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

Abstract

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

Description

Invention Field

[0001] This invention relates to SOS1 inhibitors, pharmaceutical compositions comprising the same, and their use for the prevention or treatment of diseases. Background of the Invention

[0003] RAS family proteins are small GTPases encoded by the RAS gene, including KRAS (Kirsten murine sarcoma virus oncogene homolog), HRAS (Harvey murine sarcoma virus oncogene homolog), and NRAS (neuroblastoma RAS virus oncogene homolog), and any mutants thereof. Intracellularly, RAS proteins switch between inactive and activated states; they are inactive when bound to guanine diphosphate (GDP) and activated when bound to guanine triphosphate (GTP). The intrinsic GTPase activity of RAS proteins is weak, and their intrinsic GDP-GTP nucleotide exchange rate is low. The transition between their inactivated and activated states is regulated by two types of factors: GTPase activating proteins (GAPs), which catalyze the hydrolysis of GTP bound to RAS proteins into GDP, thus inactivating the RAS protein; and guanine nucleotide exchange factors (GEFs), including SOS1 (Son of Sevenless 1), which catalyze the binding of RAS proteins to GTP, thereby promoting RAS protein activation. In its activated state, RAS proteins can activate a series of downstream effector proteins (including RAF and phosphatidylinositol kinase PI3K) to activate multiple signal transduction pathways, such as the RAF / MEK / ERK (MAPK) pathway and the PI3K / AKT / mTOR pathway, thereby regulating various cellular processes such as cell proliferation, survival, metabolism, movement, 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 consequently, persistent activation of downstream effector pathways. RAS is one of the most frequently mutated oncogenes in human cancers. KRAS mutations (such as G12, G13, and Q61) are widespread in various human cancers, including lung cancer, colorectal cancer, and pancreatic cancer. HRAS and NRAS mutations also occur in different types of human cancer. RAS protein mutations, overexpression, and gene amplification are potential resistance mechanisms to various anticancer drugs, such as EGFR antibodies cetuximab and panitumumab, and EGFR tyrosine kinase inhibitor osimertinib.

[0004] The SOS protein was first discovered in fruit flies, and SOS1 is the human homolog of the fruit fly SOS protein. The SOS1 protein is a multidomain protein composed of 1333 amino acids, consisting of an N-terminal domain, a Dbl homology domain (DH), a Pleckstrin homology domain (PH), a Rasexchanger motif (REM), a CDC25 homology domain, and a C-terminal domain. Among them, the REM and CDC25 homology domains together form the catalytic functional domain, which is an essential part of the SOS1 protein to perform the catalytic function of guanine nucleotide exchange factor. Studies have shown that SOS1 plays a crucial role in the activation and signal transduction of mutant RAS proteins in RAS-mutant cancers. SOS1 knockout inhibits the survival and proliferation of KRAS-mutant tumor cells. Re-expression of the mutant SOS1 at its catalytic site in SOS1-knockout KRAS-mutant tumor cells prevents the cells from regaining survival and proliferation, demonstrating that the guanine nucleotide exchange catalytic activity of SOS1 plays a key role in the survival and proliferation of KRAS-mutant tumor cells. Besides regulating mutant RAS proteins, SOS1 can also participate in signal activation and transduction processes in tumor cells through other mechanisms. SOS1 can bind to the growth factor receptor-binding protein Grb2 to form the SOS1-Grb2 complex, which in turn binds to activated receptor tyrosine kinases (such as EGFR, ErbB2 / 3 / 4, VEGFR1 / 2 / 3, PDGFR-A / B, FGFR1 / 2 / 3, IGF1R, ALK, ROS1, TRK-A / B / C, RET, c-MET, AXL, etc.) or is recruited by other cell surface membrane receptors (such as TCR, BCR, CSF1R). SOS1 can also act as a guanine nucleotide exchange factor to activate the GTPase RAC1, which is associated with various human cancers and other diseases. Studies have shown that SOS1 mutations exist in embryonal rhabdomyosarcoma, testicular Sertoli cell tumors, cutaneous granulosa cell tumors, and lung adenocarcinoma, and overexpression of SOS1 protein has also been found in bladder cancer and prostate cancer.

[0005] SOS2 is a homolog of SOS1 in mammalian cells and also functions as a guanine nucleotide exchanger. Studies in mouse gene knockout models have shown that germline SOS1 knockout leads to mid-pregnancy embryonic death, while adult mice with SOS1 knockout can survive. In contrast, SOS2 knockout has no significant phenotypic changes in embryos or mature mice, while adult mice with both SOS1 and SOS2 knockout die rapidly. This suggests that selectively targeting SOS1 may achieve a high therapeutic index for RAS-mutant tumors regulated by SOS1.

[0006] Inhibiting the binding of SOS1 catalytic sites to RAS proteins can block SOS1-mediated RAS protein activation, thereby inhibiting downstream signal transduction of RAS proteins (such as ERK phosphorylation activation). SOS1 inhibitors with this mechanism of action have inhibitory effects on mutant RAS protein-dependent tumor cells, such as KRAS mutant tumor cell lines (e.g., inhibiting proliferation, survival, metastasis). Invention Overview

[0008] This invention provides compounds for use as SOS1 inhibitors, which exhibit excellent inhibitory activity against SOS1. The SOS1 inhibitors of this invention inhibit the interaction and activation of SOS1 with RAS proteins, particularly showing significant inhibitory effects on the interaction between SOS1 and KRAS mutant proteins. This provides pharmacological benefits to cancer patients carrying mutations in RAS and its 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). Furthermore, the SOS1 inhibitors will also provide pharmacological benefits in RAC1-dependent cancers and other diseases associated with RAS signaling pathway dysregulation, such as neurofibromatosis, Noonan syndrome (NS), cardiofacial-skin syndrome (CFC), and hereditary gingival fibroma type 1.

[0009] The compounds of the present invention also possess superior properties such as better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, suitable half-life and duration of action), and improved safety (lower toxicity and / or fewer side effects, wider therapeutic window).

