KRAS G12D mutant target-directed compound

Abstract

This disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof. The compound of formula (I) is a KRAS G12D mutation-targeting compound. This disclosure also relates to pharmaceutical compositions comprising the compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, and to methods for treating diseases such as cancer associated with the KRAS G12D mutation. [Formula 1] JPEG2026534527000081.jpg58102

Description

TECHNICAL FIELD

[0001] The present disclosure is directed to a new series of KRAS G12D mutation targeting compounds as defined herein, pharmaceutical compositions containing these KRAS G12D mutation targeting compounds, and methods of treating cancers associated with the KRAS G12D mutation using the aforementioned targeting compounds. BACKGROUND ART

[0002] The KRAS gene provides instructions for producing the KRAS protein that relays signals promoting cell differentiation and growth (proliferation).

[0003] The KRAS protein is a GTPase that binds to guanosine triphosphate (GTP) and converts it to guanosine diphosphate (GDP) via hydrolysis. This gene alternates between two forms: an "active" form that can bind GTP and transmit signals promoting proliferation, and an "inactive" form that binds GDP after the conversion of GTP to GDP and cannot transmit signals. The KRAS protein typically maintains a balance between the inactive state and the active state so that cell proliferation is properly regulated.

[0004] When this KRAS protein is damaged, a KRAS mutation occurs, which may cause the gene to mutate and its form to change. The most common KRAS mutations are known as KRAS G12C, G12D and G12V mutations. The nomenclature "G12X" relates to the amino acid position (the 12th position) on the KRAS protein where the mutation occurs, and the amino acid substitution (X) involved in the mutation. Typically, these mutated (altered) forms of the KRAS protein (KRAS mutations) mean that the normal function of the gene is modified. The reversible nature of the KRAS protein (from GTP activity to GDP activity) is impaired, thus the active state remains predominant, leading cells to proliferate in an uncontrolled manner.

[0005] KRAS mutations are associated with several cancers, including non-small cell lung cancer, colorectal cancer, and pancreatic cancer. KRAS is one of the most frequently mutated gene families in human cancers. When the structure of the KRAS protein discussed above changes, cells proliferate in a way that is not regulated by this protein, leading to tumorigenesis and cancer progression.

[0006] KRAS mutant proteins were initially considered "drug-undetectable" because no specific and potent molecules capable of directly targeting the KRAS protein had been identified. However, in recent years, KRAS G12C inhibitors have been identified. These inhibitors typically work by covalently "binding" to the nucleophilic cysteine ​​at position 12 of the active site of the KRAS protein, i.e., G12C, when the KRAS protein is in an "inactive" state, irreversibly stabilizing this state and preventing the KRAS protein with the KRAS G12C mutation from directing excessive cell proliferation.

[0007] However, no selective inhibitors that can target KRAS G12D, a more common and oncogenic mutation of the KRAS protein, have yet been approved.

[0008] Because the mutation sites, and therefore the target sites for inhibitors, differ significantly in chemical properties between KRAS G12C (cysteine) and KRAS G12D (aspartic acid), identified KRAS G12C inhibitors cannot be used. The arrangement of other regions in the complex structure of the KRAS protein must also be considered. In addition, selective inhibition of KRAS G12D mutations presents a significant challenge compared to KRAS G12C mutations, as the inhibitor must bind selectively with sufficiently high affinity without typically benefiting from covalent interactions (binding to aspartic acid is typically thought to require non-covalent interactions).

[0009] Therefore, there is a need for novel KRAS G12D mutation-targeting compounds that can target KRAS G12D mutations and enable the treatment of diseases such as cancers associated with KRAS G12D mutations.

[0010] The purpose of this disclosure is to provide solutions to the above-mentioned or other problems. [Overview of the Initiative]

[0011] According to a first aspect of this disclosure, a compound of formula (I) [ka] Alternatively, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof are provided. [In the formula, R1 is C≡CH or C 1~4 Selected from alkyl groups, R2 is selected from phenyl or monocyclic 5-membered or 6-membered heteroaryls, and phenyl and monocyclic 5-membered or 6-membered heteroaryls are C 1~4 They may be appropriately substituted with one or more substituents selected from alkyl and halogens. n is between 1 and 6. m is either 1 or 2. L1 is (IIa), (IIb), and (IIc) below [ka] Selected from, R4 and R6 are independently selected from H or F. R7 is C 1~4 It is alkyl.

[0012] A second aspect of this disclosure provides a pharmaceutical composition comprising a compound of formula (I) as defined above in the first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, and a pharmaceutically acceptable carrier or excipient.

[0013] A third aspect of this disclosure provides a compound of formula (I) as defined above in the first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above in the second aspect of this disclosure, for use as a pharmaceutical.

[0014] A fourth aspect of this disclosure provides a compound of formula (I) as defined above in the first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above in the second aspect of this disclosure, for use in the treatment or prevention of diseases associated with KRAS G12D mutations, such as cancers associated with KRAS G12D mutations.

[0015] A fifth aspect of this disclosure provides a compound of formula (I) as defined above in the first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above in the second aspect of this disclosure, for use in the manufacture of a pharmaceutical for use in the treatment of diseases associated with KRAS G12D mutations, such as cancers associated with KRAS G12D mutations.

[0016] A sixth aspect of this disclosure provides a method for treating a disease associated with a KRAS G12D mutation in a subject requiring such treatment, such as a cancer associated with a KRAS G12D mutation, comprising administering to the subject an effective amount of a compound of formula (I) as defined above in the first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above in the second aspect of this disclosure.

[0017] According to a seventh aspect of this disclosure, a compound of formula (I) as defined above in a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above in a second aspect of this disclosure, is provided for use in the treatment of diseases associated with KRAS G12D mutations, such as cancers associated with KRAS G12D mutations.

[0018] According to an eighth aspect of this disclosure, a compound of formula (I) as defined above in a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above in a second aspect of this disclosure, is provided for use in the degradation of a KRAS protein having a KRAS G12D mutation.

[0019] According to a ninth aspect of this disclosure, a compound of formula (I) as defined above in a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above in a second aspect of this disclosure, is provided for use in the degradation of intracellular KRAS G12D mutations.

[0020] According to a tenth aspect of this disclosure, a compound of formula (I) as defined above in a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition as defined above in a second aspect of this disclosure, is provided for use in degrading the KRAS G12D mutation in the KRAS protein.

[0021] This disclosure finds that the compounds of this disclosure can be applied to the treatment of subjects with diseases such as cancer in which a KRAS G12D mutation has been diagnosed or detected.

[0022] definition As used herein, unless otherwise specifically indicated, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings that they may have in the art:

[0023] As used herein, the term “KRAS G12D mutation” refers to a mutation in the 12th amino acid, glycine, of the KRAS protein. The 12th amino acid, glycine, is replaced by aspartic acid. The location of the mutation can be referenced to the wild-type KRAS protein, e.g., Uniprot accession number P01116 (SEQ ID NO: 1). This mutation is a modified version of the KRAS protein in which normal function is impaired. This mutant protein can be called the “KRAS G12D mutant protein.” As discussed above, the reversible nature of the KRAS protein (from GTP activity to GDP activity) is impaired, and therefore the active state remains dominant, causing cells to proliferate in an uncontrolled manner. This term is well known in the art.

[0024] As used herein, the terms “disease associated with KRAS G12D mutation” or “cancer associated with KRAS G12D mutation” refer to a disease or cancer in which some amount of KRAS G12D mutation has been diagnosed or detected. This is typically done by PCR-based KRAS sequencing of clinical samples.

[0025] As used herein, the term “wild-type” refers to the most common form, appearance, or strain of the naturally occurring KRAS protein. This is a normal, non-mutant form of the naturally occurring KRAS protein. This means that there is no mutation at the 12th amino acid of the KRAS protein. The sequence of the wild-type KRAS protein can be found at Uniprot accession number P01116: MTEYKLVVVGA GGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCIIM(Sequence ID 1).

[0026] As used herein, the term “disease” is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, disease, abnormality, pathology, illness, condition, or syndrome that impairs physiological function, regardless of the nature of its etiology (or whether the underlying etiology of the disease is actually established). Therefore, the term encompasses conditions resulting from trauma, injury, surgery, radiation ablation, poisoning, or nutritional deficiencies.

[0027] As used herein, the terms “treatment” or “to treat” include interventions that restore or mitigate cell proliferation and tumorigenesis, as well as the progression of diseases such as cancer, by eliminating (or mitigating) the cause thereof (e.g., by the degradation of the KRAS G12D mutant protein of the KRAS protein) (e.g., administration to a subject of a compound of formula (I) according to a first aspect of the Disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof). In this case, the term is used synonymously with the term “therapy.” Accordingly, treatment of diseases such as cancer associated with KRAS G12D mutations according to the Disclosure may be characterized by the (direct or indirect) action of a compound of formula (I) according to a first aspect of the Disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof. Accordingly, compounds of formula (I) according to the first aspect of this disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, have been found to be applicable to methods for degrading KRAS G12D mutations, preventing cell proliferation, reducing tumorigenesis (or even reducing tumor size), and preventing or mitigating the progression of diseases such as cancer.

[0028] In addition, the terms “treatment” or “treating” include interventions that prevent or delay the onset or progression of diseases such as cancer associated with the KRAS G12D mutation, or reduce (or eradicate) their incidence in a treated population (e.g., administration to subjects of a compound of formula (I) according to a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof). In this case, the term “treatment” is used synonymously with the terms “prevention” or “prevention.”

[0029] The term “subject” (which should be read as including “individual,” “animal,” “patient,” or “mammal” where permitted by context) defines any subject to which the treatment is applicable, in particular mammalian subjects. Mammalian subjects include, but are not limited to, humans, livestock, farm animals, zoo animals, sporting animals, pet animals, e.g., dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, primates, e.g., apes, monkeys, orangutans and chimpanzees, canids, e.g., dogs and wolves, felines, e.g., cats, lions and tigers, equids, e.g., horses, donkeys and zebras, food animals, e.g., cows, pigs and sheep, ungulates, e.g., deer and giraffes, rodents, e.g., mice, rats, hamsters and guinea pigs. Preferably, in the context of this disclosure, the subject is human.

[0030] With respect to the KRAS G12D mutation, the terms “degradation,” “degradation,” or “degradation” or similar terms, as used herein, mean the partial or complete physical breakdown of the undesirable KRAS G12D protein. The KRAS G12D mutant protein is depleted, and the cell is no longer able to proliferate in an uncontrolled manner.

[0031] As used herein, the “effective dose” or “therapeutic effective dose” of a compound of formula (I) according to a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, defines an amount sufficient to produce a desired effect, such as treatment or prevention, that can be administered to a subject without excessive toxicity, irritation, allergic reaction, or other problems or complications, is commensurate with a reasonable benefit / risk ratio, and is sufficient to produce a treatment or prevention that manifests as a permanent or transient improvement of the subject’s condition. This dose will vary from subject to subject depending on the individual’s age and general condition, mode of administration, and other factors. Therefore, it is impossible to determine an exact effective dose, but those skilled in the art will be able to determine an appropriate “effective” dose in any individual case using routine experiments and general background knowledge. Therapeutic outcomes in this context include eradication or reduction of symptoms, reduction of pain or discomfort, extension of survival, improvement of motor function, and other indicators of clinical improvement. Therapeutic outcomes do not need to be complete cures on their own and may be used in combination with other agents.

[0032] The term “pharmaceutically acceptable salt” as applied to the compounds of formula (I) according to the first aspect of this disclosure defines any organic or inorganic acid addition salt of a free base that is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit / risk ratio. Suitable pharmaceutically acceptable salts are well known in the art. Examples include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid), organic carboxylic acids (e.g., acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, dihydroxymaleic acid, benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, and mandelic acid), and organic sulfonic acids (e.g., methanesulfonic acid and p-toluenesulfonic acid).

[0033] The term “solvate” as applied to the compounds of formula (I) according to the first aspect of this disclosure means the physical association of the compound with one or more solvent molecules, whether organic or inorganic. This physical association may include hydrogen bonding. In certain cases, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be isolated. The solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate containing non-stoichiometric amounts of solvent molecules may result from a partial loss of solvent from a solvate. “Solvate” encompasses both solution-phase solvates and solvable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

[0034] The term “hydrate” as applied to the compound of formula (I) according to the first aspect of this disclosure refers to a compound in which the compound is associated with water in molecular form, i.e., the H-OH bond is not broken, and can be represented, for example, by the formula R·H2O, where R is the compound of formula (I) according to the first aspect of this disclosure. A given compound can form two or more hydrates, for example, a monohydrate (R·H2O) or a polyhydrate (R·nH2O, where n is an integer), including, for example, a dihydrate (R·2H2O), a trihydrate (R·3H2O), or a hemihydrate, such as R·n / 2H2O, R·n / 3H2O, R·n / 4H2O, etc. (where n is an integer).

