CN116194446A - SOS1 inhibitor, pharmaceutical composition containing same and application thereof - Google Patents

Abstract

式(I)的SOS1抑制剂、包含其的药物组合物、及其用于预防或治疗疾病的用途。

SOS1 inhibitors of formula (I), pharmaceutical compositions comprising them, and uses thereof for preventing or treating diseases.

Description

SOS1 inhibitors, pharmaceutical compositions comprising them and uses thereof field of invention

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

Background of the invention

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

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

SOS2 is a homologue of SOS1 in mammalian cells and also functions as a guanine nucleotide exchange factor. Studies on mouse gene knockout models have shown that SOS1 germline knockout can cause mouse embryos to die in the second trimester, while adult mice can continue to survive after SOS1 knockout, in contrast, SOS2 knockout has no effect on embryonic and mature None of the mice showed any obvious phenotypic changes, whereas adult SOS1/2 double-knockout mice died rapidly, suggesting that selective targeting of SOS1 may achieve a high therapeutic index for RAS-mutant tumors regulated by SOS1.

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

Summary of the invention

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

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

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

in:

X ¹ , X ² , X ³ and X ⁴ are each independently selected from C═O, CH ₂ , CHR, C(R) ₂ and NLR ² , preferably, at least among X ¹ , X ² , X ³ and X ⁴ One for NLR ² ;

L is selected from direct bond, C _1-6 alkylene, C(=O), O, S(=O), S(=O) ₂ and NR ⁴ ;

Ring B is selected from C _3-10 hydrocarbon rings, 3-10 membered heterocyclic rings, C _6-10 aromatic rings and 5-14 membered heteroaromatic rings, and at most 2 ring members in the hydrocarbon rings and heterocyclic rings are C (= O);

Each occurrence of R and R ¹ is independently selected from halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _{1- 6} alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _3-10 Cyclohydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl group, 5-14 membered heteroaryl group and C _6-12 aralkyl group, the cyclohydrocarbyl and heterocyclic group at most 2 ring members are C(=O), when m is greater than 1 and/or n is greater than 1, two R ¹ and/or two R together with the atoms they are connected to optionally form a C _3-10 hydrocarbon ring , 3-10 membered heterocyclic ring, C _6-10 membered aromatic ring or 5-14 membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O);

R ² is selected from H, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl , C _2-6 alkynyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O) R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 Alkyl-NR ⁵ R ⁶ , -C _1-6 alkylene-O(P=O)(OH) ₂ and -OC _1-6 alkylene-NR ⁵ R ⁶ ;

R ³ and R ⁴ are each independently selected from H, halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6 alkyl, -O-(3-10 membered heterocyclyl), C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl, C _2-6 alkynyl , saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl , -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O ) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ - C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 alkylene-O(P=O)(OH) ₂ and -OC _1-6 alkylene-NR ⁵ R ⁶ ;

The above groups are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, _-NH2 , -CN, _-NO2 , _C1-6 Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _{6- 12} Aralkyl, =N-OR ⁵ , -C(=NH)NH ₂ , -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O) -NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ and -OC _1-6 alkylene-NR ⁵ R ⁶ , the alkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, -NH ₂ , -CN, -NO ₂ , C _1-6 alkyl , C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl;

R ⁵ and R ⁶ are each independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered Heteroaryl and C _6-12 aralkyl; and

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

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

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

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

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

Detailed description of the invention

definition

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

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

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

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

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

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

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

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

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

As used herein, the terms "()arylene" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the terms "C _6-10 ()arylene" and "C _6-10 aromatic ring" mean an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or (ylidene) naphthyl (naphthalene ring). ()Arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.) . The ()arylene group and the aromatic ring are optionally fused with another ring (such as a _C3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring or a 5-14 membered heteroaryl ring), the fused group is, for example,

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

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

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

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

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

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

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

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

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

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

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

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

实楔形

或虚楔形

描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。 Solid lines can be used in this article

solid wedge

or imaginary wedge

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

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

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

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

Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, seabenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid Salt, Pamoate, Phosphate/Hydrogen Phosphate/Dihydrogen Phosphate, Pyroglutamate, Saccharate, Stearate, Succinate, Tannin, Tartrate, Toluene Sulfonate, trifluoroacetate and xinafoate.

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

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

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

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

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: 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.