[0010] One aspect of the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound has the structure of formula (I):

[0011]

[0012] in:

[0013] X 1 X 2 X 3 and X 4 Each is independently selected from C=O, CH2, CHR, C(R)2 and NLR 2 Preferably, X 1 X 2X 3 and X 4 At least one of them is NLR 2 ;

[0014] L is selected from direct bond, C 1-6 Alkylene, C(=O), O, S(=O), S(=O)2 and NR 4 ;

[0015] Ring B is selected from C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings and 5-14 membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocycle are C (=O);

[0016] R and R 1 Each time it appears, it is independently selected from halogen, -NH2, -CN, -NO2, -OH, -OC. 1-6 Alkyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkylene-OH, Halogenated C 1-6 alkylene-OH, C 2-6 alkenyl, C 2-6 Alkyne group, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon groups, saturated or partially unsaturated 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups, wherein at most two ring members of the cyclic hydrocarbon group and heterocyclic group are C (=O), and when m is greater than 1 and / or n is greater than 1, the two R groups are C (=O). 1 And / or two Rs together with the atoms they are attached to optionally constitute C. 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocycle are C (=O);

[0017] R 2 Selected from H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkylene-OH, Halogenated C 1-6 alkylene-OH, C 2-6 alkenyl, C 2-6 Alkyne group, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon groups, saturated or partially unsaturated 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -C(=O)R 5 -OC(=O)R 5 -C(=O)OR5 -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 R 6 -C 1-6 Alkylenes -O(P=O)(OH)2 and -OC 1-6 Alkylene-NR ５ R 6 ;

[0018] R 3 and R 4 Each is independently selected from H, halogens, -NH2, -CN, -NO2, -OH, -OC 1-6 Alkyl, -O- (3-10 membered heterocyclic), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkylene-OH, Halogenated C 1-6 alkylene-OH, C 2-6 alkenyl, C 2-6 Alkyne group, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon groups, saturated or partially unsaturated 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -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 -NR5 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 Alkylenes -O(P=O)(OH)2 and -OC 1-6 Alkylene-NR 5 R 6 ;

[0019] 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 R6 -C 1-6 Alkylene-NR ５ R 6 and -OC 1-6 Alkylene-NR 5 R 6 The alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, oxo, -NH2, -CN, -NO2, C. 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl groups;

[0020] 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; and

[0021] m is an integer selected from 0, 1, 2, 3, and 4.

[0022] Another aspect of the invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is preferably a solid dosage form, a semi-solid dosage form, a liquid dosage form or a gaseous dosage form.

[0023] Another aspect of the invention provides the use of the compounds of the invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs of the invention, or pharmaceutical compositions of the invention, in the preparation of a medicament used as an SOS1 inhibitor.

[0024] Another aspect of the invention provides compounds of the invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs of the invention, or pharmaceutical compositions of the invention, which are used as SOS1 inhibitors.

[0025] Another aspect of the invention provides a method for preventing or treating SOS1-related diseases, the method comprising administering to an individual in need an effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug of the invention or a pharmaceutical composition of the invention. Invention Details

[0027] definition

[0028] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0029] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0030] As used herein, the term "alkylene" means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0031] 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" is used to refer to... 1-6 "Alkyl" refers to a linear or branched group with 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Ci5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C" 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0032] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing a double bond and having 2–6 carbon atoms ("C"). 2-6The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-alkenyl) form, pure Z (iso-alkenyl) form, or any mixture thereof.

[0033] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0034] 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 spirocyclic, fused, or bridged systems (e.g., bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.)) which is optionally substituted with one or more (e.g., one to three) 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 (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 6 cyclic carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0035] As used herein, the terms “cycloalkylene group,” “cycloalkylene group,” and “hydrocarbon ring” refer to a saturated (i.e., “cycloalkylene group” and “cycloalkylene group”) or unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic (including spirocyclic, fused, or bridged systems) hydrocarbon ring having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) cyclic carbon atoms, including but not limited to (cycloalkylene group), cyclopropyl (ring), (cycloalkylene group), (cycloalkylene group), cyclopentyl (ring), (cyclohexyl (ring), (cycloalkylene group), (cycloheptyl (ring), (cycloalkylene group), (cyclooctyl (ring), (cycloalkylene group), (cyclohexenyl (ring), etc.

[0036] As used herein, the terms “heterocyclic group,” “sub-heterocyclic group,” and “heterocycle” refer to a cyclic group having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S, and the remaining ring atoms are C-based saturated (i.e., heterocyclic alkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring). For example, “3-10 membered (sub)heterocyclic group” is a saturated or partially unsaturated (sub)heterocyclic group having 2 to 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 heterocyclic groups and heterocyclic groups include, but are not limited to: (heterocyclic)epoxyalkyl, (heterocyclic)aziridinyl, (heterocyclic)azetidinyl, (heterocyclic)oxetanyl, (heterocyclic)tetrahydrofuranyl, (heterocyclic)dioxolinyl, (heterocyclic)pyrrolylyl, (heterocyclic)pyrrolidone, (heterocyclic)imidazylyl, (heterocyclic)pyrrolinyl, (heterocyclic)tetrahydropyranyl, (heterocyclic)piperidinyl, (heterocyclic)morpholinyl, (heterocyclic)dithianyl, (heterocyclic)thiomorpholinyl, (heterocyclic)piperazinyl, or (heterocyclic)trithianyl. The groups also encompass bicyclic systems, including spirocyclic, fused, or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclic and heterocyclic groups may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0037] As used herein, the terms “(aryl)aryl” and “aromatic ring” refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated π-electron system. For example, as used herein, the term “C…” 6-10 (Asyl) aryl" and "C 6-10 "Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or ()naphthyl (naphthalene ring). The ()aryl and aromatic rings are optionally substituented with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted. (Aromatic) aryl and aromatic rings are optionally substituted with another ring (e.g., C10). 3-10 Fused groups (hydrocarbon rings, 3-10 membered heterocycles, or 5-14 membered heteroaromatic rings), the fused groups being, for example,...

[0038] As used herein, the terms “(sub)heteroaryl” and “heteroary ring” refer to monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, the "(hybrid)aryl" or "heteroary ring" is selected from (thiopheneyl), (furanyl), (pyrrolyl), (oxazolyl), (thiazolyl), (imidazolyl), (pyrazolyl), (isoxazolyl), (isothiazolyl), (oxadiazolyl), (triazolyl), (thiadiazolyl, etc., and their benzo[derivatives]; or (pyridyl), (pyridazinyl), (pyrimidinyl), (pyrazinyl), (triazinyl), etc., and their benzo[derivatives]. The "(hybrid)aryl" and "heteroary ring" may also optionally be combined with another ring (e.g., C14). 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Fused aromatic rings (or 5-14 membered heteroaromatic rings), the fused groups being, for example,

[0039] As used herein, the term "aralkyl" preferably refers to an aryl or heteroaryl-substituted alkyl group, wherein the aryl, heteroaryl, and alkyl groups are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0040] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br or I.