[0035] As used herein, the term “prodrug” as applied to the compound of formula (I) according to the first aspect of this disclosure means a pharmacodynamically acceptable derivative such as an ester, amide, or phosphate, and therefore the in vivo biotransformation product of the resulting derivative is the active drug as defined in the compound of formula (I) according to the first aspect of this disclosure. A reference by Goodman and Gilman, which generally describes prodrugs (The Pharmaco-logical Basis of Therapeutics, 8th ed, McGraw-HiM, Int. Ed. 1992, "Biotransformation of Drugs", pp. 13-15), is incorporated herein by reference. Prodrugs of the compound of formula (I) according to the first aspect of this disclosure are prepared by modifying a functional group present in the compound in such a way that the modification is cleaved into the parent compound in a routine operation or in vivo. A prodrug of a compound of formula (I) according to a first aspect of this disclosure includes a compound in which the amino group of a compound of formula (I) according to a first aspect of this disclosure is bonded to any group that cleaves to form a free amino group when the prodrug is administered to a subject. This term includes all of their positional isomers.

[0036] In its broadest form, the Disclosure intends to describe all optical isomers of the compound of formula (I) according to the first aspect of the Disclosure, or of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes.

[0037] In its broadest aspects, this disclosure intends to encompass all optical isomers, racemates, enantiomers, and diastereoisomers of the compound of formula (I) according to the first aspect of this disclosure as described herein, or of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes. Those skilled in the art will understand that the compound may be produced in optically active and racemates. Where other forms of isomeric centers, such as chiral centers or stereocenters, exist in the compound of formula (I) according to the first aspect of this disclosure, or of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, all such forms of one or more isomers, including enantiomers and diastereoisomers, are intended to be covered herein. Compounds of formula (I) according to a first aspect of this disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof containing a chiral center or stereocenter (or multiple chiral centers or stereocenters), can be used as racemic mixtures, enantiomer-enriched mixtures, or racemic mixtures can be separated using known techniques, and individual enantiomers can be used individually. Accordingly, references to specific compounds of formula (I) according to a first aspect of this disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, encompass mixtures of diastereoisomers, individual diastereoisomers, mixtures of enantiomers, and individual enantiomers.

[0038] Accordingly, this disclosure intends to describe all optical isomers and racemates of the compound of formula (I) according to the first aspect of this disclosure, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, and unless otherwise indicated (e.g., by the use of dash-wedge structures), the compounds described herein are intended to encompass all possible optical isomers of the compounds thus illustrated. Where the stereochemical form of the compound of formula (I) according to the first aspect of this disclosure, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes is important to the pharmaceutically usefulness, this disclosure intends to describe the use of isolated eutomers.

[0039] All references to specific chemical compounds in this specification should be construed to encompass the compound itself, and where appropriate, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof.

[0040] "C 1~4 The term "alkyl" refers to a straight or branched alkyl group having 1 to 4 carbon atoms. C 1~4 For a part of the scope of alkyl, all subgroups thereof such as C 1~3 alkyl, C 1~2 alkyl, C 2~4 alkyl, C 2~3 alkyl and C 3~4 alkyl are contemplated. Examples of said C 1~4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0041] "Halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine, most preferably fluorine.

[0042] "Optional" or "optionally" means that the subsequently described event or circumstance may but does not necessarily occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0043] The terms “heteroaryl” and “heteroaromatic ring” refer to monocyclic aromatic rings containing 5 to 6 ring atoms, one or more of which are non-carbon atoms such as nitrogen, sulfur, or oxygen. A heteroaryl ring may contain up to 4 heteroatoms, for example up to 3 or 2 heteroatoms, or for example a single heteroatom. The heteroaromatic ring may be bonded to the rest of the molecule via either the heteroatoms or carbon atoms of the ring system. Examples of heteroaryl groups, but not limited to, include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, oxatriazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridadinyl, pyrazinyl, triazinyl, and thiadiazolyl. In some embodiments, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or it may be inherently non-basic, as in the case of the nitrogen in indole or pyrrole. Generally, the number of basic nitrogen atoms present in a heteroaryl group containing all amino group substituents of the ring is less than five.

[0044] It will be understood that a chemical group or chemical moiety is bonded to the rest of the molecule by the first listed atom or group. In some cases, the "-" symbol also indicates that chemical groups or chemical moieties are bonded to each other or to the rest of the molecule. In formulas, the tilde symbol [ka] This also indicates that chemical groups or chemical moies are bonded to each other or to the rest of the molecule.

[0045] The term "one or more substituents" preferably refers to one or two substituents. [Modes for carrying out the invention]

[0046] This disclosure provides a solution to an unmet need for KRAS G12D mutation-targeted compounds for the treatment of KRAS G12D mutations, including cancers associated with KRAS G12D mutations.

[0047] A compound of formula (I) according to a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, functions as a proteolytic target-directed chimera (PROTAC) composed of two protein-binding molecules linked by a linker (to the left and to the right of the compound illustrated in formula (I)). The linker comprises L1 as shown in formula (I).

[0048] The compound of formula (I) according to a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, functions by inducing selective intracellular proteolysis. As illustrated in formula (I), the left side of the compound of formula (I) according to a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, is bound to an undesirable KRAS G12D mutation and is linked to an E3 ubiquitin recognition unit (the right side of the compound of formula (I)) via a central linker (containing L1 as shown in formula (I)).

[0049] The left-hand side of the compound of formula (I), or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope, is as follows: [ka]

[0050] The right-hand side of the compound of formula (I), or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope, is as follows: [ka]

[0051] The left side of the compound of formula (I) according to a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, interacts with the protein of interest, in this case the KRAS G12D mutant protein, the KRAS G12D protein. The right side of the compound of formula (I) is an E3 ubiquitin recognition unit, which can interact with an E3 ubiquitin ligase protein. The left and right sides are linked by a central linker (containing L1 as shown in formula (I)).

[0052] Ultimately, the structure and arrangement of the compound of formula (I) according to the first aspect of this disclosure means that the E3 ubiquitin recognition unit (to the right of the compound of formula (I) shown in the illustration) interacts with the E3 ubiquitin ligase protein, facilitating the transfer of ubiquitin from the ubiquitin carrier to the target KRAS G12D mutation, thereby favorably resulting in the selective degradation of the KRAS G12D mutation. The compound of formula (I) according to the first aspect of this disclosure, or any pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, brings the undesirable KRAS G12D mutant protein into close proximity with the E3 ubiquitin ligase protein, thereby catalyzing the degradation of the mutant protein. This favorably reduces the instance of the undesirable KRAS G12D mutant protein, thereby mitigating cell proliferation and tumorigenesis, as well as cancer progression, by eliminating its cause (or mitigating its effects).

[0053] Advantageously, the compounds of formula (I) according to the first aspect of this disclosure, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, are particularly advantageous in that they are more selective for the degradation of the KRAS G12D mutation than the KRAS G12C mutation and the KRAS wild type.

[0054] Compounds of formula (I) according to a first aspect of this disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, demonstrate potent effects against the degradation of KRAS G12D mutant proteins.

[0055] The inventors believe that the advantageous effects on the potency and selectivity of the compound of formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope according to the first aspect of this disclosure on the degradation of the KRAS G12D mutant protein are due to the structure and arrangement of the compound of formula (I). The inventors believe that the structure and arrangement of the linker between the left and right sides of the illustrated compound of formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope, in particular the structure and arrangement of the linker containing L1 as described herein, play a crucial role in this effect.

[0056] The compounds of formula (I) or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopic linkers as described herein are listed below. [ka]

[0057] The linker of the compound of formula (I) according to this disclosure, or of its pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope, begins on the left side of the compound and contains a cyclopropyl (m is 1) or cyclobutyl (m is 2) aliphatic group. The linker links the left side of the compound to the right side of the compound as discussed above. The linker ends on the right side of the molecule, (CH2) n and includes the CO portion. The structure of this linker is important for achieving the advantages of the present disclosure described above. Linked to a tertiary amine linkage (part of L1), preferably an oxygen atom (part of L1) and a carbon chain (CH2) n The structural importance of the aliphatic group attached to it lies in the fact that the linker has sufficient length to interact with the E3 ubiquitin ligase protein and form an optimal structural configuration for creating a productive triple complex.

[0058] The structures of the compound of formula (I) or any pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof according to the first aspect of this disclosure ensure that the compound reliably and potently binds to the target KRAS G12D mutation and ligates an E3 ubiquitin ligase protein to the compound, thereby enabling selective and potent degradation of the KRAS G12D mutant protein.

[0059] For the compound of formula (I) according to the first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, R1, R2, L1, m, and n may be as described below. Each of the R1, R2, L1, m, and n described below can be applied to all embodiments of the first aspect of this disclosure.

[0060] R 1 R1 is C≡CH or C 1~4 Selected from alkyl groups.

[0061] Preferably, R1 is C≡CH, methyl, or ethyl. More preferably, R1 is C≡CH or ethyl. More preferably, R1 is C≡CH.

[0062] R 2 R2 is selected from phenyl or monocyclic 5-membered or 6-membered heteroaryls, and phenyl and 5-membered or 6-membered heteroaryls are C 1~4 It may be optionally substituted with one or more substituents selected from alkyl and halogen. Preferably, R2 is phenyl, which may be optionally substituted with one or more halogen substituents such as fluorine, and one or more C 1~4 It is selected from five-membered or six-membered heteroaryls, which may be optionally substituted with alkyl substituents.

[0063] Preferably, R2 is selected from phenyl or a monocyclic five-membered heteroaryl, and phenyl and five-membered heteroaryls are C 1~4It may be optionally substituted with one or more substituents selected from alkyl and halogen. More preferably, R2 is phenyl, which may be optionally substituted with one or more halogen substituents such as fluorine, and one or more C 1~4 It is selected from a 5-membered heteroaryl that may be optionally substituted with alkyl substituents.

[0064] More comfortably, R2 is C 1~4 Selected from phenyl or thiazole, which may be optionally substituted with one or more substituents selected from alkyl and halogens.

[0065] More preferably, R2 may be phenyl, which may be appropriately substituted with one or more halogen substituents such as fluorine, or one or more C 1~4 This is a thiazole that may be appropriately substituted with alkyl substituents.

[0066] For all of the above descriptions of R2, the phenyl or 5-membered or 6-membered heteroaryl is preferably substituted with one or more of the substituents described.

[0067] More preferably, R2 is phenyl substituted with one or more halogen substituents such as fluorine, or one or more C 1~4 This is a thiazole substituted with an alkyl substituent.

[0068] For all explanations of R2 above, the halogen is preferably fluorine.

[0069] More preferably, R2 is selected from compounds of formula (IIIa) or (IIIb). [ka]

[0070] More preferably, R2 is a compound of formula (IIIa).

[0071] n n is between 1 and 6.

[0072] Preferably, n is 1 to 4. More preferably, n is 1 to 3. Most preferably, n is 2.

[0073] m m is 1 or 2. Preferably, m is 1.

[0074] L 1 L1 is selected from (IIa), (IIb), and (IIc) below. [ka] [In the formula, R4 and R6 are each independently selected from H or F.] R7 is C 1~4 It is alkyl.

[0075] In (IIa) and (IIb), it will be understood that the carbon atom to which R4 or R6 is bonded also has H bonded to it.

[0076] Preferably, R7 is methyl or ethyl. More preferably, R7 is methyl.

[0077] (IIa), (IIb), and (IIc) are advantageous because they contain tertiary amines. These tertiary amines are protonated at physiological pH (the pH typically found in the human body, approximately 7.4) and interact more strongly with E62 of KRAS.

[0078] Preferably, L1 has formula (IIa) or (IIb), more preferably formula (IIb).

[0079] Preferably, if L1 has formula (IIa), then R4 is F.

[0080] Preferably, when L1 is formula (IIb), either or both R4 and R6 are F. More preferably, both R4 and R6 are F. Most preferably, R6 is H and R4 is F. If R4 and R6 are not selected from F, it will be understood that they are H.

