Diazabicyclo octane inhibitors of KRAS (G12D) and uses thereof

Abstract

Small molecule inhibitors of KRAS (G12D) mutant oncoproteins having the structural formula: as well as pharmaceutically acceptable salts and compositions thereof are provided, which are useful for the treatment of cancer and related conditions.

Description

Related applications

[0001] This application claims priority to International Application No. PCT / CN2023 / 090892, filed on April 26, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] The Kirsten rat sarcoma virus homolog (KRAS) gene, discovered in the early 1980s as a human oncogene, encodes a monomeric small 21kDa GTPase, which has long been a difficult target for cancer drugs (Chang et al., PNAS, 1982, 79:4848-52; McCoy et al., Nature, 1983, 302:79-8). KRAS acts as a molecular switch promoting cell growth by cycling between GTP-bound and GDP-bound states. In the GTP-bound state, KRAS sends growth signals through the RAF-MAPK and PI3K-AKT-mTOR pathways. Subsequently, KRAS hydrolyzes GTP to GDP with the help of GTPase activator protein (GAP). This GDP-bound state "turns off" KRAS-promoted growth signal transduction. Then, with the assistance of guanine nucleotide exchange factors (such as SOS1), KRAS can subsequently be "reactivated" through the exchange of GDP with GTP (Cox and Der, Small GTPases, 2010, 1:2-27; Kerk et al., Nat Rev Cancer, 2021, 21:510-525). Preventing this exchange by locking KRAS in its GDP-bound state is a practical method to inhibit its growth-promoting activity.

[0003] The human KRAS gene is encoded on chromosome 12p12.1 and is one of the most frequently mutated genes in human cancer (Pylayeva-Gupta et al., Nat Rev Cancer, 2011, 11:761-774). Mutations that prevent GTP hydrolysis lock KRAS into an active GTP-binding state and reprogram cells to proliferate permanently. KRAS with a glycine (G) mutation to aspartic acid (D) at codon 12 produces a long-term active KRAS (G12D) oncoprotein, which was observed in 6.8% of cancer cases by next-generation sequencing analysis (Zhou et al., Pathol Oncol Res, 2020, 26:2835-2837). In tumor type-specific studies, KRAS (G12D) has been associated with poor clinical outcomes and has been observed in 17% of lung cancer, 14.3% of colorectal cancer, and 48% of pancreatic tumors (Aredo et al., Lung Cancer, 2019, 133:144-150; Olmedillas-López et al., World J Gastroenterol, 2017, 23(39):7087-709; Miglio et al., Pathol Res Pract, 2014, 210:307-11; Gou et al., Br J Cancer, 2020, 22:857-867), as well as other cancers. Historically, oncogenic KRAS mutants were considered untreatable (McCormick F, Biochem J, 2019, 476:356-74). However, the discovery of the allosteric pocket in GDP-binding KRAS has allowed for the search for small molecule inhibitors (Ostrem et al., Nature, 2013, 503: 548-51). Furthermore, the G12D mutation provides a unique chemical binding space by replacing a small, flexible amino acid residue (G) with an acidic amino acid residue (D) that has only a hydrogen side chain. This alteration in the KRAS protein structure offers a unique target for small molecule drugs that specifically inhibit the oncogenic activity of KRAS (G12D). Therefore, it is desirable to design and develop small molecule drugs targeting KRAS (G12D) with sufficient bioavailability to treat diseases such as cancer. Summary of the Invention

[0004] This article provides small molecule inhibitors of the mutant KRAS (G12D) oncoprotein. Inhibitors of KRAS (G12D) include those with structural formula I: (I) And pharmaceutically acceptable salts and compositions containing such salts, wherein R1 Y and As defined herein, the use of these compounds, salts, and compositions for the treatment of diseases, such as cancer, that respond to inhibition of KRAS (G12D) is also disclosed. Detailed Implementation

[0005] 1. Overview of Compounds As part of the first embodiment, compounds of formula I are provided herein: (I); Or its pharmaceutically acceptable salt, in which Y is CN, C(O)CN, or optionally surrounded by 1 to 3 halogens, CN, OH, O(C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)ynyl, -COR a’ and -C(O)OR a’ (C1-C4) alkyl groups substituted with radicals; R 1 It is hydrogen, halogen, OH, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, -CHO, -C(O)OR b’ -C(O)ONR a’ R b’ Alternatively, it may be a 5- to 6-membered heteroaryl group substituted with 1 to 3 groups selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy and cyano groups; R a’ and R b’ Each is independently selected from hydrogen and (C1-C4) alkyl groups, or R a’ and R b’ Together with the nitrogen to which it is attached, it forms an optionally substituted heterocyclic group; and It is an optional substituted heteroaryl group.

[0006] 2. Definition As used herein, the articles “a” and “an” refer to one or more (e.g., at least one) grammatical objects of the article. When used in conjunction with the term “contains”, the use of the words “a” or “an” can mean “one”, but also aligns with the meanings of “one or more,” “at least one,” and “one or more.”

[0007] As used herein, the terms “comprising” or “including” are used to refer to compositions, methods and their respective components present in a given embodiment, but are open to including unspecified elements.

[0008] As used herein, unless otherwise stated, the term "alkyl" means a saturated straight-chain or branched acyclic hydrocarbon having 1 to 10 carbon atoms, such as (C1-C6)alkyl or (C1-C4)alkyl. Representative straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl; while saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, and 2,5-dimethylhexyl. 2,2-Dimethylpentyl, 2,2-Dimethylhexyl, 3,3-Dimethylpentyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylpentyl, 3-Ethylpentyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, 2-Methyl-4-Ethylpentyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2-Methyl-4-Ethylhexyl, 2,2-Diethylpentyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, 3,3-Diethylhexyl, etc.

[0009] As used herein, unless otherwise stated, the term "alkynyl" means a saturated straight-chain or branched acyclic hydrocarbon having 2 to 10 carbon atoms and at least one carbon-carbon triple bond (e.g., (C2-C6) alkynyl or (C2-C4) alkynyl). Representative straight-chain and branched alkynyl groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-hepynyl, 2-hepynyl, 6-hepynyl, 1-octyynyl, 2-octyynyl, 7-octyynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, etc.

[0010] The term "oxo" refers to the group =O.

[0011] As used herein, the term "haloalkyl" means that one or more (including all) hydrogen atoms in an alkyl group are replaced by a halogen group, wherein each halogen group is independently selected from -F, -Cl, -Br, and -I. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, etc.