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

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

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

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

compound

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

in:

X ¹ , X ² , X ³ and X ⁴ are each independently selected from C═O, CH ₂ , CHR, C(R) ₂ and NLR ² , preferably, at least among X ¹ , X ² , X ³ and X ⁴ One for NLR ² ;

L is selected from direct bond, C _1-6 alkylene, C(=O), O, S(=O), S(=O) ₂ and NR ⁴ ;

Ring B is selected from C _3-10 hydrocarbon rings, 3-10 membered heterocyclic rings, C _6-10 aromatic rings and 5-14 membered heteroaromatic rings, and at most 2 ring members in the hydrocarbon rings and heterocyclic rings are C (= O);

Each occurrence of R and R ¹ is independently selected from halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _{1- 6} alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _3-10 Cyclohydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl group, 5-14 membered heteroaryl group and C _6-12 aralkyl group, the cyclohydrocarbyl and heterocyclic group at most 2 ring members are C(=O), when m is greater than 1 and/or n is greater than 1, two R ¹ and/or two R together with the atoms they are connected to optionally form a C _3-10 hydrocarbon ring , 3-10 membered heterocyclic ring, C _6-10 membered aromatic ring or 5-14 membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocyclic ring are C(=O);

R ² is selected from H, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl , C _2-6 alkynyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O) R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 Alkyl-NR ⁵ R ⁶ , -C _1-6 alkylene-O(P=O)(OH) ₂ and -OC _1-6 alkylene-NR ⁵ R ⁶ ;

R ³ and R ⁴ are each independently selected from H, halogen, -NH ₂ , -CN, -NO ₂ , -OH, -OC _1-6 alkyl, -O-(3-10 membered heterocyclyl), C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 alkenyl, C _2-6 alkynyl , saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl , -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O ) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ - C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O)-NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ , -C _1-6 alkylene-O(P=O)(OH) ₂ and -OC _1-6 alkylene-NR ⁵ R ⁶ ;

The above groups are each optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, _-NH2 , -CN, _-NO2 , _C1-6 Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-10 membered heterocyclic group, C _6-10 aryl, 5-14 membered heteroaryl, C _{6- 12} Aralkyl, =N-OR ⁵ , -C(=NH)NH ₂ , -C(=O)R ⁵ , -OC(=O)R ⁵ , -C(=O)OR ⁵ , -OR ⁵ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , -S(=O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(=O)NR ⁵ R ⁶ , -NR ⁵ -C(=O)R ⁶ , -NR ⁵ -C(=O)OR ⁶ , -NR ⁵ -S(=O) ₂ -R ⁶ , -NR ⁵ -C(=O) -NR ⁵ R ⁶ , -C _1-6 alkylene-NR ⁵ R ⁶ and -OC _1-6 alkylene-NR ⁵ R ⁶ , the alkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, -NH ₂ , -CN, -NO ₂ , C _1-6 alkyl , C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl and C _6-12 aralkyl;

R ⁵ and R ⁶ are each independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered Heteroaryl and C _6-12 aralkyl; and

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

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

并且 Ring A is

and

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

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

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

Preferably, R ^is cyclobutanyl, cyclohexane, piperidinyl or tetrahydropyranyl optionally replaced by one or more selected from -C(=O)CH and _-C (= Substituents of O) N(CH ₃ ) ₂ are substituted;

More preferably, -LR ² is selected from

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 bicyclo[1.1.1]pentane ring, a 2-oxabicyclo[2.1.1]hexane ring, a benzene ring or a thiophene ring, most preferably a benzene ring or a thiophene ring.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof , wherein each occurrence of R ¹ is independently selected from halogen, -NH ₂ , C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylene-OH, halogenated C _{1 -6} alkylene-OH, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic group, C _6-10 aryl and 5-14 membered heteroaryl, The alkylene, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from one or more independently selected from halogen, -OH, C _3-6 cycloalkyl, 3-10 membered Heterocyclyl, C _6-10 aryl and 5-14 membered heteroaryl are substituted by substituents;

When m is greater than 1, two ^R together with the atoms they are connected to optionally together constitute a C _3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C _6-10 aromatic ring or a 5-14 membered heteroaromatic ring, At most 2 ring members in the hydrocarbon ring and heterocycle are C(=O), and the hydrocarbon ring, heterocycle, aromatic ring and heteroaromatic ring are optionally substituted by one or more halogens;

并且m为1或2。 Preferably, each occurrence of R ¹ is independently selected from CF ₃ , NH ₂ ,

and m is 1 or 2.