[0081] Therefore, L1 preferably has formula (IId). [ka]

[0082] The presence of an electron-withdrawing group (F) on the piperidine ring of formula (IIa) or (IIb) is advantageous in that it lowers the pKa of the tertiary amine (piperidine nitrogen). Preferably, the electron-withdrawing group (F) lowers the pKa of the tertiary amine (piperidine nitrogen) to less than 10, for example, less than 8. However, this does not reduce the potency of the compound of formula (I) according to the first aspect of this disclosure, or any pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof. The cellular activity and KRAS G12D selectivity of the compound of formula (I) according to the first aspect of the present invention are improved by independently selecting one or both of R4 and R6 to be F.

[0083] When R4 and R6 are independently selected such that one or both are F, for example, when L1 has the formula (IId) shown below, the compound of formula (I) according to the first aspect of the present invention, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope, may be a diastereomer, i.e., a mixture of cis and trans, or a mixture of enantiomers, such as a mixture of cis enantiomers or a mixture of trans enantiomers, or it may be a cis or trans enantiomer. Preferably, the compound of formula (I) according to the first aspect of the present disclosure, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope, may be a mixture of cis enantiomers or a cis enantiomer. The presence of substituent F introduces chirality to the compound of formula (I) according to the first aspect of the present disclosure, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope. Accordingly, the present disclosure encompasses the mixtures of diastereoisomers or enantiomers detailed above for all compounds of formula (I), or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, independently selected such that one or both of R4 and R6 are F.

[0084] Accordingly, the following embodiments of the first aspect of this disclosure are contemplated.

[0085] According to one embodiment, a first aspect of the present disclosure relates to a compound of formula (Ia). [ka] or comprising a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof. [In the formula, R1 is C≡CH or C 1~4 Selected from alkyl groups, R2 is selected from phenyl or monocyclic 5-membered or 6-membered heteroaryls, and phenyl and 5-membered or 6-membered heteroaryls are C 1~4They may be appropriately substituted with one or more substituents selected from alkyl and halogens. n is between 1 and 6. L1 is (IIa), (IIb), and (IIc) below [ka] Selected from, R4 and R6 are independently selected from H or F. R7 is C 1~4 It is alkyl.

[0086] In this embodiment, preferred bases or values ​​for R1, R2, R4, R6, and R7, L1, and n may be as described above.

[0087] According to further embodiments, a first aspect of the present disclosure relates to a compound of formula (Ib) or (Ic). [ka] or comprising a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof. [In the formula, R1 is C≡CH or C 1~4 Selected from alkyl groups, R2 is selected from phenyl or monocyclic 5-membered or 6-membered heteroaryls, and phenyl and 5-membered or 6-membered heteroaryls are C 1~4 They may be appropriately substituted with one or more substituents selected from alkyl and halogens. n is between 1 and 6. R4 and R6 are each independently selected from H or F.

[0088] In this embodiment, preferred R1, R2, R4, and R6, as well as the base or value of n, may be as described above.

[0089] According to further embodiments, the first aspect of the present disclosure relates to a compound of formula (Ic). [ka] or comprising a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof. [In the formula, R1 is C≡CH or C 1~4 Selected from alkyl groups, R2 is selected from phenyl or monocyclic 5-membered or 6-membered heteroaryls, and phenyl and 5-membered or 6-membered heteroaryls are C 1~4 They may be appropriately substituted with one or more substituents selected from alkyl and halogens. n is between 1 and 6. R4 and R6 are each independently selected from H or F.

[0090] In this embodiment, preferred R1, R2, R4, and R6, as well as the base or value of n, may be as described above.

[0091] According to further embodiments, the first aspect of the present disclosure relates to a compound of formula (Id). [ka] or containing pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof. [In the formula, R1 is C≡CH or C 1~4 Selected from alkyl groups, R2 is selected from phenyl or monocyclic 5-membered or 6-membered heteroaryls, and phenyl and 5-membered or 6-membered heteroaryls are C 1~4 They may be appropriately substituted with one or more substituents selected from alkyl and halogens. R4 and R6 are each independently selected from H or F.

[0092] In this embodiment, preferred R1, R2, R4, and R6 groups may be as described above.

[0093] According to further embodiments, the first aspect of the present disclosure relates to a compound of formula (Ie). [ka] or comprising a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof. [In the formula, R2 is selected from phenyl or monocyclic 5-membered or 6-membered heteroaryls, and phenyl and 5-membered or 6-membered heteroaryls are C 1~4 They may be appropriately substituted with one or more substituents selected from alkyl and halogens. R4 and R6 are each independently selected from H or F.

[0094] In this embodiment, preferred R2, R4, and R6 groups may be as described above.

[0095] According to further embodiments, the first aspect of the present disclosure relates to a compound of formula (If). [ka] or comprising a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof. [In the formula, R4 and R6 are each independently selected from H or F.]

[0096] In this embodiment, preferred R4 and R6 groups may be as described above.

[0097] Preferably, the compound of formula (I) according to the first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, is selected from the following compounds: [ka] [ka] [ka]

[0098] More preferably, a compound of formula (I) according to a first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, [ka] [ka] Selected from.

[0099] Compounds of formula (I), or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, or pharmaceutical compositions according to a second aspect of this disclosure, can be used in the treatment of diseases associated with KRAS G12D mutations, such as cancers associated with KRAS G12D mutations. Accordingly, this disclosure envisions a method of medical treatment or prevention involving the administration of a compound of formula (I) according to a first aspect of this disclosure as described herein, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, or a compound of formula (I) according to a first aspect of this disclosure as described herein, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, for medical use (e.g., for treatment or prevention / prevention). This disclosure also envisions the administration of pharmaceutical compositions containing a compound of formula (I) according to a first aspect of this disclosure, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes.

[0100] It will be understood by those skilled in the art that the compounds of formula (I) according to the first aspect of this disclosure, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, are KRAS G12D mutation targeting compounds. These compounds selectively degrade KRAS G12D mutant proteins. By binding to and degrading KRAS proteins exhibiting the KRAS G12D mutation (KRAS G12D mutant proteins), these compounds provide treatment for diseases associated with this KRAS G12D mutation, such as cancer associated with the KRAS G12D mutation. Degradation of the KRAS G12D mutation means that cell proliferation is prevented or significantly reduced, and therefore, for example, tumor growth is reduced (or even reduced in size), and the spread of diseases such as cancer is reduced. Thus, the compounds of formula (I) according to the first aspect of this disclosure, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, can be considered antitumor agents.

[0101] A compound of formula (I) according to a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to a second aspect of this disclosure, may target any disease associated with KRAS G12D mutations, including any cancer associated with KRAS G12D mutations.

[0102] Preferably, the KRAS G12D mutation can be diagnosed or identified before administration of a compound of formula (I) according to a first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, or before administration of a pharmaceutical composition according to a second aspect of the present disclosure.

[0103] Various types of malignancies may exhibit KRAS G12D mutations. Cancers typically associated with KRAS G12D mutations include lung cancer, non-small cell lung cancer, colorectal cancer, pancreatic cancer, invasive ductal carcinoma, biliary tract malignancies, gastric cancer, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, breast cancer, ovarian cancer, and other gastrointestinal cancers such as esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma.

[0104] Accordingly, compounds of formula (I) according to the first aspect of this disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes thereof, or pharmaceutical compositions according to the second aspect of this disclosure, are particularly effective in treating cancers associated with KRAS G12D mutations, especially lung cancer, non-small cell lung cancer, colorectal cancer, pancreatic cancer, invasive ductal carcinoma, biliary tract malignancies, gastric cancer, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, breast cancer, ovarian cancer, and other gastrointestinal cancers such as esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma.

[0105] Preferably, a compound of formula (I) according to a first aspect of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to a second aspect of the present disclosure, is used to treat any disease associated with KRAS G12D mutation, such as any cancer associated with KRAS G12D mutation, such as lung cancer, non-small cell lung cancer, colorectal cancer, pancreatic cancer, invasive ductal carcinoma, biliary tract malignancies, gastric cancer, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia and breast cancer, ovarian cancer, and other gastrointestinal cancers such as esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma.

[0106] Preferably, the compound of formula (I) according to the first aspect of this disclosure, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes, or the pharmaceutical composition according to the second aspect of this disclosure, are used to treat diseases associated with KRAS G12D mutations in the human body, such as cancers associated with KRAS G12D mutations. However, they can also be used to treat diseases associated with KRAS G12D mutations in animals, such as cancers with KRAS G12D mutations. In particular, the compound of formula (I) according to the first aspect of this disclosure, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes, or the pharmaceutical composition according to the second aspect of this disclosure, can be used to treat commercial animals such as livestock. Alternatively, the compound of formula (I) according to the first aspect of this disclosure, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs or isotopes, or the pharmaceutical composition according to the second aspect of this disclosure, can be used to treat pet animals such as cats and dogs.

[0107] With respect to a compound of formula (I) according to a first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to a second aspect of this disclosure, the dose of the compound of formula (I) administered will vary, for example, depending on the mode of administration, the desired treatment, the type of disease such as cancer, and the combination regimen (such as a combination with chemotherapy or radiation).

[0108] The therapeutic dose sizes of the compound of formula (I) according to a first aspect of this disclosure, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, naturally vary according to well-known medical principles, depending on the nature and severity of the cancer, the age and sex of the animal or patient, and the route of administration.

[0109] Compounds of formula (I) according to a first aspect of this disclosure may be available, stored, and / or administered in the form of pharmaceutically acceptable salts.

[0110] Exemplary pharmaceutically acceptable salts are prepared from formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvate, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, algenic acid, β-hydroxybutyric acid, galactaric acid, and galacturonic acid. Preferred pharmaceutically acceptable salts include pharmaceutically acceptable basic salts such as metal ion salts and organic ion salts. Metal ion salts include, but are not limited to, suitable alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts, and other physiologically acceptable metal ions. Such salts can be prepared from ions of aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Organic salts can be prepared from tertiary amines and quaternary ammonium salts, including trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of the above salts can be prepared by those skilled in the art from the corresponding compounds by conventional means. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs," ME Aulton, Churchill Livingstone, 1988.

[0111] Compounds of formula (I) according to a first aspect of this disclosure can be obtained, stored, and / or administered, for example, in the form of a conjugate with a biomolecule or in the form of a particle encapsulated.

[0112] Compounds of formula (I) according to a first aspect of this disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, can be provided for use in pharmaceutical compositions.

[0113] Accordingly, this disclosure encompasses pharmaceutical compositions according to a second aspect of the disclosure as described herein. All preferred or appropriate features of the first aspect of the disclosure can be applied to the second aspect of the disclosure, and vice versa.

[0114] Pharmaceutical compositions according to a second aspect of this disclosure may include stabilizers, antioxidants, colorants, and diluents, as well as pharmaceutically acceptable additives. The components of the pharmaceutical composition are selected such that side effects are minimized and the performance of the compound of formula (I) according to a first aspect of this disclosure, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope, is not impaired to the extent that it renders the treatment ineffective.

[0115] Compounds of formula (I) according to the first aspect of this disclosure, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, can be formulated into pharmaceutical compositions for various modes of administration, such as pharmaceutical compositions according to the second aspect of this disclosure. It will be understood that compounds of formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes thereof, can be administered together with pharmaceutically acceptable carriers or excipients.

[0116] Pharmaceutical compositions according to a second aspect of this disclosure can be administered to the target subject by any preferred route of administration, including, but not limited to, oral, enteral administration such as rectal, gastric or duodenal administration, parenteral administration including nasal administration, transdermal administration, intrathecal administration, transmucosal administration, subcutaneous, intramuscular, intravenous, intraperitoneal and intradermal administration, oral buccal or sublingual administration, topical administration, or inhalation.

[0117] Pharmaceutically acceptable excipients and carriers are known in the art. Considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Lippincott, Williams and Wilkins), 2000; Lieberman et al., ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY (1980); and Kibbe et al., ed., Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington (1999).

[0118] Pharmacokinetically acceptable excipients and carriers are modified depending on the mode of administration. Suitable pharmaceutically acceptable carriers or excipients include isotonic solutions of water, physiological saline, phosphate-buffered saline, Ringer's lactate solution, approximately 5% glucose solution (D5W), aqueous glucose solution, Ringer's solution, hydroxypropyl β-cyclodextrin, phosphate buffer, alcohols (such as ethanol, isopropanol, or hexadecyl alcohol), glycols (such as propylene glycol or polyethylene glycol), glycerol ketal (such as 2,2-dimethyl-1,3-dioxolane-4-methanol), ethers (such as poly(ethylene glycol) 400), oils, fatty acids, fatty acid esters or glycerides, calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate.