[0012] "Alkoxy" refers to an alkyl group linked by an oxygen atom and is represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0013] "Haloalkoxy" is a haloalkyl group that is attached to another part by an oxygen atom, such as -OCHF2 or -OCF3.

[0014] As used in this article, the term "halogen" or "halo" refers to F, Cl, Br, or I.

[0015] As used herein, the term "heterocyclic group" means a 4- to 12-membered monocyclic or polycyclic (e.g., bridged bicyclic, fused bicyclic, or spirobicyclic) saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. Heterocycles can be linked by any heteroatom or carbon atom, provided the valence allows. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidone, pyrrolylalkyl, piperidinyl, piperazine, oxiranyl, dioxanyl, oxiranyl, dioxanyl, dihydrofuranyl, dihydropyranyl, isoindolinyl, dihydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, diazabicyclooctyl, hexahydropyrrolazine, 2-azaspiro[3.3]heptyl, 2,7-diazaspiro[3.5] Nonyl, 2-azaspiro[3.5]nonyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3,6-diazabicyclo[3.1.1]heptyl, octahydro-1H-pyrrolo[2,3-c]pyridyl, 1,4-dioxa-8-azaspiro[4.5]decyl, or 1,2,3,6-tetrahydropyridyl, etc. Optional substituents on the heterocyclic group can be present at any substituted position, including, for example, positions where the valence allows for the linkage of the heterocyclic group.

[0016] The term "spiral" refers to two rings sharing a single ring atom (e.g., carbon).

[0017] The term "fusion" refers to two rings sharing two adjacent ring atoms.

[0018] The term "bridging" refers to two rings sharing three ring atoms with each other.

[0019] As used herein, the term "heteroaryl" refers to a 5- to 12-membered aromatic group containing 1 to 4 heteroatoms selected from N, O, and S. Heteroaryls can be monocyclic or bicyclic. Where valence permits, heteroaryls can be linked by any heteroatom or carbon atom. Representative heteroaryl groups include pyridinyl, furanyl, thiopheneyl, pyrroleyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazoleyl, benzoxazolyl, benzofuranyl, indolazilyl, imidazopyridyl, tetrazolyl, benzoimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indoleyl, tetrahydroindoleyl, azaindoleyl, imidazopyridyl, quinazolinyl, purinyl, benzothiapheneyl, etc. Optional substituents on the heteroaryl group can be present at any substituted position, including, for example, the linking position of the heteroaryl group where the valence allows.

[0020] When used to describe chemical groups that can have multiple attachment points, the hyphen (-) indicates the attachment point of the group to the variable that defines it. For example, -(C1-C4)alkylaryl means that the attachment point of these groups appears on an alkyl group.

[0021] For example in " The hash key represents the attachment point between the described group and the defined variable.

[0022] The term "KRAS" refers to the protein products of the KRAS proto-oncogene and GTPase gene.

[0023] The term "KRAS(G12D)" refers to the protein product of the KRAS gene carrying a mutation that causes the glycine at position 12 of KRAS to be replaced by aspartic acid.

[0024] "with KRAS" G12D "Combined chemical entity" refers to the chemical entity associated with KRAS. G12D A significant portion of a small molecule or larger molecule that is bound together. In some respects, it is associated with KRAS. G12D The combined chemical entities are small molecules. In some respects, with KRAS G12D The combined chemical entities are small molecules with a molecular weight of less than 2,000 g / mol. In some respects, they are associated with KRAS. G12D The combined chemical entity induces KRAS G12D Conformational changes in the middle.

[0025] The term "SOS1" refers to the protein product of the SOS1 gene, which functions as a guanine nucleotide exchange factor for the RAS protein.

[0026] The compounds described herein may have a chiral center and / or a geometric center (E- and Z-isomers). It will be understood that this disclosure covers all stereoisomers and geometric isomers. The tautomer forms of the compounds described herein are also part of this disclosure.

[0027] When the stereochemistry of the disclosed compound is named or described in terms of structure, the weight purity of the named or described stereoisomer relative to all other stereoisomers is at least 60%, 70%, 80%, 90%, 99%, or 99.9%. The percentage of weight purity relative to all other stereoisomers is the ratio of the weight of one stereoisomer to the weight of the described stereoisomer plus the weights of the other stereoisomers.

[0028] When used in pharmaceuticals, a pharmaceutically acceptable salt of the disclosed compounds refers to a non-toxic "pharmaceutically acceptable salt". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic salts or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of the present teaching having an acidic group (such as carboxylic acid) can form pharmaceutically acceptable salts with a pharmaceutically acceptable base. Suitable pharmaceutically acceptable base salts include, for example, ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts). Compounds having a quaternary ammonium group also contain anti-anions, such as chlorides, bromides, iodides, acetates, perchlorates, etc. Other examples of such salts include hydrochlorides, hydrobromic acids, sulfates, methanesulfonates, nitrates, benzoates, and salts formed with amino acids (such as glutamic acid).

[0029] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or loading agent that does not impair the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or loading agents that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine, sorbic acid, potassium sorbate), mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0030] As used herein, the term "subject" refers to both humans and non-human animals, including veterinary subjects. The term "non-human animal" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dogs, cats, horses, cattle, chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a human, which may be referred to as a patient.

[0031] As used herein, the terms “treat,” “treating,” or “treatment” preferably refer to actions that achieve a benefit or desired clinical outcome, including but not limited to the reduction or improvement of one or more signs or symptoms of a disease or condition, reduction of disease severity, stabilization (i.e., non-deterioration) of a disease state, improvement or remission of a disease state, reduction of the rate or time of disease progression, and remission (whether partial or complete remission). “Treatment” may also mean extended survival compared to expected survival without treatment. Treatment does not require a cure.

[0032] "Therapeutic effective dose" refers to an amount sufficient to treat the subject's disease. Therapeutic effective doses can be administered once or multiple times. In one aspect, a therapeutic effective dose is a dose of about 0.01 to about 100 mg / kg body weight / day.

[0033] The terms "administer," "administering," or "administration" include any method of delivering a pharmaceutical composition or agent to a specific area within or on the body of a subject. In some embodiments, the agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, percutaneously, or via a mucosa. In some embodiments, the agent is administered intravenously. In some embodiments, the agent is administered orally. The administration of the agent can be performed collaboratively by multiple people. The administration of the agent includes, for example, providing the subject with a prescription for the agent to be administered and / or providing instructions for taking the specific agent directly or through another person; it can also be self-delivered, such as orally, subcutaneously, intravenously via a central catheter, etc.; or delivered by a trained professional, such as intravenously, intramuscularly, intratumorally, etc.

