A class of KRAS-SOS1 inhibitors, preparation methods and applications thereof

Abstract

The present invention discloses a class of KRAS-SOS1 inhibitors, preparation methods and applications thereof, wherein the structure of the inhibitor is shown in Formula I, wherein the definitions of each substituent are as described in the specification and claims. The compounds of the present invention have the activity of inhibiting KRAS-SOS1 protein-protein interaction and can be used to treat tumors caused by KRAS mutations.

Description

Technical Field

[0001] The present invention relates to the fields of drug design and medicinal chemistry, and specifically, to a compound having the activity of inhibiting KRAS-SOS1 protein-protein interaction, and a preparation method and application thereof. Background Art

[0002] Rat sarcoma viral oncogene (RAS) protein is a type of guanine nucleotide binding protein with GTP hydrolase activity, which plays a key role in cell growth, proliferation and differentiation. RAS is an important "switch" in the intracellular signal transduction pathway. When RAS binds to GTP, it is in an activated state (on), and when it binds to GDP, it is in an inactivated state (off). Guanine nucleotide exchange factors (GEFs) (such as SOS) can promote the binding of RAS to GTP, thereby activating multiple carcinogenic-related signaling pathways, such as RAF-ME-ERK, P13K-AKT-mTOR and Ral-GDS.

[0003] Kirsten rat sarcoma viral oncogene (KRAS) is an important member of the RAS protein family, and KRAS mutation is the cause of many tumors. When the KRAS gene mutates, KRAS loses its GTP hydrolysis activity and is in an activated state of continuous binding to GTP, causing abnormal activity of downstream signaling pathways, thereby promoting the occurrence and development of tumors. KRAS mutations can be seen in multiple solid tumors, accounting for 90% of pancreatic cancer, 10-15% of lung cancer (mainly non-small cell lung cancer), and 30%-40% of colorectal cancer. Therefore, blocking the KRAS signaling pathway is a potential anti-cancer approach.

[0004] However, due to the high affinity of KRAS to the endogenous ligand GTP, the surface of KRAS protein is relatively smooth and has no obvious molecular binding pockets, so it is difficult to find binding pockets for small molecule compounds on its surface. So far, there is no effective drug for the treatment of KRAS mutant tumors in clinical practice. Since the conversion of KRAS-GDP to KRAS-GTP is achieved through the catalysis of GEF SOS1, this step is the rate-limiting step of KRAS activation. Therefore, designing small molecule compounds targeting the KRAS-SOS1 protein-protein interaction interface is an effective means to develop KRAS inhibitors.

[0005] In October 2020, Boehringer Ingelheim announced that the first SOS1 protein inhibitor BI1701963 entered the clinical development stage. In February of the same year, Bayer also announced that it had discovered a class of KRAS-SOS interaction inhibitors. However, clinical studies have found that the effect of monotherapy is not outstanding, and it can only "stagnate" the tumor, but cannot kill the tumor. Therefore, in order to meet clinical needs, it is necessary to further develop KRAS-SOS1 inhibitors with diverse structures and better activities. Summary of the invention

[0006] The object of the present invention is to provide a class of compounds having the activity of inhibiting KRAS-SOS1 protein-protein interaction.

[0007] In a first aspect of the present invention, there is provided a compound represented by general formula (I), or an optical isomer, cis-trans isomer, enantiomer, diastereomer, racemate, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof,

[0008]

[0009] In the formula, Indicates a single bond or a double bond;

[0010] In the B ring, when When it is a double bond, R2 does not exist; R1 is independently selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein the substitution refers to substitution by one or more substituents selected from the following group: halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkyl;

[0011] In the B ring, when When it is a single bond, R1 is a carbonyl group (C=O); R2 is selected from the following group: hydrogen, substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkylamino, C1-C6 carboxyl, C1-C6 amide; wherein the substitution refers to substitution by one or more substituents selected from the following group: halogen, amino, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C3-C8 cycloalkyl, C1-C6 alkylCO-, C1-C6 haloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -CONH2;

[0012] In the A ring, two are double bonds, Z1 and Z2 are C; or two are single bonds, Z1 and Z2 are each independently CH or N;

[0013] R3 is selected from the following group: hydrogen, halogen, hydroxyl, cyano, nitro, C1-C6 alkyl, C1-C6 alkylamino, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 alkylOCO-, 6-10 membered aryl (C1-C6 alkylene), C3-C8 cycloalkyl, C1-C6 haloalkoxy or -OR A ; R A Selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 haloalkoxy, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-8 membered heteroaryl, benzyl;

[0014] R6 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 alkylamino, C2-C6 alkenylene, C2-C6 alkynylene, C3-C8 cycloalkyl, C1-C6 haloalkoxy, or -OR B ; R B Selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 haloalkoxy, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-8 membered heteroaryl, benzyl;

[0015] R7 and R8 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, cyano or nitro;

[0016] A1 is selected from the group consisting of C3-C12 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-8 membered heteroaryl;

[0017] R4 is a substituent on A1, the number y is 0, 1, 2 or 3, each independently selected from the following group: hydroxyl, halogen, cyano, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl;

[0018] A2 is selected from the group consisting of absent, C3-C12 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-8 membered heteroaryl;

[0019] When A2 is present, R5 is a substituent on A2, the number z is 0, 1, 2 or 3, each independently selected from the following group: hydroxyl, halogen, cyano, nitro, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, -C1-C6 alkyleneNHC1-C6 alkyl, -C1-C6 alkyleneN(C1-C6 alkyl)2;

[0020] * indicates racemic, S configuration or R configuration.