[0119] Pharmaceutical compositions according to the second aspect of this disclosure may, conveniently, be presented in unit dosage forms, such as tablets and sustained-release capsules, and liposomal formulations, and may be prepared by any method well known in the pharmaceutical field. Pharmaceutical formulations according to the second aspect of this disclosure are typically prepared by mixing an active substance (compound (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof) with a conventionally pharmaceutically acceptable carrier or excipient. Pharmaceutical compositions according to the second aspect of this disclosure may also contain other pharmacological agents and conventional additives such as stabilizers, wetting agents, emulsifiers, fragrances, and buffers. Pharmaceutical compositions according to the second aspect of this disclosure may be further prepared by known methods such as granulation, compression, microencapsulation, and spray coating. Pharmaceutical compositions according to the second aspect of this disclosure may be prepared by conventional methods in dosage forms such as tablets, capsules, granules, powders, syrups, suspensions, suppositories, or injections. Liquid formulations can be prepared by dissolving or suspending the active substance in water or other suitable vehicle (carrier or excipient). Tablets and granules can be coated in conventional ways. To maintain therapeutically effective plasma concentrations for extended periods, compounds of formula (I) disclosed herein, or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, can be incorporated into sustained-release formulations.

[0120] Accordingly, this disclosure encompasses the use of pharmaceutical compositions comprising a compound of formula (I) according to the first aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, or a compound of formula (I) according to the second aspect of this disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, in the uses and treatment methods according to the third through tenth aspects of this disclosure as defined herein. It will be understood that all preferred or appropriate features of the first aspect of this disclosure can be applied to all other aspects of this disclosure, and vice versa.

[0121] All publications, patents, patent applications, and other references referenced herein are incorporated herein by reference in whole for all purposes as if each individual publication, patent, or patent application were specifically indicated to be incorporated by reference and contained in its entirety.

[0122] Any features, integers, characteristics, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of this disclosure should be understood to be applicable to any other aspect, embodiment, or example described herein, insofar as they do not conflict with such descriptions. [Examples]

[0123] Herein, the present disclosure is described with reference to specific embodiments. These embodiments are merely illustrative and for illustrative purposes only, and are not intended in any way to limit the scope of the claimed exclusive rights or the present disclosure described herein. These embodiments constitute the best form currently contemplated for carrying out the present disclosure.

[0124] The following abbreviations are used. Acetyl ACN Acetonitrile Acetic acid (ACOH) AcOK Potassium Acetate aq aqueous solution DABCO 1,4-Diazabicyclo[2.2.2]octane DCM Dichloromethane DIPEA Diisopropylethylamine DMA (dimethylacetamide) DMF Dimethylformamide DMSO (Dimethyl Sulfoxide) EDCl.HCl 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl ethyl acetate h time HOBt 1-hydroxybenzotriazole HPLC (High-Performance Liquid Chromatography) LC-MS (Liquid Chromatography-Mass Spectrometry) m-CPBA meta-chloroperoxybenzoic acid min MOMCl chloromethyl methyl ether MsCl methanesulfonyl chloride MS mass spectrometry NIS N-iodosuccinimide Pd(dppf)Cl2(1,1'-bis(diphenylphosphin)ferrocene)dichloropalladium(II) PTSA (p-toluenesulfonic acid) rac- Enantiomer racemic mixture rt room temperature SPhos Pd G3 (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TFA (Trifluoroacetic Acid) Tf2O Trifluoromethanesulfonic acid anhydride THF (Tetrahydrofuran) In the compound structure, the two stereocenters have a fixed relative position and are therefore represented as &1. Both enantiomers exist.

[0125] Experimental method Unless otherwise specified, reactions were carried out at room temperature. Preparative flash chromatography was performed using silica gel (100-200 mesh).

[0126] Preparative HPLC was performed using one of the following methods: Instrument - Agilent-1260 infinity, column: Sunfire C8 (19×250) mm, 5 μ, or Sunfire C18 (19×250) mm, 5 μ, solvent: solvent A = 5 mM ammonium acetate in water, solvent B = acetonitrile / solvent A = 0.1% TFA, solvent B = acetonitrile, detection wavelength 214 nm. Instrument - Waters 2767 autoprep with 2998 detector, column: X TERRA C18 (19×250) mm, 10 μ, or Sunfire C18 (19×250) mm, 10 μ, solvent: solvent A = 5 mM ammonium acetate in water, solvent B = acetonitrile / solvent A = acetonitrile, solvent B = 0.1% TFA in water, detection wavelength 214 nm. The purest fraction was collected, concentrated, and dried under vacuum. The compounds were typically dried in a vacuum oven at 40°C before purity analysis. Compound analysis is performed using a Waters Acquity UPLC, Waters 3100 PDA detector, SQD, column: Acquity BEH C-18, 1.7 micron, 2.1 × 100 mm, gradient [time (min) / solvent A in B (%)]: 0.00 / 10, 1.00 / 10, 2.00 / 15, 4.50 / 55, 6.00 / 90, 8.00 / 90, 9.00 / 10, 10.00 / 10, solvent: solvent A = 5 mM ammonium acetate in water, solvent B = acetonitrile, injection volume 1 μL, detection wavelength 214 nm, column temperature 30 °C, flow rate 0.3 mL / min or Waters Acquity UPLC, Waters 3100 PDA detector, SQD, column: Acquity The procedure was performed using HSS-T3, 1.8 micron, 2.1 × 100 mm, gradient [time (min) / solvent B in solvent A (%)]: 0.00 / 10, 1.00 / 10, 2.00 / 15, 4.50 / 55, 6.00 / 90, 8.00 / 90, 9.00 / 10, 10.00 / 10, solvent: solvent A = 0.1% trifluoroacetic acid in water, solvent B = acetonitrile, injection volume 1 μL, detection wavelength 214 nm, column temperature 30°C, and flow rate 0.3 mL / min.

[0127] 400 MHz 1H nuclear magnetic resonance (NMR) spectra were recorded using an Avance Bruker AV400 spectrometer. Chemical shifts (δ) in the NMR spectra are expressed in ppm relative to the residual solvent peak. Abbreviations have the following meanings: b = broad signal, s = single line, d = double line, t = triple line, dd = double double line, ddd = double double line. Abbreviations can be combined, and other patterns are not abbreviated.

[0128] The prepared compounds were named using ChemBioDraw Ultra 13.0 by CambridgeSoft.

[0129] If intermediate synthesis is not performed, the compound is commercially available.

[0130] Examples and intermediate compounds Synthesis Route 1 (2S,4R)-1-((2S)-2-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound (1)) [ka]

[0131] 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine 7-Chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (5.0 g, 23.2 mmol) was dissolved in toluene (90 mL, 847 mmol), to which DIPEA (20.3 mL, 116 mmol) and POCl3 (8.67 mL, 92.8 mmol) were added at 0°C. The reaction mixture was warmed to room temperature and stirred at 120°C for a further 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with DCM (100 mL), and filtered through a small silica bed. The silica bed was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to obtain 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine as a brown, waxy solid. Yield (5.8 g, crude). The crude product was used in the next step without further purification.

[0132] tert-butyl3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.39 g, 20.7 mmol) in DCM (99.6 mL), DIPEA (26.9 mL, 154 mmol) was added dropwise at room temperature under an N2 atmosphere. The reaction mixture was stirred at room temperature for 15 minutes, cooled to -40°C, and a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (5.8 g, 23 mmol) in DCM (50 mL) was added dropwise. The resulting reaction mixture was stirred further at -40°C for 0.5 hours. The crude reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried, filtered, and concentrated under reduced pressure. The crude residue was purified by elution with 50% HCl in hexane using combi-flash chromatography with a 40 g silica gel column to obtain tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a pale yellow solid. Yield: 4.5 g, 46%. CHNOS MS (ESI+) m / z 428.21 [M+H] + .; 1 H NMR (400 MHz, DMSO-d6): δ 9.06 (s, 1H), 4.47 (bs, 2H), 4.29 (s, 2H), 3.69 (bs, 2H), 1.77- 1.81 (m, 2H), 1.69-1.62 (m, 2H), 1.46 (s, 9H).

[0133] tert-butyl3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.0 g, 7.0 mmol) in DMSO (15 mL), KF (3.26 g, 56 mmol) and cyclopropane-1,1-diyldimethanol (1.43, 14 mmol) were added at room temperature. The reaction mixture was stirred at 90 °C for 18 hours. The reaction mixture was cooled to room temperature, quenched with ice water (50 mL), and the resulting suspension was filtered. The resulting solid was dissolved in ELISA (30 mL), washed with brine (50 mL), dried, filtered, and concentrated under vacuum to obtain the crude residue. The crude residue was purified by elution with 40% SiO2 in hexane using combiflash chromatography with a 12 g silica column to obtain tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. Yield: 1.2 g, crude (78% by LCMS). MS(ESI+)m / z 494.30[M+H] (CHNOS). + .

[0134] tert-butyl3-(7-chloro-8-fluoro-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 2.43 mmol) in 15 mL of HCl, Et3N (3.38 mL, 24.3 mmol) and MsCl (0.94 mL, 12.1 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (15 mL) and extracted with HCl (3 × 15 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried, filtered, and concentrated under reduced pressure to obtain crude tert-butyl 3-(7-chloro-8-fluoro-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown, waxy solid. Yield: 980 mg (crude). The crude product was used in the next step without further purification.

[0135] tert-butyl3-(7-chloro-8-fluoro-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Methyl 3-(4-piperidyloxy)propionate HCl (626 mg, 2.8 mmol) was added at room temperature to a DMA (20 mL) solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.4 mmol) and K2CO3 (1.16 g, 8.39 mmol). The resulting reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and quenched with ice water (20 mL). The precipitated solid was filtered and washed with water (20 mL). The solid product was dissolved in HCl (20 mL), washed with water (20 mL) and brine (20 mL), dried, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by elution with 40% HCl in hexane using combiflash chromatography with a 40 g silica gel column to obtain tert-butyl 3-(7-chloro-8-fluoro-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. Yield: 660 mg, crude, 78% by LC-MS. CHNOS m / z 663.63[M+H] + .

[0136] tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 1.5 M K3PO4 aqueous solution (800 mg, 3.77 mmol) was added at room temperature to a solution of tert-butyl 3-(7-chloro-8-fluoro-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.754 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (464 mg, 0.905 mmol) in n-BuOH (2.0 mL). The reaction mixture was purged with N2(g) for 15 minutes, and SPhos Pd G3 (58.8 mg, 0.075 mmol) was added at room temperature. The resulting reaction mixture was again purged with N2(g) for 5 minutes. The reaction vessel was sealed, and the reaction mixture was stirred at 75°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with H2O (20 mL), and extracted with RINKAN (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried, filtered, and concentrated under reduced pressure. The crude product was purified by elution with 40% ELISA in hexane using combiflash chromatography with a 12 g silica gel column to obtain tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid. Yield: 230 mg (26% by LC-MS). MS(ESI+)m / z of CHNOS: 1013.66[M+H] + This was used in the next process without further purification.

[0137] 3-((1-((1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanoic acid A solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 0.789 mmol) in a mixture of THF (3.0 mL) and MeOH (3.0 mL) was added to a solution of LiOH.H2O (166 mg, 3.95 mmol) in H2O (0.5 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, acidified to pH 3-4 with 1.0 M HCl aqueous solution, and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain 3-((1-((1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanoic acid as a light brown solid. Yield: 410 mg (crude, 46% by LC-MS). MS(ESI+)m / z of CHNOS: 999.59[M+H] + The crude material was used in the next process without further refinement.

[0138] 3-((1-((1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanoic acid To a stirred solution of 3-((1-((1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanoic acid (400 mg, 0.4 mmol) in DMF (4.0 mL), CsF (608 mg, 4 mmol) was added at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-cold water (10 mL) and extracted with ELISA (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL) and brine (20 mL), dried, filtered, and concentrated under reduced pressure to obtain 3-((1-((1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanoic acid. Yield: 280 mg (crude, 45% by LC-MS). MS(ESI+)m / z of CHNOS: 843.91[M+H] + The crude material was used in the next process without further refinement.