选自

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

selected from

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

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

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

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

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

Pharmaceutical compositions and methods of treatment

In some embodiments, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation. In some embodiments, the pharmaceutical composition may also include one or more additional therapeutic agents.

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

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

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

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

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

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

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

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

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

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

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

The amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician. Generally, the effective dosage is about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg human this would amount to about 0.007 mg/day to about 3500 mg/day, eg about 0.7 mg/day to about 700 mg/day. Dosage levels up to the lower limit of the foregoing range may be sufficient in some cases, while in other cases larger doses may still be employed without causing any deleterious side effects, provided that the larger dose is first administered. The dose is divided into several smaller doses to be administered throughout the day.

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

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

"Individual" as used herein includes a human or non-human animal. Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (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.).

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

Example

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

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

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

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

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

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

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

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

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

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

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

Abbreviations in the present invention have the following meanings:

abbreviation meaning

_CCl4 carbon tetrachloride DIEA/DIPEA N,N-Diisopropylethylamine DMSO Dimethyl sulfoxide EDC 1,2-Dichloroethane Fe iron HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCl hydrochloric acid H ₂ O water K ₂ CO ₃ potassium carbonate MeOH Methanol MeONa Sodium methoxide NaBH ₃ CN Sodium cyanoborohydride NH ₄ Cl ammonium chloride Pd(PPh ₃ ) ₄ Tetrakis(triphenylphosphine)palladium PPh ₃ Triphenylphosphine TLC TLC r.t./rt room temperature _ZnCl2 Zinc chloride

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

The first step: Dissolve acetamidine (2.4g, 23.1mmol) in methanol (50mL), add sodium methoxide (3.2g, 58.4mmol) and 1-(tert-butyl) 3-methyl 4-oxopiperidine - 1,3-dicarboxylate (5.0 g, 19.5 mmol). The reaction solution was stirred at 60°C for 6 hours. The reactant was cooled, concentrated under reduced pressure, diluted with water (100 mL), added hydrochloric acid (2M) to the system to adjust the pH to neutral, extracted with ethyl acetate (2x100 mL), and concentrated the organic phase under reduced pressure to obtain compound 301-1 (5.0 g) as a white solid, yield 96%. ESI-MS: 266[M+H] ⁺ .

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

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

Step 4: Dissolve 301-3 (1.7g, 3.5mmol) in dioxane (20mL), add hydrochloric acid (4M, solution in dioxane) (5mL), and stir the reaction solution at room temperature, TLC monitored the completion of the raw material reaction, and concentrated under reduced pressure to remove the solvent to obtain compound 301-4 (1.3 g), which was a white solid with a yield of 90%. ESI-MS: 382[M+H] ⁺ .

Step 5: Dissolve 301-4 (150mg, 0.4mmol) in methanol (5mL), add cyclobutanone (50mg, 0.7mmol), anhydrous zinc chloride (145mg, 1.0mmol) and sodium cyanoborohydride ( 68 mg, 1.0 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2×20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 301-5 (120 mg) as a yellow solid with a yield of 76%. ESI-MS: 436[M+H] ⁺ .

The sixth step: 301-5 (120mg, 0.3mmol) was dissolved in ethanol (5mL) and water (2mL), iron powder (157mg, 2.8mmol) and ammonium chloride (150mg, 2.8mmol) were added, and the reaction solution was placed in Stir at 90°C for 2 hours. The reactant was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2x10 mL), the organic phase was concentrated under reduced pressure, and the concentrate Separation and purification by high-pressure preparative liquid chromatography to obtain (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-cyclobutyl-2-methyl - 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (53.79 mg), which is a white solid, yield 49%. ESI-MS: 406 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ: ppm 6.83(s, 1H), 6.79-6.77(m, 2H), 6.67(s, 1H), 5.52-5.50(m, 2H), 5.40-5.34 (m, 1H), 3.34-3.31(m, 2H), 3.18(s, 3H), 2.98-2.94(m, 2H), 2.92(s, 3H), 2.10-2.07(m, 2H), 1.92-1.87 (m, 2H), 1.72-1.66 (m, 2H), 1.45 (d, J=4.0Hz, 3H).