[0021] In another preferred embodiment, the compound has a structure selected from the following group:

[0022]

[0023] In another preferred embodiment, in ring B, when When it is a double bond, R2 does not exist; R1 is independently selected from the following group: substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein the substitution refers to substitution by one or more substituents selected from the following group: halogen, amino, hydroxyl, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 haloalkyl;

[0024] when When it is a single bond, R1 is a carbonyl group (C=O); R2 is selected from the following group: hydrogen, substituted or unsubstituted C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkylamino, C1-C4 carboxyl, C1-C4 amide; wherein the substitution refers to substitution by one or more substituents selected from the following group: halogen, amino, hydroxyl, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C3-C6 cycloalkyl, C1-C4 alkylCO-, C1-C4 haloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), -CONH2.

[0025] In another preferred embodiment, R3 is selected from the following group: hydrogen, halogen, hydroxyl, cyano, nitro, C1-C4 alkylOCO-, phenyl (C1-C4 alkylene), C1-C4 alkyl, C1-C4 alkylamino, C2-C4 alkenylene, C2-C4 alkynylene, C3-C6 cycloalkyl, C1-C4 haloalkoxy or -OR A ; R A Selected from the following group: hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkoxy, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, benzyl.

[0026] In another preferred embodiment, R6 is selected from the following group: hydrogen, halogen, hydroxyl, cyano, nitro, C1-C4 alkyl, C1-C4 alkylamino, C2-C4 alkenylene, C2-C4 alkynylene, C3-C6 cycloalkyl, C1-C4 haloalkoxy or -OR B ; R BSelected from the following group: hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkoxy, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, benzyl.

[0027] In another preferred embodiment, the heterocycloalkyl group (heterocyclic group) contains 1 or 2 heteroatoms selected from N, S or O, preferably, contains 1 heteroatom selected from S or O.

[0028] In another preferred embodiment, R7 and R8 are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, cyano or nitro;

[0029] * indicates racemic, S configuration or R configuration.

[0030] In another preferred embodiment, A1 is selected from the following group: C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl;

[0031] R4 is a substituent on A1, the number y is 0, 1, 2 or 3, each independently selected from the following group: hydroxyl, halogen, cyano, nitro, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl.

[0032] In another preferred embodiment, the heteroaryl group contains 1 or 2 heteroatoms selected from N, S or O, preferably, contains 1 heteroatom selected from S or O.

[0033] In another preferred embodiment, A1 is selected from the following group: phenyl, thienyl (such as ).

[0034] In another preferred embodiment, A2 is selected from the following group: absent, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl;

[0035] When A2 exists, R5 is a substituent on A2, and the number z is 0, 1, 2 or 3, each independently selected from the following group: hydroxyl, halogen, cyano, nitro, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, -C1-C4 alkyleneNHC1-C4 alkyl, -C1-C4 alkyleneN(C1-C4 alkyl)2.

[0036] In another preferred embodiment, the definition of each substituent is the corresponding group in the specific compound, which will not be repeated here one by one.

[0037] In another preferred embodiment, the compound is selected from the following group:

[0038]

[0039]

[0040]

[0041] The second aspect of the present invention provides a pharmaceutical composition comprising:

[0042] The compound represented by the general formula (I) of the first aspect, or its optical isomers, cis-trans isomers, enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites; and

[0043] A pharmaceutically acceptable carrier.

[0044] The third aspect of the present invention provides the use of the compound represented by the general formula (I) described in the first aspect or the pharmaceutical composition described in claim 8 for preparing a drug for preventing and / or treating cell proliferation diseases related to the KRAS signal transduction pathway; for preparing a KRAS-SOS1 protein-protein interaction inhibitor; for preventing and / or treating a disease caused by a KRAS mutation.

[0045] The compounds of the present invention have the activity of inhibiting KRAS-SOS1 protein-protein interaction, wherein the cellular activity level of some compounds is in micromolar, and have the potential to treat cell proliferation diseases related to the KRAS signal transduction pathway.

[0046] In another preferred embodiment, the disease is selected from the group consisting of pancreatic cancer, lung cancer, and colorectal cancer.

[0047] In another preferred embodiment, the lung cancer is non-small cell lung cancer.

[0048] The present invention discovered a class of compounds that have the activity of inhibiting KRAS-SOS1 protein-protein interaction, among which some compounds can significantly inhibit the proliferation of KRAS G12C-dependent tumor cells MIA PaCa-2 and NCI-H358. This result provides a new research idea for the treatment of tumors caused by KRAS mutations.

[0049] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1The inhibitory activity of the compounds on MIA PaCa-2 (A) and NCI-H358 (B) cells is shown. DETAILED DESCRIPTION

[0051] The inventors of the present application have conducted extensive and in-depth research and developed a class of compounds that have the activity of inhibiting KRAS-SOS1 protein-protein interaction, some of which have cell activity at the micromolar level. On this basis, the present invention was completed.

[0052] the term

[0053] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0054] In the present invention, the term "C1-C6" refers to having 1, 2, 3, 4, 5 or 6 carbon atoms, "C1-C8" refers to having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "5-14 membered" refers to having 5-14 ring atoms, and so on.

[0055] The term "alkyl" refers to a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C1-C6" in "C1-C6 alkyl" refers to a group arranged in a linear or branched form containing 1, 2, 3, 4, 5, or 6 carbon atoms.

[0056] The term "C1-C6 alkoxy" refers to the oxygen ether form of the aforementioned straight or branched alkyl, i.e. -O-alkyl. Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i-PrO, n-PrO, i-BuO, c-PrO, n-BuO or t-BuO.

[0057] The term "C1-C6 alkylamino" refers to a straight or branched alkyl group substituted with an amino group. For example, "C1-C6 alkylamino" refers to a straight or branched alkyl group substituted with an amino group having 1 to 6 carbon atoms, including but not limited to H2N-CH2-, H2N-CH2CH2-, H2N-CH2CH2CH2-, H2N-CH(CH3)CH2-, etc.

[0058] The term "C1-C6 alkylene" refers to a group formed after a C1-C6 alkyl group loses a hydrogen atom, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, or the like.