[0139] tert-butyl3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-((4-(3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 3-((1-((1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanoic acid (280 mg, 0.3332 mmol) was dissolved in DMF (4.0 mL) and EDCI.HCl (191 mg, 0.997 mmol), HOBt (153 mg, 0.997 mmol), and DIPEA (0.29 mL, 1.66 mmol) were added at room temperature. The resulting reaction mixture was stirred at room temperature for 10 minutes, and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.HCl (192 mg, 0.399 mmol) was added at room temperature. The resulting reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice-cold water (20 mL) and extracted with ELISA (3 × 25 mL). The combined organic layers were washed with water (2 × 30 mL) and brine (50 mL), dried, filtered, and concentrated under reduced pressure to obtain tert-butyl3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-((4-(3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a light brown solid. Yield: 310 mg (crude, 62% by LC-MS). CHNOS MS(ESI+) m / z 1269.60 [M+H] + The crude material was used in the next process without further refinement.

[0140] (2S,4R)-1-((2S)-2-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (J31-237) Stirred tert-butyl3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-((4-(3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1- To a solution of oxobutan-2-yl)amino)-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (260 mg, 0.205 mmol) in 1,4-dioxane (2.0 mL), 4.0 N HCl was added in 1,4-dioxane (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was polished with Et2O (5.0 mL) and dried under reduced pressure to obtain the desired product as an HCl salt. This was further purified by preparative HPLC using TFA buffer to obtain (2S,4R)-1-((2S)-2-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, a TFA salt, as an off-white solid. Yield: 22 mg, 9% (based on free base). CHNOS MS (ESI+) m / z 1125.47 [M+H] + ; LC purity 96.10% (retention time - 4.89 minutes); 1H NMR (400 MHz, DMSO-d6+ d-TFA): δ 9.35 (s, 1H), 9.24 (s, 1H), 7.96-8.02 (m, 1H), 7.42-7.50 (m, 4H), 7.39 (d, J = 8.0 Hz, 2H), 7.25 (s, 1H), 4.87-4.95 (m, 1H), 4.31-4.75 (m, 6H), 4.20-4.29 (m, 3H), 3.87-3.98 (m, 3H), 3 .43-3.72 (m, 6H), 2.92-3.29 (m, 4H), 2.35-2.47 (m, 4H), 1.5-2.21 (m, 12H), 1.37 (d, J = 6.8 Hz, 3H), 0.72-0.98 (m, 13H).

[0141] Intermediate synthesis 1 Methyl 3-(piperidine-4-yloxy)propanoate.HCl [ka]

[0142] tert-butyl(E)-4-((3-methoxy-3-oxopropa-1-en-1-yl)oxy)piperidine-1-carboxylate To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10 g, 49.7 mmol) in DCM (50 mL), methylpropa-2-in oate (5.01 g, 59.6 mmol) and N-methylmorpholine (8.19 mL, 74.5 mmol) were added under an N2 atmosphere at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layer was washed with brine (100 mL), dried, filtered, and concentrated. The crude product was purified by elution with 10% ethylethanol in hexane using combiflash chromatography with a 40 g silica column to obtain tert-butyl(E)-4-((3-methoxy-3-oxopropa-1-en-1-yl)oxy)piperidine-1-carboxylate as a colorless liquid. Yield: 11g, 77%. 1H NMR (400 MHz, DMSO-d6): δ 7.61 (d, J = 12.4 Hz, 1H), 5.30 (d, J = 12.4 Hz, 1H), 4.30-4.40 (m, 1H), 3.53-3.67 (m, 5H), 3.07 (bs, 2H), 1.80-1.90 (m, 2H), 1.44-1.49 (m, 2H), 1.41 (s, 9H).

[0143] tert-butyl 4-(3-methoxy-3-oxopropoxy)piperidine-1-carboxylate A solution of tert-butyl(E)-4-((3-methoxy-3-oxopropoxy)piperidine-1-carboxylate (10.9 g, 38.2 mmol) in MeOH (100 mL) was purged with N2 (g) for 10 minutes, and 10% Pd / C (5.5 g) was added at room temperature. The reaction mixture was stirred under H2 pressure (1 atm) at room temperature for 16 hours. The crude reaction mixture was filtered through a Celite bed. The Celite bed was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to obtain tert-butyl4-(3-methoxy-3-oxopropoxy)piperidine-1-carboxylate as a colorless liquid. Yield: 10.1 g, 92%. 1 H NMR (400 MHz, DMSO-d6): δ 3.53-3.68 (m, 7H), 3.40-3.49 (m, 1H), 3.03 (bs, 2H), 2.51-2.56 (m, 2H), 1.70-1.79 (m, 2H), 1.42 (s, 9H), 1.20-1.34 (m, 2H).

[0144] Methyl 3-(piperidine-4-yloxy)propanoate.HCl To a solution of tert-butyl 4-(3-methoxy-3-oxopropoxy)piperidine-1-carboxylate (10 g, 34.8 mmol) in 1,4-dioxane (50 mL), 4.0 N HCl in dioxane (35 mL, 1.01 mol) was added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude residue was polished with Et2O (20 mL) and dried under reduced pressure to obtain methyl 3-(4-piperidyloxy)propionate.HCl as an off-white solid product. Yield: 6.4 g, 98%. 1 H NMR (400 MHz, DMSO-d6): δ 8.90 (bs, 2H), 3.53-3.68 (m, 6H), 3.05 (bs, 2H), 2.92 (bs, 2H), 2.51-2.59 (m, 2H), 1.88-1.99 (m, 2H), 1.60-1.71 (m, 2H).

[0145] The following intermediates were prepared according to intermediate synthesis 1 (step 1) in the same manner as tert-butyl(E)-4-((3-methoxy-3-oxopropa-1-en-1-yl)oxy)piperidine-1-carboxylate.

[0146] [Table 1]

[0147] The following intermediates were prepared according to intermediate synthesis 1 (step 2) in the same manner as tert-butyl 4-(3-methoxy-3-oxopropoxy)piperidine-1-carboxylate.

[0148] [Table 2]

[0149] The following intermediates were prepared according to intermediate synthesis 1 (step 3) in the same manner as methyl 3-(piperidine-4-yloxy)propanoate HCl.

[0150] [Table 3]

[0151] Intermediate Synthesis 2 ((2-Fluoro-6-(Methoxymethoxy)-8-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-yl)Naphthalene-1-yl)Ethinyl)Triisopropylsilane [ka]

[0152] 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol To a 1,4-dioxane (100 mL) solution of stirred 7-fluoronaphthalene-1,3-diol (10 g, 56.1 mmol) and (bromoethinyl)triisopropylsilane (15.4 g, 58.9 mmol), AcOK (11 g, 112 mmol) was added at room temperature under an N2 atmosphere. The reaction mixture was purged with N2 (g) for 10 minutes, and [Ru(p-cymene)Cl2]2 (3.44 g, 5.61 mmol) was added. The reaction mixture was again purged with N2 (g) for 5 minutes and stirred at 110°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a Celite bed. The Celite bed was washed with ELISA (100 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by elution with 10% toluene in hexane using column chromatography with silica gel silica (100-200 mesh) to obtain 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol as a black solid. Yield: 16.8 g, 79%. CHNOS MS (ESI+) m / z 359.25 [M+H] + .; 1 H NMR (400 MHz, DMSO-d6): 10.04 (s, 1H), 9.57 (s, 1H), 7.61-7.65 (m, 1H), 7.23-7.27 (m, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 1.12-1.16 (m, 21H).

[0153] 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (16.5 g, 43.7 mmol) and DIPEA (22.8 mL, 131 mmol) were dissolved in DCM (50 mL), to which MOMCl (4.32 mL, 56.8 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for a further 0.5 hours. The crude reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried, filtered, and concentrated under reduced pressure. The crude residue was purified by elution with 5% Â in hexane by column chromatography using silica gel (100-200 mesh) to obtain 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol as a yellow solid. Yield: 11.8g, 43%. CHNOS MS (ESI+) m / z 403.24 [M+H] + .; 1 H NMR (400 MHz, DMSO-d6): 10.29 (s, 1H), 7.75-7.78 (m, 1H), 7.32-7.37 (m, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 5.23 (s, 2H), 3.39 (s, 3H), 1.12-1.16 (m, 21H).

[0154] 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yltrifluoromethanesulfonate To a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (11.6 g, 28.8 mmol) and DIPEA (15.1 mL, 86.4 mmol) in DCM (150 mL), Tf2O (7.62 mL, 43.2 mmol) was added dropwise at -40°C. The reaction mixture was stirred for a further 1 hour at -40°C. The crude reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried, filtered, and concentrated under reduced pressure. The crude residue was purified by elution with 2% toluene in hexane using column chromatography with silica gel (100-200 mesh) to obtain 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yltrifluoromethanesulfonate as a yellow oil. Yield: 8.3 g, 53%. 1 H NMR (400 MHz, DMSO-d6): 8.09-8.13 (m, 1H), 7.77 (d, J = 2.6 Hz, 1H), 7.62-7.67 (m, 1H), 7.50 (d, J = 2.6 Hz, 1H), 5.37 (s, 2H), 3.42 (s, 3H), 1.10-1.14 (m, 21H).

[0155] ((2-Fluoro-6-(Methoxymethoxy)-8-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-yl)Naphthalene-1-yl)Ethinyl)Triisopropylsilane 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yltrifluoromethanesulfonate (8.3 g, 15.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.88 g, 31 mmol) were dissolved in toluene (415 mL, 3.9 mol), to which AcOK (4.57 g, 46.6 mmol) was added at room temperature. The reaction mixture was purged with N2 (g) for 15 minutes, and Pd(dppf)Cl2 (2.27 g, 3.1 mmol) was added. The resulting reaction mixture was again purged with N2 (g) for 5 minutes and stirred at 130°C for 5 hours. The reaction mixture was cooled to room temperature and filtered through a Celite bed. The Celite bed was washed with ELISA (30 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by elution with 2% siRNA in hexane using column chromatography with silica gel (100-200 mesh) to obtain the desired compound as a yellow solid. The solid was further polished with CH3CN (5.0 mL) to obtain ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane as an off-white solid. Yield: 3.3 g, 39%. MS (ESI+) m / z of CHNOS: 513.29 [M+H] + .; 1 H NMR (400 MHz, CDCl3): 7.63-7.67 (m, 1H), 7.49 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.16-7.21 (m, 1H), 5.26 (s, 2H), 3.49 (s, 3H), 1.41 (s, 12H), 1.14-1.19 (m, 21H).

[0156] The following intermediates were prepared according to synthetic route 1 (step 5) in the same manner as tert-butyl3-(7-chloro-8-fluoro-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0157] [Table 4]

[0158] The following intermediates were prepared according to synthetic route 1 (step 6) in the same manner as tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-((4-(3-methoxy-3-oxopropoxy)piperidine-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0159] [Table 5] [Table 6]

[0160] Intermediate Synthesis 3 tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(((3-methoxy-3-oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka]

[0161] 2-Chloro-3-fluoro-5-iodopyridine-4-amine To a solution of 2-chloro-3-fluoro-4-pyridylamine (10 g, 68.2 mmol) in ACN (120 mL), NIS (18.4 g, 81.9 mmol) and PTSA (588 mg, 3.41 mmol) were added at room temperature. The resulting reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was diluted with water (200 mL). The precipitated solid was filtered, washed with saturated Na₂SO₃ aqueous solution (100 mL) and water (100 mL), and dried under reduced pressure to obtain 2-chloro-3-fluoro-5-iodo-4-pyridylamine as a brown solid. Yield: 17.1 g, 92%. MS (ESI+) m / z of CHNOS: 272.91 [M+H] + .; 1 H NMR (400 MHz, CDCl3): δ 8.17 (s, 1H), 4.84 (bs, 2H).

[0162] Ethyl 4-amino-6-chloro-5-fluoronicotinate A solution of 2-chloro-3-fluoro-5-iodo-4-pyridylamine (17 g, 62.4 mmol) and Et3N (43.5 mL, 312 mmol) in EtOH (300 mL) was purged with N2 (g) for 15 minutes, and Pd(PPh3)2Cl2 (4.37 g, 6.24 mmol) was added at room temperature. The resulting reaction mixture was stirred under a CO atmosphere (70 PSI) at 90°C for 16 hours. The reaction mixture was cooled to room temperature and filtered through a Celite bed. The Celite bed was washed with ELISA (100 mL). The filtrate was concentrated under reduced pressure. The solid residue was diluted with cooled EtOH (50 mL), stirred for 15 minutes, and filtered. The solid was washed with cooled EtOH (20 mL) and dried under reduced pressure to obtain ethyl 4-amino-6-chloro-5-fluoronicotinate as an off-white solid. Yield: 7.4 g, 54%. CHNOS MS(ESI-)m / z 217.19[MH] + .