[0041] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in a ring, and optionally also comprising one or more (e.g., one, two, three, or four) ring members selected from N, O, C=O, S, S=O, and S(=O)2, which are connected to the remainder of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any of the remaining ring atoms, wherein the nitrogen-containing heterocycle is optionally benzofused, and preferably connected to the remainder of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any of the carbon atoms in the fused benzene ring.

[0042] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0043] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0044] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0045] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0046] Unless otherwise specified, as used herein, the connection point of a substituent may be located at any suitable position of the substituent.

[0047] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0048] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., ... 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0049] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0050] Solid lines may be used in this article. solid wedge Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0051] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0052] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, 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, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0053] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0054] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, hexafluorophosphates, hymenates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodates / iodides, hydroxyethyl sulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthylcarbamates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthyl salts, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, glycosides, stearates, succinates, tannins, tartrates, toluenesulfonates, trifluoroacetates, and xinofoate.

[0055] Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0056] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts for the compounds of the present invention are known to those skilled in the art.

[0057] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0058] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0059] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides; those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, 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. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0060] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0061] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0062] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0063] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0064] compound

[0065] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound has the structure of formula (I):

[0066]

[0067] in:

[0068] X 1 X 2 X 3 and X 4Each is independently selected from C=O, CH2, CHR, C(R)2 and NLR 2 Preferably, X 1 X 2 X 3 and X 4 At least one of them is NLR 2 ;

[0069] L is selected from direct bond, C 1-6 Alkylene, C(=O), O, S(=O), S(=O)2 and NR 4 ;

[0070] Ring B is selected from C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings and 5-14 membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocycle are C (=O);

[0071] R and R 1 Each time it appears, it is independently selected from halogen, -NH2, -CN, -NO2, -OH, -OC. 1-6 Alkyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkylene-OH, Halogenated C 1-6 alkylene-OH, C 2-6 alkenyl, C 2-6 Alkyne group, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon groups, saturated or partially unsaturated 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups, wherein at most two ring members of the cyclic hydrocarbon group and heterocyclic group are C (=O), and when m is greater than 1 and / or n is greater than 1, the two R groups are C (=O). 1 And / or two Rs together with the atoms they are attached to optionally constitute C. 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Aromatic rings or 5-14 membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocycle are C (=O);

[0072] R 2 Selected from H, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkylene-OH, Halogenated C 1-6 alkylene-OH, C 2-6 alkenyl, C 2-6 Alkyne group, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon groups, saturated or partially unsaturated 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C6-12 Aryl alkyl group, -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 R 6 -C 1-6 Alkylenes -O(P=O)(OH)2 and -OC 1-6 Alkylene-NR 5 R 6 ;

[0073] R 3 and R 4 Each is independently selected from H, halogens, -NH2, -CN, -NO2, -OH, -OC 1-6 Alkyl, -O- (3-10 membered heterocyclic), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkylene-OH, Halogenated C 1-6 alkylene-OH, C 2-6 alkenyl, C 2-6 Alkyne group, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon groups, saturated or partially unsaturated 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 heteroaryl, C 6-12 Aryl alkyl group, -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 R 6 -C 1-6 Alkylenes -O(P=O)(OH)2 and -OC 1-6 Alkylene-NR 5 R 6 ;

[0074] 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 R 6 and -OC 1-6 Alkylene-NR 5 R 6 The alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and aralkyl groups are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, oxo, -NH2, -CN, -NO2, C. 1-6 Alkyl, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-14 quinone heteroaryl and C 6-12 Aryl alkyl groups;

[0075] 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; and

[0076] m is an integer selected from 0, 1, 2, 3, and 4.

[0077] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound has the structure of formula (II):

[0078]

[0079] Ring A is and

[0080] n is an integer selected from 0, 1, 2 or 3.

[0081] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein L is a direct bond, -CH2-, or C (=O).

[0082] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R２ C is saturated or partially unsaturated 3-10 A cyclic hydrocarbon group or a 3-10 membered heterocyclic group that is saturated or partially unsaturated, wherein the cyclic hydrocarbon group and the heterocyclic group are optionally composed of one or more members selected from -C(=O)R 5 and -C(=O)NR 5 R 6 Substituents of the substituents;

[0083] Preferably, R 2 It is cyclobutyl, cyclohexyl, piperidinyl or tetrahydropyranyl, which is optionally substituted by one or more substituents selected from -C(=O)CH3 and -C(=O)N(CH3)2;

[0084] More preferably, -LR 2 Selected from

[0085] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein ring B is a bicyclic [1.1.1]pentane ring, a 2-oxabicyclic [2.1.1]hexane ring, a benzene ring, or a thiophene ring, most preferably a benzene ring or a thiophene ring.

[0086] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 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 Substitution of aryl and 5-14 membered heteroaryl groups;

[0087] When m is greater than 1, the two R 1 Together with the atoms it is attached to, they optionally constitute C 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10Aromatic rings or 5-14 membered heteroaromatic rings, wherein at most two ring members of the hydrocarbon ring and heterocycle are C (=O), and the hydrocarbon ring, heterocycle, aromatic ring and heteroaromatic ring are optionally substituted by one or more halogens;

[0088] Preferably, R 1 Each time it appears, it is independently selected from CF3, NH2, And m is 1 or 2.

[0089] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein Selected from

[0090] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 3 Selected from H and C 1-6 Alkyl; preferably, R 3 It is a methyl group.

[0091] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 4 Selected from H and C 1-6 Alkyl; preferably, R 4 For H.

[0092] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound has the structure of formula (III):

[0093]

[0094] This invention covers compounds obtained by arbitrarily combining various embodiments.

[0095] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound is selected from:

[0096]

[0097] Pharmaceutical compositions and treatment methods

[0098] In some embodiments, the present invention provides a pharmaceutical composition comprising a preventatively or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is preferably a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form. In some embodiments, the pharmaceutical composition may also comprise one or more other therapeutic agents.

[0099] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs of the present invention, or pharmaceutical compositions of the present invention, in the preparation of a medicament used as an SOS1 inhibitor.