[0059] The term "C2-C4 alkenylene" refers to a group formed after a C2-C4 alkenyl group loses a hydrogen atom, for example, -CH=CH-, -CH2CH=CH-, or the like.

[0060] The term "C2-C4 alkynylene" refers to a group formed after a C2-C4 alkynyl group loses a hydrogen atom, for example, -C≡C-, -CH2C≡C-, or the like.

[0061] The term "C3-C8 cycloalkyl" refers to a 3-8 membered all-carbon monocyclic, condensed or bridged ring group, each ring containing 3-8 carbon aliphatic hydrocarbon groups, one or more of which may contain one or more double bonds, but none of which has a completely conjugated π electron system. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene or norbornane, etc.

[0062] The term "C3-C8 heterocycloalkyl" refers to a 3- to 8-membered monocyclic, condensed or bridged ring containing at least one heteroatom, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. The number of the heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from O, S, and N. For example: tetrahydrofuran ring, tetrahydropyrrole ring, etc.

[0063] The term "aromatic ring" or "aryl" refers to a group having at least one aromatic ring structure, i.e., a carbocyclic aromatic group having a conjugated π electron system, such as a benzene ring, a naphthalene ring, a biphenyl ring, etc. "Substituted aryl" means that one or more positions in the aryl are substituted, especially 1 to 3 substituents, which can be substituted at any position.

[0064] The term "heteroaromatic ring" or "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N). Heteroaryl is monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocyclic groups. Examples of heteroaryl include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl and pyrrolopyrimidinyl. "Heteroaryl" may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.

[0065] The term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.

[0066] The term "haloalkyl" refers to a straight chain or branched haloalkyl group, such as "C1-C6 haloalkyl", which refers to a straight chain or branched haloalkyl group having 1 to 6 carbon atoms containing one or more same or different halogen atoms, including but not limited to -CH2Cl, -CHCl2, -CCl3, -CH2F, -CHF2, -CF3, -CH2Br, -CHBr2, -CBr3, CF3CH2, CCl3CH2, CBr3CH2.

[0067] The term "haloalkoxy" refers to a straight or branched alkoxy group substituted with a halogen, such as "C1-C6 haloalkoxy", which refers to a straight or branched haloalkoxy group having 1 to 6 carbon atoms, including but not limited to chloromethoxy, chloroethoxy, chloropropoxy, chloroisopropoxy, chlorobutoxy, bromomethoxy, bromoethoxy, bromopropoxy, bromoisopropoxy and bromobutoxy, etc.

[0068] The term "C1-C6 carboxyl" refers to a C1-C6 alkyl group substituted with a carboxyl group.

[0069] The term "C1-C6 amide" refers to (C1-C6 alkyl)-CONH-

[0070] The term "substituted" refers to one or more hydrogen atoms in a group being replaced by the same or different substituents. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), C1-C8 alkyl, C3-C12 cycloalkyl, -OR1, -SR1, =O, =S, -C(O)R1, -C(S)R1, =NR1, -C(O)OR1-C(S)OR1, -NR1R1, -C(O)NR1R1, cyano, nitro, -S(O)2R1, -OS(O)OR1, etc.; wherein R1 is independently selected from -H, alkyl, haloalkyl. Unless otherwise stated, it is assumed that any unsatisfied heteroatom has sufficient hydrogen atoms to supplement its valence.

[0071] In the present invention, the substitution is mono- or poly-substitution, and the poly-substitution is di-, tri-, tetra- or penta-substitution. The di-substitution means having two substituents, and so on.

[0072] The salts that the compounds of the present invention may form also belong to the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts. The term "salt" used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred.

[0073] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including an inorganic base and an organic base. When the compound provided by the present invention is a base, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid, including an inorganic acid and an organic acid. Such acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydroiodic acid, hydrochloric acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, tartaric acid and p-toluenesulfonic acid. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including an inorganic base and an organic base. Including but not limited to: ammonium, calcium, magnesium, potassium and sodium salts, etc.

[0074] Unless otherwise specified, in the present invention, all compounds appearing are intended to include all possible optical isomers, such as single chiral compounds, or mixtures of various chiral compounds (i.e., racemates). Among all compounds of the present invention, each chiral carbon atom can be optionally in R configuration or S configuration, or a mixture of R configuration and S configuration.

[0075] Preparation method

[0076] The preparation method of the compound of the present invention comprises the following steps:

[0077] Synthesis of intermediate A5:

[0078]

[0079]

[0080] Metal-catalyzed coupling of commercially available compound A-1 affords aromatic ketone A-2;

[0081] A-2 reacts with chiral amines to undergo nucleophilic reaction and reduce imine A-3 to obtain a diastereoisomer mixture, which is separated to obtain the desired A-4;

[0082] A-4 can be cleaved to give chiral aromatic benzimidazole A-5.

[0083] Synthesis of intermediate B-4:

[0084]

[0085] Commercially available aromatic acetone compound B-1 is reacted with sulfinamine to obtain imine B-2, B-2 is reduced, and B-3 is hydrolyzed under acidic conditions to obtain B-4.

[0086] Synthesis of compounds of formula II and III:

[0087] Solution 1:

[0088]

[0089] Compound C-4 is obtained through nucleophilic reaction, metal-catalyzed coupling and nucleophilic reaction.

[0090] Option 2:

[0091]

[0092] Compound D-2 is obtained through a two-step nucleophilic reaction.

[0093] Option 3:

[0094]

[0095] Compound E-3 is obtained by acid hydrolysis, nucleophilic substitution and metal-catalyzed coupling reaction.

[0096] Option 4:

[0097]

[0098] Compound F-2 was obtained by acidification hydrolysis and nucleophilic substitution reaction.