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

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

The second step: 302-1 (110mg, 0.2mmol) was dissolved in ethanol (5mL) and water (2mL), iron powder (135mg, 2.4mmol) and ammonium chloride (129mg, 2.4mmol) were added, and the reaction solution was Stir at 90°C for 2 hours. The reactant was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2x10 mL), the organic phase was concentrated under reduced pressure, and the concentrate Separation and purification by high-pressure preparative liquid chromatography to obtain (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(tetrahydro -2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (38.11 mg) as a white solid, yield 36%. ESI-MS: 436 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ: ppm 6.83(s, 1H), 6.79-6.76(m, 2H), 6.68(s, 1H), 5.53-5.51(m, 2H), 5.41-5.33 (m, 1H), 3.97-3.93(m, 2H), 3.39(s, 2H), 3.36-3.30(m, 2H), 2.76-2.73(m, 2H), 2.67-2.61(m, 1H), 2.58 -2.56 (m, 2H), 2.23 (s, 3H), 1.83-1.80 (m, 2H), 1.63-1.54 (m, 2H), 1.45 (d, J=4.0Hz, 3H).

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

The first step: Dissolve compound 301-2 (2.0g, 7.1mmol) in dimethyl sulfoxide (20mL), add (R)-1-(5-bromothien-2-yl)ethan-1-amine salt salt (2.0g, 8.5mmol) and N,N-diisopropylethylamine (2.7g, 21.3mmol), and the reaction solution was stirred at 150°C for 16 hours. The reactant was cooled, diluted with water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (methanol:dichloromethane=0-8%) to obtain the compound 303-1 (1.7 g), which is a pale yellow solid, yield 53%. ESI-MS: 453[M+H] ⁺ .

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

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

The fourth step: 303-3 (120mg, 0.3mmol) was dissolved in methanol (5mL), cyclobutanone (43mg, 0.6mmol), anhydrous zinc chloride (130mg, 0.9mmol) and sodium cyanoborohydride ( 61 mg, 0.9 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2x20 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by high-pressure preparative liquid chromatography to obtain (R)-6- Cyclobutyl-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methyl-5,6,7,8 - Tetrahydropyrido[4,3-d]pyrimidin-4-amine (52.76 mg) as a white solid, yield 38%. ESI-MS: 462 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ: ppm 7.43 (d, J=8.0Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.35-7.28 (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), 3.31(s, 2H), 3.19-3.11(m, 2H) , 2.97-2.90(m, 1H), 2.52-2.51(m, 2H), 2.31(s, 3H), 2.13(s, 6H), 2.07-2.05(m, 2H), 1.90-1.83(m, 2H) , 1.70-1.64 (m, 2H), 1.61 (d, J=4.0Hz, 3H).

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

Step 1: Dissolve 301-4 (130mg, 0.3mmol) in methanol (5mL), add N,N-dimethyl-4-oxocyclohexane-1-carboxamide (101mg, 0.6mmol), Zinc chloride hydrate (121 mg, 0.9 mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2×20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 304-1 (110 mg) as a yellow solid with a yield of 69%. ESI-MS: 535[M+H] ⁺ .

The second step: 304-1 (110mg, 0.2mmol) was dissolved in ethanol (5mL) and water (2mL), iron powder (135mg, 2.4mmol) and ammonium chloride (129mg, 2.4mmol) were added, and the reaction solution was Stir at 90°C for 2 hours. The reactant was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2x10 mL), the organic phase was concentrated under reduced pressure, and the concentrate Separation and purification by high-pressure preparative liquid chromatography to obtain (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl -7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-N,N-dimethylcyclohexane-1-carboxamide (52.33 mg) as a white solid , yield 52%. ESI-MS: 505 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: ppm 9.01 (d, J=8.0 Hz, 1H), 6.87 (s, 2H), 6.76 (s, 1H), 5.55-5.47 (m, 1H), 4.22(s, 2H), 3.75-3.22(m, 4H), 3.03(s, 3H), 2.81(s, 3H), 2.63-2.58(m, 1H), 2.53(s, 6H), 2.25-2.23( m, 2H), 1.90-1.87 (m, 2H), 1.67-1.61 (m, 2H), 1.55 (d, J=4.0Hz, 3H), 1.50-1.47 (m, 2H).

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

Compound 303-3 (120 mg, 0.3 mmol) was dissolved in methanol (5 mL), N, N-dimethyl-4-oxocyclohexane-1-carboxamide (101 mg, 0.6 mmol) was added, anhydrous Zinc (130 mg, 0.9 mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2x20 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by high-pressure preparative liquid chromatography to obtain (R)-4- (4-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyridine And[4,3-d]pyrimidin-6(5H)-yl)-N,N-dimethylcyclohexane-1-carboxamide (135.88 mg) as a white solid, yield 81%. ESI-MS: 561 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ: ppm9.03 (d, J=8.0Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.56-7.49 (m, 2H), 7.42 (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).