[0034] 3. Compounds As part of the second embodiment, the compound of formula I is the compound of formula II: (II) Or its pharmaceutically acceptable salt, in which X 1a Selected from S, O or -NR a ; L 1It is an optionally substituted (C1-C6) alkylene; R 5a Selected from 5- to 10-membered heterocyclic groups and -NR'R''; R' and R'' are each independently selected from hydrogen and optionally substituted (C1-C4) alkyl groups, or R' and R'' together with the attached nitrogen form an optionally substituted heterocyclic group; and It is an optionally substituted aryl group or an optionally substituted 5 to 10 heteroaryl group, and the remaining variables are as described above for Formula I.

[0035] As part of the third embodiment, the compound of formula I is the compound of formula III: (III); Or its pharmaceutically acceptable salt, in which X 2 X 3 X 4 X 5 Each is independently selected from N and CR 3 ;as well as R 3 and R 4 Independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, deuterated (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkynyl, (C1-C4)alkenyl, halogen, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl, cyano, NH2, -NH(C1-C4)alkyl, -N[(C1-C4)alkyl] The (C3-C6)cycloalkyl and the (C3-C6)cycloalkyl of the (C3-C6)cycloalkyl are optionally substituted with 1 to 3 groups selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy and cyano, wherein the remaining variables are as described above for Formula I.

[0036] As part of the fourth embodiment, in the compound of formula III, X 2 X 4 and X 5 It is N; and X 3 It is CF, where the remaining variables are as described in Formula I or Formula III of the third embodiment above. Alternatively, as part of the fourth embodiment, in the compound of Formula III, X 2 It is CR 3 X 3 It's CF, and X 4 and X 5N is the variable, where the remaining variables are as described in Formula I or Formula III of the third embodiment described above. In another alternative, as part of a fourth embodiment, in the compound of Formula III, X... 2 It is CR 3 and X 3 X 4 and X 5 N is the variable, where the remaining variables are as described in Formula I or Formula III of the third embodiment above. In yet another alternative, as part of a fourth embodiment, in the compound of Formula III, X... 2 X 3 X 4 and X 5 N is the variable, where the remaining variables are as described in Formula I or Formula III of the third embodiment above. In yet another alternative, as part of a fourth embodiment, in the compound of Formula III, X... 2 X 3 and X 4 It is N; and X 5 It is CR 3 The remaining variables are as described in Formula I or Formula III of the third embodiment described above. In yet another alternative, as part of a fourth embodiment, in the compound of Formula III, X... 2 X 3 and X 5 It is N; and X 4 It is CR 3 The remaining variables are as described in Formula I or Formula III of the third embodiment described above. In yet another alternative, as part of a fourth embodiment, in the compound of Formula III, X... 2 and X 5 It is N, X 3 It's CF, and X 4 It is CR 3 The remaining variables are as described in Formula I or Formula III of the third embodiment described above. In yet another alternative, as part of a fourth embodiment, in the compound of Formula III, X... 2 and X 4 It is N, X 3 It's CF, and X 5 It is CR 3 The remaining variables are as described in Formula I or Formula III of the third embodiment above.

[0037] As part of the fifth embodiment, in the compound of formula III, R 3 The components are selected from hydrogen, F, Cl, CN, methyl, CF3, ethyl, and cyclopropyl, wherein the remaining variables are as described in Formula I or Formula III of the third or fourth embodiment above.

[0038] As part of the sixth embodiment, in the compound of formula III, X 1 It is oxygen, wherein the remaining variables are as described in Formula I or Formula III in any of the third to fifth embodiments described above. Alternatively, as part of a sixth embodiment, in the compound of Formula III, X 1 It is sulfur, wherein the remaining variables are as described in Formula I or Formula III in any of the third to fifth embodiments described above. In another alternative, as part of a sixth embodiment, in the compound of Formula III, X 1 It is NMe, where the remaining variables are as described in Equation I or Equation III in any of the third to fifth embodiments described above.

[0039] As part of the seventh embodiment, in the compound of formula III, R 4 Selected from hydrogen, F, Me, CF3, CHF2, cyclopropyl, OMe, OEt, OiPr, OCD3, OCF3, NH2, NHMe, NMe2 and SMe, wherein the remaining variables are as described in Formula I or Formula III in any of the third to sixth embodiments described above.

[0040] As part of the eighth embodiment, in the compound of formula III, L 1 Selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CD2-, , , , , , and ; R 8a and R 9a Each is independently selected from hydrogen, halogen, CN, (C1-C4)alkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, or R. 8a and R 9a Together with the attached carbon, it forms a cycloalkyl or heterocyclic group; and R 10 The components are selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, wherein the remaining variables are as described in Formula I or Formula III in any of the third to seventh embodiments described above.

[0041] As part of the ninth embodiment, in the compound of formula III, R 5a Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and The remaining variables are as described in Formula I or Formula III in any of the third to eighth embodiments described above.

[0042] As part of the tenth embodiment, in the compound of formula III, R 3 Selected from , , , , , , , , , , , , , , , , , , , , , , , , and The remaining variables are as described in Formula I or Formula III in any of the third to ninth embodiments described above.

[0043] As part of the eleventh embodiment, the compound of formula I, II, or III is of formula III. a Compounds: (III a ) Or its pharmaceutically acceptable salt, in which X 2 It is CH or N; R 2 It is selected from 1 to 3 R c The 4- to 6-membered monocyclic heterocyclic group substituted with a group, or optionally substituted with 1 to 3 groups selected from R d 6 to 10 membered bicyclic heterocyclic groups substituted with groups; R 5 It is a (C2-C4) ynyl group; R 6 It is hydrogen or halogen; R 7 It is hydrogen or OH; R 8 and R 9 It forms together with the carbon attached to it. , or ; R 8a and R 9a Each is independently selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, deuterated (C1-C4)alkoxy, and (C1-C4)haloalkoxy; or R 8a and R 9a Together with the attached carbon, it forms a (C3-C6) cycloalkyl or a 4- to 8-membered monocyclic heterocyclic group, wherein the (C3-C6) cycloalkyl and the 4- to 8-membered monocyclic heterocyclic group are optionally substituted by 1 to 3 groups selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy and cyano groups; R 10 Selected from hydrogen and optionally substituted (C1-C4) alkyl groups; R a and R b Each is independently selected from hydrogen and (C1-C4) alkyl groups; and R c and R dEach is independently selected from halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, cyano, OH, oxo, -C(O)OR a -C(O)R a -SO2R a -S(O)R a -SO2NR a R b -NR a C(O)R b -NR a SO2R b -NR a R b And NO, where the remaining variables are as described for Equation I.