[0100] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs of the present invention, or pharmaceutical compositions of the present invention, which are used as SOS1 inhibitors.

[0101] In some embodiments, the present invention provides a method for preventing or treating SOS1-related diseases, the method comprising administering to an individual in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug of the present invention, or a pharmaceutical composition of the present invention.

[0102] In some implementations, the SOS1-related diseases include cancers (e.g., 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), and RAS diseases (e.g., 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, and hereditary gingival fibromatosis).

[0103] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0104] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The compositions may also contain small amounts of wetting agents, emulsifiers, or pH buffers as needed. Oral formulations may contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0105] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as by injection (e.g., intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulations or by inhalation.

[0106] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0107] 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, and syrups.

[0108] As used in this article, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to some extent.

[0109] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.).

[0114] In some embodiments, the pharmaceutical compositions of the present invention may also contain one or more additional therapeutic or preventative agents. Example

[0115] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0116] The structure of the compound was determined by nuclear magnetic resonance spectroscopy (NMR). 1 Confirmation was performed using 1H NMR or mass spectrometry (MS).

[0117] Chemical shift (δ) is given in parts per million (ppm). 1 H NMR measurements were performed on a Bruker BioSpin GmbH 400 NMR spectrometer. The test solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS).

[0118] LC-MS determinations were performed on a Shimadzu LC-MS-2020 liquid chromatography-mass spectrometry system (manufacturer: Shimadzu, model: Shimadzu LC-MS-2020).

[0119] The preparative high performance liquid chromatography was performed using a Waters 2767 (Waters Sunfire, C18, 19×250mm 10µm column).

[0120] Thin-layer chromatography (TLC) was performed using Huanghai brand HSGF 254 (5×20em) silica gel plates, while preparative thin-layer chromatography was performed using Yantai-produced GF 254 (0.4~0.5nm) silica gel plates.

[0121] The reaction was detected by thin-layer chromatography (TLC) or LC-MS. The developing solvent systems used included dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate. The developing solvent system was adjusted according to the polarity of the compounds to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

[0122] The microwave reaction was performed using a BiotageInitiator+ (400W, RT~300℃) microwave reactor.

[0123] Column chromatography typically uses 200-300 mesh silica gel as the stationary phase in chemical processing. Eluent systems include dichloromethane and methanol systems and n-hexane and ethyl acetate systems. The eluent system is adjusted according to the polarity of the compounds to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

[0124] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~30℃).

[0125] The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, or Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0126] The abbreviations used in this invention have the following meanings:

[0127]

[0128]

[0129] Example 1: Preparation of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-cyclobutyl-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-amine (compound 301)

[0130]

[0131] Step 1: Ethamidin (2.4 g, 23.1 mmol) was dissolved in methanol (50 mL), and sodium methoxide (3.2 g, 58.4 mmol) and 1-(tert-butyl)-3-methyl-4-oxopiperidin-1,3-dicarboxylate (5.0 g, 19.5 mmol) were added. The reaction mixture was stirred at 60 °C for 6 hours. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water (100 mL), and the pH was adjusted to neutral by adding hydrochloric acid (2 M). The mixture was extracted with ethyl acetate (2 x 100 mL), and the organic phase was concentrated under reduced pressure to give compound 301-1 (5.0 g) as a white solid in 96% yield. ESI-MS: 266 [M + H] + .

[0132] Step 2: 301-1 (5.0 g, 18.9 mmol) was dissolved in 1,2-dichloroethane (70 mL), and carbon tetrachloride (3.2 g, 21.1 mmol) and triphenylphosphine (5.5 g, 21.1 mmol) were added. The reaction mixture was reacted at 70 °C for 8 hours. The reaction mixture was cooled, and the solution was concentrated under reduced pressure. The concentrate was purified by column chromatography (ethyl acetate: petroleum ether = 0-60%) to give compound 301-2 (4.7 g), a pale yellow solid, in 89% yield. ESI-MS: 284 [M+H] + .

[0133] Step 3: 301-2 (2.0 g, 7.1 mmol) was dissolved in dimethyl sulfoxide (20 mL), and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride (2.3 g, 8.5 mmol) and N,N-diisopropylethylamine (2.7 g, 21.3 mmol) were added. The reaction mixture was stirred at 150 °C for 16 hours. The reaction mixture was cooled, diluted with water (50 mL), extracted with ethyl acetate (100 mL), and the organic phase was concentrated under reduced pressure. The concentrate was purified by column chromatography (methanol:dichloromethane = 0-8%) to give compound 301-3 (1.7 g), a pale yellow solid, in 50% yield. ESI-MS: 482 [M+H] + .

[0134] Step 4: Dissolve 301-3 (1.7 g, 3.5 mmol) in dioxane (20 mL), add hydrochloric acid (4 M, solution in dioxane) (5 mL), stir the reaction mixture at room temperature, monitor the reaction of the starting material by TLC until complete, concentrate under reduced pressure to remove the solvent to obtain compound 301-4 (1.3 g), which is a white solid with a yield of 90%. ESI-MS: 382 [M+H] + .

[0135] Step 5: Dissolve 301-4 (150 mg, 0.4 mmol) in methanol (5 mL), add cyclobutanone (50 mg, 0.7 mmol), anhydrous zinc chloride (145 mg, 1.0 mmol), and sodium cyanoborohydride (68 mg, 1.0 mmol), and stir the reaction mixture at room temperature for 15 hours. Quench the reaction with water, concentrate under reduced pressure, dilute with water (10 mL), extract with ethyl acetate (2 x 20 mL), and concentrate the organic phase under reduced pressure to give compound 301-5 (120 mg) as a yellow solid, yield 76%. ESI-MS: 436 [M+H] + .

[0136] Step 6: Dissolve 301-5 (120 mg, 0.3 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (157 mg, 2.8 mmol) and ammonium chloride (150 mg, 2.8 mmol), and stir the reaction solution at 90 °C for 2 hours. Cool the reaction mixture, 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 separate and purify the concentrate by high-performance liquid chromatography (HPLC) to obtain (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-cyclobutyl-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (53.79 mg), which is a white solid with a yield of 49%. ESI-MS: 406 [M+H]+ . 1 H-NMR (400MHz, DMSO-d6) δ: ppm 6.83(s, 1H), 6.79-6.77(m, 2H), 6.67(s, 1H), 5.52-5.50(m, 2H), 5.40-5.34(m, 1H), 3.34-3.31(m, 2H), 3.18(s, 3H ), 2.98-2.94 (m, 2H), 2.92 (s, 3H), 2.10-2.07 (m, 2H), 1.92-1.87 (m, 2H), 1.72-1.66 (m, 2H), 1.45 (d, J=4.0Hz, 3H).