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

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

The second step: 306-1 (130mg, 0.3mmol) was dissolved in ethanol (5mL) and water (2mL), iron powder (135mg, 2.4mmol) and ammonium chloride (129mg, 2.4mmol) were added, and the reaction solution was Stir at 90°C for 2 hours. The reactant was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2x10 mL), the organic phase was concentrated under reduced pressure, and the concentrate Separation and purification by high-pressure preparative liquid chromatography to obtain (R)-1-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2 -Methyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)piperidin-1-yl)ethan-1-one (88.72 mg) as a white solid, Yield 73%. ESI-MS: 477 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) 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).

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

Compound 303-3 (100 mg, 0.3 mmol) was dissolved in methanol (5 mL), 1-acetylpiperidin-4-one (71 mg, 0.5 mmol), anhydrous zinc chloride (116 mg, 0.8 mmol) and cyano Sodium borohydride (54 mg, 0.8 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2x20 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by high-pressure preparative liquid chromatography to obtain (R)-1- (4-(4-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-2-methyl-7,8- Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)piperidin-1-yl)ethan-1-one (30.64 mg) as a white solid, yield 23%. ESI-MS: 533 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ: ppm 9.70 (br, 1H), 7.69 (d, J=8.0Hz, 1H), 7.56-7.49 (m, 2H), 7.42 (d, J=8.0 Hz, 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 , 2H), 4.00-3.97(m, 4H), 3.44-3.30(m, 2H), 3.10-3.03(m, 1H), 2.97(s, 2H), 2.67-2.66(m, 4H), 2.58-2.50 (m, 7H), 2.04-2.01 (m, 4H), 1.69 (d, J=4.0Hz, 3H), 1.66-1.52 (m, 2H).

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

The first step: Dissolve tetrahydro-2H-pyridine-4-carboxylic acid (40mg, 0.9mmol) in N,N-dimethylformamide (3mL), add HATU (137mg, 0.4mmol), N,N -Diisopropylethylamine (116mg, 0.9mmol) and compound 301-4 (130mg, 0.3mmol), the reaction solution was stirred at room temperature for 15 hours. It was diluted with water (10 mL), extracted with ethyl acetate (2×20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 308-1 (110 mg) as a yellow solid, yield 74%. ESI-MS: 494[M+H] ⁺ .

The second step: 308-1 (110mg, 0.2mmol) was dissolved in ethanol (5mL) and water (2mL), iron powder (135mg, 2.4mmol) and ammonium chloride (129mg, 2.4mmol) were added, and the reaction solution was Stir at 90°C for 2 hours. The reactant was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2x10 mL), the organic phase was concentrated under reduced pressure, and the concentrate Separation and purification by high-pressure preparative liquid chromatography to obtain (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7 , 8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (68.34 mg) as a white solid, yield 67%. ESI-MS: 494 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) 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).

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

Dissolve tetrahydro-2H-pyran-4-carboxylic acid (40mg, 0.9mmol) in N,N-dimethylformamide (3mL), add HATU (137mg, 0.4mmol), N,N-diisopropyl Ethylamine (116 mg, 0.9 mmol) and compound 303-3 (100 mg, 0.3 mmol), and the reaction solution was stirred at room temperature for 15 hours. Dilute with water (10 mL), extract with ethyl acetate (2x20 mL), concentrate the organic phase under reduced pressure, and purify the concentrate by high-pressure preparative liquid chromatography to give (R)-(4-((1-(5-( 2-((Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (66.78 mg) as a white solid, yield 51%. ESI-MS: 520 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ: ppm 9.76 (br, 1H), 7.70 (d, J=8.0Hz, 1H), 7.51-7.48 (m, 2H), 7.44 (d, J=8.0 Hz, 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).

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

The first step: Dissolve compound 301-4 (130mg, 0.3mmol) in methanol (5mL), add tetrahydro-2H-pyran-4-carbaldehyde (68mg, 0.6mmol), anhydrous zinc chloride (121mg, 0.9 mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2×20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 310-1 (110 mg) as a yellow solid with a yield of 76%. ESI-MS: 480[M+H] ⁺ .