[0099] Wherein, LG is independently selected from chlorine, bromine, -OTf, -OTs, etc.; Q is a single bond or does not exist; R1, R2, R3, R4, R5, R6, A1, A2, y, and z are defined as described above; -Hal is a halogen.

[0100] Pharmaceutical composition

[0101] The present invention also provides a pharmaceutical composition, which comprises an active ingredient within a safe and effective amount range and a pharmaceutically acceptable carrier.

[0102] The "active ingredient" described in the present invention refers to the compound of formula I described in the present invention.

[0103] The "active ingredients" and pharmaceutical compositions described in the present invention are used to prepare drugs for treating cell proliferation diseases related to the KRAS signal transduction pathway. The "active ingredients" and pharmaceutical compositions described in the present invention can be used as KRAS-SOS1 protein-protein interaction inhibitors for preparing drugs for preventing and / or treating diseases caused by KRAS mutations.

[0104] "Safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably, 10-200 mg of active ingredient per dose. Preferably, the "one dose" is one tablet.

[0105] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0106] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0107] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0108] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices.

[0109] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.

[0110] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0111] The compounds of the present invention can be administered alone or in combination with other therapeutic drugs (such as anti-tumor drugs).

[0112] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0113] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0114] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0115] Unless otherwise specified, the starting materials used in the present invention are all purchased commercially.

[0116] Certain abbreviations used in the reaction schemes and examples are defined as follows.

[0117] DCM: dichloromethane; THF: tetrahydrofuran; DMSO: dimethyl sulfoxide; DIPEA: N,N-diisopropylethylamine; EA: ethyl acetate; TLC: thin layer chromatography; TEA: triethylamine; DMF: dimethylformamide.

[0118] Example 1 Synthesis of Compound A1

[0119] Synthesis of intermediate B-4a in reaction formula 1:

[0120]

[0121] Step 1: Dissolve compound 1 (2.5 mL), compound 2 (3.06 g) and tetraethoxytitanium (9.1 mL) in anhydrous THF (50 mL) and stir at room temperature overnight. Add brine to quench the reaction, dilute the resulting mixture with ethyl acetate and filter with diatomaceous earth; then dissolve the crude residue in DCM and filter. After the filtrate is concentrated under reduced pressure to remove the solvent, compound 3 (6.37 g) is obtained. LC-MS (ESI, m / z): 294 (M+H) + .

[0122] Step 2: Add 3.0 M methylmagnesium bromide in 2-methyltetrahydrofuran (10 mL) dropwise to a solution of compound 3 (2.94 g) in THF (20 mL). After the mixture was reacted at room temperature for 1 h, ammonium chloride was added to quench, extracted with ethyl acetate, and concentrated under reduced pressure to obtain compound 4.

[0123] Step 3: Add acetyl chloride (2.1 mL) dropwise to a solution of compound 4 (3.1 g) in methanol (7 mL). After the mixture was reacted at room temperature for 2 h, it was concentrated under reduced pressure to remove the solvent. DCM was added to the residue and stirred for 30 minutes. The suspension was filtered and dried to obtain the hydrochloride of 1-(4-bromothiophen-2-yl)ethan-1-amine (1.58 g, total yield of three steps: 60%). 1 H NMR (500MHz, DMSO-d6): δ8.67(s,2H),7.72(s,1H),7.33(s,1H),4.70(d,J=7.2Hz,1H),1.58(d,J=6.8,3H).

[0124] Synthesis of intermediate C-2a in reaction formula 2:

[0125]

[0126] Step 4: Compound B-4a (800 mg) and compound 5 (930 mg) were dissolved in D-MSO (10 mL), and DIPEA (1.1 mL) was added to the mixture. The reaction solution was reacted at 80°C for 2 h and then cooled to room temperature. Water was added to quench the reaction, extracted with EA, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether: ethyl acetate = 4:1 as the eluent to obtain C-2a (1.04 g, yield: 74%). 1 H NMR (500MHz, DMSO-d6): δ8.64(d,J=8.0Hz,1H),7.70(s,1H),7.53(s,1H),7.11(s,2H),5.76(p,J=7.3Hz,1H),3.90(s,6H),1.69(d,J=6.9Hz,3H). LC-MS(ESI,m / z): 428(M+H) + .

[0127] Synthesis of intermediate D-1a in reaction formula 3:

[0128]

[0129] Step 5: Add acetic acid (10 mL) to C-2a (428 mg), and stir the reaction solution at 100°C. After TLC detection of the complete reaction of the raw materials, cool the reaction solution to room temperature. Add saturated sodium bicarbonate solution to the reaction solution and adjust the pH value to 7. Filter the suspension and dry it. Obtain D-1a (400 mg, yield: 97%). 1 H NMR (500MHz, DMSO-d6): δ10.55(s,1H),8.32(d,J=8.1,1H),7.60(d,J=2.1Hz,1H),7.50(d,J=1.4Hz,1 H), 7.05 (s, 1H), 6.68 (s, 1H), 5.79 (p, J = 7.1Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 1.63 (d, J = 7.0Hz, 3H). LC-MS(ESI,m / z): 410(M+H) + .

[0130] Reaction formula 4: Synthesis of compound A1:

[0131]

[0132] Step 6: Dissolve D-1a (50 mg) and compound 6 (30 mg) in 1,4-dioxane (1 mL) and water (250 μL), add potassium carbonate (60 mg) and tetrakistriphenylphosphine palladium (14 mg) to the mixture. Heat and stir at 95 ° C for 8 h under nitrogen protection. After the reaction is complete, cool the reaction solution to room temperature, add water to quench the reaction, extract with EA, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by thin layer chromatography with dichloromethane: methanol = 10: 1 as solvent to obtain compound A1 (10 mg, yield: 21%). 1 H-NMR (500MHz, DMSO-d6): δ10.55(s,1H),8.14(d,J=8.11Hz,1H),7.65(s,1H),7.47-7.43(m,2H),7.32–7.25(m,4H), 7.05(s,1H),5.96(quin,J=7.16Hz,1H),3.87(s,3H),3.79(s,3H),3.56(s,2H),2.22(s,3H),1.72(d,J=6.84Hz,3H). LC-MS(ESI,m / z): 451(M+H) + .