[0137] Example 2: Preparation of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-amine (compound 302)

[0138]

[0139] Step 1: 301-4 (130 mg, 0.3 mmol) was dissolved in methanol (5 mL), and tetrahydro-4H-pyran-4-one (60 mg, 0.6 mmol), anhydrous zinc chloride (121 mg, 0.9 mmol), and sodium cyanoborohydride (61 mg, 0.9 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated under reduced pressure to give compound 302-1 (110 mg), a yellow solid, in 76% yield. ESI-MS: 466 [M+H] + .

[0140] Step 2: Dissolve 302-1 (110 mg, 0.2 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (135 mg, 2.4 mmol) and ammonium chloride (129 mg, 2.4 mmol), and stir the reaction solution at 90 °C for 2 hours. Cool the reaction mixture, 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 separate and purify the concentrate by high-performance liquid chromatography (HPLC) to obtain (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (38.11 mg), a white solid with a yield of 36%. ESI-MS: 436 [M+H] + .1 H-NMR (400MHz, DMSO-d6) δ: ppm 6.83 (s, 1H), 6.79-6.76 (m, 2H), 6.68 (s, 1H), 5.53-5.51 (m, 2H), 5.41-5.33 (m, 1H), 3.97-3.93 (m, 2H), 3.39 (s, 2H), 3.36-3.30 (m, 2H) ), 2.76-2.73 (m, 2H), 2.67-2.61 (m, 1H), 2.58-2.56 (m, 2H), 2.23 (s, 3H), 1.83-1.80 (m, 2H), 1.63-1.54 (m, 2H), 1.45 (d, J=4.0Hz, 3H).

[0141] Example 3: Preparation of (R)-6-cyclobutyl-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-amine (compound 303)

[0142]

[0143] Step 1: Compound 301-2 (2.0 g, 7.1 mmol) was dissolved in dimethyl sulfoxide (20 mL), and (R)-1-(5-bromothiophene-2-yl)ethyl-1-amine hydrochloride (2.0 g, 8.5 mmol) and N,N-diisopropylethylamine (2.7 g, 21.3 mmol) were added. The reaction mixture was stirred at 150 °C for 16 hours. The reaction mixture was cooled, diluted with water (50 mL), extracted with ethyl acetate (100 mL), and the organic phase was concentrated under reduced pressure. The concentrate was purified by column chromatography (methanol:dichloromethane = 0-8%) to give compound 303-1 (1.7 g), a pale yellow solid, in 53% yield. ESI-MS: 453 [M+H] + .

[0144] Step 2: 303-1 (1.7 g, 3.8 mmol) was dissolved in dioxane / water (5:1) (30 mL). (2-((dimethylamino)methyl)phenyl)boronic acid (1.0 g, 5.7 mmol), tetrakis(triphenylphosphine)palladium (462 mg, 0.4 mmol), and potassium carbonate (1.6 g, 11.4 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. It was diluted with water (50 mL), extracted with ethyl acetate (100 mL), and the organic phase was concentrated under reduced pressure. The concentrate was purified by column chromatography (methanol:dichloromethane = 0-8%) to obtain compound 303-2 (1.5 g), a pale yellow solid, in 78% yield. ESI-MS: 508 [M+H]+ .

[0145] Step 3: Dissolve 303-2 (1.7 g, 3.0 mmol) in dioxane (20 mL), add hydrochloric acid (4 M, a solution of dioxane) (5 mL), stir the reaction mixture at room temperature, monitor the reaction of the starting material by TLC until complete, concentrate under reduced pressure to remove the solvent to obtain compound 303-3 (1.0 g), which is a white solid with a yield of 83%. ESI-MS: 408 [M+H] + .

[0146] Step 4: Dissolve 303-3 (120 mg, 0.3 mmol) in methanol (5 mL), add cyclobutanone (43 mg, 0.6 mmol), anhydrous zinc chloride (130 mg, 0.9 mmol), and sodium cyanoborohydride (61 mg, 0.9 mmol), and stir the reaction mixture at room temperature for 15 hours. Quench the reaction with water, concentrate under reduced pressure, dilute with water (10 mL), extract with ethyl acetate (2 x 20 mL), concentrate the organic phase under reduced pressure, and purify the concentrate by high-performance liquid chromatography (HPLC) to give (R)-6-cyclobutyl-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (52.76 mg), a white solid, in 38% yield. ESI-MS: 462 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: ppm7.43 (d, J=8.0Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.35-7.2 8 (m, 2H), 7.15 (d, J=4.0Hz, 1H), 7.00-6.96 (m, 2H), 5.79-5.76 (m, 1H), 3.37 (s, 2H), 3.3 1(s, 2H), 3.19-3.11(m, 2H), 2.97-2.90(m, 1H), 2.52-2.51(m, 2H), 2.31(s, 3H), 2.13( s, 6H), 2.07-2.05 (m, 2H), 1.90-1.83 (m, 2H), 1.70-1.64 (m, 2H), 1.61 (d, J=4.0Hz, 3H).

[0147] Example 4: Preparation of (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N,N-dimethylcyclohexane-1-carboxamide (compound 304)

[0148]

[0149] Step 1: 301-4 (130 mg, 0.3 mmol) was dissolved in methanol (5 mL), and N,N-dimethyl-4-oxocyclohexane-1-carboxamide (101 mg, 0.6 mmol), anhydrous zinc chloride (121 mg, 0.9 mmol), and sodium cyanoborohydride (61 mg, 0.9 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated under reduced pressure to give compound 304-1 (110 mg), a yellow solid, in 69% yield. ESI-MS: 535 [M+H] + .

