressure, and purify the concentrate by column chromatography (methanol:methylene chloride = 0-10%) to obtain compound 201-9 (70 mg) at a yield of 32%. ESI-MS: 435 [M+H] + .

[0160] Tenth step: 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 stir the reaction at 90°C for 2 hours. Cool the reaction, 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 10 mL), concentrate the organic phase under reduced pressure, and purify the concentrate 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 at a yield of 41%. ESI-MS: 405 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) 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).

[0161] Example 7: Preparation of (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine (Compound 203)

[0162]

[0163] First step: Compound 201-8 (300 mg, 1.3 mmol) was dissolved in isopropanol (6 mL), (R)-1-(5-bromothiophen-2-yl)ethan-1-amine hydrochloride (470 mg, 2.0 mmol) and N,N-diisopropylethylamine (516 mg, 4.0 mmol) were added, and the reaction solution was stirred at 110 °C for 16 h under reflux. After cooling, the reaction solution was 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]quinolin-4-amine (203-1) (203 mg) at a yield of 38%. ESI-MS: 406 [M+H] +

[0164] Second step: 203-1 (140 mg, 0.3 mmol) was dissolved in 1,4-dioxane:water (5:1) (6 mL), (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) were added, and the reaction solution was reacted at 100 °C for 16 h under nitrogen protection. After cooling, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (10 mL), and the organic phase was concentrated under reduced pressure. The concentrate was separated and purified by 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)-2-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinolin-4-amine (compound 203) (30.43 mg) as a white solid at a yield of 19%. ESI-MS: 461 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) 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).

[0165] Example 8: Preparation of (R)-2-(6-methyl-8-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-1H-pyrazolo[3,4-g]quinolin-1-yl)ethan-1-ol (506)

[0166]

[0167] First Step: Dissolve 1H-indazole-6-carboxylic acid methyl ester (5.0 g, 28.4 mmol) in sulfuric acid / acetic acid mixture (1:2, 30 mL), add concentrated nitric acid (8 mL) under ice bath, stir at room temperature for 16 hours. Pour the reaction solution into ice water, extract with ethyl acetate (2 x 100 mL), concentrate the organic phase under reduced pressure, separate and purify the concentrate 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), yellowish oil, yield 89%. ESI-MS: 222 [M+H] +

[0168] Second Step: Dissolve 506-1 (5.6 g, 25.2 mmol) in acetonitrile (40 mL), add potassium carbonate (10.4 g, 75.7 mmol) and ((2-bromoethoxy)methyl)benzene (6.0 g, 27.7 mmol), and react the solution at 80°C for 4 hours. Cool the reaction solution, concentrate under reduced pressure, dilute with water (100 mL), extract with ethyl acetate (2 x 100 mL), concentrate the organic phase under reduced pressure, separate and purify the concentrate by column chromatography (ethyl acetate: petroleum ether = 0~60%), to obtain 1-(2-(benzyloxy)ethyl)-5-nitro-1H-indazole-6-carboxylic acid methyl ester (506-2) (4.0 g), yellowish solid, yield 45%. ESI-MS: 356 [M+H] +

[0169] Third Step: Dissolve (506-2) (2.0 g, 5.6 mmol) in methanol (20 mL), add iron powder (3.1 g, 56.1 mmol) and a solution of ammonium chloride (3.0 g, 56.1 mmol) dissolved in water (5 mL), and react the solution 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-carboxylic acid methyl ester (506-3) (1.6 g), brown solid, yield 89%. ESI-MS: 326 [M+H] +

[0170] Fourth step: (506-3) (1.6 g, 4.9 mmol) was dissolved in acetonitrile (15 mL), concentrated hydrochloric acid was added dropwise until the generated precipitate dissolved, then the reaction solution was stirred at 80 °C for 16 hours. After cooling, the generated precipitate was filtered, the filter cake was washed with acetonitrile, and dried to obtain 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] +

[0171] Fifth step: (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. After cooling, it was 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-methyl-1H-pyrazolo[3,4-g]quinazoline (506-5) (200 mg), yellow solid, yield 40%. ESI-MS: 353 [M+H] +

[0172] Sixth step: (506-5) (120 mg, 0.3 mmol) was dissolved in toluene (5 mL), (R)-1-(3-(trifluoromethyl)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) were added, and the reaction was carried out at 100 °C for 13 hours under nitrogen protection. After cooling, it was filtered, 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]quinazolin-8-amine (506-6) (30 mg), brown solid, yield 21%. ESI-MS: 506 [M+H] +

[0173] Seventh step: dissolve (506-6) (30 mg, 0.1 mmol) in toluene (2 mL), add trifluoroacetic acid (1 mL), and react at 70 °C 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 purify the concentrate by high-pressure preparative liquid chromatography 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) as a white solid. Yield 41%. ESI-MS: 416 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) 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).