[0133] Example 2 Synthesis of Compound A2

[0134] Reaction 5

[0135]

[0136] Step 1: Dissolve D-1a (41 mg) obtained in step 5 of compound A1 in anhydrous DMF (1 mL), cool to 0°C and add sodium hydride (4.4 mg). After reacting at 0°C for 1 h, add potassium iodide (14.2 mg). React at room temperature until the reaction of the raw material is complete as detected by TLC, add water to quench the reaction, extract with EA, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by column chromatography using dichloromethane: methanol = 40: 1 as the eluent to obtain 7 (27 mg, yield: 64%). 1 H NMR (500MHz, Chloroform-d6): δ7.33(s,1H),6.90(d,J=1.5Hz,1H),6.79(t,J=1.2Hz,1H),6.73(d,J=8.3 Hz, 1H), 6.58 (s, 1H), 5.87 (p, J = 7.0Hz, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.56 (s, 3H), 1.60 (d, J = 6.9Hz, 3H). LC-MS(ESI,m / z): 424(M+H) + .

[0137] Step 2: Prepare compound A2 (11 mg, yield: 23%) in the same manner as step 6 of Example 1. 1 H NMR(500MHz,Chloroform-d6)δ7.43-7.38(m,1H),7.37-7.31(m,1H),7.30-7.27(m,3H),7.17(s,2H),6.68(s,1H),6.58 (s,1H),6.04(p,J=7.1Hz,1H),3.98(s,3H),3.94(s,3H),3.79(s,2H),3.59(s,3H),2.38(s,3H),1.72(d,J=6.8Hz,3H). LC-MS(ESI,m / z): 465(M+H) + .

[0138] Embodiment 3-4

[0139] Compounds A3-A4 were synthesized with reference to the above Example A2.

[0140] Example 5 Synthesis of Compound A5

[0141] Synthesis of intermediate A-5a in reaction formula 6

[0142]

[0143] Step 1: Dissolve compound 8 (10 g) in anhydrous 1,4-dioxane (100 mL), add TEA (10 mL), compound 9 (17.3 g) and bis(triphenylphosphine)palladium(II) chloride (2.6 g). Heat and stir at 80 ° C for 12 h under nitrogen protection. After the reaction is complete, cool the reaction solution to room temperature. Add 1.0N hydrochloric acid solution to the reaction solution and stir at room temperature overnight. Extract with EA, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography with petroleum ether: ethyl acetate = 60:1 as eluent to obtain 10 (5.5 g, yield: 64%). 1 H NMR (500MHz, Chloroform-d6): δ8.94 (t, J = 1.8 Hz, 1H), 8.77-8.63 (m, 1H), 8.53 (t, J = 1.6 Hz, 1H), 2.74 (s, 3H).

[0144] Step 2: Compound 10 (5.3 g), (R)-(+)-2-methyl-2-propanesulfenamide (4.1 g) and tetraethoxytitanium (13 mL) were dissolved in anhydrous THF (50 mL). The reaction solution was reacted at 80°C for 5 h and then cooled to room temperature. Ice water was added to quench the reaction. The resulting mixture was diluted with ethyl acetate and filtered through diatomaceous earth. The crude residue was then dissolved in DCM and filtered. The filtrate was concentrated under reduced pressure to remove the solvent to obtain 11 (5.5 g, yield: 72%).

[0145] Step 3: 11 (2.7 g) was dissolved in a mixed solvent of tetrahydrofuran (25 mL) and water (0.5 mL), cooled to -50°C and sodium borohydride (540 mg) was added. After TLC detected that the reaction of the raw material was complete, ice water was added to quench the reaction, extracted with EA, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether: ethyl acetate as the eluent to obtain diastereomer 12 (1.7 g, yield: 63%). 1H NMR (500MHz, DMSO-d6) δ8.63(t,J=1.8Hz,1H),8.38(d,J=2.1Hz,1H),8.30(d,J=1.7Hz,1H ), 6.07 (d, J = 8.6 Hz, 1H), 4.69 (dq, J = 8.6, 6.9 Hz, 1H), 1.45 (d, J = 6.9 Hz, 3H), 1.14 (s, 9H). LC-MS(ESI,m / z): 339(M+H) + .

[0146] Step 4: Add 4.0N hydrochloric acid solution (2.5ml) to a solution of 7 (1.7g) in 1,4-dioxane (20ml). The reaction solution was reacted at room temperature until the reaction of the raw material was complete as detected by TLC. The reaction solution was concentrated and the residue was washed with ether to obtain (R)-1-(3-nitro-5(trifluoromethyl)phenyl)ethane-1-amine hydrochloride (1.2g, yield: 88%). 1H NMR (500MHz, DMSO-d6): δ8.77 (t, J=1.9Hz, 1H), 8.73 (s, 2H), 8.55-8.50 (m, 1H), 8.48-8.44 (m, 1H), 4.76 (q, J=6.8Hz, 1H), 3.37 (s, 31H), 1.59 (d, J=6.8Hz, 3H). LC-MS (ESI, m / z): 235 (M+H) + .

[0147] Step 5: Add 5% palladium on carbon (10 mg) to a solution of 13 (270 mg) hydrochloride in methanol (5 ml). Pass hydrogen into the reaction solution and react at room temperature and pressure for 1-2 h. Filter the reaction solution with diatomaceous earth, collect the filtrate and concentrate under reduced pressure to obtain (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (769 mg, yield: 90%).