[0044] As part of the twelfth implementation, Formula III a The compound is a compound of formula IV: (IV) Or its pharmaceutically acceptable salt, wherein the variables are as described in formula I or III above. a As described in any of the embodiments. Alternatively, as part of the twelfth embodiment, the compound of formula III is the compound of formula V: (V); Or its pharmaceutically acceptable salt, wherein the variables are as described in formula I or III above. a As described in any of the embodiments. In another alternative, as part of the twelfth embodiment, the compound of formula III is the compound of formula VI: (VI) Or its pharmaceutically acceptable salt, wherein the variables are as described in formula I or III above. a As described in any of them. In yet another alternative, as part of the twelfth embodiment, the compound of formula III is the compound of formula VII: (VII) Or its pharmaceutically acceptable salt, wherein the variables are as described in formula I or III above. a As described in any of them.

[0045] As part of the thirteenth embodiment, R in compounds of formulas I to VII or their pharmaceutically acceptable salts... 1 It is hydrogen, wherein the other variables are as described in formulas I to VIII above and in any of the first to twelfth embodiments.

[0046] As part of the fourteenth implementation, in Formula IIIa X is N in the compound or its pharmaceutically acceptable salt, where the remaining variables are as shown in Equation III above. a As described in any of embodiments VII or thirteen.

[0047] As part of the fifteenth implementation, in Formula III a R in compounds or their pharmaceutically acceptable salts 3 It is a halogen, where the other variables are as shown in Equation III above. a As described in any of embodiments VII, thirteenth, or fourteenth. Alternatively, as part of a fifteenth embodiment, R in a compound of formula III or a pharmaceutically acceptable salt thereof. 3 It is fluorine, and the other variables are as shown in Equation III above. a As described in any of embodiments VII, thirteenth, or fourteenth.

[0048] As part of the sixteenth implementation, in Formula III a R in compounds or their pharmaceutically acceptable salts 5 It is a (C2) ynyl group, where the other variables are as shown in Equation III above. a As described in any of embodiments VII, or in any of embodiments thirteen to fifteen.

[0049] As part of the seventeenth implementation, in Formula III a R in compounds or their pharmaceutically acceptable salts 6 It is a halogen, where the other variables are as shown in Equation III above. a As described in any of embodiments VII, or in any of embodiments thirteen through sixteen. Alternatively, as part of the ninth embodiment, in formula III. a R in compounds or their pharmaceutically acceptable salts 6 It is fluorine, and the other variables are as shown in Equation III above. a As described in any of embodiments VII, or in any of embodiments thirteen to sixteenth.

[0050] As part of the eighteenth implementation, in Formula III a R in compounds or their pharmaceutically acceptable salts 7 It is OH, where the other variables are as shown in Equation III above. a As described in any of embodiments VII, or in any of embodiments thirteen to seventeenth.

[0051] As part of the nineteenth implementation, in Formula III a R in compounds or their pharmaceutically acceptable salts4 The components are selected from hydrogen, (C1-C4)alkoxy, deuterated (C1-C4)alkoxy, -N[(C1-C4)alkyl]2, halogen, (C3-C6)cycloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkyl, and NH2, wherein the remaining variables are as described in Formula III above. a As described in any of embodiments VII, or in any of embodiments thirteen through eighteen. Alternatively, as part of the nineteenth embodiment, in formula III. a R in compounds or their pharmaceutically acceptable salts 4 The derivatives are selected from hydrogen, methyl, methoxy, isopropoxy, OCD3, OCDF2, OCHF2, -N(CH3)2, NH2, chlorine, and cyclopropyl, with the remaining variables as shown in Formula III above. a As described in any of embodiments VII, or any of embodiments thirteen through eighteen. In another alternative, as part of the nineteenth embodiment, in formula III... a R in compounds or their pharmaceutically acceptable salts 4 The variables are selected from methoxy and OCD, with the remaining variables as shown in Formula III above. a As described in any of embodiments VII, or in any of embodiments thirteen to eighteen.

[0052] As part of the twentieth implementation, in Formula III a R in compounds or their pharmaceutically acceptable salts 2 It is selected from 1 to 3 R c The group substituted with a 4 to 6-membered monocyclic heterocyclic group or optionally with 1 to 3 groups selected from R d The group substituted with a 7 to 10-membered nitrogen-containing fused or spirobicyclic heterocyclic group, wherein the remaining variables are as described in Formula III above. a As described in any of embodiments VII, or in any of embodiments thirteen through nineteen. Alternatively, as part of the twentieth embodiment, in formula III. a R in compounds or their pharmaceutically acceptable salts 2 It is a nitrogen-containing heterocyclic butyl, piperidinyl, morpholinyl, or pyrrolidinyl group, each of which is composed of 1 to 3 groups selected from R c Substitution of the group, or R 2 It is 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[3.1.0]hexyl, 1,4-dioxa-8-azaspiro[4.5]decyl, hexahydro-1H-pyrrolazinyl, or 1,2,3,6-tetrahydropyridyl, each optionally composed of 1 to 3 derivatives selected from R d The groups are substituted, and the remaining variables are as shown in Formula III above. aAs described in any of embodiments VII, or in any of embodiments thirteen through nineteen. In another alternative, as part of the twentieth embodiment, in formula III... a R in compounds or their pharmaceutically acceptable salts 2 The derivative is selected from 3-azabicyclo[3.1.0]hexyl, piperidinyl, and hexahydro-1H-pyrrolazinyl, wherein the piperidinyl group is optionally surrounded by 1 to 3 derivatives selected from R c The group substitution and the 3-azabicyclo[3.1.0]hexyl group and the hexahydro-1H-pyrrolazinyl group are each optionally replaced by 1 to 3 groups selected from R d The groups are substituted, and the remaining variables are as shown in Formula III above. a As described in any of embodiments VII, or in any of embodiments thirteen to nineteenth.