[0150] Step 2: Dissolve 304-1 (110 mg, 0.2 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (135 mg, 2.4 mmol) and ammonium chloride (129 mg, 2.4 mmol), and stir the reaction solution at 90 °C for 2 hours. Cool the reaction mixture, 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 separate and purify the concentrate by high-performance liquid chromatography to obtain (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N,N-dimethylcyclohexane-1-carboxamide (52.33 mg), which is a white solid with a yield of 52%. ESI-MS: 505 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: ppm 9.01 (d, J=8.0Hz, 1H), 6.87 (s, 2H), 6.76 (s, 1H), 5.55-5.47 (m, 1H), 4.22 (s, 2H), 3.75-3.22 (m, 4H), 3.03 (s, 3H), 2.81 (s, 3H), 2. 63-2.58 (m, 1H), 2.53 (s, 6H), 2.25-2.23 (m, 2H), 1.90-1.87 (m, 2H), 1.67-1.61 (m, 2H), 1.55 (d, J=4.0Hz, 3H), 1.50-1.47 (m, 2H).

[0151] Example 5: Preparation of (R)-4-(4-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N,N-dimethylcyclohexane-1-carboxamide (compound 305)

[0152]

[0153] Compound 303-3 (120 mg, 0.3 mmol) was dissolved in methanol (5 mL), and N,N-dimethyl-4-oxocyclohexane-1-carboxamide (101 mg, 0.6 mmol), anhydrous zinc chloride (130 mg, 0.9 mmol), and sodium cyanoborohydride (61 mg, 0.9 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated under reduced pressure, and the concentrate was purified by high-performance liquid chromatography (HPLC) to give (R)-4-(4-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N,N-dimethylcyclohexane-1-carboxamide (135.88 mg), a white solid in 81% yield. ESI-MS: 561 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: ppm9.03 (d, J=8.0Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.56-7.49 (m, 2H), 7.4 2 (d, J=8.0Hz, 1H), 7.18 (d, J=4.0Hz, 1H), 7.11 (d, J=4.0Hz, 1H), 5.94-5.87 (m, 1H), 4.43 (s, 2H), 4. 17-4.16(m, 2H), 3.42-3.41(m, 2H), 3.08-3.00(m, 6H), 2.81(s, 3H), 2.78-2.66(m, 6H), 2.55(s, 3H) , 2.15-1.91 (m, 2H), 1.93-1.86 (m, 3H), 1.71 (d, J=4.0Hz, 3H), 1.72-1.62 (m, 2H), 1.59-1.50 (m, 2H).

[0154] Example 6: Preparation of (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)piperidin-1-yl)ethyl-1-one (compound 306)

[0155]

[0156] Step 1: Compound 301-4 (130 mg, 0.3 mmol) was dissolved in methanol (5 mL), and 1-acetylpiperidin-4-one (85 mg, 0.6 mmol), anhydrous zinc chloride (121 mg, 0.9 mmol), and sodium cyanoborohydride (61 mg, 0.9 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated under reduced pressure to give compound 306-1 (130 mg), which was a yellow solid with a yield of 86%. ESI-MS: 507 [M+H]+

[0157] Step 2: Dissolve 306-1 (130 mg, 0.3 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (135 mg, 2.4 mmol) and ammonium chloride (129 mg, 2.4 mmol), and stir the reaction solution at 90 °C for 2 hours. Cool the reaction mixture, 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 separate and purify the concentrate by high-performance liquid chromatography to obtain (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)piperidin-1-yl)ethyl-1-one (88.72 mg), which is a white solid with a yield of 73%. ESI-MS: 477 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: ppm 8.82 (d, J=8.0Hz, 1H), 6.85 (s, 2H), 6.76 (s, 1H), 5.54-5.47 (m, 1H), 4.59-4.55 (m, 1H), 4.12 (s, 2H), 4.04-4.00 (m, 1H), 3.57- 3.50 (m, 2H), 3.11-3.55 (m, 3H), 2.59-2.50 (m, 7H), 2.12-2.09 (m, 2H), 2.03 (s, 3H), 1.70-1.67 (m, 2H), 1.54 (d, J=4.0Hz, 3H).

[0158] Example 7: Preparation of (R)-1-(4-(4-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)piperidin-1-yl)ethyl-1-one (compound 307)

[0159]

[0160] Compound 303-3 (100 mg, 0.3 mmol) was dissolved in methanol (5 mL), and 1-acetylpiperidin-4-one (71 mg, 0.5 mmol), anhydrous zinc chloride (116 mg, 0.8 mmol), and sodium cyanoborohydride (54 mg, 0.8 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated under reduced pressure, and the concentrate was purified by high-performance liquid chromatography (HPLC) to give (R)-1-(4-(4-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)piperidin-1-yl)ethyl-1-one (30.64 mg), which was a white solid with a yield of 23%. ESI-MS: 533 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: ppm 9.70 (br, 1H), 7.69 (d, J = 8.0Hz, 1H), 7.56-7.49 (m, 2H), 7.42 (d, J = 8.0Hz, 1H), 7.16 (d , J=4.0Hz, 1H), 7.08 (d, J=4.0Hz, 1H), 5.91-5.84 (m, 1H), 4.55-4.52 (m, 1H), 4.43 (s, 2 H), 4.00-3.97(m, 4H), 3.44-3.30(m, 2H), 3.10-3.03(m, 1H), 2.97(s, 2H), 2.67-2.66( m, 4H), 2.58-2.50 (m, 7H), 2.04-2.01 (m, 4H), 1.69 (d, J=4.0Hz, 3H), 1.66-1.52 (m, 2H).

[0161] Example 8: Preparation of (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone (compound 308)

[0162]

[0163] Step 1: Tetrahydro-2H-pyran-4-carboxylic acid (40 mg, 0.9 mmol) was dissolved in N,N-dimethylformamide (3 mL), and HATU (137 mg, 0.4 mmol), N,N-diisopropylethylamine (116 mg, 0.9 mmol), and compound 301-4 (130 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. The solution was diluted with water (10 mL), extracted with ethyl acetate (2 x 20 mL), and the organic phase was concentrated under reduced pressure to give compound 308-1 (110 mg) as a yellow solid, in 74% yield. ESI-MS: 494 [M+H] + .

[0164] Step 2: Dissolve 308-1 (110 mg, 0.2 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (135 mg, 2.4 mmol) and ammonium chloride (129 mg, 2.4 mmol), and stir the reaction solution at 90 °C for 2 hours. Cool the reaction mixture, 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 separate and purify the concentrate by high-performance liquid chromatography (HPLC) to obtain (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone (68.34 mg), which is a white solid with a yield of 67%. ESI-MS: 494 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: ppm 9.00 (d, J=8.0Hz, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 5.57-5.49 (m, 1H), 4.52-4.49 (m, 1H), 4.44 (s, 2H), 3.88-3 .84(m, 4H), 3.45-3.39(m, 2H), 3.05-3.01(m, 1H), 2.99-2.83(m, 2H), 2.72-2.71(m, 1H), 2.51(s, 3H), 1.63-1.53(m, 7H).