[0163] 4-amino-6-chloro-5-fluoronicotinic acid To a solution of ethyl 4-amino-6-chloro-5-fluoronicotinate (11.7 g, 53.5 mmol) in THF (110 mL), a solution of NaOH (8.56 g, 214 mmol) in water (55 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and acidified to pH 2 with 2.0 M HCl. The precipitated solid was filtered, washed with water (100 mL), and dried under vacuum to obtain 4-amino-6-chloro-5-fluoronicotinic acid as an off-white solid. Yield: 8.4 g, 82%. CHNOS MS (ESI-) m / z 189.01 [MH] + .; 1 H NMR (400 MHz, DMSO-d6): δ 13.43 (bs, 1H), 8.35 (s, 1H), 7.63 (bs, 2H).

[0164] 7-Chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidine-4(1H)-one To a solution of 4-amino-6-chloro-5-fluoronicotinic acid (5.0 g, 26.2 mmol), POCl3 (50 mL, 532 mmol) was slowly added at room temperature. The reaction mixture was stirred at 90°C for 3 hours. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated under vacuum to obtain the crude residue. The crude residue was dissolved in dry THF (30 mL) and added dropwise to a solution of NH4SCN (5.99 g, 78.7 mmol) in dry THF (20 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for a further 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with Depositphotos (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried, filtered, and concentrated under vacuum to obtain the residue. The residue was polished with HCl (30 mL) and dried under reduced pressure to obtain 7-chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidine-4(1H)-one as a yellow solid. Yield: 4.1 g, 68%. CHNOS MS (ESI-) m / z 230.0 [MH] + .; 1 H NMR (400 MHz, DMSO-d6): δ 13.35 (bs, 1H), 12.93 (bs, 1H), 8.64 (s, 1H).

[0165] 7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4(3H)-one 7-Chloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidine-4(1H)-one (4.0 g, 17.3 mmol) was dissolved in DMF (40 mL) and MeONa (933 mg, 17.3 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and CH3I (1.08 mL, 17.3 mmol) was added dropwise. The resulting suspension was stirred at room temperature for 4 hours. The reaction mixture was poured into ice-cold water (100 mL). The precipitated solid was filtered, washed with cold water (50 mL), and dried under vacuum to obtain 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4(3H)-one as a yellow solid. Yield: 3.8 g, 89%. MS (ESI-) m / z of CHNOS: 243.99 [MH] + .; 1 H NMR (400 MHz, DMSO-d6): δ 13.26 (bs, 1H), 8.79 (s, 1H), 2.60 (s, 3H).

[0166] 4,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine 7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4(3H)-one (3.8 g, 15.5 mmol) was dissolved in POCl3 (46 mL) and DIPEA (5.39 mL, 30.9 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. The solvent was concentrated under reduced pressure. The crude residue was purified by elution with 20% SiO2 in hexane using combi-flash chromatography with a 12 g silica gel column to obtain 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine as an off-white solid. Yield: 2.8 g, 68%. CHNOS MS (ESI+) m / z 264.0 [M+H] + .; 1 H NMR (400 MHz, CDCl3): δ 9.10 (s, 1H), 2.71 (s, 3H).

[0167] tert-butyl3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a 100 mL solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.93 g, 13.8 mmol) in DCM, DIPEA (12.4 mL, 71 mmol) was added dropwise at room temperature under an N2 atmosphere. The reaction mixture was cooled to -40°C and stirred for 5 minutes, and then a 15 mL solution of 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.8 g, 10.6 mmol) in DCM was added at -40°C. The resulting reaction mixture was stirred at -40°C for 0.5 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried, filtered, and concentrated under reduced pressure. The crude residue was purified by elution with 50% HCl in hexane using combiflash chromatography with a 40 g silica gel column to obtain tert-butyl 3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a pale yellow solid. Yield: 4.5 g, 96%. CHNOS MS (ESI+) m / z 440.24 [M+H] + .; 1 H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 4.22-4.4.60 (m, 4H), 3.60-3.68 (m, 2H), 2.61 (s, 3H), 1.95 (t, J = 4.6 Hz, 2H), 1.64-1.71 (m, 2H), 1.48 (s, 9H).

[0168] tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (810 mg, 1.82 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.12 g, 2.18 mmol) in n-BuOH (24 mL), K3PO4 (6.06 mL, 1.5 M aqueous solution, 9.09 mmol) was added at room temperature under an N2 atmosphere. The reaction mixture was degassed under an N2 (g) atmosphere for 15 minutes, and S PhosPdG3 (142 mg, 0.182 mmol) was added. The reaction mixture was degassed again for 10 minutes, and the reaction vial was sealed. The reaction mixture was stirred at 75°C for 2 hours. The reaction mixture was cooled to room temperature and quenched with ice water (100 mL). The resulting suspension was filtered through a sintering funnel and washed with ice water (20 mL). The solid product was dissolved in Depositphotos (20 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried with (Na₂SO₄), filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by elution with 40% siRNA in hexane using combiflash chromatography with a 12 g silica column to obtain tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid. Yield: 810 mg, 56%. CHNOS MS (ESI+) m / z 790.76 [M+H] + .; 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.08-8.12 (m, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 8.8 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 5.36 (s, 2H), 4.79-4.82 (m, 1H), 4.05-4.34 (m, 3H), 3.78-3.82 (m, 1H), 3.42 (s, 3H), 3.32-3.35 (m, 1H), 2.54 (s, 3H),1.80-1.87 (m, 3H), 1.59-1.63 (m, 1H), 1.45 (s, 9H), 0.80-0.82 (m, 18H), 0.41-0.51 (m, 3H).

[0169] tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.01 mmol) in toluene (32 mL, 325 mmol), m-CPBA (524 mg, 3.04 mmol) was added in small increments at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with saturated sodium sulfite aqueous solution (50 mL) and extracted with toluene (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by elution in 60% ethyl acetate in hexane using combiflash chromatography with a 12 g silica column to obtain tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. Yield: 680 mg, 82%. CHNOS MS (ESI+) m / z 822.45 [M+H] + . ; 1 H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.11-8.15 (m, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.59 (t, J = 8.8 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 5.37 (s, 2H), 4.91-4.93 (m, 1H), 4.23-4.42 (m, 3H), 3.90-4.10 (m, 1H), 3.41 (s, 3H), 3.40 (s, 3H), 3.38-3.39 (m, 1H), 1.61-1.92 (m, 4H), 1.43 (s, 9H), 0.76-0.82 (m, 18H), 0.39-0.51 (m, 3H).

[0170] tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (580 mg, 0.706 mmol) in CH3CN (5.0 mL), Cs2CO3 (690 mg, 2.12 mmol) and DABCO (7.91 mg, 0.071 mmol) were added at room temperature. The vial was sealed and the reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with siRNA (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by elution with 90% ELISA in hexane using combiflash chromatography with a 12 g silica column to obtain tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white solid. Yield: 420 mg, 72%. MS (ESI+) m / z 844.66 [M+H] (CHNOS) + .; 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.08-8.12 (m, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 8.8 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 5.36 (s, 2H), 4.73-4.76 (m, 1H), 4.61-4.64 (m, 1H), 4.19-4.34 (m, 5H), 3.72-3.75 (m, 1H), 3.33-3.46 (m, 6H), 1.63-1.86 (m, 4H), 1.46 (s, 9H), 0.78-0.85 (m, 18H), 0.43-0.49 (m, 3H), 0.50-0.53 (m, 4H).

[0171] tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Desmartin periodinane (764 mg, 1.8 mmol) was added in small amounts at room temperature to a stirred solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (380 mg, 0.450 mmol) in DCM (15.0 mL, 237 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated Na2S2O3 aqueous solution (30 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (40 mL), dried to (Na2SO4), filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by elution with 90% siRNA in hexane using combiflash chromatography with a 12 g silica column to obtain tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white solid. Yield: 350 mg (94% by LCMS, 85%). MS(ESI+)m / z of CHNOS: 842.48[M+H] + .

[0172] tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(((3-methoxy-3-oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-formylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.416 mmol) in DCM (5.0 mL), methyl 3-(methylamino)propionate (146 mg, 3 equivalents, 1.25 mmol) and AcOH (4.99 mg, 0.083 mmol) were added at room temperature. The reaction mixture was stirred at room temperature under an N2 atmosphere for 5 hours, and then Na(OAc)3BH (80.9 mg, 1.25 mmol) was added. The resulting reaction mixture was stirred at room temperature for a further 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layer was washed with saturated NaHCO3 aqueous solution (20 mL) and brine (30 mL), dried, filtered, and concentrated under vacuum to obtain tert-butyl 3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(((3-methoxy-3-oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid. Yield: 290 mg (crude, 47% by LC-MS). MS(ESI+)m / z of CHNOS: 943.98 [M+H] + The crude product was used in the next process without further refinement.

[0173] The following intermediates were prepared according to synthesis route 1 (step 7) in the same manner as 3-((1-((1-(((4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanoic acid.

[0174] [Table 7] [Table 8]

[0175] Intermediate synthesis 4 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)-1-(2',6'-difluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide.HCl [ka]

[0176] tert-butyl((S)-1-((2S,4R)-2-(((S)-1-(4-bromophenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.0 g, 5.81 mmol) was dissolved in dry DMF (30 mL) and HOBt (2.35 g, 17.4 mmol), EDCI.HCl (3.34 g, 17.4 mmol), and DIPEA (5.0 mL, 29 mmol) were added at room temperature under an N2 atmosphere. The reaction mixture was stirred at room temperature for 15 minutes, and (S)-1-(4-bromophenyl)ethane-1-amine (1.39 g, 6.97 mmol) was added. The reaction mixture was stirred at room temperature for a further 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL), and extracted with ELISA (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried, and concentrated under reduced pressure in (Na2SO4). The crude residue was purified by elution with 50% ethyl acetate in hexane using combiflash chromatography with a 12 g silica column to obtain tert-butyl((S)-1-((2S,4R)-2-(((S)-1-(4-bromophenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate as a white solid. Yield: 2.0 g, 65%. CHNOS MS(ESI+) m / z 526.24[M+H] + .

[0177] tert-butyl((S)-1-((2S,4R)-2-(((S)-1-(2',6'-difluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate To a solution of tert-butyl((S)-1-((2S,4R)-2-(((S)-1-(4-bromophenyl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (1.0 g, 1.9 mmol) in 1,4-dioxane (20 mL) and water (4.0 mL), Na2CO3 (604 mg, 5.7 mmol) was added at room temperature. The reaction mixture was purged with N2 (g) for 10 minutes, and (2,6-difluorophenyl)boronic acid (1.5 g, 9.5 mmol) and Pd(dppf)Cl2 (139 mg, 0.190 mmol) were added at room temperature. The reaction mixture was again purged with N2 (g) for 5 minutes. The reaction vessel was sealed, and the reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (30 mL), dried, filtered, and concentrated under reduced pressure. The crude residue was purified by elution with 50% ethyl acetate in hexane using combiflash chromatography with a 40 g silica gel column to obtain tert-butyl((S)-1-((2S,4R)-2-(((S)-1-(2',6'-difluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate as an off-white solid. Yield: 700 mg, 66%. CHNOS MS(ESI+) m / z 560.30[M+H] + .

[0178] (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)-1-(2',6'-difluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide.HCl To a solution of tert-butyl ((S)-1-((2S,4R)-2-(((S)-1-(2',6'-difluoro-[1,1'-biphenyl]-4-yl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (690 mg, 1.23 mmol) in DCM (5 mL) was added 4.0 N HCl in 1,4-dioxane (0.7 mL) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was triturated with Et₂O (5.0 mL) and dried under vacuum to obtain N-[(S)-1-(2',6'-difluoro-4-biphenylyl)ethyl]-(2S,4R)-1-[(S)-2-amino-3,3-dimethylbutyryl]-4-hydroxy-2-pyrrolidinecarboxamide.HCl as an off-white solid. Yield: 570 mg. MS (ESI+) for CHNOS m / z 460.31 [M+H] + . The crude product was used in the next step without further purification.