The second step: 310-1 (110mg, 0.2mmol) was dissolved in ethanol (5mL) and water (2mL), iron powder (135mg, 2.4mmol) and ammonium chloride (129mg, 2.4mmol) were added, and the reaction solution was Stir at 90°C for 2 hours. The reactant was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2x10 mL), the organic phase was concentrated under reduced pressure, and the concentrate Separation and purification by high-pressure preparative liquid chromatography to obtain (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-((tetrafluoromethyl) Hydrogen-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (66.47 mg) as a white solid, yield rate of 67%. ESI-MS: 450 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) 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).

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

Compound 303-3 (100 mg, 0.3 mmol) was dissolved in methanol (5 mL), tetrahydro-2H-pyran-4-carbaldehyde (57 mg, 0.5 mmol), anhydrous zinc chloride (116 mg, 0.8 mmol) and cyanide were added Sodium borohydride (54 mg, 0.8 mmol), and the reaction solution was stirred at room temperature for 15 hours. Add water to quench the reaction, concentrate under reduced pressure, dilute with water (10 mL), extract with ethyl acetate (2x20 mL), concentrate the organic phase under reduced pressure, and purify the concentrate by high-pressure preparative liquid chromatography to obtain (R)-N- (1-(5-(2-((Dimethylamino)methyl)phenyl)thiophen-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) as a white solid, yield 23%. ESI-MS: 506 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: ppm 7.44 (d, J=8.0 Hz, 1H), 7.38-7.37 (m, 1H), 7.36-7.30 (m, 2H), 7.15 (d, J =4.0Hz, 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).

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

Step 1: Dissolve compound 301-2 (1.0g, 3.5mmol) in dimethyl sulfoxide (20mL), add (R)-1-(4-bromothiophen-2-yl)ethan-1-amine salt salt (1.0g, 4.2mmol) and N,N-diisopropylethylamine (1.4g, 10.2mmol), and the reaction solution was stirred at 150°C for 16 hours. The reactant was cooled, diluted with water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (methanol:dichloromethane=0-8%) to obtain the compound 312-1 (900 mg), which is a light yellow solid, yield 56%. ESI-MS: 453[M+H] ⁺ .

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

Step 3: Dissolve 312-2 (450mg, 0.9mmol) in dioxane (5mL), add hydrochloric acid (4M, solution in dioxane) (3mL), stir the reaction solution at room temperature, TLC After monitoring the completion of the raw material reaction, the solvent was concentrated under reduced pressure to obtain compound 312-3 (300 mg) as a white solid with a yield of 82%. ESI-MS: 408[M+H] ⁺ .

Step 4: Dissolve 312-3 (100mg, 0.3mmol) in methanol (5mL), add 1-acetylpiperidin-4-one (71mg, 0.5mmol), anhydrous zinc chloride (116mg, 0.8mmol) and sodium cyanoborohydride (54 mg, 0.8 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2x20 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by high-pressure preparative liquid chromatography to obtain (R)-1- (4-(4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-2-methyl-7,8- Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)piperidin-1-yl)ethan-1-one (58.03 mg) as a white solid, yield 48%. ESI-MS: 533 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ: ppm 9.45(s, 1H), 7.42-7.40(m, 1H), 7.39-7.29(m, 3H), 7.25(s, 1H), 6.95(d , J=6.0Hz, 1H), 5.82-5.74(m, 1H), 4.45-4.41(m, 1H), 3.89-3.85(m, 1H), 3.36-3.30(m, 5H), 3.06-2.99(m , 1H), 2.77-2.74(m, 2H), 2.68-2.60(m, 1H), 2.59-2.57(m, 2H), 2.30(s, 3H), 2.12(s, 6H), 2.00(s, 3H ), 1.86-1.80 (m, 2H), 1.61 (d, J=8.0Hz, 3H), 1.53-1.51 (m, 2H).

biological assay

Experimental example 1. KRAS::SOS1 HTRF binding analysis

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

Reagent:

·GST-SOS1(aa564-1049), in-house production

· His-KRAS G12C (aa1-169), in-house production

· MAb Anti-6his-Tb cryptate Gold, purchased from Cisbio (catalogue number 61HI2TLA)

· MAb Anti-GST-XL665, purchased from Cisbio (Cat. No. 61GSTXLA)

Assay plate: ProxiPlate-384Plus from PerkinElmer (Cat# 6008280)

Assay Buffer: PPI, purchased from Cisbio (Catalog No. 61DB10RDF)

Assay protocol:

Dissolve the compound to be tested in DMSO, prepare a stock solution with a concentration of 10mM, and dilute the compound concentration to 2mM with DMSO as the initial concentration for the determination, serially dilute the compound solution with a 2mM initial concentration 3 times, and dilute 10 concentrations in total, using Labcyte The Echo instrument transfers 0.1 μL of the compound solution of each concentration to a 384-well assay plate (duplicate, double-duplex well);

Add 5 μL of specific concentration of His-KRAS G12C to 0.1 μL of compound solution, and centrifuge at 1000 rpm for 1 min on an Eppendorf5810R centrifuge;

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

Incubate the 384-well assay plate at 25°C for 15 minutes;

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

Incubate the 384-well assay plate at 25°C for 2 hours;

• Finally, the plate was read using a Perkin Elmer Envision 2104 instrument to obtain a signal ratio of 665/615nm.