[0148] Synthesis of intermediate E-1a in reaction formula 7:

[0149]

[0150] E-1a was prepared in the same manner as in the fourth step of Example 1 (yield: 80%). 1 H NMR (500MHz, DMSO-d6): δ8.52(d,J=7.9Hz,1H),7.78(s,1H),7.09(s,1H),6.87(d,J=1.6Hz,1H),6.83(t,J=1.8Hz ,1H),6.73(d,J=2.0Hz,1H),5.59(s,2H),5.45(p,J=7.1Hz,1H),3.93(s,3H),3.90(s,3H),1.57(d,J=7.0Hz,3H). LC-MS(ESI,m / z): 427(M+H) + .

[0151] Reaction formula 8: Synthesis of compound A5:

[0152]

[0153] Compound A5 was prepared in the same manner as in step 5 of Example 1 (yield: 80%). 1 H NMR (500MHz, DMSO-d6): δ10.48(s,1H),8.25(d,J=7.9Hz,1H),7.74(s,1H),6.85-6.80(m,2H),6.74 -6.67(m,2H),5.58(s,2H),5.49(p,J=7.1Hz,1H),3.84(s,3H),3.80(s,3H),1.53(d,J=7.0Hz,3H). LC-MS(ESI,m / z): 409(M+H) + .

[0154] Example 6 Synthesis of Compound A6

[0155] Reaction 9

[0156]

[0157] Step 1: The same as Step 4 and Step 5 of Example 1 were used to prepare 14.

[0158] Step 2: Prepare 16 in the same manner as in the first step of Example 2. 1 H NMR (500MHz, DMSO-d6): δ8.60(t,J=1.8Hz,1H),8.54(d,J=7.1Hz,1H),8.37–8.35(m,1H),8.35(d,J=1.6Hz,1H),7.7 5(s,1H),6.96(s,1H),5.69(p,J=7.0Hz,1H),4.84(q,J=9.2Hz,2H),3.94(s,3H),3.88(s,3H),1.67(d,J=7.0Hz,3H). LC-MS(ESI,m / z): 521(M+H) + .

[0159] Step 3: Compound A6 was prepared in the same manner as in Step 5 of Example 5. 1 H NMR (500MHz, DMSO-d6): δ8.35(d,J=7.6Hz,1H),7.76(s,1H),6.95(s,1H),6.86(s,1H),6.82(t,J=1.8Hz,1H),6.70(t,J =2.0Hz,1H),5.55(s,2H),5.43(p,J=7.1Hz,1H),4.86(q,J=9.2Hz,2H),3.90(s,3H),3.87(s,3H),1.56(d,J=7.0Hz,3H). LC-MS(ESI,m / z): 491(M+H) + .

[0160] Examples 7-12

[0161] Compounds A7-A12 were synthesized with reference to the above Example A6.

[0162] Example 13 Synthesis of Compound A13

[0163] Reaction 10

[0164]

[0165] Add excess sodium methoxide to a solution of E-1a (44 mg) in methanol (2 mL), heat under reflux until the reaction of the raw material is complete as detected by TLC. Add water to quench the reaction, and filter to obtain a solid. Dissolve the solid in ethyl acetate, concentrate under reduced pressure, and purify the residue by column chromatography using petroleum ether: ethyl acetate = 2:1 as the eluent to obtain compound A13 (37 mg, yield: 88%). 1H NMR (500MHz, DMSO-d6): δ8.13(d,J=7.7Hz,1H),7.70(s,1H),6.91(s,1H),6.84-6.78(m,2H),6.67(t,J=1. 9Hz, 1H), 5.53 (s, 2H), 5.39 (p, J = 7.0Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.75 (s, 3H), 1.52 (d, J = 7.1Hz, 3H). LC-MS(ESI,m / z): 423(M+H) + .

[0166] Examples 14-19

[0167] Compounds A14-A19 were synthesized with reference to the above Example A13.

[0168] Example 20 Synthesis of Compound A20

[0169] Reaction 11

[0170]

[0171] Step 1: Prepare 18 in the same manner as step 4 of Example 1.

[0172] Step 2: Dissolve 18 (115 mg) in anhydrous dichloromethane (5 mL), cool the solution to -50 °C and add 1.0 N dichloromethane solution of boron tribromide (1 mL) dropwise. React until the reaction is complete as detected by TLC. Add ice water dropwise at -50 °C to quench the reaction, extract with EA, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by column chromatography using petroleum ether: ethyl acetate = 6:1 as the eluent to obtain 19 (100 mg, yield: 90%). LC-MS (ESI, m / z): 384 (M+H) + .

[0173] Step 3: Add 20 (70 mg) and potassium carbonate solid (42 mg) to a solution of 19 (110 mg) in DMF (4 mL). The reaction solution was reacted at 80°C until the reaction of the raw materials was complete as detected by TLC. A large amount of saturated aqueous sodium carbonate solution was added to the mixture to adjust the pH value to alkaline, extracted with EA, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 21. LC-MS (ESI, m / z): 454 (M+H) + .

[0174] Step 4: Prepare 22 in the same manner as step 5 of Example 1.

[0175] Step 5: Prepare 23 in the same manner as in the first step of Example 2.

[0176] Step 6: Prepare compound A16 in the same manner as step 6 of Example 1.1 H NMR (500MHz, DMSO-d6): δ8.59(d,J=8.2Hz,1H),7.82(t,J=2.2Hz,1H),7.51-7.4 5(m,2H),7.37-7.28(m,6H),5.88(p,J=7.1Hz,1H),5.17-5.11(m,1H),3.92(dd,J =10.1,4.5Hz,1H),3.84(ddd,J=13.2,6.7,3.0Hz,1H),3.79(td,J=8.1,7.6,2.7H z,2H),3.62(s,2H),2.30–2.19(m,4H),2.05-1.92(m,1H),1.70(d,J=6.9Hz,3H). LC-MS (ESI, m / z): 491 (M+H) + .