[0053] As part of the twenty-first embodiment, in Formula III a R in any compound or its pharmaceutically acceptable salt c and R d Each is independently selected from halogen, cyano, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) alkyl, (C1-C4) haloalkoxy, -S(O)R a and -SO2NR a R b The remaining variables are as shown in Equation III above. a As described in any of embodiments VII, or in any of embodiments thirteen through twentieth. In another alternative, as part of the twenty-first embodiment, in formula III... a R in any compound or its pharmaceutically acceptable salt c and R d Each is independently selected from fluorine, cyano, CF3, methoxy, isopropyl, OCF3, -S(O)CH3, and -SO2N(CH3)2, wherein the remaining variables are as shown in Formula III above. a As described in any of embodiments VII, or in any of embodiments thirteen through twentieth. In yet another alternative, as part of the twenty-first embodiment, R in any compound of formula III or a pharmaceutically acceptable salt thereof... c and R d Each is fluorine, and the other variables are as shown in Equation III above. a As described in any of embodiments VII, or in any of embodiments thirteen to twentieth.

[0054] As part of the twenty-second implementation, in Formula III aR in any compound or its pharmaceutically acceptable salt 8 and R 9 Together The remaining variables are as shown in Equation III above. a As described in any of embodiments VII, or in any of embodiments thirteen to twenty-one.

[0055] As part of the twenty-third embodiment, Y in any of the compounds of formulas I to VII or their pharmaceutically acceptable salts is selected from CN, C(O)CN, or halogenated, CN, OH, O(C1-C4)alkyl, -COR a’ or -C(O)OR a’ The substituted (C1-C4) alkyl group, wherein the remaining variables are as described in any one of Formulas I to VII above, or in any one of the second to twenty-second embodiments. Alternatively, as part of the twenty-third embodiment, Y in any compound of Formulas I to VII or its pharmaceutically acceptable salt is selected from CN, C(O)CN, CH2CN, (CH2)2CN, CH2CF3, (CH2)2CH3, (CH2)2OH, (CH2)3OH, CH2C(O)CH3, CH2CHCF2, (CH2)3CN, CH(CH3)(CH2)2CN, (CH2)2C(O)OH, (CH2)2CH2F, and CH2C(O)OH, wherein the remaining variables are as described in any one of Formulas I to VII above, or in any one of the second to twenty-second embodiments.

[0056] Other compounds, which are included in this disclosure, are further disclosed in the examples. These include pharmaceutically acceptable salts and neutral forms.

[0057] 4. Uses, formulations, and application The compounds and compositions described herein are generally used in anticancer therapies. In one aspect, the disclosed compounds and compositions can act as inhibitors of KRAS (G12D). Their mechanisms of action include, but are not limited to, inhibition of KRAS (G12D), thereby blocking downstream signals that may lead to inhibition of cancer cell growth and / or induction of cancer cell apoptosis or other KRAS or KRAS (G12D) function. In one aspect, the disclosed compounds effectively inhibit KRAS (G12D).

[0058] Therefore, this application provides a method for treating conditions that respond to inhibition of KRAS (G12D), comprising administering a therapeutically effective amount of one or more of the compounds or compositions described herein to a subject in need of such treatment. This application also provides the use of one or more of the compounds or compositions described herein in the preparation of a medicament for treating conditions that respond to inhibition of KRAS (G12D). Further, the use of the compounds or compositions described herein for treating conditions that respond to inhibition of KRAS (G12D) is provided.

[0059] In one aspect, the condition treated by the compounds and compositions of the present invention is cancer. The terms "cancer" or "tumor," as well known in the art, refer to cells present in a subject's body that exhibit typical characteristics of cancerous cells, such as uncontrolled proliferation, immortality, potential metastasis, rapid growth and proliferation rate, reduced cell death / apoptosis, and certain characteristic morphological features. Cancer cells typically exist in the form of solid tumors. However, cancer also includes non-solid tumors (such as hematologic malignancies, e.g., leukemia), where cancer cells originate in the bone marrow. As used herein, the term "cancer" includes both pre-malignant and malignant cancers. Cancers include, but are not limited to: acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, and chronic myeloid leukemia. Leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt lymphoma, proliferative disorders (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythrocytic leukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, etc. Liposarcoma, liposarcoma, lung cancer, lymphoendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, T-cell or B-cell-derived lymphomas, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma. Non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinoma and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial malformation, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.Other cancers include primary cancers, metastatic cancers, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gallbladder cancer, bile duct cancer, small bowel cancer, urinary tract cancer, kidney cancer, urethral cancer, female reproductive tract cancer, uterine cancer, gestational trophoblastic disease, male reproductive tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary cancer, hemangioma, bone and soft tissue sarcoma, Kaposi's sarcoma, neurosarcoma, eye cancer, meningeal cancer, glioblastoma, neuroma, neuroblastoma, schwannoma, solid tumors caused by hematopoietic malignancies (such as leukemia), metastatic melanoma, recurrent or refractory ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumors, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small cell lung cancer, malignant glioma... Gestational tumors, epithelial ovarian cancer, primary peritoneal serous carcinoma, metastatic liver cancer, neuroendocrine carcinoma, refractory malignant tumors, triple-negative breast cancer, HER2-amplified breast cancer, nasopharyngeal carcinoma, oral cancer, cholangiocarcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma (SCCHN), non-medullary thyroid carcinoma, recurrent glioblastoma multiforme, neurofibroma type 1, CNS cancers, liposarcoma, leiomyosarcoma, salivary gland carcinoma, mucosal melanoma, acral / lentiginesoid melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumors, triple-negative breast cancer, colorectal cancer, sarcoma, melanoma, renal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumors, mantle cell lymphoma, and refractory malignant tumors.

[0060] As used in this article, "solid tumor" is understood to be any pathogenic tumor that can be palpated or detected using imaging methods and exhibits abnormal three-dimensional growth. Solid tumors are distinct from hematologic malignancies (such as leukemia). However, the cells of hematologic malignancies originate from the bone marrow; therefore, the tissue that produces cancer cells is potentially hypoxic solid tissue.

[0061] "Tumor tissue" or "tumor-like tissue" is understood as the cells, extracellular matrix, and other naturally occurring components associated with solid tumors.

[0062] The specific dosage and treatment regimen for any given patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, the judgment of the attending physician, and the severity of the specific disease being treated. The amount of the compound described herein in the composition will also depend on the specific compound in the composition.

[0063] Example Chemical synthesis The following representative embodiments are intended to help illustrate the present disclosure and are not intended to limit the scope of the invention, nor should they be construed as limiting the scope of the invention. Unless otherwise stated, the general starting materials used are obtained from commercial sources or prepared in other embodiments.

[0064] abbreviation: DMF: Dimethylformaldehyde DCM&CH2Cl2: Dichloromethane EtOAc: Ethyl acetate PE: Petroleum ether THF: Tetrahydrofuran MeOH: Methanol CDI: 1,1'-carbonylbis-1H-imidazolium DIEA: N,N-Diisopropylethylamine HOBt: 1-Hydroxybenzotriazole hydrate EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate TFA: Trifluoroacetic acid DEA: Diethanolamine DMAP: 4-Dimethylaminopyridine MTBE: Methyl tert-butyl ether The compounds described herein were prepared according to the steps outlined in Scheme 1.