[0165] Example 9: Preparation of (R)-(4-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone (compound 309)

[0166]

[0167] Tetrahydro-2H-pyran-4-carboxylic acid (40 mg, 0.9 mmol) was dissolved in N,N-dimethylformamide (3 mL), and HATU (137 mg, 0.4 mmol), N,N-diisopropylethylamine (116 mg, 0.9 mmol) and compound 303-3 (100 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. Dilute with water (10 mL), extract with ethyl acetate (2 x 20 mL), concentrate the organic phase under reduced pressure, and purify the concentrate by preparative high-performance liquid chromatography (HPLC) to give (R)-(4-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(tetrahydro-2H-pyran-4-yl)methyl ketone (66.78 mg), a white solid in 51% yield. ESI-MS: 520 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: ppm 9.76 (br, 1H), 7.70 (d, J=8.0Hz, 1H), 7.51-7.48 (m, 2H), 7.44 (d, J=8.0Hz, 1H), 7.16 (d, J=4.0Hz, 1H), 7.09 (d, J=4.0Hz, 1H), 5.92-5.88 (m, 1H), 4.51-4.31(m, 5H), 4.92-3.77(m, 5H), 3.05-3.00(m, 1H), 2.88-2.87(m, 2H), 2.54(s, 6H), 2.51(s, 3H), 1.71(d, J=8.0Hz, 3H), 1.63-1.57(m, 4H).

[0168] Example 10: Preparation of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-amine (compound 310)

[0169]

[0170] Step 1: Compound 301-4 (130 mg, 0.3 mmol) was dissolved in methanol (5 mL), and tetrahydro-2H-pyran-4-carboxaldehyde (68 mg, 0.6 mmol), anhydrous zinc chloride (121 mg, 0.9 mmol), and sodium cyanoborohydride (61 mg, 0.9 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated under reduced pressure to give compound 310-1 (110 mg), which was a yellow solid with a yield of 76%. ESI-MS: 480 [M+H] + .

[0171] Step 2: Dissolve 310-1 (110 mg, 0.2 mmol) in ethanol (5 mL) and water (2 mL), add iron powder (135 mg, 2.4 mmol) and ammonium chloride (129 mg, 2.4 mmol), and stir the reaction solution at 90 °C for 2 hours. Cool the reaction mixture, 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 separate and purify the concentrate by high-performance liquid chromatography (HPLC) to obtain (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (66.47 mg), a white solid with a yield of 67%. ESI-MS: 450 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: ppm 8.96 (d, J=8.0Hz, 1H), 6.87 (s, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 5.53-5.49 (m, 1H), 4.14-4.13 (m, 2H), 3.89-3.85 (m, 2H), 3.46-3. 30 (m, 4H), 3.11-3.04 (m, 4H), 2.52.2.50 (m, 4H), 2.14-2.13 (m, 1H), 1.73-1.64 (m, 2H), 1.54 (d, J=8.0Hz, 3H), 1.31-1.20 (m, 3H).

[0172] Example 11: Preparation of (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-amine (compound 311)

[0173]

[0174] Compound 303-3 (100 mg, 0.3 mmol) was dissolved in methanol (5 mL), and tetrahydro-2H-pyran-4-carboxaldehyde (57 mg, 0.5 mmol), anhydrous zinc chloride (116 mg, 0.8 mmol), and sodium cyanoborohydride (54 mg, 0.8 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated under reduced pressure, and the concentrate was purified by high-performance liquid chromatography (HPLC) to give (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (29.30 mg), a white solid in 23% yield. ESI-MS: 506 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: ppm 7.44 (d, J=8.0Hz, 1H), 7.38-7.37 (m, 1H), 7.36-7.30 (m, 2H), 7.15 (d, J=4.0Hz, 1H), 7.01-6.96 (m, 2H), 5.80-5.73 (m, 1H), 3.84-3.81 ( m, 3H), 3.40-3.34 (m, 2H), 3.29-3.19 (m, 4H), 2.64-2.60 (m, 4H), 2.35-2.34 (m, 2H), 2.31 (s, 3H), 2.14-2.11 (m, 7H), 1.62-1.61 (m, 6H).

[0175] Example 12: Preparation of (R)-1-(4-(4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)piperidin-1-yl)ethyl-1-one (compound 312)

[0176]

[0177] Step 1: Compound 301-2 (1.0 g, 3.5 mmol) was dissolved in dimethyl sulfoxide (20 mL), and (R)-1-(4-bromothiophene-2-yl)ethyl-1-amine hydrochloride (1.0 g, 4.2 mmol) and N,N-diisopropylethylamine (1.4 g, 10.2 mmol) were added. The reaction mixture was stirred at 150 °C for 16 hours. The reaction mixture was cooled, diluted with water (50 mL), extracted with ethyl acetate (100 mL), and the organic phase was concentrated under reduced pressure. The concentrate was purified by column chromatography (methanol:dichloromethane = 0–8%) to give compound 312-1 (900 mg) as a pale yellow solid, in 56% yield. ESI-MS: 453 [M+H] + .

[0178] Step 2: 312-1 (900 mg, 2.0 mmol) was dissolved in dioxane / water (5:1) (15 mL). (2-((dimethylamino)methyl)phenyl)boronic acid (534 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol), and potassium carbonate (823 mg, 6.0 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. It was diluted with water (50 mL), extracted with ethyl acetate (100 mL), and the organic phase was concentrated under reduced pressure. The concentrate was purified by column chromatography (methanol:dichloromethane = 0–8%) to obtain compound 312-2 (450 mg), a pale yellow solid, in 45% yield. ESI-MS: 508 [M+H] + .

[0179] Step 3: Dissolve 312-2 (450 mg, 0.9 mmol) in dioxane (5 mL), add hydrochloric acid (4 M, solution in dioxane) (3 mL), stir the reaction mixture at room temperature, monitor the reaction of the starting materials by TLC until complete, concentrate under reduced pressure to remove the solvent to obtain compound 312-3 (300 mg), which is a white solid with a yield of 82%. ESI-MS: 408 [M+H] + .