[0174] Example 9: Preparation of (R)-2,6-dimethyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-6H-[1,4]oxazino[3,2-g]quinazolin-7(8H)-one (Compound 507)

[0175]

[0176] First step: 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). Heat the reaction to 60 °C and stir for 5 hours. Cool the reaction, filter, wash the filter cake with acetone (20 mL). Concentrate the filtrate under reduced pressure, recrystallize from petroleum ether (500 mL), filter, wash the filter cake with petroleum ether (20 mL), and dry to obtain compound 507-1 (6.7 g) as a light yellow solid. Yield 83%. ESI-MS: 270 [M+H] + .

[0177] Second Step: Dissolve 507-1 (6.7 g, 24.9 mmol) in ethanol / water (100 mL / 100 mL). At room temperature, add iron powder (100 mesh, 14.0 g, 250 mmol), ammonium chloride (13.4 g, 250 mmol) and acetic acid (68%, 8 mL). Heat the reaction to 90 °C and stir for 16 hours. Cool the reaction, filter through celite, wash the filter cake with ethyl acetate (50 mL), concentrate the filtrate under reduced pressure, extract with ethyl acetate / water (1:1, 800 mL), then wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the concentrate by column chromatography on medium pressure silica gel (eluent: ethyl acetate: petroleum ether = 0-50%) to give compound 507-2 (3.7 g) as a light yellow solid. Yield 71%. ESI-MS: 208 [M+H] + .

[0178] Third Step: Dissolve 507-2 (3.7 g, 17.9 mmol) in N,N-dimethylformamide (40 mL). At room temperature, add potassium carbonate (7.4 g, 53.7 mmol) and iodomethane (1.7 mL, 26.9 mmol). Heat the reaction to 60 °C and stir for 10 hours. Pour the reaction into ice water (200 mL) and extract with ethyl acetate (2 x 200 mL), then wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give compound 507-3 (3.4 g) as a light yellow solid. Yield 85%. ESI-MS: 222 [M+H] + .

[0179] Fourth Step: Dissolve 507-3 (3.4 g, 15.4 mmol) in acetic acid (30 mL). At room temperature, slowly add nitric acid (68%, 10.0 mL) dropwise. Heat the reaction to 60 °C and stir for 10 hours. Pour the reaction into ice water (200 mL) and extract with ethyl acetate (2 x 200 mL), then wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the concentrate by column chromatography on medium pressure silica gel (eluent: ethyl acetate: petroleum ether = 0-50%) to give compound 507-4 (2.6 g) as a light yellow solid. Yield 63%. ESI-MS: 267 [M+H] + .

[0180] Step 5: Dissolve 507-4 (2.6 g, 9.8 mmol) in ethanol / water (20 mL / 20 mL). Stir at room temperature, add iron powder (100 mesh, 5.5 g, 98 mmol) and ammonium chloride (5.2 g, 98 mmol), heat to 90 °C, stir for 10 h. Cool the reaction, filter through celite, wash the filter cake with ethyl acetate (50 mL), concentrate the filtrate under reduced pressure, extract with ethyl acetate / water (1:1, 200 mL), then wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the concentrate by column chromatography on medium pressure silica gel (eluent: ethyl acetate: petroleum ether = 0-50%) to give compound 507-5 (1.7 g) as a light yellow solid. Yield 74%. ESI-MS: 237 [M+H] + .

[0181] Step 6: Add 507-5 (1.7 g, 7.2 mmol) to acetonitrile (20 mL). Stir at room temperature, add hydrochloric acid in dioxane (4 N, 20 mL). Heat the reaction to 90 °C, stir for 12 h, which produces a large amount of solid. Cool the reaction, filter, wash the filter cake with water (20 mL), and dry in oven to give compound 507-6 (1.3 g) as an off-white solid. Yield 71%. ESI-MS: 246 [M+H] + .

[0182] Step 7: Add 507-6 (1.3 g, 5.3 mmol) to phosphorus oxychloride (25 mL). Heat the reaction to 100 °C, stir for 10 h, concentrate the reaction directly under reduced pressure, dissolve the concentrate in dichloromethane (80 mL), wash with saturated aqueous sodium bicarbonate solution (3 x 80 mL), then wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the concentrate by column chromatography on medium pressure silica gel (eluent: ethyl acetate: petroleum ether = 0-30%) to give compound 507-7 (0.91 g) as a light yellow solid. Yield 65%. ESI-MS: 264 [M+H] + .

[0183] Eighth step: Dissolve 507-7 (100 mg, 0.4 mmol) in dimethyl sulfoxide (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), and stir the reaction at 130 °C for 16 hours. Cool the reaction, dilute with water (10 mL), extract with ethyl acetate (20 mL), concentrate the organic phase under reduced pressure, and purify the concentrate by column chromatography (methanol:dichloromethane = 0-8%) to obtain (R)-2,6-dimethyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-6H-[1,4]oxazino[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-d6) 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).

[0184] Biological Assay

[0185] Experimental Example 1. KRAS::SOS1 HTRF binding assay

[0186] This assay can be used to examine the potency of a compound to inhibit the protein-protein interaction between SOS1 and KRAS G12C This demonstrates the molecular mode of action of the compound. Low IC 50 values indicate high potency of SOS1 inhibitor compounds in this assay setting.