[0065] Option 1 Preparation of Compound 1 Step 1: 3-{2-[(1-{3-azabicyclo[3.1.0]hexane-3-ylmethyl}cyclopropyl)methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-[2-(triisopropylsilyl)ethynyl]naphth-1-yl]-5-methoxypyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. At 0 °C under a nitrogen atmosphere, a solution of IM2 (5.01 g, 29.927 mmol, 1.5 equivalence, purchased from PharmarBlock) in THF (100 mL) was treated with t-BuONa (5.75 g, 59.853 mmol, 3 equivalence) for 30 min, followed by dropwise addition of a solution of IM1 (17 g, 19.951 mmol, 1 equivalence, purchased from WUXI AppTec) in THF (200 mL) at 0 °C for 2 h. The reaction was quenched by adding H2O (200 mL). The aqueous layer was extracted with DCM (3 x 200 mL). The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to obtain a yellow solid, 1-1 (11.7 g, 62.44%). LCMS: (ES, m / z): 939.2 [M+H] + .

[0066] Step 2: (1R,5S)-3-(2-((1-((3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. A solution of 1-1 (11.7 g, 12.457 mmol, 1 equivalent) and CsF (18.92 g, 124.570 mmol, 10 equivalents) in DMF (200 mL) was stirred for 2 h at room temperature under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 x 500 mL). The resulting mixture was concentrated under vacuum. The crude product was used directly in the next step without further purification. LCMS:(ES, m / z): 782.9 [M+H] + .

[0067] Step 3: 4-{2-[(1-{3-azabicyclo[3.1.0]hexane-3-ylmethyl}cyclopropyl)methoxy]-4-{3,8-diazabicyclo[3.2.1]octane-3-yl}-8-fluoro-5-methoxypyridino[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphth-2-ol. 1,4-Dioxane (50 mL, 1645.639 mmol, 143.15 equivalents) containing HCl (gas) was slowly added dropwise to a solution (100 mL) of 1-2 in ACN, and the solution was stirred at 0 °C for 1 h under a nitrogen atmosphere. The mixture was neutralized to pH 10 with NH3·H2O. The aqueous layer was extracted with DCM (3 x 100 mL). The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (SHIMADZU) under the following conditions: column, XBridge Shield RP18 OBD column. The mobile phase was 5 µm; the mobile phase was H2O (10 mmol / L NH4HCO3) and MeOH (60% MeOH, reaching 80% within 20 min); the detector was UV 254 nm. 1–3 (3.2 g) of white solid were obtained.

[0068] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.13 (s, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.21 (d, J = 2.6 Hz, 1H), 4.29 – 4.17 (m, 2H), 4.13 – 4.10 (m, 1H), 3.87 (d, J = 7.7 Hz, 5H), 3.47 (d, J =6.1 Hz, 2H), 3.42 – 3.37 (m, 1H), 2.96 (dd, J = 8.6, 5.2 Hz, 2H), 2.75 – 2.62(m, 1H), 2.42 – 2.32 (m, 2H), 2.29 – 2.17 (m, 2H), 1.65 – 1.55 (m, 4H), 1.35– 1.29 (m, 2H), 1.23 (s, 1H), 0.61 – 0.55 (m, 3H), 0.38 (q,J = 4.2 Hz, 2H),0.29 – 0.25 (m, 1H). LCMS:(ES, m / z): 638.95 [M+H] + .

[0069] Step 4: 2-(3-(2-[(1-(3-azabicyclo[3.1.0]hexane-3-ylmethylcyclopropyl)methoxy]-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxypyridino[4,3-d]pyrimidin-4-yl-3,8-diazabicyclo[3.2.1]octane-8-yl)acetonitrile. DIEA (48.56 mg, 0.375 mmol, 3 equivalents) was added dropwise to a stirred mixture of 1-3 (80 mg, 0.125 mmol, 1 equivalent) and 2-bromoacetonitrile (30.05 mg, 0.250 mmol, 2 equivalents) in DMF (1 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 1 minute under a nitrogen atmosphere. h. The reaction was monitored by LC-MS. After the reaction was complete, the product was separated by Pre-HPLC (column: XBridge BEH Shield RP18 5 m, 30 mm X 150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 55% B to 75% B over 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.22). This produced a yellow solid compound 1 (17.91 mg, 20.51%).

[0070] 1 H NMR (DMSO- d 6 , 400 MHz): δ 10.16 (s, 1H), 7.99 (dd, J = 9.2, 5.9 Hz, 1H), 7.48 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.23 (d, J = 2.6 Hz, 1H), 4.23 (q, J = 10.8 Hz, 2H), 4.13 (d, J = 12.2 Hz, 1H), 3.97 (s, 1H), 3.92 (d, J =9.7 Hz, 4H), 3.58 (s, 2H), 3.43 (d,J = 10.0 Hz, 4H), 3.01 – 2.93 (m, 2H), 2.39(q, J = 12.2 Hz, 2H), 2.24 (d, J = 8.4 Hz, 2H), 1.86 (d, J = 6.6 Hz, 2H), 1.70 –1.51 (m, 2H), 1.36 – 1.29 (m, 2H), 0.57 (d, J = 5.3 Hz, 3H), 0.40 (s, 2H), 0.27(dq, J = 8.0, 3.7 Hz, 1H). LCMS: m / z 677.9 [M+H] + .

[0071] Option 2 Preparation of compound 2 Step 1: 4-{2-[(1-{3-azabicyclo[3.1.0]hexane-3-ylmethyl}cyclopropyl)methoxy]-8-fluoro-4-[8-(imidazol-1-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl]-5-methoxypyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphth-2-ol. Under a nitrogen atmosphere, at room temperature, DIEA (115.34 mg, 0.891 mmol, 1 equivalent) and DMAP (18.17 mg, 0.148 mmol, 0.5 equivalent) were added in portions to a stirred mixture of 1-3 (190 mg, 0.297 mmol, 1 equivalent) and CDI (96.47 mg, 0.594 mmol, 2 equivalent) in THF (4 mL). The resulting mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The reaction was monitored by LC-MS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to obtain a yellow solid 2-1 (110 mg, 50.46%).

[0072] LCMS:(ES, m / z): 733[M+H] + .