[0179] The following intermediates were prepared in a similar manner to tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-((4-(3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropoxy)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate according to Synthetic Route 1 (Step 9).

[0180] [Table 9] [Table 10] [Table 11] Table 12

[0181] Intermediate synthesis 5 tert-butyl3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-(((3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

change

[0182] Stirred tert-butyl3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((trimethylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(((3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-di To a solution of methyl-1-oxobutan-2-yl)amino)-3-oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (340 mg, 0.248 mmol) in DMF (3.0 mL), CsF (377 mg, 2.48 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with ice-cold water (5 mL) and stirred for 10 minutes. The resulting suspension was filtered through a sintered funnel, and the solid cake was washed with water (20 mL). The solid product was dried under vacuum to obtain tert-butyl3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-(((3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a light brown solid. Yield: 315 mg (crude, 44% by LC-MS). CHNOS MS(ESI+)m / z 1199.96[M+H] + The crude product was used in the next process without further refinement.

[0183] The following intermediates were prepared in the same manner as tert-butyl3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-((1-(((3-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3-oxopropyl)(methyl)amino)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, according to intermediate synthesis 5.

[0184] [Table 13] [Table 14] [Table 15]

[0185] The following compounds were prepared according to synthesis route 1 (step 10) in the same manner as (2S,4R)-1-((2S)-2-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0186] [Table 16] [Table 17] Table 18 Table 19

[0187] ((2S,4R)-1-((2S)-2-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound (4))

change

[0188] (2S,4R)-1-((2S)-2-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide. A solution of TFA (25 mg, 0.022 mmol) in MeOH (4.0 mL) was degassed for 5 minutes, and 10% Pd / C (50 mg) was added to it at room temperature under an N2 atmosphere. The reaction mixture was stirred under H2 (g) pressure (1 atm) at room temperature for a further 4 hours. The progress of the reaction was monitored by LC-MS. The reaction mixture was filtered through a small Celite bed. The Celite bed was thoroughly washed with MeOH (10 mL). The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative HPLC using TFA buffer to obtain ((2S,4R)-1-((2S)-2-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-yl)oxy)propanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide as an off-white solid. Yield: 3.6 mg, 14% (based on free base). MS (ESI+) m / z of CHNOS: 1129.53 [M+H] + .; 1H NMR (400 MHz, DMSO-d6+ d-TFA): δ 9.79 (s, 1H), 9.28 (s, 1H), 7.67-7.73 (m, 1H), 7.35-7.58 (m, 4H), 7.23-7.30 (m, 1H), 7.02-7.20 (m, 2H), 4.65-4.94 (m, 3H), 4.16-4.55 (m, 7H), 3.86-4.03 (m, 2H), 3.42-3.72 (m, 8H), 2.90-3.26 (m, 4H), 2.36-2.47 (m, 5H), 1.59-2.16 (m, 11H), 1.29-1.38 (m, 3H), 0.68-0.94 (m, 16H).

[0189] Biological assays The results of the biological assays for compounds (1) to (6) are shown in Table 1 below.

[0190] KRAS G12D Nucleotide Exchange Assay The biochemical potency of the compound was assessed by evaluating the inhibition of SOS1-mediated nucleotide exchange in KRAS G12D. Inhibition was evaluated using the Aurora Biolabs KRAS G12D nucleotide exchange assay kit (catalog number: 5727-4123NK). SOS1-mediated exchange of fluorescently labeled GTP was monitored by TR-FRET. Compounds solubilized in DMSO (100× final concentration) were dispensed as a dilution series into 384-well white assay plates. GST-tagged KRAS G12D was diluted 440-fold from stock with 1× assay buffer. 4 μL of diluted KRAS G12D was pre-incubated with 2 μL of the compound at room temperature for 30 minutes. SOS1 stock was diluted 800-fold with 1× assay buffer, and 4 μL was added to a master mix containing 10 μL of dye solution prepared with terbium-labeled anti-GST antibody (1:200 in 1× assay buffer) and fluorescently labeled GTP (1:40 in 1× assay buffer). 14 μL of the master mix (SOS1, antibody, GTP) was added to a pre-incubated KRAS G12D and compound mix and incubated in a sealed plate at room temperature for a further 2 hours. For the negative control, SOS1 and GTP were replaced with 1× assay buffer. GTP binding to KRAS was quantified by measuring the fluorescence ratio at 665 nm / 620 nm using Clariostar plus.

[0191] The results are shown in Table 1 below.

[0192] KRAS G12C Nucleotide Exchange Assay The biochemical potency of the compound was assessed by evaluating the inhibition of SOS1-mediated nucleotide exchange in KRAS G12C. Inhibition was evaluated using the Aurora Biolabs KRAS G12C nucleotide exchange assay kit (catalog number: 5727-4122NK). SOS1-mediated exchange of fluorescently labeled GTP was monitored by TR-FRET. Compounds solubilized in DMSO (100× final concentration) were dispensed as a dilution series into 384-well white assay plates. GST-tagged KRAS G12C was diluted 380-fold from stock with 1× assay buffer. 4 μL of diluted KRAS G12C was pre-incubated with 2 μL of compound at room temperature for 30 minutes. SOS1 stock was diluted 2000-fold with 1× assay buffer, and 4 μL was added to a master mix containing 10 μL of dye solution prepared with terbium-labeled anti-GST antibody (1:200 in 1× assay buffer) and fluorescently labeled GTP (1:40 in 1× assay buffer). 14 μL of the master mix (SOS1, antibody, GTP) was added to the pre-incubated KRas G12C and compound mix and incubated in a sealed plate at room temperature for a further 2 hours. For the negative control, SOS1 and GTP were replaced with 1× assay buffer. GTP binding to KRAS was quantified by measuring the fluorescence ratio at 665 nm / 620 nm using Clariostar plus.

[0193] The results are shown in Table 1 below.

[0194] KRAS wild-type nucleotide exchange assay The biochemical potency of the compound was assessed by evaluating the inhibition of SOS1-mediated nucleotide exchange in KRAS wild-type. Inhibition was evaluated using the Aurora Biolabs KRAS wild-type nucleotide exchange assay kit (catalog number: 5727-4121NK). SOS1-mediated exchange of fluorescently labeled GTP was monitored by TR-FRET. Compounds solubilized in DMSO (100× final concentration) were dispensed as a dilution series into 384-well white assay plates. GST-tagged KRAS wild-type was diluted 210-fold from stock with 1× assay buffer. 4 μL of diluted KRAS wild-type was pre-incubated with 2 μL of the compound at room temperature for 30 minutes. SOS1 stock was diluted 800-fold with 1× assay buffer, and 4 μL was added to a master mix containing 10 μL of dye solution prepared with terbium-labeled anti-GST antibody (1:200 in 1× assay buffer) and fluorescently labeled GTP (1:40 in 1× assay buffer). 14 μL of the master mix (SOS1, antibody, GTP) was added to a pre-incubated mix of wild-type KRAS and the compound, and incubated in a sealed plate at room temperature for a further 2 hours. In the negative control, SOS1 and GTP were replaced with 1× assay buffer. GTP binding to KRAS was quantified by measuring the fluorescence ratio at 665 nm / 620 nm using Clariostar plus.

[0195] The results are shown in Table 1 below.

[0196] Phosphorylated ERK assay (pERK) The levels of phosphorylated ERK1 / 2 in AsPC-1 cells (ATCC CRL-1682) were determined using the state-of-the-art HTRF-based phosphorylated ERK1 / 2 (THR202 / TYR204) detection kit (Cisbio, catalog number: 64AERPET). The state-of-the-art phosphorylated ERK1 / 2 (Thr202 / Tyr204) is detected in a sandwich assay using two different specific antibodies: one Eu3+-cryptate-labeled antibody (donor) and the other d2-labeled antibody (acceptor). AsPC-1 cells expressing KRAS G12D were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and penicillin / streptomycin. 50 μL of cells were placed in 2 × 10⁶ well plates. 6 Cells were seeded at a rate of 100,000 cells / mL (1 well). The plates were incubated overnight at 37°C in 5% CO2. The compounds were solubilized in DMSO and titrated with DMSO. The compound dilution was diluted to 1 / 500 in RPMI medium (10% FBS, penicillin / streptomycin), and 50 μL was added to the pre-incubated cells (final DMSO concentration was 0.1%). The plates were incubated for a further 24 hours at 37°C in 5% CO2. The medium was removed, and 50 μL of replenished lysis buffer (blocking reagent in lysis buffer at a ratio of 1:100) was added to the wells. The plates were incubated at room temperature for 50 minutes with shaking (300 rpm). 16 μL of the lysate was added to a 96-well small-volume HTRF plate. 4 μL of premix antibody solution (d2 antibody and Eu-cryptate antibody diluted 1:20 in detection buffer) was added to the wells containing the lysate. The plates were sealed and incubated at 20°C for 4 hours, and read using a Clariostar Plus with a 665nm / 620nm ratio. For the negative control, supplemented lysis buffer was used instead of the lysis solution.

[0197] The results are shown in Table 1 below.

[0198] KRAS degradation assay (DC) 50 ) KRAS protein levels, standardized against the housekeeping protein α-tubulin, were determined using a protein simple automated Western blot system on a Jess machine. AsPC-1 cells expressing KRAS G12D were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and penicillin / streptomycin. MiaPaCa-2 (ATCC CRL-1420) expressing KRAS G12C were cultured in DMEM (10% FBS, 2.5% horse serum, 1× penicillin / streptomycin). 1 mL of cells were seeded at 300,000 cells / mL in a 12-well plate and incubated overnight at 37°C and 5% CO2. The compound was solubilized in DMSO and titrated with DMSO. 1 μL of the compound was added to each well of the pre-incubated cells and incubated for a further 24 hours. The medium was removed and the cells were washed with 1 mL of PBS. Cells were lysed in 200 μL of chilled RIPA buffer containing 1×HALT protease and phosphatase inhibitors at 4°C for 10 minutes. The lysates were quantified for protein using the Bradford assay to ensure that the protein concentrations in the lysates were similar across concentrations. For both AsPC-1 and MiaPaCa-2 cell lysates, the lysates were probed using the Jess system with mouse-α-tubulin (Novus catalog number: NB100-690). For AsPC-1 lysates, rabbit-Ras (G12D mutant specific) (D8H7) (Cell signalling, catalog number: 14429) and rabbit-K-Ras (E2M9G) (Cell signalling, catalog number: 71835) were used. Secondary antibodies were 20× anti-rabbit NIR (Protein simple, catalog number: 043-819) and 20× anti-mouse IR (Protein simple, catalog number: 043-822). The area under the probe signal curve (AUC) was generated using Protein Simple's Compass software, and KRAS was normalized relative to α-tubulin for each sample. DC50 (concentration that reduces KRAS protein levels by 50%) was generated using GraphPad Prism.

[0199] The results are shown in Table 1 below.

[0200] 3D cell proliferation assay The compounds were tested for their antiproliferative effects using a 3D cell proliferation assay. AsPC-1 cells expressing KRAS G12D were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and penicillin / streptomycin. MiaPaCa-2 (ATCC CRL-1420) expressing KRAS G12C was cultured in DMEM (10% FBS, 2.5% horse serum, 1× penicillin / streptomycin). The specific cell lines used contained specific driver mutations; ASPC-1 expressed KRASG12D, and MiaPaCa expressed KRASG12C. 100 μL of cells were seeded at 5000 cells / well in a low-adhesion 96-well plate (S-Bio, catalog number MS-9096WZ) using appropriate medium. The plate was incubated overnight at 37°C and 5% CO2. The compound was solubilized in DMSO and then diluted with DMSO. After diluting the compound 1:90.9 with RPMI-1640 (10% FBS, 1× penicillin / streptomycin), 10 μL was added to the cells (final DMSO concentration was 0.1%). Staurosporine was used as a baseline control at a final concentration of 1 μM (0.1% DMSO). The plate was incubated for a further 72 hours. 50 μL of 3D cell titer GLO reagent (Promega) was added to each well, and the plate was shaken at 250 rpm for 5 minutes at room temperature. The plate was incubated at room temperature for a further 25 minutes. The plate was read using a Perkin Elmer Envision plate reader with an luminescence filter. The baseline (staurosporine control well) was subtracted from all data before generating IC50 using sigmoid 4-parameter fit (with data constraints) in GraphPad prism.