[0177] Example 21 Synthesis of Compound A21

[0178] Reaction 12

[0179]

[0180] The same method as that of preparing 21 was used to prepare 24. The same method as that of Example 10 was used to prepare compound A21. 1 H NMR (500MHz, Chloroform-d): δ7.67(s,1H),7.62(dd,J=8.7,3.3Hz,2H),7.53(d,J=7.7Hz,1H),7.46(t,J=7.7Hz,1H),7.29(d,J=9.0Hz ,1H),7.01(s,1H),5.67(p,J=7.0Hz,1H),5.05–5.00(m,1H),4.05-3.97(m,3H),3.95(m,4H),2.25-2.16(m,2H),1.69(d,J=6.9Hz,3H). LC-MS(ESI,m / z): 434(M+H) + .

[0181] Embodiment 22

[0182] Compound A22 was synthesized by referring to the above Example A21.

[0183] Example 23 Synthesis of Compound A23

[0184] Reaction 13

[0185]

[0186] Step 1: Add DL-methionine (3 g) to a suspension of compound 25 (3 g) in methanesulfonic acid (15 mL) at room temperature. After the reaction solution was reacted at 80°C for 10 h, it was cooled to room temperature and quenched with ice water. Saturated aqueous sodium hydroxide solution was added to the mixed solution to adjust the pH to alkaline, and extracted with ethyl acetate. The organic phase was removed. Dilute hydrochloric acid solution was added to the aqueous phase to adjust the pH of the solution to acidic, and stirred at room temperature for 2 h. Filter the precipitate to obtain 26 (2.3 g yield: 80%). 1 H NMR (500MHz, DMSO-d6) δ9.95(s,1H),8.10(s,1H),7.29(s,1H),3.77(s,3H). LC-MS(ESI,m / z): 209(M+H) + .

[0187] Step 2: 26 (208 mg) was dissolved in a mixture of phosphorus trichloride (2 mL) and N, N-dimethylaniline (32 μL). The reaction solution was condensed and refluxed at 100°C until the reaction of the raw material was complete as detected by TLC. After cooling the reaction solution to 0°C, the reaction was quenched with ice water, the pH was adjusted to between 8 and 9 with a saturated sodium bicarbonate solution, extracted with EA, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether: ethyl acetate = 4:1 as the eluent to obtain 27 (195 mg, yield: 83%). 1 H NMR (500MHz, DMSO-d6): δ10.93(s,1H),7.40(s,1H),7.37(s,1H),4.00(s,3H). LC-MS(ESI,m / z): 245(M+H) + .

[0188] Step 3: Prepare 28 in the same manner as step 4 of Example 1. LC-MS (ESI, m / z): 414 (M+H) + .

[0189] Step 4: Prepare 29 in the same manner as in step 3 of Example 15. LC-MS (ESI, m / z): 484 (M+H) + .

[0190] Step 5: Prepare 30 in the same manner as in Step 5 of Example 1. LC-MS (ESI, m / z): 466 (M+H) + .

[0191] Step 6: Prepare 31 in the same manner as in the first step of Example 2. 1H NMR (500MHz, DMSO-d6): δ8.37(d,J=8.3Hz,1H),7.70(d,J=1.9Hz,1H),7.52(d,J=1.5Hz,1H),7.07(s,1H),6.83(s,1H),5.80(p,J=7.1Hz,1H) ,5.05(ddd,J=6.3,4.3,2.0Hz,1H),3.95(s,3H),3.92-3.74(m,4H),3. 49(s,3H),2.27-2.15(m,1H),2.03-1.92(m,1H),1.64(d,J=6.9Hz,3H). LC-MS(ESI,m / z): 480(M+H) + .

[0192] Step 7: Prepare compound A23 in the same manner as in step 6 of Example 1. 1 H NMR (500MHz, DMSO-d6): δ8.36(d,J=8.3Hz,1H),7.72(d,J=1.4Hz,1H),7.49(d,J=1.4Hz, 1H),7.46(dd,J=6.7,2.2Hz,1H),7.34-7.25(m,4H),6.82(s,1H),5.87(p,J=7.3Hz,1H), 5.04(tt,J=4.4,2.0Hz,1H),3.94(s,3H),3.89-3.75(m,4H),3.60(s,2H),3.49(s,3H),2 .24(s,3H),2.22-2.15(m,1H),1.97(dt,J=13.6,5.2Hz,1H),1.71-1.66(d,J=6.9Hz,3H). LC-MS(ESI,m / z): 521(M+H) + .

[0193] The structures and characterization results of compounds A1-A19 are as follows:

[0194]

[0195]

[0196]

[0197]

[0198]

[0199] Example 20 Pharmacological Experiment

[0200] This example involves an experiment on the inhibition rate of the GDP / GTP exchange rate of the KRAS G12C protein by the compound and a pharmacological experiment on the KRASG12C-dependent tumor cell proliferation inhibition activity. Unless otherwise specified, the experimental materials required for the pharmacological experiment were purchased commercially.

[0201] KRAS G12C protein GDP / GTP exchange rate inhibition experiment

[0202] (I) Reagents, consumables and instruments

[0203]

[0204] (II) Experimental steps

[0205] 1. Treatment of Compounds

[0206] Prepare the compound at 400 times the final concentration. For example, if the final concentration is 25 μM, prepare it at 400 times the final concentration, i.e. 10 mM. Use an automatic micro-well pipette to dilute the compound to the set number of concentration points.

[0207] 2. Transfer compounds to 384-well reaction plate

[0208] The diluted compounds were transferred from the Echo 384-well plate to the 384-well reaction plate by using an ultrasonic nanoliter liquid handling system. Both the negative control and the positive control were transferred with 75 nL of 100% DMSO.