[0073] Step 2: 3-{2-[(1-{3-azabicyclo[3.1.0]hexane-3-ylmethyl}cyclopropyl)methoxy]-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methoxypyridino[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carbonylcyanide. A solution of 2-1 (110 mg, 0.150 mmol, 1 equivalent) in TMSCN (5 mL) and TEA (2 mL) was stirred for 4 h at 100 °C under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge BEH C18 OBD Prep Column 130, 5 m, 30 mm x 150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 48% B to 77% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 8.88). This yielded a yellow solid compound 2 (9.09 mg, 8.22%).

[0074] 1 H NMR (DMSO- d 6 , 400 MHz): δ 10.16 (s, 1H), 7.98 (dd, J = 9.2, 5.9 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.22 (t, J = 2.4 Hz, 1H), 4.67 (t, J = 13.2 Hz, 1H), 4.63 – 4.55 (m, 1H), 4.39 – 4.11 (m, 4H), 4.02 –3.81 (m, 4H), 3.64 (t, J = 13.1 Hz, 1H), 3.46 (s, 1H), 2.95 (dd, J = 8.6, 7.0 Hz, 2H), 2.38 (d, J = 14.0 Hz, 2H), 2.23 (d,J = 8.5 Hz, 1H), 2.06 – 1.98 (m, 1H), 1.84 (s, 3H), 1.31 (t, J = 4.6 Hz, 2H), 1.24 (s, 1H), 0.63 – 0.48 (m, 3H), 0.39(q, J = 4.2 Hz, 2H), 0.25 (td, J = 7.7, 3.7 Hz, 1H). LCMS: (ES, m / z): 692.1 [M+H] + .

[0075] Prepare the following compounds in Table 1 using appropriate starting materials according to the method described above.

[0076] Table 1. Structure of the compounds

[0077] Bioassay / Detection cell lines The following cancer cell lines were used: AGS gastric cancer [heterozygous G12D] (ATCC, CRL-1739); A-427 lung cancer [heterozygous G12D] (ATCC, HTB-53); ASPC1 pancreatic cancer [homozygous G12D] (ATCC, CRL-1682); and SW1990 pancreatic cancer [homozygous G12D] (ATCC, CRL-2172). Cell lines were cultured primarily according to ATCC recommendations.

[0078] Cancer cell line proliferation (CellTiter-Glo® assay) AGS, A-427, ASPC1, SW1990, and GP2D cells were seeded at 4,000 cells / well in 96-well tissue culture plates and incubated for 72 hours at 37°C / 5% CO2 in 100 μl of medium. Serial 3-fold dilutions of each test compound were prepared from 20 μM to 1.02 nM. Each cell line was then treated with various concentrations of the test compound, resulting in a final concentration of 0.5% DMSO / well, followed by incubation at 37°C / 5% CO2 for 72 hours. 100 μl of CellTiter-Glo ®Reagents (Promega Corporation, Madison, WI) were added to each well and processed according to the manufacturer's instructions. The results were analyzed and IC calculated using GraphPad 7 software. 50 Values. The results are listed in Table 2. AGS proliferation assay: A. EC50 < 100 nM; B. EC50 = 100-1000 nM; C. EC50 > 1000 nM; GP2D proliferation assay: A. EC50 < 100 nM; B. EC50 = 100-1000 nM; C. EC50 > 1000 nM; MKN1 proliferation assay: A. EC50 < 100 nM; B. EC50 = 100-1000 nM; C. EC50 > 1000 nM; Table 2. Cell line proliferation data of the compounds

[0079] Although this disclosure has been described in conjunction with specific embodiments, it should be understood that the claimed disclosure should not be unduly limited to these specific embodiments. In fact, those skilled in the art to which this disclosure pertains intend and understand that various modifications to the described implementations of this disclosure are within the scope of this disclosure as represented by the following claims.

[0080] All patents and publications mentioned in this specification are incorporated herein by reference to the same extent that each individual patent and publication is specifically and individually indicated by reference.

Claims

1. A compound of formula I: (I) Or its pharmaceutically acceptable salt, in which Y is CN, C(O)CN, or optionally surrounded by 1 to 3 halogens, CN, OH, O(C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)ynyl, -COR a’ and -C(O)OR a’ (C1-C4) alkyl groups substituted with radicals; R 1 It is hydrogen, halogen, OH, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl, -CHO, -C(O)OR b’ -C(O)ONR a’ R b’ Or optionally substituted with 1 to 3 5- to 6-membered heteroaryl groups selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy and cyano groups; R a’ and R b’ Each is independently selected from hydrogen and (C1-C4) alkyl groups, or R a’ and R b’ Together with the nitrogen to which it is attached, it forms an optionally substituted heterocyclic group; and It is an optional substituted heteroaryl group.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula II: (II) in X 1a Selected from S, O or -NR a ; L 1 It is an optionally substituted (C1-C6) alkylene; R 5a Selected from 5- to 10-membered heterocyclic groups and -NR ’ R ’’ ; R ’ and R ’’ Each is independently selected from hydrogen and optionally substituted (C1-C4) alkyl groups, or R ’ and R ’’ Together with the nitrogen to which it is attached, it forms an optionally substituted heterocyclic group; and It is an optionally substituted aryl group or an optionally substituted 5 to 10 heteroaryl group.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula III: (III); Or its pharmaceutically acceptable salt, in which X 2 X 3 X 4 X 5 Each is independently selected from N and CR 3 ;as well as R 3 and R 4 Independently selected from hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, deuterated (C1-C4)alkoxy, (C1-C4)haloalkoxy, (C1-C4)alkynyl, (C1-C4)alkenyl, halogen, (C3-C6)cycloalkyl, -O(C3-C6)cycloalkyl, cyano, NH2, -NH(C1-C4)alkyl, -N[ [(C1-C4)alkyl]2, -P(O)[(C1-C4)alkyl]2, and -S(C1-C4)alkyl, wherein the (C3-C6)cycloalkyl and the (C3-C6)cycloalkyl of the -O(C3-C6)cycloalkyl are optionally substituted with 1 to 3 groups selected from halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and cyano.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 2 X 4 and X 5 It is N; and X 3 It's CF.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 2 It is CR 3 X 3 It's CF, and X 4 and X 5 It is N.

6. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 2 It is CR 3 and X 3 X 4 and X 5 It is N.

7. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 2 X 3 X 4 and X 5 It is N.

8. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 2 X 3 and X 4 It is N; and X 5 It is CR 3 .

9. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 2 X 3 and X 5 It is N; and X 4 It is CR 3 .

10. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 2 and X 5 It is N, X 3 It's CF, and X 4 It is CR 3 .

11. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X 2 and X 4 It is N, X 3 It's CF, and X 5 It is CR 3 .

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 11, wherein R 3 Selected from hydrogen, F, Cl, CN, methyl, CF3, ethyl and cyclopropyl.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 12, wherein X 1 It is oxygen.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 12, wherein X 1 It's sulfur.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 12, wherein X 1 It is NMe.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 15, wherein R 4 Selected from hydrogen, F, Me, CF3, CHF2, cyclopropyl, OMe, OEt, OiPr, OCD3, OCF3, NH2, NHMe, NMe2 and SMe.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 16, wherein L 1 Selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CD2-, , , , , , and ; R 8a and R 9a Each is independently selected from hydrogen, halogen, CN, (C1-C4)alkyl, (C3-C6)cycloalkyl, aryl, heteroaryl, or R. 8a and R 9a Together with the attached carbon, it forms a cycloalkyl or heterocyclic group; and R 10 It is selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, aryl, and heteroaryl.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 17, wherein R 5a Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 18, wherein R 3 Selected from , , , , , , , , , , , , , , , , , , , , , , , , and .

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound has formula III a : (III a ) Or its pharmaceutically acceptable salt, in which X 2 It is CH or N; R 2 It is selected from 1 to 3 R c The 4- to 6-membered monocyclic heterocyclic group substituted with a group, or optionally substituted with 1 to 3 groups selected from R d 6 to 10 membered bicyclic heterocyclic groups substituted with groups; R 5 It is a (C2-C4) ynyl group; R 6 It is hydrogen or halogen; R 7 It is hydrogen or OH; R 8 and R 9 It forms together with the carbon attached to it. , or ; R 8a and R 9a Each is independently selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, deuterated (C1-C4)alkoxy, and (C1-C4)haloalkoxy; or R 8a and R 9a Together with the attached carbon, it forms a (C3-C6) cycloalkyl or a 4- to 8-membered monocyclic heterocyclic group, wherein the (C3-C6) cycloalkyl and the 4- to 8-membered monocyclic heterocyclic group are optionally substituted by 1 to 3 groups selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy and cyano groups; R 10 Selected from hydrogen and optionally substituted (C1-C4) alkyl groups; R a and R b Each is independently selected from hydrogen and (C1-C4) alkyl groups; and R c and R d Each is independently selected from halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, cyano, OH, oxo, -C(O)OR a -C(O)R a -SO2R a -S(O)R a -SO2NR a R b -NR a C(O)R b -NR a SO2R b -NR a R b and NO.

21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein the compound has formula IV: (IV); Or its pharmaceutically acceptable salt.

22. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein the compound has formula V: (V)； Or its pharmaceutically acceptable salt.

23. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein the compound has formula VI: (WE); Or its pharmaceutically acceptable salt.

24. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein the compound has formula VII: (VII); Or its pharmaceutically acceptable salt.

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein R 1 It is hydrogen.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 25, wherein X is N.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 26, wherein R 3 It is halogen.

28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 27, wherein R 3 It's fluorine.

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 28, wherein R 5 It is a (C2) ynyl group.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 29, wherein R 6 It is halogen.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 30, wherein R 6 It's fluorine.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 31, wherein R 7 It is OH.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 32, wherein R 4 It is selected from hydrogen, (C1-C4)alkoxy, deuterated (C1-C4)alkoxy, -N[(C1-C4)alkyl]2, halogen, (C3-C6)cycloalkyl, (C1-C4)haloalkoxy, (C1-C4)alkyl and NH2.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 33, wherein R 4 Selected from hydrogen, methyl, methoxy, isopropoxy, OCD3, OCDF2, OCHF2, -N(CH3)2, NH2, chlorine and cyclopropyl.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 34, wherein R 4 Selected from methoxy and OCD3.

36. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 35, wherein R 2 It is selected from 1 to 3 R c The group substituted with a 4- to 6-membered nitrogen-containing monocyclic heterocyclic group, or optionally with 1 to 3 groups selected from R d The group is substituted with a 7 to 10-membered nitrogen-containing fused or spirocyclic bicyclic heterocyclic group.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 36, wherein R 2 It is a nitrogen-containing heterocyclic butyl, piperidinyl, morpholinyl, or pyrrolidinyl group, each of which is composed of 1 to 3 groups selected from R c Substitution of the group, or R 2 It is 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[3.1.0]hexyl, 1,4-dioxa-8-azaspiro[4.5]decyl, hexahydro-1H-pyrrolazinyl, or 1,2,3,6-tetrahydropyridyl, each optionally composed of 1 to 3 derivatives selected from R d The group is substituted.

38. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 37, wherein R 2 The derivative is selected from 3-azabicyclo[3.1.0]hexyl, piperidinyl, and hexahydro-1H-pyrrolazinyl, wherein the piperidinyl group is optionally surrounded by 1 to 3 derivatives selected from R c The group substitution and the 3-azabicyclo[3.1.0]hexyl group and the hexahydro-1H-pyrrolazinyl group are each optionally replaced by 1 to 3 groups selected from R d The group is substituted.

39. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 38, wherein R c and R d Each is independently selected from halogen, cyano, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) alkyl, (C1-C4) haloalkoxy, -S(O)R a and -SO2NR a R b .

40. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 39, wherein R c and R d Each is independently selected from fluorine, cyano, CF3, methoxy, isopropyl, OCF3, -S(O)CH3 and -SO2N(CH3)2.

41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 40, wherein R c and R d They are both fluorine.

42. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 41, wherein R 8 and R 9 Together .

43. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 42, wherein Y is selected from CN, C(O)CN, or is halogenated, CN, OH, O(C1-C4)alkyl, -COR a’ or -C(O)OR a’ Substituted (C1-C4) alkyl groups.

44. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, wherein Y is selected from CN, C(O)CN, CH2CN, (CH2)2CN, CH2CF3, (CH2)2CH3, (CH2)2OH, (CH2)3OH, CH2C(O)CH3, CH2CHCF2, (CH2)3CN, CH(CH3)(CH2)2CN, (CH2)2C(O)OH, (CH2)2CH2F and CH2C(O)OH.

45. The compound according to claim 1, wherein the compound is selected from any one of the following: Or a pharmaceutically acceptable salt of any of the aforementioned.

46. ​​A pharmaceutical composition comprising the compound of any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

47. A method for treating cancer in a subject, comprising administering to the subject an effective amount of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of claim 46.

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