[0187] Reagents:

[0188] • GST-SOS1 (aa564-1049), produced in-house

[0189] • His-KRAS G12C (aa1-169), produced in-house

[0190] • MAb Anti-6his-Tb cryptate Gold, purchased from Cisbio (cat# 61HI2TLA)

[0191] • MAb Anti-GST-XL665, purchased from Cisbio (cat# 61GSTXLA)

[0192] Assay plate: ProxiPlate-384 Plus, purchased from PerkinElmer (cat# 6008280)

[0193] Assay buffer: PPI, purchased from Cisbio (cat# 61DB10RDF)

[0194] Assay protocol:

[0195] • The test compound was dissolved in DMSO, prepared stock concentration at 10 mM, and diluted the compound concentration to 2 mM with DMSO as the assay starting concentration, serially diluted the 2 mM starting concentration compound solution for 10 concentrations, 0.1 μL of each concentration compound solution was transferred to the 384-well assay plate (in duplicate, double-replicate) using Labcyte Echo instrument;

[0196] • 5 μL of His-KRAS G12C at specific concentration was added to the 0.1 μL compound solution, centrifuged at 1000 rpm for 1 min on Eppendorf 5810R centrifuge;

[0197] • Subsequently, 5 μL of GST-SOS1 at specific concentration was added, also centrifuged at 1000 rpm for 1 min on Eppendorf 5810R centrifuge;

[0198] • The 384-well assay plate was incubated at 25 °C for 15 min;

[0199] • Then, 10 μL of MAb Anti-6his-Tb and MAb Anti-GST-XL665 mixture was added, centrifuged at 1000 rpm for 1 min on Eppendorf 5810R centrifuge;

[0200] • The 384-well assay plate was incubated at 25 °C for 2 h;

[0201] • Finally, the plate was read using Perkin Elmer Envision 2104 instrument, and the 665 / 615 nm signal ratio was obtained.

[0202] Each plate contained the following controls:

[0203] • DMSO + KRAS + SOS1 + MAb Anti-6his-Tb + MAb Anti-GST-XL665

[0204] Result calculation:

[0205] IC was calculated and analyzed using a 4-parameter regression equation 50 The results of the assay are shown in the table below.

[0206] 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

[0207] Various modifications to the application will be apparent to those skilled in the art from the foregoing description, which modifications are intended to fall within the scope of the application. Each reference cited in this application, including all patents, patent applications, journal articles, books, and any other publications, are incorporated herein by reference in their entireties.

Claims

1. A compound or a pharmaceutically acceptable salt or isotope-labeled compound thereof, wherein the compound has the structure of formula (II), (III), (IV) or (V): in: Ring B is a benzene ring or a thiophene ring; R is independently selected from C each time it appears. 1-6 Alkyl or C 1-6 alkylene-OH; R 1 Each time it appears, it is independently selected from halogen, -NH2, 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 groups, saturated or partially unsaturated 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 membered heteroaryl groups, wherein the alkylene, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally selected independently by one or more halogens, -OH, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl and 5-14 heteroaryl and -C 1-6 Alkylene-NR 5 R 6 Substituents of the substituents; R 2 and R 2 Each is independently selected from H, -OC 1-6 Alkyl groups and -O- (3-10 membered heterocyclic groups); R 3 C 1-6 alkyl; R 4 For H; R 5 and R 6 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups; m is an integer selected from 0, 1, 2, 3, and 4; and n is 0 or 1; The condition is that the compound is not one of the following compounds:

2. The compound of claim 1 or a pharmaceutically acceptable salt or isotopically labeled compound thereof, wherein R is independently methyl or -CH2CH2-OH each time it appears.

3. The compound of claim 1 or a pharmaceutically acceptable salt or isotope-labeled compound thereof, wherein R 1 Each time it appears, it is independently selected from CF3, NH2, and And m is 1 or 2.

4. The compound of claim 1 or a pharmaceutically acceptable salt or isotope-labeled compound thereof, wherein... Selected from 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or isotope-labeled compound thereof, wherein R 2 and R 2 One of them is H, and the other is H, -OCH3, or 6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or isotope-labeled compound thereof, wherein R 3 It is a methyl group.

7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or isotope-labeled compound thereof, wherein the compound is selected from:

8. A pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of any one of claims 1-7 or a pharmaceutically acceptable salt or isotope-labeled compound thereof, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, wherein it is a solid dosage form, a semi-solid dosage form, a liquid dosage form or a gaseous dosage form.

10. Use of any compound of claims 1-7 or a pharmaceutically acceptable salt or isotopically labeled compound thereof, or the pharmaceutical composition of claim 8 or 9, in the preparation of a medicament used as an SOS1 inhibitor.

11. The use of claim 10, wherein the drug is used for the prevention or treatment of cancer or RAS disease.

12. The use of claim 11, wherein the cancer is selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, 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.

13. The use of claim 10, wherein the medicament is used for the prevention or treatment of neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial-dermal syndrome (CFC), Legg's syndrome, or hereditary gingival fibromatosis.

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