Each plate contains the following controls:

·DMSO+KRAS+SOS1+MAb Anti-6his-Tb+MAb Anti-GST-XL665

Result calculation:

_IC50 values were calculated and analyzed using a 4 parameter regression equation. The measurement results are shown in the table below.

Compound number SOS1-KRAS ^G12C Interaction Assay (IC ₅₀ , nM) 301 247.4

302 116.5 303 136.6 304 83.3 305 86.7 306 54.3 307 32 309 124.1 311 117.7 312 85.4

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

Claims (13)

1. 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):

   

   wherein:

   X ¹ 、X ² 、X ³ and X ⁴ Each independently selected from c= O, CH ₂ 、CHR、C(R) ₂ And N-L-R ² Preferably X ¹ 、X ² 、X ³ And X ⁴ At least one of them is N-L-R ² ；

   L is selected from direct bond, C _1-6 Alkylene group, C (=o), O, S (=o), S (=o) ₂ And NR ⁴ ；

   Ring B is selected from C _3-10 Hydrocarbon ring, 3-10 membered heterocycle, C _6-10 Aromatic rings and 5-14 membered heteroaromatic rings, up to 2 ring members of which are C (=o);

   r and R ¹ Each at each occurrence is independently selected from halogen, -NH ₂ 、-CN、-NO ₂ 、-OH、-O-C _1-6 Alkyl, C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 Alkenyl, C _2-6 Alkynyl, saturated or partially unsaturated C _3-10 Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 Aralkyl groups, up to 2 ring members of the cyclic hydrocarbon and heterocyclic groups being C (=o), when m is greater than 1 and/or n is greater than 1, two R ¹ And/or two R together with the atom to which they are attached optionally form C _3-10 Hydrocarbon ring, 3-10 membered heterocycle, C _6-10 An aromatic ring or a 5-14 membered heteroaromatic ring, up to 2 ring members of the hydrocarbon ring and the heterocyclic ring being C (=o);

   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 Alkynyl, saturated or partially unsaturated C _3-10 Cycloalkyl, saturated or partially unsaturated 3-to 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) ₂ R ⁵ 、-S(＝O) ₂ NR ⁵ R ⁶ 、-NR ⁵ R ⁶ 、-C(＝O)NR ⁵ R ⁶ 、-NR ⁵ -C(＝O)R ⁶ 、-NR ⁵ -C(＝O)OR ⁶ 、-NR ⁵ -S(＝O) ₂ -R ⁶ 、-NR ⁵ -C(＝O)-NR ⁵ R ⁶ 、-C _1-6 alkylene-NR ⁵ R ⁶ 、-C _1-6 alkylene-O (p=o) (OH) ₂ and-O-C _1-6 alkylene-NR ⁵ R ⁶ ；

   R ³ And R is ⁴ Each independently selected from H, halogen, -NH ₂ 、-CN、-NO ₂ 、-OH、-O-C _1-6 Alkyl, -O- (3-10 membered heterocyclic group), C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 alkylene-OH, halogenated C _1-6 alkylene-OH, C _2-6 Alkenyl, C _2-6 Alkynyl, saturated or partially unsaturated C _3-10 Cycloalkyl, saturated or partially unsaturated 3-to 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) ₂ R ⁵ 、-S(＝O) ₂ NR ⁵ R ⁶ 、-NR ⁵ R ⁶ 、-C(＝O)NR ⁵ R ⁶ 、-NR ⁵ -C(＝O)R ⁶ 、-NR ⁵ -C(＝O)OR ⁶ 、-NR ⁵ -S(＝O) ₂ -R ⁶ 、-NR ⁵ -C(＝O)-NR ⁵ R ⁶ 、-C _1-6 alkylene-NR ⁵ R ⁶ 、-C _1-6 alkylene-O (p=o) (OH) ₂ and-O-C _1-6 alkylene-NR ⁵ R ⁶ ；