[0209] 3. Prepare 1x reaction buffer

[0210] The 1x reaction buffer contains 50 mM Tris (PH 7.5), 50 mM NaCl, 1 mM EDTA, 0.1% BSA, 14 mM MgCl2, 0.01% Tween-20, and 1 mM DTT.

[0211] 4. Prepare 3x KRAS G12C enzyme solution, 6x SOS1 enzyme solution, 6x GTP solution, and 3x detection solution

[0212] Use 1x reaction buffer to prepare 3x KRAS G12C enzyme solution, 6x SOS1 enzyme solution, 6x GTP solution, and 3x detection solution (Antibody-IRDye and GDP-Tracer).

[0213] 5. Transfer 3x KRAS G12C Enzyme Solution

[0214] Transfer 10 μL of 3x KRAS G12C enzyme solution to the reaction plate, and for the negative control wells, replace the enzyme solution with 10 μL of 1x reaction buffer. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes.

[0215] 6. Transfer 6x SOS1 enzyme solution

[0216] Transfer 5 μL of 6x SOS1 enzyme solution to the reaction plate.

[0217] 7. Transfer 6x GTP solution

[0218] Transfer 5 μL of 6x GTP solution to the reaction plate.

[0219] 8. Transfer 3x Detection Solution

[0220] Transfer 10 μL of 3x detection solution to the reaction plate and centrifuge at 1000 rpm for 1 minute.

[0221] 9. Reading

[0222] The fluorescence signal value (Ex580 / Em620) was continuously read for 2 hours (once every 5 minutes) using the SpectraMax Paradigm microplate reader.

[0223] 10. Inhibition rate calculation and IC50 fitting

[0224] Copy the values ​​from the plate reader and calculate the slope value, where the maximum value refers to the reading of the positive control and the minimum value refers to the reading of the negative control. Inhibition rate (%) = (maximum value - sample value) / (maximum value - minimum value) × 100%.

[0225] The data were imported into LC-MS Excel and IC50 values ​​were fitted using XLFit excel add-in version5.4.0.8;

[0226] Fitting formula: Y = Bottom + (Top-Bottom) / (1 + (IC50 / X)^HillSlope).

[0227] KRAS G12C-dependent tumor cell proliferation inhibitory activity test

[0228] (I) Reagents, consumables, and instruments

[0229]

[0230] (II) Experimental steps

[0231] MIA PaCa-2 and NCI-H358 cells in the logarithmic growth phase were seeded into 96-well culture plates at a density of about 3,000 cells per well, with 100 μL per well, and cultured overnight. After the cells adhered overnight, the compound was diluted in a gradient manner with the culture medium and added to the cells, and a solvent negative control group and a BAY-293 positive control group were set up and gently shaken to mix. After 72 hours of culture in the incubator, the effect of the compound on cell proliferation was detected using the CellTiter Glo kit. The reading was performed using a multifunctional microplate reader.

[0232] The positive compound BAY-293 has the following structural formula:

[0233] The IC of the compound on tumor cell growth was calculated using the following formula: 50 value:

[0234] Inhibition rate = (1-(compound well value-blank value) / (DMSO well value-blank value))*100

[0235] Table 1: Inhibitory activity of some compounds on the GDP / GTP exchange rate of KRAS G12C

[0236] Example No. <![CDATA[IC 50 (μM)]]> Example No. <![CDATA[IC 50 (μM)]]> A2 0.721 A11 0.388 A4 1.135 A12 0.893 A5 1.048 A13 1.254 A7 7.617 A14 6.710 A8 1.343 A16 0.978 A9 0.905 A17 0417 A10 0.674 A18 8.288 A21 1.396 A22 0.208 A23 0.452 BAY-293 0.096

[0237] Table 2: Effects of some compounds at different concentrations on the GDP / GTP exchange rate of KRAS G12C

[0238]

[0239] From the above, it can be seen that the tested compounds have a certain inhibitory activity on the GDP / GTP exchange rate of KRAS G12C.

[0240] Table 3: Proliferation inhibitory activity of some compounds on KRAS G12C-dependent tumor cells

[0241]

[0242] The inhibitory activity of the compounds on MIA PaCa-2 (A) and NCI-H358 (B) cells was also shown in Figure 1 As shown, from the above results, it can be seen that the tested compounds have a significant inhibitory effect on the proliferation of KRAS G12C-dependent tumor cells MIA PaCa-2 and NCI-H358.

[0243] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, In the formula, represents a single bond, R1 is a carbonyl group (C=O); R2 is selected from the group consisting of: unsubstituted C1-C4 alkyl; R3 is selected from the group consisting of: -OR A ; R A Selected from the group consisting of C1-C4 alkyl, 3-6 membered heterocycloalkyl; R6 is selected from the group consisting of hydrogen, -OR B ; R B Selected from the group consisting of: C1-C4 alkyl; R7 is hydrogen; R8 is C1-C4 alkyl; A1 is a thienyl group; R4 is a substituent on A1, and the number y is 0; A2 is phenyl; R5 is a substituent on A2, the number z is 1, and is selected from the following group: -C1-C4 alkylene NHC1-C4 alkyl; * represents racemization, S configuration or R configuration.

2. The compound according to claim 1, characterized in that The compound is:

3. A compound, characterized in that The compound is selected from the group consisting of:

4. A pharmaceutical composition, characterized in that Include: A compound as claimed in any one of claims 1 to 3; and A pharmaceutically acceptable carrier.

5. Use of the compound according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4, characterized in that: Used to prepare drugs for preventing and / or treating cell proliferation diseases related to the KRAS signal transduction pathway; used to prepare KRAS-SOS1 protein-protein interaction inhibitors; or used to prepare drugs for preventing and / or treating diseases caused by KRAS mutations.

6. The use according to claim 5, characterized in that The disease is selected from the group consisting of pancreatic cancer, lung cancer, and colorectal cancer.

7. The use according to claim 6, characterized in that The lung cancer is non-small cell lung cancer.

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