[0201] The results are shown in Table 1 below.

[0202] Cytotoxicity assay HepG2 (ATCC HB-8065) ​​is a KRAS wild-type hepatocellular carcinoma cell line commonly used in cytotoxicity assays. HepG2 cells were cultured in EMEM, 10% FBS, and penicillin / streptomycin at 37°C and 5% CO2. 100 μL of HepG2 cells were seeded at 2000 cells per well in a 96-well white plate. The plate was incubated overnight at 37°C and 5% CO2. The compound was solubilized in DMSO and titrated with DMSO. The compound titration was diluted 1 / 10 with penicillin / streptomycin-free EMEM 10% FBS. The medium was removed from the wells, and 90 μL of pre-warmed penicillin / streptomycin-free EMEM 10% FBS was added to each well. 10 μL of the diluted compound was added to each well (final DMSO 1%). 20% DMSO was used as a 100% cell death control. 100 μL of culture medium (1% DMSO) was added to a separate well as a blank correction well. The plate was incubated at 37°C and 5% CO2 for a further 24 hours. 100 μL of Cell titer GLO (Promega) was added to each well. After shaking the plate at 350 rpm for 5 minutes, luminescence was measured using a Perkin Elmer Envision plate reader. The data was blank-corrected, and IC50 was generated using Dotmatics (4-parameter fit).

[0203] The results are shown in Table 1 below.

[0204] [Table 20]

[0205] Embodiment 1. Compound of formula (I) [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof [In the formula, R1 is C≡CH or C 1~4 Selected from alkyl groups, R2 is selected from phenyl or monocyclic 5-membered or 6-membered heteroaryls, where monocyclic phenyl and 5-membered or 6-membered heteroaryls are C 1~4 They may be appropriately substituted with one or more substituents selected from alkyl and halogens. n is between 1 and 6. m is either 1 or 2. L1 is (IIa), (IIb), and (IIc) below [ka] Selected from, R4 and R6 are independently selected from H or F. R7 is C 1~4 It is alkyl.

[0206] 2. R1 is C≡CH, methyl, or ethyl. Preferably, R1 is C≡CH or ethyl. more preferably, R1 is C≡CH. A compound of formula (I) according to Embodiment 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

[0207] 3. R2 may be optionally substituted with one or more halogen substituents, phenyl, and one or more C 1~4 A compound of formula (I) according to Embodiment 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, selected from a 5-membered or 6-membered heteroaryl, which may be optionally substituted with alkyl substituents.

[0208] 4. R2 is selected from phenyl or monocyclic 5-membered heteroaryl, and phenyl and monocyclic 5-membered heteroaryl are C 1~4 They may be appropriately substituted with one or more substituents selected from alkyl and halogens. Preferably, R2 is selected from phenyl optionally substituted with one or more halogen substituents, and one or more C 1~4 5-membered heteroaryl optionally substituted with alkyl substituents, the compound of formula (I) according to Embodiment 3, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof.

[0209] 5. R2 is selected from phenyl or thiazole optionally substituted with one or more substituents selected from C 1~4 alkyl and halogen, Preferably, R2 is phenyl optionally substituted with one or more halogen substituents, or one or more C 1~4 thiazole optionally substituted with alkyl substituents, the compound of formula (I) according to Embodiment 3 or 4, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof.

[0210] 6. R2 is phenyl substituted with one or more halogen substituents, or one or more C 1~4 thiazole substituted with alkyl substituents, the compound of formula (I) according to any one of Embodiments 3 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof.

[0211] 7. The compound of formula (I) according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein the halogen for R2 is fluorine.

[0212] 8. The compound of formula (I) according to any one of Embodiments 3 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein phenyl, 5-membered or 6-membered heteroaryl, or thiazole is substituted with one or more substituents.

[0213] 9. R2 is a compound of formula (IIIa) or formula (IIIb) [ka] A compound of formula (I) according to any of Embodiments 3 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, selected from, preferably, R2 being the compound of formula (IIIa).

[0214] 10. A compound of formula (I) according to any of Embodiments 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein n is 1 to 4, preferably 1 to 3, and more preferably 2.

[0215] 11. A compound of formula (I) according to any of Embodiments 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, wherein m is 1.

[0216] 12. A compound of formula (I) according to any of Embodiments 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein R7 is methyl or ethyl, preferably methyl.

[0217] 13. A compound of formula (I) according to any of Embodiments 1 to 12, wherein L1 has formula (IIa) or formula (IIb), preferably formula (IIb), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof.

[0218] 14. A compound of formula (I) according to any of Embodiments 1 to 13, wherein L1 has formula (IIa) and R4 is F, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof.

[0219] 15. A compound of formula (I) according to any of Embodiments 1 to 13, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein L1 has formula (IIb) and one or both of R4 and R6 are F.

[0220] 16. A compound of formula (I) according to any of Embodiments 1 to 13 or 15, wherein L1 has formula (IIb) and both R4 and R6 are F, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof.

[0221] 17. A compound of formula (I) according to any of Embodiments 1 to 13 or 15, wherein L1 has formula (IIb), R6 is H, and R4 is F, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof.

[0222] 18. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, of formula (Ia) [ka] A compound of formula (I) according to any of Embodiments 1 to 17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

[0223] 19. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, of formula (Ib) [ka] A compound of formula (I) according to any of embodiments 1 to 18, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

[0224] 20. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, of formula (Ic) [ka] A compound of formula (I) according to any of embodiments 1 to 18, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

[0225] 21. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, of formula (Id) [ka] A compound of formula (I) according to any of embodiments 1 to 18 and 20, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

[0226] 22. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, of formula (Ie) [ka] A compound of formula (I) according to any of embodiments 1 to 18, 20, and 21, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

[0227] 23. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, of formula (If) [ka] A compound of formula (I) according to any of embodiments 1 to 18 and 20 to 22, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

[0228] 24. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, is subject to the following [ka] [ka] [ka] [ka] A compound of formula (I) according to any of Embodiments 1 to 23, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, selected from the above.

[0229] 25. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, [ka] [ka] [ka] A compound of formula (I) according to any of Embodiments 1 to 24, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, selected from the above.

[0230] 26. A pharmaceutical composition comprising a compound of formula (I) according to any of Embodiments 1 to 25, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, and a pharmaceutically acceptable carrier or excipient.

[0231] 27. A compound of formula (I) according to any of Embodiments 1 to 25, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to Embodiment 26, for use as a pharmaceutical.

[0232] 28. A compound of formula (I) according to any of Embodiments 1 to 25, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to Embodiment 26, for use in the treatment or prevention of diseases associated with KRAS G12D mutations, preferably cancers associated with KRAS G12D mutations.

[0233] 29. A compound of formula (I) according to any of Embodiments 1 to 25, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to Embodiment 26, for use in the manufacture of a pharmaceutical for use in the treatment of diseases associated with KRAS G12D mutations, preferably cancers associated with KRAS G12D mutations.

[0234] 30. A method for treating a disease associated with a KRAS G12D mutation, preferably a cancer associated with a KRAS G12D mutation, in a subject requiring such treatment, comprising administering to the subject an effective amount of a compound of formula (I) according to any of Embodiments 1 to 25, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to Embodiment 26.

[0235] 31. A compound of formula (I) according to any of Embodiments 1 to 25, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to Embodiment 26, for use in the treatment of diseases associated with KRAS G12D mutations, preferably cancers associated with KRAS G12D mutations.

[0236] 32. A compound of formula (I) according to any of Embodiments 1 to 25, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to Embodiment 26, for use in the degradation of KRAS proteins having the KRAS G12D mutation.

[0237] 33. A compound of formula (I) according to any of Embodiments 1 to 25, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to Embodiment 26, for use in the degradation of intracellular KRAS G12D mutations.

[0238] 34. A compound of formula (I) according to any of Embodiments 1 to 25, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to Embodiment 26, for use in degrading the KRAS G12D mutation in the KRAS protein.

[0239] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature referenced herein and / or enumerated in the applicant data sheet, including U.S. Provisional Patent Application No. 63 / 586,342 filed September 28, 2023, are incorporated herein by reference in their entirety, insofar as they do not conflict with the description herein. The aspects of the embodiments may be modified as necessary, using concepts from various patents, applications, and publications, and to provide further embodiments.

Claims

1. Compound of formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof [In the formula, R １ C≡CH or C １～４ Selected from alkyl groups, R ２ It is selected from phenyl or monocyclic five-membered or six-membered heteroaryls, and monocyclic phenyl and five-membered or six-membered heteroaryls are C １～４ They may be appropriately substituted with one or more substituents selected from alkyl and halogen groups. n is between 1 and 6. m is either 1 or 2. L １ (IIa), (IIb), and (IIc) below 【Chemistry 2】 Selected from, R ４ and R ６ Each is independently selected from H or F, R ７ is C １～４ alkyl.]

2. R １ However, C≡CH, methyl or ethyl, Preferably R １ However, C≡CH or ethyl, More R １ C ≡ CH, A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

3. R ２ However, phenyl and one or more C substituents may be appropriately substituted with one or more halogen substituents. １～４ Selected from five-membered or six-membered heteroaryls, which may be appropriately substituted with alkyl substituents, Preferably, R ２ However, it is selected from phenyl or monocyclic five-membered heteroaryl, and phenyl and monocyclic five-membered heteroaryl are C １～４ They may be appropriately substituted with one or more substituents selected from alkyl and halogen groups. More specifically, R ２ However, phenyl and one or more C substituents may be appropriately substituted with one or more halogen substituents. １～４ Selected from five-membered heteroaryls, which may be appropriately substituted with alkyl substituents, More specifically, R ２ However, C １～４ Selected from phenyl or thiazole, which may be appropriately substituted with one or more substituents selected from alkyl and halogens, More specifically, R ２ However, phenyl may be appropriately substituted with one or more halogen substituents, or one or more C １～４ Thiazoles may be appropriately substituted with alkyl substituents. More specifically, R ２ However, phenyl substituted with one or more halogen substituents, or one or more C １～４ Thiazoles substituted with alkyl substituents, A compound of formula (I) as described in claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

4. R ２ However, compounds of formula (IIIa) or (IIIb) 【Transformation 3】 Selected from, Preferably, R ２ However, the compound is of formula (IIIa), The compound of formula (I) as described in claim 3, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

5. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein n is 1 to 4, preferably 1 to 3, more preferably 2, and / or m is 1.

6. R ７ The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein the compound is methyl or ethyl, preferably methyl.

7. L １ A compound of formula (I) according to any one of claims 1 to 6, having formula (IIa) or formula (IIb), preferably formula (IIb), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof.

8. L １ has formula (IIa), R ４ A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein F is present.

9. L １ has formula (IIb), R ４ and R ６ One or both of them are F, preferably R ６ H is R ４ A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, wherein F is present.

10. A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, is defined by formula (Ia) 【Chemistry 4】 Preferably formula (Ib) or formula (Ic) 【Transformation 5】 Preferably, formula (Id) 【Transformation 6】 Preferably, formula (Ie) 【Transformation 7】 Preferably, the formula (If) 【Transformation 8】 A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof.

11. The compound, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or isotopes, are as follows: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 Therefore, preferably 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 A compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or isotope thereof, selected from the above.

12. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, and a pharmaceutically acceptable carrier or excipient.

13. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to claim 12, for use as a pharmaceutical.

14. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to claim 12, for use in the treatment or prevention of diseases associated with KRAS G12D mutations, preferably cancers associated with KRAS G12D mutations.

15. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to claim 12, for the manufacture of a pharmaceutical for use in the treatment of diseases associated with the KRAS G12D mutation, preferably cancers associated with the KRAS G12D mutation.

16. A method for treating a disease associated with the KRAS G12D mutation, preferably a cancer associated with the KRAS G12D mutation, in a subject requiring such treatment, comprising administering to the subject an effective amount of a compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to claim 12.

17. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to claim 12, for use in the treatment of diseases associated with the KRAS G12D mutation, preferably cancers associated with the KRAS G12D mutation.

18. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to claim 12, for use in the degradation of a KRAS protein having a KRAS G12D mutation.

19. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or the pharmaceutical composition according to claim 12, for use in degrading intracellular KRAS G12D mutations.

20. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or isotope thereof, or a pharmaceutical composition according to claim 12, for use in degrading the KRAS G12D mutation in the KRAS protein.

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