   Each of the foregoing groups is optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: halogen, -OH, oxo, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 Aralkyl, =n-OR ⁵ 、-C(＝NH)NH ₂ 、-C(＝O)R ⁵ 、-OC(＝O)R ⁵ 、-C(＝O)OR ⁵ 、-OR ⁵ 、-SR ⁵ 、-S(＝O)R ⁵ 、-S(＝O) ₂ R ⁵ 、-S(＝O) ₂ NR ⁵ R ⁶ 、-NR ⁵ R ⁶ 、-C(＝O)NR ⁵ R ⁶ 、-NR ⁵ -C(＝O)R ⁶ 、-NR ⁵ -C(＝O)OR ⁶ 、-NR ⁵ -S(＝O) ₂ -R ⁶ 、-NR ⁵ -C(＝O)-NR ⁵ R ⁶ 、-C _1-6 alkylene-NR ⁵ R ⁶ and-O-C _1-6 alkylene-NR ⁵ R ⁶ The alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are further optionally substituted with one or moreA substituent independently selected from the group consisting of: halogen, -OH, oxo, -NH ₂ 、-CN、-NO ₂ 、C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group;

   R ⁵ and R is ⁶ Each at each occurrence is independently selected from H, C _1-6 Alkyl, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl and C _6-12 An aralkyl group; and is also provided with

   m is an integer selected from 0, 1, 2, 3 and 4.
2. The compound of claim 1, 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):

   

   ring A is

   

   And is also provided with

   n is an integer selected from 0, 1, 2 or 3.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein L is a direct bond, -CH ₂ Or C (=o).
4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph thereofForms, solvates, N-oxides, isotopically-labeled compounds, metabolites or prodrugs thereof, wherein R ² C being saturated or partially unsaturated _3-10 A cyclic hydrocarbon group or a saturated or partially unsaturated 3-10 membered heterocyclic group, wherein the cyclic hydrocarbon group and heterocyclic group are optionally substituted with one or more groups selected from-C (=o) R ⁵ and-C (=O) NR ⁵ R ⁶ Is substituted by a substituent of (a);

   preferably, R ² Is cyclobutyl, cyclohexyl, piperidinyl or tetrahydropyranyl, optionally substituted with one or more groups selected from-C (=O) CH ₃ and-C (=O) N (CH) ₃ ) ₂ Is substituted by a substituent of (a);

   more preferably, -L-R ² Selected from the group consisting of

   

   
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein ring B is a bicyclo [1.1.1] pentane ring, a 2-oxabicyclo [2.1.1] hexane ring, a benzene ring, or a thiophene ring, most preferably a benzene ring or a thiophene ring.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R ¹ Each at each occurrence is independently selected from halogen, -NH ₂ 、C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _1-6 alkylene-OH, halogenated C _1-6 Alkylene groupradical-OH, saturated or partially unsaturated C _3-10 Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C _6-10 Aryl and 5-14 membered heteroaryl, said alkylene, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being independently selected from one or more of halogen, -OH, C _3-6 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Substituents for aryl and 5-14 membered heteroaryl;

   When m is greater than 1, two R ¹ Optionally together with the atoms to which they are attached form C _3-10 Hydrocarbon ring, 3-10 membered heterocycle, C _6-10 An aromatic ring or a 5-14 membered heteroaromatic ring, up to 2 ring members of which are C (=o), and which are optionally substituted with one or more halogens;

   preferably, R ¹ Each at each occurrence is independently selected from CF ₃ 、NH ₂ 、

   

   And m is 1 or 2.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein

   

   Selected from the group consisting of

   

   
8. The compound of any one of claims 1-7, 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 An alkyl group; preferably, R ³ Is methyl.
9. The compound of any one of claims 1-8, 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 An alkyl group; preferably, R ⁴ H.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (III):

    
11. the compound of any one of claims 1-10, 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:

    
12. a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and a pharmaceutically acceptable carrier, preferably in a solid, semi-solid, liquid or gaseous formulation.
13. Use of a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvent compound, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the prevention or treatment of cancer (e.g. pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma), RAS diseases (e.g. neurofibromatosis type 1 (NF 1), noonan Syndrome (NS), noonan syndrome with multiple spots (NSML), capillary-arteriovenous syndrome (avcm), avcs-face malformation (CS), genetics-fibrous disease and genetics syndrome (CFC-co-morbid).