[0180] Step 4: Dissolve 312-3 (100 mg, 0.3 mmol) in methanol (5 mL), add 1-acetylpiperidin-4-one (71 mg, 0.5 mmol), anhydrous zinc chloride (116 mg, 0.8 mmol) and sodium cyanoborohydride (54 mg, 0.8 mmol), and stir the reaction solution at room temperature for 15 hours. The reaction was quenched with water, concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated under reduced pressure, and the concentrate was purified by high-performance liquid chromatography (HPLC) to give (R)-1-(4-(4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)piperidin-1-yl)ethyl-1-one (58.03 mg), a white solid in 48% yield. ESI-MS: 533 [M+H] + . 1 H-NMR (400MHz, DMSO-d6) δ: ppm9.45 (s, 1H), 7.42-7.40 (m, 1H), 7.39-7.29 (m, 3H), 7.25 (s, 1 H), 6.95 (d, J=6.0Hz, 1H), 5.82-5.74 (m, 1H), 4.45-4.41 (m, 1H), 3.89-3.85 (m, 1H), 3.36-3.3 0(m, 5H), 3.06-2.99(m, 1H), 2.77-2.74(m, 2H), 2.68-2.60(m, 1H), 2.59-2.57(m, 2H), 2.30(s , 3H), 2.12 (s, 6H), 2.00 (s, 3H), 1.86-1.80 (m, 2H), 1.61 (d, J=8.0Hz, 3H), 1.53-1.51 (m, 2H).

[0181] Biological assay

[0182] Experimental Example 1. KRAS::SOS1 HTRF Binding Analysis

[0183] This assay can be used to examine the inhibition of SOS1 and KRAS by compounds. G12C The effectiveness of protein-protein interactions between them. This demonstrates the molecular interaction mode of the compounds. Low IC50 50 The value indicates the potency of the SOS1 inhibitor compound in the following assay setting.

[0184] Reagents:

[0185] • GST-SOS1 (aa564-1049), internally produced

[0186] His-KRAS G12C(aa1-169), internally produced

[0187] • MAb Anti-6his-Tb cryptate Gold, purchased from Cisbio (catalog number 61HI2TLA)

[0188] MAb Anti-GST-XL665, purchased from Cisbio (catalog number 61GSTXLA).

[0189] Test plate: ProxiPlate-384Plus, purchased from PerkinElmer (catalog number 6008280).

[0190] Assay buffer: PPI, purchased from Cisbio (catalog number 61DB10RDF)

[0191] Measurement protocol:

[0192] • Dissolve the analyte in DMSO to prepare a stock solution with a concentration of 10 mM. Dilute the compound concentration to 2 mM with DMSO as the starting concentration for the assay. Continuously dilute the 2 mM starting concentration compound solution three times to obtain a total of 10 concentrations. Use a LabcyteEcho instrument to transfer 0.1 μL of each concentration of compound solution to a 384-well assay plate (two copies, double duplicates).

[0193] • Add 5 μL of His-KRAS G12C at a specific concentration to 0.1 μL of the compound solution and centrifuge at 1000 rpm for 1 min on an Eppendorf 5810R centrifuge.

[0194] • Then add 5 μL of GST-SOS1 at a specific concentration, and centrifuge at 1000 rpm for 1 min in an Eppendorf 5810R centrifuge.

[0195] • Incubate the 384-well plate at 25°C for 15 min;

[0196] Then add 10 μL of the MAb Anti-6his-Tb and MAb Anti-GST-XL665 mixture and centrifuge at 1000 rpm for 1 min on an Eppendorf 5810R centrifuge;

[0197] • The 384-well plate was incubated at 25°C for 2 hours;

[0198] Finally, the Perkin Elmer Envision 2104 instrument was used to read the board and obtain the 665 / 615nm signal ratio.

[0199] Each plate contains the following controls:

[0200] ·DMSO+KRAS+SOS1+MAbAnti-6his-Tb+MAbAnti-GST-XL665

[0201] Result calculation:

[0202] IC was calculated and analyzed using a 4-parameter regression equation. 50 Values. The measurement results are shown in the table below.

[0203]

[0204]

[0205] In addition to those described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein said compound has the structure of formula (III): ； Equation (III) in: L is selected from direct bond, C 1-6 Alkylene and C (=O); Ring B is a benzene ring or a thiophene ring; R 1 Each time it appears, it is independently selected from halogen, -NH2, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl and C 6-10 Aryl group, wherein the aryl group is optionally coated with -C 1-6 Alkylene-NR 5 R 6 replace; R 2 Selected from saturated C 3-6 Cycloalkyl groups and saturated 3-6 membered heterocyclic groups, wherein the cycloalkyl groups and heterocyclic groups are optionally composed of one or more groups selected from -C(=O)R 5 and -C(=O)NR 5 R 6 Substituents of the substituents; R 3 and R 4 Each is independently selected from H and C. 1-6 alkyl; R 5 and R 6 Each time it appears, it is independently selected from H and C. 1-6 alkyl; m is an integer selected from 0, 1, 2, 3, and 4; n is 0; and The condition is that the compound is not one of the following compounds: 。 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is a direct bond, -CH2- or C (=O).

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is cyclobutyl, cyclohexyl, piperidinyl or tetrahydropyranyl, which is optionally substituted by one or more substituents selected from -C(=O)CH3 and -C(=O)N(CH3)2.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein -LR 2 Selected from , , , , and .

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

6. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein... Selected from , , , , , , , , , , , , , , , and .

7. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 3 It is a methyl group.

8. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 4 For H.

9. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 301 302 303 304 305 306、 307 308 309 310. 311 and 312.

10. A pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

12. Use of any compound of claims 1-9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 10 or 11, in the preparation of a medicament used as an SOS1 inhibitor.

13. The use of claim 12, wherein the drug is used for the prevention or treatment of cancer.

14. The use of claim 12, wherein the drug is used to prevent or treat diseases related to RAS signaling pathway dysregulation.

15. The use of claim 13, wherein the cancer is selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

16. The use of claim 13, wherein the cancer is selected from endometrial cancer and cervical cancer.

17. The use of claim 14, wherein the disease associated with RAS signaling pathway dysregulation is selected from neurofibromatosis type 1, Noonan syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardiofacial-dermal syndrome, Legg's syndrome, and hereditary gingival fibromatosis.

18. The use of claim 17, wherein the Noonan syndrome is Noonan syndrome with multiple spots.

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